Novel indole-derived azylpiperazines of general formula (I), wherein, inter alia, R.sub.1 is NH.sub.2 or NO.sub.2, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3 and R.sub.4 are H, Z is --C-- and X is 0. Methods for preparing such derivatives and the therapeutical uses thereof are also disclosed.

The present application is a U.S. national application filed under 35 USC 
371 of PCT/FR94/01343, filed Nov. 17, 1994, which in turn is based upon 
the priority of French application 9313875, filed Nov. 19, 1993. 
The present invention relates to new indole-derived arylpiperazines, to 
processes for their preparation and to their therapeutic uses. 
The compounds according to the present invention are ligands having a very 
high affinity and a very good selectivity for the receptors commonly known 
as 5HT.sub.1 -like receptors and more particularly for the receptors known 
as 5HT.sub.1B and 5HT.sub.1D receptors, according to the new nomenclature 
recently proposed by P. Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 
233-236, 1993). 
Medicaments including (alone or in association with other therapeutic 
agents) the active principles of the present invention are employed in the 
treatment, both curative and preventive, of diseases related to 
dysfunctioning of 5HT.sub.1-like receptors, including 5HT.sub.1B, 
5HT.sub.1D.alpha. and 5HT.sub.1D.beta. receptors, to their deregulation 
or to modifications in the activity of the endogenous ligand (generally 
serotonin). 
It has moreover been demonstrated that serotonin could play a role in 
certain diseases such as depression, pain, obsessional convulsive 
disorders, panic attacks, obesity, schizophrenia, anxiety, certain sexual 
disfunctionings or alternatively certain forms of degeneration such as 
Parkinson's or Alzheimer's disease refer, for example, to: S. Langer, N. 
Brunello, G. Racagni and J. Mendlecvicz, "Serotonin receptors subtypes: 
pharmacological significance and clinical implications", edited by Karger 
(1992), B. E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992), D. 
G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, Suppl. 4, 6-13 (1992), 
E. Zifa and G. Fillion, Pharmacological Reviews, 44, 401-458 (1992), and 
R. W. Fuller, J. Clin. Psychiatry, 53, 36-45 (1992)!. 
The compounds of the present invention are powerful and selective ligands 
of 5HT.sub.1-like receptors which can act as agonists, partial agonists or 
antagonists as regards these receptors and can therefore be applied in the 
disorders related to serotonin mentioned above. 
The majority of the compounds of the present invention are in addition 
powerful (as regards their affinity and as regards their intrinsic 
activity or effectiveness) and selective agonists of 5HT.sub.1B and 
5HT.sub.1D receptors. Agonists of 5HT.sub.1-like receptors and more 
particularly of 5HT.sub.1D receptors have a selective vasoconstrictive 
activity and are used in the treatment of migraine and vasospastic 
disorders (see, for example, A. Doenicke et al., The Lancet, 1, 1309-1311 
(1988), M. D. Ferrari and P. R. Saxena, Cephalalgia, 13, 151-165 (1993), 
S. J. Peroutka, Headache, 30, 5-11 (1990), M. A. Moskowitz, TIPS, 13, 
307-311 (1992), W. Feniuk, P. P. Humphrey, M. S. Perren, H. E. Connor and 
E. T. Whalley, J. Neurol., 238, S57-S61 (1991) and A. V. Deligonis and S. 
J. Peroutka, Headache, 31, 228-231 (1991)!. 
The compounds of the present invention, which are, for the most part, 
powerful and selective agonists of 5HT.sub.1-like receptors, are therefore 
more particularly employed in the curative and prophylactic treatment of 
"classic" (with aura) and "common" (without aura) migraine attacks, facial 
vascular pain, chronic vascular cephalalgias and vasospastic disorders. 
The prior state of the art in this field is illustrated in particular by 
French Patent Applications F 9215919 (30/12/92) and F 9307982 (30/6/93), 
which describe new indole compounds derived respectively from piperazines 
and from arylamines as ligands of 5HT.sub.1B -5HT.sub.1D receptors. 
Patent Application FR 2,671,971, which describes 5-O-carboxymethylated 
derivatives of tryptamine which have a good affinity for 5HT.sub.1D 
receptors. 
European Patent Applications 0,313,397, 0,486,666, 0,494,774-A1, 
0,497,512-A2, 0,501,568-A1, 0,464,558 and 0,548,813-A1 and Patent 
Application WO 92/13856, which describe heterocyclic derivatives derived 
from tryptamine as agonists of 5HT.sub.1-like receptors. 
European Patent Applications 0,533,266, 0,533,267 and 0,533,268, which 
claim benzamides derived from arylpiperazine as antagonists of the 
5HT.sub.1D receptor. 
Nevertheless, these patent applications do not in any case describe or 
suggest the indolic piperazine derivatives which form part of the present 
invention: the present invention describes a new class of indole-derived 
arylpiperazines which is distinguished from the closest derivatives of the 
prior art (and in particular from French Patent Application F 9215919, 
filed on 30/12/92) not only by their novel and different chemical 
structure but also by their biological profile and their therapeutic 
potential, since many compounds according to the present invention have 
the advantage of combining, for the first time in the same molecule, a 
very strong affinity for 5HT.sub.1B or 5HT.sub.1D receptors, a high 
selectivity with respect to 5HT.sub.1A receptors and a notable agonist 
effectiveness (intrinsic activity). 
The present invention relates to compounds of formula I: 
##STR2## 
to their preparation and to the medicaments containing them. 
In the formula (I), 
R.sub.1 represents an NH.sub.2, NO.sub.2, NH--NH.sub.2, NH--OH, NCOR.sub.7 
(OH), NR.sub.5 R.sub.6, NHCOR.sub.7, NHCONR.sub.5 R.sub.7, NHSO.sub.2 
R.sub.7, NHCO.sub.2 R.sub.7, SO.sub.2 R.sub.7, SO.sub.2 NHR.sub.7, 
NHCH.sub.2 SR.sub.7, NHCH.sub.2 S(O)R.sub.7, NHCH.sub.2 SO.sub.2 R.sub.7, 
CN, NHCONH.sub.2, SO.sub.2 NH.sub.2, N(SO.sub.2 R.sub.7).sub.2, CH.sub.2 
NR.sub.5 R.sub.6, CH.sub.2 NHCOR.sub.7, CH.sub.2 NHCONR.sub.5 R.sub.6, 
CH.sub.2 NHSO.sub.2 R.sub.7, CH.sub.2 NHCO.sub.2 R.sub.7 or OSO.sub.2 
R.sub.7 radical which can be in the o, m or p position on the aromatic 
ring. 
R'.sub.1 represents one or a number of substituents which can be in various 
positions on the aromatic ring, such as H, methyl, ethyl, propyl, 
isopropyl, n-buryl, s-butyl, t-butyl, trifluoromethyl, 
2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, cycloalkyl, OH, SR.sub.5, 
OR.sub.5 or a halogen (chlorine, fluorine, bromine or iodine), or 
alternatively R'.sub.1 can be identical to R.sub.1. 
Z represents C=O, C=S, SO.sub.2, (CH.sub.2).sub.n or alternatively 
--CO(CH.sub.2).sub.n -- in which n is between 1 and 5. 
R.sub.2 and R'.sub.2, which are identical or different, each represent a 
hydrogen atom, a linear or branched alkyl radical or a phenyl, benzyl, 
cycloalkyl or arylalkyl radical which are optionally substituted by one or 
a number of substituents chosen from halogen atoms or alkyl, aryl, acycl, 
alkoxy and alkylthio radicals. 
X represents CH.sub.2 or O or the R.sub.1 R'.sub.1 group represents a C--C 
double bond. 
R.sub.3 represents a hydrogen atom, a linear or branched alkyl radical or a 
phenyl, alkyl, aryl, COR.sub.7, CO.sub.2 R.sub.7, CONHR.sub.7 or SO.sub.2 
R.sub.7 radical. 
R.sub.4 represents a hydrogen, chlorine, fluorine or bromine atom or a 
linear or branched alkyl radical. 
R.sub.5 and R.sub.6, which are identical or different, each represent a 
hydrogen atom, a linear or branched alkyl radical, such as a methyl, 
ethyl, n-propyl, isopropyl, n-butyl, s-butyl or t-butyl, or an arylalkyl 
radical, such as a benzyl or a phenethyl. 
R.sub.7 represents a linear or branched alkyl radical comprising from 1 to 
5 carbon atoms, a trifluoromethyl or 2,2,2-trifluoroethyl, an aryl radical 
(such as phenyl), a heterocycle (such as a 5-membered heterocycle 
containing one or a number of sulfur, oxygen or nitrogen atoms) or an 
arylalkyl (such as a benzyl or a phenethyl) in which the aromatic ring may 
be variously substituted in various positions by alkyl (methyl, ethyl, 
propyl or butyl), trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, thiol, 
ether (OCH.sub.3, OC.sub.2 H.sub.5 or OCH(Me).sub.2), thioether (SCH.sub.3 
or SC.sub.2 H.sub.5), halogen (chlorine, fluorine, bromine or iodine), 
nitrile, acetyl, carbonyl (COR.sub.5), carboxyl (CO.sub.2 R.sub.5), nitro 
(NO.sub.2), amine (NRSR.sub.6), NHSO.sub.2 R.sub.5, NHCO.sub.2 R.sub.5, 
NHCOR.sub.5, NHCONR.sub.5 R.sub.6 or NHSO.sub.2 NR.sub.5 R.sub.6 residues. 
their salts, solyates and bioprecursors which are acceptable in therapeutic 
use. 
In the preceding definitions and those which will be cited below, except 
when otherwise mentioned, the alkyl, alkoxy or alkylthio radicals contain 
1 to 6 straight- or branched-chain carbon atoms and the cycloalkyl 
portions contain 3 to 7 carbon atoms. In the formula (I), the halogen 
atoms are preferably chlorine, fluorine or bromine atoms. 
The compounds of formula (I) containing one or a number of asymmetric 
centers have isomer forms. 
The racemates and the pure enantiomers of these compounds also form part of 
this invention. 
The invention also comprises the salts, solyates (for example hydrates) and 
bioprecursors of these compounds which are acceptable in therapeutic use. 
Mention will be made, among the salts which are acceptable in therapeutic 
use of the indoles of general formula (I), of the salts formed by addition 
with organic or inorganic acids and for example the hydrochlorides, the 
hydrobromides, the sulfates, the fumarates and the maleares. Other salts 
may be useful in the preparation of the compounds of formula (I), for 
example adducts with creatinine sulfate. 
The expression "bioprecursors" as used in the present invention applies to 
compounds in which the structure differs from that of the compounds of 
formula (I) but which, administered to an animal or to a human being, are 
converted in the body to a compound of formula (I). 
A valuable class of compounds according to the invention comprises those 
which correspond to the general formula (Ia) 
##STR3## 
in which R.sub.1, R'.sub.1, Z, X, R.sub.5 and R.sub.6 are defined as above 
in the formula (I), and their salts, solyates (for example hydrates) and 
bioprecursors which are acceptable in therapeutic use. 
The invention also comprises the preparation, by the processes described 
below, of the compounds of general formula (I) and of their salts, 
solyates (such as hydrates) or bioprecursors which are acceptable in 
therapeutic use. 
Generally, the compounds of general formula (I) in which R.sub.6 represents 
a hydrogen are prepared from derivatives of formula (II) 
##STR4## 
in which R'.sub.1, R.sub.1, Z, R.sub.2, R'.sub.2, X, R.sub.3, R.sub.4 and 
R.sub.5 are described as above and R'.sub.6 represents a COR.sub.8 or 
CO.sub.2 R.sub.8 group, preferably CO.sub.2 R.sub.8 in which R.sub.8 is 
preferably a t-butyl or benzyl residue. Conversion of the compounds of 
formula (II) in which R'.sub.6 is a CO.sub.2.sup.t Bu (BOC) group to 
compounds of formula (I) in which R.sub.6 is a hydrogen is preferably 
carried out using an acid, such as trifluoroacetic acid or hydrochloric 
acid, in an organic solvent, such as ether, tetrahydrofuran, toluene, 
dichloromethane, chloroform, methanol, ethanol or isopropanol, at a 
temperature of between -15.degree. C. and 40.degree. C. Conversion of the 
compounds of formula (II) in which R'.sub.6 is a CO.sub.2 CH.sub.2 C.sub.6 
H.sub.5 (commonly called Z) group to a compound of formula (I) in which 
R.sub.6 is a hydrogen is preferably carried out by catalytic 
hydrogenation, using for example palladium-on-charcoal as catalyst, under 
atmospheric hydrogen pressure, in a solvent, such as THF, ethanol, 
isopropanol or ethyl acetate, which can contain up to 10% of acetic or 
citric acid, at a temperature of between 0.degree. and 60.degree. C. In 
the following definitions, the expression "R.sub.6 described as above" 
should be regarded as implying that R.sub.6 can also represent R'.sub.6. 
The preparation of the derivatives of formula (I) in which R'.sub.1, 
R.sub.1, Z, R.sub.2, R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 
are described as above and X represents an oxygen atom are prepared, 
generally, by condensation of a derivative of general formula (III) 
##STR5## 
in which R.sub.1, R'.sub.1, Z, R.sub.2 and R'.sub.2 are defined as in the 
formula (I) and L represents a leaving group, such as a halogen 
(preferably a bromine, iodine or chlorine atom) or an O-mesylate, 
O-triflate or O-tosylate, with a derivative of serotonin of general 
formula (IV): 
##STR6## 
in which the R.sub.3, R.sub.4, R.sub.5 and R.sub.6 residues are described 
as above. 
The preparation of the derivatives of formula (I) by condensation of the 
derivatives of formula (III) with the derivatives of formula (IV) can be 
carried out, generally, in the presence of an organic base (NaH, KH, 
Et.sub.3 N, DBU, DBN, TMP, DIPEA, t-BuOK) or an inorganic base (K.sub.2 
CO.sub.3, KHCO.sub.3, NaHCO.sub.3, CS.sub.2 CO.sub.3, KOH, NaOH, 
CaCO.sub.3 and the like), in an anhydrous solvent, such as THF, DMF, DMSO, 
acetone, diethyl ketone, methyl ethyl ketone, acetonitrile or DME, at a 
temperature of between 20.degree. and 140.degree. C., in the present or in 
the absence of a salt as catalyst which may be KI, Bu.sub.4 NI, LiI, 
AgBF.sub.4, AgCIO.sub.4, Ag.sub.2 CO.sub.3, KF, Bu.sub.4 NF or CsF. The 
choice of the experimental conditions for carrying out the condensation 
between the derivatives of formula (III) and (IV) in order to obtain the 
derivatives of formula (I) is very clearly dependent on the nature of the 
substituents in the reactants (III) and (IV) and more particularly on the 
nature of the Z, R.sub.2 and R'.sub.2 groups. By way of example, when Z is 
a carbonyl (CO) functional group, R.sub.2 is a hydrogen atom and X a 
halogen, condensation between (III) and (IV) to give (I) is preferably 
carried out at 80.degree. C., in methyl ethyl ketone, in the presence of 
an excess of K.sub.2 CO.sub.3 and of a catalytic amount of KI. When Z is a 
carbonyl group and when R.sub.2 and R'.sub.2 are both other than a 
hydrogen, the preferred method comprises the reaction of a derivative of 
formula (IV) with this derivative of formula (III), in the presence of a 
silver salt such as silver tetrafluoroborate and of an inorganic base such 
as K.sub.2 CO.sub.3. When the Z group is defined as (CH.sub.2).sub.n, 
condensation between the (III) and (IV) derivatives is carried out in a 
solvent such as DMF or DMSO, in the presence of a base such as DBU or 
DIPEA, at 100.degree. C., in the presence of a catalytic amount of 
Bu.sub.4 NI or of KI. An alternative method comprises the condensation of 
the (III) and (IV) derivatives, under neutral conditions, in DMF, in the 
presence of a large excess of a fluoride such as KF, CsF or Bu.sub.4 NF. 
The compounds of general formula (III) in which the R.sub.1, R'.sub.1, 
R.sub.2, R'.sub.2 and L substituents are defined as above are prepared by 
methods which differ according to the nature of the Z residue. Thus, the 
derivatives of formula (III) in which Z is a carbonyl group forming part 
of an amide functional group are obtained by reaction of the piperazines 
of general formula (V). 
##STR7## 
in which the R.sub.1 and R'.sub.1 residues are defined as in the formula 
(I), with a derivative of formula (VI) 
##STR8## 
in which R.sub.2 and R'.sub.2 are defined as in the formula (I) and Z 
represents C=0. This reaction, which makes possible the preparation of the 
derivatives of formula (III) in which Z=CO and X=Cl from the arylamines 
(V) and the acid chlorides (VI), is a well known reaction for the 
formation of amides from an amine and from an acid chloride and can be 
carried out in a solvent such as dichloromethane, THF, chloroform, 
acetone, methyl ethyl ketone, DME or acetonitrile, at a temperature of 
between -20.degree. C. and 80.degree. C., in the presence of a base, such 
as a tertiary amine (DBU, Et.sub.3 N or DIPEA) or inorganic bases, such as 
carbonates (KHCO.sub.3, NaHCO.sub.3, K.sub.2 CO.sub.2, Na.sub.2 CO.sub.3 
or Cs.sub.2 CO.sub.3), sodium hydroxide or alternatively potassium 
hydroxide. 
The derivatives of formula (III) in which Z represents a --(CH.sub.2).sub.n 
-- group are generally prepared by condensation of an arylamine of formula 
(V) with a derivative of formula (VII) 
##STR9## 
in which L represents a leaving group, such as a chlorine, a bromine, an 
iodine or a mesylate, tosylate or triflate group, R.sub.2 and R'.sub.2 are 
defined as in the formula (I) and L' can be either identical to L or 
represents an OR' group in which R' is defined as a protective group for 
an alcohol, such as a silyl ether (SiMe.sub.3, Si.sup.t BuMe.sub.2 or 
SiC.sub.6 H.sub.5 Me.sub.2), a tetrahydropyran or alternatively a benzyl 
or a trityl. It is clearly understood that, in the case where L' is other 
than L, condensation between the piperazine of formula (V) and the 
intermediate (VII) is followed by hydrolysis of the OR' protective group 
in order to give anintermediate alcohol derivative which is converted to a 
leaving group which results in the compounds (III) in which R.sub.1, 
R'.sub.1, R.sub.2, R'.sub.2 and L are defined as above. In the procedure 
mentioned above, hydrolysis of the OR' functional group to an alcohol is 
carried out by the described and appropriate methods according to the 
nature of R' (with reference to the work by T. W. Greene, "Protective 
Groups in Organic Synthesis", John Wiley & Sons, 1981) and the conversion 
of the alcohol thus obtained to the leaving group (so as to obtain the 
compounds (III)! is carried out by techniques and methods which are well 
known for this type of conversion, such as the use of SOCl.sub.2 or 
POCl.sub.3 in dichloromethane for the formation of derivatives of formula 
(III) in which L=Cl, the use of PBr.sub.3 or Br.sub.2 PPh.sub.3 for the 
formation of derivatives of formula (III) in which L=Br, the use of 
PI.sub.3 or P.sub.2 I.sub.4 for the formation of derivatives of formula 
(III) in which L=I, the use of tosyl chloride for the formation of 
derivatives of formula (III) in which L=OTos, the use of mesyl chloride 
for the formation of derivatives of formula (III) in which L=OMes and 
finally the use of triflic anhydride for the formation of derivatives of 
formula (III) in which L=OTf. 
The derivatives of formula (III) in which Z=SO.sub.2 are generally prepared 
by reaction of the piperazine derivatives of general formula (V), in which 
the R.sub.1 and R'.sub.1 groups are defined as in the general formula (I), 
with a derivative of formula (VI) in which R.sub.2 and R'.sub.2 are 
defined as in the formula (I) and Z represents SO.sub.2. 
The compounds of general formula (I) can also be prepared by another 
process which comprises the treatment of an arylpiperazine of general 
formula (V) defined as above with a derivative of serotonin of general 
formula (VIII. 
##STR10## 
in which the R.sub.2, R'.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 
residues are defined as described above in the formula (I) and L is 
defined as a leaving group, such as a halogen (preferably a bromine, 
iodine or chlorine atom), a mesylate, a rosylate or a triflate, or the 
precursor of a leaving group, such as a hydroxyl radical. 
The preparation of the derivatives of formula (I) in which Z represents a 
--(CH.sub.2).sub.n -- residue by this process is carried out by 
condensation between a piperazine derivative of formula (V) and an 
intermediate of general formula (VIII) in the presence of an organic base 
(NaH, .sup.t BuOK, DBU or DIPEA) or an inorganic base (KOH, K.sub.2 
CO.sub.3, NaHCO.sub.3 or Cs.sub.2 CO.sub.3) in an anhydrous solvent, such 
as THF, DMF, DMSO, acetonitrile or methylethyl ketone, at a temperature of 
between 20.degree. and 100.degree. C. 
The intermediates of formula (VIII) can be prepared by condensation of a 
derivative of serotonin of formula (IV) 
##STR11## 
in which R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are defined as in the 
formula (I), with a derivative of formula (IX) 
##STR12## 
in which L' and L" can be simultaneously halogens (chlorine, bromine or 
iodine) if R.sub.2 and R'.sub.2 represent a hydrogen atom; in the other 
cases, L' represents an OR group where R is a conventional protective 
group, such as a silyl (trimethylsilyl, triethylsilyl or .sup.t 
butyldimethylsilyl), benzyl, tetrahydropyranyl or trityl group, and in 
this case L" represents a leaving group, such as a halogen (preferably a 
chlorine, an iodine or a bromine), an OMes, an OTos or an OTf. In this 
case, after condensation, L', which represents OR, will be deprotected and 
converted to the leaving group L as defined in the formula (VIII) by the 
methods described above. 
This condensation reaction between the intermediates (IV) and (IX) as 
described above is carried out in basic medium (in the present of a base, 
such as NaH, KH, .sup.t BuOK, K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, DIPEA 
or DBU) in an anhydrous solvent, such as DMSO, DMF, THF, acetonitrile, 
methyl ethyl ketone or DME, at a temperature of between 0.degree. and 
100.degree. C. 
In the specific case of the derivatives of formula (I) in which R.sub.1, 
R'.sub.1, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above but 
where Z represents --(CH.sub.2)--, a preferred method of synthesis 
comprises the reduction of the corresponding derivatives of formula (I) in 
which Z represents CO by a reducing agent which makes possible the 
conversion of an amide to an amine, such as borane (BH.sub.3.Me.sub.2 S) 
or LiAlH.sub.4, use being made of the methods and techniques which are 
well known for this type of reduction. 
In the case of the derivatives of formula (I) in which R.sub.1, R'.sub.1, 
Z, R.sub.2, R'.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described 
as above and in which X=CH.sub.2, a general method of synthesis comprises 
the condensation of an intermediate of general formula (X) 
##STR13## 
in which L is a leaving group defined as above and Z, R.sub.2, R'.sub.2, 
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above, with an 
arylpiperazine of general formula (V) in which R.sub.1 and R'.sub.1 are 
defined as above. The methods used for obtaining the products of general 
formula (I) in which X=CH.sub.2 by condensation of the intermediates (X) 
and (V) vary according to the nature of the Z residue and may be 
comparable, according to the variation in Z, to the methods described 
previously for the synthesis of the products (III) by condensation of the 
intermediates (V) and (VI). 
The indole derivatives of general formula (X) in which Z=CO, L is a leaving 
group such as a halogen, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 
are described as above and R'.sub.2 is a hydrogen can be obtained by 
condensation of a 5-bromoindole derivative of formula (XI) 
##STR14## 
in which R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are defined as above, with 
an acid or an ester derived from this unsaturated acid of general formula 
(XII) 
##STR15## 
in which the R.sub.2 residue is defined as above, use being made of a 
palladium (o) catalysis according to the method for the alkylation of 
aromatics well known as the Heck reaction, followed by reduction of the 
double bond by catalytic hydrogenation (atmospheric H.sub.2, Pd/C, 
methanol) and by conversion of the acid or of the ester thus formed to the 
derivative X by methods and techniques which are well known to the person 
skilled in the art for the conversion of a carboxylic acid or of a 
corresponding ester to the acid chloride X (L=Cl, Z=CO) or to an activated 
ester capable of being condensed with an amine in order to form an amide 
(in particular by intermediate formation of a mixed anhydride with ethyl 
chloroformate). 
The derivatives of general formula (I) in which R.sub.1, R'.sub.1, R.sub.2, 
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above, Z=X=CH.sub.2 
and R'.sub.2 =H are prepared from the products of general formula (I) in 
which R.sub.1, R'.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 
are described as above, Z=CO, X=CH.sub.2 and R'.sub.2 =H by reduction of 
the amide functional group with a reducing agent well known for this type 
of reaction, such as lithium aluminum hydride, in an aprotic solvent, such 
as ether or THF. 
The derivatives of general formula (I) in which R.sub.1, R'.sub.1, R.sub.2, 
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above, Z=SO.sub.2, 
X=CH.sub.2 and R'.sub.2 =H are prepared by the Heck condensation from an 
intermediate of formula (XI) with an unsaturated sulfonamide of formula 
(XIII) 
##STR16## 
in a solvent such as triethylamine in the presence of a phosphine such as 
tri(O-tolylphosphine) at a temperature of between 60.degree. and 
100.degree. C. 
The methods for the preparation of derivatives of formula (I) from other 
derivatives of formula (I) in which at least one of the R.sub.1, R'.sub.1, 
Z, R.sub.2, R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 or R.sub.6 substituents 
are different, by techniques and methods well known to the person skilled 
in the art, must also be regarded as an integral part of this invention. 
In particular, the present invention also claims a method for the 
preparation of numerous compounds of general formula (I), in which R.sub.1 
is an NH.sub.2, NH--NH.sub.2, NHOH, NR.sub.5 R.sub.6, NHCOR.sub.7, 
NHCONR.sub.5 R.sub.7, NHSO.sub.2 R.sub.7 or NHCO.sub.2 R.sub.7 radical in 
the ortho, meta or para position, from compounds of general formula (Ib) 
prepared as described above and in which R.sub.1, Z, R.sub.2, R'.sub.2, X, 
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above. 
##STR17## 
Thus, the compounds of general formula (Ic), in which R'.sub.1, Z, R.sub.2, 
R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above 
##STR18## 
are prepared by reduction of the nitro group by methods and techniques 
well known for this type of reduction (with reference, for example, to: R. 
C. Larouk "Comprehensive Organic Transformation", p. 412 (1989), VCH.), 
such as atmospheric hydrogenation catalyzed by paladium-on-charcoal, the 
use of SnCl.sub.2 or of zinc or alternatively of rhodium catalyst in the 
presence of hydrazine. 
This last method additionally makes it possible to control the reduction of 
the nitro group and also to isolate the intermediate hydroxylamine of 
general formula (Id), which also forms part of this invention. 
##STR19## 
The synthetic intermediates of general formula (Ie), in which R.sub.1, Z, 
R.sub.2, R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described 
as above 
##STR20## 
can also be prepared from the anilines of structure Ic, after reaction 
with nitrous acid (HNO.sub.2), by using methods and techniques well known 
for this type of conversion (cf. Patai, "The Chemistry of Diazonium and 
Diazo Groups", Wiley, N.Y., 1978). 
These intermediates (Ie) make it possible to prepare the products of 
general formula (Ia), in which R'.sub.1, Z, R.sub.2, R'.sub.2, X, R.sub.3, 
R.sub.4, R.sub.5 and R.sub.6 are described as above but in which R.sub.1 
=SO.sub.2 NHR.sub.7, after reaction with SO.sub.2 in the presence of 
cupric chloride (Gilbert, Synthesis, 1-10, 1969), followed by condensation 
of the intermediate sulfonyl chloride with an amine (R.sub.7 NH.sub.2) in 
the presence of a base, such as pyridine, triethylamine or DMAP. 
The intermediates (Ie) also make it possible to prepare the products of 
general formula (Ia), in which R'.sub.1, Z, R.sub.2, R'.sub.2, X, R.sub.3, 
R.sub.4, R.sub.5 and R.sub.6 are described as above but in which R.sub.1 
=NH--NH.sub.2, after reduction of the diazonium group, in particular by 
using sodium sulfite (Na.sub.2 SO.sub.3) (Huisgen and Lux, Chem. Bet. 93, 
540, 1960). 
The compounds of general formula (I), in which the R.sub.1 group represents 
NR.sub.5 R.sub.6, NHCOR.sub.7, NHCONR.sub.5 R.sub.7, NHSO.sub.2 R.sub.7, 
NHCO.sub.2 R.sub.7 in the ortho, meta or para position, can also be 
obtained from the compounds of formula (Ic) in which R'.sub.1, Z, R.sub.2, 
R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above 
by various reactants and methods which depend on the nature of the R.sub.1 
group. Thus, the compounds of formula (I) in which R.sub.1 represents an 
NR.sub.5 R.sub.6 group (in which R.sub.6 =H or R.sub.5) are prepared by 
reaction in a basic medium (in the presence of an organic base, such as 
DBU, .sup.t BuOK, DMAP or DIPEA, or an inorganic base, such as CS.sub.2 
CO.sub.3, HaH or KH) of the intermediate (Ic) with corresponding 
alkylating agents (R.sub.5 --L in which L represents a chlorine, bromine 
or iodine atom or an O-mesyl, O-toxyl or O-trifluorasulfonyl radical). 
Control of the reaction (time, solvent, temperature or number of 
equivalents of R.sub.5 --L) makes it possible to obtain the mono- or 
dialkylated aniline. 
The compounds of general formula (I) in which R.sub.1 represents 
NHCOR.sub.7 are also prepared by reaction of the corresponding anilines of 
formula (Ic) after reaction with an acylating agent, such as an acid 
chloride (ClCOR.sub.7) or an anhydride (R.sub.7 CO).sub.2 O!, in the 
presence of a base, such as triethylamine, pyridine or DMAP, in a polar 
aprotic solvent, such as DMF or dichloromethane. 
The compounds of formula (I) in which R.sub.1 represents NHCOOR.sub.7 are 
also accessible by a similar reaction in which the amine of formula (Ic) 
is condensed with a chloroformate of structure ClCOOR.sub.7. 
The compounds of formula (I) in which R.sub.1 represents NHSO.sub.2 R.sub.7 
are themselves also accessible by a similar reaction which comprises the 
condensation of the aniline of formula (Ic) with a sulfonyl chloride of 
formula ClSO.sub.2 R.sub.7. 
The compounds of formula (I) in which R.sub.1 represents NHCONR.sub.5 
R.sub.7 can also be obtained from the corresponding aniline (Ic) by 
different methods. Thus, the amines of general formula (Ic) can be 
converted beforehand to isocyanates of formula (I) in which R.sub.1 
represents N=C=O (cf. Patai, "The Chemistry of Cyanates and Their Thio 
Derivatives, pt. 2, Wiley, N.Y., 1977; pp 619-818 and 1003-1221), followed 
by the addition reaction of an amine of formula HNR.sub.5 --R.sub.7 in the 
presence of a base such as Et.sub.3 N. Alternatively, the compounds of 
formula (I) in which R.sub.1 =NHCONR.sub.5 R.sub.7 can also be prepared by 
condensation of the aniline of formula (Ic) with an intermediate of 
formula ClCONR.sub.5 R.sub.7 in the presence of a base, such as ET.sub.3 N 
or DMAP, in a polar aprotic solvent, such as CH.sub.2 CL.sub.2 or DMF. 
The derivatives of general formula (I) in which R.sub.1, R'.sub.1, R.sub.2, 
R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described as above 
and Z represents C=S are obtained by reaction of the compounds of general 
formula (I), in which R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, X, R.sub.3, 
R.sub.4, R.sub.5 and R.sub.6 are described as above and Z represents C=O, 
with Lawesson's reagent 
2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide!in 
toluene. 
The derivatives of general formula (I) in which R.sub.1, R'.sub.1, Z, 
R.sub.2, R'.sub.2, X, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are described 
as above and in which R.sub.3 represents a hydrogen can be converted to 
derivatives of formula (I) in which R.sub.3 represents an alkyl, benzyl, 
COR.sub.7, CO.sub.2 R.sub.7, CONHR.sub.7 or SO.sub.2 R.sub.7 radical by 
reaction in basic medium with, respectively, an alkyl halide, a benzyl 
halide, an acid chloride, a chloroformate, a chloroformamide or a sulfonyl 
chloride by methods and techniques well known for this type of reaction 
and which, by way of example, are described in "The Chemistry of Indoles", 
edited by R. S. Sundberg, vol. 18 of "Organic Chemistry, A Series of 
Monographs", Academic Press, NY, 1970. 
It will be understood that, in some of the above conversions, it may be 
necessary or desirable to protect possible sensitive groups of the 
molecule in question in order to avoid undesirable side reactions. This 
can be carried out by the use of conventional protective groups such as 
those described in "Protective Groups in Organic Synthesis", edited by J. 
F. McOwie, Plenum Press, 1973 and in T. W. Greene, "Protective Groups in 
Organic Synthesis", John Wiley & Sons, 1981. The protective groups can be 
removed during any suitable subsequent stage, by using methods and 
techniques also described in the references cited above. Thus, in some 
specific cases, it may be necessary to protect the indole nitrogen during 
the preparation of compounds of formula (I) in which R.sub.3 represents a 
hydrogen. 
When it is desired to isolate a compound according to the invention in the 
salt form, for example in the form of a salt formed by addition with an 
acid, this can be done by treating the free base of general formula (I) 
with an appropriate acid, preferably in an equivalent amount, or with 
creatinine sulfate, in an appropriate solvent. 
When the processes described above for preparing the compounds of the 
invention give mixtures of stereoisomers, these isomers can be separated 
by conventional methods, such as preparative chromatography. 
When the new compounds of general formula (I) have one or a number of 
asymmetric centers, it can be prepared in the form of a racemic mixture or 
in the form of enantiomers, whether by enantioselective synthesis or by 
resolution. The compounds of formula (I) having at least one asymmetric 
center can, for example, be separated into their enantiomers by the usual 
techniques, such as the formation of diastereomeric pairs by formation of 
a salt with an optically active acid, such as (-)-di-p-toluoyl-1-tartaric 
acid, (+)-di-p-toluoyl-1-tartaric acid, (+)-camphorsulfonic acid, 
(-)-camphorsulfonic acid, (+)-phenylpropionic acid or (-)-phenylpropionic 
acid, followed by fractional crystallization and regeneration of the free 
base. The compounds of formula (I) in which R.sub.6 is a hydrogen 
comprising at least one asymmetric center can also be resolved by 
formation of diastereomeric amides which are separated by chromatography 
and hydrolyzed in order to release the chiral auxiliary. 
Generally, the compounds of formula (I) can be purified by the usual 
methods, for example by crystallization (in particular when the compounds 
of formula (I) are isolated in the salt form), chromatography or 
extraction.

The examples which follow illustrate the invention without, however, 
limiting the scope thereof. 
EXAMPLE 1 
2-3-(2-Aminoethyl)-1-H-indol-5-yloxy!-1-(4-nitrophenyl)piperazin-1-yl!eth 
anone hydrochloride 
##STR21## 
1A: 3-(2-N-tert-butoxycarbonyl)aminoethyl)-1-H-indol-5-ol 
The creatine sulfate monohydrate salt of serotonin (102 g, 252 mmol) is 
treated with di-tert-butyl dicarbonate (82.6 g, 378 mmol) in water (2.1 l) 
in the presence of 2N sodium hydroxide (420 ml) at room temperature. After 
1 hour, the reaction mixture is diluted with ethyl acetate (3 l) and 
stirred for 10 minutes. The two phases formed are separated by settling; 
the organic phase is washed with water, dried over sodium sulfate, 
filtered and then evaporated to dryness. The syrup obtained is 
chromatographed on a column of silica gel eluted with a 
dichloromethane/methanol (20/1, v/v) mixture. The pure compound is 
isolated in the form of a brown syrup (65.9 g, 95%). Elemental analysis 
(C.sub.15 H.sub.20 N.sub.2 O.sub.3), % calculated: C 65.20, H 7.30, N 
10.14, % found: C 64.15, H 7.47, N 9.77. 
Proton nuclear maguetic resonance spectrum, CDCl.sub.3 (ppm): 1.44 s, 9H 
(t-Bu); 2.86 t, 2H (CH.sub.2); 3.45 m, 2H (CH.sub.2); 4.68 s, 1H (NH); 
5.59 s, 1H (O--H); 6.77-7.26 m, 4H (Ar+ethylenic); 7.99 s, 1H (NH). 
1B: 2-chloro-1-4-nitrophenyl)piperazin-1-yl!ethanone 
(4-Nitrophenyl)piperazine (7 g, 33.8 mmol) in solution in methyl ethyl 
ketone (223 ml), in the presence of calcium carbonate (10.1 g; 101.4 
mmol), is treated at 0.degree. C. and dropwise with chloroacetyl chloride 
(3.2 ml; 40.5 mmol). After 1 hour at 0.degree. C., the reaction mixture is 
diluted with ethyl acetate, filtered through celite and washed with water 
and then with a sodium chloride solution. The organic phase is dried over 
sodium sulfate, filtered and evaporated. The brown solid obtained (7.8 g, 
82%) is used without additional purification in the following stage. 
1C: 
2-3-(2-N-(tert-butoxycarbonyl)aminoethyl)-1-H-indol-5-yloxy!-1-4-(4-nitr 
ophenyl)piperazin-1-yl!ethanone. 
A mixture of the compound 1A (9.67 g, 35.01 mmol) and of the compound 1B 
(24.8 g, 87.5 mmol) in methyl ethyl ketone (400 ml), in the presence of 
potassium carbonate (12.1 g, 87.5 mmol) and of potassium iodide (581 mg; 
3.5 mmol), is heated at reflux for 5 hours. The compound 1A (2.0 g, 7.2 
mmol) is again added and the reaction mixture is stirred at reflux for an 
additional 1 hour. The mixture is then diluted with dichloromethane, 
filtered through celite and washed with water and then with a sodium 
chloride solution. The organic phase is dried over sodium sulfate, 
filtered and then evaporated to dryness. The syrup obtained is 
chromatographed on a column of silica gel eluted with a 
dichloromethane/acetone (3/1, v/v) mixture. The pure product is obtained 
in the form of an orange powder (18.2 g, 83%). 
Elemental analysis (C.sub.27 H.sub.33 N.sub.5 O.sub.6), % calculated: C 
61.94, H 6.35, N 13.38, % found: C 61.19, H 6.22, N 13.02. 
Proton nuclear magnetic resonance spectrum, CDCl.sub.3 (ppm): 
1.44 s, 9H (t-Bu); 3.86 t, 4H (CH.sub.2); 3.83 m, 4H (CH.sub.2); 4.65 s, 1H 
(NH); 4.79 s, 2H (COCH.sub.2 O); 6.79-7.30 m, 6H (Ar+ethylenic); 8.11-8.16 
m, 3H (Ar+NH). Melting point: 198.degree. C. 
1: 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!e 
thanone hydrochloride. 
The product 1C (930 mg, 1.77 mmol) in solution in toluene (46 ml) is 
treated with trifluoroacetic acid (10 ml). After 1 h 30 at room 
temperature, the mixture is diluted with dichloromethane and washed with 
2N sodium hydroxide and then with water. The organic phase is dried over 
sodium sulfate, filtered and evaporated to dryness. The syrup obtained is 
chromatoraphed on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is obtained in the form of a yellow syrup (317 mg, 45%). This 
compound is diluted in methanol and the bishydrochloride is formed by 
addition of the necessary amount of hydrochloric acid in methanol. 
Elemental analysis (C.sub.22 H.sub.27 N.sub.5 O.sub.4 Cl.sub.2), % 
calculated: C 53.23, H 5.48, N 14.11, % found: C 53.83, H 5.77, N 13.80. 
1H nuclear magnetic resonance spectrum, d6-DMSO (ppm): 
2.99 s, 4H (CH.sub.2); 3.54-3.71 m, 8H (CH.sub.2), 4.84 s, 2H (COCH.sub.2 
O); 6.77-6.83 dd, 1H (ethylenic); 7.01-7.29 m, 5H (Ar); 8.06-8.11 m, 5H 
(Ar+NH.sub.3.sup.+); 10.85 d, 1H (NH). Melting point: 206.degree. C. 
EXAMPLE 2 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(aminopheryl)piperazin-1-yl!etha 
none hydrochloride 
##STR22## 
The product 1 (5 g, 9.5 mmol), in suspension in methanol (250 ml) in the 
presence of a catalytic amount of palladium-on-charcoal (505 mg, 0.47 
mmol), is hydrogenated in a Parr apparatus, under a pressure of 40 psi. 
After 12 hours, the mixture is filtered through celite and the latter is 
washed a number of times with methanol, which makes it possible to obtain 
the virtually pure reduction product in the filtrate. The celite is then 
washed with dichloromethane, which makes it possible to recover the 
unreacted starting material. 
The filtrate containing the product formed is evaporated to dryness and the 
syrup obtained is chromatographed on a column of silica gel eluted with a 
dichloromethane acetone (3/1, v/v) mixture. The pure product is obtained 
in the form of a yellow syrup (2.8 g, 60%). 
1H nuclear magnetic resonance spectrum, CDCl.sub.3 (ppm): 1.44 
s, 9H (t-Bu); 2.18 s, 2H (NH.sub.2); 2.87-3.80 m, 12H (CH.sub.2); 4.66 s, 
1H (NH); 4.77 s, 2H (COCH.sub.2 O); 6.63-7.28 m, 8H (Ar+ethylenic); 8.16 
s, 1H (NH). 
2: 2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-aminophenyl)piperazin-1- 
yl!ethanone hydrochloride 
The product 2A (252 mg, 0.51 mmol), in solution in toluene (13 ml) is 
treated with trifluoroacetic acid (3 ml) at room temperature. After 1 
hour, the mixture is diluted with ethyl acetate and washed with 2N sodium 
hydroxide, with water and then with a saturated sodium chloride solution. 
The organic phase is dried over sodium sulfate, filtered and evaporated. 
The syrup obtained is chromatographed on a column of silica gel eluted 
with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The 
pure product is isolated in the form of a yellow syrup (174 mg, 87%). The 
compound obtained is dissolved in methanol and the hydrochloride is formed 
by addition of the necessary amount of hydrochloric acid in methanol. 
Elemental analysis (C.sub.22 H.sub.30 N.sub.5 O.sub.2 Cl.sub.3.2H.sub.2 O), 
% calculated: C 49.03, H 6.36, N 12.99, % found: C 49.37, H 6.18, N 12.67. 
1H nuclear magnetic resonance spectrum, d6-DMSO (ppm): 
2.99-3.70 m, 12H (CH.sub.2); 4.83 s, 2H (COCH.sub.2 O); 6.76-6.82 dd, 1H 
(ethylenic); 7.05-7.28 m, 7H (Ar); 8.13 s, 3H (NH.sub.3.sup.+); 10.86 s, 
1H (NH). Melting point: 196.degree. C. 
EXAMPLE 3 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
acetamide hydrochloride 
##STR23## 
The product 2A (300 mg, 0.61 mmol), in solution in pyridine (7.5 ml), is 
treated at 0.degree. C. with acetic anhydride (60 ml, 0.61 mmol). After 
stirring for 2 hours at room temperature, the mixture is diluted with 
ethyl acetate and washed successively with a saturated copper sulfate 
solution, water and finally with a saturated sodium chloride solution. The 
organic phase is dried over sodium sulfate, filtered and evaporated to 
dryness. The syrup obtained is chromatographed on a column of silica gel 
eluted with a dichloromethane/acetone (2/1, v/v) mixture. The pure product 
is obtained in the form of a yellow syrup (249 mg; 77%). This compound is 
then deprotected according to the method described for the preparation of 
Example 2. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in methanol, in the compound 3 (113 mg, 
36%). 
Elemental analysis (C.sub.24 H.sub.31 N.sub.5 O.sub.3 Cl.sub.2.0.5H.sub.2 
O), % calculated: C 55.71, H 6.23, N 13.53, % found: C 55.70%, H 6.40, N 
13.46. 
1H nuclear magnetic resonance spectrum, d6-DMSO (ppm): 
2.00 s, 3H (CH.sub.3); 2.76-3.16 m, 8H (CH.sub.2); 3.68 m, 6H (CH.sub.2 
+H.sub.2 O); 4.82 s, 2H (COCH.sub.2 O); 6.77-6.82 dd, 1H (ethylenic); 
6.97-7.50 m, 7H (Ar); 8.01 s, 3H (NH.sub.3.sup.+); 9.85 s, 1H (NH); 10.86 
s, 1H (NH). Melting point: 169.degree. C. 
EXAMPLE 4 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
benzamide hydrochloride 
##STR24## 
The compound 4 is obtained from the product 2A (700 mg, 1.42 mmol) and 
benzoyl chloride (0.16 ml, 1.42 mmol) according to the procedure described 
for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in methanol, in the compound 4 (560 mg, 
66%). 
Elemental analysis (C.sub.29 H.sub.33 N.sub.5 O.sub.3 Cl.sub.2.2H.sub.2 O), 
% calculated: C 57.43, H 6.15, N 11.55; % found: C 57.32, H 5.97, N 11.53. 
1H NMR, d6-DMSO (ppm): 3.00 s, 4H (CH.sub.2); 3.35-3.42 d, 4H (CH.sub.2); 
3.89 s, 4H (CH.sub.2); 4.87 s, 2H (COCH.sub.2 O); 6.78-6.84 dd, 1H 
(ethylenic); 7.21-7.99 m, 12H (Ar); 8.10 s, 3H (NH.sub.3.sup.+); 10.35 s, 
1H (NH); 10.86 s, 1H (NH). Melting point: 184.degree.-185.degree. C. 
EXAMPLE 5 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
methanesulfonamide hydrochloride 
##STR25## 
The compound 5 is obtained from the product 2A (201 mg, 0.407 mmol) and 
mehanesulfonic chloride (31 .mu.l; 0.407 mmol) according to the procedure 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in methanol, in the compound 5 (151 mg, 
66%). 
Elemental analysis (C.sub.23 H.sub.31 N.sub.5 O.sub.5 SCl.sub.2.2H.sub.2 
O), % calculated: C 49.11, H 5.91, N 12.45; % found: C 49.88, H 5.73, N 
11.97. 
1H NMR, d6-DMSO (ppm): 2.89 s, 3H (MeSO.sub.2); 2.99-3.19 m, 8H (CH.sub.2); 
3.68 s, 4H (CH.sub.2); 4.82 s, 2H (COCH.sub.2 O); 6.77-6.82 dd, 1H 
(ethylenic); 7.01-7.29 m, 7H (Ar); 8.02 s, 3H (NH.sub.3.sup.+); 9.41 s, 1H 
(NH); 10.85 s, 1H (NH). Melting point: 150.degree. C. 
EXAMPLE 6 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
(methanesulfonyl)methanesulfonamide hydrochloride 
##STR26## 
The product 2A (500 mg, 1.01 mmol), in solution in dichloromethane (12.5 
ml) in the presence of triethylamine (0.56 ml, 4.04 mmol), is treated with 
mesyl chloride (0.17 ml, 2.03 mmol) at 0.degree. C. After leaving 
overnight at room temperature, the mixture is diluted with dichloromethane 
and washed with water. The organic phase is dried over sodium sulfate, 
filtered and evaporated to dryness. The syrup obtained is chromatographed 
on a column of silica gel eluted with an ethyl acetate/dichloromethane 
(2/1, v/v) mixture. The pure product is obtained in the form of a 
colorless syrup (127 mg, 20%). 
This compound is then deprotected according to the method described for the 
preparation of Example 2. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in mathenol, in the compound 6 (109 mg, 
90%). 
Elemental analysis (C.sub.24 H.sub.33 N.sub.5 O.sub.6 S.sub.2 Cl.sub.2), % 
calculated: C 46.30, H 5.34, N 11.25; % found: C 46.47, H 5.47, N 10.96. 
1HNMR, d6-DMSO (ppm): 2.99-3.90 m, 18H (MeSO.sub.2 --+CH.sub.2); 4.83 s, 2H 
(COCH.sub.2 O); 6.78-6.83 dd, 1H (ethylenic); 6.97-7.33 m, 7H (Ar); 7.96 
s, 3H (NH.sub.3.sup.+); 10.85 s, 1H (NH). Melting point: 202.degree. C. 
EXAMPLE 7 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
ethanesulfonamide hydrochloride 
##STR27## 
The compound 7 is obtained from product 2A (800 mg; 1.6 mmol) and 
ethanesulfonic chloride (0.15 ml, 1.6 mmol) according to the procedure 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure 
product is isolated in the form of an orange syrup which results, after 
treatment with hydrochloric acid in methanol, in the compound 7 (730 mg, 
78%). 
Elemental analysis (C.sub.24 H.sub.33 N.sub.5 O.sub.4 S.sub.1 
Cl.sub.2.H.sub.2 O), % calculated: C 50.00, H 5.95, N 12.54; % found: C 
50.00, H 5.75, N 12.54. 
1H NMR, d6-DMSO (ppm): 1.15-1.22 t, 3H (CH.sub.3); 2.94-3.16 m, 10H 
(CH.sub.2); 3.73 m, 4H (CH.sub.2); 4.82 s, 2H (COCH.sub.2 O); 6.77-6.82 
dd, 1H (ethylenic); 7.13-7.28 m, 7H (Ar); 7.99 s, 3H (NH.sub.3.sup.+); 
9.55 s, 1H (NH); 10.84 s 1H (NH). Melting point: 222.degree. C. 
EXAMPLE 8 
Thiophene-2-{N-4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin 
-1-yl)phenyl!sulfonamide hydrochloride 
##STR28## 
The compound 8 is obtained from the product 2A (800 mg, 1.62 =mmol) and 
thiophene sulfonic chloride (296 mg, 1.62 mmol) according to the procedure 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure 
product is isolated in the form of a yellow powder which results, after 
treatment with hydrochloric acid in methanol, in the compound 8 (575 mg, 
57%). 
Elemental analysis (C.sub.26 H.sub.31 N.sub.5 O.sub.4 S.sub.2 
Cl.sub.2.H.sub.2 O), % calculated: C 49.52, H 5.27, N 11.11; % found: C 
50.44, H 5.49, N 10.86. 
1H NMR, d6-DMSO (ppm): 2.99-3.16 m, 8H (CH.sub.2); 3.67 s, 4H (CH.sub.2), 
4.81 s, 2H (COCH.sub.2 O); 6.76-6.81 dd, 1H (ethylenic indole); 7.00-7.28 
m, 8H (Ar +ethylenic thiophene); 7.48 dd, 1H (ethylenic thiophene); 7.88 
dd, 1H (ethylenic thiophene); 8.06 s, 3H (NH.sub.3.sup.+); 10.13 s, 1H 
(NH); 10.86 s, 1H (NH). 
Melting point: 185.degree. C. 
EXAMPLE 9 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yl-oxy!acetyl}piperazin-1-yl)phenyl 
!(thiophene-2-sulfonyl)-thiophene-2-sulfonamide hydrochloride 
##STR29## 
The compound 9 is obtained from the product 2A (800 mg, 1.62 mmol) and 
thiophene sulfonic chloride (335 mg, 1.94 mmol) according to the procedure 
described for the preparation of Example 6. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/6.5/15, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in methanol, in the compound 2 (380 mg, 
32%). 
Elemental analysis (C.sub.30 H.sub.33 N.sub.5 O.sub.6 S.sub.4 Cl.sub.2), % 
calculated: C 7.49, H 4.35, N 9.23; % found: C 47.62 H 4.40, N 9.20 H NMR, 
d6-DMSO (ppm): 3.00 s, 4H (CH.sub.2); 3.27 s, 4H (CH.sub.2), 3.63 s, 4H 
(CH.sub.2); 4.82 s, 2H (COCH.sub.2 O); 6.77-7.30 m, 10H, (Ar+ethylenic); 
7.70 d, 2H (ethylenic); 8.05 s, 3H (NH.sub.3.sup.+); 8.20 d, 2H 
(ethylenic); 10.85 s, 1H (NH). 
Melting point: 180.degree. C. 
EXAMPLE 10 
3,5-Dimethylisoxazole-4-{N-4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acet 
yl}-piperazin-1-yl)phenyl!sulfonamide hydrochloride 
##STR30## 
The compound 10 is obtained from the product 2A (800 mg, 1.62 mmol) and 
3,5-dimmethylisoxazole-4-sulfonic chloride (317 mg, 1.62 mmol) according 
to the procedure described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 10 (576 mg, 
55%). 
Elemental analysis (C.sub.27 H.sub.34 N.sub.6 O.sub.5 S.sub.1 Cl.sub.2 ; 
H.sub.2 O), % calculated: C 50.11, H 5.67, N 12.99; % found: C 50.21, H 
5.22, N 12.52. 
1H NMR, d6-DMSO (ppm): 2.15 s, 3H (Me); 2.33 s, 3H (Me), 2.92-3.07 m, 8H 
(CH.sub.2); 3.64 s, 4H (CH.sub.2); 4.80 s, 3H (COCH.sub.2 O); 6.77-6.82 
dd, 1H (ethylchic); 6.95-7.28 m, 7H (Ar); 7.88 s, 3H (NH.sub.3.sup.+); 
9.98 s, 1H (NH); 10.84 s, 1H (NH). 
Melting point: 193.degree. C. 
EXAMPLE 11 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-N-{ethoxycarbonyl}aminophenyl 
)piperazin-1-yl!-ethanone hydrochloride 
##STR31## 
The compound 11 is obtained from the product 2A (600 mg, 1.21 mmol) and 
ethyl chloroformate (0.13 ml, 1.33 mmol) according to the procedure 
described for the preparation of Example 6. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 11 (230 mg, 
38%). 
Elemental analysis (C.sub.25 H.sub.32 N.sub.5 O.sub.4 Cl), % calculated: C 
59.81; H 6.42, N 13.95; % found: C 60.26, H 6.52, N 13.49. 
1H NMR, d6-DMSO (ppm): 1.22 t, 3H (CH.sub.3); 2.81-3.03 m, 8H (CH.sub.2); 
3.64 s, 4H (CH.sub.2); 4.03-4.14 q, 2H (CH.sub.2); 4.80 s, 2H (COCH.sub.2 
O); 6.75-6.80 dd, 1H (ethylchic); 6.80-7.33 m, 7H (Ar); 9.34 s, 1H (NH); 
10.74 s, 1H (NH). 
Melting point: 153.degree. C. 
EXAMPLE 12 
2,2,2-Trifluoroethane 
4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!- 
sulfonamide hydrochloride 
##STR32## 
The compound 12 is obtained from the product 2A (800 mg, 1.62 mmol) and 
trifluoroethane sulfonic chloride (0.36 ml, 3.24 mmol) according to the 
procedure described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is obtained in the form of a green-yellow syrup which results, 
after treatment with hydrochloric acid in methanol, in the compound 12 
(643 mg, 65%). 
1H NMR, d6-DMSO (ppm): 2.99-3.16 m, 8H (CH.sub.2); 3.67 s, 4H (CH.sub.2), 
4.82 s, 2H (COCH.sub.2 O); 6.76-6.82 dd, 1H (ethylenic); 6.99-7.55 m, 7H 
(Ar); 7.55 s, 2H (CF.sub.3 CH.sub.2 SO.sub.2); 8.07 s, 3H 
(NH.sub.3.sup.+); 10.12 s, 1H (NH); 10.85 s, 1H (NH). 
EXAMPLE 13 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
isopropanesulfonamide hydrochloride 
##STR33## 
The compound 13 is obtained from the product 2A (800 mg, 1.62 mmol) and 
isopropylsulfonic chloride (0.18 ml, 1.62 mmol) according to the procedure 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 13 (381 mg, 41%). 
1H NMR, d6-DMSO (ppm): 11.22 d, 6H (Me); 2.99-3.17 m, 9H (CH.sub.2 +CH); 
3.73 m, 4H (CH.sub.2); 4.83 s, 2H (COCO.sub.2 O); 6.78-7.03 dd, 1H 
(ethylenic); 7.16-7.28 m, 7H (Ar); 8.07 s, 3H (NH.sub.3.sup.+); 9.59 s, 1H 
(NH); 10.86 s, 1H (NH). 
EXAMPLE 14 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-nitrophenyl)piperazin-1-yl)et 
hanone hydrochloride 
##STR34## 
The compound 14 is obtained from (2-nitrophenyl)piperazine (15 g, 72.5 
mmol), chloroacetyl chloride (5.78 ml, 72.56 mmol) and the compound 1A 
(10.9 g, 39.6 mmol) according to the procedure described for the 
preparation of Example 1. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 14 (22 g, 67%). 
Elemental analysis (C.sub.22 H.sub.26 N.sub.5 O.sub.4 Cl.13H.sub.2 O), % 
calculated: C 54.67, H 5.96, N 14.49, Cl 7.33; % found: C 54.63, H 5.74, N 
14.25, Cl 7.65. 
1H NMR, d6-DMSO. (ppm): 3.00 m, 8H (CH.sub.2); 3.63 s, 4H (CH.sub.2), 4.81 
s, 2H (COCH.sub.2 O); 6.78-6.83 dd, 1H (ethylenic); 7.15-7.87 m, 7H (Ar); 
8.00s, 3H (NH.sub.3.sup.+); 10.85 s, 1H (NH). 
Melting point: 130.degree. C. 
EXAMPLE 15 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl)et 
hanethione hydrochloride 
##STR35## 
The compound 1, in the base form (600 mg, 1.42 mmol), in solution in 
toluene (12 ml) in the presence of Lawesson's reagent (401 mg, 0.99 mmol), 
is heated at reflux for 3 hours. The mixture is brought back to room 
temperature, diluted with dichloromethane and washed with water (twice). 
The organic phase is dried over sodium sulfate, filtered and evaporated to 
dryness. The syrup obtained is chromatoraphed on a column of silica gel 
eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) 
mixture. The pure product is isolated in the form of a syrup which 
results, after treatment with hydrochloric acid in ether, in the compound 
15 (378 mg, 52%). 
EXAMPLE 16 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(hydroxyamino)phenyl)piperazi 
n-1-yl)ethanone hydrochloride 
##STR36## 
The compound 1C, (5 g, 9.54 mmol), in solution in THF (120 ml) in the 
presence of a catalytic amount of Rhodium-on-alumina (490 mg, 0.48 mmol), 
is treated at 0.degree. C. with hydrazine hydrate (1.16 ml, 23.8 mmol). 
The mixture is stirred at room temperature for 4 hours and the catalyst is 
then filtered off on celite; the mixture is diluted with dichloromethane 
and washed with water. The organic phase is dried with sodium sulfate, 
filtered and evaporated to dryness. The syrup obtained is chromatographed 
on a column of silica gel eluted with a dichloromethane/ethyl acetate (5/1 
and then 2/1, v/v) mixture. The pure product is obtained in the form of a 
green-yellow syrup. 
This product is then deprotected according to the method described for the 
preparation of Example 2. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (90/9.5/0.5, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 16 (780 mg, 21%). 
EXAMPLE 17 
2-{5-4-(4-Nitrophenylpiperazine-1-sulfonylmethoxy!-1H-indol-3-yl}ethylamin 
e hydrochloride 
##STR37## 
The compound 17 is obtained from (4-nitrophenyl)piperazine (1 g, 4.82 
mmol), chloromethanesulfonyl chloride (719 mg, 4.82 mmol) and the compound 
1A (739 mg, 2.63 mmol) according to the procedure described for the 
preparation of Example 1. The pure product is isolated in the form of a 
syrup which results, after treatment with hydrochloric acid in ether, in 
the compound 17 (420 mg, 30%). 
EXAMPLE 18 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!pr 
opane-1-one hydrochloride 
##STR38## 
The compound 18 is obtained from (4-nitrophenyl)piperazine (1 g, 4.82 
mmol), .alpha.-methylchloroacetyl chloride (0.46 ml, 4.82 mmol) and the 
compound 1A (739 mg, 2.63 mmol) according to the procedure described for 
the preparation of Example 1. The pure product is isolated in the form of 
a syrup which results, after treatment with hydrochloric acid in ether, in 
the compound 18 (470 mg, 35%). 
EXAMPLE 19 
2-3-(2-(Dimethylamino)ethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperaz 
in-1-yl!ethanone hydrochloride 
##STR39## 
The compound 19 is obtained from (4-nitrophenyl)piperazine (200 mg, 0.96 
mmol), chloroacetyl chloride (76 ml, 0.96 mmol) and bufotenine (108 mg, 
0.53 mmol) according to the procedure described for the preparation of 
Example 1. The pure product is isolated in the form of a syrup which 
results, after treatment with hydrochloric acid in ether, in the compound 
19 (69 mg, 25%). 
EXAMPLE 20 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(dimethylamino)phenyl)piperaz 
in-1-yl!ethanone hydrochloride 
##STR40## 
The product 2A (800 mg, 1.62 mmol), in solution in tetrahydrofuran (27 ml) 
in the presence of tetrabutylammonium bromide (157 mg, 0.486 mmol) and of 
sodium hydroxide solution (6N) (2.7 ml, 16.2 mmol), is treated with 
dimethyl sulfate (0.61 ml, 6.48 mmol). After stirring for 2 h 30 at room 
temperature, the mixture is diluted with dichloromethane and washed with 
water. The organic phase is dried over sodium sulfate, filtered and 
evaporated to dryness. 
The syrup obtained is chromatoraphed on a column of silica gel eluted with 
a dichloromethane/acetone (4/1, v/v) mixture. 
This product is then deprotected according to the method described for the 
preparation of Example 2. 
The pure product is isolated in the form of a syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 20 (344 mg, 
40%). 
EXAMPLE 21 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yl-oxy!acetyl}piperazin-1-yl)phenyl 
!benzenesulfonamide hydrochloride 
##STR41## 
The compound 21 is obtained from the product 2A (800 mg, 1.62 mmol) and 
benzenesulfonic chloride (0.21 ml, 1.62 mmol) according to the procedure 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 21 (450 mg, 47%). 
Elemental analysis: (C.sub.28 H.sub.32 N.sub.5 O.sub.4 SCl.1.2H.sub.2 O), % 
calculated: C 56.83, H 5.86, N 11.84; % found: C 56.66, H 5.56, N 11.67. 
1H NMR, d6-DMSO (ppm): 2.98-3.02 m, 8H (CH.sub.2); 3.60 m, 4H (CH.sub.2); 
4.79s, 2H (COCH.sub.2 O); 6.75-7.72 m, 13 H (Ar+ethylenic); 7.99 s, 3H 
(NH3.sup.+); 9.90 s, 1H (NH); 10.84 s, 1H (NH). 
Melting point: 263.degree. C. 
EXAMPLE 22 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-methoxy-4-nitrophenyl)piperaz 
in-1-yl!ethanone hydrochloride 
##STR42## 
The compound 22 is obtained from (2-methoxy-4-nitrophenyl)piperazine (1.64 
g, 6.92 mmol), chloroacetyl chloride (0.55 ml, 6.92 mmol) and the compound 
1A (1.06 g, 3.8 mmol) according to the procedure described for the 
preparation of Example 1. Purification of the product in the base form is 
carried out by chromatoraphy on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 22 (747 mg, 
71%). 
Elemental analysis 1H NMR, d6-DMSO (ppm): 
EXAMPLE 23 
2-(5-{2-4-(4-Nitrophenyl)piperazin-1-yl!-ethoxy}-1H-indol-3-yl)ethylamine 
hydrochloride 
##STR43## 
EXAMPLE 23A 
2-5-(2-Chloroethoxy)-1H-indol-3-yl!-N-(tert-butoxycarbonyl)aminoethyl 
The product 1A (5 g, 18.09 mmol), in solution in methyl ethyl ketone (25 
ml) in the presence of potassium carbonate (15 g, 108.5 mmol), is treated 
with 1-bromo-2-chloroethane. After 24 hours at reflux, the mixture is 
diluted with dichloromethane, filtered through celite and evaporated to 
dryness. The brown syrup obtained is chromatographed on a column of silica 
gel eluted with a dichloromethane/acetone (30/1, v/v) mixture. The pure 
product is obtained in the form of white crystals (5.2 g, 84%). 
Elemental analysis (C.sub.17 H.sub.23 N.sub.2 O.sub.3 Cl), % calculated: C 
60.26, H 6.84, N 8.27; % found: C 60.37, H 6.98, N 8.21. 
1H NMR, CDCl.sub.3 (ppm): 1.46 s, 9H (t-Bu); 2.88-2.95 t, 2H (CH.sub.2); 
3.45 m, 2H (CH.sub.2); 3.81-3.87 t, 2H (CH.sub.2); 4.26-4.32 t, 2H 
(CH.sub.2); 4.65 s, 1H (NH); 6.87-6.93 dd, 1H (ethylenic); 7.01-7.29 m, 3H 
(Ar); 8.16 s, 1H (NH). 
Melting point: 129.degree. C. 
EXAMPLE 23B 
2-(5-{2-4-(4-Aminophenyl)piperazin-1-yl!-ethox}-1H-indol-3-yl)ethylamine 
hydrochloride 
A mixture of the product 23A (1.03 g, 3.07 mmol) and 
(4-nitrophenyl)piperazine (636 mg, 3.07 mmol) in dimethylformamide (1.5 
ml) in the presence of potassium carbonate (1.27 g, 9.3 mmol) and 
potassium iodide (166 mg, 0.3 mmol) is heated at 80.degree. C. for 31 
hours. The mixture is then diluted with ethyl acetate and washed with 
water and then with a saturated sodium chloride solution. The organic 
phase is dried over sodium sulfate, filtered and evaporated to dryness. 
The yellow solid obtained is purified on a column of silica gel eluted 
with a dichloromethane/methanol (30/1, v/v) mixture. The pure product is 
isolated in the form of a yellow solid (1.46 g, 94%). 
This product is deprotected according to the method described for the 
preparation of Example 2. The product is chromatographed on a column of 
silica gel eluted with a dichloromethane/methanol/aqueous ammonia 
(80/18.5/1.5, v/v) mixture. 
The pure product is isolated in the form of a yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 23 (1.17 
g, 78%). 
Elemental analysis (C.sub.22 H.sub.29 N.sub.5 O.sub.3 Cl.sub.2.1.5H.sub.2 
O), % calculated: C 51.87, H 6.33, N 13.75; % found: C 52.41, H 6.18, N 
13.68. 
1H NMR, d6-DMSO (ppm): 3.01-3.58 m, 12H (CH.sub.2); 4.19 m, 2H (CH.sub.2); 
4.48 m, 2H (CH.sub.2); 6.79-6.84 dd, 1H (ethylenic); 7.11-7.31 m, 5H (Ar); 
8.09-8.13 m, 5H (Ar+NH.sub.3.sup.+); 10.91 s, 1H (NH); 11.74 s, 1H 
(NH.sup.+). 
Melting point: 148.degree. C. 
EXAMPLE 24 
3-3-(2-aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!prop- 
2-en-1-one hydrochloride 
##STR44## 
EXAMPLE 24A 
2-(5-bromo-1H-indol-3-yl)-N-(tert-butoxycarbonyl)ethylamine 
5-Bromotryptamine (43 g, 180 mmol), in solution in tetrahydrofuran (500 ml) 
in the presence of sodium hydroxide solution (2N) (260 ml), is treated 
with di-tert-butyl dicarbonate (60 g, 275 mmol) at room temperature. 
After stirring overnight at room temperature, the mixture is diluted with 
ethyl acetate and washed with water and then with a saturated sodium 
chloride solution. The organic phase is dried over sodium sulfate, 
filtered and evaporated to dryness. The syrup obtained is chromatographed 
on a column of silica gel eluted with a toluene/ethyl acetate (80/20, v/v) 
mixture. The pure product is obtained in the form of a syrup which 
crystallizes from petroleum ether to give a beige powder (27 g, 44%). 
Melting point: 103.degree. C. 
EXAMPLE 24B 
Methyl 3-3-(2-(N-tert-butoxycarbonylamino)ethyl)-1H-indol-5-yl!acrylate 
The product 24A (5 g, 14.7 mmol) is heated in the presence of methyl 
acrylate (2 ml, 22.1 mmol), trethylamine (10 ml), tri-o-tolylphosphine (90 
mg, 0.29 mmol) and palladium acetate (33 mg, 1.47 mmol) at 100.degree. C. 
in a long narrow cylindrical bottle with a screw top. After stirring 
overnight, the same amounts of tri-o-tolylphosphine and palladium acetate 
are added. After 5 hours, the mixture is diluted with ethyl acetate and 
the precipitate formed is filtered off on celite. The filtrate is washed 
with water and then with a saturated sodium chloride solution. The organic 
phase is dried over sodium sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted 
with a dichloromethane/ethyl acetate (15/1 then 10/1, v/v) mixture. The 
pure product is obtained in the form of a pale yellow syrup (4.36 g, 86%). 
Elemental analysis (C.sub.19 H.sub.24 N.sub.2 O.sub.4), % calculated: C 
66.26, H 7.02, N 8.13; % found: C 65.40, H 6.74, N 7.79. 
1H NMR, CDCl.sub.3 (ppm): 1.44 s, 9H (t-Bu); 2.92-2.99 m, 2H (CH.sub.2); 
3.45-3.48 m, 2H (CH.sub.2); 3.82 s, 3H (COOMe); 4.64 s, 1H (NH); 6.39-6.47 
d, 1H (ethylenic); 7.05-7.89 m, 5H (Ar+ethylenics); 8.31 s, 1H (NH). 
EXAMPLE 24C 
3-3-(2-N-{tert-butoxycarbonyl}aminoethyl)-1H-indol-5-yl!acrylic acid 
The product 24B (2 g, 5.80 mmol), in solution in ethanol (20 ml) and water 
(0.2 ml), is treated with potassium hydroxide pellets (650 mg, 11.6 mmol). 
After 3 hours at reflux, the mixture is diluted with ethyl acetate and 
washed with a normal hydrochloric acid solution, with water and then with 
a saturated sodium chloride solution. The organic phase is dried over 
sodium sulfate, filtered and evaporated to dryness. The product 24C is 
obtained pure in the form of a white powder (1.85 g, 97%). 
Melting point: 179.degree.-181.degree. C. 
EXAMPLE 24 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!prop- 
2-en-1-one hydrochloride 
The product 24C (500 mg, 1.51 mmol), in solution in anhydrous 
dichloromethane (18 ml) in the presence of N-methylmorpholine (illegible! 
ml, 1.66 mmol), is treated at -15.degree. C., under nitrogen, with ethyl 
chloroformate (0.16 ml, 1.66 mmol). After stirring for 15 minutes at 
-10.degree. C., (4-nitrophenyl)piperazine (781 mg, 3.77 mmol) is added and 
the mixture is stirred from -10.degree. C. to room temperature for 1 hour. 
The mixture is then diluted with dichloromethane and washed with a 
saturated sodium bicarbonate solution, with water and then with a 
saturated sodium chloride solution. The organic phase is dried over sodium 
sulfate, filtered and evaporated to dryness. The syrup obtained is 
chromatographed on a column of silica gel eluted with a 
dichloromethane/methanol (40/1, v/v) mixture. The pure product is isolated 
in the form of a syrup (564 mg, 72%). This product is then deprotected 
according to the method described for the preparation of Example 2. 
The pure product is isolated in the form of a syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 24 (277 mg, 
50%). 
EXAMPLE 25 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!propa 
n-1-one hydrochloride 
##STR45## 
EXAMPLE 25A 
3-3-(2-N-{tert-butoxycarbonyl}aminoethyl)-1H-indol-5-yl!proplonic acid 
The product 24C (500 mg, 1.51 mmol), in solution in methanol (4 ml) in the 
presence of a catalytic amount of palladium-on-charcoal (30 mg), is 
hydrogenated by hydrogen gas. After 1 h 30 at room temperature, the 
mixture is diluted with dichloromethane, filtered through celite and 
evaporated to dryness. The pure product is obtained by recrystallization 
from ether to give a beige powder (483 mg, 96%). 
Elemental analysis (C.sub.18 H.sub.24 N.sub.2 O.sub.4), % calculated: C 
65.04, H 7.28, N 8.43: % found: C 64.57, H 7.35, N 8.25. 
1H NMR, d6-DMSO (ppm): 1.38 s, 9H (t-Bu); 2.50-3.40 m, 8H (CH.sub.2); 
6.87-7.32 m, 4H (Ar +ethylenic); 10.68 s, 1H (NH); 12.05 s, 1H (NH). 
EXAMPLE 25 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!propa 
n-1-one hydrochloride 
The compound 25 is obtained from the compound 25A (640 mg, 1.92 mmol) and 
4-nitrophenylpiperazine (981 mg, 4.73 mmol) according to the method 
described for the preparation of Example 24 from 24C. The pure product is 
obtained in the form of a syrup which results, after treatment with 
hydrochloric acid in ether, in the compound 25 (531 mg, 56%). 
Elemental analysis (C.sub.23 H.sub.29 Cl.sub.2 N.sub.5 O.sub.3.1.7H.sub.2 
O), % calculated: C 52.62, H 6.22, N 13.34, Cl 13.50; % found: C 52.56, H 
5.93, N 13.16, Cl 14.72. 
1H NMR, d6-DMSO (ppm): 2.69 m, 2H; 2.88-3.00 m, 6H; 3.42 m, 4H; 3.60 broad 
s, 4H; 6.94-7.42 m, 6H; 8.05 d, 2H; 8.14 s, 3H; 10.88 s, 1H. 
Melting point: 145.degree. C. 
EXAMPLE 26 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
-4-nitrophenylsulfonamide hydrochloride 
##STR46## 
Method A 
The compound 26 is obtained from the product 2A (768 mg, 1.55 mmol) and 
4-nitrobenzenesulfonyl chloride (689 mg, 3.10 mmol) according to the 
procedure described for the preparation of Example 3. 
Purification of the product, in the base form, is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The 
pure product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 26 (391 
mg, 44%). 
Elemental analysis (C.sub.28 H.sub.32 N.sub.6 O.sub.6 S.sub.1 --2.5H.sub.2 
O), % calculated: C 48.28, H 5.35, N 12.06, Cl 10.18, % found: C 48.09, H 
5.05, N 11.84, Cl 9.85. 
1H NMR, d6-DMSO (ppm): 2.96-3.14 m, 8H; 3.62 m, 4H; 4.78 s, 2H; 6.73-6.79 
dd, 1H; 6.95-7.26 m, 7H; 7.89-7.94 m, 5H; 8.33-8.37 d, 2H; 10.31 s, 1H; 
10.83 s, 1H. 
Melting point: 190.degree. C. 
Mass spectrum (DCI/NH.sub.3): m/z 579 (M+H). 
Method B 
26A-4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenylamine 
1-(4-Nitrophenyl)piperazine (50 g, 241.2 mmol), in solution in 
dichloromethane (11) in the presence of triethylamine (50.3 ml, 361.8 
mmol), is treated with di-tert-butyl dicarbonate (63.2 g, 289.4 mmol) at 
room temperature for 1 hour. The mixture is then diluted with 
dichloromethane and washed with water. The organic phase is dried over 
sodium sulfate, filtered and evaporated to dryness. 
The crude product obtained is taken up in methanol and is hydrogenated at 
atmospheric pressure in the presence of a catalytic amount of (5%) 
palladium-on-charcoal (2 g, 0.94 mmol). 
After stirring for 28 h at room temperature, the mixture is filtered 
through celite and evaporated to dryness. The syrup obtained is 
chromatographed on a column of silica gel eluted with a hexane/ethyl 
acetate (1/1, v/v) mixture. The pure product is isolated in the form of a 
pale pink powder (57 g, 85%). 
Elemental analysis (C.sub.15 H.sub.25 N.sub.3 O.sub.2), % calculated: C 
64.95, H 8.35, N 15.14; % found: C 64.95, H 8.31, N 14.89. 
1H NMR, d6-DMSO (ppm): 1.42 s, 9H; 2.83 t, 4H; 3.42 t, 4H; 4.62 s, 2H; 6.49 
d, 2H; 6.70 d, 2H. 
Melting point: 96.degree. C. 
26B--N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-nitrobenzenesulfo 
namide 
The compound 26A (37.6 g, 135.5 mmol), in a solution of dichloromethane (1 
l) in the presence of triethylamine (20.7 ml, 149.1 mmol), is treated at 
0.degree. C. with 4-nitrobenzenesulfonyl chloride (30.04 g, 135.5 mmol). 
After stirring for 3h 30 from 0.degree. C. to room temperature, 
4-nitrobenzenesulfonyl chloride (9.1 g; 40.6 mmol) is again added. After 2 
h 30, the reaction mixture is diluted with dichloromethane, washed with 
water, dried over sodium sulfate, filtered and evaporated to dryness. The 
dark green syrup obtained is taken up in methanol while hot and then 
cooled in order to obtain crystallization of the expected product, which 
is isolated by filtration on a buchner and washing with ether. A yellow 
powder (50 g, 80%) is obtained, which powder is used straight away in the 
following reaction. 
26C--4-Nitro-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide 
The above product (50 g, 108.1 mmol), in solution in toluene (1.3 l), is 
treated at room temperature with trifluoroacetic acid (180 ml). After 3 h 
30, the mixture is evaporated to dryness and coevaporated 5 times with 
toluene. The syrup obtained is purified on a silica column eluted with a 
dichloromethane/methanol/aqueous ammonia (90/9.5/0.5, v/v) and then 
(85/14/1, v/v) mixture. The product 26C and isolated in the form of a pale 
yellow powder (29 g, 75%). 
1H NMR, d6-DMSO (ppm): 3.20 m, 8H; 6.88 m, 4H; 7.93 d, 2H; 8.37 d, 2H; 9.29 
s, 1H. 
Melting point: 240.degree. C. 
26D--N-4-(4-{2-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!a 
cetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide 
3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetic acid (1 g, 
2.99 mmol), prepared according to a method described above (Patent 
Application FR 2699918-A), in solution in anhydrous dichloromethane (50 
ml) in the presence of N-methylmorpholine (0.45 ml, 4.5 mmol), is treated 
at -15.degree. C. and under nitrogen with ethyl chloroformate (0.37 ml, 
3.9 mmol). 
After stirring for 30 minutes, the compound 26C (2.2 g, 6.0 mmol) is added 
and the mixture is stirred from -15.degree. C. to room temperature for 4 
hours. The mixture is diluted with ethyl acetate and washed with a 
saturated sodium bicarbonate solution, then with water and finally with a 
saturated sodium chloride solution. The organic phase is dried over sodium 
sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/ethyl acetate (2/1 then 1/1, v/v) mixture. The product 
26D is isolated in the form of a pale yellow powder (1.3 g, 65%). 
Elemental analysis (C.sub.33 H.sub.38 N.sub.6 O.sub.8), % calculated: C 
58.39, H 5.64, N 12.38; % found: C 58.49, H 5.61, N 12.03. 
1H NMR, d6-DMSO (ppm): 1.34 s, 9H; 2.70 t, 2H; 3.09 m, 6H; 3.57 s, 4H; 4.74 
s, 2H; 6.71-7.21 m, 9H; 7.89 d, 2H; 8.34 d, 2H; 10.16 s, 1H; 10.63 s, 1H. 
Melting point: 237.degree. C. 
26--N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)ph 
enyl!-4-nitrophenylsulfonamide hydrochloride 
The compound 26D (2.76 g, 4.06 mmol), in suspension in toluene (82 ml), is 
treated at room temperature with trifluoroacetic acid (11 ml). After 
stirring for 3 h, the mixture is evaporated to dryness and coevaporated 4 
times with toluene. The syrup obtained is chromatographed on a column of 
silica gel eluted with a dichloromethane/methanol/aqueous ammonia 
(85/14/1, v/v) mixture. The pure product is isolated in the form of an 
orangey-yellow syrup which results, after treatment with hydrochloric acid 
in ether, in the compound 26 (2.38 g, 90%). 
The examples 27 to 34 are prepared according to the method described for 
the preparation of Example 3 from 2A. 
##STR47## 
__________________________________________________________________________ 
Examples 
Y Reactants Base/solvents/T .degree.C. 
Yd (%) 
M.p. (.degree.C.) 
Empirical 
__________________________________________________________________________ 
formulae 
27 
##STR48## Et.sub.3 N/CH.sub.2 Cl.sub.2 /50.degree. 
C. 16 244 C.sub.24 H.sub.29 
N.sub.5 O.sub.4.2HCl 
7 
28 
##STR49## 
##STR50## Et.sub.3 N/CH.sub.2 Cl.sub.2 /25.degree. 
C. 31 176 C.sub.30 H.sub.33 
N.sub.5 O.sub.3.2HCl 
9 
29 
##STR51## 
##STR52## pyridine/25.degree. C. 
46 192 C.sub.30 H.sub.33 
N.sub.5 O.sub.4.2HCl 
. 
30 
##STR53## (CF.sub.3 CO).sub.2 O 
Et.sub.3 N/CH.sub.2 Cl.sub.2 /25.degree. 
C. 20 183 C.sub.24 H.sub.26 
N.sub.5 O.sub.3 
F.sub.3.2HCl 
31 Me.sub.2 NSO.sub.2 
Me.sub.2 NSO.sub.2 Cl 
pyridine/25.degree. C. 
47 170 C.sub.24 H.sub.32 
N.sub.6 O.sub.4 
S.sub.1.2HCl 
32 
##STR54## 
##STR55## pyridine/25.degree. C. 
51 234 C.sub.27 H.sub.29 
N.sub.5 O.sub.3 
S.sub.1.2HCl 
33 
##STR56## 
##STR57## Et.sub.3 N/CH.sub.2 Cl.sub.2 /25.degree. 
C. 28 167 C.sub.29 H.sub.31 
N.sub.5 O.sub.4.2HCl 
34 
##STR58## 
##STR59## pyridine/25.degree. C. 
45 190 C.sub.29 H.sub.30 
N.sub.6 O.sub.5.2HCl 
__________________________________________________________________________ 
EXAMPLE 35 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-aminophenyl)piperazin-1-yl!propa 
n-1-one hydrochloride 
##STR60## 
35A--3-3-(2-{N-tert 
-Butoxycarbonyl}aminoethyl)-1H-indol-5-yl!-1-4-(4-aminophenyl)piperazin-1 
-yl!propan-1-one 
The compound 35A is prepared from the compound 25 (5.8 g, 11.1 mmol) under 
the conditions described for the preparation of Example 2 from 1C. The 
pink foam obtained (5.24 g, 96%) is used in the crude state in the 
following reaction. 
35--3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-aminophenyl)piperazin-1-yl!p 
ropan-1-one hydrochloride 
The product 35A (575 mg, 1.17 mmol) is then deprotected according to the 
method described for the preparation of Example 2 from 2A. 
Purification of the product, in the base form, is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 35 in the form 
of a pinkish powder (330 mg, 72%). 
Elemental analysis (C.sub.23 H.sub.32 Cl.sub.3 N.sub.5 O.H.sub.2 O), % 
calculated: C 53.24, H 6.60, N 13.50, Cl 20.50; % found: C 53.40; H 6. 
illegible!, N 13.53; Cl 18.84. 
1H NMR d6-DMSO (ppm): 2.70 t, 2H; 2.88-3.13 m, 10H; 3.63 s, 4H; 4.70 broad 
s, 3H; 6.97-7.42 m, 8H; 8.15 s, 3H; 10.90 s, 1H. 
Melting point: 189.degree. C. 
EXAMPLE 36 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!-propionyl}piperazin-1-yl)phenyl 
!methanesulfonamide hydrochloride 
##STR61## 
The compound 36 is prepared from the compound 35A (1.2 g, 2.43 mmol) and 
mesyl chloride (0.188 ml, 2.43 mmol) according to the method described for 
the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
chloroform/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 36 in the 
form of a beige powder (1.06 g, 77%). 
Elemental analysis (C.sub.24 H.sub.33 Cl.sub.2 N.sub.5 O.sub.3 
S.sub.1.H.sub.2 O), % calculated: C 51.43, H 6.29, N 12.49, Cl 12.65; % 
found: C 51.66, H 6.29, N 12.38, Cl 10.59. 
1HNMR, d6-DMSO (ppm): 2.70 t, 2H; 2.87-3.15 m, 13H; 3.73 s, 4H; 6.99 d, 1H; 
7.18-7.42 m, 7H; 8.13 s, 3H; 9.70 s, 1H; 10.89 s, 1H. 
Melting point: 179.degree. C. 
Mass spectrum (DCI/NH.sub.3): m/z 470 (M+H) 
EXAMPLE 37 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}piperazin-1-yl)phenyl! 
-N-dimethylsulfonurea hydrochloride 
##STR62## 
The compound 37 is prepared from the compound 35A (1.2 g, 2.43 mmol) and 
dimethylsulfamoyl chloride (0.39 ml, 3.64 mmol) according to the method 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 37 in the form 
of a beige powder (580 mg, 60%). 
Elemental analysis (C.sub.25 H.sub.36 Cl.sub.2 N.sub.6 O.sub.3 
S.sub.1.1.1H.sub.2 O), % calculated: C 50.77, H 6.51, N 14.21, Cl 11.99; % 
found: C 50.74, H 6.60, N 13.89, Cl 10.61. 
1H NMR, d6-DMSO (ppm): 2.66-2.75 m, 8H; 2.88-3.16 m, 10H; 3.76 broad s, 4H; 
7.00 d, 1H; 7.15-7.29 m, 6H; 7.43 s, 1H; 8.11 s, 3H; 9.91 s, 1H; 10.89 s, 
1H. 
Melting point: 166.degree. C. 
EXAMPLE 38 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!-propionyl}piperazin-1-yl)phenyl 
!-4-nitrobenzenesulfonamide hydrochloride 
##STR63## 
The compound 38 is prepared from the compound 35A (906 mg, 1.84 mmol) and 
4-nitrobenzenesulfonyl chloride (613 mg, 2.76mmol) according to the method 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of an orange syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 38 in the form 
of an orange powder (896 mg, 71%). 
Elemental analysis (C.sub.29 H.sub.34 Cl.sub.2 N.sub.6 O.sub.5 S.2H.sub.2 
O), % calculated: C 50.80, H 5.59, N 12.26, Cl 10.34; % found: C 50.83, H 
5.50, N 12.11, Cl 10.33. 
1H NMR, d6-DMSO (ppm): 2.78 t, 2H; 2.90 t, 2H; 3.00-3.16 m, 8H; 3.66 broad 
s, 4H; 6.96-7.41 m, 8H; 7.97 d, 2H; 8.09 broad s, 3H; 8.37 d, 2H; 10.56 s, 
1H; 10.88 s, 1H. 
Melting point: 184.degree. C. 
EXAMPLE 39 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}piperazin-1-yl)phenyl! 
benzamide hydrochloride 
##STR64## 
The compound 39 is prepared from the compound 35A (1.08 g, 2.18 mmol) and 
benzoyl chloride (0.25 ml, 2.18 mmol) according to the method described 
for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 39 in the form 
of a white powder (869 mg, 68%). 
Elemental analysis (C.sub.30 H.sub.35 Cl.sub.2 N.sub.5 O.sub.2.H.sub.2 O), 
% calculated: C 61.43; H 6.36; N 11.94, Cl 12.09; % found: C 61.54, H 
6.17, N 11.84, Cl 11.79. 
1H NMR, d6-DMSO (ppm): 2.72 t, 2H; 2.93-3.01 m, 6H; 3.21 m, 4H; 3.81 broad 
s, 4H; 7.00 d, 1H; 7.19-7.55 m, 8H; 7.81 d, 2H; 7.97 d, 2H; 8.14 broad s, 
3H; 10.39 s, 1H; 10.90 s, 1H. 
Melting point: 209.degree. C. 
EXAMPLE 40 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-ethyl}piperazin-1-yl)phenylamin 
e hydrochloride 
##STR65## 
40A: 
4-(4-{2-3-(2-{N-tert-butoxycarbonyl!aminoethyl)-1H-indol-5-yloxy!ethyl}pi 
perazin-1-yl)phenylamine 
The compound 40A is prepared from the compound 23A (7.1 g, 13.9 mmol) 
according to the conditions described for the preparation of Example 2 
from 1C. 
The brown syrup obtained is chromatographed on a column of silica gel 
eluted with a dichloromethane/acetone (1/1, v/v) mixture. The pure product 
is isolated in the form of a pink foam (6.45 g, 97%). 
1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.07 d, 2H; 2.65 m, 4H; 2.75 m, 4H; 2.93 
m, 2H; 3.09-3.17 m, 4H; 4.11 t, 2H; 4.56 s, 1H; 6.47-6.58 m, 2H; 6.68-6.75 
m, 2H; 6.86-6.90 m, 2H; 7.06-7.08 m, 2H; 7.21 d, 1H; 10.64 s, 1H. 
40: 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}-piperazin-1-yl)phenylami 
ne hydrochloride 
The product 40A (700 mg, 1.46 mmol), in solution in dichloromethane (12 
ml), is treated with a solution (.about.1.5M) of hydrochloric acid in 
ether (16 ml). After stirring for 1 hour, the mixture is evaporated to 
dryness and the product formed is desalified. The syrup obtained is 
chromatographed on a column of silica gel eluted with a 
dichloromethane/ethyl acetate (80/18.5/1.5, v/v) mixture. The pure product 
is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 40 in the form 
of a pale pink powder (669 mg, 87%). 
Elemental analysis (C.sub.22 H.sub.33 Cl.sub.4 N.sub.5 O.2H.sub.2 O), % 
calculated: C 48.31, H 6.52, N 12.80, C1 25.93; % found: C 48.31, H 6.65, 
N 12.55, Cl 24.95. 
1H NMR, d6-DMSO (ppm): 3.02 m, 4H; 3.30 m, 4H; 3.65 m, 4H; 3.88 d, 2H; 4.51 
broad s, 2H; 6.83 dd, 1H; 7.09-7.33 m, 7H; 8.21 broad s, 3H; 10.35 broad 
s, 3H; 10.95 s, 1H; 11.59 s, 1H. 
Melting point: 200.degree. C. (decomposition). 
EXAMPLE 41 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenyl!m 
ethanesulfonamide hydrochloride 
##STR66## 
The compound 41 is prepared from product 40A (1 g, 2.08 mmol) and 
methanesulfonyl chloride (0.194 ml, 2.50 mmol) according to the method 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 41 in the 
form of a white powder (1.01 g, 92%). 
Elemental analysis (C.sub.23 H.sub.33 Cl.sub.2 N.sub.5 O.sub.3 s.H.sub.2 
O), % calculated: C 50.36, H 6.43, N 12.77, Cl 12.93; % found: C 50.34, H 
6.16, N 12.46, Cl 14.31. 
1H NMR, d6-DMSO (ppm): 2.86 s, 3H; 3.00 broad s, 4H; 3.15-3.38 m, 4H; 
3.60-3.80 m, 6H; 4.48 t, 2H; 6.80 dd, 1H; 6.97 d, 2H; 7.12 d, 2H; 
7.20-7.30 m, 3H; 8.17 broad s, 3H; 9.36 s, 1H; 10.91 s, 1H; 11.49 s, 1H 
Melting point: 230.degree. C. (decomposition). 
EXAMPLE 42 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
methylcarbamate hydrochloride 
##STR67## 
The compound 42 is prepared from the product 40A (1.5 g, 3.13 mmol) and 
ethyl chloroformate (0.27 ml; 3.44 mmol) according to the method described 
for the preparation of Example 6. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The 
pure product is isolated in the form of a purple syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 42 in the 
form of a mauve powder (612 mg, 36%). 
Elemental analysis: (C.sub.24 H.sub.34 Cl.sub.3 N.sub.5 O.sub.3.0.8H.sub.2 
O), % calculated: C 51.35, H 6.35, N 12.48, Cl 18.95; % found: C 51.30; H 
6.37; N 12.13; Cl 19.02 
1HNMR, d6-DMSO (ppm): 3.00-3.30 m, 6H; 3.61 s, 3H; 3.68-3.90 m, 8H; 4.48 t 
2H; 6.80 dd, 1H; 6.94 d, 2H; 7.21-7.35 m, 5H; 8.17 broad s, 3H; 9.44 s, 
1H; 10.91 s, 1H; 11.41 s, 1H. 
Melting point: 166.degree. C. (decomposition). 
EXAMPLE 43 
2-(5-{2-4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl)ethoxy}-1-H-indol-3-yl)e 
thylamine hydrochloride 
##STR68## 
The compound 43 is prepared from the compound 23A (650 mg, 1.92 mmol) and 
(2-methoxy-4-nitrophenyl)piperazine (545 mg; 2.3 mmol) according to the 
conditions described for the preparation of Example 23. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 43 in the form 
of a yellow powder (777 mg, 79%). 
Elemental analysis: (C.sub.23 H.sub.31 Cl.sub.2 N.sub.5 O.sub.4.1H.sub.2 
O), % calculated: C 52.08, H illegible!.27, N 13.20, Cl 13.37; % found: C 
52.14; H 6.14; N 13.05; Cl 13.43 
1H NMR, d6-DMSO (ppm): 3.03 s, 4H; 3.36 m, 4H; 3.63 m, 4H; 3.83 m, 2H; 3.94 
s, 3H; 4.50 t, 2H; 6.84 dd, 1H; 7.13 d, 1H; 7.24-7.32 m, 3H; 7.74 d, 1H; 
7.86 dd, 1H; 8.15 broad s, 3H; 10.93 s, 1H; 11.60 s, 1H. 
Melting point: 210.degree. C. (decomposition). 
EXAMPLE 44 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!piperazin-1-yl)benzonitril 
e hydrochloride 
##STR69## 
44A: 4-(4-{2-3-(2-{N-tert-butoxylcarbonyl}aminoethyl)-1H 
-indol-5-yloxy!ethyl!piperazin-1-yl)benzonitrile 
The compound 44A is prepared from the product 23A (2.8 g, 8.19 mmol) and 
(4-cyanophenyl)piperazine (3.06 g, 8.19 mmol) according to the method 
described for the preparation of Example 23. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/ethyl acetate (5/1, v/v) mixture. The pure product is 
isolated in the form of a colorless syrup (2.03 g, 50%). 
1H NMR, CDCl.sub.3 (ppm): 1.42 s, 9H; 2.74-2.94 m, 8H; 3.36 m, 6H; 4.20 t, 
2H; 4.62 broad s, 1H; 6.83 m, 3H; 7.04 dd, 2H; 7.24 m, 1H; 7.50 m, 2H; 
8.11 s, 1H. 
44: 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!-piperazin-1yl)benzonitri 
le hydrochloride 
The product 44A (707 mg, 1.44 mmol) is then deprotected according to the 
method described for the preparation of Example 2 from 2A. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 44 in the form 
of a white powder (496 mg; 76%). 
Elemental analysis (C.sub.23 H.sub.27 N.sub.5 O.sub.1.2.3HCl.H.sub.2 O), % 
calculated: C 56.22, H 6.42, N 14.25, Cl 16.59; % found: C 56.84, H 6.40, 
N 14.04, Cl 16.72. 
1H NMR, d6-DMSO (ppm): 3.02 s, 4H; 3.37 m, 4H; 3.62 m, 4H; 4.11 m, 2H; 4.49 
t, 2H; 6.84 dd, 1H; 7.13 d, 2H; 7.23-7.32 m, 3H; 7.67 d, 2H; 8.14 broad s, 
3H; 10.93 s, 1H; 11.58 broad s, 1H. 
Melting point: 160.degree. C. 
EXAMPLE 45 
2-(5-{2-4-(4-(Aminomethyl)phenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)eth 
yl!methylamine hydrochloride 
##STR70## 
The compound 44A (600 mg, 1.23 mmol), in solution in anhydrous 
tetrahydrofuran (10 ml), is treated under nitrogen and at 0.degree. C. 
with a molar solution of lithium aluminum hydride in tetrahydrofuran (2.5 
ml, 2.46 mmol). The mixture is then stirred at 80.degree. C. for 12 h. The 
mixture is then treated with sodium sulfate/water and then filtered 
through celite. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 45 in the 
form of a yellow powder (281 mg, 44%). 
Elemental analysis: (C.sub.24 H.sub.36 Cl.sub.3 N.sub.5 O.sub.1.1.3H.sub.2 
O), % calculated: C 53.35, H 7.20, N 12.96, Cl 19.68; % found: C 53.37, H 
7.19, N 12.70; Cl 19.66. 
1H NMR, d6-DMSO (ppm): 3.09-3.28 m, 8H; 3.49-3.93 m, 8H; 4.53 s, 2H; 6.84 
dd, 1H; 7.05 d, 2H; 7.23-7.42 m, 5H; 8.39 broad s, 3H; 9.16 broad s, 2H; 
10.94 s, 1H; 11.55 broad s, 1H. 
Melting point: 84.degree. C. (decomposition). 
EXAMPLE 46 
2-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitri 
le hydrochloride 
##STR71## 
46A: 
2-(4-{2-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetyl}p 
iperazin-1-yl)benzonitrile 
The compound 46A is prepared from (2-cyanophenyl)piperazine (1 g; 5.34 
mmol), chloroacetyl chloride (0.43 ml, 5.34 mmol) and the compound 1A (660 
mg, 2.39 mmol) according to the procedure described for the preparation of 
the compound 1B. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/acetone (5/1, v/v) mixture. The pure product is isolated 
in the form of a colorless syrup (1.01 g, 84%). 
1H NMR CDCl.sub.3 (ppm): 1.40 s, 9H; 2.88 t, 2H; 3.16 m, 4H; 3.41 t, 2H; 
3.84 t, 2H; 4.60 broad s, 1H; 4.75 s, 2H; 6.86 dd, 1H; 6.94-7.09 m, 4H; 
7.23 m, 1H; 7.43-7.58 m, H; 8.10 broad s, 1H. 
46: 
2-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitr 
ile hydrochloride 
The product 46A (741 mg, 1.47 mmol) is then deprotected according to the 
method described in the preparation of Example 2 from 2A. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 46 in the form 
of a white powder (388 mg; 60%). 
Elemental analysis (C.sub.23 H.sub.26 ClN.sub.5 O.sub.2.1.4H.sub.2 O), % 
calculated: C 59.39, H 6.24; N 15.06; Cl 7.62; % found: C 59.72, H 5.85, N 
14.79, Cl 8.14. 
1HNMR, d6-DMSO (ppm): 3.00-3.20 m, 8H; 3.69 m, 4H; 4.83 s, 2H; 6.79 dd, 1H; 
7.10-7.29 m, 5H; 7.58-7.76 m, 2H; 8.08 broad s, 3H; 10.88 s, 1H. 
Melting point: 107.degree. C. (decomposition). 
EXAMPLE 47 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-aminomethylphenyl)piperazin-1 
-yl)ethanone hydrochloride 
##STR72## 
47A: 
2-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1-4-(2-(amin 
omethyl)phenyl)piperazinl-yl)ethanone 
The compound 46A (3.4 g; 6.8 mmol), in solution in tetrahydrofuran (114 ml) 
in the presence of Raney Nickel (.about.200 mg, catalytic), is subjected 
to an atmospheric pressure of hydrogen for 48 hours at room temperature. 
The mixture is filtered through celite and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/methanol/aqueous ammonia (90/9/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup (2.97 g; 86%). 
1H NMR, d6-DMSO (ppm): 1.36 s, 9H; 2.70-2.88 m, 6H; 3.17 m, 4H; 3.62 broad 
s, 4H; 3.77 s, 2H; 4.77 s, 2H; 6.75 dd, 1H; 6.87 t, 1H; 7.00-7.24 m, 6H; 
7.43 dd, 1H; 10.65 s, 1H. 
47: 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-(aminomethyl)phenyl)piperazi 
nlyl!ethanone hydrochloride 
The compound 47A (600 mg; 1.18 mmol) is then deprotected according to the 
method described for the preparation of Example 40. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 47 in the form 
of a white powder (506 mg, 83%). 
Elemental analysis: (C.sub.23 H.sub.32 Cl.sub.3 N.sub.5 O.sub.2.1.6H.sub.2 
O), % calculated: C 50.62, H 6.50, N 12.83, Cl 19.49; % found: C 50.85, H 
6.36, N 12.64, Cl 18.00. 
1HNMR, d6-DMSO (ppm): 2.80-2.99 m, 8H; 3.69 broad s, 4H; 4.11 s, 6H; 4.82 
s, 2H; 6.77 dd, 1H; 7.15-7.54 m, 7H; 8.16 broad s, 3H; 8.45 broad s, 3H; 
10.86 s, 1H. 
Melting point: 198.degree. C. (decomposition). 
EXAMPLE 48 
N-2-4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzylm 
ethanesulfonamide hydrochloride 
##STR73## 
The compound 48 is prepared from the compound 47A (800 mg; 1.58 mmol) and 
mesyl chloride (0.27 ml; 3.16 mmol) according to the method described for 
the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (83/16/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 48 in the form 
of a white powder (585 mg, 71%). 
Elemental analysis: (C.sub.24 H.sub.31 N.sub.5 O.sub.4 S.1.5HCl.1H.sub.2 
O), % calculated: C 51.63, H 6.23, N 12.54, Cl 9.52; % found: C 51.98, H 
6.11, N 12.45, Cl 8.94. 
1H NMR, d6-DMSO (ppm): 2.80-3.00 m, 11H; 3.67 broad s, 4H; 4.26 d, 2H; 4.82 
s, 2H; 6.79 dd, 1H; 7.09-7.47 m, 7H; 8.01 broad s, 3H; 10.85 s, 1H. 
Melting point: 250.degree. C. 
EXAMPLE 49 
N-2-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl!benzene 
sulfonamide hydrochloride 
##STR74## 
The compound 49 is prepared from the compound 47A (800 mg; 1.58 mmol) and 
benzenesulfonyl chloride (0.22 ml; 1.70 mmol) according to the method 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19.5/0.5, v/v) mixture. The 
pure product is isolated in the form of a colorless syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 49 in the 
form of a white powder (674 mg, 73%). 
Elemental analysis: (C.sub.29 H.sub.34 ClN.sub.5 O.sub.4 S), % calculated: 
C 59.63, H 5.87, N 11.99, Cl 6.07; % found: C 59.34, H 5.85, N 11.81, Cl 
6.21. 
1H NMR, d6-DMSO (ppm): 2.75 m, 4H; 3.00 m, 4H; 3.50 broad s, 4H; 4.04 s, 
2H; 4.78 s, 2H; 6.77 dd, 1H; 7.01-7.33 m, 7H; 7.55 m, 3H; 7.80 m, 2H; 7.99 
broad s, 4H; 10.84 s, 1H. 
Melting point: 240.degree. C. 
EXAMPLE 50 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)benzonitr 
ile hydrochloride 
##STR75## 
50A--4-(4-{2-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acet 
yl}piperazin-1-yl)benzonitrile 
The compound 50A is prepared from (4-cyanophenyl)piperazine (30.1 g, 160.9 
mmol), chloroacetyl chloride (12.8 ml, 160.9 mmol) and the compound 1A 
(7.2 g, 26.06 mmol) according to the procedure described for the 
preparation of the compound 1B. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
an ethyl acetate/dichloromethane (2/1, v/v) mixture. The pure product is 
isolated in the form of a white powder (10.9 g, 83%). 
Elemental analysis (C.sub.28 H.sub.33 N.sub.5 O.sub.4), % calculated: C 
66.78, H 6.61, N 13.91, % found: C 66.92, H 6.73, N 13.64. 
1H NMR, CDCl3 (ppm): 1.36 s, 9H; 2.83 t, 2H; 3.25-3.40 m, 6H; 3.75 m, 4H; 
4.71 s, 2H; 6.83 m, 3H; 6.97 s, 1H; 7.03 d, 1H; 7.22 d, 1H; 7.45 m, 2H; 
8.75 broad s, 1H. 
50--4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzo 
nitrile hydrochloride 
The product 50A (1 g, 1.98 mmol) is then deprotected according to the 
method described for the preparation of Example 1 from 2A. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 50 in the form 
of a white powder (728 mg, 88%). 
Elemental analysis (C.sub.23 H.sub.25 N.sub.5 O.sub.2.1.3HCl.0.8H.sub.2 O), 
% calculated: C 59.37, H 6.04, N 15.05, Cl 9.91; % found: C 59.46, H 5.92, 
N 14.87, Cl 9.77. 
1H NMR, d6-DMSO (ppm): 2.99 m, 4H; 3.45 m, 4H; 3.68 m, 4H; 4.83 s, 2H; 6.78 
dd, 1H; 7.03 d, 2H; 7.19 dd, 2H; 7.26 d, 1H; 7.61 d, 2H; 8.03 broad s, 3H; 
10.86 s, 1H. 
Melting point: 224.degree.-226.degree. C. 
EXAMPLE 51 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(aminomethyl)phenyl)piperazin 
-1-yl!ethanone hydrochloride 
##STR76## 
51A: 2-3-(2-{N-tert 
-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(aminomethyl)phenyl) 
piperazin-1-yl!-ethanone 
The compound 50A (800 mg, 1.59 mmol) is hydrogenated under the conditions 
described for the preparation of the product 47A from 46A. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The 
pure product is isolated in the form of a colorless syrup (800 mg, 99%). 
1H NMR, CDCl.sub.3 (ppm): 1.44 s, 9H; 2.91 t, 2H; 3.17 m, 4H; 3.46 m, 2H; 
3.80 m, 6H; 4.66 broad s, 1H; 4.78 s, 2H; 6.90 m, 3H; 7.02 d, 1H; 7.11 d, 
1H; 7.21-7.29 m, 4H; 8.14 broad s, 1H. 
51: 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(aminomethyl)phenyl)piperazi 
n-1-yl!ethanone hydrochloride 
The compound 51A (500 mg, 0.98 mmol) is then deprotected under the 
conditions described for the preparation of Example 2 from 2A. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (75/20/5, v/v) mixture. The pure 
product is isolated in the form of a beige solid which results, after 
treatment with hydrochloric acid in ether in the compound 51 in the form 
of a pale yellow powder (304 mg, 60%). 
Elemental analysis (C.sub.23 H.sub.32 Cl.sub.3 N.sub.5 O.sub.2.1.5H.sub.2 
O), % calculated: C 50.79, H 6.49, N 12.88, Cl 19.55; % found: C 50.68, H 
6.46, N 12.71, Cl 20.09. 
1HNMR, d6-DMSO (ppm): 2.98 broad s, 4H; 3.20-3.37 m, 4H; 3.69 m, 4H; 3.90 
m, 2H; 4.82 s, 2H; 6.77 dd, 1H; 7.10 d, 2H; 7.18 d, 2H; 7.25 d, 1H; 7.38 
d, 2H; 8.13 broad s, 3H; 8.35 broad s, 3H; 10.85 s, 1H. 
Melting point: 185.degree. C. (decomposition). 
EXAMPLE 52 
N-4-(4-(2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzyl! 
methanesulfonamide hydrochloride 
##STR77## 
The compound 52 is prepared from the product 51A (900 mg, 1.77 mmol) and 
mesyl chloride (0.14 ml, 1.77 mmol) under the conditions described for the 
preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a beige solid which results, after 
treatment with hydrochloric acid in ether, in the compound 52 in the form 
of a white powder (277 mg, 28%). 
Elemental analysis (C.sub.24 H.sub.33 Cl.sub.2 N.sub.5 O.sub.4 S.0.3H.sub.2 
O), % calculated: C 51.12, H 6.01, N 12.42, Cl 12.57; % found: C 51.12, H 
6.15, N 12.26, Cl 11.78. 
1HNMR, d6-DMSO (ppm): 2.80 s, 3H; 2.97 broad s, 4H; 3.25 m, 4H; 3.74 m, 4H; 
4.05 s, 2H; 4.81 s, 2H; 6.75 dd, 1H; 7.17-7.29 m, 7H; 7.49 broad s, 1H; 
8.05 broad s, 3H; 10.83 s, 1H. 
Melting point: 154.degree. C. (decomposition). 
EXAMPLE 53 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-amino-2-methoxyphenyl)piperaz 
in-1-yl!ethanone hydrochloride 
##STR78## 
53A: 
2-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1-4-(4-amino 
-2-methoxyphenyl)piperazin-1-yl!ethanone 
The compound 22 in its protected form (NHBOC) (3.06 g, 5.53 mmol) is 
treated under the conditions described for the preparation of Example 2 
from 1C. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/acetone (2/1, v/v) mixture. The pure product is isolated 
in the form of a beige foam (2.3 g, 81%). 
1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.72 m, 6H; 3.18 m, 2H; 3.60-3.75 m, 7H; 
4.77 s, 2H; 6.05-6.31 m, 2H; 6.75-6.89 m, 2H; 7.07 dd, 2H; 7.23 d, 1H; 
10.67 s, 1H. 
53: 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-amino-2-methoxyphenyl)pipera 
zin-1-yl!ethanone hydrochloride 
The compound 53A (600 mg, 1.14 mmol) is then deprotected according to the 
method described for the preparation of Example 40 from 40A. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 53 in the form 
of a white powder (441 mg, 73%). 
Elemental analysis (C.sub.23 H.sub.32 Cl.sub.3 N.sub.5 O.sub.3.2.2H.sub.2 
O), % calculated: C 48.25, H 6.41, N 12.23, Cl 18.58; % found: C 48.03, H 
6.19, N 12.06, Cl 18.72. 
1H NMR, d6-DMSO (ppm): 3.00-3.16 m, 8H; 3.71 m, 4H; 3.81 s, 3H; 4.83 s, 2H; 
6.77-6.96 m, 3H; 7.10-7.29 m, 4H; 8.14 broad s, 3H; 10.87 s, 1H. 
Melting point: .about.190.degree. C. 
EXAMPLE 54 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)-3-meth 
oxyphenyl!methanesulfonamide hydrochloride 
##STR79## 
The compound 54 is prepared from the product 53A (1.0 g, 1.91 mmol) and 
mesyl chloride (0.16 ml, 2.10 mmol) according to the method described for 
the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a beige solid which results, after 
treatment with hydrochloric acid in ether, in the compound 54 in the form 
of a beige powder (745 mg; 68%). 
Elemental analysis (C.sub.24 H.sub.33 Cl.sub.2 N.sub.5 O.sub.5 S.2H.sub.2 
O), % calculated: C 47.21, H 6.11, N 11.47, Cl 11.61; % found: C 47.49; H 
5.82; N 11.29, Cl 11.76. 
1HNMR, d6-DMSO (ppm): 2.97-3.16 m, 11H; 3.79 m, 7H; 4.82 s, 2H; 6.80 dd, 
1H; 6.85 d, 2H; 7.10-7.28 m, 4H; 8.04 broad s, 3H; 9.68 s, 1H; 10.85 s, 
1H. 
Melting point: 195.degree. C. (decomposition). 
EXAMPLE 55 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitronaphth-1-yl)piperazin-1- 
yl!ethanone hydrochloride 
##STR80## 
The compound 55 is prepared from (4-nitronaphthyl)piperazine (2.47 g, 9.56 
mmol), chloroacetyl chloride (1.37 ml, 17.2 mmol) and the compound 1A (350 
mg, 1.26 mmol) according to the method described for the preparation of 
Example 1. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of yellow crystals which results, after 
treatment with hydrochloric acid in ether, in the compound 55 in the form 
of an orange powder (340 mg, 49%). 
Elemental analysis (C.sub.26 H.sub.28 ClN.sub.5 O.sub.4.2H.sub.2 O), % 
calculated: C 57.19, H 5.91, N 12.83, Cl 6.49; % found: C 57.59, H 5.52, N 
12.69, Cl 7.02. 
1H NMR, d6-DMSO (ppm): 2.97 m, 4H; 3.13-3.21 m, 4H; 3.82 m, 4H; 4.84 s, 2H; 
6.78 dd, 1H; 7.17-7.27 m, 4H; illegible!65-7.82 m, 2H; 8.01 large s, 3H; 
8.26-8.35 m, 2H; 8.51 d, 1H; 10.84 s, lillegible!. 
Melting point: 183.degree. C. 
EXAMPLE 56 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl 
methanesulfonate hydrochloride 
##STR81## 
The compound 56 is prepared from 4-(piperazin-1-yl)phenyl methanesulfonate 
(1.62 g, 6.3 mmol), chloroacetyl chloride (0.60 ml, 7.54 mmol) and the 
compound 1A (1.16 g, 4.2 mmol) according to the method described for the 
preparation of Example 1. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 56 in the form 
of a beige powder (504 mg, 22%). 
Elemental analysis (C.sub.23 H.sub.30 Cl.sub.2 N.sub.4 O.sub.5 S.1H.sub.2 
O), % calculated: C 49.18, H 5.71, N 9.97, Cl 12.62; % found: C 49.13, H 
5.67, N 9.82, Cl 11.39. 
1H NMR, d6-DMSO (ppm): 2.97 m, 4H; 3.22 s, 4H; 3.29 s, 3H; 3.65 m, 4H; 4.80 
s, 2H; 6.77 dd, 1H; 7.02-7.26 m, 7H; 8.00 broad s, 3H; 10.84 s, 1H. 
Melting point: 238.degree.-240.degree. C. (decomposition). 
EXAMPLE 57 
6-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!he 
xan-1-one hydrochloride 
##STR82## 
57A: 6-Chloro-1-4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one 
(4-Nitrophenyl)piperazine (3.0 g, 14.48 mmol) in solution in methyl ethyl 
ketone (105 ml) in the presence of potassium carbonate (6 g, 43.4 mmol), 
is treated under nitrogen and at 0.degree. C. with 6-chlorohexanoic 
chloride (10.2 g, 15mmol). After stirring for 2 hours from 0.degree. C. to 
room temperature, the mixture is diluted with ethyl acetate and washed 
with sodium hydroxide solution (2N) and then with water. The organic phase 
is dried over sodium sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/acetone (30/1 then 10/1, v/v) mixture. The product 57A 
is obtained in the form of yellow crystals (4.1 g, 84%). 
57B: 
6-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitro 
phenyl)piperazin-1-yl!hexan-1-one 
A mixture of the compound 1A (1.87 g, 6.77 mmol) and the compound 57A (4.1 
g, 12.2 mmol) in dimethylformamide (11 ml) in the presence of cesium 
carbonate (3.3 g, 10.1 mmol) is heated at 70.degree. C. for 24 h. The 
mixture is diluted with ethyl acetate and washed with water. The organic 
phase is dried over sodium sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/ethyl acetate (2/1 then 1/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup (2.5 g, 63%). 
1H NMR, d6-DMSO (ppm): 1.34 s, 9H; 1.44-1.72 m, 6H; 2.36 t, 2H; 2.70 t, 2H; 
3.12 m, 2H; 3.46 m, 4H; 3.56 m, 4H; 3.92 t, 2H; 6.66 dd, 1H; 6.84 t, 1H; 
6.96 m, 3H; 7.04 d, 1H; 7.17 d, 1H; 8.04 d, 2H; 10.58 s, 1H. 
57: 
6-3-(2-Aminoethyl)-1H-indol-B-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!h 
exan-1-one hydrochloride 
The compound 57B (500 mg; 0.86 mmol) is then deprotected according to the 
method described for the preparation of Example 1 from 1C. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 57 in the form 
of a yellow powder (315 mg, 71%). 
Elemental analysis (C.sub.26 H.sub.34 ClN.sub.5 O.sub.4.1H.sub.2 O), % 
calculated: C 58.08, H 6.77, N 13.02, Cl 7.25; % found: C 57.96, H 6.47, N 
12.73, Cl 7.48. 
1H NMR, d6-DMSO (ppm): 1.44-1.76 m, 6H; 2.37 t, 2H; 2.96 m, 4H; 3.54 m, 8H; 
3.94 t, 2H; 6.70 dd, 1H; 6.95-7.04 m, 3H; 7.15-7.23 m, 2H; 8.02 m, 5H; 
10.77 s, 1H. 
Melting point: 100.degree. C. 
EXAMPLE 58 
6-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-aminophenyl)piperazin-1-yl!he 
xan-1-one hydrochloride 
##STR83## 
58A: 6-(3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol 
-5-yloxy!-1-4-(4-aminophenyl)piperazin-1-yl!hexan-1-one 
The compound 57B (2.01 g, 3.46 mmol) is hydrogenated under the conditions 
described for the preparation of Example 2A. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/acetone (3/1, v/v) mixture. The pure product is isolated 
in the form of a beige syrup (1.89 g, 99%). 
1H NMR, d6-DMSO (ppm): 1.35 s, 9H; 1.40-1.72 m, 6H; 2.34 t, 2H; 2.68-2.86 
m, 6H; 3.12 m, 2H; 3.52 broad s, 4H; 3.92 t, 2H; 4.59 s, 2H; 6.46 d, 2H; 
6.67 m, 3H; 6.84 t, 1H; 7.00 dd, 2H; 7.17 d, 1H. 
58: 
6-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-aminophenyl)piperazin-1-yl!h 
exan-1-one hydrochloride 
The compound 58A (500 mg, 0.91 mmol) is then deprotected under the 
conditions described for the preparation of Example 1 from 1C. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 58 in the 
form of a pale pink powder (270 mg, 60%). 
Elemental analysis (C.sub.26 H.sub.38 Cl.sub.3 N.sub.5 O.sub.2.1.4H.sub.2 
O), % calculated: C 53.46, H 7.04; N 11.99, Cl 18.21; % found: C 53.44, H 
6.96, N 11.80, Cl 17.13. 
1H NMR, d6-DMSO (ppm): 1.40-1.80 m, 6H; 2.40 t, 2H; 2.99 broad s, 4H; 3.18 
broad s, 4H; 3.64 m, 4H; 3.97 t, 2H; 6.70 dd, 1H; 7.07-7.28 m, 7H; 8.09 
broad s, 3H; 10.82 s, 1H. 
Melting point: 150.degree. C. 
EXAMPLE 59 
N-4-(4-{6-3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanoyl}piperazin-1-yl)pheny 
l!methane sulfonamide hydrochloride 
##STR84## 
The compound 59 is prepared from the product 58A (690 mg, 1.25 mmol) and 
mesyl chloride (107 .mu.l, 1.37 mmol) under the conditions described for 
the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a pale yellow syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 59 in the 
form of a beige powder (658 mg, 92%). 
Elemental analysis (C.sub.27 H.sub.39 Cl.sub.2 N.sub.5 O.sub.4 S.0.5H.sub.2 
O.0.3EtOH), % calculated: C 53.20, H 6.61, N 11.49, Cl 11.63; % found: C 
53.24, H 6.96, N 11.10, Cl 10.12. 
1H NMR, d6-DMSO (ppm): 1.53-1.75 m, 6H; 2.41 t, 2H; 2.93 s, 3H; 2.99 broad 
s, 4H; 3.23 broad s, 4H; 3.72 broad s, 4H; 3.97 t, 2H; 6.75 d, 1H; 
7.07-7.25 m, 7H; 8.04 broad s, 3H; 9.62 s, 1H; 10.81 s, 1H. 
Melting point: 141.degree. C. 
EXAMPLE 60 
N-4-(4-{6-3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanol}piperazin-1-yl)benzyl 
!benzenesulfonamide hydrochloride 
##STR85## 
The compound 60 is prepared from the product 58A (690 mg, 1.25 mmol) and 
benzenesulfonyl chloride (176 .mu.l, 1.37 mmol) under the conditions 
described for the preparation of Example 3. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a beige syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 60 in the form 
of a beige powder (550 mg, 67%). 
Elemental analysis (C.sub.32 H.sub.41 Cl.sub.2 N.sub.5 O.sub.4 S.0.5H.sub.2 
O % calculated: C 57.22, H 6.30, N 10.43, Cl 10.56; % found: C 57.31, H 
6.20, N 10.18, Cl 9.41. 
1HNMR, d6-DMSO (ppm): 1.52-1.75 m, 6H; 2.34 t, 2H; 2.99-3.08 m, 8H; 3.61 
broad s, 4H; 3.96 t, 2H; 6.73 dd, 1H; 6.97-7.26 m, 7H; 7.53-7.74 m, 5H; 
8.05 broad s, 3H; 10.05 s, 1H; 10.82 s, 1H. 
Melting point: 132.degree. C. 
EXAMPLE 61 
5-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!pe 
ntan-1-one hydrochloride 
##STR86## 
61A: 
5-3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitro 
phenyl)piperazin-1-yl!pentan-1-one 
The compound 61A is prepared from (4-nitrophenyl)piperazine (1.1 g, 5.20 
mmol), 5-chloropentanoyl chloride (2.6 ml, 20.8 mmol) and the compound 1A 
(800 mg, 2.89 mmol) under the conditions described for the preparation of 
the compound 57B. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/acetone (10/1, v/v) mixture. The pure product is 
isolated in the form of a yellow syrup (685 mg, 42%). 
1H NMR, d6-DMSO (ppm): 1.35 s, 9H; 1.71 m, 4H; 2.46 t, 2H; 2.70 t, 2H; 3.13 
m, 2H; 3.47 m, 4H; 3.58 broad s, 4H; 3.95 t, 2H; 6.69 dd, 1H; 6.84 t, 1H; 
6.95-7.19 m, 5H; 8.05 d, 2H; 10.58 s, 1H. 
61: 
5-3-(2-Aminoethyl)-1H-indol-5-yloxyl-1-4-(4-nitrophenyl)piperazin-1-yl!p 
entan-1-one hydrochloride 
The product 61A (300 mg, 0.530 mmol) is then deprotected under the 
conditions described for the preparation of Example 1 from 1C. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v)mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 61 in the form 
of a yellow powder (211 mg, 75%). 
Elemental analysis (C.sub.25 H.sub.32 ClN.sub.5 O.sub.4.1.7H.sub.2 O), % 
calculated: C 56.38, H 6.70, N 13.15, Cl 6.66; % found: C 56.33, H 6.58, N 
12.88, Cl 7.34. 
1H NMR, d6-DMSO (ppm): 1.75 m, 4H; 2.46 t, 2H; 2.99 m, 4H; 3.51 m, 4H; 3.62 
broad s, 4H; 4.00 t, 2H; 6.73 dd, 1H; 6.99-7.27 m, 5H; 7.99 broad s, 3H; 
8.08 d, 2H; 10.80 s, 1H. 
Melting point: 120.degree. C. 
EXAMPLE 62 
5-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(aminophenyl)piperazin-1-yl!pent 
an-1-one hydrochloride 
##STR87## 
The compound 62 is prepared from the product 61A (560 mg, 0.99 mmol) under 
the conditions described for the preparation of Example 2. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The 
pure product is isolated in the form of a colorless syrup which results, 
after treatment with hydrochloric acid in ether, in the compound 62 in the 
form of a pink powder (270 mg, 50%). 
Elemental analysis (C.sub.25 H.sub.36 Cl.sub.3 N.sub.5 O.sub.2.1.5H.sub.2 
O), % calculated: C 52.50, H 6.87, N 12.24, Cl 18.59; % found: C 52.42, H 
6.94, N 12.01, Cl 17.36. 
1H NMR d6-DMSO (ppm): 1.72 broad s, 4H; 2.43 t, 2H; 2.97 broad s, 4H; 3.14 
m, 4H; 3.62 broad s, 4H; 3.97 t, 2H; 6.71 dd, 1H; 7.06-7.24 m, 7H; 8.03 
broad s, 3H; 10.79 s, 1H. 
Melting point: 170.degree. C. 
EXAMPLE 63 
4-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!bu 
tan-1-one hydrochloride 
##STR88## 
The compound 63 is prepared from (4-nitrophenyl)piperazine (2.0 g, 9.65 
mmol), 4-chlorobutanoyl chloride (4.3 ml, 38.6 mmol) and the compound 1A 
(1.48 g, 5.36 mmol) under the conditions described for the preparation of 
Example 57. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 63 in the form 
of a yellow powder (919 mg, 35%). 
Elemental analysis (C.sub.24 H.sub.30 ClN.sub.5 O.sub.4.H.sub.2 O), % 
calculated: C 56.97, H 6.37, N 13.84, Cl 7.01; % found: C 56.88, H 6.12, N 
13.68, Cl 8.89. 
1HNMR, d6-DMSO (ppm): 1.96 t, 2H; 2.54 t, 2H; 2.97 broad s, 4H; 3.49 m, 4H; 
3.61 m, 4H; 4.00 t, 2H; 6.72 dd, 1H; 6.95-7.25 m, 5H; 8.05 m, 5H; 10.82 s, 
1H. 
Melting point: 120.degree. C. 
EXAMPLE 64 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-cy 
anophenylsulfonamide hydrochloride 
##STR89## 
64A: 
N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-cyanobenzenesulfonami 
de 
The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 
ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 
0.degree. C. with 4-cyanobenzenesulfonyl chloride (2.18 g, 10.81 mmol). 
After stirring for 4 h from 0.degree. C. to room temperature, 
4-cyanobenzenesulfonyl chloride (0.64 g, 3.24 mmol) is again added. After 
2 h 00, the reaction mixture is diluted with dichloromethane, washed with 
water, dried over sodium sulfate, filtered and evaporated to dryness. The 
dark green syrup obtained is chromatographed on a column of silica gel, 
eluted with a dichloromethane/acetone (25/1, v/v) mixture. The pure 
product is isolated in the form of a yellow syrup (3.28 g, 69%). 
Elemental analysis (C.sub.22 H.sub.26 N.sub.4 O.sub.4 S.sub.1.0.6H.sub.2 
O), % calculated: C 58.29, H 6.07, N 12.36, % found: C 58.17, H 5.76, N 
12.03. 
1H NMR, d6-DMSO (ppm): 1.37 s, 9H; 2.97 t, 4H; 3.35 m, 4H; 6.83 q, 4H; 7.79 
d, 2H; 8.00 d, 2H; 10.08 s, 1H. 
64: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
cyanophenylsulfonamide hydrochloride 
The compound 64 is prepared from the product 64A (3.2 g, 7.23 mmol) under 
the conditions described for the preparation of Example 26 from 26B. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 64 (1.1 g). 
EXAMPLE 65 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-( 
trifluoromethane)phenylsulfonamide hydrochloride 
##STR90## 
65A: 
N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-(trifluoromethane)ben 
zenesulfonamide 
The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 
ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 
0.degree. C. with 4-(trifluoromethane)benzenesulfonyl chloride (2.64 g, 
10.81 mmol). After stirring for 4 h from 0.degree. C. to room temperature, 
4-cyanobenzenesulfonyl chloride (0.75 g, 3.24 mmol) is again added. After 
2 h 00, the reaction mixture is diluted with dichloromethane, washed with 
water, dried over sodium sulfate, filtered and evaporated to dryness. The 
syrup obtained is chromatographed on a column of silica gel eluted with a 
dichloromethane/acetone (30/1, v/v) mixture. The pure product is isolated 
in the form of a yellow syrup (3.50 g, 67%). 
Elemental analysis (C.sub.22 H.sub.26 N.sub.3 O.sub.4 S.sub.1 
F.sub.3.0.4H.sub.2 O), % calculated: C 53.63, H 5.48, N 8.53; % found: C 
53.61, H 5.61, N 8.40. 
1H NMR, d6-DMSO (ppm): 1.41 s, 9H; 3.00 t, 4H; 3.38 m, 4H; 6.87 q, 4H; 7.91 
q, 4H; 10.13 broad s, 1H. 
65: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
(trifluoromethane)phenylsulfonamide hydrochloride 
The compound 65 is prepared from the product 65A (3.5 g, 7.20 mmol) under 
the conditions described for the preparation of Example 26 from 26B. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 65 (0.97 g). 
EXAMPLE 66 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-m 
ethoxyphenylsulfonamide hydrochloride 
##STR91## 
66A: 
N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-methoxybenzenesulfona 
mide 
The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 
ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 
0.degree. C. with 4-methoxybenzenesulfonyl chloride (2.23 g, 10.81 mmol). 
After stirring for 4 h from 0.degree. C. to room temperature, 
4-methoxybenzenesulfonyl chloride (0.67 g, 3.24 mmol) is again added. 
After 2 h 00, the reaction mixture is diluted with dichloromethane, washed 
with water, dried over sodium sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted 
with a dichloromethane/acetone (30/1, v/v) mixture. The pure product is 
isolated in the form of a yellow syrup (4.1 g, 84%). 
Elemental analysis (C.sub.22 H.sub.29 N.sub.3 O.sub.5 S.sub.1.0.3H.sub.2 
O), % calculated: C 58.34, H 6.59, N 9.28; % found: C 58.38, H 6.49, N 
9.08. 
1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.96 t, 4H; 3.38 t, 4H; 3.77 s, 3H; 6.83 
q, 4H; 7.01 d, 2H; 7.58 d, 2H; 9.69 s, 1H. 
66: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
methoxyphenylsulfonamide hydrochloride 
The compound 66 is prepared from the product 66A (4.1 g, 9.1 mmol) under 
the conditions described for the preparation of Example 26 from 26B. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 66 (1.6 g). 
EXAMPLE 67 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-f 
luorophenylsulfonamide hydrochloride 
##STR92## 
67A: 
N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-fluorobenzenesulfonam 
ide 
The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 
ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 
0.degree. C. with 4-fluorobenzenesulfonyl chloride (2.1 g, 10.81 mmol). 
After stirring for 4 h from 0.degree. C. to room temperature, 
4-fluorobenzenesulfonyl chloride (0.63 g, 3.24 mmol) is again added. After 
2 h 00, the reaction mixture is diluted with dichloromethane, washed with 
water, dried over sodium sulfate, filtered and evaporated to dryness. The 
syrup obtained is chromatographed on a column of silica gel, eluted with a 
dichloromethane/acetone (30/1, v/v) mixture. The pure product is isolated 
in the form of a yellow foam (3.6 g, 76%). 
Elemental analysis (C.sub.21 H.sub.26 N.sub.3 O.sub.4 S.sub.1 
F.sub.1.0.3H.sub.2 O), % calculated: C 57.21, H 6.08, N 9.53; % found: C 
57.36, H 6.01, N 9.45. 
1H NMR, d6-DMSO (ppm): 1.39 s, 9H; 2.98 t, 4H; 3.39 t, 4H; 6.84 q, 4H; 7.36 
m, 2H; 7.71 m, 2H; 9.86 s, 1H. 
67: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
fluorophenylsulfonamide hydrochloride 
The compound 67 is prepared from the product 67A (3.6 g, 8.26 mmol) under 
the conditions described for the preparation of Example 26 from 26B. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 67 (1.2 g). 
EXAMPLE 68 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-a 
cetamidophenylsulfonamide hydrochloride 
##STR93## 
68A: 
N-4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-acetamidobenzenesulfo 
namide 
The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 
ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 
0.degree. C. with 4-acetamidobenzenesulfonyl chloride (2.5 g, 10.81 mmol). 
After stirring for 4 h from 0.degree. to room temperature, 
4-acetamidobenzenesulfonyl chloride (0.76 g, 3.24 mmol) is again added. 
After 1 h 00, the reaction mixture is diluted with dichloromethane, washed 
with water, dried over sodium sulfate, filtered and evaporated to dryness. 
The syrup obtained is chromatographed on a column of silica gel eluted 
with a dichloromethane/acetone (6/1, v/v) mixture. The pure product is 
isolated in the form of a purple foam (3.5 g, 69%). 
Elemental analysis (C.sub.23 H.sub.30 N.sub.4 O.sub.5 S.sub.1.1H.sub.2 O), 
% calculated: C 56.08, H 6.55, N 11.37; % found: C 56.16, H 6.29, N 11.00. 
1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.03 s, 3H; 2.95 t, 4H; 3.37 t, 4H; 6.82 
q, 4H; 7.60 q, 4H; 9.70 s, 1H; 10.26 s, 1H. 
68: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
acetamidophenylsulfonamide hydrochloride 
The compound 68 is prepared from the product 68A (3.6 g, 8.26 mmol) under 
the conditions described for the preparation of Example 26 from 26B. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a syrup which results, after treatment 
with hydrochloric acid in ether, in the compound 68 (1.1 g). 
EXAMPLE 69 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-a 
minophenylsulfonamide hydrochloride 
##STR94## 
69A: 
N-4-(4-{2-3-(2-{N-tert-Butoxycarbonyl}amino)-1H-indol-5-yloxy!acetyl}pip 
erazin-1-yl)phenyl!-4-aminophenylsulfonamide hydrochloride 
The compound 69A is prepared from the compound 26C (1.3 g, 1.96 mmol) 
according to the method described for the preparation of Example 2A from 
1C. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/methanol/aqueous ammonia (95/4/1, v/v) mixture. The pure 
product is isolated in the form of an orange foam (1.2 g, 95%). 
1H NMR, d6-DMSO (ppm): 1.37 s, 9H; 2.73 t, 2H; 3.03-3.16 m, 6H; 3.60 broad 
s, 4H; 4.77 s, 2H; 5.91 s, 2H; 6.50 d, 2H; 6.74-6.93 m, 6H; 7.06 dd, 2H; 
7.20-7.33 m, 4H, 9.41 s, 1H; 10.66 s, 1H. 
69: 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4- 
aminophenylsulfonamide hydrochloride 
The compound 69A (560 mg, 0.86 mmol) is then deprotected under the 
conditions described for the preparation of Example 1 from 1C. 
Purification of the product in the base form is carried out by 
chromatography on a column of silica gel eluted with a 
dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure 
product is isolated in the form of a colorless syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 69 in the form 
of a white powder (407 mg, 72%). 
Elemental analysis (C.sub.28 H.sub.35 Cl.sub.3 N.sub.6 O.sub.4.3.2H.sub.2 
O), % calculated: C 46.99, H 5.83, N 11.74, Cl 14.86; % found: C 46.95, H 
5.82, N 11.42, Cl 14.37. 
1HNMR, d6-DMSO (ppm) 2.96 broad s, 4H; 3.23 broad d, 4H; 3.71 m, 4H; 4.79 
s, 2H; 6.56 d, 2H; 6.75 dd, 1H; 6.92-7.38 m, 9H; 8.01 broad s, 3H; 9.75 s, 
1H; 10.82 s, 1H. 
Melting point: 186.degree. C. 
EXAMPLE 70 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-( 
methanesulfonylamino)phenylsulfonamide hydrochloride 
##STR95## 
The compound 70 is prepared from the compound 69A (300 mg, 0.46 mmol) and 
methanesulfonyl chloride (36 .mu.l, 1.46 mmol) according to the method 
described for the preparation of Example 3. 
The syrup obtained is chromatographed on a column of silica gel eluted with 
a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The 
pure product is isolated in the form of a syrup which results, after 
treatment with hydrochloric acid in ether, in the compound 70 (30 mg, 
10%). 
The specific compounds of the present invention, then, may be identified as 
follows: 
A compound selected from the group consisting of: 
2-3-(2-Aminoethyl)-1-H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!e 
thanone. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(aminophenyl)piperazin-1-yl!etha 
none. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!acetamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!benzamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!methethanesulfonamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1-methylsulfonyl-1H-indol-5-yloxy!acetyl}piper 
azin-1-yl)phenyl!methanesulfonamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!ethanesulfonamide. 
Thiophene-2-{N-4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin 
-1-yl)phenyl!sulfonamide. 
Thiophene-2-{N-4-(4-{2-3-(2-aminoethyl)-1-(thiophene-2-sulfonyl)-1H-indol 
-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide. 
3,5-Dimethylisoxazole-4-{N-4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acet 
yl}piperazin-1-yl)phenyl!sulfonamide. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-N-{ethoxycarbonyl}aminophenyl 
)piperazin-1-yl!ethanone. 
2,2,2-Trifluoroethane 
4-(4-{2-3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!s 
ulfonamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
isopropanesulfonamide. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-nitrophenyl)piperazin-1-yl)et 
hanone. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl)et 
hanethione. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(hydroxyamino)phenyl)piperazi 
n-1-yl)ethanone. 
2-{5-4-(4-Nitrophenylpiperazine 
-1-sulfonylmethoxy!-1H-indol-3-yl}ethylamine. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!pr 
opane-1-one. 
2-3-(2-(Dimethylamino)ethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperaz 
in-1-yl!ethanone. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(dimethylamino)phenyl)piperaz 
in-1-yl!ethanone. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!benzenesulfonamide. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-methoxy-4-nitrophenyl)piperaz 
in-1-yl!ethanone. 
2-(5-{2-4-(4-Nitrophenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethylamine. 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!prop- 
2-en-1-one. 
3-3-(2-Aminoethyl)-1H-indol-5-yl!-1-4-(4-nitrophenyl)piperazin-1-yl!propa 
n-1-one. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl! 
-4-nitrophenylsulfonamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!-2-phenylacetamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!-2-methoxybenzamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!-2,2,2-trifluoroacetamide. 
3-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!-1,1-dimethylsulfonurea. 
Thiophene-2-carboxylic acid 4-(4-{2-3-2-aminoethyl) 
indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!amide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!phenylcarbamate. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!-4-nitrobenzamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!methylcarbamate. 
3-3-(2-Aminoethyl)-1H 
-indol-5-yl!-1-4-(4-aminophenyl)-piperazin-1-yl!propan-1-one. 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl 
!methanesulfonamide. 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl 
!-N-dimethylsulfonylurea. 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl 
!-4-nitrobenzenesulfonamide. 
N-4-(4-{3-3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl 
!benzamide. 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-ethyl}piperazin-1-yl)phenylamin 
e. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenyl!m 
ethanesulfonamide. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
!methylcarbamate. 
2-(5-{2-4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl) 
-ethoxy}-1-H-indol-3-yl)ethylamine. 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!-piperazin-1-yl)benzonitri 
le. 
2-(5-{2-4-(4-(Aminomethyl)phenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)eth 
yl!methylamine. 
2-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)benzonitr 
ile. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(2-aminomethylphenyl)piperazin-1 
-yl!ethanone. 
N-2-4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzyl 
methanesulfonamide. 
N-2-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl!benzen 
esulfonamide. 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzonitr 
ile. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-(aminomethyl)phenyl)piperazin 
-1-yl!ethanone. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzyl 
!methane sulfonamide. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-amino-2-methoxyphenyl)piperaz 
in-1-yl!ethanone. 
N-4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)-3-met 
hoxyphenyl!methanesulfonamide. 
2-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitronaphth-1-yl)piperazin-1- 
yl!ethanone. 
4-(4-{2-3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl 
methanesulfonate. 
6-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!he 
xan-1-one. 
6-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-aminophenyl)piperazin-1-yl!he 
xan-1-one. 
N-4-(4-{6-3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanoyl}-piperazin-1-yl)phen 
yl!methanesulfonamide. 
N-4-(4-{6-3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanol}-piperazin-1-yl)benzy 
l!benzenesulfonamide. 
5-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!pe 
ntan-1-one. 
5-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(aminophenyl)-piperazin-1-yl!-pe 
ntan-1-one. 
4-3-(2-Aminoethyl)-1H-indol-5-yloxy!-1-4-(4-nitrophenyl)piperazin-1-yl!bu 
tan-1-one. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-c 
yanophenylsulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-( 
trifluoromethane)phenyl sulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-m 
ethoxyphenylsulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-f 
luorophenylsulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-a 
cetamidophenylsulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-a 
minophenylsulfonamide. 
N-4-(4-{2-3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-( 
methanesulfonylamino)phenylsulfonamide, and 
their salts which are acceptable for therapeutic use. 
STUDY OF THE AFFINITY FOR 5-HT.sub.1D RECEPTORS 
This study is carried out according to the technique described by Pauwells 
et al. (Biochem. Pharmacol, 46, 535-538, 1993). 
Preparation of the membranes 
Sheep brains are removed in the local abattoir and transported in ice. The 
caudate nuclei are removed, weighed and homogenized with a Polytron for 20 
sec (speed 6-7) in 20 volumes of Tris-HCl 50 mM, pH 7.7. The homogenate is 
centrifuged for 10 min at 48,000 g with an L5 50E centrifuge (Beckman). 
The pellet, taken up in 20 volumes of Tris-HCl 50 mm, pH 7.7, is placed in 
a water bath at 37.degree. C. for 10 min and then recentrifuged for 10 min 
at 48,000 g. The pellet then obtained is immediately frozen in fractions 
containing 0.5g of tissue. 
Affinities 
The pellet is defrosted and homogenized with a Dounce in 80 volumes of 
Tris-HCl 50 mM, pH 7.7, containing 4 mM CaCl.sub.2, 10 .mu.M of pargyline 
and 0.1% of ascorbic acid. 
Affinity is produced at 25.degree. C. by incubating for 30 min: 
0.1 ml of buffer or 10 .mu.M, as final concentration, of sumatriptan, in 
order to obtain the non-specific binding 
0.8 ml of membrane 
0.1 ml of 3H-5HT (15 to 30 Ci:mM, New England Nuclear France). 
The incubation is brought to an end by rapid filtration through GF/B 
filters and rinsing with 3 times 3 illegible! ice-cold buffer, using a 
harvester manufactured by Brandel which makes it possible illegible! to 
filter illegible!samples. The filters are introduced into vials 
containing illegible!ml of illegible! illegible! scintillant (Packard) 
and the radioactivity measured with a Tri-carb 4640 counter (Packard). The 
IC.sub.50 (concentration which inhibits the specific affinity by 50%) is 
determined graphically. 
The affinities of the various products which form part of this invention 
for 5HT.sub.1A and 5HT.sub.1B receptors were measured according to the 
techniques described in: 
Peroutka S. J. Pharmacological differentiation and characterization of 
5HT.sub.1A, 5HT.sub.1B and 5HT.sub.1C binding sites in rat frontal cortex. 
J. Neurochem., 45, 529-540, 1986. 
______________________________________ 
Examples of the affinity profile of several molecules 
(IC.sub.50 .times. 10-9M) 
5-HT.sub.1D 5-HT.sub.1A 
Ratio.sup.# 
Example* mean mean 1A/1D 
______________________________________ 
4 1 75 75 
6 4.3 79 18 
7 1.6 44 28 
8 1.2 26 22 
9 5 38 8 
10 1 20 20 
11 2.4 105 44 
14 1 9.5 10 
______________________________________ 
*The examples are the ones described in the text in order to illustrate 
the invention 
.sup.# Ratio of the IC.sub.50 values of each product for the 5HT.sub.1A 
and 5HT.sub.1D receptors 
STUDY OF THE AGONIST ACTIVITY WITH RESPECT TO THE 5-HT.sub.1B RECEPTORS 
The measurements were carried out with respect to the inhibition of the 
formation of cAMP stimulated by forskolin, mediated by a 5-HT.sub.1B 
receptor, in an OK kidney epithelial cell line as described elsewhere (P. 
J. Pauwels and C. Palmier, Neuropharmacology, awaiting publication). 
The studies carried out show that the majority of the products of the 
invention, like serotonin, are capable of effectively blocking the 
formation of cAMP in this test. Thus, Examples 1, 2, 3 and 5 have an 
EC.sub.50 of between 0.3 and 1.2 nM. 
Study of the affinity and of the agonist activity with respect to human 
receptors 
Human 5HT.sub.1Da and 5HT.sub.1Db receptors were cloned according to the 
sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 
(1991) and Weinshenk et al., Proc. Natl. Acad. Sci., 89, 3630 (1992). 
The transient transfection and the stable transfection of the genes of 
these receptors was carried out in Cos-7 and CHO-K.sub.1 cell lines by 
using an electroporator. 
The HeLa HA7 cell line expressing the 5HT.sub.1A human receptor was 
obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultured according 
to the method of Fargin et al., J. Biol. Chem., 264, 14848 (1989). 
The binding of the derivatives of the present invention with human 
5HT.sub.1Da, 5HT.sub.1Db and 5HT.sub.1A receptors was studied according to 
the method described by P. Pauwels and C. Palmier (Neuropharmacology, 33, 
67, 1994). 
The incubation media for these binding measurements comprise 0.4 ml of cell 
membrane preparation, 0.05 ml of a tritiated ligand 3H!-SCT (final 
concentration: 2 nM) for the 5HT.sub.1Da and 5HT.sub.1Db receptors and 
3H!-80H-DPAT (final concentration: 1 nM) for the 5HT.sub.1A receptor! and 
0.05 ml of the molecule to be tested (final concentrations from 0.1 nM to 
1000 nM) or 10 .mu.M (final concentration) of serotonin (5HT.sub.1Da and 
5HT.sub.1Db) or 1 .mu.M (final concentration) of spiroxatrin (5HT.sub.1A 
). 
The inhibition of the formation of cyclic AMP (stimulated by forskolin) 
mediated by the human 5HT.sub.1Db receptor was studied in CHO-K1 cells 
transfected by the receptor according to the technique described 
previously for the 5HT.sub.1B receptor (P. Pauwels and C. Palmier, 
Neuropharmacology, 33, 67, 1994). 
Illustration of the profile of several molecules of the present invention 
______________________________________ 
Ki (nM) 
Example 5HT.sub.1Da 
5HT.sub.1Db 
5HT.sub.1A 
EC.sub.50 * (nM) 
______________________________________ 
1 0.5 1 25 1.2 
3 1.7 3.3 78.6 20 
5 0.7 3.2 73 6.5 
26 0.25 0.5 16.5 6.5 
33 2.8 2 39 9 
41 1.1 0.7 28 2.6 
59 1.3 1.3 9.3 0.52 
______________________________________ 
*Inhibition of the 5HT.sub.1Db cyclase stimulated by forskolin 
The several examples described above clearly show that the products of the 
present invention are excellent ligands for human 5HT.sub.1Da and 
5HT.sub.1Db receptors and are excellent agonists with respect to the human 
5HT.sub.1Db receptor. 
The new arylpiperazine-derived indole compounds which form part of this 
invention are ligands having an exceptional affinity for the 5-HT.sub.1D 
and 5-HT.sub.1B receptors, as is demonstrated by the examples described 
above. Many compounds which are an integral part of the present invention 
have the additional advantage of being particularly selective for the 5 
HT.sub.1D receptor with respect to the 5 HT.sub.1A, 5 HT.sub.1C, 5 
HT.sub.2, .alpha..sub.1, .alpha..sub.2 and D.sub.2 receptors. The 
selectivity of the compounds of the present invention and in particular 
their preferential affinity for the 5 HT.sub.1D receptor with respect to 
the 5 HT.sub.1A receptor represents a very important advantage with 
respect to the ligands of the 5 HT.sub.1D receptor known to date (cf. 
Annual Reports in Medicinal Chemistry, vol. 27, chapter 3, p. 25; Academic 
Press, 1992). 
In human therapeutics, the compounds of general formula (I) according to 
the invention are particularly useful in the treatment and prevention of 
disorders related to serotonin in the central nervous system and in the 
vascular system. These compounds can therefore be used in the treatment 
and prevention of depression, compulsive obsessional disorders, eating 
disorders, such as bulimia and anorexia, aggressiveness, alcoholism, 
nicotine addiction, hypertension, nausea, sexual dysfunctioning, asocial 
behavior, anxiety, migraine, Alzheimer's disease and memory disorders. 
The present invention also relates to the medicaments comprising at least 
one compound of formula (I) in the pure state or in the form of a 
composition in which it is combined with any other pharmaceutically 
compatible product, which can be inert or physiologically active. The 
medicaments according to the invention can be employed orally, 
parenterally, rectally or topically. 
Tablets, pills, powders (gelatin capsules or cachets) or granules can be 
used as solid compositions for oral administration. In these compositions, 
the active principle according to the invention is mixed with one or a 
number of inert diluents, such as starch, cellulose, sucrose, lactose or 
silica, under an argon stream. These compositions can also comprise 
substances other than the diluents, for example one or a number of 
lubricating agents such as magnesium stearate or talc, a coloring agent, a 
coating agent (dragees) or a varnish. 
Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and 
elixirs containing inert diluents such as water, ethanol, glycerol, 
vegetable oils or paraffin oil can be used as liquid compositions for oral 
administration. These compositions can comprise substances other than the 
diluents, for example wetting, sweetening, thickening, flavoring or 
stabilizing substances. 
The sterile compositions for parenteral administration can preferably be 
suspensions, emulsions or nonaqueous or aqueous solutions. Water, 
propylene glycol, a polyethylene glycol, vegetable oils, in particular 
olive oil, injectable organic esters, for example ethyl oleate, or other 
suitable organic solvents can be used as solvent or vehicle. These 
compositions can also contain adjuvants, in particular wetting, 
isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization 
can be carried out in several ways, for example by aseptic filtration, by 
incorporating sterilizing agents in the composition, by irradiation or by 
heating. They can also be prepared in the form of solid sterile 
compositions which can be dissolved at the time of use in sterile water or 
any other injectable sterile medium. 
The compositions for rectal administration are suppositories or rectal 
capsules which contain, besides the active product, excipients such as 
cocoa butter, semi-synthetic glycerides or poly(ethylene glycol)s. 
The compositions for topical administration can be, for example, creams, 
lotions, eyedrops, mouthwashes, nosedrops or aerosols. 
The doses depend on the desired effect, on the duration of treatment and on 
the administration route used; they are generally between 0.001 g and 1 g 
(preferably between 0.005 g and 0.25 g) per day, preferably orally, for an 
adult with unit doses ranging from 0.1 mg to 500 mg of active substance 
and preferably from 1 mg to 50 mg. 
Generally, the doctor will determine the appropriate dosage depending on 
the age, weight and all the other factors specific to the subject to be 
treated. The following examples illustrate compositions according to the 
invention in these examples, the term "active component" denotes one or a 
number (generally one) of the compounds of formula (I) according to the 
present invention!: 
Tablets 
They can be prepared by direct compression or by passing through a wet 
granulation. The procedure by direct compression is preferred but it may 
not be suitable in all cases, depending on the doses and the physical 
properties of the active component. 
A--By direct compression 
______________________________________ 
mg for 1 tablet 
______________________________________ 
Active component 10.0 
Microcrystalline cellulose, B.P.C. 
89.5 
Magnesium stearate 0.5 
100.0 
______________________________________ 
The active component is passed through a sieve with a mesh size of 250 
.mu.m per side, mixing is carried out with the excipients and compression 
is carried out using 6.0 mm dies. Tablets having other mechanical 
strengths can be prepared by modifying the compressive weight with use of 
appropriate dies. 
B--Wet granulation 
______________________________________ 
mg for one tablet 
______________________________________ 
Active component 10.0 
Lactose, pharmaceutical grade 
74.5 
Starch, pharmaceutical grade 
10.0 
Pregelatinized maize starch, 
5.0 
pharmaceutical grade 
Magnesium stearate 
0.5 
Weight at compression 
100.0 
______________________________________ 
The active component is passed through a sieve with a mesh size of 250 
.mu.m and mixing is carried out with the lactose, the starch and the 
pregelatinized starch. The mixed powders are moistened-with purified 
water, granulation is carried out, drying is carried out, sieving is 
carried out and mixing with magnesium stearate is carried out. The 
lubricated granules are compressed as in the direct compression formulae. 
A thin coating layer can also be applied to the tablets by means of 
appropriate film-forming materials, for example methylcellulose or 
hydroxypropylmethylcellulose, according to conventional techniques. The 
tablets can also be coated with sugar. 
Capsules 
______________________________________ 
mg for one capsule 
______________________________________ 
Active component 
10.0 
*Starch 1500 89.5 
Magnesium stearate, 
0.5 
pharmaceutical grade 
Filling weight 100.0 
______________________________________ 
*a form of directly compressible starch supplied by the firm Colorcon Ltd 
Orpington, Kent, United Kingdom. 
The active component is passed through a sieve with a mesh size of 250 
.mu.m and mixing with the other substances is carried out. The mixture is 
introduced into hard gelatin No. 2 capsules on a suitable filling machine. 
Other dosage units can be prepared by modifying the filling weight and, 
when necessary, by changing the size of the capsule. 
Syrup 
______________________________________ 
mg per dose of 5 ml 
______________________________________ 
Active component 10.0 
Sucrose, pharmaceutical grade 
2750.0 
Glycerol, pharmaceutical grade 
500.0 
Buffer 
Flavor 
Colorant q.s. 
Preservative 
Distilled water 5.0 
______________________________________ 
The active component, the buffer, the flavor, the colorant and the 
preservative are dissolved in part of the water and the glycerol is added. 
The remainder of the water is heated to 80.degree. C. and the sucrose is 
dissolved therein and the solution is then cooled. The two solutions are 
combined, the volume is adjusted and mixing is carried out. The syrup 
obtained is clarified by filtration. 
Suppositories 
______________________________________ 
Active component 10.0 mg 
*Witepsol H15 remainder to 
1.0 g 
______________________________________ 
*Tradename for Adeps Solidus from the European Pharmacopeia. 
A suspension of the active component in Witepsol H15 is prepared and it is 
introduced into an appropriate machine with 1 g suppository molds. 
Liquid for administration by intravenous injection 
______________________________________ 
g/l 
______________________________________ 
Active component 2.0 
Water for Injection, pharmaceutical grade 
1000.0 
remainder to 
______________________________________ 
It is possible to add sodium chloride in order to adjust the tonicity of 
the solution and to adjust the pH to the maximum stability and/or in order 
to facilitate dissolution of the active component by means of a dilute 
alkali or acid or by adding appropriate buffer salts. The solution is 
prepared, is clarified and is introduced into phials of appropriate size 
which are sealed by melting the glass. It is also possible to sterilize 
the liquid for injection by heating in an autoclave according to one of 
the acceptable cycles. It is also possible to sterilize the solution by 
filtration and to introduce into a sterile phial under aseptic conditions. 
The solution can be introduced into the phials under a gaseous atmosphere. 
Cartridges for inhalation 
______________________________________ 
g/cartridge 
______________________________________ 
Mironized active component 
1.0 
Lactose, pharmaceutical grade 
39.0 
______________________________________ 
The active component is micronized in a fluid-energy mill and converted to 
the form of fine particles before mixing with lactose for tablets in a 
high energy mixer. The pulverulent mixture is introduced into hard gelatin 
No. 3 capsules on an appropriate encapsulating machine. The contents of 
the cartridges are administered using a powder inhaler. 
Pressurized aerosol with a metering valve 
______________________________________ 
mg/dose 
per 1 container 
______________________________________ 
Micronized active component 
0.500 120 mg 
Oleic acid, pharma- 
0.050 12 mg 
ceutical grade 
Trichloroofluoromethane for 
22.25 5.34 g 
pharmaceutical use 
Dichlorodifluoromethane for 
60.90 14.62 g 
pharmaceutical use 
______________________________________ 
The active component is micronized in a fluid-energy mill and reduced to 
the form of fine particles. The oleic acid is mixed with the 
trochlorofluoromethane at a temperature of 10.degree.-15.degree. C. and 
the micronized medicament is introduced into the solution using a mixer 
with a high shearing effect. The suspension is introduced in a measured 
amount into aluminum aerosol containers to which are attached appropriate 
metering valves delivering a dose of 85 mg of the suspension; the 
dichlorodifluoromethane is introduced into the containers by injection 
through the valves.