Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them

The invention relates to new substituted 1-phenyl-3-pyrazolecarboxamides having a great affinity for human neurotensin receptors, to a process for preparing them and to pharmaceutical compositions containing them as active principles. More particularly, this invention relates to the discovery that the affinity for neurotensin receptors, especially human neurotensin receptors, is increased by substituting the phenyl group of 1-phenyl-3-pyrazolecarboxamide compounds with particular groups.

The present invention relates to new substituted 
1-phenyl-3-pyrazolecarboxamides having a great affinity for human 
neurotensin receptors, to a process for preparing them and to 
pharmaceutical compositions containing them as active principles. 
The first synthetic non-peptide potential medicinal products capable of 
binding to neutotensin receptors have been described in EP-0,477,049. They 
are amides of 3-pyrazolecarboxylic acid, variously substituted with amino 
acids, which displace iodinated neurotensin from its receptor, at doses of 
less than one micromole, on guinea pig brain membranes. This series led to 
the development of a compound, 
2-(1-(7-chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl)carbonylam 
ino!-2-adamantanecarboxylic acid, SR 48692, endowed with potent and 
selective neurotensin-antagonist activity (D. Gully et al., Proc. Natl. 
Acad. Sci. USA, 1993, 90, 65-69). 
The feature of the series of products described in EP-0,477,049 is the 
presence at position 1 of the pyrazole ring of, in particular, a phenyl, 
naphthyl or 4-quinolyl group, substituted or unsubstituted. More 
especially, SR 48692 possesses a 7-chloro-4-quinolyl group in position 1 
of the pyrazole. The products described in this document having a 
1-naphthyl or 4-chloro-1-naphthyl group in position 1 of the pyrazole ring 
have an extremely high affinity for the guinea pig neurotensin receptor, 
since their IC.sub.50 is of the order of 1 to 10 nanomoles, whereas their 
affinity for the human receptor is lower since their IC.sub.50 is from 10 
to 100 nmol. 
It has now been found that, by substituting the phenyl group of 
1-phenyl-3-pyrazolecarboxamide compounds with particular groups, the 
affinity for neurotensin receptors is increased, and more especially the 
affinity for human neurotensin receptors is increased. 
In addition, the compounds according to the present invention show in vivo 
a broader spectrum of activity than the compounds described in 
EP-0,477,049 as antagonists of the neurotensin receptors. 
Thus, the present invention relates, according to one of its aspects, to 
new substituted 1-phenyl-3-pyrazolecarboxamides of formula: 
##STR1## 
in which: --R.sub.1 represents a group chosen from: 
--T--CN; 
--C(NH.sub.2).dbd.NOH; 
--C(.dbd.NOH)NH(CH.sub.2).sub.r NR.sub.5 R.sub.6 ; 
--T--C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ; 
--C(NH.sub.2).dbd.NO(CH.sub.2).sub.r NR.sub.5 R.sub.6 ; 
--T--CONR.sub.a R.sub.b ; 
--T--CONR.sub.7 R.sub.c ; 
--Y--CO.sub.2 R.sub.7 ; 
--OR.sub.d ; 
--T--NR.sub.5 R.sub.6, on condition that R.sub.5 and R.sub.6 do not 
simultaneously represent hydrogen when T represents a direct bond; 
--T--N(R.sub.7)COR.sub.e ; 
--SO.sub.2 NR.sub.a R.sub.b ; 
--T--N(R.sub.7)SO.sub.2 R'.sub.7 ; 
--T--NR.sub.27 R.sub.28 ; 
--NR.sub.a R.sub.b represents a group chosen from: 
##STR2## 
--NR.sub.7 (CH.sub.2).sub.q CN; --NR.sub.7 (CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.NR.sub.14 ; 
--NR.sub.7 (CH.sub.2).sub.q CONH.sub.2 ; --NR.sub.7 (CH.sub.2).sub.q 
CO.sub.2 R.sub.7); 
--NR.sub.21 (CH.sub.2).sub.s CR.sub.7 R.sub.8 (CH.sub.2).sub.t NR.sub.25 
R.sub.26 ; 
R.sub.c represents a group chosen from: 
--X--OR.sub.7 ; --CHR.sub.20 CO.sub.2 R.sub.7 ; --(CH.sub.2).sub.4 
CH(NH.sub.2)CO.sub.2 R.sub.7 ; 
R.sub.d represents a group chosen from: 
--X--NR.sub.5 R.sub.6 ; --Y--CONR.sub.5 R.sub.6 ; --Y--CO.sub.2 R.sub.7 ; 
--Y--SO.sub.2 NR.sub.5 R.sub.6 ; 
##STR3## 
R.sub.e represents a group chosen from: 
##STR4## 
--(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ; --NR.sub.18 
R.sub.19 ; 
R.sub.2 and R.sub.3 each independently represent hydrogen, a (C.sub.1 
-C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkylmethyl, a (C.sub.3 
-C.sub.8)cycloalkyl, a halogen, a nitro, a trifluoromethyl, a group 
--OR.sub.4, a group --NR.sub.5 R.sub.6, a 1-pyrrolyl, a cyano, a 
carbamoyl; 
or R.sub.2 and R.sub.3 together constitute a trimethylene, tetramethylene 
or pentamethylene group; 
R.sub.4 represents hydrogen; a (C.sub.1 -C.sub.6)alkyl; a (C.sub.3 
-C.sub.4)alkenyl; a (C.sub.3 -C.sub.8)cycloalkyl; a (C.sub.3 
-C.sub.8)cycloalkylmethyl; a (C.sub.1 -C.sub.4)alkoxy(C.sub.1 
-C.sub.4)alkylene; a benzyl; 
R.sub.5 and R.sub.6 each independently represent a hydrogen, a (C.sub.1 
-C.sub.6)alkyl; a (C.sub.3 -C.sub.8)alkenyl; a (C.sub.3 
-C.sub.8)cycloalkylmethyl; a benzyl; or R.sub.5 and R.sub.6, together with 
the nitrogen atom to which they are attached, represent a heterocycle 
chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine, 
piperazine substituted at position 4 with R.sub.9, aziridine, azetidine 
and perhydroazepine; 
R'.sub.5 and R'.sub.6 each independently represent a hydrogen or a (C.sub.1 
-C.sub.6)alkyl; or alternatively, R'.sub.5 and R'.sub.6, together with the 
nitrogen atom to which they are attached, represent a heterocycle chosen 
from: pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine 
which is unsubstituted or substituted at position 4 with a (C.sub.1 
-C.sub.6)alkyl; 
R'.sub.7 represents a (C.sub.1 -C.sub.4)alkyl; a phenyl which is 
unsubstituted or substituted one or more times with a (C.sub.1 
-C.sub.4)alkyl; a group --X--NR.sub.5 R.sub.6 ; 
R.sub.7 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl or a benzyl; 
R.sub.8 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a hydroxyl, or 
R.sub.7 and R.sub.8, together with the carbon atom to which they are 
attached, constitute a (C.sub.3 -C.sub.5)cycloalkane; 
R.sub.9 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a group 
--X--OH or a group --X--NR'.sub.5 R'.sub.6, a (C.sub.3 -C.sub.8)alkenyl; 
R.sub.10 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a 
carbamoyl, a cyano; 
R.sub.11 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group --X--OH, 
a group --X--NR'.sub.5 R'.sub.6 ; 
R.sub.12 and R.sub.13 each independently represent a hydrogen or a (C.sub.1 
-C.sub.4)alkyl; 
R.sub.14 represents hydrogen, R.sub.14 can, in addition, represent a 
(C.sub.1 -C.sub.4)alkyl when R.sub.12 represents hydrogen and R.sub.13 
represents a (C.sub.1 -C.sub.4)alkyl; 
or R.sub.13 and R.sub.14 together represent a group Z; 
R.sub.15 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group 
--(CH.sub.2).sub.S NR.sub.5 R.sub.6 ; 
R.sub.16 represents hydrogen, a (C.sub.1 -C.sub.8)alkyl, a (C.sub.3 
-C.sub.8)-cycloalkyl, a phenyl, a 2-piperidyl, a 3-piperidyl, a 
4-piperidyl; 
R.sub.17 represents a (C.sub.1 -C.sub.6)alkyl, a phenyl, a benzyl, a 
hydroxy(C.sub.1 -C.sub.4)alkyl, an amino(C.sub.1 -C.sub.4)alkyl; 
R.sub.18 and R.sub.19 each independently represent a hydrogen, a (C.sub.1 
-C.sub.4)alkyl; R.sub.18 can, in addition, represent a group 
--(CH.sub.2).sub.q --NR.sub.5 R.sub.6 ; 
or R.sub.18 and R.sub.19, together with the nitrogen atom to which they are 
attached, represent a heterocycle chosen from: pyrrolidine, piperidine, 
morpholine, thiomorpholine, piperazine substituted at position 4 with 
R.sub.9 ; 
R.sub.20 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a 
hydroxyphenylmethyl, preferably a 4-hydroxyphenyl-methyl, a 
hydroxy(C.sub.1 -C.sub.4)alkyl, a mercapto(C.sub.1 -C.sub.4) alkyl; a 
--(CH.sub.2).sub.3 --NH--C(.dbd.NH)NH.sub.2 group, a --(CH.sub.2).sub.4 
NH.sub.2 group, a group --CH.sub.2 --Im in which Im represents a 
4-imidazolyl; 
R.sub.21 represents a (C.sub.1 -C.sub.4)alkyl, an allyl or a benzyl; 
R.sub.22 and R.sub.23 each independently represent a (C.sub.1 
-C.sub.6)alkyl; or alternatively R.sub.22 and R.sub.23, together with the 
nitrogen atom to which they are attached, represent a heterocycle chosen 
from: pyrrolidine, piperidine, morpholine and perhydroazepine; 
R.sub.24 represents a (C.sub.1 -C.sub.4)alkyl, a benzyl, an allyl, a 
hydroxy(C.sub.1 -C.sub.4)alkyl, a (C.sub.1 -C.sub.4)alkoxy(C.sub.1 
-C.sub.4)alkyl; 
Q.sup..crclbar. represents an anion; 
R.sub.25 represents hydrogen or a (C.sub.1 -C.sub.6)alkyl; 
R.sub.26 represents a (C.sub.1 -C.sub.4)alkoxycarbonyl, a 
benzyloxycarbonyl; a (C.sub.1 -C.sub.4)alkylcarbonyl; 
R.sub.27 represents a hydrogen; a (C.sub.1 -C.sub.4)alkyl, a (C.sub.1 
-C.sub.4)alkylcarbonyl; a group --CO--(CH.sub.2).sub.r --OH; a group 
SO.sub.2 R'.sub.7 ; 
R.sub.28 represents a group --X--NR.sub.5 R.sub.6 ; 
s=0 to 3; 
t=0 to 3, on the condition that (s+t), in a same group, is greater than or 
equal to 1; 
r=2 to 5; 
q=1 to 5; 
T represents a direct bond or (C.sub.1 -C.sub.7)alkylene; 
X represents a (C.sub.2 -C.sub.7)alkylene; 
Y represents a (C.sub.1 -C.sub.7)alkylene; 
Z represents a (C.sub.2 -C.sub.6)alkylene; 
the bivalent radicals A and E, together with the carbon atom and the 
nitrogen atom to which they are attached, constitute a saturated 4- to 
7-membered heterocycle which can, in addition, be substituted with one or 
more (C.sub.1 -C.sub.4)alkyls; 
the bivalent radicals G and L, together with the nitrogen atoms to which 
they are attached, constitute a piperazine or imidazolidine or imidazoline 
ring, the said rings being optionally substituted on the carbon atoms with 
one or more (C.sub.1 -C.sub.4)alkyls; 
the group --NH--AA(OH) represents the residue of an amino acid: 
##STR5## 
where X.sub.a is hydrogen and X'.sub.a is hydrogen, a (C.sub.1 
-C.sub.5)alkyl or a non-aromatic C.sub.3 -C.sub.15 carbocyclic radical; or 
alternatively, X.sub.a and X'.sub.a, together with the carbon atom to 
which they are attached, form a non-aromatic C.sub.3 -C.sub.15 carbocycle; 
their salts and their quaternary ammonium salts formed with acyclic or 
cyclic tertiary amines and their solvates. 
When a compound according to the invention comprises one or more asymmetric 
carbon atoms, each of the optical isomers forms part of the invention, as 
does the racemic form. 
When a compound according to the invention possesses several tautomeric 
forms, each of these forms part of the invention. This is the case, in 
particular, when the substituent R.sub.1 contains a substituted amidine 
group --C(NR.sub.12 R.sub.13).dbd.NR.sub.14. 
When the group --NH(AA)OH represents the residue of a cycloaliphatic amino 
acid, the amino or amino-methyl groups may be in the endo position or in 
the exo position with respect to the ring system; in both cases, the 
compounds of formula (I) form part of the invention. 
According to the present invention, alkyl or alkylene is understood to mean 
an unbranched or branched alkyl or alkylene qualified by the number of 
carbon atoms it contains; halogen is understood to mean a chlorine, 
bromine, fluorine or iodine atom. 
Non-aromatic C.sub.3 -C.sub.15 carbocyclic radicals comprise saturated or 
unsaturated, fused or bridged mono- or polycyclic radicals, optionally 
terpenic. These radicals are optionally mono- or polysubstituted with a 
C.sub.1 -C.sub.4 alkyl. 
Monocyclic radicals include cycloalkyls, for example cyclopropyl, 
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl. 
In the above residue of the amino acid, when X.sub.a and X'.sub.a, together 
with the carbon atom to which they are attached, form a non-aromatic 
C.sub.3 -C.sub.15 carbocycle, the said carbocycle is as defined for the 
corresponding radicals above. 
Among polycyclic non-aromatic carbocycles, adamantane, bicyclo3.3.1!nonane 
and norbornane are the preferred members. The radical corresponding to 
adamantane may be 1-adamantyl when X.sub.a is hydrogen, or 
2-adamantylidene when X.sub.a and X'.sub.a, together with the carbon atom 
to which they are attached, form a carbocycle. 
Among monocyclic non-aromatic carbocycles, cyclopentane and cyclohexane are 
especially preferred. 
The salts of the compounds of the invention can be internal salts or 
alternatively salts with alkali metals, preferably sodium or potassium, 
and alkaline-earth metals, preferably calcium, and with organic bases such 
as diethylamine, tromethamine, meglumine (N-methyl-D-glucamine), lysine, 
arginine, histidine, choline or diethanolamine, or optically pure organic 
bases such as .alpha.-methylbenzylamine. 
The salts of the compounds of formula (I) according to the present 
invention also comprise those with inorganic or organic acids which permit 
an appropriate separation or crystallization of the compounds of formula 
I, such as picric acid, oxalic acid or an optically active acid, for 
example a mandelic acid or a camphorsulphonic acid, and preferably those 
which form pharmaceutically acceptable salts such as the hydrochloride, 
acetate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, 
maleate, fumarate, 2-naphthalenesulphonate, isethionate, 
benzenesulphonate, para-toluenesulphonate, tartrate, citrate or edisilate. 
The quaternary ammonium salts with acyclic or cyclic tertiary amines are 
formed by substitution of the amine with a (C.sub.1 -C.sub.4)alkyl, a 
benzyl, an allyl, a hydroxy(C.sub.1 -C.sub.4)alkyl or a (C.sub.1 
-C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkylene; the anion preferably being a 
pharmaceutically acceptable anion. 
Advantageously, the invention relates to compounds of formula (Ip): 
##STR6## 
in which: R.sub.1p represents a group chosen from: 
--T--CN; 
--C(NH.sub.2).dbd.NOH; 
--C(--NOH)NH(CH.sub.2).sub.r NR.sub.5 R.sub.6 ; 
--T--C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ; 
--C(NH.sub.2).dbd.NO(CH.sub.2).sub.r NR.sub.5 R.sub.6 ; 
--T--CONR.sub.a R.sub.b ; 
--T--CONR.sub.7 R.sub.c ; 
--Y--CO.sub.2 R.sub.7 ; 
--OR.sub.d ; 
--T--NR.sub.5 R.sub.6, on condition that R.sub.5 and R.sub.6 do not 
simultaneously represent hydrogen when T represents a direct bond; 
--T--N(R.sub.7)COR.sub.e ; 
--SO.sub.2 NR.sub.a R.sub.b ; 
--T--N(R.sub.7)SO.sub.2 R'.sub.7 ; 
--NR.sub.a R.sub.b represents a group chosen from: 
--NR.sub.5 R.sub.6 ; --NR.sub.9 (CH.sub.2).sub.s CR.sub.7 R.sub.8 
(CH.sub.2).sub.t NR.sub.5 R.sub.6 ; 
##STR7## 
--NR.sub.7 (CH.sub.2).sub.q CN; --NR.sub.7 (CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.NR.sub.14 ; 
R.sub.c represents a group chosen from: 
--X--OR.sub.7 ; --CHR.sub.20 CO.sub.2 R.sub.7 ; --(CH.sub.2).sub.4 
CH((NH.sub.2)CO.sub.2 R.sub.7 ; 
R.sub.d represents a group chosen from: 
##STR8## 
R.sub.e represents a group chosen from: 
##STR9## 
--(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 ; --NR.sub.18 
R.sub.19 ; 
R.sub.2p and R.sub.3p each independently represent hydrogen, a (C.sub.1 
-C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkylmethyl, a (C.sub.3 
-C.sub.4)cycloalkyl, a halogen, a nitro, a trifluoromethyl, a group 
--OR.sub.4, a group --NR.sub.5 R.sub.6, a 1-pyrrolyl, a cyano, a 
carbamoyl; 
or R.sub.2p and R.sub.3p together constitute a trimethylene, tetramethylene 
or pentamethylene group; 
R.sub.4p represents hydrogen; a (C.sub.1 -C.sub.6)alkyl; a (C.sub.3 
-C.sub.4)alkenyl; a (C.sub.3 -C.sub.8)cycloalkyl; a (C.sub.3 
-C.sub.8)cycloalkylmethyl; a (C.sub.1 -C.sub.4)alkoxy(C.sub.1 
-C.sub.4)alkyl; a benzyl; 
R.sub.5 and R.sub.6 each independently represent a hydrogen, a (C.sub.1 
-C.sub.6)alkyl; or R.sub.5 and R.sub.6, together with the nitrogen atom to 
which they are attached, represent a heterocycle chosen from: pyrrolidine, 
piperidine, morpholine, thiomorpholine, piperazine substituted at position 
4 with R.sub.9 ; 
R'.sub.7 represents a (C.sub.1 -C.sub.4)alkyl; 
R.sub.7 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl or a benzyl; 
R.sub.8 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a hydroxyl, or 
R.sub.7 and R.sub.8, together with the carbon atom to which they are 
attached, constitute a (C.sub.3 -C.sub.5)cycloalkane; 
R.sub.9 represents hydrogen, a methyl, a group --X--OH or a group 
--X--NR.sub.5 R.sub.6 ; 
R.sub.10 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a 
carbamoyl, a cyano; 
R.sub.11 represents a hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group --X--OH, 
a group --X--NR.sub.5 R.sub.6 ; 
R.sub.12 and R.sub.13 each independently represent a hydrogen or a (C.sub.1 
-C.sub.4)alkyl; 
R.sub.14 represents hydrogen, R.sub.14 can, in addition, represent a 
(C.sub.1 -C.sub.4)alkyl when R.sub.12 represents hydrogen and R.sub.13 
represents a (C.sub.1 -C.sub.4)alkyl; 
or R.sub.13 and R.sub.14 together represent a group Z; 
R.sub.15 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a group 
--(CH.sub.2).sub.s NR.sub.5 R.sub.6 ; 
R.sub.16 represents hydrogen, a (C.sub.1 -C.sub.8)alkyl, a (C.sub.3 
-C.sub.8)cycloalkyl, a phenyl, a 2-piperidyl, a 3-piperidyl, a 
4-piperidyl; 
R.sub.17 represents a (C.sub.1 -C.sub.6)alkyl, a phenyl, a benzyl, a 
hydroxy(C.sub.1 -C.sub.4)alkyl, an amino(C.sub.1 -C.sub.4)alkyl; 
R.sub.18 and R.sub.19 each independently represent a hydrogen, a (C.sub.1 
-C.sub.4)alkyl; R.sub.18 can, in addition, represent a group 
--(CH.sub.2).sub.q --NR.sub.5 R.sub.6 ; 
or R.sub.18 and R.sub.19, together with the nitrogen atom to which they are 
attached, represent a heterocycle chosen from: pyrrolidine, piperidine, 
morpholine, thiomorpholine, piperazine substituted at position 4 with 
R.sub.9 ; 
R.sub.20 represents hydrogen, a (C.sub.1 -C.sub.4)alkyl, a benzyl, a 
hydroxyphenylmethyl, a hydroxy(C.sub.1 -C.sub.4)alkyl, a mercapto(C.sub.1 
-C.sub.4)alkyl; a --(CH.sub.2).sub.3 --NH--C(.dbd.NH)NH.sub.2 group, a 
--(CH.sub.2).sub.4 NH.sub.2 group, a group --CH.sub.2 --Im in which Im 
represents a 4-imidazolyl; 
s=0 to 3; 
t=0 to 3, on the condition that (s+t) is greater than or equal to 1; 
r=2 to 5; 
q=1 to 5; 
T represents a direct bond or (C.sub.1 -C.sub.7)alkylene; 
X represents a (C.sub.2 -C.sub.7)alkylene; 
Y represents a (C.sub.1 -C.sub.7)alkylene; 
Z represents a (C.sub.2 -C.sub.6)alkylene; 
the bivalent radicals A and E, together with the carbon atom and the 
nitrogen atom to which they are attached, constitute a saturated 5- to 
7-membered heterocycle which can, in addition, be substituted with one or 
more (C.sub.1 -C.sub.4)alkyls; 
the bivalent radicals G and L, together with the nitrogen atoms to which 
they are attached, constitute a piperazine or imidazolidine or imidazoline 
ring, the said rings being optionally substituted on the carbon atoms with 
one or more (C.sub.1 -C.sub.4)alkyls; 
the group --NH--AA.sub.p (OH) represents the residue of an amino acid: 
##STR10## 
where X.sub.a is hydrogen and X'.sub.a is hydrogen, a (C.sub.1 
-C.sub.5)alkyl or a non-aromatic C.sub.3 -C.sub.15 carbocyclic radical; or 
alternatively X.sub.a and X'.sub.a, together with the carbon atom to which 
they are attached, form a non-aromatic C.sub.3 -C.sub.15 carbocycle; and 
their salts. 
Preferred compounds according to the invention correspond to the formula: 
##STR11## 
in which: R".sub.4 represents hydrogen, a methyl or a cyclopropylmethyl; 
AA"(OH) represents a 2-carboxy-2-adamantyl, .alpha.-carboxycyclohexylmethyl 
or 9-carboxybicyclo3.3.1!nonan-9-yl group; 
among the substituents w.sub.2, w.sub.3, w.sub.4 and w.sub.5, at least one 
is hydrogen and at least one other is other than hydrogen, such that: 
either 
(i) 
w.sub.5 is hydrogen; 
w.sub.3 is hydrogen or methyl; 
w.sub.2 is (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 
-C.sub.4)alkoxy, chlorine or trifluoromethyl, or w.sub.2 and w.sub.3 
together form a 1,4-butylene group; 
w.sub.4 is chosen either from the following groups: 
(i1) dialkylaminoalkylaminocarbonyl 
##STR12## 
(i2) dialkylaminoalkyl(N-methyl)aminocarbonyl 
##STR13## 
(i3) dialkylaminoalkyl(N-ethyl)aminocarbonyl 
##STR14## 
(i4) cyanoalkyl(N-methyl)aminocarbonyl 
##STR15## 
(i5) aminoalkylaminocarbonyl H.sub.2 N--ALK--NH--CO-- 
(i6) aminoalkyl(N-methyl)aminocarbonyl 
##STR16## 
(i7) (N'-methyl)-(N'-alkoxycarbonyl)aminoalkyl-(N-methyl)carbonyl 
##STR17## 
(i8)amidinoalkylaminocarbonyl 
##STR18## 
(i9)pyrrolidinoalkylaminocarbonyl 
##STR19## 
(i10)morpholinoalkylaminocarbonyl 
##STR20## 
(i11)alkylaminoalkyl(N-methyl)aminocarbonyl 
##STR21## 
(i12) 2(1H)-imidazolinylalkylaminocarbonyl 
##STR22## 
(i13) bis(dialkylaminoalkyl)aminocarbonyl (ALK.sub.2 N--ALK').sub.2 N--CO- 
- 
(i14) aminocarbonylalkyl(N-methyl)aminocarbonyl 
##STR23## 
(i15) carboxyalkyl(N-methyl)aminocarbonyl 
##STR24## 
(i16) a group of structure 
##STR25## 
(i17) 2-pyridylaminocarbonyl 
##STR26## 
(i18) 1-benzyl-4-piperidylaminocarbonyl 
##STR27## 
(i19) 3-quinuclidinylaminocarbonyl 
##STR28## 
(i20) 4-piperidylaminocarbonyl 
##STR29## 
(i21) 2,2,6,6-tetramethyl-4-piperidylaminocarbonyl 
##STR30## 
(i22) aminocarbonyl H.sub.2 N--CO-- 
(i23) 4-alkylpiperazinocarbonyl 
##STR31## 
(i24) 4-dialkylaminopiperidinocarbonyl 
##STR32## 
(i25) 3-dialkylaminopyrrolidinocarbonyl 
##STR33## 
(i26) dialkylaminoalkyl(N-methyl)aminosulphonyl 
##STR34## 
(i27) dialkylaminoalkyl(N-benzyl)aminosulphonyl 
##STR35## 
(i28) 1-alkyl-2-pyrrolidinylmethylaminocarbonyl 
##STR36## 
(i29) allylaminocarbonyl CH.sub.2 .dbd.CH--CH.sub.2 --NH--CO-- 
(i30) dialkylaminoalkyl(N-acetyl)amino 
##STR37## 
(i31) dialkylaminoalkylamino 
##STR38## 
(i32) dialkylaminoalkylcarboxamido 
##STR39## 
or alternatively w.sub.4 is chosen from the following groups: (i33) 
piperidinoalkylcarboxamido 
##STR40## 
(i34) glycinamido H.sub.2 N--CH.sub.2 --CO--NH-- 
(i35) tosylamido 
##STR41## 
(i36) aminoalkylsulphonamido H.sub.2 N--ALK'--SO.sub.2 NH-- or H.sub.2 
N--CH.sub.2 --SO.sub.2 NH-- 
(i37) trialkylammonioalkyl(N-methyl)aminocarbonyl salt 
##STR42## 
ALK being (C.sub.1 -C.sub.4)alkyl and ALK' being (C.sub.2 
-C.sub.5)alkylene; 
or 
(ii) 
w.sub.2 and w.sub.5 are hydrogen 
w.sub.3 is chlorine 
w.sub.4 is cyano or aminocarbonyl 
or 
(iii) 
w.sub.2 and w.sub.5 are hydrogen, w.sub.3 is isopropyl and w.sub.4 is 
dialkylaminoalkylaminocarbonyl 
##STR43## 
ALK and ALK' being as defined above; or 
(iv) 
w.sub.2 and w.sub.5 are hydrogen, w.sub.3 is 
dialkylaminoalkyl-(N-methyl)aminocarbonyl 
##STR44## 
and w.sub.4 is chloro; ALK and ALK' being as defined above; 
or 
(v) 
w.sub.3 and w.sub.4 are hydrogen 
w.sub.2 is chloro, (C.sub.1 -C.sub.4)alkoxy or (C.sub.1 -C.sub.4)alkyl 
w.sub.5 is 
(v1) dialkylaminoalkyl(N-methyl)aminocarbonyl 
##STR45## 
(v2) dialkylaminoalkylcarbonylamino 
##STR46## 
ALK and ALK' being as defined above; their internal salts and their 
pharmaceutically acceptable salts, their quaternary ammonium salts and 
their solvates. 
A preferred group of compounds according to the invention consists of the 
compounds of formula: 
##STR47## 
in which: R.sub.1, R.sub.2 and R.sub.3 are as defined above for (I); 
R.sub.4y represents hydrogen, a (C.sub.1 -C.sub.4)alkyl group, an allyl or 
a cyclopropylmethyl; and 
the group --NH--AA.sub.y --(OH) represents either a residue selected from 
the residue of 2-aminoadamantane-2-carboxylic acid, of 
(S)-.varies.-aminocyclohexaneacetic acid and of 
9-aminobicyclo3.3.1!-nonane-9-carboxylic acid, or the residue of 
2-aminonorbornane-2-carboxylic acid; 
their salts and their quaternary ammonium salts formed with acyclic or 
cyclic tertiary amines and their solvates. 
Among the compounds of formula (Iy) as defined above, preference is given 
to those in which: 
R.sub.1, as defined for (I), is at position 4 or 5; 
R.sub.2 is at position 2 and represents a group chosen from: hydrogen, a 
(C.sub.1 -C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkyl, a (C.sub.3 
-C.sub.8)cycloalkylmethyl, a (C.sub.1 -C.sub.6)alkoxy, a (C.sub.3 
-C.sub.8)cycloalkyloxy, a chlorine, a trifluoromethyl; 
R.sub.3 is at position 3 and represents hydrogen, a (C.sub.1 
-C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkyl, a (C.sub.3 
-C.sub.8)cycloalkylmethyl; 
or R.sub.2 and R.sub.3 together constitute a trimethylene, a tetramethylene 
or a pentamethylene; 
their salts and their quaternary ammonium salts formed with acyclic or 
cyclic tertiary amines and their solvates. 
In particular, preference is given to the compounds of formula (Iy'): 
##STR48## 
in which: R.sub.1, R.sub.2 and R.sub.3 represent, respectively, R.sub.1p, 
R.sub.2p and R.sub.3p as defined above for (Ip); 
R'.sub.4y represents a (C.sub.1 -C.sub.4)alkyl or cyclopropylmethyl group; 
and 
the group --NH--AA'.sub.y --(OH) represents the residue of 
2-aminoadamantane-2-carboxylic acid or of 
(S)-.alpha.-aminocyclohexaneacetic acid or of 
2-aminonorbornane-2-carboxylic acid. 
Among the compounds of formula (Iy') as defined above, preference is given 
to those in which: 
R.sub.1 represents R.sub.1p as defined for (I) and is at position 4 or 5; 
R.sub.2 is at position 2 and represents a group chosen from: hydrogen, a 
(C.sub.1 -C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkyl, a (C.sub.1 
-C.sub.6)alkoxy, a chlorine, a trifluoromethyl; 
R.sub.3 is at position 3 and represents hydrogen or a (C.sub.1 
-C.sub.6)alkyl; 
or R.sub.2 and R.sub.3 together constitute a trimethylene, a tetramethylene 
or a pentamethylene; and their salts. 
Very special preference is given to the compounds of formula: 
##STR49## 
in which: R.sub.4y and NH--AA.sub.y (OH) are as defined above for (Iy); 
R.sub.1x is at position 4 or 5 and represents a group chosen from 
--T--CONR.sub.a R.sub.b, --SO.sub.2 NR.sub.a R.sub.b, --T--NR.sub.5 
R.sub.6, --N(R.sub.7)COR.sub.e, --OR.sub.d, --N(R.sub.7)SO.sub.2 R'.sub.7, 
--T--NR.sub.27 R.sub.28 ; the groups --T--, R.sub.a, R.sub.b, R.sub.d, 
R.sub.e, R.sub.5, R.sub.6, R.sub.7, R'.sub.7, R.sub.27 and R.sub.28 being 
as defined above for (I); 
R.sub.2x and R.sub.3x each independently represent hydrogen; a (C.sub.1 
-C.sub.6)alkyl; a (C.sub.3 -C.sub.8)cycloalkyl; a (C.sub.3 
-C.sub.8)cycloalkylmethyl; 
on condition that R.sub.2x and R.sub.3x do not simultaneously represent 
hydrogen; 
or R.sub.2x and R.sub.3x together constitute a tetramethylene group; 
their salts and their quaternary ammonium salts formed with acyclic or 
cyclic tertiary amines and their solvates. 
Among the compounds of formula (Ix), preference is given to those of 
formula Ix' 
##STR50## 
in which: R'.sub.4y represents a (C.sub.1 -C.sub.4)alkyl or 
cyclopropylmethyl group and NH--AA'.sub.y (OH) is as defined above for 
(Iy'); 
R'.sub.1x represents a group chosen from --T--CONR.sub.a R.sub.b, 
--SO.sub.2 NR.sub.a R.sub.b, --Y--NR.sub.5 R.sub.6, --N(R.sub.7)COR.sub.e, 
--OR.sub.d ; the groups --T--, --NR.sub.a R.sub.b, R.sub.d, R.sub.e, 
R.sub.5, R.sub.6 and R.sub.7 being as defined above for (Ip); 
R'.sub.2x represents a (C.sub.1 -C.sub.6)alkyl, a (C.sub.3 
-C.sub.8)cycloalkyl; 
R'.sub.3x represents hydrogen or a (C.sub.1 -C.sub.6)alkyl; 
or R'.sub.2x and R'.sub.3x together constitute a tetramethylene group; 
and their salts. 
Among the compounds of formula (Iy), a preferred group consists of the 
compounds of formula: 
##STR51## 
in which R.sub.4 y, R.sub.1x and NH--AA.sub.y (OH) are as defined above; 
preferably represents R'.sub.4y, R.sub.1p and NH--AA'y(OH) as defined for 
(Iy') their salts and their quaternary ammonium salts formed with acyclic 
or cyclic tertiary amines and their solvates. 
The compounds of the following formula are chosen more especially: 
##STR52## 
in which: R.sub.1x, R.sub.2x and R.sub.3x are as defined above for (Ix) 
preferably R'.sub.1x, R'.sub.2x and R'.sub.3x as defined above for (Ix'), 
R'.sub.1x preferably being at the para position; 
their salts and their quaternary ammonium salts formed with acyclic or 
cyclic tertiary amines and their solvates. 
Preferentially, the invention relates to 
2-5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic 
acid, its internal salt and its salts which are preferably 
pharmaceutically acceptable, and its solvates. 
According to another of its aspects, the present invention relates to a 
process for the preparation of the substituted 
1-phenyl-3-pyrazole-carboxamides of formula (I) and their salts, 
characterized in that: 
1) a functional derivative of a 1-phenyl-3-pyrazolecarboxylic acid of 
formula: 
##STR53## 
in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the meanings given 
above for the compound of formula (I) and R'.sub.1 represents a precursor 
of R.sub.1 chosen from nitro, amino, phthalimido, halo, hydroxyl, sulpho, 
hydroxy(C.sub.1 -C.sub.7)alkylene, cyano, carboxyl, (C.sub.1 
-C.sub.4)alkoxycarbonyl and benzyloxycarbonyl groups, is treated with an 
amino acid, optionally protected by protective groups which are customary 
in peptide synthesis, of formula: 
EQU H--HN--AA(OH) (III) 
in which --NH--AA(OH) is as defined above for the compound of formula (I); 
2) where appropriate, the functional acid derivative thereby obtained, of 
formula: 
##STR54## 
is subjected to a subsequent treatment suitable for converting the 
substituent R'.sub.1, a precursor of R.sub.1, to the substituent R.sub.1 ; 
3) if necessary, the compound thereby obtained in step 1) or in step 2) is 
deprotected to yield the corresponding free acid of formula (I); 
4) where appropriate, a salt of the compound (I) thereby obtained or its 
quaternary ammonium salt is prepared. 
As a functional derivative of the substituted 1-phenyl-3-pyrazolecarboxylic 
acid of formula (II) or (II'), it is possible to use the acid chloride, 
the anhydride, a mixed anhydride, a C.sub.1 -C.sub.4 alkyl ester, an 
activated ester, for example the p-nitrophenyl ester, or the free acid 
appropriately activated, for example with N,N'-dicyclohexylcarbodiimide or 
with benzotriazol-1-yloxytris(dimethylamino)phosphonium 
hexafluorophosphate (BOP). 
The amino acids of formula (III) may be used either as they are, or after 
prior protection of the carboxyl group with protective groups which are 
customary in peptide synthesis, as described, for example, in Protective 
Groups in Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, 1973, page 
183, or in Protective Groups in Organic Synthesis, II Ed. J. F. W. Greene 
and P. G. M. Wuts, John Wiley & Sons, 1991, page 224. 
For this protection, the carboxyl group of the amino acid (III) may be 
quite simply esterified, for example in the form of the methyl, benzyl or 
tert-butyl ester, the esterifying group then being removed by acid or 
basic hydrolysis or by hydrogenolysis. Protection by esterification can be 
used only when the group R.sub.1 or R'.sub.1 does not contain, for its 
part also, either an ester group which must be preserved, as in the case 
where, for example, R.sub.1 might represent a group O--Y--COOR.sub.7 or 
--Y--COOR.sub.7 or --T--CONR.sub.7 CHR.sub.20 COOR.sub.7 or 
--T--CONR.sub.7 (CH.sub.2).sub.4 CH(NH.sub.2)CO.sub.2 R.sub.7 with R.sub.7 
=alkyl, or, in any case, a group liable to be affected during the 
unblocking of the ester group. Protection of the carboxyl group of the 
amino acid (III) may also be performed by silylation, for example with 
bis-(trimethylsilyl)acetamide, it being possible for the said protection 
to be performed in situ. The silyl ester of the compound (I) is then 
readily removed during the isolation of the final product by simple 
acidification, hydrolysis or exchange with an alcohol. 
Thus, in step 1) of the process, the chloride of a 
1-phenyl-3-pyrazolecarboxylic acid, obtained by reacting thionyl chloride 
with an acid of formula (II) or (II'), may be reacted with an amino acid 
of formula (III), in a solvent such as acetonitrile, THF, DMF or DCM, 
under an inert atmosphere, at room temperature, for a time between a few 
hours and a few days, in the presence of a base such as pyridine, sodium 
hydroxide or triethylamine. 
A variant of step 1) consists in preparing the acid chloride or the mixed 
anhydride of a 1-phenyl-3-pyrazolecarboxylic acid by reacting isobutyl or 
ethyl chloroformate with an acid of formula (II) or (II'), in the presence 
of a base such as triethylamine, and in reacting it with an 
N,O-bis(trimethylsilyl) derivative of an amino acid of formula (III), 
obtained by reacting bis(trimethylsilyl)acetamide or 
1,3-bis(trimethyl-silyl)urea or bis(trifluoromethylsilyl)acetamide with an 
amino acid of formula (III), in solvents such as acetonitrile and DCM, 
under an inert atmosphere, and for a time between 1 hour and a few days, 
at a temperature between room temperature and the refluxing temperature of 
the solvent. 
Another variant to the procedure of step 1) consists in reacting the mixed 
anhydride of a 1-phenyl-3-pyrazolecarboxylic acid of formula (II) or (II') 
with an amino acid of formula (III), in a solvent such as DCM, under an 
inert atmosphere, at room temperature, for a time between 1 day and a few 
days, in the presence of a base such as triethylamine. 
When the compound of formula (I) possesses a basic function and is obtained 
in the form of a free base, salification is performed by treatment with 
the chosen acid in an organic or aqueous solvent. By treatment of the free 
base, dissolved, for example, in an alcohol such as isopropanol, with a 
solution of the chosen acid in the same solvent, the corresponding salt is 
obtained, which salt is isolated according to standard techniques. Thus, 
for example, the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, 
dihydrogen phosphate, methanesulphonate, methyl sulphate, oxalate, 
maleate, fumarate or 2-naphthalene-sulphonate is prepared. 
When the compound of formula (I) possesses a basic function and is isolated 
in the form of one of its salts, for example the hydrochloride or oxalate, 
the free base may be prepared by neutralization of the said salt with an 
inorganic or organic base such as sodium hydroxide or triethylamine, or 
with an alkali metal carbonate or bicarbonate such as sodium or potassium 
carbonate or bicarbonate. 
When the product of formula (I) is obtained in acid form, it may be 
converted to a metal salt, in particular an alkali metal salt such as the 
sodium salt or an alkaline-earth metal salt such as the calcium salt, 
according to standard processes. 
The compounds of formula (I) or (I') can under-go a dehydration in the 
presence of an anhydride, for example acetic anhydride, to form an 
oxazolone derivative of formula: 
##STR55## 
in which R.sub.1, R'.sub.1, R.sub.2, R.sub.3, R.sub.4, X.sub.a and 
X'.sub.a have the meanings given above for (I) and R'.sub.1 represents a 
precursor of R.sub.1 as defined above. 
These compounds are new and constitute a further aspect of the invention. 
Among the compounds of formula (Ic) and (I'c), preference is given to those 
for which X.sub.a and X'.sub.a, together with the carbon atom to which 
they are attached, constitute an adamantane ring system or a 
bicyclo3.3.1!nonane, or alternatively X.sub.a is hydrogen and X'.sub.a 
represents a cyclohexane. 
From a compound of formula (I'c) or (Ic), a compound of formula (I) or (I') 
is prepared again by hydrolysis in an acid medium or in a basic medium, 
for example in the presence of an alkali metal salt such as potassium 
tert-butylate. 
The intermediate preparation of a compound of formula (Ic) may be useful to 
permit the purification of a compound of formula (I). Moreover, the 
intermediate preparation of a compound of formula (I'c) may be useful to 
permit the conversion of a substituent R'.sub.1 to another substituent 
R'.sub.1 or R.sub.1, the acid function of the group NHAA(OH) being 
protected in the oxazolone group. 
The substituted 1-phenyl-3-pyrazolecarboxylic acids of the formula: 
##STR56## 
in which R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the definitions given 
above for the compounds (I) and R'.sub.1 represents a precursor of R.sub.1 
chosen form halo, nitro, amino, phthalimido, hydroxyl, hydroxy(C.sub.1 
-C.sub.7)alkylene, sulpho, cyano, carboxyl, (C.sub.1 
-C.sub.4)alkoxycarbonyl and benzyloxycarbonyl groups, as well as their 
functional derivatives of the acid function, are key intermediates in the 
preparation of the compounds of formula (I). When R'.sub.1 is other than 
carboxyl or halo, the compounds of formula (II) and (II') are new, and 
they constitute a further aspect of the present invention. 
The acids of formulae (II) and (II'), the chlorides of the acids of 
formulae (II) and (II'), the C.sub.1 -C.sub.4 alkyl esters of the acids of 
formulae (II) and (II'), which can also be precursors of the said acids 
(in particular the methyl, ethyl and tert-butyl esters), and the mixed 
anhydride of the acids of formulae (II) and (II') with isobutyl or ethyl 
chloroformate are especially preferred intermediate products. 
The process for preparing the compounds (II) or (II') via the esters (IIa) 
or (II'a) is represented by the following scheme: 
##STR57## 
M: Na, K Alk: Me, Et 
Alk': (C.sub.1 -C.sub.4)alkyl 
In the first step a), a strong base such as a metal alcoholate is reacted 
with a ketone of formula 1 in which R.sub.4 is as defined above, and then 
(step b) an equimolar amount of ethyl oxalate in an alkanol such as, for 
example, methanol or ethanol is reacted according to L. Claisen, Ber., 
1909, 42, 59. After precipitation in an ether such as ethyl ether or 
isopropyl ether, the enolates 2 are separated by filtration. It is also 
possible to prepare a lithium enolate according to W. V. Murray et al., J. 
Heterocyclic Chem., 1989, 26, 1389. 
The metal enolate 2 thereby prepared and an excess of phenylhydrazine 
derivative 3, or of a salt of the latter, are then heated to reflux of 
acetic acid (step c) to obtain the esters IIa or II'a. 
On saponification of the esters IIa or II'a by the action of an alkaline 
agent such as, for example, potassium hydroxide, sodium hydroxide or 
lithium hydroxide, followed by acidification, the acids II or II' are 
obtained (step d). 
Among the compounds of formula 3, some are new and constitute a further 
subject of the present invention. 
Thus, the compounds of formula: 
##STR58## 
in which: R'.sub.2 and R'.sub.3 each independently represent a hydrogen, a 
(C.sub.1 -C.sub.6)alkyl, a (C.sub.3 -C.sub.8)cycloalkyl, a (C.sub.3 
-C.sub.8)cycloalkylmethyl; 
or R'.sub.2 and R'.sub.3 together constitute a trimethylene, tetramethylene 
or pentamethylene group; 
R.sub.y is at position 4 or at position 5 and represents a group chosen 
from: cyano, carboxyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, 
benzyloxycarbonyl, sulpho, (C.sub.1 -C.sub.4)alkylsulphonylamino, (C.sub.1 
-C.sub.4)alkylphenylsulphonylamino, carbamoyl, (C.sub.1 
-C.sub.4)alkylcarboxamido; 
on condition that R'.sub.2 and R'.sub.3 do not simultaneously represent 
hydrogen and on condition that R'.sub.2 is other than methyl when R.sub.y 
is a sulpho group; and their salts, are new and constitute a further 
subject of the present invention. 
The phenylhydrazine derivatives (3) may be prepared according to 
Houben-Weyl, 1967, X-2, 169. For example, it is possible to carry out 
diazotization of the corresponding phenylamine in the presence of sodium 
nitrite, followed by reduction of the diazonium salt, for example by the 
action of stannous chloride. When the phenyl contains an 
electron-attracting substituent such as cyano or nitro, a fluorophenyl 
derivative may also be substituted with hydrazine hydrate to obtain the 
corresponding hydrazinophenyl derivative. The substituted phenylamines are 
known or prepared by known methods. For example, the aminosulphonic acids 
are prepared according to Houben-Weyl, Methoden der Organischen Chemie. 
Verlag, 1955, vol. IX, 450. 
The phenylhydrazine derivatives substituted with a group R.sub.1 =YCO.sub.2 
R.sub.7 are prepared from corresponding aniline or nitrophenyl 
derivatives. 
The conversion of a compound of formula I' or respectively of formula II' 
or of formula II'a in which the phenyl group is substituted with R'.sub.1 
to a compound of formula I or respectively of formula II or of formula IIa 
in which the phenyl group is substituted with R.sub.1 is performed by 
standard methods well known to a person skilled in the art. 
The compounds of formula IIa or II'a in which R.sub.1 or R'.sub.1 
represents a carboxyl or carboxy(C.sub.1 -C.sub.7)alkylene group enable 
compounds of formula IIa in which R.sub.1 represents a group --TCONR.sub.a 
R.sub.b to be prepared, with an amine HNR.sub.a R.sub.b, by reaction of 
the acid chloride prepared in an intermediate step, or of any other 
activated derivative of the acid such as the mixed anhydrides, activated 
esters or derivatives obtained with 1,3-dicyclohexylcarbodiimide. 
In the same way, the compounds of formula I' in which R'.sub.1 represents a 
group --TCOOH enable the compounds of formula I in which R.sub.1 
represents a group --TCONR.sub.a R.sub.b to be prepared; the carboxylic 
acid function of the amino acid residue NHAA(OH) must then be protected in 
an intermediate step, for example by an ester group such as tert-butyl 
ester or by formation of the oxazolone derivative of formula (Ic). 
From a compound of formula I or respectively Ic, or respectively from an 
ester of formula IIa, or respectively from an alkali metal salt of an acid 
of formula II, in which compounds the substituent R.sub.1 is a group 
TCONH(CH.sub.2).sub.s CR.sub.7 R.sub.8 (CH.sub.2).sub.t NR.sub.5 R.sub.6, 
a compound of formula I or respectively of formula Ic or respectively of 
formula IIa, or respectively an alkali metal salt of acid of formula II, 
in which compounds the substituent R.sub.1 is a group TCONR.sub.9 
(CH.sub.2).sub.s CR.sub.7 R.sub.8 (CH.sub.2).sub.t NR.sub.5 R.sub.6, may 
be prepared by the action of an iodide of formula R.sub.9 I. 
The compounds of formula IIa or respectively II or respectively Ic in which 
R.sub.1 represents a carboxy-(C.sub.1 -C.sub.7)alkylene group enable the 
compounds of formula IIa or respectively II or respectively I in which 
R.sub.1 represents a group --TCONR.sub.7 R.sub.c to be prepared by 
reacting the acid chloride prepared in an intermediate step with a 
compound NHR.sub.7 R.sub.c, that is to say with a compound of formula 
NHR.sub.7 XOR.sub.7 or a compound of formula HNR.sub.7 CHR.sub.20 CO.sub.2 
R.sub.7 or a compound of formula HNR.sub.7 (CH.sub.2).sub.4 
CH--(NHPro)CO.sub.2 R.sub.7 in which Pro represents a protecting group of 
the amine function used traditionally in peptide chemistry, for example 
tert-butoxycarbonyl or benzyloxycarbonyl. 
By reacting the compounds of formula I in which R.sub.1 represents a 
--CH.sub.2 CONH.sub.2 group with sodium peroxide, the compounds of formula 
I in which R.sub.1 represents a carboxymethyl group are obtained. By 
reducing the compounds of formula I in which R.sub.1 represents a 
--CH.sub.2 CN group, for example by hydrogenation in the presence of a 
catalyst such as Raney.RTM. nickel, the compounds of formula I in which 
R.sub.1 represents a --CH.sub.2 CH.sub.2 NH.sub.2 group are obtained. The 
latter compounds enable compounds of formula I in which R.sub.1 represents 
a group --CH.sub.2 CH.sub.2 NR.sub.5 R.sub.6, a group --CH.sub.2 CH.sub.2 
N(R.sub.7)COR.sub.e or a group --CH.sub.2 CH.sub.2 N(R.sub.7)SO.sub.2 
R'.sub.7 to be prepared by methods known to a person skilled in the art 
Similarly, the compounds of formula (I) in which R.sub.1 represents a group 
--T'--CN, T' being a direct bond or a (C.sub.1 -C.sub.6)alkylene, enable 
compounds of formula I to be prepared in which R.sub.1 represents a group 
--T'--CH.sub.2 NH.sub.2, and then compounds of formula I in which R.sub.1 
is a group --T'--CH.sub.2 NR.sub.5 R.sub.6, a group --T'--CH.sub.2 
N(R.sub.7)COR.sub.e or a group --T'--CH.sub.2 N(R.sub.7)SO.sub.2 R'.sub.7. 
The catalytic reduction may be carried out according to Catalytic 
Hydrogenation, R. L. Augustine-Marcel Dekker, 1967, 96-97; it may be 
applied to the compounds of formula I in which R.sub.2 and R.sub.3 are 
other than a nitro or a cyano and R.sub.4 is other than a (C.sub.3 
-C.sub.4)alkenyl. The substitution of the amino group may be performed by 
different processes described, for example, in Catalytic Hydrogenation, R. 
L. Augustine-M. Dekker, 1965, 102-113, and Catalytic Hydrogenation over 
Platinum Metals, P. N. Rylander--Academic Press, 1967, 291. Thus, for 
example, the addition of an aldehyde of formula R.sub.V CHO to an amino 
group yields an imine group which, on catalytic hydrogenation, is 
converted to secondary amine --NHCH.sub.2 R.sub.V in which R.sub.V 
represents a hydrogen or a (C.sub.1 -C.sub.3)alkyl. The addition of a 
ketone of formula RCOR' yields an amine --NHCHRR' in which --CHRR' 
represents a group R.sub.5, and R.sub.6 is hydrogen. The addition of a 
(C.sub.1 -C.sub.4)alkyl halide also enables an amino group substituted 
with one or two (C.sub.1 -C.sub.4)alkyls to be prepared. The addition of a 
suitable dihalide enables compounds to be prepared in which R.sub.5 and 
R.sub.6, together with the nitrogen atom to which they are attached, 
constitute a heterocycle chosen from pyrrolidine, piperidine, morpholine, 
thiomorpholine and piperazine substituted at position 4 with R.sub.9, 
aziridine, azetidine and perhydroazepine. 
The compounds of formula IIa in which R.sub.1 represents a group 
T--NHSO.sub.2 R'.sub.7 enable compounds of formula II'a in which R.sub.1 
represents a group T--N(XNR.sub.5 R.sub.6)SO.sub.2 R'.sub.7 to be prepared 
by the action of a halide of formula HalXNR.sub.5 R.sub.6. In an acid 
medium, compounds of formula II in which R.sub.1 is a group TNHXNR.sub.5 
R.sub.6 which represents TNHR.sub.28, may then be prepared. To obtain the 
compounds of formula I in which R.sub.1 represents a group TNR.sub.27 
R.sub.28, substitution of the nitrogen is performed by known methods, 
either on a compound of formula II or on a compound of formula I. 
The compounds of formula II'a, or respectively the compounds of formula II' 
or the compounds of formula I', in which R'.sub.1 represents a nitro group 
may be converted to compounds of formula II'a, or respectively of formula 
II' or of formula I', in which R'.sub.1 is an amino group; then, by known 
methods, the compounds of formula IIa, or respectively of formula II or of 
formula I, in which R.sub.1 represents a group --N(R.sub.7)COR.sub.e or 
NR.sub.5 R.sub.6 are prepared. 
The compounds of formula II'a, or respectively of formula II' or of formula 
I', in which R'.sub.1 is an amino group also enable compounds of formula 
II'a, or respectively of formula II' or of formula I', in which R'.sub.1 
represents a hydroxyl group to be prepared; then, by known methods, the 
compounds of formula IIa, or respectively of formula II or of formula I, 
in which R.sub.1 represents a group --OR.sub.d are prepared. 
From the compounds of formula II'a in which R'.sub.1 is a group --Y--OH, 
compounds of formula II'a in which R'.sub.1 is a group --Y--C.sub.1 may be 
prepared by the action of hydrochloric acid or thionyl chloride; by the 
action of a sulphonic acid derivative on these same compounds bearing the 
substituent --Y--OH, compounds of the formula II'a in which R'.sub.1 is 
the group --Y--OSO.sub.2 W, W representing a methyl, a trifluoromethyl or 
a tolyl, may be prepared. The action of an amine NHR.sub.5 R.sub.6 on 
compounds of formula II'a substituted with a group --Y--C.sub.1 or a group 
--Y--O--SO.sub.2 W enables compounds of formula IIa in which R.sub.1 
represents a group --Y--NR.sub.5 R.sub.6 to be prepared. 
When R.sub.2 represents a nitro or cyano and R.sub.3 represents hydrogen, 
the action of a compound R.sub.d OH in a basic medium on a compound of 
formula II'a, or respectively of formula II' or respectively of formula 
I', in which R'.sub.1 is a halogen at the ortho or para position with 
respect to R.sub.2 enables compounds of formula IIa, or respectively of 
formula II or respectively of formula I, in which R.sub.1 is a group 
--OR.sub.d to be prepared. 
When R.sub.2 and R.sub.3 are other than a halogen atom, a compound of 
formula IIa, or respectively of formula II or respectively of formula I, 
in which R.sub.1 is a cyano may also be prepared from a compound of 
formula II'a, or respectively of formula II' or respectively of formula 
I', in which R'.sub.1 is a halogen, by the action of a cyanide derivative, 
for example the cuprous cyanide. 
The compounds of formula I in which R.sub.1 is a cyano group enable the 
compounds of formula I in which R.sub.1 is a carbamoyl group to be 
prepared by reaction with hydrogen peroxide in the presence of a base such 
as sodium hydroxide. In the same way, the compounds of formula II in which 
R.sub.1 is a carbamoyl group are prepared from the compounds of formula 
IIa in which R.sub.1 is a cyano group. 
The compounds of formula I in which R.sub.1 is a cyano group also enable 
the compounds of formula I in which R.sub.1 represents a 
--C(NH.sub.2).dbd.NOH group or a group 
--C(NH.sub.2).dbd.NO(CH.sub.2).sub.r NR.sub.5 R.sub.6 to be prepared by 
reaction with hydroxylamine, where appropriate O-substituted with 
--(CH.sub.2).sub.q NR.sub.5 R.sub.6, in the presence of a base such as 
potassium carbonate. 
From the compounds of formula IIa, or respectively of formula II or 
respectively of formula I, in which R.sub.1 represents a 
C(NH.sub.2).dbd.NOH group, the compounds of formula IIa, or respectively 
of formula II or respectively of formula I, in which R.sub.1 represents 
C(.dbd.NOH)NH(CH.sub.2).sub.r NR.sub.5 R.sub.6 are prepared according to 
Chem. Ber., 1970, 103, 2330-2335. 
By reducing the compounds of formula IIa, or respectively of formula II or 
of formula I, in which R.sub.1 represents a cyano group, for example by 
hydrogenation in the presence of a catalyst such as platinum oxide, 
followed by reaction with an acid chloride or a suitable anhydride or 
respectively with a sulphonyl chloride, the compounds of formula IIa, or 
respectively of formula II or of formula I, in which R.sub.1 represents a 
group --CH.sub.2 NHCOR.sub.16 or respectively --CH.sub.2 NHSO.sub.2 
R'.sub.7 are obtained. Similarly, the compounds of formula IIa, or 
respectively of formula II or of formula I, in which R.sub.1 represents a 
group --CH.sub.2 N(R.sub.7)COR.sub.16 or a group --CH.sub.2 
N(R.sub.7)SO.sub.2 R'.sub.7, with R.sub.7 other than hydrogen, are 
obtained by performing an alkylation reaction on the amide obtained in an 
intermediate step. 
When the hydrogenation of a compound of formula II'a or respectively of 
formula II' or respectively of formula I', in which R'.sub.1 represents a 
cyano group is performed in the presence of an amine HNR.sub.5 R.sub.6, a 
compound of formula I or respectively of formula II or respectively of 
formula IIa, in which R.sub.1 represents a group CH.sub.2 NR.sub.5 R.sub.6 
is obtained. 
The reaction of the compounds of formula I in which R.sub.1 represents a 
group TCN or --T--CON(R.sub.7)(CH.sub.2).sub.q CN or a group 
--T--N(R.sub.7)CO(CH.sub.2).sub.q CN or a group --SO.sub.2 
N(R.sub.7)(CH.sub.2).sub.q CN with hydrochloric acid in alcoholic solution 
AlkOH enables the corresponding imidate of formula: 
--T--C(.dbd.NH)OAlk, --T--CONR.sub.7 (CH.sub.2).sub.q C(.dbd.NH)OAlk, 
--T--N(R.sub.7)CO--(CH.sub.2).sub.q C(.dbd.NH)OAlk or --SO.sub.2 
N(R.sub.7)(CH.sub.2).sub.q C(.dbd.NH)OAlk in which Alk is a (C.sub.1 
-C.sub.4)alkyl to be obtained in an intermediate step. 
If the imidate is reacted with an equimolar amount of amine HNR.sub.12 
R.sub.13, the compounds of formula I in which R.sub.1 represents: 
a group --TC(NR.sub.12 R.sub.13).dbd.NR.sub.14 
a group --TCON(R.sub.7)(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 
or 
a group --TN(R.sub.7)CO(CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.N--R.sub.14 or 
a group --SO.sub.2 N(R.sub.7)(CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.NR.sub.14 with R.sub.14 .dbd.H are obtained. 
If the imidate is reacted with an excess of amine NH.sub.2 R.sub.13, in 
which R.sub.13 is other than hydrogen, the compounds of formula I in which 
R.sub.1 represents: 
a group --TC(NHR.sub.13).dbd.NR.sub.13 
a group --TCON(R.sub.7)(CH.sub.2).sub.q C(NHR.sub.13).dbd.N--R.sub.13 or 
a group --TN(R.sub.7)CO(CH.sub.2).sub.q C(NHR.sub.13).dbd.NR.sub.13 or 
a group --SO.sub.2 N(R.sub.7) (CH.sub.2).sub.q C(NHR.sub.13).dbd.NR.sub.13 
are obtained. 
If the imidate is reacted with a diamine of formula H.sub.2 
N--Z--NHR.sub.12, the compounds of formula I in which R.sub.1 represents: 
a group --TC(NR.sub.12 R.sub.13).dbd.NR.sub.14 
a group --TCON(R.sub.7)(CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.N--R.sub.14 or 
a group --TN(R.sub.7)CO(CH.sub.2).sub.q C(NR.sub.12 R.sub.13).dbd.NR.sub.14 
or 
a group --SO.sub.2 N(R.sub.7)(CH.sub.2).sub.q C(NR.sub.12 
R.sub.13).dbd.NR.sub.14, in which R.sub.13 and R.sub.14 together 
constitute a C.sub.2 -C.sub.6 alkylene group and R.sub.12 represents a 
hydrogen or a (C.sub.1 -C.sub.4)alkyl, are obtained. 
A compound of formula (I) in which R.sub.1 contains an optionally 
substituted amidino radical may also be prepared according to the methods 
described in The chemistry of amidines and imidates, Saul Patai, 1975, 
John Wiley and Sons. 
From the compounds of formula I, or respectively of formula II or IIa, in 
which R.sub.1 represents a group --TCONR.sub.7 (CH.sub.2).sub.q CN, 
compounds of formula I, or respectively II or IIa, in which R.sub.1 
represents a group --TCONR.sub.7 (CH.sub.2).sub.q CONH.sub.2 or a group 
--TCONR.sub.7 (CH.sub.2).sub.q CO.sub.2 R.sub.7 are prepared by known 
reactions. 
When R'.sub.1 =SO.sub.3 H, a compound II'a in which R'.sub.1 .dbd.SO.sub.2 
Cl is prepared and then converted to another compound IIa in which R.sub.1 
is an aminosulphonyl group, optionally substituted, by the action of a 
suitable amine HNR.sub.a R.sub.b. 
The compounds of formula I comprising a quaternary ammonium group are 
obtained from the corresponding amino compounds by the action of a 
compound of formula QR.sub.24 in which Q can form anion, for example an 
iodide. 
The amino acids of formula III include, for example, glycine, alanine, 
leucine, norleucine, isoleucine, valine, 1-adamantylglycine, 
2-adamantylglycine, cyclopropylglycine, cyclopentylglycine, 
cyclohexylglycine, cycloheptylglycine, 1-aminocyclopropanecarboxylic acid, 
1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 
1-aminocyclohexanecarboxylic acid, 1-aminocycloheptanecarboxylic acid, 
1-amino-4-methylcyclohexanecarboxylic acid, 2-amino-2-adamantanecarboxylic 
acid, 2-aminobicyclo3. 2.1!octane-2-carboxylic acid, 
9-aminobicyclo3.3.1!nonane-9-carboxylic acid and 
2-aminobicyclo2.2.1!heptane-2-carboxylic or 
2-amino-2-norbornanecarboxylic acid. 
The amino acids of formula III are commercial products or may be very 
readily prepared according to standard methods. In particular, the 
non-commercial amino acids (III) are prepared according to the Strecker 
synthesis, Ann, 1850, 75, 27 or according to the synthesis of H. T. 
Bucherer et al., J. Pract. Chem., 1934, 141, 5, followed by a hydrolysis 
to yield the amino acids; for example, 2-amino-2-adamantanecarboxylic acid 
and 9-aminobicyclo3.3.1!nonane-9-carboxylic acid are prepared according 
to H. T. Nagasawa et al., J. Med. Chem., 1973, 16, (7), 823. 
.alpha.-Amino-1-adamantylacetic and .alpha.-amino-2-adamantylacetic acids 
are prepared according to B. Gaspert et al., Croatica Chemica Acta, 1976, 
48 (2), 169-178. 
2-Amino-2-norbornanecarboxylic acid is prepared according to H. S. Tager et 
al., J. Am. Chem. Soc., 1972, 94, 968. 
.alpha.-Aminocycloalkylcarboxylic acids are prepared according to J. W. 
Tsang et al., J. Med. Chem., 1984, 27, 1663. 
(R)- and (S)-cyclopentylglycines are prepared according to European Patent 
Application EP 477,049. 
(R)- and (S)-cyclohexylglycines are prepared according to Rudman et al., J. 
Am. Chem. Soc., 1952, 74, 551. 
(R)- and (S)-cyclohexylglycines may also be prepared by catalytic 
hydrogenation of (R)- and (S)-phenylglycines. 
.alpha.-Aminocycloalkylcarboxylic acids of R or S configuration may also be 
prepared by stereospecific enzymatic hydrolysis of the corresponding 
racemic N-acetyl derivatives according to J. Hill et al., J. Org. Chem., 
1965, 1321. 
The compounds of formula (I) and their salts possess a very great affinity 
for human neurotensin receptors in the tests described by D. Gully et al. 
in Proc. Natl. Acad. Sci. USA, 1993, 90, 65-69. 
The compounds of formula I and their salts were studied in vivo. Working 
according to the technique described by M. Poncelet et al. in Naunyn 
Schmiedberg's Arch. Pharmacol., 1994, 60, 349-357, it is observed that a 
compound according to the invention, administered orally, antagonizes the 
contralateral pivoting induced by unilateral intrastriatal injection of 
neurotensin in mice. 
Moreover, working according to the technique described by D. Nisato et al. 
in Life Sciences, 1994, 54, 7, 95-100, it is found that a compound 
according to the invention, administered intravenously, inhibits the 
increase in blood pressure induced by intravenous injection of neurotensin 
in guinea pigs. 
The compounds described in Patent EP 0,477,049 exhibit a lower activity in 
these tests than that of the compounds according to the present invention. 
The compounds of the present invention are of low toxicity; in particular, 
their acute toxicity is compatible with their use as a medicinal product. 
For such a use, an effective amount of a compound of formula I, or of one 
of its pharmaceutically acceptable salts, is administered to mammals for 
the treatment of neurotensin-dependent pathologies. Thus, the compounds of 
the present invention may be used for the treatment of neuropsychiatric 
disorders, especially those associated with a dysfunction of the 
dopaminergic systems, for example psychoses, more especially 
schizophrenia, and diseases of movement such as Parkinson's disease (D. R. 
Handrich et al., Brain Research, 1982, 231, 216-221 and C. B. Nemeroff, 
Biological Psychiatry, 1980, 15 (2), 283-302). They may be used to 
diagnose and/or treat malignant neoplastic diseases, for example human 
meningiomas which are not surgically accessible (P. Mailleux, Peptides, 
1990, 11, 1245-1253), cancers of the prostate (I. Sehgal et al., Proc. 
Nat. Acad. Sci., 1994, 91, 4673-4677) and small cell cancers of the lung 
(T. Sethi et al., Cancer Res., 1991, 51, 3621-3623). They may be used in 
the treatment of motor, secretory, ulcerous and/or tumoral 
gastro-intestinal disorders (review by A. Shulkes in "Gut Peptides: 
Biochemistry and Physiology, Ed. J. Waish and G. J. Dockray, 1994"). Thus, 
the compounds I according to the invention may be used in the treatment of 
complaints such as: irritable bowel syndrome, diarrhoea, colitis, ulcers, 
tumours of the gastro-intestinal tract, dyspepsia, pancreatitis and 
oesophagitis. They may also be of value as modulators of food intake 
(Beck, B. Metabolism, 1995, 44, 972-975). The compounds according to the 
invention may be indicated as diuretics, as well in the case of 
cardiovascular disorders, and also in the case of pathologies associated 
with a histamine release such as inflammatory processes (D. E. Cochrane et 
al., Faseb J., 1994, 8, 7, 1195). These compounds may also be useful for 
treating certain disorders caused by stress, such as migraines, neurogenic 
pruritus and interstitial cystitis (Theoharides T. C. et al., Endocrinol., 
1995, 136, 5745-5750). The compounds of the present invention may also be 
of value in analgesia, by acting on the effects of morphine (M. O. Urban, 
J. Pharm. Exp. Ther., 1993, 265, 2, 580-586). 
Thus, the subject of the present invention, according to another of its 
aspects, is pharmaceutical compositions containing as active principles 
the compounds of formula I or their possible pharmaceutially acceptable 
salts. 
In the pharmaceutical compositions of the present invention for oral, 
sublingual, subcutaneous, intramuscular, intravenous, transdermal or 
rectal administration, the active principles may be adminisered, in 
single-dose administration forms, as a mixture or with standard 
pharmaceutical vehicles, to animals and human beings. Suitable single-dose 
administration forms comprise forms for oral administration, such as 
tablets, gelatin capsules, powders, granules and oral solutions or 
suspensions, forms for administration by inhalation, forms for sublingual 
and buccal administration, forms for subcutaneous, transcutaneous, 
intramuscular or intravenous administration and forms for rectal 
administration. 
In order to obtain the desired effect, the dose of active principle can 
vary between 0.5 and 1000 mg per day, and preferably between 2 and 500 mg. 
Each single dose can contain from 0.5 to 250 mg of active principle, and 
preferably from 1 to 125 mg, in combination with a pharmaceutical vehicle. 
This single dose can be administered 1 to 4 times daily. 
When a solid composition is prepared in the form of tablets, the active 
principle is mixed with a pharmaceutical vehicle such as gelatin, starch, 
lactose, magnesium stearate, talc, gum arabic or the like. It is possible 
to coat the tablets with sucrose or with other suitable substances, or 
they may alternatively be treated in such a way as to have a sustained or 
delayed activity and to release continuously a predetermined amount of 
active principle. 
A gelatin capsule preparation is obtained by mixing the active principle 
with a diluent and pouring the mixture obtained into soft or hard gelatin 
capsules. 
A preparation in syrup or elixir form can contain the active principle 
together with a sweetener, preferably a zero-calorie sweetener, and 
methylparaben and propylparaben as antiseptic, as well as an agent 
imparting flavour and a suitable colorant. 
The water-dispersible powders or granules can contain the active principle 
mixed with dispersing agents or wetting agents, or suspending agents such 
as polyvinylpyrrolidone and the like, as well as with sweeteners or 
flavour correctors. 
For rectal administration, suppositories are employed, which are prepared 
with binding agents melting at rectal temperature, for example cocoa 
butter or polyethylene glycols. 
For parenteral administration, aqueous suspenions, isotonic saline 
solutions or sterile and injectable solutions are used, which contain 
pharmacologically compatible dispersing and/or wetting agents, for example 
propylene glycol or butylene glycol. 
The active principle may also be formulated in the form of microcapsules, 
optionally with one or more vehicles or additives. 
To improve the solubility of the products of the invention, the compounds 
of formula I or their pharmaceutically acceptable salts may also be 
presented in the form of complexes with cyclodextrins.

In the description and in the examples, the following abbreviations are 
used: 
MeOH: methanol 
EtOH: ethanol 
Ether: ethyl ether 
Ethereal hydrogen chloride=a saturated solution of hydrochloric acid in 
ether 
Ethanolic hydrogen chloride=a saturated solution of hydrochloric acid in 
ethanol 
Iso ether: isopropyl ether 
AcOEt: ethyl acetate 
MeCN: acetonitrile 
DCM: dichloromethane 
DMF: dimethylformamide 
DMSO: dimethyl sulphoxide 
THF: tetrahydrofuran 
HCl: hydrochloric acid 
H.sub.2 SO.sub.4 : sulphuric acid 
AcOH: acetic acid 
TFA: trifluoroacetic acid 
NaOH: sodium hydroxide 
KOH: potassium hydroxide 
LiOH: lithium hydroxide 
NH.sub.4 OH: ammonium hydroxide 
Na.sub.2 SO.sub.4 : sodium sulphate 
NaHCO.sub.3 : sodium hydrogen carbonate 
NaHSO.sub.3 : sodium hydrogen sulphite 
Na.sub.2 CO.sub.3 : sodium carbonate 
K.sub.2 CO.sub.3 : potassium carbonate 
P.sub.2 O.sub.5 : phosphorus pentoxide 
NBS: N-bromosuccinimide 
POCl.sub.3 : phosphorus oxychloride 
NaNO.sub.2 : sodium nitrite 
SOCl.sub.2 : thionyl chloride 
SnCl.sub.2 : stannous chloride 
CuCN: suprous cyanide 
Me, MeO: methyl, methoxy 
Et: ethyl 
iPr: isopropyl 
iBu: isobutyl 
n-Bu: n-butyl 
t-Bu: tert-butyl 
Bz: benzyl 
m.p.: melting point 
RT: room temperature 
Silica H: silica gel 60 H marketed by MERCK (DARMSTADT ) 
NMR: nuclear magnetic resonance 
Except where otherwise stated, NMR spectra are recorded at 200 MHz in 
DMSO-d.sub.6. Chemical shifts .delta. are expressed in parts per million 
(ppm) relative to tetramethylsilane as internal reference. 
s: singlet 
bs: broad singlet 
ss: split singlet 
d: doublet 
dd: doublet of doublet 
t: triplet 
qr: quartet 
qt: quintet 
sp: septet 
u.c.: unresolved complex 
mt: multiplet 
PREATION 1.1 
Methyl 4-(2,6-dimethoxyphenyl)-4-oxido-2-oxo-3-butenoate sodium salt: 
Compound A. 
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl 
oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of 
sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous 
MeOH. The reaction mixture is heated to reflux for 7 hours and left 
overnight at RT. It is poured into 2 litres of isopropyl ether and left 
stirring for 15 minutes. The expected product is obtained by filtration, 
washing with isopropyl ether and drying under vacuum, m=120 g, 
m.p.=178.degree. C. 
Ethyl 4-(2,6-dimethoxyphenyl)-4-oxido-2-oxo-3-butenoate potassium salt: 
Compound A.sub.1. 
A solution of 13.4 g of 95% potassium tertbutylate in 72 ml of ethanol is 
added over 6 minutes to a solution, stirred and heated to 50.degree. C., 
of 18 g of 2,6-dimethoxyacetophenone in 54 ml of ethanol. The mixture is 
heated to reflux, 16.3 ml of ethyl oxalate are added over 9 minutes and 
refluxing is continued for 1 hour. 40 ml of ethanol are then distilled off 
and the mixture is allowed to cool with stirring for two and a half hours. 
The mixture is filtered, and the precipitate is washed with 40 ml of 
ethanol and dried under vacuum at 60.degree. C. for 17 hours to obtain 31 
g of expected product. 
NMR: 1.2:t:3H; 3.6:s:6H; 4:mt:2H; 5.5:s:1H; 6.55:d:2H; 7.1:t:1H. 
PREATION 1.2 
Ethyl 
4-2-(cyclopropylmethyloxy)-6-methoxy-phenyl!-4-oxido-2-oxo-3-butenoate 
sodium salt. 
A) 2-(Cyclopropylmethyloxy)-6-methoxyacetophenone. 
32.7 ml of a 50% solution of caesium hydroxide in water are added at RT to 
a solution of 26 g of 2-hydroxy-6-methoxyacetophenone in 400 ml of 
2-propanol, and the mixture is left stirring for 15 minutes at RT. It is 
concentrated under vacuum, the residue is taken up with 2-propanol, the 
mixture is concentrated under vacuum, toluene is then added and the 
resulting mixture is concentrated under vacuum. The residue is dissolved 
in 200 ml of DMF, 25.3 g of cyclopropylmethyl bromide are added and the 
mixture is heated to 80.degree. C. for 2 hours 30 minutes. It is 
concentrated under vacuum, the residue is taken up with water, the mixture 
is extracted with AcOEt, the organic phase is washed with a saturated NaCl 
solution and dried over Na.sub.2 SO.sub.4 and the solvent is evaporated 
off under vacuum. 32.7 g of the expected product are obtained. 
B) Ethyl 
4-2-(cyclopropylmethyloxy)-6-methoxy-phenyl!-4-oxido-2-oxo-3-butenoate 
sodium salt. 
A solution of 32.6 g of the compound obtained in the preceding step and 
20.1 ml of diethyl oxalate in 100 ml of EtOH is added slowly to a solution 
of sodium ethylate prepared from 3.4 g of sodium and 60 ml of EtOH. The 
mixture is heated overnight at 60.degree. C., allowed to cool to RT and 
concentrated under vacuum. The residue is taken up with pentane, and the 
precipitate formed is drained, washed with pentane and dried under vacuum. 
41.2 g of the expected product are obtained. 
PREATIONS OF THE HYDRAZINES 3 
PREATION 2.1 
3-Isopropyl-4-hydrazinobenzoic acid hydrochloride. 
A) 2-Isopropylacetanilide. 
This compound is described in Bull. Soc. Chim., France, 1949, 144. 
A mixture containing 300 ml of toluene and 31 ml of 2-isopropylaniline is 
cooled in ice, and 22 ml of acetic anhydride are added slowly. After 40 
minutes with stirring at RT, the reaction medium is evaporated and the 
residue is then taken up with petroleum ether. The precipitate formed is 
drained. 35.9 g of the expected product are obtained after crystallization 
in petroleum ether, m.p.=81.degree. C. 
B) 4-Bromo-2-isopropylacetanilide. 
This compound is described in J. Med. Chem., 1974, 17(2), 221. 
A few drops of a solution of 10.1 ml of bromine in 180 ml of acetic acid 
are added slowly to a mixture containing 34.8 g of the compound obtained 
in the preceding step in 250 ml of acetic acid, and the mixture is then 
heated to 50.degree. C.; after cooling, a few drops of the solution are 
added again and the mixture is heated to 50.degree. C., this being 
continued until the addition is complete. The reaction medium is gradually 
heated to reflux and then allowed to return to RT over-night. The 
precipitate formed is filtered off and then added to a dilute solution of 
NaHSO.sub.3. The product is filtered off again, rinsed with water and then 
dried over P.sub.2 O.sub.5. 27.4 g of the expected product are obtained, 
m.p.=134.degree. C. 
The compound of step B) may also be prepared according to the procedure 
described below. 
B') 4-Bromo-2-isopropylacetanilide. 
A mixture is prepared containing 117.6 g of 2-isopropylacetanilide in 330 
ml of DMF, and 117.6 g of NBS in 330 ml of DMF are added over 25 minutes. 
The mixture is left stirring at RT for 5 hours and then poured into 1.5 
litres of water while cooling the reaction medium with ice. The 
precipitate formed is filtered off, rinsed with water and then dried at 
50.degree. C. under vacuum. The filtrate is extracted with DCM (twice), 
washed with water and then dried over Na.sub.2 SO.sub.4 to obtain a second 
fraction of the expected product. By combining the different purified 
fractions, 158 g of the expected product are obtained, m.p.=134.degree. C. 
C) 4-Cyano-2-isopropylacetanilide. 
A mixture containing 26.48 g of the product obtained in the preceding step, 
60 ml of DMF, 1 ml of water and 10.25 g of cuprous cyanide is stirred 
under reflux for 10 hours. After cooling, the mixture is poured into a 
solution of 50 g of sodium cyanide in 150 ml of water at 40.degree. C. The 
precipitate formed is filtered off and rinsed several times with water. 
16.7 g of the expected product are obtained, m.p.=134.degree. C. 
D) 4-Cyano-2-isopropylaniline hydrochloride. 
16.13 g of the compound obtained in the preceding step, 65 ml of 100% 
ethanol and 40 ml of 1N HCl are mixed, and the mixture is stirred under 
reflux for 19 hours. After one night at RT, 10% NaOH solution is added 
until a pH of 10 is obtained. The reaction medium is extracted twice with 
DCM, and the organic phase is dried over Na.sub.2 SO.sub.4 and 
concentrated under vacuum. The residue is dissolved in ether and ethereal 
hydrogen chloride is added. The precipitate formed is filtered off and 
rinsed with ether. 15.32 g of the expected product are obtained, which 
product crystallizes in the Et.sub.2 O/HCl mixture, m.p.=188.degree. C. 
E) 4-Amino-3-isopropylbenzoic acid hydrochloride. 
This compound is described in J. Med. Chem., 1974, 17(2), 221. 
A mixture containing 1 g of the compound obtained in the preceding step, 
2.86 g of ground potassium hydroxide, 6 ml of water and 0.5 ml of 
dimethoxyethane is heated to reflux for 12 hours. After cooling, 
concentrated HCl is added until a pH of 1 is obtained, and the mixture is 
then extracted twice with DCM; the organic phase is dried over Na.sub.2 
SO.sub.4 and concentrated. 0.96 g of the expected product is obtained, 
m.p.=128.degree. C. 
F) 3-Isopropyl-4-hydrazinobenzoic acid hydrochloride. 
A mixture containing 0.96 g of the product obtained in the preceding step, 
22 ml of concentrated HCl and 20 ml of acetic acid is cooled to -5.degree. 
C., 0.36 g of NaNO.sub.2 in 4 ml of water is added and the mixture is then 
left stirring at 0.degree. C. for 1 hour 15 minutes. It is cooled to 
-10.degree. C., and 3.73 g of stannous chloride dihydrate in 4 ml of 
concentrated HCl are added. The temperature is allowed to rise to 
18.degree. C., and the precipitate formed is then filtered off and rinsed 
with 1 ml of dilute HCl. 0.96 g of the expected product is obtained after 
drying over P.sub.2 O.sub.5. 
PREATION 2.1a 
3-Isopropyl-4-hydrazinobenzoic acid hydrochloride may also be prepared 
according to the procedure described below. 
A) 4-Bromo-2-isopropylacetanilide. 
200 ml of acetic anhydride are added over 10 minutes to 300 ml of 
2-isopropylaniline while the temperature is maintained below 60.degree. C. 
After 45 minutes of stirring at RT, a solution of one equivalent of NBS in 
720 ml of DMF is added. After 2 hours of stirring, the mixture is poured 
into 5.7 1 of water/AcOEt (2:1; v/v) mixture, settling is allowed to take 
place, and the organic phase is separated, dried over Na.sub.2 SO.sub.4 
and evaporated under vacuum. The residue is solidified in isopropyl ether 
and filtered off to obtain 367 g of the expected product. 
B) 4-Cyano-2-isopropylacetanilide. 
10.25 g of the product of step A and 1.2 equivalents of cuprous cyanide in 
20 ml of DMF are heated to reflux for 6 hours. The mixture is cooled to 
20.degree. C. and poured into a mixture of 200 ml of AcOEt and 200 ml of 
20% ammonium hydroxide. The organic phase is washed again with 50 ml of 
20% ammonium hydroxide and then twice with saturated NaCl solution. After 
drying over Na.sub.2 SO.sub.4, it is evaporated under vacuum, and the 
residue is treated with isopropyl ether, filtered off and dried at 
40.degree. C. under vacuum to obtain 6.15 g of the expected product. 
The compound of step B may also be prepared according to the procedure 
below: 
B') Argon is bubbled through a stirred mixture of 22.16 g of product of 
step A and 0.6 equivalent of zinc cyanide in 67 ml of anhydrous DMF. The 
mixture is heated to 80.degree. C. and 2 g of 
tetrakis(triphenylphosphine)-palladium(O) are added while the mixture is 
protected from light. After 3 hours of stirring at 80.degree. C., the 
mixture is allowed to cool to RT and 120 ml of 4% ammonium hydroxide and 
200 ml of AcOEt are added, and the combined organic phases are washed 
again with 4% ammonium hydroxide. They are dried over Na.sub.2 SO.sub.4 
and evaporated under vacuum, and the residue is treated with isopropyl 
ether, filtered off and dried under vacuum to obtain 15 g of the expected 
nitrile. 
C) 4-Amino-3-isopropylbenzoic acid hydrochloride. 
A mixture of 100 g of the product of step B with 500 ml of concentrated HCl 
and 500 ml of AcOH is heated to reflux for 10 hours. It is concentrated 
under vacuum, and the precipitate is filtered off and dried under vacuum 
to obtain 103.8 g of expected product. 
D) 3-Isopropyl-4-hydrazinobenzoic acid hydrochloride. 
A solution of 27.7 g of NaNO.sub.2 in 250 ml of water is added slowly to a 
mixture, cooled to -5.degree. C., of 59 g of the product of step C with 
1050 ml of AcOH and 1420 ml of concentrated HCl. After1 hour 20 minutes of 
stirring at 0.degree. C., the mixture is cooled to -10.degree. C. and a 
solution of 236 g of SnCl.sub.2 .multidot.2H.sub.2 O in 250 ml of 
concentrated HCl is added. The temperature is allowed to rise to RT, and 
the precipitate is filtered off, washed with concentrated HCl and dried 
under vacuum to obtain 56.36 g of expected product. 
PREATION 2 
3-Isopropyl-4-hydrazinobenzenesulphonic acid hydrochloride. 
A) 4-Amino-3-isopropylbenzenesulphonic acid. 
5.7 ml of H.sub.2 SO.sub.4 are added to 10 ml of water, the mixture is 
heated to 80.degree. C. and 13.5 g of 2-isopropylaniline are then added. 
The water is evaporated off by heating under vacuum, and the temperature 
is then gradually raised over one and a half hours to reach 260.degree. C. 
After 3 hours with stirring and under vacuum at 260.degree. C., the 
reaction medium is allowed to return to RT and to atmospheric pressure, 
and is then heated for 30 minutes in the presence of 15 ml of NaOH and 100 
ml of water in order to dissolve the reaction medium. The insoluble matter 
is filtered off, and the mixture is cooled to 5.degree. C. and then 
acidified to pH 1 by adding concentrated H.sub.2 SO.sub.4. The precipitate 
formed is filtered off, washed with 5 ml of cold water and dried to obtain 
20 g of the expected product. 
NMR: 1.1:d:6H; 2.95:mt:1H; 6.85:d:1H; 7.45:dd:1H; 7.6:d:1H. 
B) 3-Isopropyl-4-hydrazinobenzenesulphonic acid hydrochloride. 
10 ml of ice and 3.2 g of NaNO.sub.2 are added to a solution of 10 g of the 
product prepared in the preceding step in 10 ml of 30% NaOH and 20 ml of 
water. This solution is poured slowly into a solution of 30 ml of 
concentrated HCl in 20 ml of water at a temperature of between -5.degree. 
C. and -15.degree. C. The mixture is left stirring for one hour at this 
temperature, and 26 g of stannous chloride dihydrate in 40 ml of 
concentrated HCl are then added at a temperature of between 0.degree. C. 
and -5.degree. C. After two and a half hours with stirring at RT, the 
product obtained is filtered off and then dried under vacuum in the 
presence of P.sub.2 O.sub.5. 9.7 g of the expected product are thereby 
obtained. 
NMR: 1.2:d:6H; 3.15:mt:1H; 6.8:d:1H:7.45:d:1H; 7.55:s:1H; 7.9:bs:1H; 
10:bs:3H. 
PREATION 2.3 
4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid hydrochloride. 
A) 4-Amino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid. 
4-Nitro-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid is described in 
Chem. Pharm. Bull., 1984, 32, 3968. The hydrogenation of 1.48 g of this 
nitro derivative is performed in methanol in the presence of Raney.RTM. 
nickel. After 4 hours with stirring, the catalyst is filtered off, the 
mixture is evaporated to dryness and the residue is taken up with ether 
and filtered off to obtain 1 g of the expected product. m.p.=180.degree. 
C. (dec.). 
B) 4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid 
hydrochloride. 
A solution of 0.26 g of NaNO.sub.2 in 1 ml of water is added to a solution, 
cooled to -5.degree. C., of 0.73 g of 
4-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid in 10 ml of 
concentrated HCl. After one and a half hours of stirring at -5.degree. C., 
a solution of 3.4 g of SnCl.sub.2 .multidot.2H.sub.2 O in 34 ml of 
concentrated HCl is added at -5.degree. C. The mixture is stirred for 1 
hour at RT and filtered, and the product is washed with concentrated HCl 
and dried under a stream of dry nitrogen to obtain 0.67 g of the expected 
hydrazine. 
PREATION 2.4 
4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acid hydrochloride. 
A) 4-Amino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acid. 
A hot suspension of 20 g of sulphamic acid in 40 ml of N-methylpyrrolidone 
is added to a solution of 10 g of 5,6,7,8-tetrahydronaphthylamine in 100 
ml of 1,2-dichlorobenzene. The mixture is heated with stirring for 7 hours 
at 150.degree. C. The product is filtered off and washed with 
dichlorobenzene and then with toluene. The precipitate is resuspended in 
70 ml of water and neutralized to pH 7 with 5.5 ml of 30% sodium 
hydroxide. The insoluble matter is filtered off and the aqueous phase is 
extracted with ether. The aqueous phase is adjusted to pH 5 by adding HCl, 
at 5.degree. C.; the mixture is filtered, and the residue is washed with 
water and dried to obtain 7.5 g of the expected product. 
B) 4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acid 
hydrochloride. 
1 g of NaNO.sub.2 is added to a solution of 3 g of the acid obtained in 
step A in 10 ml of water and 2 ml of 30% sodium hydroxide. This solution 
is poured over 1 hour into 10 ml of concentrated HCl cooled to 5.degree. 
C. After stirring for 3 hours at 5.degree. C., a solution of 7.5 g of 
SnCl.sub.2 .multidot.2H.sub.2 O in 15 ml of concentrated HCl is added 
slowly while the temperature is maintained at 5.degree. C. The mixture is 
left stirring for one and a half hours at RT and filtered, and the residue 
is dried under vacuum to obtain 2.86 g of the expected product. 
NMR (D.sub.20 --NaOD): 1.6:mt: 4H; 2.25:mt: 2H; 2.9:mt: 2H; 6.75:d: 1H; 
7.6:d: 1H. 
PREATION 2.5 
4-Hydrazino-3-methylbenzamide hydrochloride. 
A) 4-Amino-3-methylbenzamide. 
This product is prepared by catalytic hydrogenation of 
3-methyl-4-nitrobenzamide, m.p.=124.degree. C. 
B) 4-Hydrazino-3-methylbenzamide hydrochloride. 
0.5 g of the compound of step A is dissolved in 10 ml of 1N HCl and 5 ml of 
concentrated HCl. The mixture is cooled to 0.degree. C. and a solution of 
230 mg of NaNO.sub.2 in 3 ml of water is added. After 15 minutes at 
-10.degree. C., a solution of 1.5 g of SnCl.sub.2 .multidot.2H.sub.2 O in 
5 ml of concentrated HCl is added. After 1 hour the precipitate is 
filtered off and dried under vacuum over P.sub.2 O.sub.5 to obtain 390 mg 
of the expected product. 
PREATION 2.6 
2,3-Dimethyl-4-hydrazinobenzoic acid hydrochloride. 
A solution of 1.87 g of NaNO.sub.2 in 7 ml of water is added slowly to a 
solution, cooled to -5.degree. C., of 4.5 g of 4-amino-2,3-dimethylbenzoic 
acid in 135 ml of concentrated HCl. After 2 hours of stirring at 
-5.degree. C., a solution of 25 g of SnCl.sub.2 .multidot.2H.sub.2 O in 
250 ml of concentrated HCl is added at -10.degree. C., and the mixture is 
stirred for 30 minutes at -5.degree. C. and then 2 hours at RT. The 
mixture is filtered, and the precipitate is washed with 5 ml of 
concentrated HCl and dried under a stream of dry nitrogen and then under 
vacuum to obtain 5.5 g of expected product. 
NMR: 2.1:s:3H; 2.4:s:3H; 6.8:d:2H; 7.6:d:2H; 8.2:s:1H; 10:bs:2H. 
PREATION 2.7 
4-Hydrazino-3-methoxybenzoic acid hydrochloride. 
A solution of 2.17 g of NaNO.sub.2 in 40 ml of H.sub.2 O is added slowly to 
a solution, cooled to 0.degree. C., of 5 g of 4-amino-3-methoxybenzoic 
acid in 50 ml of concentrated HCl. After 1 hour 15 minutes of stirring at 
0.degree. C., the mixture is cooled to -10.degree. C., and a solution of 
23.6 g of SnCl.sub.2 .multidot.2H.sub.2 O in 20 ml of concentrated HCl and 
20 ml of water is added over 30 min. After one and a half hours of 
stirring at -10.degree. C., the mixture is filtered, and the precipitate 
is washed with 50 ml of pentane to obtain, after drying, 6 g of expected 
product. 
NMR: 3.8:s:3H; 7:d:1H; 7.4:s:1H; 7.5:dd:1H; 8:bs:1H; 10.6:bs:2H. 
PREATION 2.8 
2-Chloro-4-hydrazinobenzonitrile hydrochloride. 
5 g of 4-amino-2-chlorobenzonitrile and 40 ml of concentrated HCl in 30 ml 
of THF are mixed at -5.degree. C.; 2.26 g of NaNO.sub.2 in 30 ml of water 
are added and the mixture is left stirring for 2 hours, 30 g of SnCl.sub.2 
.multidot.2H.sub.2 O in 30 ml of concentrated HCl are then added and 
stirring is maintained at -5.degree. C. for 30 minutes. 
After a return to RT, the insoluble matter is filtered off, NaCl is added 
and the mixture is stirred again. The expected product crystallizes with 
NaCl; it is taken up in ethanol while the NaCl is filtered off. After 
evaporation of the solvents, 4.25 g of the expected product are obtained. 
PREATION 2.4 
3-Cyclopropyl-4-hydrazinobenzoic acid hydrochloride. 
A) 4-Acetamido-3-cyclopropylbenzonitrile. 
1.67 g of CuCN are added to a solution of 4.3 g of 
4-bromo-2-cyclopropylacetanilide (prepared according to J. Am. Chem. Soc., 
1968, 90 3404) in 100 ml of DMF, and the mixture is heated to reflux for 
24 hours. It is poured into 30 ml of water, the resulting mixture is 
filtered, and the precipitate is washed with water and then stirred for 30 
minutes in a mixture of 59 ml of water and 25 ml of ethylenediamine. After 
extraction with 100 ml of AcOEt, drying over Na.sub.2 SO.sub.4 and 
evaporation under vacuum, 2.39 g of the expected product are obtained. 
NMR: 0.6:u.c.:2H; 0.9:u.c.:2H; 1.9: u.c.:1H; 2.1:s:3H; 7.3:d:1H; 7.5:dd:1H; 
7.8:d:1H; 9.5:bs:1H. 
B) 4-Amino-3-cyclopropylbenzonitrile hydrochloride. 
A mixture of 2.39 g of the product of step A dissolved in 45 ml of ethanol 
with 36 ml of water and 5 ml of concentrated HCl is stirred for 12 hours 
under reflux. The ethanol is evaporated off under vacuum, and the 
precipitate is filtered off, washed with 1 ml of water and dried under 
vacuum to obtain 1.5 g of the expected product. 
NMR: 0.5:u.c.:2H; 0.9:u.c.:2H; 1.6: u.c.:1H; 6.7:d:1H; 7.1-7.3:mt:2H; 
8:bs:2H. 
C) 4-Amino-3-cyclopropylbenzoic acid hydrochloride. 
1.3 g of the product of step B in 21 ml of 50% KOH are stirred for 29 hours 
under reflux. After acidification to pH 1 with concentrated HCl, the 
mixture is filtered and the residue is dried under vacuum to obtain 0.96 g 
of the expected product. 
NMR: 0.5:u.c.:2H; 0.9:u.c.:2H; 1.7:u.c.:1H; 5.9:bs:2H; 6.6:d:1H; 7.4:s:1H; 
7.5:mt:1H; 12:bs:1H. 
D) 3-cyclopropyl-4-hydrazinobenzoic acid hydrochloride. 
A solution of 0.38 g of NaNO.sub.2 in 4.5 ml of water is added slowly to a 
solution, cooled to -5.degree. C., of 0.95 g of the product obtained in 
step C in 22 ml of concentrated HCl and 21 ml of AcOH, and the mixture is 
stirred for 1 h 15 min at 0.degree. C. It is cooled to -10.degree. C., and 
a solution of 3.76 g of SnCl.sub.2 .multidot.2H.sub.2 O in 8 ml of 
concentrated HCl is added slowly. After 4 hours of stirring at RT, the 
mixture is filtered, and the residue is washed with 2 ml of concentrated 
HCl and dried under vacuum to obtain 1 g of expected product. 
NMR: 0.6:u.c.:2H; 1:u.c.:2H; 1.9: u.c.:1H; 7.1:d:1H; 7.6:s:1H; 7.8:d:1H; 
8.4:s:1H; 10.7:bs: 
PREATION 2.10 
5-Hydrazino-2-chlorobenzoic acid hydrochloride. 
A solution of 2.11 g of NaNO.sub.2 in 40 ml of water is added over 30 
minutes to a suspension, cooled to -2.degree. C., of 5 g of 
5-amino-2-chlorobenzoic acid in 50 ml of concentrated HCl. The solution is 
stirred for 2 hours at -3.degree. C. and cooled to -10.degree. C., and a 
solution of 23 g of SnCl.sub.2 .multidot.2H.sub.2 O in 20 ml of 
concentrated HCl and 20 ml of water is added over 30 minutes. The mixture 
is stirred for one and a half hours at 0.degree. C. and filtered, and the 
precipitate is dried to obtain 4 g of expected product. 
NMR: 7.6:bs:2H; 7.7:bs:1H; 8.4:bs: 1H; 11.0:bs:3H. 
PREATION 2.11 
3-Hydrazino-4-methylbenzoic acid hydrochloride. 
A solution of 2.74 g of NaNO.sub.2 in 28 ml of water is added over 30 
minutes to a solution, cooled to -5.degree. C., of 5 g of 
3-amino-4-methylbenzoic acid in 120 ml of concentrated HCl and 40 ml AcOH, 
and the mixture is left stirring for 1 hour 20 minutes at 0.degree. C. 
After cooling to -10.degree. C., a solution of 27.6 g of SnCl.sub.2 
.multidot.2H.sub.2 O in 28 ml of concentrated HCl is added slowly. After 
stirring for 1 hour at RT, filtration, washing of the precipitate with 5 
ml of 1N HCl and drying over P.sub.2 O.sub.5 under vacuum, 6.15 g of the 
expected product are obtained. 
By working according to the above procedures, starting from correctly 
substituted aniline derivatives, the hydrazines described in Table 1 below 
are prepared. 
TABLE 1 
______________________________________ 
##STR59## 
M.p. or NMR 
Preparation 
R.sub.1 or R'.sub.1 
R.sub.2 R.sub.3 
(Salt) 
______________________________________ 
2.12 
4-SO.sub.3 H 2-CH.sub.3 
3-CH.sub.3 
NMR 
(H.sub.2 SO.sub.4) 
2.13 5-CO.sub.2 H 
2-Cl H NMR 
(HCl) 
2.14 3-CO.sub.2 H 
4-F H NMR 
2.15 4-CN 2-CF.sub.3 
H 125 
2.16 4-CO.sub.2 H 
2-CF.sub.3 
H 170(dec.) 
(HCl) 
2.17 5-CO.sub.2 H 
2-OCH.sub.3 
H NMR 
(HCl) 
______________________________________ 
NMR: 
Preparation 2.12:2:s:3H; 2.4:s:3H; 6.5:d:1H; 7.5:d:1H; 9.9:bs:3H. 
Preparation 2.13:7.6:bs:2H; 7.7:bs: 1H; 8.4:bs:1H; 11.0:bs:3H. 
Preparation 2.14:7.3:u.c.:2H; 7.4:u.c. 1H; 8.4:bs:1H; 10.8:bs:3H. 
Preparation 2.17:3.8:s:3H; 4.4:bs:1H; 7.0:d:1H; 3.6:d:1H; 10.0:bs:3H. 
PREATION 2.18 
N-(4-Hydrazino-3-isopropylphenyl)-4-methyl-benzenesulphonamide oxalate. 
A) N-(2-Bromo-5-isopropyl-4-nitrophenyl)-4-methylbenzenesulphonamide. 
A solution of 23.47 g of N-(4-nitrophenyl)-4-methylbenzenesulphonamide in 
230 ml of THF is cooled to -30.degree. C., 100 ml of a 2M solution of 
isopropylmagnesium chloride in ether is added and the mixture is left 
stirring for 30 minutes at -30.degree. C. 10.3 ml of bromine are then 
added at -30.degree. C., the mixture is left stirring for 15 minutes at 
this temperature and the temperature is then allowed to rise to 20.degree. 
C. 55 ml of triethylamine are then added and the mixture is left stirring 
for 1 hour at RT. Water is added, the mixture is acidified to pH 3-4 by 
adding 10% HCl solution, the organic phase is separated after settling has 
taken place, the aqueous phase is extracted with ether and the combined 
organic phases are dried over Na.sub.2 SO.sub.4. The organic phase is 
stirred in the presence of animal charcoal, filtered and concentrated 
under vacuum. The residue is taken up in EtOH and the crystallized product 
formed is drained. 11.6 g of the expected product are obtained, 
m.p.=132.degree. C. 
NMR: 1.0:d:6H; 2.32:s:3H; 3.12:s: 1H; 7.14:s:1H; 7.36:d:2H; 7.65:d:2H; 
8.08: s:1H; 10.25:bs:1H. 
B) N-(4-Amino-3-isopropylphenyl)-4-methyl-benzenesulphonamide. 
A mixture of 11.5 g of the compound obtained in the preceding step and 1 g 
of palladium on charcoal (5% Pd) in 200 ml of MeOH and 30 ml of DMF is 
hydrogenated for 7 hours at RT and at a pressure of 1 bar. The catalyst is 
filtered off and the filtrate is concentrated under vacuum. The residue is 
taken up with water, the mixture is neutralized to pH 7 by adding 10% NaOH 
solution and extracted with AcOEt, the organic phase is dried over 
Na.sub.2 SO.sub.4 and the solvent is evaporated off under vacuum. 8 g of 
the expected product are obtained. 
NMR: 1.01:d:6H; 2.4:s:3H; 2.89:mt: 1H; 4.91:bs:2H; 6.42-6.68:u.c.:3H; 
7.35:d: 2H; 7.56:d:2H; 9.38:s:1H. 
C) N-(4-Hydrazino-3-isopropylphenyl)-4-methyl-benzenesulphonamide oxalate. 
A mixture of 6.68 g of the compound obtained in the preceding step and 70 
ml of concentrated HCl solution is stirred at 0.degree. C., a solution of 
1.48 g of NaNO.sub.2 in 5 ml of water is added and the resulting mixture 
is left stirring for 1 hour at 0.degree. C. A solution of 11.35 g of 
sodium dithionite in 60 ml of water is then added and stirring is 
continued for 1 hour at 0.degree. C. 120 g of powdered sodium acetate and 
300 ml of water are then added and the reaction mixture is left stirring 
for 30 minutes at 0.degree. C. It is extracted with AcOEt, the organic 
phase is dried over Na.sub.2 SO.sub.4 and filtered, a solution of 1.98 g 
of oxalic acid in a minimum amount of EtOH is added to the filtrate and 
the mixture is concentrated under vacuum. The residue is taken up in 
isopropyl ether, the mixture is left stirring for 12 hours and the 
precipitate formed is drained. 4.84 g of the expected product are 
obtained, which product is used without further treatment. 
PREATION 2.19 
1-Hydrazino-2-methyl-4-nitrobenzene hydrofluoride. 
A mixture of 4.6 g of 1-fluoro-2-methyl-4-nitrobenzene and 3 ml of 
hydrazine hydrate in 45 ml of 2-propanol is heated to reflux for 2 hours. 
3 ml of hydrazine hydrate are added, refluxing is continued for 2 hours 
and the mixture is left overnight with stirring at RT. The precipitate 
formed is drained. 3.53 g of the expected product are obtained, 
m.p.=182.degree. C. 
PREATION 2.20 
N-(4-Hydrazino-3-isobutylphenyl)-4-methylbenzenesulphonamide hydrobromide. 
A) N-(2-Bromo-5-isobutyl-4-nitrophenyl)-4-methylbenzenesulphonamide. 
This compound is prepared according to the procedure described in step A of 
Preparation 2.18, from 10 g of 
N-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 42.6 ml 
of a 2M solution of isobutylmagnesium chloride in ether, followed by 4.4 
ml of bromine and 23.4 ml of triethylamine. 5.9 g of the expected product 
are obtained, m.p.=170.degree. C. 
NMR: 0.8:d:6H; 1.7:mt:1H; 2.35:s: 3H; 2.6:d:2H; 7.2:s:1H; 7.3:d:2H; 7.4:d: 
2H; 8.2:s:1H; 10.25:s:1H. 
B) N-(4-Amino-3-isobutylphenyl)-4-methylbenzenesulphonamide. 
This compound is prepared according to the procedure described in step B of 
Preparation 2.18, from 4.7 g of the compound obtained in the preceding 
step. 2.8 g of the expected product are obtained. 
NMR: 0.8:d:6H; 1.75:mt:1H; 2.2:d: 2H; 2.4:s:3H; 4.8:s:2H; 6.45:d:1H; 6.5:d 
1H; 6.65:dd:1H; 7.35:d:2H; 7.55:d:2H; 9.4:s:1H. 
C) N-(4-Hydrazino-3-isobutylphenyl)-4-methyl-benzenesulphonamide 
hydrobromide. 
This compound is prepared according to the procedure described in step C of 
Preparation 2.18, from 2.5 g of the compound obtained in the preceding 
step, 35 ml of concentrated HCl, 50 ml of acetic acid and 0.53 g of 
NaNO.sub.2, followed by 4.78 g of sodium dithionite in 50 ml of water, 140 
g of sodium acetate and 70 ml of water. After 30 minutes of stirring at 
0.degree. C., hydrobromic acid is added at 0.degree. C. and the 
crystallized product is drained and dried. 1.9 g of the expected product 
are obtained. 
NMR: 0.65:d:6H; 1.6:mt:1H; 2.05:d: 2H; 2.2:s:3H; 6.05:bs:1H; 6.4:bs:1H; 
6.6-6.8:u.c.:2H; 7.2:d:2H; 7.4:d:2H. 
PREATION 2.21 
N-(4-Hydrazino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamide oxalate. 
A) N-(2-Bromo-5-cyclopentyl-4-nitrophenyl)-4-methylbenzenesulphonamide. 
This compound is prepared according to the procedure described in step A of 
Preparation 2.18, from 15 g of 
N-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 64 ml 
of a 2M solution of cyclopentylmagnesium chloride in ether, followed by 
6.8 ml of bromine and 35 ml of triethylamine. 6.1 g of the expected 
product are obtained, m.p.=122.degree. C. 
NMR (DMSO+TFA): 1.25:mt:2H; 1.5-1.7: u.c.:4H; 1.95:mt:2H; 2.36:s:3H; 
3.2:qt: 1M; 7.12:s:2H; 7.4:d:2H; 7.7:d:2H; 8.08:s:1H. 
B) N-(4-Amino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamide. 
This compound is prepared according to the procedure described in step B of 
Preparation 2.18, from 6 g of the compound obtained in the preceding step. 
4.25 g of the expected product are obtained, m.p.=128.degree. C. 
NMR (DMSO+TFA): 1.25:mt:2H; 1.5-1.75: u.c.:4H; 1.95:mt:2H; 2.3:s:3H; 
3.0:qt:1H; 7.0:dd:1H; 7.12:d:1H; 7.2:d:1H; 7.34:d: 2H; 7.65:d:2H. 
C) N-(4-Hydrazino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamide 
oxalate. 
This compound is prepared according to the procedure described in step C of 
Preparation 2.18, from 3.35 g of the compound obtained in the preceding 
step, 20 ml of H.sub.2 SO.sub.4, 50 ml of acetic acid, 10 ml of water and 
0.69 g of NaNO.sub.2, followed by 5.5 g of sodium dithionite in 50 ml of 
water and 200 g of sodium acetate and 300 ml of water. 2.42 g of the 
expected product are obtained. 
PREATION 2.22 
4-Hydrazino-2-isopropylbenzoic acid hydrochloride. 
A) 4-Iodo-3-isopropylacetanilide. 
This compound is prepared according to the process described in Bull. Soc. 
Chim. Jap., 1989, 62, 1349. 
5.7 g of zinc chloride and 10.8 g of benzyltrimethylammonium dichloroiodate 
are added at RT to a solution of 5 g of 3-isopropylacetanilide in 150 ml 
of acetic acid, and the mixture is left stirring for 2 days. It is 
concentrated under vacuum, the residue is taken up with 100 ml of a 5% 
solution of sodium hydrogen sulphite, the mixture is brought to pH 5-6 by 
adding 10% Na.sub.2 CO.sub.3 solution and extracted 4 times with 200 ml of 
chloroform and the organic phase is dried over Na.sub.2 SO.sub.4. After 
filtration, the filtrate is chromatographed on 100 g of alumina, eluting 
with chloroform. 5.2 g of the expected product are obtained. 
NMR: 1.1:d:6H; 2.0:s:3H; 3.06:u.c.: 1H; 7.28:dd:1H; 7.5:d:1H; 7.72:d:1H; 
10.0: bs:1H. 
B) 4-Iodo-3-isopropylaniline. 
A mixture of 5.1 g of the compound obtained in the preceding step in 40 ml 
of 96% EtOH and 25 ml of concentrated NaOH is heated to reflux for 6 
hours. It is concentrated under vacuum and extracted with ether, the 
organic phase is dried over Na.sub.2 SO.sub.4 and the solvent is 
evaporated off under vacuum. 5 g of the expected product are obtained in 
the form of an oil. 
NMR: 1.16:d:6H; 2.94:u.c.:1H; 5.2:bs:2H; 6.2:dd:1H; 6.6:d:1H; 7.4:d:1H. 
C) 4-Amino-2-isopropylbenzoic acid. 
40 ml of water and 11 g of K.sub.2 CO.sub.3 are added to a solution of 5 g 
of the compound obtained in the preceding step in 60 ml of DMF, and the 
solution is then degassed for 10 minutes by bubbling nitrogen through it. 
0.5 g of palladium(II) acetate are then added and the reaction mixture is 
thereafter degassed for 10 minutes by bubbling nitrogen through it. It is 
placed under a pressure of 1 bar of carbon monoxide for 10 hours and with 
stirring. The solution is filtered, the filter is washed 4 times with 20 
ml of water and the filtrate is concentrated under vacuum. The residue is 
taken up with 50 ml of water and 10 ml of saturated NaCl solution, the 
aqueous phase is washed with ether and acidified to pH 3.5-4 by adding 
concentrated HCl and extracted with AcOEt, the organic phase is washed 
with saturated NaCl solution and dried over Na.sub.2 SO.sub.4 and the 
solvent is evaporated off under vacuum. 2 g of a crude product are 
obtained, which product is taken up in 20 ml of a saturated solution of 
HCl gas in methanol, and the mixture is heated to reflux overnight. It is 
concentrated under vacuum, the residue is taken up in 20 ml of water, and 
the mixture is alkalinized to pH 8 by adding concentrated NaOH and 
extracted with 30 ml of DCM. 0.8 ml of acetic anhydride, NaHCO.sub.3 and 
Na.sub.2 SO.sub.4 are added to the organic phase, which is left stirring. 
After filtration, the filtrate is concentrated under vacuum and the 
residue is chromatographed on silica, eluting with a DCM/ether (50:50; 
v/v) mixture. 0.8 g of 4-acetamido-2-isopropylbenzoic acid methyl ester is 
obtained in the form of an oil. A mixture of 0.8 g of the product obtained 
and 3 g of KOH in 10 ml of water and 2 ml of 1,2-dimethoxyethane is heated 
to reflux overnight. After cooling to RT, the reaction mixture is washed 
with ether, the aqueous phase is acidified to pH 3-4 by adding 
concentrated HCl and extracted with AcOEt, the organic phase is dried over 
Na.sub.2 SO.sub.4 and the solvent is evaporated off under vacuum. 0.6 g of 
the expected product is obtained. 
NMR: 1.17:d:6H; 4.0:sp:1H; 5.7:bs:2H; 6.36:dd:1H; 6.80:d:1H; 7.6:d:1H; 
11.80:BS:1H. 
D) 4-Hydrazino-2-isopropylbenzoic acid hydrochloride. 
A mixture of 0.5 g of the compound obtained in the preceding step in 7 ml 
of concentrated HCl is cooled to 0.degree. C., a solution of 0.23 g of 
NaNO.sub.2 in 4 ml of water is added and the resulting mixture is left 
stirring for 1 hour 30 minutes at 0.degree. C. It is cooled to -10.degree. 
C. and a solution of 2.6 g of SnCl.sub.2. 2H.sub.2 O in 5 ml of 
concentrated HCl and 3 ml of water is added, and the resulting mixture is 
left stirring for 2 hours at 0.degree. C. The precipitate formed is 
drained, washed with concentrated HCl and dried at 50.degree. C. under 
vacuum. 0.36 g of the expected product is obtained. 
NMR: 1.15:d:6H; 3.98:u.c.:1H; 6.7:dd 1H; 6.96:d:1H; 7.8:d:1H; 8.2:bs:1H; 
13: bs:4H. 
PREATION 2.23 
1-Hydrazino-4-nitro-5,6,7,8-tetrahydronaphthalene hydrochloride. 
A) 1-Acetamido-5,6,7,8-tetrahydronaphthalene. 
A mixture of 24.39 g of 1-amino-5,6,7,8-tetrahydronaphthalene and 18.6 ml 
of acetic anhydride in 230 ml of DCM is left stirring for 1 hour at RT. It 
is concentrated under vacuum, the residue is taken up with ether and the 
precipitate formed is drained. 26.8 g of the expected product are 
obtained, m.p.=158.degree. C. 
B) 1-Amino-4-nitro-5,6,7,8-tetrahydronaphthalene. 
A mixture of 13 g of the compound obtained in the preceding step in 72 ml 
of concentrated sulphuric acid is cooled to 0.degree. C., a mixture of 
4.55 ml of nitric acid (d=1.4) and 22 ml of concentrated sulphuric acid is 
added and the resulting mixture is left stirring for 45 minutes at 
0.degree. C. The reaction mixture is poured onto ice and the precipitate 
formed is drained. The precipitate is taken up in 145 ml of EtOH, 30 ml of 
concentrated HCl and 30 ml of water and the mixture is heated to reflux 
for 1 hour 30 minutes. 70 ml of the reaction mixture are evaporated, 220 
ml of water are added to the remaining solution, the pH is brought to 7 by 
adding concentrated ammonium hydroxide solution and the precipitate formed 
is drained and dried. The precipitate is taken up with 210 ml of 
nitrobenzene, the mixture is cooled 0.degree. C. and a stream of HCl gas 
is bubbled through it for 50 minutes. The precipitate formed is drained 
and washed with ether. The precipitate is taken up with MeOH, the mixture 
is neutralized by adding concentrated ammonium hydroxide solution, water 
is added and the precipitate is drained. 5.15 g of the expected product 
are obtained after drying, m.p.=114.degree. C. 
C) 1-Hydrazino-4-nitro-5,6,7,8-tetrahydronaphthalene hydrochloride. 
A mixture of 3.8 g of the compound obtained in the preceding step in 70 ml 
of concentrated HCl is cooled to 3.degree. C., a solution of 1.34 g of 
NaNO.sub.2 in 2 ml of water is added and the resulting mixture is left 
stirring for 2 hours at 3.degree. C. A solution of 18.2 g of SnCl.sub.2 
.multidot.2H.sub.2 O in 90 ml of concentrated HCl is then added, the 
mixture is left stirring for 30 minutes at 3.degree. C. and the 
temperature is then allowed to rise to RT. The precipitate formed is 
drained and dried. 6.3 g of the expected product are obtained, mixed with 
tin salts. 
NMR (DMSO+TFA): 1.7:mt:4H; 2.55:mt:2H; 2.85:mt:2H; 6.88:d:1H; 7.85:d:1H. 
PREATION 2.24 
3-Diethylamino-N-(4-isopropyl-3-hydrazinophenyl)-propionamide. 
A) 3-Diethylamino-N-(4-isopropyl-3-nitrophenyl)-propionamide oxalate. 
4 g of 4-isopropyl-3-nitroaniline (prepared according to J. Org. Chem., 
1954, 19, 1067) are treated by heating to reflux for 1 hour with 8.14 ml 
of bis-(trimethylsilyl)acetamide in 20 ml of acetonitrile, and the acid 
chloride prepared from 4 g of 3-(N,N-diethylamino)propanoic acid 
hydrochloride in DCM is added, followed by 8.9 ml of triethylamine. After 
1 hour of stirring at RT, the mixture is evaporated to dryness, the 
residue is extracted with DCM, and the mixture is washed with water and 
then with 5% NaOH. After drying over Na.sub.2 SO.sub.4, the mixture is 
evaporated under vacuum, the oil obtained is redissolved in the minimum 
Mount of ethanol, and 1.2 g of oxalic acid are added. After 2 hours of 
stirring, the mixture is filtered to obtain 4.5 g of the expected oxalate, 
m.p.=165.degree. C. 
B) 3-Diethylamino-N-(4-isopropyl-3-aminophenyl)-propionamide oxalate. 
A solution of 4.5 g of nitro derivative obtained in the preceding step in 
100 ml of MeOH and 10 ml of DMF is hydrogenated for 5 hours with 
Raney.RTM. nickel. After the catalyst has been filtered off, the mixture 
is concentrated under vacuum, precipitation is induced by adding isopropyl 
ether and the mixture is left stirring for 1 hour at RT. After filtration, 
3 g of the expected aniline oxalate are obtained, m.p.=127.degree. C. 
C) 3-Diethylamino-N-(4-isopropyl-3-hydrazinophenyl)propionamide. 
0.67 g of NaNO.sub.2 dissolved in the minimum amount of water is added to a 
mixture, cooled to 0.degree. C, of 2.7 g of amine obtained in the 
preceding step and 30 ml of concentrated HCl, and the resulting mixture is 
left stirring for 1 hour at 0.degree. C. 5 g of sodium dithionite 
dissolved in the minimum amount of water are then added and the mixture is 
stirred for a further 30 minutes at 0.degree. C. 50 g of powdered sodium 
acetate are added and the mixture is stirred for 30 minutes at 0.degree. 
C. 50 g of water are added and a few impurities are extracted with AcOEt. 
The aqueous phase is saturated with NaCl, the pH is raised to 9 with 20% 
NH.sub.4 OH and extracted with DCM, and the organic phase is dried over 
Na.sub.2 SO.sub.4 and evaporated under vacuum. The residue is allowed to 
crystallize in pentane overnight and is filtered off to obtain 3.26 g of 
expected hydrazine, m.p.=77.degree.-80.degree. C. 
PREATIONS OF THE ESTERS IIa, II'a 
PREATION 3.1 
1-(4-Carboxy-2-isopropylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxyl 
ic acid methyl ester. 
(II'a:R'.sub.1 =4--CO.sub.2 H; R.sub.2 =2-iPr; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture containing 0.96 g of the product obtained in Preparation 2.1 and 
1.2 g of compound A obtained in Preparation 1.1 in 15 ml of acetic acid is 
brought to reflux for 5 hours. After 3 days at RT, it is poured into a 
mixture of water and ice. The precipitate formed is filtered off, rinsed 
with water and then dried over P.sub.2 O.sub.5. 1.34 g of the expected 
product are obtained, m.p.=228.degree.-230.degree. C. 
NMR: 0.85:d:6H; 2.55:sp:1H; 3.5:s:6H; 3.75:s:3H; 6.5:d:2H; 6.75:s:1H; 
7.05-7.3:u.c.:2H; 7.7:d:1H; 13.05:bs:1H. 
PREATION 3.1a 
1-(4-Carboxy-2-isopropylphenyl)-5-(2.6-dimethoxy-phenyl)-3-pyrazolecarboxyl 
ic acid ethyl ester. 
By reacting the product of Preparation 2.1 or 2.1a with compound A1 
according to the procedure of Preparation 3.1, and after recrystallization 
in AcOEt, the expected ethyl ester is obtained, m.p.=231.degree. C. 
PREATION 3.2 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphen 
yl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4--CON(CH.sub.3)(CH.sub.3).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A) 
1-(4-Chloroformyl-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecar 
boxylic acid methyl ester. 
A mixture is prepared containing 26 g of the product obtained in 
Preparation 3.1 and 170 ml of thionyl chloride. It is left stirring at RT 
for 1 day. It is evaporated under vacuum, the residue is taken up with 
DCM, the mixture is evaporated and the operation is repeated 3 times. 
B) 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-isopropylphe 
nyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic acid methyl ester. 
9.3 ml of triethylamine and 9.9 ml of N,N,N'-trimethyl-1,3-propanediamine 
are added to 50 ml of DCM. The product obtained in the preceding step in 
280 ml of DCM is added under nitrogen, and the mixture is left stirring at 
RT for three and a half hours. After washing with water (twice), the 
mixture is dried over MgSO.sub.4 and evaporated under vacuum. The residue 
is taken up with ether. After the insoluble matter has been filtered off, 
and evaporation, the residue is chromatographed on silica, eluting with 
DCM/MeOH/H.sub.2 O (95:5:0.5; v/v/v, to 88:12:0.8; v/v/v). 24.5 g of the 
expected product are obtained. 
NMR: 0.95:d:6H; 1.7:u.c.:2H; 1.9-2.4: u.c.:8H; 2.95:ss:3H; 3.5:u.c.:2H; 
3.7:s: 6H; 3.9:s:9H; 6.7:d:2H; 6.9:s:1H; 7.1-7.5: u.c.:4H. 
PREATION 3.2a 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphen 
yl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid ethyl ester. 
A) 
1-(4-Chloroformyl-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecar 
boxylic acid ethyl ester. 
26 g of the product of Preparation 3.1 or 3.1a are added to 50 ml of 
SOCl.sub.2 cooled to 5.degree., and the mixture is stirred for 5 hours at 
RT while nitrogen is bubbled through in the dry state. After evaporation 
under vacuum, the residue is taken up with DCM and evaporated under 
vacuum; the operation is repeated twice. 
The acid chloride may also be prepared according to the procedure A' below: 
A') 2.5 ml of SOCl.sub.2 is added to a solution of 5 g of the product of 
Preparation 3.1 or 3.1a in 50 ml of DCM, and the mixture is heated to 
reflux for 3 hours and evaporated under vacuum, the residue is taken up 
with DCM and the mixture is evaporated under vacuum; the operation is 
carried out twice. 
B) 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-isopropylphe 
nyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic acid ethyl ester. 
A solution of acid chloride obtained in step A in 220 ml of DCM is added 
under dry nitrogen to a solution of 9 ml of triethylamine and 9.5 ml of 
N,N,N'-trimethyl-1,3-propanediamine in 50 ml of DCM, and the mixture is 
stirred overnight. It is washed twice with water and the aqueous phases 
are extracted twice with DCM. The combined organic phases are dried over 
MgSO.sub.4 and evaporated under vacuum. The residue is stirred with 300 ml 
of ether, some insoluble matter is filtered off, and the filtrate is 
decolorized on animal charcoal and evaporated to obtain 28.8 g of the 
expected product in the form of an oil. 
NMR (DMSO+TFA): 1:d:6H; 1.3:t:3H; 1.8-2.1:u.c.:2H; 2.65:qt:1H; 
2.7-3.05:u.c.: 9H; 3.15:mt:2H; 3.5:mt:2H; 3.65:s:6H; 4 .35:qr:2H; 
6.6:d:2H; 6.85:s:1H; 7.2-7.4:u.c.:4H. 
The product of step B may also be obtained according to the procedure 
described below: 
B') A solution of the acid chloride obtained in step A' in 37.5 ml of DCM 
is added to a solution of 1.32 g of N,N,N'-trimethyl-1,3-propanediamine in 
37.5 ml of 3N sodium hydroxide. After 1 hour of stirring, 25 ml of 
chloroform and 25 ml of water are added, settling is allowed to take 
place, and the organic phase is separated, dried over Na.sub.2 SO.sub.4 
and evaporated under vacuum to obtain 6.1 g of the expected product. 
PREATION 3.3 
1-4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl 
)-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4--CONHCH.sub.2 CH.sub.2 CN; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3). 
0.935 g of 3-aminopropionitrile hemifumarate is mixed with 3.7 ml of 1.3N 
NaOH, the mixture is extracted with DCM, the organic phase is dried over 
Na.sub.2 SO.sub.4 and the solvent is evaporated off under vacuum. The 
residue is taken up in 6 ml of DCM, 0.96 ml of triethylamine is added, and 
a solution of 2.45 g of the compound obtained in step A of Preparation 3.2 
in 30 ml of DCM is then added slowly. The mixture is left stirring 
overnight at RT and under a nitrogen atmosphere. Some insoluble matter is 
filtered off, the filtrate is washed with water, with saturated 
NaHCO.sub.3 solution and with water and dried over Na.sub.2 SO.sub.4, and 
the solvent is evaporated off under vacuum. 2.24 g of the expected product 
are obtained, m.p.=114.degree.-116.degree. C. (dec.). 
NMR: 1:d:6H; 2.7:mt:1H; 2.8:t:2H; 3.5:q:2H; 3.65:s:6H; 3.9:s:3H; 6.7:d: 2H; 
6.9:s:1H; 7.3-7.4:u.c.:2H; 7.75:d:1H; 7.9:s:1H; 9:t:1H. 
By reacting the appropriate primary amine with the compound obtained in 
Preparation 3.2, step A, and working according to the procedure described 
for Preparation 3.2, step B, the esters described in Table 2 below are 
prepared. 
TABLE 2 
______________________________________ 
##STR60## 
Preparation 
R.sub.1 M.p .degree.C. or NMR 
______________________________________ 
3.4 CONH(CH.sub.2).sub.3 NMe.sub.2 
NMR 
3.5 CONH(CH.sub.2).sub.2 NMe.sub.2 
NMR 
3.6 CONH(CH.sub.2).sub.3 NEt.sub.2 
NMR 
(IIa. HCl) 
3.7 
##STR61## NMR 
3.8 
##STR62## NMR 
3.9 
##STR63## NMR 
3.10 
##STR64## NMR 
3.11 
##STR65## NMR 
______________________________________ 
NMR: 
Preparation 3.4:1:d:6H; 1.65:mt:2H; 2.1:s:6H; 2.25:t:2H; 2.6:mt:1H; 
3.25:u.c.:2H; 3.6:s:6H; 3.85:s:3H; 6.6:d:2H; 6.85:s:1H; 7.2-7.3:u.c.:2H; 
7.6:dd:1H; 7.8:d: 1H; 8.6:t:1H. 
Preparation 3.5:(DMSO+TFA) 1:d:6H; 2.6mt:2H; 2.8:s:6H; 3.25:mt:2H; 
3.6:u.c.+s: 8H; 3.85:s:3H; 6.6:d:2H; 6.8:s:1H; 7.2-7.4:u.c.:2H; 7.7:d:1H; 
7.8:d:1H. 
Preparation 3.6:(DMSO+TFA): 0.9:d:6H; 1.15:t:6H; 1.8-2:u.c.:2H; 2.6:mt:1H; 
3.1: mt:4H; 3.3:t:2H; 3.55:u.c.+s:8H; 3.8:s: 3H; 6.5:d:2H; 6.8:s:1H; 
7.15-7.3:u.c.:2H; 7.6:dd:1H; 7.8:bs:1H. 
Preparation 3.7:1.05:d:6H; 1.7:mt:4H; 2.45-2.75:u.c.:7H; 3.4:mt:2H; 
3.7:s:6H; 3.9:S:3H; 6.65:d:2H; 6.9:s:1H; 7.3-7.4:u.c.: 2H; 
7.7-7.9:u.c.:2H; 8.6:t:1H. 
Preparation 3.8:1.05:d:6H; 2.7:mt:1H; 3.7:s:6H; 3.9:s:3H; 6.7:d:2H; 
6.9:s:1H; 7.2-7.4:u.c.:3H; 7.85-8.5:u.c.:5H; 11:s:1H. 
Preparation 3.9:0.9:s:6H; 1.05:d:6H; 2.25:s:2H; 2.3:s:6H; 2.7:mt:1H; 3.2:d: 
2H; 3.7:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:bs 1H; 7.3-7.4:u.c.:2H; 
7.6-7.8:u.c.:2H; 8.7:t:1H. 
Preparation 3.10:1:d:6H; 1.4-1.9:u.c.: 4H; 2:t:2H; 2.6:mt:1H; 2.8:d:2H; 
3.5:s: 2H; 3.6:s:6H; 3.6-3.85:u.c.:1H; 3.85:s:3H; 6.6:d:2H; 6.85:s:1H; 
7.1-7.4:u.c.:5H; 7.65 d:1H; 7.8:s:1H; 8.3:d:1H. 
Preparation 3.11 (DMSO+TFA): 1.05:d:6H; 1.6-2.3:u.c.:5H; 2.7:mt:1H; 
3.2-3.4:u.c.: 5H; 3.5-3.8:u.c.+s:7H; 3.9:s:3H; 4.3-4.4:u.c.: 1H; 
6.65:d:2H; 6.9:s:1H; 7.3-7.4:mt:2H; 7.8:d:1H; 7.9:s:1H. 
PREATION 3.12 
5-(2,6-Dimethoxyphenyl)-1-(2-isopropyl-4-sulphophenyl)-3-pyrazolecarboxylic 
acid methyl ester. 
(II'a:R'.sub.1 =4-SO.sub.3 H; R.sub.2 =2-iPr; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture containing 0.82 g of 3-isopropyl-4-hydrazinobenzenesulphonic acid 
obtained in Preparation 2.2 and 1.26 g of compound A obtained in 
Preparation 1.1 in 15 ml of acetic acid is heated to reflux for 5 hours. 
After evaporation, the residue is dissolved in DCM, and the solution is 
washed with normal HCl and decolorized on activated charcoal. It is dried 
and evaporated, the residue is then stirred under reflux in isopropyl 
ether and the mixture is filtered while hot. 1.28 g of the expected 
product are obtained. 
NMR: 1:d:6H; 2.6:mt:1H; 3.6:s:6H; 3.8:s:3H; 6.6:d:2H; 6.8:s:1H; 7.15:d: 1H; 
7.3:t:1H; 7.4:d:1H; 7.5:s:1H. 
PREATION 3.13 
5-(2,6-Dimethoxyphenyl-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylamino 
)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =-4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A) 
5-(2,6-Dimethoxyphenyl)-1-(4-chlorosulphonyl-2-isopropylphenyl)-3-pyrazole 
carboxylic acid methyl ester. 
1.08 g of the product obtained in Preparation 3.12 and 4 ml of POCl.sub.3 
are left stirring at RT for 24 hours, and stirring is then continued at 
70.degree. C. for a further 24 hours. The reaction medium is evaporated 
twice with toluene and 1.6 g of the expected product are obtained. 
B) 
5-(2,6-Dimethoxyphenyl)-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylami 
no)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylic acid methyl ester. 
1.8 ml of N,N,N'-trimethyl-1,3-propanediamine and then 2 ml of 
triethylamine are added to a suspension of 1.6 g of the product obtained 
in the preceding step in 10 ml of toluene and 5 ml of DCM. The mixture is 
left stirring for 3 hours at RT and then one and a half hours at 
50.degree. C. After filtration and evaporation to dryness, the residue is 
extracted with ether and then with AcOEt. The organic phase is washed with 
water, dried over Na.sub.2 SO.sub.4 and evaporated under vacuum. 1.13 g of 
the expected product are obtained. 
NMR: 0.85:d:6H; 1.45:mt:2H; 2:s: 6H; 2.6:s+mt:4H; 2.85:t:2H; 3.5:s:6H; 3.8: 
s:3H; 6.5:d:2H; 6.8:s:1H; 7.2:t:1H; 7.4: d:1H; 7.5-7.6:u.c.:2H. 
PREATION 3.14 
5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-5,6,7,8-tetrahydro-1-naphthyl)-3-pyraz 
olecarboxylic acid methyl ester. 
(II'a:R'.sub.1 =4-CO.sub.2 H; R.sub.2, R.sub.3 =--(CH.sub.2).sub.4 --; 
R.sub.4 =CH.sub.3). 
A mixture of 0.67 g of hydrazine obtained in Preparation 2.3 and 0.83 g of 
compound A in 6 ml of AcOH is stirred under reflux for 2 hours. It is 
extracted with DCM, and the organic phase is washed with water, dried over 
MgSO.sub.4 and evaporated under vacuum. The residue is chromatographed on 
silica, eluting with a DCM/MeOH (100:2; v/v) mixture to obtain 0.7 g of 
expected product. 
NMR: 1.4-2:u.c.:4H; 2.3-3.1:u.c.:4H; 3.4-4:u.c. 9H; 6.6:d:2H; 
6.8-7.6:u.c.:4H; 12.95:bs:1H. 
PREATION 3.15 
5-(2,6-Dimethoxyphenyl)-1-{4-N-(3-(N',N'-dimethylamino)propyl)carbamoyl!-5 
,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4-CONH(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 --; R.sub.4 =CH.sub.3). 
A solution of 0.7 g of product obtained in Preparation 3.14 in 6 ml of 
SOCl.sub.2 and 30 ml of DCM is heated for one and a half hours at 
40.degree. C. It is evaporated under vacuum, the acid chloride is then 
redissolved in 5 ml of DCM, the mixture is cooled to 5.degree. C. and 
0.225 ml of N,N-dimethylpropylenediamine and 0.225 ml of triethylamine are 
added. After stirring for 2 hours at RT, the mixture is evaporated under 
vacuum, the residue is redissolved in DCM, and the mixture is washed with 
water, dried over MgSO.sub.4 and evaporated under vacuum to obtain 0.79 g 
of expected product. 
PREATION 3.16 
5-(2,6-Dimethoxyphenyl)-1-(4-sulpho-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazo 
lecarboxylic acid methyl ester. 
(II'a:R'.sub.1 =4-SO.sub.3 H; R.sub.2, R.sub.3 =--(CH.sub.2).sub.4 --; 
R.sub.4 =CH.sub.3). 
A mixture of 0.5 g of hydrazine obtained in Preparation 2.4 and 0.62 g of 
compound A in 4 ml of AcOH is heated to reflux for four and a half hours. 
It is evaporated under vacuum, the residue is redissolved in DCM, and the 
mixture is washed twice with 1N HCl, dried over MgSO.sub.4 and evaporated 
to obtain 1 g of expected product. 
NMR: 1.7:bs:4H; 2.5:u.c.:2H; 3.2: u.c.:2H; 3.7:s:6H; 3.95:s:3H; 6.7:d:2H; 
6.8-6.9:u.c.:2H; 7.35:t:1H; 7.55:d:1H. 
PREATION 3.17 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)amin 
osulphonyl!-5,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylic acid methyl 
ester. 
(IIa:R.sub.1 =4-SO.sub.2 NMe(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2, R.sub.3 
=(CH.sub.2).sub.4 ; R.sub.4 =CH.sub.3). 
A mixture containing 1 g of acid obtained in Preparation 3.16 and 3 ml of 
POCl.sub.3 is stirred for hours at RT and then three and a half hours at 
70.degree. C. It is evaporated under vacuum, toluene is added and the 
mixture is evaporated under vacuum (twice). The solution of the sulphonyl 
chloride thereby obtained in 10 ml of DCM is added to a solution of 1.5 ml 
of N,N,N'-trimethylethylenediamine and 1.5 ml of triethylamine in 10 ml of 
DCM at 5.degree. C. The mixture is left stirring for 4 days at 10.degree. 
C., filtered and evaporated under vacuum. After redissolution in DCM, 
washing with water and extraction of the aqueous phase with DCM, the 
organic phase is dried over MgSO.sub.4 and evaporated under vacuum to 
obtain 1.07 g of expected sulphonamide, m.p.=90.degree. C. 
NMR: 1.6-1.8:u.c.:4H; 2.1:s:6H; 2.35: t:2H; 2.4-2.6:u.c. 2H; 2.9:s:3H; 
3.1:mt:2H; 3.2:t:2H; 3.6:s:6H; 3.9:s:3H; 6.7:d:2H; 6.9:s:1H; 7.1:d:1H; 
7.4:t:1H; 7.7:d:1H. 
PREATION 3.18 
5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-2-methyl-phenyl)-3-pyrazolecarboxyli 
c acid methyl ester. 
(IIa:R.sub.1 =4-CONH.sub.2 ; R.sub.2 =2-CH.sub.3 ; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A suspension of 0.39 g of the hydrazine obtained in Preparation 2.5 and 450 
mg of compound A in 5 ml of AcOH is heated to reflux for 8 hours. 100 ml 
of water are added to the reaction medium; the precipitate formed is 
filtered off, then placed in 10 ml of isopropyl ether and heated to reflux 
for 30 minutes, and is filtered off. 300 mg of the expected product are 
obtained, m.p.=219.degree. C. On filtration of the aqueous phase 24 hours 
later, a second crop of 70 mg of expected product are obtained in the form 
of needles. 
NMR: 2.05:s:3H; 3.5:s:6H; 3.8:s: 3H; 6.6:d:2H; 6.8:s:1H; 7:d:1H; 7.2:t: 1H; 
7.4:bs:1H; 7.6:d:1H; 7.7:s:1H; 7.9:bs 1H. 
PREATION 3.19 
5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2,3-di-methylphenyl)-3-pyrazolecarboxy 
lic acid methyl ester. 
(II'a:R'.sub.1 =4-CO.sub.2 H; R.sub.2 =2-CH.sub.3 ; R.sub.3 =3-CH.sub.3 ; 
R.sub.4 =CH.sub.3). 
A mixture of 4.5 g of the product of Preparation 2.6 and 12 g of compound A 
in 50 ml of AcOH is heated to reflux with stirring for 3 hours. 
Precipitation is induced by pouring the mixture into 300 ml of ice-cold 
water, and the precipitate is filtered off and washed with 50 ml of water. 
After stirring in 50 ml of ether, filtration and drying under vacuum over 
P.sub.2 O.sub.5, 5 g of expected product are obtained, m.p.=240.degree. C. 
PREATION 3.20 
5-(2,6-Dimethoxyphenyl)-1-{2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)ethyl) 
carbamoyl!phenyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4-CONH(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =2-OCH.sub.3 ; 
R.sub.3 =3-CH.sub.3 ; R.sub.4 =CH.sub.3). 
After a solution of 2 g of the product of Preparation 3.19 in 10 ml of 
SOCl.sub.2 and 40 ml of DCM has been heated for one and a half hours at 
40.degree. C., it is evaporated under vacuum, the acid chloride is 
redissolved in 10 ml of DCM and the mixture is poured into a solution of 
0.54 ml of N,N-dimethylaminoethylenediamine in 10 ml of DCM. 0.68 ml of 
triethylamine is added and the mixture is stirred for 2 hours at RT. After 
evaporation under vacuum, extraction with 100 ml of DCM, washing with 
water, drying over MgSO.sub.4 and evaporation under vacuum, 1.8 g of 
expected product are obtained. 
NMR: 1.9:s:3H; 2.2:s+s:9H; 2.4:t: 2H; 3.4:u.c.:2H; 3.6:s:6H; 3.8:s:3H; 6.6: 
d:2H; 6.8:s:1H; 6.9-7.1:dd:2H; 7.3:t:1H; 8.2:t:1H. 
PREATION 3.21 
5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2-methoxy-phenyl)-3-pyrazolecarboxylic 
acid methyl ester. 
(II'a: R'.sub.1 =4-CO.sub.2 H; R.sub.2 =2-0CH.sub.3 ; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture of 4.8 g of the product of Preparation 2.7 and 5.6 g of compound 
A in 60 ml of AcOH is left stirring for 6 hours under reflux. After 
precipitation with 300 ml of ice-cold water, stirring for 30 minutes, 
filtration, washing with water and then with pentane and drying, 6 g of 
expected product are obtained, m.p.=210.degree. C. 
PREATION 3.22 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-methoxy-phenyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-OCH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 2.5 g of the product of Preparation 3.21 in 30 ml of DCM and 
5 ml of SOCl.sub.2 is heated to reflux for three and a half hours. After 
evaporation under vacuum followed by 2 azeotropic evaporations with 20 ml 
of DCM, the acid chloride formed is redissolved in 40 ml of DCM, and the 
mixture is added to a solution of 1.1 ml of 
N,N-diethyl-N'-methylethylenediamine and 1 ml of triethylamine in 40 ml of 
DCM and left stirring for 15 hours at RT. After evaporation under vacuum, 
the residue is chromatographed on silica, eluting with a solvent gradient 
ranging from a DCM/MeOH (90:10; v/v) mixture to a DCM/MeOH/H.sub.2 O 
(80:20:0.7; v/v/v) mixture to obtain 1.73 g of the expected product. 
NMR: 0.7-1.1:mt:6H; 2.2-3.7:mt:20H; 3.85:s:3H; 6.55:d:2H; 6.8:s:1H; 
6.95:mt: 2H; 7.3:mt:2H. 
PREATION 3.23 
1-(4-Carboxy-2-chlorophenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic 
acid ethyl ester. 
(II'a:R'.sub.1 =4-CO.sub.2 H; R.sub.2 =2-Cl; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
3-Chloro-4-hydrazinobenzoic acid is described in Patent U.S. 3,959,309. 5.6 
g of this acid and 8.75 g of compound A.sub.1 in 100 ml of AcOH are heated 
to reflux for 6 hours. The reaction mixture is poured into 500 ml of 
ice-cold water, and the precipitate formed is filtered off and then washed 
with water, pentane and then isopropyl ether. The product is dried under 
vacuum to obtain 2 g of the expected compound. 
PREATION 3.24 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-chlorophenyl}-3-pyrazolecarboxylic acid ethyl ester. 
(IIa:R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-OCH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 2.5 g of the product of Preparation 3.23 in 30 ml of DCM and 
4.5 ml of SOCl.sub.2 is heated to reflux for 4 hours. After evaporation 
under vacuum followed by 2 azeotropic evaporations with 20 ml of DCM, the 
acid chloride formed is redissolved in 40 ml of DCM, and the mixture is 
then poured into a solution of 1.1 ml of 
N,N-diethyl-N'-methylethylenediamine and 1 ml of triethylamine in 4 ml of 
toluene and left stirring for 15 hours at RT. After evaporation under 
vacuum, extraction of the residue with 100 ml of DCM, 2 washes with water, 
drying over Na.sub.2 SO.sub.4 and evaporation under vacuum, the residue is 
chromatographed on silica H, eluting with a DCM/MeOH (90:10; v/v) mixture 
and then DCM/MeOH/H.sub.2 O (90:10:0.5; v/v/v) to obtain 2.6 g of expected 
product. 
NMR (DMSO+TFA): 2.8:s:3H; 3 to 3.7: u.c.:17H; 6.6:d:2H; 6.8:s:1H; 
7.05:u.c.: 2H; 7.3:u.c. 2H. 
PREATION 3.25 
5-(2,6-Dimethoxyphenyl)-1-4-(N-(2-morpholino-ethyl)carbamoyl)-2-chlorophen 
yl!-3-pyrazolecarboxylic acid ethyl ester. 
##STR66## 
A solution of 2.63 g of the product of Preparation 3.23 in 4.5 ml of 
SOCl.sub.2 and 30 ml of DCM is stirred under reflux for 4 hours. After 
evaporation under vacuum followed by 2 azeotropic evaporations with 30 ml 
of toluene, the acid chloride formed is redissolved in 40 ml of DCM, and 
the mixture is added to a solution of 0.9 ml of 4-(2-aminoethyl)morpholine 
and 1 ml of triethylamine in 4 ml of toluene. After stirring for 15 hours 
at RT, evaporation under vacuum, redissolution of the residue in 200 ml of 
DCM, washing with 100 ml of saturated NaCl solution, drying over Na.sub.2 
SO.sub.4 and evaporation under vacuum, 3 g of expected product are 
obtained. 
NMR: 1.3:t:3H; 2.3-2.6:mt:6H; 3.3:mt 2H; 3.5:mt:10H; 4.3:qr:2H; 6.55:d:2H; 
6.8 :s:1H; 7.1-7.4:mt:3H; 6.75:dd:1H; 6.9:dd: 1H; 8.6:t:1H. 
PREATION 3.26 
5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolecarboxylic 
acid methyl ester. 
(II'a:R.sub.1 =4-CN; R.sub.2 =3-C.sub.1 ; R.sub.3 =H; R.sub.4 =CH.sub.3). 
A mixture containing 4.2 g of the compound obtained in Preparation 2.8 and 
6 g of compound A in 10 ml of AcOH is heated on a water bath for 2 hours. 
It is poured into ice-cold water, and the precipitate formed is filtered 
off and then dried to obtain 3.78 g of the expected product. 
PREATION 3.27 
5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2-cyclo-propylphenyl)-3-pyrazolecarbox 
ylic acid methyl ester. 
(II'a:R'.sub.1 =4-CO.sub.2 H; R.sub.2 =2-cyclopropyl; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture of 1.28 g of compound A and 1 g of the product of Preparation 2.9 
in 12 ml of AcOH is stirred under reflux for 7 hours. Precipitation is 
induced with 120 ml of ice-cold water, and the precipitate is filtered 
off, washed with water and dried under vacuum over P.sub.2 O.sub.5 to 
obtain 1.27 g of expected product. 
NMR: 0.5:u.c.:2H; 0.8:u.c.:2H; 1.3:t 3H; 1.5:u.c.:1H; 3.6:s:6H; 4.3:qr:2H; 
6.6 d:2H; 6.9:s:1H; 7.3:u.c.:3H;77:bs:d:1H; 13:bs:1H. 
PREATION 3.28 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-cyclopropyl-phenyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =4-CON(Me)(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 
=2-cyclo-propyl; R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 1.27 g of the product of Preparation 3.27 in 28 ml of toluene 
and 2 ml of SOCl.sub.2 is heated for 5 hours at 100.degree. C. After 
evaporation under vacuum followed by 2 azeotropic evaporations with 30 ml 
of toluene, the acid chloride obtained is redissolved in 19 ml of DCM, and 
the mixture is poured slowly into a solution of 0.53 ml of 
N,N-diethyl-N'-methylethylenediamine and 0.61 ml of triethylamine in 1.9 
ml of toluene. After stirring for 12 hours at RT, evaporation under 
vacuum, extraction with 100 ml of DCM, washing with water, drying over 
Na.sub.2 SO.sub.4 and evaporation under vacuum, 1.29 g of the expected 
product are obtained. 
NMR: 0.4-1:u.c.:10H; 1.2:t:3H; 1.4: mt:1H; 2.1-3:u.c.:9H; 3.5:u.c.:8H; 
4.3:qr: 2H; 6.5:d:2H; 6.6:s:1H; 6.8:s:1H; 6.9-7.2: mt:3H. 
PREATION 3.29 
5-(2,6-Dimethoxyphenyl)-1-(3-carboxy-4-chloro-phenyl)-3-pyrazolecarboxylic 
acid methyl ester. 
(II'a:R'.sub.1 =3-CO.sub.2 H; R.sub.2 =4-Cl; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture of 4 g of product of Preparation 2.10 and 4.6 g of compound A in 
60 ml of AcOH is heated to reflux with stirring for 5 hours. It is poured 
into 100 ml of ice-cold water, and the precipitate is filtered off and 
washed with 5 ml of water and then 20 ml of ether. It is dried under 
vacuum to obtain 3 g of expected product, m.p.=206.degree. C. 
NMR: 3.55:s:6H; 3.85:s:3H; 6.7:d: 2H; 6.9:s:1H; 7.35:dd:1H; 7.4:t:1H; 7.55: 
d:1H; 7.7:d:1H. 
PREATION 3.30 
5-(2,6-Dimethoxyphenyl)-1-{3-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)carb 
amoyl!-4-chlorophenyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =3-CON(Me)(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =4-Cl; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A solution of 1.5 g of the product of Preparation 3.29 in 20 ml of DCM and 
2.6 ml of SOCl.sub.2 is heated with stirring for three and a half hours at 
60.degree. C. After evaporation under vacuum, the acid chloride is 
redissolved in 10 ml of DCM, and the mixture is poured into a solution of 
0.5 ml of N,N,N'-trimethylethylene-diamine and 0.6 ml of triethylamine in 
2.5 ml of toluene and then left stirring for 15 hours at RT. After 
evaporation under vacuum, dissolution of the residue in 100 ml of DCM, 
washing with 100 ml of water, drying over Na.sub.2 SO.sub.4 and 
evaporation under vacuum, 0.8 g of expected product is obtained. 
PREATION 3.31 
5-(2,6-Dimethoxyphenyl)-1-(5-carboxy-2-methyl-phenyl)-3-pyrazolecarboxylic 
acid methyl ester. 
(II'a:R'.sub.1 =5-CO.sub.2 H; R.sub.2 =2-CH.sub.3 ; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A mixture of 6.15 g of the product of Preparation 2.11 and 7.76 g of 
compound A in 100 ml of AcOH is heated to reflux with stirring for one and 
a half hours. After concentration under vacuum to 5 ml, precipitation with 
20 ml of ice-cold water, filtration, washing of the precipitate with 5 ml 
of water and drying over P.sub.2 O.sub.5 under vacuum at 80.degree. C., 
9.55 g of expected product are obtained, m.p.=189.degree. C. 
NMR: 1.20:t:3H; 3.55:s:6H; 4.26:qr: 2H; 6.58:d:2H; 6.80:s:1H; 7.20:t:1H; 
7.60: d:1H; 7.70:d:1H; 7.80:dd:1H. 
PREATION 3.32 
5-(2,6-Dimethoxyphenyl)-1-{5-N-methyl-N-(3-(N',N'-dimethylamino)propyl)car 
bamoyl!-2-methyl-phenyl}-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =5-CON(Me)(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-CH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 2 g of the product of Preparation 3.31 in 10 ml of SOCl.sub.2 
is left stirring for 5 hours at RT. After evaporation under vacuum 
followed by 3 azeotropic distillations with 30 ml of DCM, the acid 
chloride formed is redissolved in 25 ml of DCM, and the mixture is poured 
into a solution of 0.81 ml of N,N,N'-trimethyl-1,3-propanediamine and 0.77 
ml of triethylamine in 5 ml of DCM and left stirring for 2 hours at RT. 
After 2 washes with 20 ml of water and 2 extractions of the aqueous phases 
with 50 ml of DCM, the DCM phases are washed twice with 20 ml of 5% 
NaHCO.sub.3 and then with 20 ml of water, then dried over MgSO.sub.4 and 
evaporated under vacuum to obtain 2.3 g of expected product (oil). 
NMR: 1.9:u.c.:2H; 2.1:s:3H; 2.6:s: 3H; 2.8:s:6H; 2.9-3.2:u.c.:2H; 
3.45:u.c.: 2H; 3.6:s:6H; 3.8:s:3H; 6.6:d:2H; 6.85:s :1H; 7.05:bs:1H; 
7.2-7.4:u.c.:3H. 
By following the above procedures, the esters of formula IIa described in 
Table 3 below are prepared, either from an ester of formula II'a 
substituted with R'.sub.1, or by the action of the appropriate hydrazine 
on compound A or compound A.sub.1. 
TABLE 3 
__________________________________________________________________________ 
##STR67## 
Prepara- M.p. .degree.C. or 
tion NMR 
(from) 
R.sub.1 or R'.sub.1 ! 
R.sub.2 
R.sub.3 
Alk (Salt) 
__________________________________________________________________________ 
3.33 4-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H Me NMR 
(3.21) 
3.34 (3.21) 
##STR68## 2-OCH.sub.3 
H Me NMR 
3.35 4-SO.sub.3 H 2-CH.sub.3 
3-CH.sub.3 
Me 208 
(2.12) 
3.36 4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2 
2-CH.sub.3 
3-CH.sub.3 
Me NMR 
(3.35) 
3.37 5-CO.sub.2 H 2-Cl H Et NMR 
(2.13) 
3.38 5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-Cl H Et NMR 
(3.37) 
3.39 4-CO.sub.2 H 2-CF.sub.3 
H Et 220 
(2.16) 
3.40 4-CONMe(CH.sub.2).sub.2 NEt.sub.2 
2-CF.sub.3 
H Et 70 (dec.) 
(3.39) NMR 
3.41 5-CO.sub.2 H 2-OCH.sub.3 
H Et NMR 
(2.14) 
3.42 5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H Et NMR 
(3.41) 
3.43 4-CONH(CH.sub.2).sub.2 N(iPr).sub.2 
2-iPr 
H Me NMR 
(3.1) 
3.44 4-CO.sub.2 H 2-iPr 
H Et NMR 
(3.1 a) 
3.45 4-CONH(CH.sub.2).sub.3 N(nBu).sub.2 
2-iPr 
H Et NMR 
(3.44) 
3.46 4-CONH(CH.sub.2).sub.2 NEt.sub.2 
2-iPr 
H Et NMR 
(3.44) 
3.47 (3.1) 
##STR69## 2-iPr 
H Me 100 
3.48 4-CON(CH.sub.2 CH.sub.2 NEt.sub.2).sub.2 
2-iPr 
H Me 92 
(3.1) 2HCl 
3.49 (3.1) 
##STR70## 2-iPr 
H Me NMR 
3.50 (3.1) 
##STR71## 2-iPr 
H Me NMR 
3.51 (3.1) 
##STR72## 2-iPr 
H Me NMR 
3.52 (3.1) 
##STR73## 2-iPr 
H Me NMR 
3.53 4-CONMe(CH.sub.2).sub.2 CN 
2-iPr 
H Me NMR 
(3.1) 
3.54 4-CONHCH.sub.2 CHCH.sub.2 
2-iPr 
H Me NMR 
(3.1) 
3.55 (3.12) 
##STR74## 2-iPr 
H Me NMR 
3.56 4-NO.sub.2 2-Me H Me 162 
(2.19) 
__________________________________________________________________________ 
NMR 
Preparation 3.33:2 to 3.8:mt:1H; 3.9:s :3H; 6.6:d:2H; 6.85:s:1H; 6.9 to 
7.4:u.c.: 4H. 
Preparation 3.36 (DMSO+TFA ):1.9:u.c.+s: 5H; 2.5:s:3H; 2.8:s:9H; 
3-3.5:u.c.:2H; 3.25 t:2H; 3.6:s:6H; 3.85:s:3H; 6.6:d:2H; 6.9:s:1H; 
7.05-7.15:u.c.:1H; 7.3:t:1H; 7.6:d:1H. 
Preparation 3.37:1.2:t:3H; 3.5:s:6H; 4.3:qr:2H; 6.5:d:2H; 6.8:s:1H; 7.2:t: 
1H; 7.6:d:1H; 7.7:s:1H; 7.85:d:1H. 
Preparation 3.38:1.4:t:3H; 1.8 to 3.3: u.c.:13H; 3.65:s:6H; 4.4:qr:2H; 
6.6:d:2H; 6.95:s:1H; 7.2 to 7.6:u.c.:4H; 7.7:d:1H. 
Preparation 3.40:0.6 to 1:u.c. 6H; 1.3:t 3H; 2.2:u.c.:2H; 2.4 to 
3.4:u.c.:7H; 3.6:s:6H; 4.1:u.c.:2H; 4.3:qd:2H; 6.6:d:2H; 6.8 :s:1H; 
7.15:u.c.:2H; 7.6:d:1H; 7.8:bs: 1H. 
Preparation 3.41:1.4:t:3H; 3.6:s:9H; 4.4:qr:2H; 6.62:d:2H; 6.81:s:1H; 
7.2:d: 1H; 7.36:t:1H; 7.8:d:1H; 8.0:dd:1H; 12.6: bs:1H. 
Preparation 3.42:1.4:t:3H; 1.8 to 2.4: bs:8H; 2.8:bs:3H; 3.2 to 3.8:bs:2H; 
3.6:s: 9H; 4.4:qd:2H; 6.6:d:2H; 6.8:s:1H; 7.0 to 7.5:u.c. 4H. 
Preparation 3.43:1.0-1.1:u.c.:18H; 2.4-2.75:2mt: 3H; 2.9-3.1:mt:2H; 
3.1-3.35:mt:2H; 3.65:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:s: 1H; 7.3-7.4:mt:2H; 
7.7:d:1H; 7.8:s:1H; 8.55 t:1H. 
Preparation 3.45:0.75:t:6H; 0.9:d:6H; 1.05-1.15:u.c.:8H; 1.5:t:2H; 
2.5-2.4:u.c.: 6H; 2.55:sp:1H; 3.15:mt:2H; 3.55:s:6H; 4.2:s: 3H; 6.5:d:2H; 
6.72:s:1H; 7.1-7.25:u.c.:2H; 7.55:dd:1H; 7.65:d:1H; 8.45:t:1H. 
Preparation 3.46:0.8-1.1:u.c.:12H; 1.25: t:3H; 2.4-2.8:u.c.:6H; 
3.1-3.4:u.c.:3H; 3.5: s:6H; 4.2:qt:2H; 6.5:d:2H; 7.2:u.c.:2H; 7.6:d:1H; 
7.8:bs:1H; 8.6:bs:1H. 
Preparation 3.49:0.9-1.15:2mt:9H; 1.5-1.9 :u.c.:4H; 2.1-2.45:2mt:2H; 
2.65:mt:1H; 2.75-3: mt:1H; 3-3.2:u.c.:2H; 3.2-3.55:u.c.:2H; 3.65:s:6H; 
3.9:s:3H; 6.65:d:2H; 6.9:s: 1H; 7.25-7.4:mt:2H; 7.7:d:1H; 7.85:s:1H; 
8.6:t:1H. 
Preparation 3.50:1.05:d:6H; 1.1-1.6: 2s+m:14H; 1.8:dd:2H; 2.65:mt:1H; 
3.7:s: 6H; 3.9:s:3H; 4.2.-4.5:u.c.:1H; 6.65:d:2H; 6.9:s:1H; 
7.9.5-7.2:mt:2H; 7.7:d:1H; 7.85: s:1H; 8.3:d:1H. 
Preparation 3.51 (DMSO+TFA ):1.0:d:6H; 1.1-1.4:u.c.:6H; 2.0-2.5:u.c.:2H; 
2.7:2u.c.: 1H; 3.0-4.2:3u.c.+s:18H; 6.7:d:2H; 6.9:s: 1H; 7.3-7.55:u.c.:4H. 
Preparation 3.52 (DMSO+TFA): 0.95:d:6H; 1.5-1.8:u.c.:2H; 1.8-2.2:u.c.:2H; 
2.6:mt: 1H; 2.75:s:6H; 2.9-3.8:2u.c.+s:10H; 3.85:s: 3H; 4.5-4.7:u.c.:1H; 
6.6:d:2H; 6.85:s:1H; 7.2-7.35:mt:4H. 
Preparation 3.53 (DMSO+TFA): 0.98:d:6H; 2.6:mt:1H; 2.7-3.8:u.c.:13H; 
3.82:s:3H; 6.58:d:2H; 6.85:s:1H; 7.15-7.37:u.c.:4H. 
Preparation 3.54:1.05:d:6H; 2.7:mt: 1H; 3.7:s:6H; 3.85-4.0:s+mt:5H; 
5.1-5.3:u.c. :2H; 5.8-6.1:u.c.:1H; 6.55:d:2H; 6.9:s:1H; 7.3-7.4:u.c. 2H; 
7.75:d:1H; 7.9:s:1H; 8.8:t:1H. 8,8:t:1H. 
Preparation 3.55:1.05:d:6H; 2:s:6H; 2.15:t:2H; 2.75:qt:1H; 3.2:t:2H; 3.7:s: 
6H; 3.9:s:3H; 4.45:s:2H; 6.7:d:2H; 7:s: 1H; 7.3-7.5:u.c.:6H; 7.55:d:1H; 
7.7-7.9:u.c.:2H. 
PREATION 3.7 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(tert-butoxycarbo 
nyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylic acid 
methyl ester. 
(IIa:R.sub.1 =4-CONMe(CH.sub.2).sub.3 N(Me)COOt-Bu; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A) N-Methyl-N-(3-methylaminopropyl)carbamic acid tert-butyl ester. 
A solution of 4.19 g of N,N'-dimethyl-1,3-propanediamine in 80 ml of THF is 
cooled to 0.degree. C., a solution of 2.68 g of di-tert-butyl dicarbonate 
in 25 ml of THF is added and the mixture is left stirring for 72 hours at 
RT. Some insoluble matter is filtered off and the filtrate is concentrated 
under vacuum. The residue is extracted with DCM, the organic phase is 
washed three times with water and dried over MgSO.sub.4 and the solvent is 
evaporated off under vacuum. 1.6 g of the expected product are obtained in 
the form of a yellow oil. 
B) 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(tert-butoxycarb 
onyl)amino!propyl!-carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylic acid 
methyl ester. 
A solution of 2.6 g of the compound obtained in step A of Preparation 3.2 
is added at RT and under a nitrogen atmosphere to a solution of 1.31 g of 
the compound obtained in the preceding step and 0.9 ml of triethylamine in 
4 ml of DCM, and the reaction mixture is left stirring overnight at RT. It 
is washed twice with water, the organic phase is dried over MgSO.sub.4 and 
the solvent is evaporated off under vacuum. The residue is chromatographed 
on silica, eluting with a toluene/AcOEt mixture from (65:35; v/v) to 
(60:40; v/v). 2.85 g of the expected product are obtained. 
NMR (DMSO+TFA): 1.0:d:6H; 1.4:d:9H; 1.6-1.9:u.c.:2H; 2.7:mt:1H; 
2.7-3.55:d+bs+u.c.:10H; 3.65:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:s:1H; 
7.3-7.45:u.c.:4H. 
PREATION 3.58 
5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-isopropylphe 
nyl!-3-pyrazolecarboxylic acid ethyl ester. 
##STR75## 
A mixture of 3.44 g of the compound obtained in Preparation 2.18 and 2.6 g 
of compound A.sub.1 in 50 ml of acetic acid is heated for 1 hour at 
70.degree. C. The reaction mixture is poured into water, the resulting 
mixture is extracted with AcOEt, the organic phase is dried over Na.sub.2 
SO.sub.4 and the solvent is evaporated off under vacuum. The residue is 
chromatographed on silica H, eluting with a DCM/MeOH (100:0.5; v/v) 
mixture. 1.26 g of the expected product are obtained. 
NMR: 0.7:d:6H; 1.22:t:3H; 2.2-2.5: u.c.:4H; 3.45:s:6H; 4.2:t:2H; 6.46:d:2H; 
6.69:s:1H; 6.75-6.9:u.c.:2H; 7.0:d:1H; 7.15-7.3:u.c.:3H; 7.5:d:2H; 
10.2:s:1H. 
PREATION 3.59 
5-(2,6-Dimethoxyphenyl)-1-4-4-methylphenyl-sulphonyl-N-(3-diethylaminopro 
pyl)amino!-2-isopropyl-phenyl!-3-pyrazolecarboxylic acid ethyl ester. 
##STR76## 
A mixture of 0.65 g of the compound obtained in 30 Preparation 3.58, 0.338 
g of (3-chloropropyl)diethylamine and 0.65 g of K.sub.2 CO.sub.3 in 5 ml 
of DMF is heated at 80.degree. C. for 2 hours. The reaction mixture is 
poured into water, the resulting mixture is extracted with AcOEt, the 
organic phase is dried over Na.sub.2 SO.sub.4 and the solvent is 
evaporated off under vacuum. The residue is chromatographed on silica H, 
eluting with a DCM/MeOH (100:5; v/v) mixture. 0.57 g of the expected 
product is obtained. 
NMR: 0.8:bs:6H; 0.95:t:6H; 1.4:t: 3H; 1.5:qt:2H; 2.3-2.65:u.c.:10H; 
3.5-3.8: u.c.:8H; 4.35:qr:2H; 6.7:d:2H; 6.75:d:1H; 6.9:s:1H; 7.05:dd:1H; 
7.2-7.6:u.c.:6H. 
PREATION 3.60 
5-2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1-(4-carboxy-2-isopropylphenyl 
)-3-pyrazolecarboxylic acid ethyl ester. 
##STR77## 
A mixture of 5.26 g of the compound obtained in Preparation 1.2 and 3.9 g 
of the compound obtained in Preparation 2.1 in 50 ml of acetic acid is 
heated at 80.degree. C. for 8 hours. The reaction mixture is poured into a 
water/ice mixture, and the precipitate formed is drained and washed with 
water and then with pentane. The precipitate is taken up with toluene and 
the solvent is evaporated off under vacuum. 5.2 g of the expected product 
are obtained. 
PREATION 3.61 
5-2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1-4-N-methyl-N-(3-dimethylam 
inopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylic acid ethyl 
ester. 
##STR78## 
This compound is prepared according to the procedures described in steps A 
and B of Preparation 3.2, from 5.2 g of the compound obtained in 
Preparation 3.60 and 2.4 ml of SOCl.sub.2, followed by 1.39 g of 
N,N,N'-trimethyl-1,3-propanediamine and 1.5 ml of triethylamine in 10 ml 
of toluene. The product is purified by chromatography on silica, eluting 
with DCM and then with a DCM/MeOH (88:2; v/v) mixture. 3.8 g of the 
expected product are obtained. 
PREATION 3.62 
5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-isobutylphen 
yl!-3-pyrazolecarboxylic acid methyl ester. 
##STR79## 
A mixture of 1.9 g of the compound obtained in Preparation 2.20 and 1.6 g 
of the compound A in 30 ml of acetic acid is heated to reflux for 45 
minutes. After cooling to RT, the reaction mixture is poured into water, 
and the precipitate formed is drained and dried. 1 g of the expected 
product are obtained after recrystallization in 2-propanol, 
m.p.=224.degree. C. 
NMR: 0.55:d:6H; 1.5:mt:1H; 1.9:d: 2H; 2.3:s:3H; 3.45:s:6H; 3.8:s:3H; 6.5:d 
2H; 6.75:s:1H; 6.8:d:1H; 6.9:dd:1H; 7.05 d:1H; 7.15-7.7:u.c.:5H; 
10.25:s:1H. 
PREATION 3.63 
5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-cyclopentylp 
henyl!-3-pyrazolecarboxylic acid methyl ester. 
##STR80## 
A mixture of 2.42 g of the compound obtained in Preparation 2.21 and 2.92 g 
of compound A in 50 ml of acetic acid is heated for 1 hour at 80.degree. 
C. The reaction mixture is poured into water, the resulting mixture is 
extracted with AcOEt, the organic phase is dried over Na.sub.2 SO.sub.4 
and the solvent is evaporated off under vacuum. The residue is 
chromatographed on silica H, eluting with a DCM/MeOH (100:1; v/v) mixture. 
0.95 g of the expected product are obtained after trituration in ether, 
m.p.=200-230" C. 
NMR: 1.0-1.8:u.c.:8H; 2.37:s:3H; 3.1-3.7:u.c.:7H; 3.82:s:3H; 6.55:d:2H; 
6.79:s 1H; 6.85-7.0:u.c.:2H; 7.05:d:2H; 7.21-7.42: u.c.:3H; 7.58:d:2H; 
10.3:s:2H. 
PREATION 3.64 
5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-3-isopropyl-phenyl)-3-pyrazolecarboxyl 
ic acid ethyl ester. 
(II'a:R'.sub.1 =4-CO.sub.2 H; R.sub.2 =3-iPr; R.sub.3 =H; R.sub.4 =Me). 
A mixture of 0.36 g of the compound obtained in Preparation 2.22 and 0.48 g 
of compound A.sub.1 in 10 ml of acetic acid is heated to reflux for 5 
hours. The reaction mixture is poured into 160 ml of ice-cold water, and 
the precipitate formed is drained, washed with water and dried. 0.52 g of 
the expected product is obtained, m.p.=180.degree. C. (dec.). 
PREATION 3.65 
1-4-N-(2-Diethylaminoethyl)carbamoyl!-3-iso-propylphenyl!-5-(2,6-dimethox 
yphenyl)-3-pyrazole-carboxylic acid ethyl ester. 
(IIa:R.sub.1 =4-CONH(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =3-iPr; R.sub.3 
=H; R.sub.4 =Me). 
This compound is prepared according to the procedure described in steps A 
and B of Preparation 3.2, from 0.5 g of the compound obtained in 
Preparation 3.64 and 5 ml of SOCl.sub.2 in 20 ml of chloroform, followed 
by 0.2 ml of N,N-diethylethylenediamine and 0.8 ml of triethylamine in 20 
ml of chloroform. 0.37 g of the expected product is obtained after 
crystallization in AcOEt, m.p.=130.degree. C. (dec.). 
PREATION 3.66 
5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetra-hydro-1-naphthyl)-3-pyrazo 
lecarboxylic acid methyl ester. 
(II'a:R'.sub.1 =4-NO.sub.2 ; R.sub.2, R.sub.3 =--(CH.sub.2).sub.4 -; 
R.sub.4 =Me). 
A mixture of 6.3 g of the compound obtained in Preparation 2.23 and 7.45 g 
of compound A in 150 ml of acetic acid is heated to reflux for 2 hours. 
After cooling to RT, 100 ml of water and 30 ml of MeOH are added and the 
crystallized product is drained. 4.6 g of the expected product are 
obtained, m.p.=212.degree. C. 
NMR: 1.7:mt:4H; 2.55:mt:2H; 2.82:mt 2H; 3.65:s:6H; 3.85:s:3H; 6.65:d:2H; 
6.9:s:1H; 7.02:d:1H; 7.33:t:1H; 7.67:d:1H. 
PREATION 3.67 
5-(2,6-Dimethoxyphenyl)-1-(5-(3-(diethylamino)-propanoylamino)-2-isopropylp 
henyl)-3-pyrazolecarboxylic acid methyl ester. 
(IIa:R.sub.1 =5-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
This compound is obtained from the hydrazine of Preparation 2.24. 
NMR (DMSO+TFA): 0.65-1.35:u.c.:12H; 2.5:qt:1H; 2.8:t:2H; 3.15:qr:4H; 
3.36:t: 3.57:s:6M; 3.8:s:3H; 6.5:d:2H; 6.78:s: 1H; 7.1-7.4:u.c.:3H; 
7.8:d:1H. 
PREATIONS OF THE ACIDS II, II' 
PREATION 4.1 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphen 
yl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid. 
(II, R.sub.1 =4-CONMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
23 g of the compound obtained in Preparation 3.2 in 230 ml of dioxane and 
6.2 g of potassium hydroxide in 6 ml of water are mixed. The mixture is 
heated to reflux for three and a half hours. After cooling, it is 
evaporated, the residue is redissolved in the minimum amount of water and 
the mixture is washed three times with ether and then acidified to pH 4 by 
adding concentrated HCl; the aqueous phase is evaporated, the residue is 
then redissolved in the minimum amount of EtOH and the KCl is filtered off 
(twice). After evaporation, 23.93 g of the expected product are obtained 
in the form of a light yellow foam, m.p.=128.degree. C. (dec.). 
NMR: 0.95:d:6H; 1.95:mt:2H; 2.45-3.3:u.c.:12H; 3.35-3.8:u.c.:8H; 6.6:d:2H; 
6.8:s 1H; 7-7.5:u.c.:4H. 
PREATION 4,1a 
1-4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphen 
yl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid potassium salt. 
A solution of 8.07 g of KOH in 133 ml of water is added to a solution of 
26.6 g of the product of Preparation 3.2a in 133 ml of ethanol. The 
solution is stirred for 8 hours, then left stirring for 15 hours and 
evaporated under vacuum to obtain the expected potassium salt. 
PREATION 4.2 
1-4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl 
)-3-pyrazolecarboxylic acid. 
(II:R.sub.1 =4-CONHCH.sub.2 CH.sub.2 CN; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3). 
A solution of 0.9 g of KOH in 3 ml of water is added to a solution of 3.04 
g of the compound obtained in Preparation 3.3 in 30 ml of 1,4-dioxane and 
a few drops of MeOH, and the mixture is left stirring over-night at RT. It 
is concentrated under vacuum, the residue is taken up with water, the 
aqueous phase is washed with ether, acidified to pH 2 by adding 10% HCl 
and extracted with DCM, the organic phase is dried over Na.sub.2 SO.sub.4 
and the solvent is evaporated off under vacuum. 2.93 g of the expected 
product are obtained, m.p.=128.degree. C. (dec.). 
NMR: 1:d:6H; 2.65:mt:1H; 2.8:t:2H; 3.5:t:2H; 3.6:s:6H; 6.6:d:2H; 6.8:s:1H; 
7.2-7.4:u.c.:2H; 7.7:dd:1H; 7.8:d:1H. 
From the esters of formula (IIa) described in Table 2, and by working 
according to the procedure described in Preparation 4.1 or Preparation 
4.2, the acids of formula (II) described in Table 4 below are obtained. 
TABLE 4 
______________________________________ 
##STR81## 
Preparation 
R.sub.1 M.p. .degree.C. or NMR 
______________________________________ 
4.3 CONH(CH.sub.2).sub.3 NMe.sub.2 
188 
NMR 
4.4 CONH(CH.sub.2).sub.2 NMe.sub.2 
178-180 (dec.) 
NMR 
4.5 CONH(CH.sub.2).sub.3 NEt.sub.2 
NMR 
4.6 
##STR82## NMR 
4.7 
##STR83## NMR 
4.8 
##STR84## 135 (dec.) NMR 
4.9 
##STR85## NMR 
4.10 
##STR86## 266 (dec.) 
______________________________________ 
PREATION 4.3 
NMR: 0.9:d:6H; 1.6:mt:2H; 2.15:s: 6H; 2.35:t:2H; 2.6:mt:1H; 3.2:u.c.:2H; 
3.55 s:6H; 6.5:d:2H; 6.6:s:1H; 7.1-7.2:u.c.: 2H; 7.7:dd:1H; 7.9:bs:1H; 
8.6:t:1H. 
PREATION 4.4 
NMR (DMSO+TFA): 1:d:6H; 2.65:mt:1H; 2.85:s:6H; 3.3:mt:2H; 3.6:mt+s:8H; 
6.6:d:2H; 6.8:s:1H; 7.25-7.4:u.c.:2H; 7.7:dd:1H; 7.85:bs: 
PREATION 4.5 
NMR: 0.95:d:6H; 1.15:t:6H; 1.8-2: u.c. 2H; 2.6:mt:1H; 3.1:mt:4H; 3.3:t:2H; 
3.6:u.c.+s:8H; 6.5:d: 2H; 7.6:dd:1H; 7.75:d:1H. 
PREATION 4.6 
NMR (DMSO+TFA): 1:d:6H; 1.8-2.2:u.c.: 4H; 2.65:mt:1H; 3:mt:2H; 3.3:mt:2H; 
3.6: bs:10H; 6.6:d:2H; 6.8:s:1H; 7.2-7.4:u.c.: 2H; 7.6-7.9:u.c.:2H; 
8.9:t:1H. 
PREATION 4.7 
1.1:d:6H; 2.7:mt:1H; 3.7:s:6H; 6.65:D:2H; 6.9:s:1H; 7.2-7.4:u.c.:3H; 
7.8-8.5:m:5H. 
PREATION 4.8 
NMR: 1-1.2:m:12H; 2.6-2.9:u.c.:9H; 3.3:d:2H; 3.7:s:6H; 6.6:d:2H; 6.8:s:1H; 
7.3-7.4:u.c.:2H; 7.7-7.9:u.c.:2H; 8.8:t:1H. 
PREATION 4.9 
NMR (DMSO+TFA): 1:d:6H; 1.8:mt:2H; 2.1:mt:2H; 2.7:mt:1H; 3-3.5:u.c.:4H; 
3.6: s:6H; 4:mt:1H; 4.3:s:2H; 6.6:d:2H; 6.8: s:1H; 7.2-7.4:u.c.:2H; 
7.4-7.6:u.c.:5H; 7.7: d:1H; 7.8:s:1H. 
PREATION 4.11 
5-(2,6-Dimethoxyphenyl)-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylamin 
o)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4--SO.sub.2 NMe(CH.sub.2 .sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A mixture containing 1.1 g of the ester obtained in Preparation 3.13 and 
280 mg of potassium hydroxide in 10 ml of water is left stirring for hours 
at RT. The reaction medium is concentrated under vacuum until 5 ml are 
obtained, and the residue is then stirred in the presence of 100 ml of 
ether and 3 ml of water. The aqueous phase is neutralized to pH 6 by 
adding 1N HCl; it is filtered, and the residue is then dried over P.sub.2 
O.sub.5 to obtain 860 mg of the expected product. 
NMR: 0.85:d:6H; 1.5:mt:2H; 2.15:s: 6H; 2.3:t:2H; 2.6:s+mt:4H; 2.9:t:2H; 
3.5: s:6H; 6.5:d:2H; 6.7:s:1H; 7.2:t:1H; 7.4: d:1H; 7.5-7.6:u.c.:2H. 
PREATION 4.12 
5-(2,6-Dimethoxyphenyl)-1-4-N-3-(N',N'-dimethylamino)propyl!carbamoyl!-5 
,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolecarboxylic acid. 
(II:R.sub.1 =4-CONH(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =CH.sub.3). 
A mixture of 0.98 g of the compound obtained in Preparation 3.15 and 0.16 g 
of LiOH in 5 ml of methanol and 1 ml of water is heated for 3 hours at 
40.degree. C. It is evaporated under vacuum, and the residue is 
neutralized to pH 6 with 1N HCl and then extracted with DCM. The organic 
phase is dried over MgSO.sub.4 and evaporated under vacuum to obtain 0.47 
g of expected product. 
NMR: 1.5-2.1:u.c.:6H; 2.3-4:u.c.:2OH; 6.5-7.6:u.c.:6H; 8.4:t:1H. 
PREATION 4.13 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)amin 
osulphonyl!-5,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylic acid 
potassium salt. 
(II:R.sub.1 =4-SO.sub.2 NMe(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =Me). 
A solution of 0.87 g of ester obtained in Preparation 3.17 in 5 ml of 
dioxane is left stirring for 8 hours at RT with 320 mg of KOH in 0.5 ml of 
water. The mixture is evaporated under vacuum and the residue is extracted 
with a mixture of 10 ml of water, 5 ml of ethanol and 100 ml of ether. 
After decantation, the gum obtained is triturated three times in ether; 
the product crystallizes. It is filtered off to obtain 0.9 g of the 
expected salt. 
PREATION 4.14 
5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-2-methyl-phenyl)-3-pyrazolecarboxyli 
c acid. 
(II:R.sub.1 =4-CONH.sub.2 ; R.sub.2 =2-CH.sub.3 ; R.sub.3 =H; R.sub.4 
=CH.sub.3). 
A solution containing 0.4 g of the compound obtained in Preparation 3.18 in 
5 ml of dioxane and 220 mg of KOH in 1 ml of water is left stirring at RT 
for 2 hours. It is acidified to pH 1 by adding concentrated HCl and then 
concentrated under vacuum. 5 ml of water are added, the gum formed is then 
stirred with 50 ml of DCM and the precipitate formed is filtered off. 330 
mg of the expected product are obtained, m.p.=275-276.degree. C. 
NMR: 2.05:s:3H; 3.55:s:6H; 6.55:d: 2H; 6.7:s:1H; 7:d:1H; 7.2:t:1H; 7.4:bs: 
1H; 7.55:d:1H; 7.7:s:1H; 7.9:bs:1H. 
PREATION 4.15 
5-(2,6-Dimethoxyphenyl)-1-{2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)ethyl) 
carbamoyl!phenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONH(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =2-CH.sub.3 ; 
R.sub.3 =3-CH.sub.3 ; R.sub.4 =CH.sub.3). 
A solution of 1.8 g of the product of Preparation 3.20 and 0.32 g of LiOH 
in 10 ml of MeOH and 2 ml of water is left stirring for 2 hours at 
40.degree. C. The pH is adjusted to 6 with 1N HCl and the mixture is 
evaporated under vacuum. After extraction of the residue with 50 ml of DCM 
and evaporation, 1.3 g of expected product are obtained. 
NMR: 1.9:s:3H; 2.2:s+s:9H; 2.5:t: 2H; 3.4:qd:2H; 3.7:s:6H; 6.6-6.7:u.c.:3H; 
6.9-7.1:u.c.:2H; 7.3:t:1H; 8.3:t:1H. 
PREATION 4.16 
5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-methoxyphenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-0CH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A mixture of 1.73 g of the product of Preparation 3.22 and 0.3 g of LiOH in 
400 ml of MeOH and 6 ml of water is left stirring under reflux for 6 
hours, and then acidified to pH 2 with concentrated HCl. After evaporation 
under vacuum and stirring of the residual oil for 30 minutes at RT with 
400 ml of chloroform, and after settling has taken place, separation and 
drying of the organic phase over Na.sub.2 SO.sub.4 and evaporation, 1.2 g 
of expected product are obtained. 
NMR: 1.05-1.4:mt:6H; 3:bs:3H; 3.1-3.9:mt:13H; 6.6:d:2H; 6.8:s:1H; 7-7.4:mt: 
4H. 
PREATION 4.17 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-chlorophenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-Cl; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A mixture of 2.6 g of the product of Preparation 3.24 dissolved in 100 ml 
of ethanol and 0.53 g of KOH in 15 ml of water is left stirring for 3 days 
at RT. After acidification to pH 3 with concentrated HCl, evaporation 
under vacuum, trituration of the residue in 10 ml of water, filtration and 
drying under vacuum over P.sub.2 O.sub.5, 1.55 g of expected product are 
obtained. 
PREATION 4.18 
5-(2,6-Dimethoxyphenyl)-1-4-(N-(2-morpholino-ethyl)carbamoyl)-2-chlorophen 
yl!-3-pyrazolecarboxylic acid. 
##STR87## 
A solution of 1.5 g of the product of Preparation 3.25 in 75 ml of ethanol 
is heated with stirring for 1 hour at 60.degree. C. with a solution of 
0.38 g of KOH in 10 ml of water. After acidification to pH 4.5 with 
concentrated HCl and evaporation under vacuum, 4 g of mixture of the 
expected product and KCl are obtained. 
NMR (DMSO+TFA): 2.9-4:mt:H; 6.5:d: 2H; 6.8:s:1H; 7.1-7.4:mt:2H; 7.8:dd:1H; 
8: d:1H; 9.1:bs:1H. 
PREATION 4.19 
5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolecarboxylic 
acid. 
(II':R.sub.1 =4-CN; R.sub.2 =3-Cl; R.sub.3 =H; R.sub.4 =CH.sub.3). 
A mixture containing 0.5 g of the compound obtained in Preparation 3.26 and 
60 mg of LiOH in 5 ml of aqueous methanol is heated on a water bath for 3 
hours. After cooling, the pH is lowered to 5 by adding 1N HCl. The 
precipitate formed is filtered off and dried to obtain 0.36 g of the 
expected compound. 
PREATION 4.20 
5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-3-chloro-phenyl)-3-pyrazolecarboxyli 
c acid. 
(II: R.sub.1 =4-CONH.sub.2 ; R.sub.2 =3-Cl; R.sub.3 =H; R.sub.4 =CH.sub.3). 
A mixture containing 0.87 g of the compound obtained in Preparation 4.19, 
390 mg of K.sub.2 CO.sub.3 and 0.4 ml of 30% hydrogen peroxide in 5 ml of 
DMSO is left stirring at RT for 24 hours. It is acidified to pH 3 by 
adding 1N HCl, water is then added, and the precipitate formed is filtered 
off and dried to obtain 0.73 g of the expected product. 
PREATION 4.21 
5-(2,6-Dimethoxyphenyl)-1-(4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carba 
moyl!-2-cyclopropyl-phenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-cyclopropyl; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 1.29 g of the product of Preparation 3.28 in 26 ml of ethanol 
is left stirring for 22 hours at RT with a solution of 0.33 g of KOH in 4 
ml of water. After acidification to pH 3 with concentrated HCl, 
evaporation and azeotropic distillation with 100 ml of toluene and then 
with 100 ml of pentane, the residue is triturated in pentane, filtered off 
and dried to obtain 1.4 g of mixture of the expected product with KCl. 
NMR: 0.4-1.2:mt:14H; 1.5:u.c.:1H; 2.1-3.8:mt:13H; 6.5:d:2H; 6.7:bs:2H; 
7:s:2H; 7.2:t:1H. 
PREATION 4.22 
5-(2,6-Dimethoxyphenyl)-1-{3-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)carb 
amoyl!-4-chlorophenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =3-CONMe(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =4-Cl; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A solution of 0.8 g of the product of Preparation 3.30 in 10 ml of dioxane 
is left stirring for 6 hours at RT with 0.22 g of KOH in 2 ml of H.sub.2. 
After evaporation under vacuum, the residue is dissolved in 5 ml of water, 
and the mixture is neutralized to pH 5 with concentrated HCl and then 
saturated with NaCl. It is extracted twice with 100 ml of DCM, and the 
organic phase is dried over Na.sub.2 SO.sub.4 and evaporated under vacuum 
to obtain 0.43 g of expected product. 
NMR: 1.9-3.15:u.c.:13H; 3.6:s:6H; 6.75:d:2H; 6.85:ss:1H; 7.1-7.35:u.c.:2H; 
7.45: t:1H; 7.57:d:1H. 
PREATION 4.23 
5-(2,6-Dimethoxyphenyl)-1-{5-N-methyl-N-(3-(N',N'-dimethylamino)propyl)car 
bamoyl!-2-methyl-phenyl}-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =5-CONMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-CH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3). 
A solution of 2.28 g of the product of Preparation 3.32 in 10 ml of dioxane 
is left stirring for 15 hours at RT with a solution of 0.65 g of KOH in 
1.5 ml of water; the mixture is evaporated under vacuum, and the residue 
is then dissolved in 20 ml of water and extracted 3 times with 50 ml of 
ether. After acidification of the aqueous phase to pH 4 by adding 1N HCl, 
and azeotropic distillation with ethanol, the residue is triturated with 
20 ml of ethanol, KCl is filtered off and the filtrate is then evaporated 
under vacuum. This removal of KCl is repeated, and the mixture is 
evaporated under vacuum to obtain 2 g of the expected product. 
NMR: 1.9:u.c.:2H; 2.2:s:3H; 2.4-3:u.c.:11H; 3.5:mt:2H; 3.65:s:6H; 
6.65:d:2H; 6.85:s:1H; 7.1:bs:1H; 7.3-7.5:u.c.:3H. 
By following the above procedures, the acids of formula II described in 
Table 5 below are prepared. 
TABLE 5 
______________________________________ 
##STR88## 
Prepara- M.p. .degree.C. 
tion or 
from R.sub.1 R.sub.2 R.sub.3 
NMR 
______________________________________ 
4.24 4-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H NMR 
(3.33) 
4.25 (3.34) 
##STR89## 2-OCH.sub.3 
H NMR 
4.26 4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2 
2-CH.sub.3 
3-CH.sub.3 
NMR 
(3.36) 
a) 4.27 
5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-Cl H NMR 
(3.38) 
4.28 4-CONMe(CH.sub.2).sub.2 NEt.sub.2 
2-CF.sub.3 
H NMR 
(3.40) 
a) 4.29 
5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H NMR 
(3.42) 
4.30 4-CONH(CH.sub.2).sub.2 N(iPr).sub.2 
2-iPr H NMR 
(3.43) 
a) 4.31 
4-CONH(CH.sub.2).sub.3 N(nBu).sub.2 
2-iPr H NMR 
(3.45) 
a) 4.32 
4-CONH(CH.sub.2).sub.2 NEt.sub.2 
2-iPr H NMR 
(3.46) 
4.33 (3.47) 
##STR90## 2-iPr H NMR 
4.34 4-CON(CH.sub.2 CH.sub.2 NEt.sub.2).sub.2 
2-iPr H NMR 
(3.48) 
4.35 (3.49) 
##STR91## 2-iPr H NMR 
4.36 (3.50) 
##STR92## 2-iPr H NMR 
4.37 (3.52) 
##STR93## 2-iPr H 196 
4.38 4-CONMe(CH.sub.2).sub.2 CN 
2-iPr H 178-180 
(3.53) NMR 
4,39 (3.55) 
##STR94## 2-iPr H 140 
______________________________________ 
The letter a) indicates that the potassium salt of the acid of the formul 
II was obtained. 
NMR: 
Preparation 4.24 (DMSO):2:u.c.:2H; 2.5:u.c.:6H; 2.8-3.5:u.c.:5H; 3.5:s:3H; 
3.6:s:6H; 6.6:d:2H; 6.8:s:1H; 7.05:u.c.:2H; 7.15 u.c.:2H. 
Preparation 4.25 :2. 1:s:3H; 2.3:u.c.:4H; 3.1 to 3.7:u.c.:13H; 6.5:d:2H; 
6.7:s:1H; 6.9:u.c.:2H; 7.25:u.c.:2H. 
Preparation 4.27:1.6-3.2:u.c.:13H; 3.6:s:6H; 6.4:s:1H; 6.6.:d:2H; 
7-8:u.c.:4H. 
Preparation 4.28:0.9:u.c.:6H; 2-3.4:u.c.:11H; 3.5:s:6H; 6.4:s:1H; 6.6:d:2H; 
7.15:u.c.:2H; 7.75:d:14H; 7.85:bs:1H. 
Preparation 4.29:1.8-2.6:u.c.:8H; 2.8: bs:3H; 3.4-3.8:bs:2H; 3.6:s:6H; 
3.64:s:3H; 6.50:s:1H; 6.60:d:2H; 7-7.50:u.c.:4H. 
Preparation 4.30 (DMSO+TFA): 1:d:6H; 1.3:d:12H; 2.65:mt:1H; 3.2:t:2H; 
3.5-3.75:u.c.:+s:10H; 6.55:d:2H; 6.8:s:1H; 7.2-7.35:mt:2H; 7.7:d:1H; 
7.8:s:1H. 
Preparation 4.31:0.8:t:6H; 0.95:d:6H; 1.1-1.4:u.c.:8H; 1.58:t:2H; 
2.15-2.4:u.c.:6H; 2.55:sp:1H; 3.2:mt:2H; 3.57:s:6H; 6.3:s:1H; 6.5:d:2H; 
7.1-7.3:u.c.:2H; 7.74:dd:1H; 7.75:d:1H; 8.45:t:1H. 
Preparation 4.32:0.9-1.1:u.c.:12H; 2.6:u.c.:6H; 2.7:u.c.:1H; 
3.2-3.4:u.c.:2H; 3.6:u.c.:6H; 6.3:s:1H; 6.6:d:2H; 7.1-7.3:u.c.:2H; 
7.6-7.8:u.c.:2H. 
Preparation 4.33:1:d:6H; 1.5-1.9:u.c.:6H; 2-2.2:u.c.:2H; 2.2:s:6H; 
2.7:s:2H; 2.8 qt:1H; 3.6:s:6H; 6.45:s:1H; 6.6:d:2H; 7.2-7.35:u.c.:2H; 
7.6:d:1H; 7.7:s:1H; 7.9: s:1H. 
Preparation 4.34:1:m:12H; 1.3:mt:6H; 2.5-3.9:u.c.+s:23H; 6.6:d:2H; 
6.8:s:1H; 7.2-7.4:u.c.:3H; 7.55:s:1H. 
Preparation 4.35 (DMSO+TFA): 1:u.c.:6H; 1.2:t:3M; 1.75-2.2:2u.c.:4H; 
2.65:mt:1H; 3:u.c.:2H; 3.4-3.7:u.c.+s:11H; 6.5:d:2H; 6.75:s:1H; 7.2:t:1H; 
7.3:d:1H; 7.65:d:1H; 7.8:s:1H. 
Preparation 4.36:1.05:d:6H; 1.5:s: 12H; 1.7:t:2H; 2.0:d:2H; 2.7:mt:1H; 
3.7:s 6H; 4.3-4.5:u.c.:1H; 6.7:d:2H; 6.85:s:1H; 7.25-7.4:mt:2H; 7.75:d:1H; 
7.9:s:1H; 8.3-8.5:u.c.:1H; 8.7:d:1H; 12.8:u.c.:1H. 
Preparation 4.38:0.95:d:6H; 2.6:mt:1H; 2.7-3.8:u.c.:13H; 6.57:d:2H; 
6.75:s:1H; 7.12-7.35:u.c.:4H; 12.7:bs:1H. 
PREATION 4.40 
1-4-N-Ethyl-N-(2-N',N'-diethylaminoethyl) carbamoyl!-2-isopropylphenyl!- 
5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONEt(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A solution of 0.48 g of the compound obtained in Preparation 4.32 and 0.28 
ml of ethyl iodide in 3 ml of THF is cooled to 5.degree. C., 0.063 g of 
60% sodium hydride in oil is then added portionwise and the mixture is 
left stirring for 24 hours at RT. 0.48 ml of a THF/water (50:50; v/v) 
mixture is added and the reaction mixture is concentrated under vacuum. 
The residue is taken up with water, the aqueous phase is washed twice with 
pentane, acidified to pH 1 by adding 1N HCl solution and extracted with 
AcOEt and then with DCM, the organic phases are dried over Na.sub.2 
SO.sub.4 and the solvents are evaporated off under vacuum. 0.14 g of the 
expected product is obtained. 
NMR (DMSO+TFA): 0.8-1.3:u.c.:15H; 2.6:u.c.:1H; 3.0-3.8:u.c.:16H; 6.5:d:2H; 
6.75:s 1H; 7.2:u.c.:4H. 
PREATION 4.41 
1-4-3-(Diethylamino)-1-pyrrolidinyl!carbonyl!-2-isopropylphenyl!-5-(2,6- 
dimethoxyphenyl)-3-pyrazole-carboxylic acid hydrochloride. 
##STR95## 
A solution of 0.11 g of KOH in 0.5 ml of water is added at RT to a solution 
of 0.44 g of the compound obtained in Preparation 3.51 in 4 ml of dioxane, 
and the mixture is left stirring overnight at RT. It is concentrated under 
vacuum, the residue is taken up with water, the aqueous phase is washed 
twice with ether and acidified to pH 2 by adding 1.2N HCl, EtOH is added 
and the mixture is concentrated under vacuum. The residue is taken up with 
EtOH, the KCl is filtered off and the filtrate is concentrated under 
vacuum. 0.39 g of the expected product is obtained. 
NMR (DMSO+TFA): 1.0:d:6H; 1.15-1.35: u.c.:6H; 2.1-2.45:u.c.:2H; 2.65:mt:1H; 
2.9-4.1:3u.c.+s:15H; 6.6:d:2H; 6.8:s:1H; 7.2-7.5:mt:3H; 7.55:s:1H. 
PREATION 4.42 
1-4-N-(2-Propenyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)- 
3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONHCH.sub.2 CH=CH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3). 
A mixture of 1.72 g of the compound obtained in Preparation 3.54 and 0.78 g 
of LiOH.H.sub.2 O in 10 ml of MeOH and 1 ml of water is left stirring for 
7 hours at RT. It is concentrated under vacuum, the residue is taken up 
with water, the aqueous phase is washed twice with ether, acidified to pH 
2-3 by adding 1.2N HCl and extracted with DCM, the organic phase is dried 
over MgSO.sub.4 and the solvent is evaporated off under vacuum. 1.64 g of 
the expected product are obtained. 
NMR: 1.0:d:6H; 2.7:qt:1H; 3.7:s: 6H; 3.95:t:2H; 5.1-5.3:u.c.:2H; 
5.8-6.1:u.c.: 1H; 6.65:d:2H; 6.85:s:1H; 7.25-7.4:u.c.: 2H; 7.75:d:1H; 
7.9:s:1H; 8.8:t:1H. 
PREATION 4.43 
1-4-N-Methyl-N-3-N'-methyl-N'-(tert-butoxy-carbonyl)amino!propyl!carbam 
oyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-CONMe(CH.sub.2).sub.3 N(Me)COOt-Bu; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
A mixture of 2.85 g of the compound obtained in 
Preparation 3.57 and 0.98 g of LiOH.H.sub.2 O in 20 ml of MeOH and 1 ml of 
water is left stirring for 3 hours 30 minutes at RT. It is concentrated 
under vacuum, the residue is taken up with water and acidified to pH 2 by 
adding a pH 2 buffer solution, and the precipitate formed is drained and 
washed with water. 2.47 g of the expected product are obtained after 
drying over P.sub.2 O.sub.5, m.p.=112.degree.-114.degree. C. 
PREATION 4.44 
1-4-(4-Methylphenylsulphonylamino)-2-isopropyl-phenyl!-5-(2,6-dimethoxyphe 
nyl!-3-pyrazolecarboxylic acid. 
##STR96## 
A mixture of 1.05 g of the compound obtained in Preparation 3.58 and 0.33 g 
of LiOH.H.sub.2 O in 5 ml of MeOH and 0.5 ml of water is heated for 3 
hours at 60.degree. C. The reaction mixture is poured into water, the 
resulting mixture is acidified to pH 2-3 by adding 10% HCl solution, and 
the precipitate formed is drained and dried. 0.92 g of the expected 
product is obtained. 
NMR: 0.7:d:6H; 2.3-2.6:u.c.:4H; 3.55: s:6H; 6.6:d:2H; 6.75:s:1H; 
6.85-7.01:u.c.: 2H; 7.11:d:1H; 7.25-7.42:u.c.:3H; 7.6:d:2H; 10.3:s:1H; 
12.75:bs:1H. 
PREATION 4.45 
1-(4-Amino-2-isopropylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic 
acid. 
(II':R'.sub.1 =4-NH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; R.sub.4 =Me). 
A mixture of 0.9 g of the compound obtained in Preparation 3.58, 11 ml of 
acetic acid and 25 ml of 70% perchloric acid is heated to reflux for 10 
minutes. The reaction mixture is poured into a water/ice mixture, some 
insoluble matter is filtered off, the filtrate is taken to pH 5 by adding 
10% NaOH and filtered, the filtrate is extracted with AcOEt, the organic 
phase is dried over Na.sub.2 SO.sub.4 and the solvent is evaporated off 
under vacuum. The residue is taken up with ether and the precipitate 
formed is drained. 0.54 g of the expected product is obtained, 
m.p.=190.degree. C. (dec.). 
NMR: 0.92:d:6H; 2.42:mt:1H; 3.65:s: 6H; 5.42:bs:2H; 6.3:dd:1H; 6.4:d:1H; 
6.6: d:2H; 6.67:s:1H; 6.85:d:1H; 7.3:t:1H. 
PREATION 4.46 
1-4-3-(Diethylamino)propanoylamino!-2-iso-propylphenyl!-5-(2,6-dimethoxyp 
henyl)-3-pyrazole-carboxylic acid. 
(II: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =Me). 
A mixture of 0.22 g of 3-diethylaminopropanoic acid hydrochloride and 2 ml 
of SOCl.sub.2 in 2 ml of DCM is heated to reflux for 1 hour and then 
concentrated under vacuum. The acid chloride thereby obtained is used 
without further treatment. Separately, a mixture of 0.47 g of the compound 
obtained in Preparation 4.45 and 0.95 ml of bis(trimethylsilyl)acetamide 
in 5 ml of acetonitrile is heated at 70.degree. C. for 1 hour. After 
cooling to RT, the acid chloride prepared above, in solution in DCM, is 
added, followed by 0.17 ml of triethylamine, and the mixture is left 
stirring for hour at RT. It is concentrated under vacuum, the residue is 
taken up with water, the pH is taken to 5 by adding 10% NaOH, the mixture 
is extracted with DCM, the organic phase is dried over Na.sub.2 SO.sub.4 
and the solvent is evaporated off under vacuum. The residue is taken up 
with ether and the precipitate formed is drained. 0.27 g of the expected 
product is obtained. 
NMR (DMSO+TFA): 0.91:d:6H; 1.2:mt:6H; 2.55:mt:1H; 2.8:t:2H; 
3.1-3.22:u.c.:4H; 3.35:t:2H; 3.6:s:6H; 6.58:d:2H; 6.75:s: 1H; 
7.1-7.3:u.c.:2H; 7.4-7.55:u.c.:2H. 
PREATION 4.47 
1-4-(3-Diethylaminopropyl)amino!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphen 
yl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-NH(CH.sub.2).sub.3 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =Me). 
A mixture of 0.55 g of the compound obtained in Preparation 3.59, 6.5 ml of 
acetic acid and 14 ml of 70% perchloric acid is heated to reflux for 10 
minutes. The reaction mixture is poured into water, the resulting mixture 
is taken to pH 5 by adding 10% NaOH and extracted with AcOEt, the organic 
phase is dried over Na.sub.2 SO.sub.4 and the solvent is evaporated off 
under vacuum. 0.5 g of the expected product is obtained. 
NMR: 1.0:mt:6H; 1.25:t:6H; 1.9:mt: 2H; 2.55:s:1H; 3.0-3.3:u.c.:8H; 
3.7:s:6H; 5.9:s:1H; 6.3-6.55:u.c.:2H; 6.65:d:2H; 6.75 s:1H; 7.0:d:1H; 
7.3:t:1H. 
PREATION 4.48 
1-4-N-Acetyl-N-(3-diethylaminopropyl)amino!-2-isopropylphenyl!-5-(2,6-dim 
ethoxyphenyl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-N(COMe)(CH.sub.2).sub.3 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =Me). 
0.38 g of the compound obtained in Preparation 4.47 and 0.36 ml of 
bis(trimethylsilyl)acetamide in 10 ml of toluene is heated for 1 hour at 
60.degree. C. 0.052 ml of acetyl chloride is added, followed by 0.1 ml of 
triethylamine, and the mixture is left stirring for 2 hours at RT. It is 
concentrated under vacuum, the residue is taken up with saturated NaCl 
solution, the mixture is extracted with AcOEt, the organic phase is dried 
over Na.sub.2 SO.sub.4 and the solvent is evaporated off under vacuum. 
0.39 g of the expected product is obtained. 
NMR: 0.95:d:6H; 1.25:t:6H; 1.6-2.0: u.c.:5H; 2.65:sp:1H; 3.0-3.3:u.c.:6H; 
3.65: s:6H; 3.75:t:2H; 6.65:d:2H; 6.85:s:1H; 7.2-7.6:u.c.:4H. 
PREATION 4.49 
1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-5-2- 
(cyclopropylmethyloxy)-6-methoxyphenyl!-3-pyrazolecarboxylic acid potassium 
salt. 
##STR97## 
A mixture of 3.8 g of the compound obtained in Preparation 3.61 and 0.92 g 
of KOH in 76 ml of EtOH and 12 ml of water is left stirring for 20 hours 
at RT. It is concentrated under vacuum, the residue is taken up with 
toluene and the solvent is evaporated off under vacuum. 3.9 g of the 
expected product are obtained. 
PREATION 4.50 
1-(2-Methyl-4-nitrophenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic 
acid. 
(II':R'.sub.1 =4-NO.sub.2 ; R.sub.2 =2-Me; R.sub.3 =H; R.sub.4 =Me). 
A mixture of 3.5 g of the compound obtained in Preparation 3.56 and 0.44 g 
of LiOH.H.sub.2 O in 20 ml of MeOH and 4 ml of water is left stirring 
overnight. It is concentrated under vacuum, the residue is taken up with 
water, the mixture is acidified to pH 3 by adding 10% HCl, and the 
precipitate formed is drained and dried. 3.2 g of the expected product are 
obtained. 
NMR: 2.9:s:3H; 3.58:s:6H; 6.6:d: 2H; 6.88:s:1H; 7.2-7.38:u.c.:2H; 7.95:dd: 
1H; 8.22:d:1H. 
PREATION 4.51 
1-(4-Amino-2-isobutylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylic 
acid. 
(II':R'.sub.1 =4-NH.sub.2 ; R.sub.2 =2-iBu; R.sub.3 =H; R.sub.4 =Me). 
This compound is prepared according to the procedure described in 
Preparation 4.45, from 0.5 g of the compound obtained in Preparation 3.62, 
6 ml of acetic acid and 14 ml of 70% perchloric acid. 0.3 g of the 
expected product is obtained. 
NMR: 0.65:d:6H; 1.55:mt:1H; 1.9:d: 2H; 3.5:s:6H; 5.05:s:2H; 
6.0-7.3:u.c.:7H. 
PREATION 4.52 
1-4-3-(Diethylamino)propanoylamino!-2-isobutyl-phenyl!-5-(2,6-dimethoxyph 
enyl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iBu; R.sub.3 
=H; R.sub.4 =Me). 
This compound is prepared according to the procedure described in 
Preparation 4.46, from 0.133 g of 3-diethylaminopropanoic acid 
hydrochloride and 1 ml of SOCl.sub.2 in 1 ml of DCM and 0.29 g of the 
compound obtained in Preparation 4.51 and 4 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.15 g of the 
expected product is obtained. 
NMR: 0.7:d:6H; 1.1:t:6H; 1.65:mt: 1H; 2.0:d:2H; 2.75:t:2H; 3.1:qr:4H; 3.3:t 
2H; 3.6:s:6H; 6.5:d:2H; 6.7:s:1H; 7.1:d 1H; 7.2:t:1H; 7.3-7.5:u.c.:2H; 
10.3:s:1H; 15:s:1H. 
PREATION 4.53 
1-4-Amino-2-cyclopentylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxyl 
ic acid. 
##STR98## 
This compound is prepared according to the procedure described in 
Preparation 4.45, from 0.9 g of the compound obtained in Preparation 3.63, 
11 ml of acetic acid and 27 ml of 70% perchloric acid. 0.52 g of the 
expected product is obtained. 
NMR (DMSO+TFA): 1.18-1.9:u.c.:8H; 2.6: mt:1H; 3.6:s:6H; 6.6:d:2H; 
6.75:s:1H; 7.1-7.4:u.c.:4H. 
PREATION 4.54 
1-4-3-(Diethylamino)propanoylamino!-2-cyclopentylphenyl!-5-(2,6-dimethoxy 
phenyl)-3-pyrazolecarboxylic acid. 
##STR99## 
This compound is prepared according to the procedure described in 
Preparation 4.46, from 0.22 g of 3-diethylaminopropanoic acid 
hydrochloride, 2 ml of SOCl.sub.2 in 5 ml of DCM, 0.5=of the compound 
obtained in Preparation 4.53 and 0.73 ml of bis(trimethylsilyl)acetamide 
in 2 ml of acetonitrile. 0.32=of the expected product is obtained. 
NMR (DMSO+TFA): 1.1-1.8:u.c.:14H; 2.5: mt:1H; 2.72:t:2H; 3.02:u.c.:4H; 
3.22:mt: 2H; 3.58:s:6H; 6.5:d:2H; 6.65:s:1H; 7.03: d:1H; 7.2:t:1H; 
7.35:dd:1H; 7.5:d:1H. 
PREATION 5.5 
1-4-N-(2-Diethylaminoethyl)carbamoyl!-3-isopropylphenyl!-5-(2,6-dimethoxy 
phenyl)-3-pyrazolecarboxylic acid potassium salt. 
(II: R.sub.1 =4-CONH(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =3-iPr; R.sub.3 
=H; R.sub.4 =Me). 
0.34 g of the compound obtained in Preparation 3.65 and 0.073 g of KOH in 6 
ml of dioxane and 2 ml of water is left stirring for 2 days at RT. It is 
concentrated under vacuum, the residue is taken up with toluene and the 
mixture is concentrated under vacuum. 0.37 g of the expected product is 
obtained, m.p. &gt;260.degree. C. 
PREATION 4.56 
5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazol 
ecarboxylic acid. 
(II':R'.sub.1 =4-NO.sub.2 ; R.sub.2, R.sub.3 =--(CH.sub.2).sub.4 -; R.sub.4 
=Me). 
A mixture of 4.2 g of the compound obtained in Preparation 3.66 is heated 
at 70.degree. C. for 2 hours with 0.8 g of LiOH.H.sub.2 O in 95 ml of EtOH 
and 5 ml of water. After cooling to RT, water is added, the mixture is 
acidified to pH 3 by adding 10% HCl, and the precipitate formed is drained 
and dried. 4.16 g of the expected product are obtained, m.p.=130.degree. 
C. 
NMR: 1.7:mt:4H; 2.55:mt:2H; 2.82:mt: 2H; 3.65:s:6H; 6.65:d:2H; 6.85:s:1H; 
7.05 d:1H; 7.35:t:1H; 7.7:d:1H; 12.95:bs:1H. 
PREATION 4.57 
5-(2,6-Dimethoxyphenyl)-1-(5-(3-diethylamino-propanoylamino)-2-isopropylphe 
nyl)-3-pyrazolecarboxylic acid. 
(II: R.sub.1 =5-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3). 
This compound is obtained from the methyl ester of Preparation 3.67. After 
recrystallization in methanol, m.p.=195-198.degree. C. 
NMR (DMSO+TFA): 0.65-1.35:u.c.:12H; 2.5 qt:1H; 2.82:t:2H; 3.15:mt:4H; 
3.36:t: 2H; 3.6:s:6H; 6.55:d:2H; 6.76:s:1H; 7.15-7.4:u.c.:3H; 7.8:d:1H. 
EXAMPLE 1 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A) 
1-4-N-Methyl-N-(3-dimethylaminopropyl)-carbamoyl!-2-isopropylphenyl!-5-( 
2,6-dimethoxyphenyl)-3-pyrazolylcarbonyl chloride hydrochloride. 
1.07 g of the acid obtained in Preparation 4.1 in 2 ml of thionyl chloride 
is left stirring under nitrogen at RT for 5 hours. The mixture is 
evaporated, and the residue is then taken up with DCM (3 times) to obtain 
the expected product, which is used in the next step without further 
treatment. 
The acid chloride may also be prepared according to the procedure below: 
A') 
1-4-N-Methyl-N-(3-dimethylaminopropyl)-carbamoyl!-2-isopropylphenyl!-5-( 
2,6-dimethoxyphenyl)-3-pyrazolylcarbonyl chloride hydrochloride. 
The potassium salt of Preparation 4.1a is redissolved in 130 ml of ethanol, 
50 ml of ethanolic hydrogen chloride are added, the inorganic matter is 
filtered off and the filtrate is evaporated under vacuum. The residue is 
redissolved in 100 ml of DCM, 11 ml of SOCl.sub.2 are added slowly and the 
mixture is heated to reflux for 4 hours. It is evaporated under vacuum, 
the residue is redissolved in 30 ml of DCM and the mixture is evaporated 
under vacuum; the operation is repeated 3 times. 
B) 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-isopropylphenyl!3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
A mixture containing 0.37 g of 2-amino-2-adamantanecarboxylic acid 
(compound B), 5 ml of acetonitrile and 0.82 ml of 
bis(trimethylsilyl)acetamide is heated to reflux under nitrogen for 40 
minutes. After a return to RT, 0.3 ml of triethylamine and the product 
obtained in the preceding step, dissolved in 15 ml of acetonitrile, are 
added. The mixture is left stirring at RT for 1 week and the solvents are 
concentrated. On adding ether, a crystallization is obtained. The crystals 
are stirred in a mixture of 1.5 ml of toluene and 1.5 ml of acetonitrile. 
The insoluble matter is filtered off and rinsed and the solvents are 
evaporated off. The residue is stirred in aqueous methanol, the mixture is 
then evaporated again and the residue is taken up with ethenol. The 
mixture is extracted with DCM, and the organic phase is washed with 
saturated NaCl solution and then chromatographed on silica, eluting with a 
DCM/MeOH/H.sub.2 O (92:8:0.7; v/v/v) mixture. 0.18 g of the expected 
product is obtained after trituration in ether, m.p.=185.degree. C. 
(dec.). 
NMR (DMSO+TFA): 0.95:d:6H; 1.6-2.2: u.c.:14H; 2.4-3:u.c.:12H; 3.1:mt:2H; 
3.5:mt: 2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H. 
Alternatively, step B may be performed in the following manner: 
A mixture of 8.79 g of compound B and 22 ml of bis(trimethylsilyl)acetamide 
in 120 ml of dry acetonitrile is heated to reflux under nitrogen for 40 
minutes and cooled to RT. A solution of the acid chloride obtained 
according to A, starting from 23.83 g of the acid obtained in Preparation 
4.1 and 140 ml of thionyl chloride, in 300 ml of dry acetonitrile is then 
added. After stirring for 15 hours at RT and evaporation under vacuum, the 
residue is redissolved in 180 ml of MeOH, 180 ml of water are added 
slowly, the mixture is stirred for one hour, the insoluble matter is 
filtered off and the filtrate is evaporated under vacuum after adding 
ethanol. After stirring in 200 ml of 1N HCl, the mixture is filtered, and 
the precipitate is washed with 1N HCl and dried under vacuum over P.sub.2 
O.sub.5 to obtain 29.8 g of the product of EXAMPLE 1, m.p.=211.degree. C. 
(dec.) after recrystallization in 2-propanol. 
EXAMPLE 1' 
Internal salt of 
2-5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!-2-adamantane-carboxylic 
acid. 
From the hydrochloride of the compound obtained in EXAMPLE 1, the internal 
salt is liberated in the following manner: 
0.97 g of the product of EXAMPLE 1 is dissolved in 10 ml of water and the 
pH is raised to 7 by adding 1.3N sodium hydroxide. The product is filtered 
off, washed with water and dried under vacuum over P.sub.2 O.sub.5 to 
obtain 0.86 g of internal salt, which is recrystallized in 3 ml of 
acetonitrile to obtain 0.5 g of the expected internal salt. 
NMR (DMSO+TFA): 1:mt:6H; 1.4-2.3:u.c. 14H; 2.3-3.4:u.c.:14H; 3.5:u.c.:2H; 
3.65:s 6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H. 
After recrystallization in 2-propanol, m.p.=238.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2: u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.1:mt 2H; 3.5:mt:2H; 3.6:s:6H; 6.6:d:2H; 6.75: s:1H; 7.1-7.5:u.c.:4H. 
The product of EXAMPLE 1' may also be prepared without isolating the 
product of EXAMPLE 1, according to the following procedure: 
A mixture of 9.7 g of compound B and 27 ml of bistrimethylsilylacetamide in 
100 ml of anhydrous DCM is heated to reflux under nitrogen for 2 hours. 
After cooling, the solution thereby obtained is poured into the solution 
of the product of step A' of EXAMPLE 1 in 100 ml of DCM, and the mixture 
is stirred overnight at RT. It is evaporated under vacuum, the residue is 
treated by stirring for 3 hours with 100 ml of MeOH and 100 ml of water 
and the pH is raised to 7-7.5 by adding saturated NaHCO.sub.3 solution. 
After 1 hour of stirring, the mixture is filtered to obtain 22.1 g of the 
expected product (HPLC purity 98.5%). 
The internal salt may also be converted to its hydrochloride (product of 
EXAMPLE 1) according to the following procedure: 
6.85 g of internal salt in a mixture of 3.5 ml of concentrated HCl and 40 
ml of water are heated while stirring. After dissolution, the mixture is 
allowed to cool with stirring, and the product is filtered off and dried 
under vacuum to obtain 6.5 g of hydrochloride. 
From the internal salt, its hydrochloride may be obtained in the following 
manner: 
0.3 g of internal salt in 3 ml of MeOH and 2 ml of DCM are dissolved while 
heating, the mixture is cooled to RT, 0.5 ml of 1.2N HCl is added, the 
mixture is concentrated under vacuum to 0.5 ml and cooled to -20.degree. 
C. and the product is filtered off to obtain 0.2 g of the product of 
EXAMPLE 1. 
EXAMPLE 2 
2-{1-4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphe 
nyl)-3-pyrazolylcarbonyl-amino)-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONHCH.sub.2 CH.sub.2 CN; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 2.6 g of the compound obtained in Preparation 4.2 and 20 ml of 
thionyl chloride is left stirring for 5 hours at RT. It is concentrated 
under vacuum, the residue is taken up with DCM and the solvent is 
evaporated off under vacuum. The acid chloride thereby obtained is used 
without further treatment. Separately, a mixture of 1.09 g of 
2-amino-2-adamantanecarboxylic acid and 4.2 ml of 
bis(trimethylsilyl)acetamide in 20 ml of acetonitrile is heated to reflux 
under a nitrogen atmosphere for 30 minutes. After cooling, a solution of 
the acid chloride prepared above in 40 ml of acetonitrile is added slowly, 
and the mixture is left stirring overnight at RT. It is concentrated under 
vacuum, the residue is taken up with MeOH, a few drops of water are added 
and the mixture is left stirring for 2 hours at RT. The precipitate is 
drained, washed with MeOH and dried. The precipitate is chromatographed on 
silica H, eluting with a DCM/MeOH (100:3; v/v) mixture and then with a 
DCM/MeOH/AcOH (100:3:0.5; v/v/v) mixture. 1.96 g of the expected product 
are obtained after crystallization in ether, m.p.=269.degree. C. 
NMR: 1:d:6H; 1.4-2.1:u.c.:12H; 2.4-2.8 :u.c.:5H; 3.4:mt:2H; 3.5:s:6H; 
6.5:d:2H; 6.6:s:1H; 7.1-7.4:u.c.:2H; 7.5:d:1H; 7.8: s:1H; 8.9:t:1H. 
EXAMPLE 3 
2-{1-4-N-(3-Aminopropyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyph 
enyl)-3-pyrazolylcarbonyl-amino)-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.3 NH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.3 g of the compound obtained in EXAMPLE 2 and 0.03 g of 
Raney.RTM. nickel in 10 ml of MeOH is hydrogenated overnight at RT and at 
atmospheric pressure, the catalyst is filtered off and washed with MeOH 
and the filtrate is partially concentrated under vacuum. The crystals 
formed are filtered off and washed with EtOH to obtain a first crop of the 
expected product. The filtrate is partially concentrated under vacuum and 
left stirring at RT. The crystals formed are drained and washed with EtOH 
to obtain a second crop. By combining both crops, 0.045 g of the expected 
product are obtained, m.p.=280.degree. C. (dec.). 
NMR: 1.1:d:6H; 1.5-2.2:u.c.:14H; 2.4-3 u.c.:5H; 3.3:mt:2H; 3.6:s:6H; 
6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 7.6:d:1H; 7.7: s:1H. 
EXAMPLE 4 
2-{1-4-N-(2-Amidinoethyl)carbamoyl!-2-iso-propylphenyl!-5-(2,6-dimethoxyp 
henyl)-3-pyrazolyl-carbonylamino)-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-COHN(CH.sub.2).sub.2 C(.dbd.NH)NH.sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl) 
Step A. A solution of 0.37 g of the compound obtained in EXAMPLE 2 in 10 ml 
of EtOH and 10 ml of anhydrous ether is cooled in an ice bath, and HCl gas 
is then bubbled through it for 50 minutes. The mixture is left for 3 days 
at +5.degree. C. and then concentrated under vacuum to obtain the 
hydrochloride of the intermediate imidate (R.sub.1 =4-CONH(CH.sub.2).sub.2 
C(.dbd.NH)OEt). 
Step B. The residue is taken up in 20 ml of anhydrous EtOH, the mixture is 
cooled in an ice bath and ammonia is bubbled through it for 35 minutes. 
The mixture is left stirring for 30 minutes at RT and concentrated under 
vacuum, the residue is taken up in water and crystallization is allowed to 
take place. After draining and then drying the crystals, the product is 
recrystallized in EtOH in the heated state. 0.3 g of the expected product 
is obtained, m.p.=257.degree. C. (dec. ). 
NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c. :14H; 2.4-2.8:u.c.:3H; 
3.4-3.7:u.c.+s:8H; 6.6 d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 7.6:dd: 1H; 
7.8:bs:1H. 
EXAMPLE 5 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(2-dihydroimidazol-2-yl-ethyl)carbamoyl! 
-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
dihydrochloride. 
##STR100## 
AA(OH)=2-carboxy-2-adamantyl) 
A mixture containing 0.49 g of the intermediate imidate described in 
EXAMPLE 4, step A and 5 ml of 1,2-diaminoethane is stirred for 30 minutes. 
The reaction medium is evaporated. On adding water, a precipitate forms 
which is filtered off and then rinsed with water. This product is 
suspended in ethanol and ethereal hydrogen chloride is added. After 
evaporation of the solvent, the product is triturated in ether, filtered 
off, rinsed with ether and then dried at 60.degree. C. over P.sub.2 
O.sub.5. 0.3 g of the expected product is obtained, m.p.=220.degree. C. 
(dec.). 
NMR: 1.05:d:6H; 1.5-2.2:u.c.:12H; 2.5 bs:2H; 2.6-2.8:u.c.:3H; 3.55:mt:2H; 
3.65: s:6H; 3.8:s:1H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:dd:1H; 7.8:d:1H. 
EXAMPLE 6 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(3-(N',N'-dimethylaminopropyl)carbamoyl! 
-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=2-carboxy-2-adamantyl). 
A mixture is prepared containing 1.45 g of the compound of Preparation 4.3, 
30 ml of DCM, 0.38 ml of isobutyl chloroformate, 0.82 ml of triethylamine 
and 17 ml of acetonitrile. The mixture is left stirring at RT for five and 
a half hours. Separately, 0.57 g of 2-amino-2-adamantanecarboxylic acid, 
10 ml of acetonitrile and 2.2 ml of bis(trimethylsilyl)acetamide are 
mixed, and the mixture is heated to reflux under nitrogen for 30 minutes. 
After cooling, the mixed anhydride formed above is added and the resulting 
mixture is left stirring at RT for 1 day. The insoluble matter is filtered 
off and removed; the solvents are evaporated off, water is then added, the 
mixture is stirred for 30 minutes and the precipitate formed is filtered 
off. A second fraction is obtained from the filtrate after adding ethanol, 
extraction with DCM (twice), drying over MgSO.sub.4 and evaporation of the 
solvents. The 2 fractions combined are chromatographed on silica, eluting 
with a DCM/MeOH/H.sub.2 O (90:10:0.8, then 88:12:1; v/v/v) mixture. 40 mg 
of the expected product are obtained after trituration in isopropyl ether 
and filtration, m.p.=220.degree. C. (dec.). 
NMR (DMSO+TFA): 1.1:d:6H; 1.5.2.2:u.c.:14H; 2.5:bs:2H; 2.75:s+mt:7H; 
3.1:u.c.:2H; 3.3:u.c.:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 
7.6:dd:1H; 7.8:d:2H. 
From the acids of formula (II) described in Table 4, and by working 
according to the procedure described in EXAMPLE 1, the compounds according 
to the invention of formula (I) described in Table 6 below are obtained. 
TABLE 6 
______________________________________ 
##STR101## 
EXAMPLE R.sub.1 M.p. .degree.C. or NMR 
______________________________________ 
7 CONH(CH.sub.2).sub.2 NMe.sub.2 
210 
NMR 
8 CONH(CH.sub.2).sub.3 NEt.sub.2 
185 
NMR 
9 
##STR102## 205 NMR 
10 
##STR103## 240 NMR 
11 
##STR104## &gt;260 NMR 
12 (a) 
##STR105## 228 NMR 
13 (a) 
##STR106## 250 NMR 
______________________________________ 
(a) unsalified compounds. 
NMR: 
EXAMPLE 7 (DMSO+TFA): 1.1:d:6H; 1.5-2.2u.c.:12H; 2.4-2.8:u.c.:3H; 2.8:s:6H; 
3.25:mt:2H; 3.5-3.7:u.c.:8H; 6.6:d:2H; 6.7:s:1H; 7.2-7.5:u.c.:2H; 
7.7:dd:1H; 7.9:d:1H. 
EXAMPLE 8: 0.8-1.2:u.c.:12H; 1.4-2.2: u.c.:14H; 2.45:bs:2H; 2.6.:mt:1H; 
2.8:mt:6H; 3.3:mt:2H; 3.5:s:6H; 6.5:d:2H; 6.65:s:1H; 7.1-7.4:u.c.:3H; 
7.6:dd:1H; 7.8:bs:1H; 8.7:t:1H. 
EXAMPLE 9 (DMSO+TFA ):0.8-1.3:u.c.:8H; 1.6-2.2:u.c.:14H; 2.3-2.8:u.c.:3H; 
3:mt:2H; 3.2-3.8:u.c.:12H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 7.65:d:1H; 
7.9:bs:1H. 
EXAMPLE 10: 1.05:d:6H; 1.6-2.2:u.c.: 12H; 2.5:bs:2H; 2.7:mt:1H; 3.6:s:6H; 
6.6:d:2H; 6.7:s:1H; 7.05-7.25:u.c.:4H; 7.8-8.2:s:1H; 11:s:1H. 
EXAMPLE 11 (DMSO+TFA): 1.1-1.3:u.c.:12H; 1.6-2.2:u.c.:12H; 2.6:bs:2H; 
2.7:mt:1H; 2.9:s:6H; 3.05:bs:2H; 3.3:bs:2H; 3.7:s:6H; 6.65:d:2H; 
6.75:s:1H; 7.25-7.45:u.c.:3H; 7.75:d:1H; 7.95:bs:1H. 
EXAMPLE 12: 1:d:6H; 1.3-2.1:u.c.:16H; 2.6:mt:1H; 2.75:mt:2H; 
3.1-3.8:u.c.:5H; 3.4 :s:2H; 3.6:s:6H; 6.5:d:2H; 6.6:s:1H; 7.1-7.3:u.c.:8H; 
7.5:d:1H; 7.7:s:1H; 8.2: d:1H. 
EXAMPLE 13 (DMSO+TFA): 1.05:d:6H; 1.3-2.3 :u.c.:17H; 2.3-2.6:u.c.:2H; 
2.65:mt:1H; 2.9-3.7:u.c.+s:12H; 4.2:u.c.:1H; 6.4:u.c.:2H; 6.7:bs:1H; 
7.0-7.3:u.c.:2H; 7.4-7.6:u.c.:1H; 7.7:bs:1H. 
EXAMPLE 14 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-N',N'-dimethylamino) 
propyl)aminosulphonyl!-2-isopropyl-phenyl!-3-pyrazolylcarbonylamino!-2-ada 
mantanecarboxylic acid hydrochloride. 
(I: R.sub.1 =4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
850 mg of the acid obtained in Preparation 4.11 and 3 ml of thionyl 
chloride are left stirring at RT for five and a half hours. 10 ml of 
toluene are added and the reaction medium is then evaporated under vacuum 
(twice). 1 g of chloride of the acid obtained in Preparation 4.11 is 
thereby obtained. A mixture containing 0.41 g of 
2-amino-2-adamantanecarboxylic acid and 3.5 ml of 
bis(trimethylsilyl)acetamide in 5 ml of acetonitrile is left stirring for 
four and a half hours. A solution of the acid chloride prepared above in 5 
ml of acetonitrile and 1 ml of triethylamine is added to this reaction 
medium, and the mixture is left stirring for 4 days at RT. 3 ml of water 
and 5 ml of methanol are added, the mixture is left stirring for 4 hours 
at RT and then filtered and the filtrate is evaporated under vacuum. The 
residue is triturated in 6 ml of 1N HCl, ethanol is then added and the 
mixture is evaporated under vacuum. The residue is stirred with 200 ml of 
DCM and 5 ml of water, settling is allowed to take place, and the organic 
phase is separated, dried over Na.sub.2 SO.sub.4 and evaporated under 
vacuum to obtain 1.26 g of crude product. The latter is recrystallized in 
5 ml of MeCN, the solution is cooled to -20.degree. C. and 0.6 g of 
expected product is filtered off, m.p.=211.degree. C. 
NMR: 1:d:6H; 1.4-2.1:u.c.:14H; 2.4-2.5:mt:2H; 2.5-2.65:mt:1H; 2.6:s:3H; 
2.65:s:6H; 2.9:mt:4H; 3.5:s:6H; 6.5:d:2H; 6.7:s:1H; 7.15-7.4:u.c.:3H; 
7.45-7.6:u.c.:2H. 
EXAMPLE 15 
2-{5-(2,6-Dimethoxyphenyl)-1-4-N-3-(N',N'-dimethylamino)propyl!carbamoyl 
!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino}-2-adamantanecarb 
oxylic acid. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
0.47 g of the compound obtained in Preparation 4.12 in solution in 5 ml of 
SOCl.sub.2 and 30 ml of DCM is heated for one and a half hours at 
40.degree. C. The mixture is evaporated under vacuum to obtain the acid 
chloride, which is redissolved in 5 ml of acetonitrile and added to the 
solution obtained by refluxing for 2 hours a mixture of 0.28 g of compound 
B, 0.69 ml of bis(trimethylsilyl)acetamide and 3 ml of acetonitrile. 0.26 
ml of triethylamine is added and the mixture is left stirring for 2 hours 
at RT. It is evaporated under vacuum, the residue is triturated in 2 ml of 
saturated NaCl solution, and the product is filtered and dried under 
vacuum to obtain 0.77 g. The product is chromatographed on silica H, 
eluting with a DCM/MeOH/water (80:20:2.5; v/v/v) mixture. The eluate is 
evaporated, and the residue is triturated in ether and filtered off to 
obtain 0.11 g of expected product, m.p.=200.degree. C. (gum). 
NMR: 1.4-2.05:u.c.:18H; 2.1:s:6H; 2.2: t:3H; 2.4-2.8:u.c.:6H; 3.2:qr:2H; 
3.6:s: 6H; 6.6:d:2H; 6.65:s:1H; 6.8-7:dd:2H; 7.2-7.3:u.c.:2H; 8.2:t:1H. 
EXAMPLE 16 
2-{5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)a 
minosulphonyl!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino}-2-a 
damantanecarboxylic acid hydrochloride. 
(I: R.sub.1 =4-SO.sub.2 NMe(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
0.5 g of the salt obtained in Preparation 4.13 in 10 ml of SOCl.sub.2 is 
left stirring for 15 hours at RT, and the mixture is then evaporated with 
toluene to obtain the acid chloride, into which a solution of the 
silylated compound B, obtained by stirring a mixture of 0.279 g of 
compound B, 2 ml of bis(trimethylsilyl)acetamide and 8 ml of acetonitrile 
for 6 hours at RT, is poured. After stirring for 20 days at RT, the 
mixture is evaporated under vacuum, and the residue is then stirred for 1 
hour at RT with 5 ml of water and 5 ml of methanol; the mixture is 
filtered and the filtrate is evaporated under vacuum and then 
chromatographed on silica H, eluting with a DCM/MeOH/AcOH mixture. The 
residue is triturated in ether and filtered off to obtain 0.31 g of the 
expected product, m.p.&gt;260.degree. C. 
NMR (DMSO+TFA): 1.6-2.3:u.c.:16H; 2.6: u.c.:2H; 2.9:bs:9H; 3.1:mt:2H; 
3.4:mt:2H; 3.6:mt:2H; 3.7:s:6H; 6.7:d:2H; 6.85:s: 1H; 7.15:d:1H; 7.4:t:1H; 
7.5:bs:1H; 7.6:d :1H. 
EXAMPLE 17 
2-5-(2,6-Dimethoxyphenyl)-1-(2-methyl-4-carbamoylphenyl)-3-pyrazolylcarbon 
ylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONH.sub.2 ; R.sub.2 =2-CH.sub.3 ; R.sub.3 =H; R.sub.4 
=CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
A suspension of 220 mg of compound B and 0.4 mg of 
bis(trimethylsilyl)acetamide in 10 ml of acetonitrile is heated to reflux 
for 1 hour. 
Separately, a solution is prepared containing 330 mg of the compound 
obtained in Preparation 4.14 and 0.15 ml of triethylamine in 10 ml of 
acetonitrile and is cooled to -5.degree. C., 0.13 ml of isobutyl 
chloroformate is added, the mixture is left stirring for 1 hour at RT, and 
the mixed anhydride obtained is added to the solution of the silylated 
compound B prepared above. The mixture is left for 8 days at RT, the 
insoluble matter is then filtered off, the filtrate is evaporated to 
dryness and the residue is then dissolved in 5 ml of DCM. The mixture is 
washed with 1.2N HCl solution, dried over Na.sub.2 SO.sub.4 and 
evaporated; 5 ml of DCM are added, and the precipitate formed is filtered 
off and then dissolved in 1 ml of MeOH. The crystals formed are filtered 
off to obtain 100 mg of the expected product, m.p.=290.degree. C. (dec.). 
NMR: 1.4-2.3:u.c.:15H; 2.55:u.c.:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.05:d: 
1H; 7.3:t:1H; 7.4:s:2H; 7.6:dd:1H; 7.75:s 1H; 7.9:s:1H. 
EXAMPLE 18 
2-{5-(2,6-Dimethoxyphenyl)-1-2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)eth 
yl)carbamoyl!phenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =2-CH.sub.3 ; 
R.sub.3 CH.sub.3 ; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 
-carboxy-2-adamantyl). 
A solution of 1.3 g of the product of Preparation 4.15 in 10 ml of 
SOCl.sub.2 and 50 ml of DCM is heated to reflux for one and a half hours. 
It is evaporated under vacuum to obtain the acid chloride, which is 
redissolved in 10 ml of acetonitrile and added to the solution obtained 
after 2 hours of heating to reflux a mixture of 0.82 g of compound B and 2 
ml of bis(trimethylsilyl)acetamide in 10 ml of acetonitrile. 0.77 ml of 
triethylamine is added and the mixture is left stirring for 15 hours at 
RT. After evaporation under vacuum, trituration in 10 ml of saturated NaCl 
solution, filtration and drying under vacuum, the product is 
chromatographed on silica H, eluting with a DCM/MeOH/water (100:10:1; 
v/v/v) mixture. After evaporation of the solvents and trituration in 
ether, the residue is filtered off to obtain 0.7 g of expected product, 
m.p.=210.degree. C. 
NMR: 1.6-2.2:u.c.:12H; 2:s:3H; 2.25: s:3H; 2.35:s:6H; 2.5-2.7:u.c.:2H+2H; 
3.4:qr :2H; 3.7:s:6H; 6.65:d:2H; 6.8:s:1H; 7.0-7.2:u.c.:2H; 
7.3-7.45:u.c.:2H; 8.4:t:1H. 
EXAMPLE 19 
2-{5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)ca 
rbamoyl!-2-methoxyphenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylic 
acid hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-OCH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
1.2 g of the product of Preparation 4.16 in 12 ml of SOCl.sub.2 and 12 ml 
of DCM are left stirring for 24 hours at RT. After evaporation under 
vacuum followed by 2 azeotropic evaporations with 30 ml of toluene, the 
acid chloride obtained is redissolved in 10 ml of acetonitrile and added 
to the solution obtained by refluxing a mixture of 0.43 g of compound B 
and 1.1 ml of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile for 1 
hour 15 minutes. The resulting mixture is left stirring under reflux for 4 
hours and evaporated under vacuum, and the residue is stirred in 4 ml of 
MeOH and 0.5 ml of H.sub.2 O; the mixture is evaporated under vacuum and 
the residue is then chromatographed on silica H, eluting with DCM/MeOH/20% 
NH.sub.4 OH (95:5:0.5; 90:10:0.5; 85:15:0.5; v/v/v) mixtures to obtain 0.3 
g of expected product, m.p.=170.degree. C. (dec.). 
NMR: 0.8:mt:3H; 1:mt:3H; 1.5-3.6:mt: 34H; 6.5:d:2H; 6.65:s:1H; 6.95:mt:2H; 
7.3 :mt:3H. 
EXAMPLE 20 
2-{5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-(N',N'-diethylaminoethyl)car 
bamoyl!-2-chlorophenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylic 
acid hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-Cl; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl. 
1.3 g of the product of Preparation 4.17 in 12 ml of DCM and 12 ml of 
SOCl.sub.2 are left stirring for 24 hours at RT. After evaporation under 
vacuum followed by 2 azeotropic evaporations with 30 ml of toluene, the 
acid chloride obtained is redissolved in 10 ml of acetonitrile and added 
to the solution obtained by refluxing a mixture of 0.46 g of compound B 
and 1.2 ml of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile for 1 
hour 15 minutes. The resulting mixture is left stirring under reflux for 4 
hours and then evaporated under vacuum, the residue is triturated in 4 ml 
of MeOH and 2 ml of water, and the mixture is stirred for 30 minutes at RT 
and evaporated under vacuum. The residue is chromatographed on silica H, 
eluting with a DCM/MeOH/20% NH.sub.4 OH (80:20:0.5; v/v/v) mixture to 
obtain 0.3 g of expected product; m.p. 160.degree. C. (dec.). 
EXAMPLE 21 
2-{5-(2,6-Dimethoxyphenyl)-1-4-N-(2-morpholinoethyl)carbamoyl!-2-chloroph 
enyl!-3-pyrazolylcarbonyl-amino}-2-adamantanecarboxylic acid hydrochloride. 
##STR107## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 1.4 g of the product of Preparation 4.18, 14 ml of SOCl.sub.2 
and 80 ml of DCM is left stirring for 18 hours at RT. After evaporation 
under vacuum followed by 2 azeotropic evaporations with 30 ml of toluene 
and redissolution of the acid chloride formed in 20 ml of acetonitrile, 
the solution is added to the solution obtained by refluxing a suspension 
of 0.53 g of compound B in 1.33 ml of bis(trimethylsilyl)acetamide and 30 
ml of acetonitrile for 4 hours. After stirring under reflux for 4 hours, 
the mixture is evaporated under vacuum, the residue is stirred with 10 ml 
of MeOH and 1 ml of water and the mixture is filtered. After stirring the 
precipitate for 1 hour with 5 ml of H.sub.2 O and 5 drops of concentrated 
HCl, filtration and washing with 1 ml of H.sub.2 O, 5 ml of pentane and 5 
ml of isopropyl ether, 0.7 g of expected product is obtained, 
m.p.=200.degree. C. 
NMR: 1.5-2.2:u.c.:12; 2.6:bs:2; 2.85: bs:4; 3.3-3.8:mt:20; 6.6:d:2H; 
6.75:s:1H; 7.3:t:1H; 7.45:mt:2H; 7.8:dd:1H; 7.95:d: 1H; 8.85:bs:1H. 
EXAMPLE 22 
2-5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolylcarbonyla 
mino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CN; R.sub.2 =3-Cl; R.sub.3 =H; R.sub.4 =CH.sub.3 ; 
AA(OH)=2-carboxy-2-adamantyl). 
A mixture containing 0.36 g of the compound obtained in Preparation 4.19, 
0,145 ml of isobutyl chloroformate and 0.145 ml of triethylamine in 5 ml 
of DCM is left stirring at RT for 3 days. Separately, a mixture containing 
0.23 g of compound B and 0.34 ml of bis(trifluoromethyl)acetamide in 2 ml 
of acetonitrile is brought to reflux for 1 hour. The 2 solutions thus 
prepared are mixed and the resulting mixture is left stirring at RT for 48 
hours. After filtration and washing with methanol, the solvents are 
evaporated off and the residue is then chromatographed on silica, eluting 
with a DCM/MeOH/AcOH (100:1:0.5; v/v/v) mixture to obtain 120 mg of the 
expected product, m.p.=292.degree. C. 
EXAMPLE 23 
2-5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-3-chlorophenyl)-3-pyrazolylcarbon 
ylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONH.sub.2 ; R.sub.2 =3-Cl; R.sub.3 =H; R.sub.4 =CH.sub.3 ; 
AA(OH)=2-carboxy-2-adamantyl). 
A mixture containing 0.73 g of the compound obtained in Preparation 4.20, 
0.263 ml of isobutyl chloroformate and 0.26 ml of triethylamine in 5 ml of 
DCM is left stirring at RT for 24 hours. 
Separately, a mixture containing 0.34 g of compound B and 0.65 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile is brought to reflux 
for 1 hour. The 2 solutions thus prepared are mixed and the resulting 
mixture is left stirring at RT for 4 days. After filtration, washing with 
1N HCl and then EtOH and drying over MgSO.sub.4, the residue is 
chromatographed on silica H, eluting with a DCM/MeOH/AcOH (100:2:1; v/v/v) 
mixture, m.p.=293.degree. C. 
EXAMPLE 24 
2-{1-4-N-Methyl-N-(2-(N',N'-dimethylamino)-ethyl)carbamoyl!-2-cyclopropyl 
phenyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarb 
oxylic acid hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-cyclopropyl; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
0.5 g of the product of Preparation 4.21 in 5 ml of DCM and 1 ml of 
SOCl.sub.2 is left stirring for 24 hours at RT. After evaporation under 
vacuum followed by 2 azeotropic distillations with 30 ml of toluene, the 
acid chloride formed is redissolved in 5 ml of acetonitrile and added to 
the solution obtained by refluxing a suspension of 0.19 g of compound B in 
0.5 ml of bis(trimethylsilyl)acetamide and 8.5 ml of acetonitrile for two 
and a half hours, and the mixture is stirred for 12 hours at RT. It is 
evaporated under vacuum, the residue is stirred for 45 minutes with 3.5 ml 
of MeOH and 1 ml of H.sub.2 O, 2.5 ml of H.sub.2 O are then added dropwise 
and the mixture is filtered. After evaporation of the filtrate under 
vacuum and drying under vacuum for 24 hours at 60.degree. C., 0.14 g of 
expected product are obtained, m.p.=135.degree. C. (dec.). 
NMR (DMSO+TFA): 0.6:u.c.:2H; 0.9:u.c.:2H; 1.2:u.c.:6H; 1.5-2.2:u.c.:12H; 
2.6:u.c.:2H; 2.9:bs:3H; 3.2:u.c.:6H; 3.6:s:6H; 3.7:u.c.:2H; 6.6:d:2H; 
6.75:s:1H; 6.85:s:1H; 7.1-7.4:u.c.:3H. 
EXAMPLE 25 
2-{1-3-N-Methyl-N-(2-(N',N'-dimethylamino)-ethyl)carbamoyl!-4-chloropheny 
l!-5-(2,6-dimethoxy-phenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarboxyli 
c acid hydrochloride. 
(I: R.sub.1 =3-CONMe(CH.sub.2).sub.2 NMe.sub.2 ; R.sub.2 =4-Cl; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=2-carboxy-2-adamantyl). 
A solution of 0.43 g of the product of Preparation 4.22 in 10 ml of DCM and 
6 ml of SOCl.sub.2 is left stirring for 15 hours at RT. After evaporation 
under vacuum followed by 2 azeotropic distillations with 30 ml of toluene, 
the acid chloride is redissolved in 3 ml of acetonitrile, and the solution 
is added to the solution obtained by refluxing a suspension of 0.17 of 
compound B in 0.5 ml of bis(trimethylsilyl)acetamide and 10 ml of 
acetonitrile for 3 hours. The mixture is stirred under reflux for 3 hours 
and then for 15 hours at RT. It is evaporated under vacuum, and the 
residue is stirred for 1 hour with 12 ml of MeOH and 6 ml of water. The 
MeOH is evaporated off under vacuum, the residue is extracted twice with 
50 ml of DCM and the organic phase is dried over Na.sub.2 SO.sub.4 and 
evaporated under vacuum to obtain 0.16 g of expected product, m.p. 
206.degree. C. (dec.). 
NMR: 1.5-2.3:u.c.:12H; 2.6-3.8:u.c.: 21H; 6.7:d:2H; 6.8:s:1H; 
7.1-7.7:u.c.:4H. 
EXAMPLE 26 
2-{1-5-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-methylphen 
yl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarboxyli 
c acid. 
(I: R.sub.1 =5-CONMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-CH.sub.3 ; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A solution of 1.7 g of the product of Preparation 4.23 in 15 ml of 
SOCl.sub.2 is left stirring for five and a half hours at RT. After 
evaporation under vacuum followed by 3 azeotropic distillations with 30 ml 
of DCM, the acid chloride formed is redissolved in 30 ml of acetonitrile, 
and the solution is added to the solution obtained by refluxing a 
suspension of 0.69 g of compound B in 1.75 ml of 
bis(trimethylsilyl)-acetamide and 6 ml of acetonitrile for 1 hour. After 
stirring for 15 hours at RT and evaporation under vacuum, the residue is 
dissolved in 13 ml of MeOH, 12 ml of water are added slowly and the 
mixture is stirred for 30 minutes at RT. After evaporation under vacuum, 
trituration of the residue in 5 ml of 1N HCl, decantation, 3 extractions 
of the residual gum with 100 ml of DCM and drying over MgSO.sub.4, the 
organic phase is evaporated and the residue is then dissolved in 15 ml of 
water. The mixture is alkalinized with 30% NaOH to pH 8 and 
crystallization is then induced ultrasonically. After filtration, the 
residue is recrystallized in toluene and dried under vacuum at 60.degree. 
C. to obtain 1.32 g of expected product, m.p.=165.degree. C. 
NMR (DMSO+TFA): 1.6-2.2:u.c.:14H; 2.2: s:3H; 2.5-3.2:u.c.:13H; 3.5:mt:2H; 
3.7:s: 6H; 6.65:d:2H; 6.8:s:1H; 7.3-7.6:u.c.:3H. 
From the acids II described in Table 5 or in the Preparations, by following 
the procedures indicated above, the compounds according to the invention 
collated in Table 7 below are prepared. 
TABLE 7 
______________________________________ 
##STR108## 
M.p. .degree.C. 
EXAMPLE or 
(from) R.sub.1 R.sub.2 R.sub.3 
NMR 
______________________________________ 
27 (4.24) 
4-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H 195 
(dec.) 
28 (4.25) 
##STR109## 2-OCH.sub.3 
H 200 (dec.) NMR 
29 (4.26) 
4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2 
2-CH.sub.3 
3- 266 
CH.sub.3 
(dec.) 
NMR 
30 (4.27) 
5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-Cl H 198 
(dec.) 
NMR 
31 (4.28) 
4-CONMe(CH.sub.2).sub.2 NEt.sub.2 
2-CF.sub.3 
H 180 
(dec.) 
NMR 
32 (4.29) 
5-CONMe(CH.sub.2).sub.2 NMe.sub.2 
2-OCH.sub.3 
H 208 
NMR 
33 (4.31) (a) 
4-CONH(CH.sub.2).sub.3 N(nBu).sub.2 
2-iPr H 165 
34 (4.40) (a) 
4-CONEt(CH.sub.2).sub.2 NEt.sub.2 
2-iPr H 230 
NMR 
35 (4.33) 
##STR110## 2-iPr H 253 (dec.) 
36 (4.39) 
##STR111## 2-iPr H 167 
______________________________________ 
(a) unsalified compound. 
NMR: 
EXAMPLE 28: 1.3-3.7:mt:26H; 6.55:d:2H; 6.65:s:1H; 6.9:mt:3H; 
7.15-7.5:mt:4H. 
EXAMPLE 29: 1.5-2.3:u.c.:17H; 2.55:s:2H; 2.8:s:9H; 2.95-3.3:u.c.:4H; 
3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7-7.7:u.c.:3H. 
EXAMPLE 30: 1.4-2.3:u.c.:12H; 2.6:bs:2H; 2.7:bs:3H; 2.8:bs:6H; 3.4:u.c.:2H; 
3.6:s:6H; 3.8:u.c.:2H; 6.6:d:2H; 6.82:s:1H; 7.2-7.8:u.c.:5H; 13.0:bs:1H. 
EXAMPLE 31 (DMSO+TFA): 1.2:t:6H; 1.5-2.2:u.c.:12H; 2.5:bs:2H; 2.9:s:3H; 
3.1-3.5:u.c.:9H; 3.6:s:6H; 3.8:u.c.:2H; 6.6:d:2H; 6.8:s:1H; 7.3:u.c.:3H; 
7.7:d:1H; 8:s:1H. 
EXAMPLE 32: 1.6-2.2:u.c.:12H; 2.45:s:6H; 2.60:bs:2H; 2.85:s:3H; 
3.40:u.c.:2H; 3.56:s:3H; 3.60:s:6H; 3.70:u.c.:2H; 6.60:d:2H; 6.78:s:1H; 
7.00:t:1H; 7.20:u.c.:3H; 7.40:bs:1H. 
EXAMPLE 34 (DMSO+TFA): 0.9-1.3:u.c.:15H; 1.6-2.2:u.c.:8H; 2.7:u.c.:1H; 
3.1-3.4:u.c.:8H; 3.6-3.8:u.c.:8H; 6.55:d:2H; 6.75:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 37 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrogen sulphate. 
0.5 g of the compound obtained in EXAMPLE 1' is added to a solution of 0.08 
g of H.sub.2 SO.sub.4 in 5 ml of MeOH, this solution is poured into 150 ml 
of ether cooled to 5.degree. C., and the precipitate formed is drained. 
0.54 g of the expected product is obtained. After recrystallization in 
water, m.p.=212.degree. C. (dec.). After recrystallization in 
2-isopropanol, m.p.=263.degree. C. 
NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.75:s:1H; 7.1-7.5:u.c.:4H. 
The product of EXAMPLE 37 may also be prepared according to the procedure 
below: 
22 ml of concentrated H.sub.2 SO.sub.4 are added slowly and with stirring 
to a suspension of 3.4 g of internal salt of EXAMPLE 1' in 34 ml of water, 
and the mixture is heated to 40' until a change is obtained in the 
appearance of the suspension. The latter is allowed to cool to RT for 4 
hours with stirring, and the product is filtered off and dried to obtain 
3.8 g of expected hydrogen sulphate. 
EXAMPLE 38 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
benzenesulphonate. 
A mixture of 0.5 g of the compound obtained in EXAMPLE 1' and 0.16 g of 
benzenesulphonic acid in 5 ml of MeOH is poured into 75 ml of ether cooled 
to 5.degree. C., and the precipitate formed is drained. 0.06 g of the 
expected product is obtained, m.p.=170.degree. C. (dec.). 
NMR (DMSO+TFA): 1:d:6H; 1.4-2.2:u.c.:14H; 2.45:bs:2H; 2.5-3.2:u.c.:12H; 
3.4:mt:2H; 3.55:s:6H; 6.5:d:2H; 6.65:s:1H; 7-7.4:u.c.:7H; 7.5:mt:2H. 
EXAMPLE 39 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
citrate. 
0.084 g of citric acid is added at RT to a solution of 0.3 g of the 
compound obtained in EXAMPLE 1' in 5 ml of EtOH and 3 ml of DCM, and the 
mixture is left stirring for 2 hours at RT. It is concentrated under 
vacuum and the residue is recrystallized in 2-propanol. 0.26 g of the 
expected product is obtained, m.p.=168.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3.3:u.c.:16H; 
3.3-3.8:s+u.c.:8H; 6.6:d:2H; 6.75:s:1H; 7.1-7.5:u.c.:4H. 
EXAMPLE 40 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
maleate. 
0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of maleic acid are 
dissolved in the heated state in 2.3 ml of 2-propanol, and the mixture is 
concentrated under vacuum. The residue is dissolved in 0.3 ml of EtOH, 
this solution is poured into 30 ml of ether and the precipitate formed is 
drained. 0.04 g of the expected product is obtained, m.p.=260.degree. C. 
(dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.55-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.5:mt:2H; 3.65:s:6H; 6.3:s:2H; 6.6:d:2H; 6.75:s:1H; 7.15-7.45:u.c.:4H. 
EXAMPLE 41 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
(S)-(+)-arginine salt. 
0.1 g of the compound obtained in EXAMPLE 1' and 0.03 g of (S)-(+)-arginine 
are dissolved in the heated state in 4 ml of MeOH, and this solution is 
concentrated to 1 ml and poured into 10 ml of ether cooled to 5.degree. C. 
0.055 g of the expected product is obtained after draining and drying over 
P.sub.2 O.sub.5, m.p.=176.degree. C. (dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:20H; 2.55:bs:2H; 2.6-3.55:u.c.:16H; 
3.65:s:6H; 3.95:t:1H; 6.6:d:2H; 6.75:s:1H; 7.15-7.4:u.c.:4H. 
EXAMPLE 42 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
edisylate. 
A) 1,2-Ethanedisulphonic acid. 
A solution of 3 g of 1,2-ethanedisulphonic acid disodium salt in 10 ml of 
water is introduced slowly into 200 ml of Dowex.RTM. 50 W.times.8 resin, 
and the product is eluted with 200 ml of demineralized water. The eluate 
is diluted by adding EtOH and concentrated under vacuum. 3.35 g of the 
expected product are obtained in the form of an oil which crystallizes at 
RT. 
B) 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid edisylate. 
0.05 g of the compound obtained in EXAMPLE 1' and 0.04 g of the compound 
obtained in step A are dissolved in the heated state in 2 ml of 
2-propanol, and the mixture is concentrated under vacuum. The residue is 
dissolved in 0.3 ml of water and 8 drops of dioxane, and crystallization 
is allowed to take place at RT. The crystallized product formed is 
drained, washed with water and dried at 90.degree. C. under vacuum. 0.042 
g of expected product is obtained, m.p.=266.degree. C. (dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.+s:14H; 
3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.75:s:1H; 7.15-7.45:u.c.:4H. 
EXAMPLE 43 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
sodium salt. 
0.206 g of the compound obtained in EXAMPLE 1' and 0.026 g of sodium 
methylate are dissolved in 1 ml of MeOH and a few drops of DCM, and this 
solution is then poured into 50 ml of ether cooled to 5.degree. C. The 
gelatinous precipitate formed is drained and dried over P.sub.2 O.sub.5 
and under vacuum. 0.15 g of the expected product is obtained, 
m.p.=191.degree. C. 
This compound may also be obtained by following the procedure described 
below. 
0.7 ml of a solution of 0.104 g of NaOH in 10 ml of MeOH is added to a 
solution of 0.1 g of the compound obtained in EXAMPLE 1' in 5 ml of MeOH 
and 4 ml of DCM, and the mixture is concentrated under vacuum. The residue 
is dissolved in 1 ml of 2-propanol, this solution is poured into 75 ml of 
ether cooled to 5.degree. C. and the precipitate formed is drained. 0.005 
g of the expected product is obtained. 
NMR: 1:d:6H; 1.4-2.3:u.c.:20H; 2.55:bs:2H; 2.6:mt:1H; 2.85:d:3H; 3.1 and 
3.4:2mt:4H; 3.6:s:6H; 6.55:s:1H; 6.6:s:2H; 6.95:s:1H; 7-7.35:u.c.:4H. 
The NMR spectrum recorded in the presence of DMSO+TFA is slightly 
different. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.1:mt: 2H; 3.5:mt:6H; 6.6:d:2H; 6.75:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 44 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
fumarate. 
0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of fumaric acid 
are dissolved in 1.5 ml of EtOH, 1.5 ml of DCM and 4 ml of MeOH, and the 
mixture is left stirring for 10 minutes at RT. It is partially 
concentrated under vacuum and crystallization is allowed to take place. 
0.025 g of the expected product is obtained after draining and washing 
with EtOH, m.p.=243.degree. C. 
NMR (DMSO+TFA): 1:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:1ON; 
3.1:mt:2H; 3.4:mt:2H; 3.6:s:6H; 6.5-6.7:d+s:3H; 6.75:s:1H; 
7.1-7.4:u.c.:5H. 
EXAMPLE 45 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
N-methyl-D-glucamine salt. 
A solution of 0.07 g of the compound obtained in EXAMPLE 1' in 5 ml of EtOH 
and 1 ml of DCM is heated s to reflux, 0.02 g of N-methyl-D-glucamine is 
added and the mixture is left stirring for 1 hour 30 minutes at RT. It is 
partially concentrated under vacuum and poured into 15 ml of ether, and 
the precipitate formed is drained. 0.032 g of the expected product is 
obtained, m.p.=90.degree. C. (gum). 
NMR (DMSO+TFA): 1:d:6H; 1.5-2.2:u.c.:14H; 2.5-2.6:mt:5H; 2.6-3.2:u.c.:14H; 
3.2-3.7:u.c.:13H; 3.85:mt:1H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 46 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
diethanolamine salt. 
0.1 g of the compound obtained in EXAMPLE 1' is dissolved in 1.5 ml of EtOH 
and 1.5 ml of DCM, 0.015 g of diethanolamine is added and the mixture is 
left stirring for 30 minutes at RT and left overnight at 5.degree. C. The 
crystallized product formed is drained. 0.03 g of the expected product is 
obtained, m.p.=200.degree. C. (dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3.25:u.c.:16H; 
3.3-3.8:u.c.+s:12H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 47 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
L(+)-tartrate. 
A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.022 g of 
L(+)-tartaric acid in 1.5 ml of EtOH and 1.5 ml of DCM is heated to 
reflux, 8 ml of EtOH are then added and refluxing is continued for 5 
minutes. After cooling to RT, the mixture is partially concentrated under 
vacuum and poured into 10 ml of ether, and the precipitate formed is 
drained. 0.07 g of the expected product is obtained after drying over 
P.sub.2 O.sub.5, m.p.=154.degree. C. (dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.4:u.c.:14H; 2.55:bs:2H; 2.6-3:u.c.:10H; 
3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 4.35:s:2H; 6.6:d:2H; 6.75:s:1H; 
7.15-7.5:u.c.:4H. 
EXAMPLE 48 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
choline salt. 
A solution of 1 ml of DCM containing 0.05 g of the compound obtained in 
EXAMPLE 1' and 0.025 ml of a 45% solution of choline hydroxide in MeOH are 
left stirring for 15 minutes at 35.degree. C., and the mixture is then 
concentrated under vacuum. The residue is triturated in 5 ml of ether and 
the precipitate formed is drained. 0.03 g of the expected product is 
obtained, m.p.=150.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.4-2.2:u.c.:14H; 2.5:bs:2H; 2.4-3:u.c.:1OH; 
3.1:bs:11H; 3.4:mt:2H; 3.5:mt:2H; 3.6:s:6H; 3.8:mt:2H; 6.6:d:2H; 6.7:s:1H; 
7.1-7.4:u.c.:4H. 
EXAMPLE 49 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
isethionate. 
A mixture of 0.1 g of the compound obtained in EXAMPLE 1' in 3 ml of 
2-propanol is heated to reflux, 0.022 g of 83% isethionic acid (obtained 
by elution of sodium isethionate on DOWEX.RTM.50 W.times.8 resin in 
H.sup.+ form) is added and crystallization is allowed to take place 
overnight. The crystallized product formed is drained. 0.055 g of the 
expected product is obtained, m.p.=230.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.55:u.c.:14H; 2.55:bs:2H; 2.6-3.05:u.c.:12H; 
3.1:mt:2H; 3.5:mt:2H; 3.6-3.7:s+mt:8H; 6.6:d:2H; 6.75:s:1H; 
7.15-7.45:u.c.:4H. 
EXAMPLE 50 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
potassium salt. 
A solution of 0.15 g of the compound obtained in EXAMPLE 1' and 0.03 g of 
potassium tert-butylate in 6.5 ml of 2-propanol is left overnight at RT 
and then concentrated under vacuum. The residue is dissolved in 0.5 ml of 
MeOH, and this solution is poured into 25 ml of isopropyl ether cooled to 
-20.degree. C. The precipitate formed is drained and dried over P.sub.2 
O.sub.5 at 80.degree. C. 0.09 g of the expected product is obtained, 
m.p.=222.degree. C. 
This compound may also be obtained by following the procedure described 
below. 
1 ml of a solution of 0.129 g of KOH in 10 ml of MeOH is added to a 
solution of 0.1 g of the compound obtained in EXAMPLE 1' in 4 ml of DCM, 
and the mixture is then concentrated under vacuum. The residue is 
dissolved in 0.5 ml of 2-propanol, this solution is poured into 75 ml of 
ether cooled to 5.degree. C. and the precipitate formed is drained. 0.015 
g of the expected product is obtained. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.1:t:2H; 3.5:t:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H. 
EXAMPLE 51 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
dihydrogen phosphate. 
A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of 
85% orthophosphoric acid in 2 ml of DCM and 3 ml of EtOH is left stirring 
for 1 hour at RT. It is partially concentrated under vacuum and poured 
into 10 ml of ether cooled to 5.degree. C., and the precipitate formed is 
drained. 0.04 g of the expected product is obtained after drying at 
60.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:m:14H; 2.5:se:2H; 2.6-3.3:u.c.:12H; 
3.5:mt:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 52 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
2-naphthalenesulphonate. 
A solution of 0.5 g of the compound obtained in EXAMPLE 1' and 0.16 g of 
2-naphthalenesulphonic acid in 5 ml of MeOH is precipitated with 25 ml of 
ether cooled to 5.degree. C., the precipitate formed is drained and the 
filtrate is kept. The precipitate is dissolved in 2 ml of MeOH, this 
solution is poured into 50 ml of ether cooled to 5.degree. C., the 
precipitate formed is drained and 0.2 g of the expected product is 
obtained. The first filtrate is precipitated with 50 ml of ether cooled to 
5.degree. C., the precipitate formed is drained and 0.27 g of second crop 
of the expected product is obtained. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H; 
3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.6:u.c.:7H; 
7.7:d:1H; 7.8-8.1:u.c.:2H; 8.2:s:1H. 
EXAMPLE 53 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(2-diisopropylaminoethyl)carbamoyl!-2-is 
opropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.2 N(iPr).sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.53 g of the compound obtained in Preparation 4.30 and 2 ml 
of SOCl.sub.2 is left stirring for 4 hours at RT. It is concentrated under 
vacuum, the residue is taken up with DCM and the mixture is evaporated 
under vacuum, the residue is taken up with DCM and the solvent is 
evaporated off under vacuum. The acid chloride thereby obtained is used 
without further treatment. Separately, a mixture of 0.19 g of compound B 
and 0.49 ml of bis(trimethylsilyl)acetamide in 2 ml of acetonitrile is 
heated to reflux under a nitrogen atmosphere for 35 minutes. After cooling 
to RT, a Solution of the acid chloride prepared above in 8 ml of 
acetonitrile is added, and the mixture is left stirring overnight at RT. 
It is evaporated under vacuum, the residue is stirred with 8.8 ml of MeOH, 
8.8 ml of water are added and the mixture is evaporated under vacuum. The 
residue is treated with 1.2N HCl solution and the precipitate formed is 
filtered off. The precipitate is treated with 10 ml of water, the mixture 
is alkalinized to pH 8 by adding 1.3N NaOH solution, and the precipitate 
is drained and washed with water. 0.475 g of the expected product is 
obtained after crystallization in the heated state in 40 ml of 
acetonitrile, m.p.=196.degree.-198.degree. C. 
NMR (DMSO+TFA): 1.1:d:6H; 1.3:d:12H; 1.6-2.2:u.c.:12H; 2.55:u.c.:2H; 
2.7:mt:1H; 3.2:u.c.:2H; 3.5-3.8:u.c.+s:10H; 6.6:d:2H; 6.75:s:1H; 
7.2-7.4:mt:2H; 7.65:d:1H; 7.85:s:1H. 
EXAMPLE 54 
2-5-(2,6-Dimethoxyphenyl)-1-4-N,N-bis(2-diethylaminoethyl)carbamoyl!-2-i 
sopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CON(CH.sub.2 CH.sub.2 NEt.sub.2).sub.2 ; R.sub.2 =2-iPr; 
R.sub.3 =H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.4 g of the compound obtained in Preparation 4.34 and 2.5 ml 
of SOCl.sub.2 is left stirring for 24 hours at RT. It is concentrated 
under vacuum, the residue is taken up with toluene and the solvent is 
evaporated off under vacuum. The acid chloride thereby obtained is used 
without further treatment. Separately, a mixture of 0.18 g of compound B 
and 0.5 ml of bis(trimethylsilyl)acetamide in 4 ml of acetonitrile is 
heated to reflux for 45 minutes. 
After cooling to RT, a solution of the acid chloride prepared above in 3 ml 
of acetonitrile is added, and the mixture is left stirring for 72 hours at 
RT. 3 ml of MeOH are added and the reaction mixture is concentrated under 
vacuum. The residue is dissolved in 3 ml of 1.2N HCl, the solution is 
washed 3 times with AcOEt, the aqueous phase is neutralized to pH 6 by 
adding concentrated NaOH solution, and the gummy product formed is 
separated after settling has taken place. The gummy product is 
chromatographed on silica H, eluting with a DCM/MeOH/NH.sub.4 OH 
(75:25:1.2; v/v/v) mixture. 0.4 g of the expected product is obtained 
after trituration in ether, m.p.=169.degree. C. 
EXAMPLE 55 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(4-piperidyl)-carbamoyl!-2-isopropylphen 
yl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid hydrochloride. 
##STR112## 
AA(OH)=2-carboxy-2-adamantyl). 
A mixture of 0.3 g of the compound obtained in 
EXAMPLE 12, 0.05 g of palladium on charcoal (10% Pd) and 0.033 ml of 
concentrated HCl in 10 ml of MeOH and 4 ml of DMF is hydrogenated for 5 
days at RT and then for 4 days at 50.degree. C., at atmospheric pressure. 
The catalyst is filtered off on Celite.RTM.and the filtrate is evaporated 
under vacuum. The residue is taken up with ether and the crystallized 
product formed is drained. 0.121 g of the expected product is obtained 
after drying over P.sub.2 O.sub.5 at 70.degree. C. under vacuum, 
m.p.=252.degree. C. 
NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c.16H; 2.4-3.5:3mt+bs:7H; 3.6:s:6H; 
3.9-4.15:u.c.:1H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:mt:2H; 7.6:d:1H; 7.8:s:1H. 
EXAMPLE 56 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(1-ethyl-2-pyrrolidinylmethyl)carbamoyl! 
-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
##STR113## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 0.48 g of the compound obtained in Preparation 4.35 and 2 ml of 
SOCl.sub.2, followed by 0.18 g of compound B and 0.46 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.2 g of the 
expected product is obtained after recrystallization in 2-propanol, 
m.p.=212.degree. C. (dec.). 
NMR (DMSO+TFA): 0.9:bs:6H; 1.05:u.c.:3H; 1.3-2.1:u.c.:14H; 2.3:bs:2H; 
2.5:u.c.:1H; 2.9:u.c.:2H; 3.2-3.6:u.c.+s:11H; 6.4:d:2H; 6.5:bs:1H; 
7-7.3:u.c.:2H; 7.45:d:1H; 7.65:bs:1H. 
EXAMPLE 57 
2-2-5-(2,6-Dimethoxyphenyl)-1-4-N-(2,2,6,6-tetramethyl-4-piperidyl)carb 
amoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid. 
##STR114## 
AA(OH)=2-carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 0.43 g of the compound obtained in Preparation 4.36 and 2 ml of 
SOCl.sub.2, followed by 0.15 g of compound B and 0.39 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile. After stirring of 
the reaction mixture overnight at RT, the precipitate formed is drained 
and washed with acetonitrile. The precipitate is taken up in 4 ml of MeOH, 
4 ml of water are added gradually and the mixture is concentrated under 
vacuum. The residue is taken up with 1.2N HCl solution and the precipitate 
is drained after trituration. The precipitate is taken up in 3 ml of 
water, the mixture is alkalinized to pH 9 by adding 1.3N NaOH solution, 
and the precipitate formed is drained and washed with water. 0.24 g of the 
expected product is obtained after drying over P.sub.2 O.sub.5, 
m.p.=270.degree.-272.degree. C. 
NMR (DMSO+TFA): 1.5:d:6H; 1.3:S:6H; 1.4:s:6H; 1.5-2.2:2u.c.:16H; 
2.65:mt:1H; 3.6:s:6H; 4.2-4.4:u.c.:1H; 6.55:d:2H; 6.7: s:1H; 
7.1-7.4:u.c.:2H; 7.6:d:1H; 7.8:s: 1H. 
EXAMPLE 58 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylamino)-1-pyrrolidinyl!carbonyl! 
-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
##STR115## 
AA(OH)=2-carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 0.39 g of the compound obtained in Preparation 4.41 and 2 ml of 
SOCl.sub.2, followed by 0.13 g of compound B and 0.34 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile. After stirring of 
the reaction mixture overnight at RT, some insoluble matter is filtered 
off and the filtrate is concentrated under vacuum. The residue is taken up 
in 5 ml of MeOH, 5 ml of water are added and the mixture is concentrated 
under vacuum. The residue is taken up with 1.2N HCl solution and the 
crystals formed are drained. The crystals are dissolved in water, the 
solution is alkalinized to pH 9 by adding 1.3N NaOH and the precipitate 
formed is drained. 0.07 g of the expected product is obtained after 
recrystallization in acetonitrile, m.p.=175.degree. C. (dec.). 
NMR (DMSO+TFA): 1.0:d:6H; 1.1-1.3:u.c.:6H; 1.5-2.8:4u.c.:17H; 
2.8-4.2:3u.c.+1s:15H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:3H; 7. 5:bs:1H. 
EXAMPLE 59 
2-5-(2,6-Dimethoxyphenyl)-1-4-4-(dimethylamino)-1-piperidyl!carbonyl!-2 
-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
##STR116## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 0.45 g of the compound obtained in Preparation 4.37 and 2 ml of 
SOCl.sub.2, followed by 0.17 g of compound B and 0.43 ml of 
bis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.26 g of the 
expected product is obtained after crystallization in the heated state in 
acetone and then in MEOW, m.p.=200.degree. C. (dec.). 
NMR (DMSO+TFA): 1.05:d:6H; 1.4-2.3:2u.c.:16H; 2.5:bs:2H; 2.7:s+mt:7H; 
2.8-3.8:2u.c.+s:10H; 4.4-4.8:u.c.:1H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:u.c.:4H. 
EXAMPLE 60 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-cyanoethyl)carbamoyl!-2-isop 
ropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 CN; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 3.48 g of the compound obtained in Preparation 4.38 and 20 ml of 
SOCl.sub.2 followed by 1.43 g of compound B and 3.6 ml of 
bis(trimethylsilyl)acetamide in 25 ml of acetonitrile. After stirring of 
the reaction mixture overnight at RT, the mixture is concentrated under 
vacuum, the residue is taken up in 64 ml of MeOH, 64 ml of water are added 
and the mixture is concentrated under vacuum. The residue is taken up in 
1.2N HCl, and the precipitate formed is drained and washed with 1.2N HCl. 
The precipitate is taken up in 5 ml of MeOH, the mixture is heated to 
reflux and allowed to cool to RT and the precipitate is drained. 3.78 g of 
the expected product are obtained after drying over P.sub.2 O.sub.5, 
m.p.=249.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:12H; 2.42-3.0:u.c.:8H; 
3.3-3.75:u.c.:8H; 6.58:d:2H; 6.73:s:1H; 7.1-7.42:u.c.:4H. 
EXAMPLE 61 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-aminopropyl)carbamoyl!-2-iso 
propylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.3 NH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 1 g of the compound obtained in EXAMPLE 60, 10 ml of 20% 
ammonium hydroxide solution and 0.1 g of Raney.RTM. nickel in 20 ml of 
EtOH is hydrogenated for 4 hours at RT and at atmospheric pressure. The 
catalyst is filtered off on Celite.RTM. and washed with EtOH and then with 
MeOH, and the filtrate is partially concentrated. The crystallized product 
formed is drained and the filtrate is concentrated under vacuum. The 
crystallized product and the concentration residue are taken up in 1.2N 
HCl, and the precipitate is drained and washed with 1.2N HCl. The 
precipitate is dissolved in water, the aqueous phase is neutralized to pH 
7 by adding 1.3N NaOH, and the precipitate formed is drained, washed with 
water and dried over P.sub.2 O.sub.5. The precipitate is taken up in 
2-propanol, the mixture is heated to reflux and allowed to cool to RT and 
the precipitate is drained. 0.54 g of the expected product is obtained 
after drying, m.p.=239-241.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.4-3.8:u.c.:8H; 3.5:mt:2H; 
3.64:s:6H; 6.6:d:2H; 6.72:s:1H; 7.1-7.45:u.c.:4H. 
EXAMPLE 62 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-carbamoylethyl)carbamoyl!-2- 
isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 CONH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.2 g of the compound obtained in EXAMPLE 60, 0.12 ml of 30% 
hydrogen peroxide solution in water and 0.18 ml of 6N NaOH in 10 ml of 95% 
EtOH is left stirring for 3 hours 30 minutes at RT. 0.06 ml of the 30% 
hydrogen peroxide solution and 0.06 ml of 6N NaOH are then added, and 
stirring is continued at RT for 1 hour 30 minutes. Some insoluble matter 
is filtered off, water is added to the filtrate, the aqueous phase is 
washed twice with DCM, acidified to pH 3 by adding 1.2N HCl and extracted 
with DCM, the organic phase is dried over MgSO.sub.4 and the solvent is 
evaporated off under vacuum. The residue is chromatographed on silica H, 
eluting with a toluene/MeOH (90:10; v/v) mixture. 0.018 g of the expected 
product is obtained after trituration in ether, 
m.p.=164.degree.-166.degree. C. 
EXAMPLE 63 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(2-carboxyethyl)carbamoyl!-2-is 
opropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.2 CO.sub.2 H; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.4 g of the compound obtained in EXAMPLE 60 and 0.042 ml of 
4-methoxybenzyl alcohol in 3 ml of DCM is cooled to 0.degree. C., a stream 
of HCl gas is bubbled through it for 30 minutes, and the reaction mixture 
is diluted by adding 17 ml of DCM and left stirring for 2 hours at 
0.degree. C. It is concentrated under vacuum, the intermediate imidate 
obtained is taken up in 9 ml of acetone, 2 ml of 1.2N HCl are added and 
the mixture is left stirring for 5 days at RT. 6 ml of DMF and 1 ml of 
1.2N HCl are added, and the mixture is heated to reflux for 3 days and 
left stirring for 72 hours at RT. It is concentrated under vacuum, the 
residue is taken up with DCM, the organic phase is extracted with 
saturated NaHCO.sub.3 solution, the aqueous phase is washed with DCM, 
acidified to pH 1 by adding concentrated HCl solution and extracted with 
DCM, the organic phase is dried over MgSO.sub.4 and the solvent is 
evaporated off under vacuum. 0.03 g of the expected product is obtained 
after trituration in ether followed by drying at 60.degree. C. over 
P.sub.2 O.sub.5, m.p.=166.degree.-168.degree. C. 
NMR (DMSO+TFA): 1:d:6H; 1.5-1.9:u.c.:12H; 1.9-2.8:u.c.:5H; 2.8-3.0:mt:3H; 
3.2-3.6:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.0-7.5:u.c.:4H. 
EXAMPLE 64 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(2-propenyl)-carbamoyl!-2-isopropylpheny 
l!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONHCH.sub.2 CH.dbd.CH.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
53, from 1.49 g of the compound obtained in Preparation 4.42 and 25 ml of 
SOCl.sub.2, followed by 0.65 g of compound B and 1.6 ml of 
bis(trimethylsilyl)acetamide in 10 ml of acetonitrile. After stirring 
overnight at RT, some insoluble matter is filtered off and the filtrate is 
concentrated under vacuum. The residue is taken up in 10 ml of MeOH, 10 ml 
of water are added, and the solid product is drained and washed with MeOH. 
The solid product is taken up in acetonitrile, the mixture is heated to 
reflux and allowed to cool to RT, and the precipitate is drained and dried 
over P.sub.2 O.sub.5. 1.6 g of the expected product are obtained, 
m.p.=304.degree. C. 
NMR: 1.1:d:6H; 1.5-2.2:u.c.:12H; 2.5:bs:2H; 2.65:qt:1H; 3.65:s:6H; 
3.9:t:2H; 5.0-5.2:u.c.:2H; 5.8-6.0:u.c.:1H; 6.6:d:6.7:s:1H; 
7.1-7.4:u.c.:3H; 7.6:d:1H; 7.85:s:1H; 8.7:t:1H. 
EXAMPLE 65 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-trimethylammoniopropyl)carba 
moyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid iodide. 
##STR117## 
AA(OH)=2-carboxy-2-adamantyl). 
A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.04 g of 
methyl iodide in 6 ml of DCM is left Stirring for 24 hours at RT. It is 
concentrated under vacuum, the residue is triturated in ether and the 
precipitate formed is drained. 0.12 g of the expected product is obtained, 
m.p.=222.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.7:qt:1H; 
2.75-3.7:u.c.:22H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H. 
EXAMPLE 66 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(tert-butoxyca 
rbonyl)amino!propyl!-carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino 
!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.3 N(Me)COOtBu; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A solution of 1.17 g of the compound obtained in Preparation 4.43 and 0.3 
ml of triethylamine in 3 ml of DMF is cooled to -10.degree. C., 0.21 ml of 
ethyl chloroformate is added under a nitrogen atmosphere and the mixture 
is left stirring for 15 minutes at -10.degree. C. Separately, a mixture of 
0.77 g of compound B and 2 ml of bis(trimethylsilyl)acetamide in 3 ml of 
DMF is heated at 80.degree. C. for 45 minutes. After cooling to RT, this 
solution is added to the solution of mixed anhydride prepared above, and 
the mixture is left stirring for 3 days at RT. Some insoluble matter is 
filtered off and the filtrate is concentrated under vacuum. The residue is 
taken up with 32 ml of MeOH, 32 ml of water are added gradually and the 
mixture is concentrated under vacuum. The residue is taken up with water, 
and the crystallized product formed is drained, washed with water and 
dried. The crystals are taken up with DCM, some insoluble matter is 
filtered off and the filtrate is chromatographed on silica, eluting with a 
DCM/MeOH mixture from (100:0.5; v/v) to (100:2.5; v/v). 1 g of the 
expected product is obtained after trituration in pentane, 
m.p.=118-120.degree. C. 
EXAMPLE 67 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-methylaminopropyl)carbamoyl! 
-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.3 NHMe; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.6 g of the compound obtained in EXAMPLE 66 and 4.2 ml of 
concentrated HCl solution in 2.7 ml of MeOH and 1.8 ml of water is left 
stirring for 20 minutes at RT. EtOH is added and the reaction mixture is 
concentrated under vacuum. The residue is taken up with EtOH and the 
solvent is evaporated off under vacuum. The residue is taken up with 
ether, and the precipitate formed is drained and washed with ether. 0.51 g 
of the expected product is obtained after drying under vacuum at 
60.degree. C., m.p.=240.degree. C. 
NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.4:u.c.:14H; 2.6:d:3H; 2.7:mt:1H; 
2.8-3.6:u.c.+s:7H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.45:u.c.:4H. 
EXAMPLE 68 
2-5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenylsulphonylamino)-2-isopropylp 
henyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
##STR118## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.92 g of the compound obtained in Preparation 4.44 and 7 ml 
of SOCl.sub.2 in 7 ml of DCM is heated for 1 hour at 40.degree. C. It is 
concentrated under vacuum, and the acid chloride thereby obtained is used 
without further treatment. Separately, a mixture of 0.54 g of compound B 
and 1.35 ml of bis(trimethylsilyl)acetamide in 5 ml of acetonitrile is 
heated to reflux for 1 hour. After cooling to RT, this solution is added 
to the acid chloride prepared above, 0.25 ml of triethylamine is added and 
the mixture is left stirring for 2 hours at RT. It is concentrated under 
vacuum, the residue is taken up with 10% HCl solution, the mixture is 
extracted with DCM, the organic phase is dried over Na.sub.2 SO.sub.4 and 
the solvent is evaporated off under vacuum. The residue is chromatographed 
on silica H, eluting with a DCM/MeOH/H.sub.2 O (100:3:0.5; v/v/v) mixture. 
0.9 g of the expected product is obtained. 
NMR (DMSO+TFA): 0.85:d:6H; 1.52-2.25:u.c.:12H; 2.34:s:3H; 
2.45-2.06:u.c.:3H; 3.55:s:6H; 6.55:d:2H; 6.65:s:1H; 6.84:dd:1H; 
6.95-7.05:u.c.:2H; 7.23-7.36:u.c.:3H; 7.58:d:2H. 
EXAMPLE 69 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylamino)propanoylamino!-2-isopropy 
lphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
68, from 0.27 g of the compound obtained in Preparation 4.46 in 5 ml of 
SOCl.sub.2 and 5 ml of DCM on the one hand, and on the other hand 0.155 g 
of compound B and 0.39 ml of bis(trimethylsilyl)acetamide in 2 ml of 
acetonitrile and 0.14 ml of triethylamine. 0.13 g of the expected product 
is obtained, m.p.=180.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.25:t:6H; 1.55-2.22:u.c.:12H; 2.5-2.72:u.c.:3H; 
2.85:t:2H; 3.2:qr:4H; 3.4:mt:2H; 3.68:s:6H; 6.6:d:2H; 6.72:s:1H; 
7.15:d:1H; 7.25-7.5:u.c.:2H; 7.58:d:1H. 
EXAMPLE 70 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-acetyl-N-(3-diethylaminopropyl)amino!-2- 
isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-N(COMe)(CH.sub.2).sub.3 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
68, from 0.38 g of the compound obtained in Preparation 4.48 and 3 ml of 
SOCl.sub.2 in 3 ml of DCM, followed by 0.164 g of compound B and 0.36 ml 
of bis(trimethylsilyl)acetamide in 2 ml of acetonitrile and 0.075 ml of 
triethylamine. 0.24 g of the expected product is obtained, 
m.p.=220.degree. C. 
NMR (DMSO+TFA): 1.0:d:6H; 1.5:t:6H; 1.45-2.2:u.c.:17H; 2.5-2.72:u.c.:3H; 
2.9-3.15:u.c.:6H; 3.6:s:6H; 3.7:t:2H; 6.59:d:2H; 6.74:s:1H; 
7.15-7.42:u.c.:5H. 
EXAMPLE 71 
2-5-(2,6-Dimethoxyphenyl)-1-4-(3-diethylamino-propyl)amino!-2-isopropylp 
henyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-NH(CH.sub.2).sub.3 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.2=of the compound obtained in EXAMPLE 70 and 1 ml of 
concentrated HCl in 5 ml of water and 5 ml of EtOH is heated to reflux for 
16 hours. Water is added, the pH is adjusted to 5 by adding 10% NaOH and 
the precipitate is drained. 0.145 g of the expected product is obtained, 
m.p.=180.degree. C. 
NMR (DMSO+TFA): 1.05:d:6H; 1.19:t:6H; 1.4-2.2:u.c.:14H; 2.4-2.63:u.c.:3H; 
2.98-3.3:u.c.:8H; 3.62:s:6H; 6.5-6.85:u.c.:5H; 7.05:d:1H; 7.3:t:1H. 
EXAMPLE 72 
2-5-2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1-4-N-methyl-N-(3-dimethy 
laminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adam 
antane-carboxylic acid hydrochloride. 
##STR119## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 3.87 g of the compound obtained in Preparation 4.49 and 2.4 ml 
of SOCl.sub.2 in 50 ml of DCM is heated at 60.degree. C. for 8 hours. It 
is concentrated under vacuum, the residue is taken up with toluene and the 
solvent is evaporated off under vacuum. The acid chloride thereby obtained 
is used without further treatment. Separately, a mixture of 1.27 g of 
compound B and 2.65 g of bis(trimethylsilyl)acetamide in 80 ml of 
acetonitrile is heated at 80.degree. C. for 3 hours. A solution of the 
acid chloride prepared above in 80 ml of acetonitrile is then added and 
the mixture is heated at 60.degree. C. for 3 hours. Some insoluble matter 
is filtered off and the filtrate is concentrated under vacuum. The residue 
is taken up in 16 ml of MeOH, 16 ml of water is added and the mixture is 
concentrated under vacuum. The residue is taken up with water, the mixture 
is extracted with DCM, the organic phase is dried over Na.sub.2 SO.sub.4 
and the solvent is evaporated off under vacuum. The residue is 
chromatographed on silica H, eluting with a DCM/MeOH/H.sub.2 O (100:5:0.5; 
v/v/v) mixture. 2.1 g of the expected product are obtained. 
EXAMPLE 73 
2-5-(2-Hydroxy-6-methoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)ca 
rbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxyli 
c acid hydrochloride. 
(I: R.sub.1 =4-CONMe(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =H; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 1 g of the compound obtained in EXAMPLE 72 and 20 ml of MeOH 
and 20 ml of HCl is heated at 60.degree. C. for 5 hours. It is 
concentrated under vacuum, the residue is taken up with toluene and the 
mixture is concentrated under vacuum. The residue is chromatographed on 
silica H, eluting with a DCM/MeOH (90:10; v/v) mixture and then with a 
DCM/MeOH/NH.sub.40 H (80:20:2; v/v/v) mixture. 0.6 g of the expected 
product is obtained, m.p. &gt;250.degree. C. 
EXAMPLE 74 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylaminopropanoyl)amino!-2-methylph 
enyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-Me; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A) 
2-5-(2,6-Dimethoxyphenyl)-1-(2-methyl-4-nitrophenyl)-3-pyrazolylcarbonyla 
mino!-2-adamantanecarboxylic acid. 
This compound is prepared according to the procedure described in EXAMPLE 
68, from 3.2 g of the compound obtained in Preparation 4.50 and 20 ml of 
SOCl.sub.2 in 40 ml of DCM, followed by 2.4 g of compound B and 6 ml of 
bis(trimethylsilyl)acetamide in 15 ml of acetonitrile and then 1.1 ml of 
triethylamine. After stirring overnight at RT, the mixture is concentrated 
under vacuum, the residue is taken up in an acetone/water mixture, and the 
precipitate formed is drained and dried. The precipitate is 
chromatographed on silica H, eluting with a DCM/MeOH/H.sub.2 O (100:3:0.2; 
v/v/v) mixture. 4.3 g of the expected product are obtained, 
m.p.=150.degree. C. 
NMR: 1.6-2.2:u.c.:12H; 2.25:s:3H; 2.62:mt:2H; 3.63:s:6H; 6.68:d:2H; 
6.88:s:1H; 7.03-7.43:u.c.:2H; 7.58:s:1H; 8.05:dd:1H; 8.28:d:1H; 
12.4:bs:1H. 
B) 
2-5-(2,6-Dimethoxyphenyl)-1-(4-amino-2-methylphenyl)-3-pyrazolylcarbonyla 
mino!-2-adamantanecarboxylic acid. 
A mixture of 4.2 g of the compound obtained in the preceding step and 0.5 g 
of Raney.RTM. nickel in 40 ml of MeOH and 2 ml of DMF is hydrogenated for 
4 hours at RT and at atmospheric pressure. The catalyst is filtered off 
and the filtrate is concentrated under vacuum. The residue is taken up 
with ether and the precipitate formed is drained. 3.37 g of the expected 
product are obtained, m.p.=205.degree. C. 
NMR: 1.42-2.1:u.c.:15H; 2.52:mt:2H; 3.57:s:6H; 5.1:bs:2H; 6.1:dd:1H; 
6.22:d:1H; 6.42-6.68:u.c.:4H; 7.17-7.25:u.c.:2H. 
C) 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylaminopropanoyl)amino!-2-methylp 
henyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
A mixture of 0.3 ml of 3-diethylaminopropanoic acid hydrochloride and 3 ml 
of SOCl.sub.2 in 6 ml of DCM is heated at 35.degree. C. for 45 minutes and 
then concentrated under vacuum. The acid chloride thereby obtained is 
added to a solution of 0.87 g of the compound obtained in the preceding 
step and 0.157 ml of triethylamine in 5 ml of DCM. The mixture is 
concentrated under vacuum and the residue is chromatographed on silica H, 
eluting with a DCM/MeOH/H.sub.2 O (100:5:0.5; v/v/v) mixture. 0.5 g of the 
expected product is obtained, m.p.=190.degree. C. 
NMR: 1.28:t:6H; 1.6-2.22:u.c.:15H; 2.5-3.2:u.c.:10H; 3.6:s:6H; 6.63:d:2H; 
6.75:s:1H; 7.05:d:1H; 7.28-7.48:u.c.:3H; 7.55:d:1H; 10.18:s:1H. 
EXAMPLE 75 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(1-piperidyl)propanoyl!amino!-2-methylp 
henyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
##STR120## 
AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
74, step C, from 0.1 g of 3-(1-piperidyl)propanoic acid and 1 ml of 
SOCl.sub.2 in 2 ml of DCM, followed by 0.337 g of the compound obtained in 
step B of EXAMPLE 74 and 0.17 ml of triethylamine in 5 ml of DCM. 0.2 g of 
the expected product is obtained, m.p.=240.degree. C. 
NMR: 1.22-2.1:u.c.:21H; 2.22-2.38:u.c.:10H; 3.58:s:6H; 6.5:d:2H; 6.6:s:1H; 
6.9:d:1H; 7.18-7.3:u.c.:3H; 7.38:d:1H; 10.1:s:1H. 
EXAMPLE 76 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylamino)propanoylamino!-2-isobutyl 
phenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iBu; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
68, from, on the one hand 0.15 g of the compound obtained in Preparation 
4.52 and 2 ml of SOCl.sub.2 in 2 ml of DCM, and on the other hand 0.084 g 
of compound B and 0.21 ml of bis-(trimethylsilyl)acetamide in 2 ml of 
acetonitrile and 0.79 ml of triethylamine. 0.014 g of the expected product 
is obtained, m.p.=180-200.degree. C. 
NMR: 0.75:d:6H; 1.15:t:6H; 1.4-2.25:u.c.:15H; 2.5:s:2H; 2.8:t:2H; 
3.1:qr:4H; 3.3:t:2H; 3.55:s:6H; 6.5:d:2H; 6.6:s:1H; 6.8-7.6:u.c.:5H; 
10.3:s:1H. 
EXAMPLE 77 
2-5-(2,6-Dimethoxyphenyl)-1-4-3-(diethylamino)propanoylamino!-2-cyclopen 
tylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
##STR121## 
AA(OH)=2-carboxy-2-adamantyl). 
This compound is prepared according to the procedure described in EXAMPLE 
68, from, on the one hand, 0.32 g of the compound obtained in Preparation 
4.54 and 2 ml of SOCl.sub.2 in 5 ml of DCM, and on the other hand 0.17 g 
of compound B and 0.42 ml of bis-(trimethylsilyl)acetamide in 2 ml of 
acetonitrile and 0.154 ml of triethylamine. 0.035 g of the expected 
product is obtained, m.p.=175-185.degree. C. 
NMR (DMSO+TFA): 1.1-2.55:u.c.:26H; 2.5-2.75:u.c.:5H; 3.15:mt:4H; 
3.35:mt:2H; 3.62:s:6H; 6.55:d:2H; 6.65:s:1H; 7.03:d:1H; 7.25:t:1H; 
7.35:dd:1H; 7.55:d:1H. 
EXAMPLE 78 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-(2-diethylaminoethyl)carbamoyl!-3-isopro 
pylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-CONH(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =3-iPr; R.sub.3 =H; 
R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.36 g of the compound obtained in Preparation 4.55 and 5 ml 
of SOCl.sub.2 in 15 ml of chloroform is left stirring overnight at RT. It 
is concentrated under vacuum, the residue is taken up with toluene and the 
mixture is concentrated under vacuum. The acid chloride thereby obtained 
is used without further treatment. Separately, a mixture of 0.123 g of 
compound B and 0.315 ml of bis(trimethylsilyl)acetamide in 10 ml of 
acetonitrile is heated to reflux for 30 minutes. This solution is added to 
a solution of the acid chloride prepared above in 15 ml of acetonitrile, 
and the mixture is heated to reflux for 3 hours. It is concentrated under 
vacuum, the residue is taken up in 15 ml of MeOH and 5 ml of water and the 
mixture is left stirring for 2 hours at RT. It is concentrated under 
vacuum, the residue is extracted with chloroform, the organic phase is 
washed with water and dried over Na.sub.2 SO.sub.4 and the solvent is 
evaporated off under vacuum. 0.35 g of the expected product is obtained 
after crystallization in chloroform, m.p.=210.degree. C. (dec.) (the 
product crystallizes with 1 mol of chloroform). 
EXAMPLE 79 
2-5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoacetylamino)-5,6,7,8-tetrahydro-1-n 
aphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-NHCOCH.sub.2 NH.sub.2 ; R.sub.2, R.sub.3 =--(CH.sub.2).sub.4 
-; .sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A) 
2-5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetrahydro-1-naphthyl)-3-pyr 
azolylcarbonylamino!-2-adamantanecarboxylic acid. 
This compound is prepared according to the procedure described in EXAMPLE 
15, from 4 9 of the compound obtained in Preparation 4.56 and 20 ml of 
SOCl.sub.2 in 20 ml of DCM, followed by 2.74 g of compound B and 6.86 ml 
of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile and 0.8 ml of 
triethylamine. After concentration under vacuum, the residue is taken up 
in EtOH and the precipitate formed is drained. The precipitate is taken up 
in MeOH, drained and washed with ether. 5.3 g of the expected product are 
obtained. 
NMR (DMSO+TFA): 1.5-2.25:u.c.:16H; 2.42-2.65:u.c.:4H; 2.8:mt:2H; 3.6:s:6H; 
6.61:d 2H; 6.75:s:1H; 7.06:d:1H; 7.3:t:1H; 7.4: s:1H; 7.65:d:1H. 
B) 
2-5-(2,6-Dimethoxyphenyl)-1-(4-amino-5,6,7,8-tetrahydro-1-naphthyl)-3-pyr 
azolylcarbonylamino!-2-adamantanecarboxylic acid. 
A mixture of 3 g of the compound obtained in the preceding step and 0.5 g 
of Raney.RTM. nickel in 200 ml of DMF is hydrogenated at RT and at 
atmospheric 2o pressure. The catalyst is filtered off and the filtrate is 
concentrated under vacuum. The residue is taken up with water and the 
precipitate formed is drained. 2.16 g of the expected product are obtained 
after drying. 
NMR (DMSO+TFA): 1.42-2.2:u.c:16H; 2.3-2.8:u.c.:6H; 3.6:s:6H; 6.55:d:2H; 
6.7:s: 1H; 6.98:d:1H; 7.12:d:1H; 7.25:t:1H. 
C) 
2-5-(2,6-Dimethoxyphenyl)-1-4-2-(tert-butoxy-carbonylamino)acetylamino! 
-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarbo 
xylic acid. 
A mixture of 0.3 g of the compound obtained in the preceding step and 0.258 
ml of bis(trimethylsilyl)-acetamide in 2 ml of toluene is heated for 1 
hour at 60.degree. C. After cooling to RT, 0.64 ml of Boc-glycine 
N-carboxy anhydride and 0.006 ml of N-methylmorpholine are added and the 
mixture is left stirring overnight at RT. A pH 4 buffer solution is added, 
the mixture is extracted with AcOEt, the organic phase is dried over 
Na.sub.2 SO.sub.4 and the solvent is evaporated off under vacuum. The 
residue is chromatographed on silica H, eluting with a DCM/MeOH mixture 
from (100:1; v/v) to (100:5; v/v). 0.14 g of the expected product is 
obtained. 
NMR (DMSO+TFA): 1.32:s:9H; 1.45-2.12: u.c.:16H; 2.35-2.6:u.c.:6H; 
3.55:s:6H; 3.65: s:2H; 6.5:d:2H; 6.62:s:1H; 6.83:d:1H; 7.13-7.3:u.c.:3H. 
D) 
2-5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoacetylamino)-5,6,7,8-tetrahydro-1- 
naphthyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid 
hydrochloride. 
A mixture of 0.14 g of the compound obtained in the preceding step and 5 ml 
of concentrated HCl in 5 ml of MeOH is left stirring for 30 minutes at RT. 
Water is added, and the precipitate formed is drained and dried. 0.06 g of 
the expected product is obtained, m.p.=220.degree. C. 
NMR: 1.59-2.5:u.c.:16H; 2.42-2.75:u.c.: 6H; 3.7:s:6H; 3.88:mt:2H; 
6.68:d:2H; 6.75: s:1H; 6.95:d:1H; 7.2-7.48:u.c.:3H; 8.2:mt: 1H; 9.85:s:1H; 
12.4:bs:1H. 
EXAMPLE 80 
2-5-(2,6-Dimethoxyphenyl)-1-4-(3-diethylaminopropanoyl)amino!-5,6,7,8-te 
trahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A mixture of 0.16 g of 3-diethylaminopropanoic acid hydrochloride and 2 ml 
of SOCl.sub.2 in 2 ml of DCM is heated at 40.degree. C. for 1 hour. It is 
concentrated under vacuum, the residue is taken up with DCM and the 
mixture is added at RT to a solution of 0.5 g of the compound obtained in 
step B of EXAMPLE 79 and 0,124 ml of triethylamine in 3 ml of DCM. After 
stirring over-night at RT, water is added, the mixture is extracted with 
DCM, the organic phases are dried over MgSO.sub.4 and the solvent is 
evaporated off under vacuum. The residue is chromatographed on silica H, 
eluting with a DCM/MeOH (100:3; v/v) mixture; 0.11 g of the expected 
product is obtained. 
NMR (DMSO+TFA): 1.21:t:6H; 1.41-2.2: u.c.:16H; 2.35-2.7:u.c.:6H; 2.84:t:2H; 
3.01-3.12:u.c.:4H; 3.35:t:2H; 3.6:s:6H; 6.55:d 2H; 6.7:s:1H; 6.9:d:1H; 
7.12-7.3:u.c.:2H. 
EXAMPLE 81 
2-5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoethylsulphonylamino)-5,6,7,8-tetrah 
ydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
(I: R.sub.1 =4-NHSO.sub.2 (CH.sub.2).sub.2 NH.sub.2 ; R.sub.2, R.sub.3 
=--(CH.sub.2).sub.4 -; R.sub.4 =Me; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
A) 2-Phthalimidoethanesulphonic acid potassium salt. 
This compound and the one of step B are prepared according to J. Am. Chem. 
Soc., 1947, 69, 1393-1401. 
A mixture containing 30 g of taurine, 25 g of potassium acetate and 90 ml 
of acetic acid is brought to reflux for 10 minutes and 37.8 g of phthalic 
anhydride are then added. The mixture is heated to reflux for two and a 
half hours and then filtered, and the product is washed with AcOH and then 
with 2-propanol; it is rinsed with ether and then dried under vacuum to 
obtain 59.14 g of the expected product. 
B) 2-Phthalimidoethanesulphonyl chloride. 
60 g of the compound obtained in step A in 300 ml of toluene are heated to 
reflux for 1 hour in the presence of 30.7 g of phosphorus pentachloride. 
30.7 g of phosphorus pentachloride are added again and refluxing is 
maintained for 90 minutes. 280 g of ice are added to the reaction medium, 
the mixture is stirred, and the insoluble matter is filtered off and then 
washed with ice-cold water. The residue is dried over P.sub.2 O.sub.5 and 
then recrystallized in dichloroethane to obtain 32 g of the expected 
product, m.p.=160.degree. C. 
C) 
2-5-(2,6-Dimethoxyphenyl)-1-4-(2-phthalimidoethylsulphonyl)-5,6,7,8-tetr 
ahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid. 
A mixture containing 0.5 g of the compound obtained in EXAMPLE 79, step B, 
0.43 ml of bis(tri-methylsilyl)acetamide and 5 ml of acetonitrile is left 
stirring at 70.degree. C. for 1 hour. The mixture is allowed to return to 
RT, and 0.63 g of the compound obtained in step B and 0.30 ml of 
triethylamine are then added. After 2 hours with stirring at RT, the 
mixture is acidified with 10% HCl solution. The mixture is filtered and 
the residue is then dried over P.sub.2 O.sub.5 to obtain 0.9 g of the 
expected product in crude form. It is recrystallized in 100% EtOH and 
decolorized on animal charcoal in DCM. The product obtained is 
chromatographed on silica H, eluting with a DCM/MeOH/H.sub.2 O (100:2:0.2; 
v/v/v) mixture to obtain 0.28 g of the expected product. 
NMR (DMSO+TFA): 1.45-2.15:u.c.:16H; 2.4-2.6:u.c.:4H; 2.75:mt:2H; 3.48:s:6H; 
3.95-4.15:u.c.:4H; 6.46:d:1H; 6.75:s:1H; 6.9:d 1H; 7.1-7.3:u.c.:2H; 
7.7-7.85:u.c.:4H. 
D) 
2-5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoethylsulphonylamino)-5,6,7,8-tetra 
hydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
A mixture containing 0.24 g of the compound obtained in the preceding step, 
2 ml of 95% EtOH and 23=1 of hydrazine hydrate is heated to reflux for 2 
hours. The reaction medium is diluted with MeOH, the crystals are then 
filtered off and heated to reflux in water and the mixture is filtered in 
the heated state. The crystals obtained are dried over P.sub.2 O.sub.5. 
They are redissolved in MeOH, ethereal hydrogen chloride is added, the 
mixture is evaporated to dryness and the residue is then taken up with 
ether and pentane. The mixture is filtered to obtain 60 mg of the expected 
product. 
NMR (DMSO+TFA): 1.48-2.18:u.c.:16H; 2.18-2.62:u.c.:4H; 2.7:mt:2H; 
3.19:mt:2H; 3.41:mt:2H; 3.62:s:6H; 6.58:d:1H; 6.7:s: 1H; 6.82:d:1H; 
7.08:d:1H; 7.28:t:1H; 7.39: s:1H. 
EXAMPLE 82 
(R)-2-Cyclohexyl-2-5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylami 
nopropyl)carbamoyl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!acetic 
acid. 
(I: R.sub.1 =4-CON(Me)(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=(R)-(.alpha.-carboxy)cyclohexylmethyl). 
1.2 g of sodium hydroxide in 20.2 ml of water and 1.62 g of 
cyclohexyl-D-glycine trifluoroacetate are mixed. 1.58 g of acid chloride 
prepared in EXAMPLE 1, step A in 40 ml of anhydrous THF are added 
dropwise, and the mixture is left stirring for 48 hours at RT. The medium 
is concentrated, ice is added and the pH is adjusted to 7 by adding 
concentrated HCl. The mixture is filtered, and the residue is washed with 
water and then with pentane and dried under vacuum. The product is ground 
and then stirred in a water/DCM mixture. The resulting mixture is 
filtered, the aqueous phase is then extracted with DCM and the organic 
phase is dried over Na.sub.2 SO.sub.4. The residue is concentrated, and 
the product is stirred in pentane and filtered off again. 380 mg of the 
expected product are obtained, m.p.=160.degree. C. 
EXAMPLE 83 
(S)-2-Cyclohexyl-2-5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylami 
nopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!acetic acid 
hydrochloride. 
(I: R.sub.1 =4-CON(Me)(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=(S)-(.alpha.-carboxy)cyclohexylmethyl). 
A mixture containing 0.57 g of (S)-cyclohexylglycine and 1.49 g of 
bis(trimethylsilyl)acetamide in 39 ml of acetonitrile is heated at 
80.degree. C. for 3 hours, and a solution of 1.93 g of the acid chloride 
prepared in EXAMPLE 1, step A, in 39 ml of acetonitrile is added dropwise. 
After 3 hours at 60.degree. C., the mixture is allowed to return to RT and 
is then filtered, and the filtrate is concentrated. 8 ml of MeOH and 3 ml 
of water are added to the residue and the mixture is left stirring for 30 
minutes. 5 ml of water are added and the mixture is concentrated. The oil 
formed is taken up in DCM, and the organic phase is washed with saturated 
NaCl solution, dried over Na.sub.2 SO.sub.4 and concentrated. The residue 
is taken up in isopropyl ether and filtered to obtain 1.12 g of the 
expected compound, m.p.=160.degree. C. 
EXAMPLE 84 
9-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!bicyclo3.3.1!nonane-9-carbo 
xylic acid. 
(I: R.sub.1 =4-CON(Me)(CH.sub.2).sub.3 NMe.sub.2 ; R.sub.2 =2-iPr; R.sub.3 
=H; R.sub.4 =CH.sub.3 ; AA(OH)=9-carboxybicyclo3.3.1!nonan-9-yl). 
585 mg of 9-aminobicyclo3.3.1!nonane-9-carboxylic acid and 1.5 ml of 
bis(trimethylsilyl)-acetamide in 39 ml of acetonitrile are mixed, and the 
mixture is heated at 80.degree. C. for 3 hours. 1 equivalent of the acid 
chloride prepared in EXAMPLE 1, step A in 39 ml of acetonitrile is added 
dropwise, and the mixture is heated at 60.degree. C. for 3 hours. After 12 
hours at RT, the insoluble matter is filtered off, the filtrate is then 
concentrated and the residue is stirred thereafter with 8 ml of MeOH and 8 
ml of water. The mixture is concentrated again and the residue is then 
extracted with DCM to obtain 900 mg of the expected product, 
m.p.=160.degree. C. 
EXAMPLE 85 
2-5-(2,6-Dimethoxyphenyl)-1-5-(3-diethylaminopropanoyl)amino!-2-isopropy 
lphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylic acid. 
(I: R.sub.1 =5-NHCO(CH.sub.2).sub.2 NEt.sub.2 ; R.sub.2 =2-iPr; R.sub.3 =H; 
R.sub.4 =CH.sub.3 ; AA(OH)=.sub.2 -carboxy-2-adamantyl). 
The acid chloride is prepared from 0.95 g of the compound of Preparation 
4.57 in 5 ml of thionyl chloride and 15 ml of DCM by heating to reflux for 
1 hour followed by evaporation. 
A mixture of 0.55 g of compound B, 1.37 ml of bis(trimethylsilyl)acetamide 
in 5 ml of acetonitrile and the acid chloride in solution in 5 ml of DCM 
and 0.5 ml Of triethylamine is heated to reflux for 1 hour. After 2 hours 
of stirring at RT, the mixture is evaporated to dryness and the residue is 
then stirred with 10 ml of water, the mixture is extracted with DCM, the 
organic phase is dried over MgSO.sub.4 and evaporated to dryness and the 
residue is crystallized in acetone to obtain 0.55 g of the expected 
product. 
NMR (DMSO+TFA): 0.8-1.35:u.c.:12H; 1.5-2.4:u.c.:12H; 2.4-2.6:u.c.:3H; 
2.8:t:2H; 3.15:qr:4H; 3.3:t:2H; 3.5:s:6H; 6.55:d: 2H; 6.65:s:1H; 
7.15-7.4:u.c.:3H; 7.75:d:1H. 
EXAMPLE 86 
Internal salt of 
2-5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid. 
The compound may also be prepared from the compound of EXAMPLE 61 according 
to the following procedure. 
A mixture containing 0.2 g of the compound of EXAMPLE 61, 0.33 ml of formic 
acid and 0.11 ml of formaldehyde is heated at 100.degree. C. for 30 
minutes. After 2 hours at RT, 1 ml of 2N HCl is added, and DCM and 
methanol are then added in order to dissolve the gum formed. The solvents 
are evaporated off, the residue is taken up with water, and the mixture is 
then neutralized with 1.3N sodium hydroxide to pH 7 while cooling the 
medium in ice. The mixture is filtered, and the residue is rinsed with 
water and then dried over P.sub.2 O.sub.5 to obtain 0.13 g of the expected 
product. 
EXAMPLE 87 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoy 
l!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid 
hydrochloride. 
Another method of preparation of the compound of EXAMPLE 1 is described 
below. 
A) 2-(Benzyloxycarbonylamino)-2-adamantanecarboxylic acid. 
1.015 g of 2-amino-2-adamantanecarboxylic acid and 6 ml of 
bis(trimethylsilyl)acetamide in 10 ml of DCM is heated to reflux for one 
and a half hours. 0.75 ml of benzyloxycarbonyl chloride is added and the 
mixture is heated at 50.degree. C. for 15 minutes. The reaction medium is 
cooled to -70.degree. C., decomposition is then effected by adding ice and 
the mixture is extracted with AcOEt. The organic phase is washed with 
water (twice) and with brine, dried over MgSO.sub.4 and evaporated under 
vacuum. The product crystallizes in hexane; 1.164 g are obtained. 
NMR (DMSO+TFA): 1.5:d:2H; 1.8:u.c.: 6H; 2:t:4H; 2.4-2.5:u.c.:2H; 5:s:2H; 
7.3: bs:5H. 
B) 2-(Benzyloxycarbonylamino)-2-adamantanecarboxylic acid tert-butyl ester. 
1.164 g of the compound of the preceding step are dissolved in 15 ml of 
DCM, 100 mg of hydrated paratoluenesulphonic acid are added, the mixture 
is then cooled to -78.degree. C. and a solution of isobutylene in 15 ml of 
DCM is added. The mixture is allowed to return to RT and is stirred for 24 
hours. 
50 .mu.l of concentrated sulphuric acid are added to dissolve the solid, 
after 5 hours the medium is cooled, saturated NaHCO.sub.3 solution is then 
added, and the organic phase is dried over MgSO.sub.4 and evaporated under 
vacuum. The residue is chromatographed on silica, eluting with a 
hexane/AcOEt (80:20; v/v) mixture, and 612 mg of the expected compound are 
obtained. 
NMR (CDCl.sub.3): 1.4:s:9H; 1.5-1.9:u.c.: 8H; 2:t:4H; 2.5:s:2H; 4.9:s:1H; 
5.1:s: 2H; 7.2-7.4:u.c.:5H. 
C) 2-Amino-2-adamantanecarboxylic acid tert-butyl ester hydrochloride. 
600 mg of the product of the preceding step are dissolved in 40 ml of EtOH, 
150 .mu.l of concentrated HCl and then 80 mg of Pd/C are added and the 
medium is then hydrogenated. After 1 hour, the catalyst is filtered off 
and the solvent is evaporated off to obtain 503 mg of the expected 
product. 
NMR (CD3OD):1.6:s:9H; 1.8-2:u.c.:8H; 2-2.2:u.c.:4H; 2.4:s:2H. 
D) 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(benzyloxycarbon 
yl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylic acid 
methyl ester. 
0.33 g of the compound of Preparation 3.57 is dissolved in 20 ml of 
methanolic hydrogen chloride. After 72 hours with stirring, the solvents 
are evaporated off. The hydrochloride obtained is dissolved in 5 ml of 
DCM, and 0.5 ml of triethylamine and 150 .mu.l of benzyloxycarbonyl 
chloride are then added. After one hour, the reaction medium is 
concentrated under vacuum I.sub.5 and the residue is then chromatographed 
on silica, eluting with a toluene/acetone (80:20 to 70:30; v/v) mixture. 
252 mg of the expected product are obtained. 
E) 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(benzyloxycarbon 
yl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylic acid. 
The compound obtained in the preceding step (252 mg) is dissolved in 2.5 ml 
of dioxane and 90 .mu.l of aqueous potassium hydroxide solution (1 g/ml). 
After 24 hours of stirring, the medium is acidified with 1 ml of 
concentrated HCl. It is extracted with AcOEt, and the organic phase is 
then dried over MgSO.sub.4 to obtain 236 mg of the expected compound. 
F) 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methyl-N'-(benzyloxycarbon 
yl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-a 
damantanecarboxylic acid tert-butyl ester. 
The acid obtained in the preceding step is dissolved in 2 ml of 
acetonitrile, 0.5 ml of carbon tetrachloride and 158 mg of 
triphenylphosphine are added and the mixture is left stirring for 2 hours. 
110 mg of the compound prepared in step C and 100 .mu.l of triethylamine 
are added to the acid chloride thus formed. Triethylamine hydrochloride 
precipitates and the mixture is left stirring for 15 minutes. Water is 
added and the mixture is then extracted with DCM; the organic phase is 
dried over MgSO.sub.4 and concentrated under vacuum. The residue is 
chromatographed on silica, eluting with a toluene/acetone (80:20; v/v) 
mixture to obtain 323 mg of the expected product. 
G) 
5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-3-N'-methylamino!propyl!carbamo 
yl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid tert-butyl ester hydrochloride. 
A mixture containing the compound of the preceding step (323 mg), 2 mg of 
Pd/C and 40 .mu.l of concentrated HCl in 15 ml of ethanol is stirred for 
24 hours under a hydrogen atmosphere. The catalyst is filtered off and the 
filtrate is evaporated under vacuum. The medium is taken up with ether and 
stirred. The white precipitate formed is filtered off to give 190 mg of 
the expected product. 
NMR (CD.sub.3 OD): 1.1:d:6H; 1.5:s:9H; 1.7-1.9:u.c.:8H; 2.2-2.3:u.c.:6H; 
2.6:s: 2.7-2.9:q+s:4H; 3:s:3H; 3.1:t:2H; 3.7: s+mt:8H; 6.6:d:2H; 6.8:s:1H; 
7.2-7.6:u.c.: 5H. 
H) 
2-5-(2,6-Dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamo 
yl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic 
acid hydrochloride. 
The compound of the preceding step (190 mg) is suspended in 50 .mu.l of 
acetonitrile, and 0.5 ml of a solution of methyl iodide in toluene (89 
.mu.l of methyl iodide in 100 ml of toluene) and 7.6 mg of silver 
carbonate are added. The insoluble matter is filtered off and the solvent 
is then evaporated off under vacuum. The medium is taken up with 2 ml of 
formic acid and 0.2 ml of concentrated HCl and stirred overnight. After 
evaporation under vacuum and trituration in ether, 90 mg of the expected 
product are obtained. 
EXAMPLE 88 
Oxazolone of the compound of EXAMPLE 1': 
##STR122## 
A solution 0.23 g of the compound of EXAMPLE 1' in 2 ml of DCM and 0.5 ml 
anhydride is stirred for 4 hours 30 minutes. It is evaporated under 
vacuum, and the residue is triturated in pentane, filtered off and dried 
to obtain 230 ml expected oxazolone, m.p.=129 ' C. (dec.). IR (KBr): 1800 
cm.sup.1. Mass spectrum:M:667.9. 
NMR: 1:d:6H; 1.5-1.9:u.c.:8H ; 2:ba: 8H; 2.1-2.5:u.c.:6H; 2.65:qt:1H; 2.9 
and 3 :2s :3H; 3.1:mt:2H; 3.4:mt:2H; 3.65:s:6H; 6.6: :d:2H; 6.9:s:1H; 
7.1-7.4:u.c.:4H.