Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compositions

This invention relates to novel compounds of general formula (I): ##STR1## and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION 
This invention relates to novel bi-cyclic compounds useful in 
pharmaceutical compositions as tachykinins antagonists, and to 
pharmaceutical compositions containing them. 
BACKGROUND OF THE INVENTION 
The receptor NK.sub.2 of tachykinins is widely expressed in the peripheral 
nervous system of Mammalia. One of the several effects caused by the 
selective stimulation of the receptor NK.sub.2 is the contraction of the 
smooth muscles. Therefore, antagonists of the receptor NK.sub.2 can be 
considered agents able to control the hypercontraction of the smooth 
muscles in any patological condition in which the release of the 
tachykinins contributes to the rise of the corrispondent disorder. In 
particular, the bronchospastic component of asthma, cough, pulmonary 
irritations and local spasms of the urinary bladder and of the ureter 
during cystitis, infections and renal colics can be considered conditions 
in which the administration of receptor NK.sub.2 antagonists can be 
effective (A. L. Magnan et al. Neuropeptides, 1993, 24, 199). Compounds 
which act as antagonists of the tachykinins, and in particular of the 
neurokinin A, are well-known in Literature. Among them, the cyclic 
compounds (B. J. Williams et al. J. Med. Chem., 1993, 36, 2) are of 
particular interest. Lipophily has been defined as an essential 
requirement in order to have an intensive antagonist activity to the 
receptor NK.sub.2 of the tachykinins of a series of cyclic pseudopeptides 
(L. Quartara et al. J. Med. Chem., 1994, 27) and particularly in case of 
bicyclic hexapeptides. WO/93/21227). Surprisingly it has been now found 
that products structurally similar to those described above, but in which, 
however, at least one hydrophilic group is present, not only keep their 
high affinity in vitro, but also show an increase in the pharmacological 
activity in vivo if compared to the corrispondent compounds which do not 
contain any hydrophilic group. 
This is even more surprising if it is taken into account that monocyclic 
peptides having antagonist properties which are similar to those of the 
tachykinins do not show any increase in the pharmacological activity when 
hydrophilic groups are introduced onto the structure of the cycle [Int. J. 
Peptide Protein Res. (1984), 44:2, 105-111]. 
SUMMARY 
This invention relates to novel compounds of the general formula (I): 
##STR2## 
wherein: X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6, same or 
different from one another, represent a --NR'CO-- or a --CONR'-- group, 
wherein R' is H or C.sub.1-3 alkyl; 
Y represents a group selected from --NRCO--, --CONR--, or --SS-- 
wherein R is H or C.sub.1-3 alkyl; 
at least one of the R.sub.1, R.sub.2, R.sub.3 and R.sub.4 groups, same or 
different from one another, is hydrophilic and the remaining groups are 
hydrophobic; 
m and n, same or different from one another, are each an integer number 
from 1 to 4; 
and to pharmaceutical compositions containing them. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to novel compounds having the general formula 
(I) 
##STR3## 
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6 ; Y, R.sub.1, 
R.sub.2, R.sub.3, R.sub.4, m and n groups are as defined above; 
processes for the preparation thereof and pharmaceutical compositions 
containing them. 
The formula (I) as reported above is considered the one giving the best 
representation of the real spatial structure of the bicyclic peptide 
according to the invention. However also the following Formula (Ia) (which 
chemically speaking is identical to Formula (I)) is given in order to 
simplify the understanding of the compounds described hereinafter and in 
the Examples with their chemical name in particular in so far as the 
groups X.sub.1-6 and Y are concerned. 
##STR4## 
The groups X.sub.1-6 and Y are in fact defined according to the 
aminoacid-sequence from the formal N- to the C-terminus of the peptide as 
they are represented in the linear structure, therefore reading Formula 
(Ia) no problem arises in the understanding of the linear structure as 
reported in the Examples. 
As it can be seen, the compounds of formula (I) as described above present 
chiral centers: it is understood that this invention relates also to the 
several enantiomers. 
More particularly the hydrophobic groups can be separately selected from 
the following: 
a) groups C.sub.n H.sub.2n+1 wherein n=0, 1-4 
b) linear- or branched alkyl groups corresponding to C.sub.n H.sub.2n -U-W 
wherein n=1-4; U.dbd.O, COO, CONH, S and W.dbd.alkyl-, aryl or 
alkylaryl-group containing from 1 to 15 carbon atoms 
c) (CH.sub.2).sub.n --C.sub.6 H.sub.3 -A-B wherein n=0, 1-3; A and B, 
placed in any of the ortho, meta or para positions, same or different from 
one another, represent H, halogen, OR, NHR, NR.sub.2, CH.sub.3, SR wherein 
R is an alkyl-, aryl- or alkylaryl-group with less than 10 C atoms 
d) (CH.sub.2).sub.n --C.sub.6 H.sub.10 R', wherein n=0, 1-3 and R'.dbd.H, 
C.sub.1-3 alkyl 
e) (CH.sub.2).sub.n -heterocycle, wherein n=0, 1-3 and for heterocycle it 
is meant: imidazolyl-2-yl, indolyl-3-yl, furanyl-3-yl, pyridyl-3-yl, 
imidazolyl-3-yl 
f) a --(CH.sub.2).sub.s -- group, wherein s=3, 4, eventually OH-substituted 
or condensed with an aromatic group, which cyclizes with one of the two 
adjacent X.sub.1-6 groups in order to produce the side chain of proline, 
hydroxyproline, octahydroindol-2-carboxylic acid, tetrahydroisoquinolinic 
acid 
g) the side chain of a natural hydrophobic amino acid 
h) the side chain of a natural hydrophilic amino acid, suitably substituted 
in order to render it hydrophobic 
i) the side chain of non-natural hydrophobic amino acids selected from the 
group consisting of: norleucine, norvaline, alloisoleucine, 
cyclohexylglycine (Chg), .alpha.-amino-n-butyric acid (Aba), 
cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanines 
mono- and di- substituted in the ortho, meta and para positions of the 
benzene ring with one or more of the following groups: C.sub.1-10 alkyl, 
C.sub.1-10 alkoxy, halogen, .beta.-2-thienylalanine, 
.beta.-3-thienylalanine, .beta.-2-furanylalanine, .beta.-3-furanylalanine, 
.beta.-2-piridylalanine, .beta.-3-piridylalanine, .beta.-4-piridylalanine, 
.beta.(1-naphtyl)alanine, .beta.-(2-naphtyl)alanine, O-alkylated serine- 
threonine- tyrosine-derivatives, S-alkyl cysteine, S-alkyl homocysteine, 
N-alkyl lysine, N-alkyl ornithine, N-alkyl 2,3 diaminopropionic acid. 
More particularly, the side chain of a hydrophobic amino acid according to 
paragraph (g) is the side chain of an amino acid selected from the group 
consisting of: glycine, alanine, valine, isoleucine, methionine, 
phenylalanine, tyrosine, tryptophan, proline, histidine, aspargine, 
glutamine. 
The side chain of a hydrophilic amino acid, suitably substituted in order 
to render it hydrophobic according to paragraph (h) is the chain of an 
amino acid selected from the group consisting of: serine, threonine, 
cysteine, aspartic acid, glutamic acid, t-carboxyglutamic acid, arginine, 
ornithine, lysine. 
Preferably, the hydrophilic groups are selected from L-Q group, wherein L 
is a chemical bond or a linear or branched C.sub.1-6 -alkyl residue and Q 
is a hydrophilic group. Preferably Q is selected from the group consisting 
of: guanidine, amine, M, OM, --CO--NH--M, --NH--CO--M, an aromatic group 
which has been mono-, di- or tri-substituted in ortho, meta, para 
positions with M or OM groups, wherein M is a hydrophilic group. 
With the term "hydrophilic group", for Q and M, it is preferably meant: 
i) eventually substituted mono-, di-, tri-glycosidic residues; 
ii) C.sub.1-6 linear o cyclic alkyl chains comprising one or more polar 
groups; 
iii) hydroxyl, amine, guanidine, carboxyl, sulfate, phosphonate, phosphate; 
iv) residues bearing substituted hydrophilic groups which in biologic 
environment are hydrolysated, re-establishing the hydrophilic function. 
As far as the definition according to paragraph (i) hereinabove is 
concerned, the following structures are preferably meant: hexoses or 
pentoses of the D or L series in .alpha. or .beta. configuration, selected 
from the group wherein: all C atoms bear a free or protected hydroxylic 
group; one or more hydroxyls are substituted by: hydrogen, an amino or 
acylamino group; C.sub.6 of hexoses and C.sub.5 of pentoses are part of a 
carboxylic group; and wherein the eventually present 2 or 3 glycosidic 
units are linked by a glycosidic bond of .alpha. or .beta. configuration. 
Specific examples of glycosidic groups as defined above are: D or L ribose, 
D or L arabinose, D or L xylose, D or L lyxose, D or L allose, D or L 
altrose, D or L glucose, D or L mannose, D or L gulose, D or L idose, D or 
L galactose, D or L talose, D or L allulose, D or L fructose, D or L 
sorbose, D or L tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or 
L-glucose, 2-deoxy-D or L-galactose, 2-deoxy-D or L-arabinose, 2-deoxy-D 
or L-ribose, D or L fucose, D or L ramnose; D-glucosamine, D-mannosamine, 
D-galactosamine, daunosamine, acosamine and N-acylate derivates thereof 
with lower fatty acids, i.e. having a N-formylic, acetylic, propionilic, 
butyric residue; glucuronic acid, galacturonic acid, cellobiose, lactose, 
maltose, D-lactosamine, cellotriose, maltotriose and protected derivates 
thereof. 
The definition according to paragraph (ii) hereinabove applies to chains 
deriving from a polyol-residue, such as tris(hydroxymethyl)methyl, D or L 
arabitol, D or L erythrol, D or L galactytol, meso-inositol, D or L 
mannitol, D or L perseitol, D or L ribitol, D or L sorbitol, D or L 
xylitol; or those deriving from the residue of tartaric acid, glucaric 
acid, gluconic acid, bycine, quinic acid, mucic acid, glucosaminic acid. 
Among the products of formula (I) as above indicated, the products wherein 
if one or both R.sub.1 and R.sub.4 groups are hydrophilic, both R.sub.2 
and R.sub.3 groups are hydrophobic and viceversa, are particularly 
preferred. Compounds of formula (I) object of the present invention can be 
synthetized by the various techniques known in Literature, see e.g. M. 
Bodansky, "Peptide Chemistry", Springer-Verlag, 1988. 
For example by means of in solution synthesis of the linear peptidic chain 
through subsequent coupling of suitably activated N-protected amino acids 
to an amino acid or to a C-protected peptidic chain, with isolation of the 
intermediates, subsequent selective de-protection of the C- and N-terminal 
chains, cyclization in polar organic solvents in diluted solution, hence 
selective de-protection of the side chains and at last cyclization of the 
same in polar organic solvents in diluted solution. The hydrophilic 
residue can be introduced both as protected amino acid derivative during 
the peptidic chain synthesis and by means of conjugation to the already 
formed peptide, as widely disclosed in Literature. Similarly a synthesis 
in solid phase of the peptidic chain from the C-terminal end to the 
N-terminal one on a insoluble polymeric support, the cyclization in solid 
phase between the previously de-protected side chains, the subsequent 
detachment from the polymeric support by means of hydrolysys in anhydrous 
hydrofluoric acid containing the suitable scavengers or in trifluoracetic 
acid containing the suitable scavengers or in aqueous bases and the 
cyclization of the monocyclic peptide in polar organic solvents in diluted 
solution, can be used for the preparation. The hydrophilic residue being 
introduced according to the above disclosed indications. According to a 
particular preparation method, the desired product can be obtained in 
solid phase using the 2-chlorotrytil resin (Barlos et al., Int. J. Peptide 
Protein Res., 37, 513-520, 1991) substituted with a protected amino acid 
having the Fmoc group at the N-terminal end; preferably the amino acid 
directly bond to the resin is the one having the R.sub.1 or R.sub.3 side 
chain. After the other amino acids being introduced in the sequence, the 
peptide is detached from the resin with diluted acetic acid and a first 
cyclization is performed between the free C-terminal and N-terminal end by 
means of the conventional classic synthesis methods. Subsequently, the 
amino acid side chains are de-protected in position 5 and 6, for example 
with trifluoracetic acid, and way is given to the second cyclization. 
Other synthetic ways are anyway possible and largely described in 
Literature as above mentioned. 
The compounds of formula (I) as above indicated have revealed to be 
powerful antagonists of the receptor NK.sub.2 of the tachykinins, and 
hence may be administered in doses which are not higher than those 
required for the known products. 
They can be therefore indicated for the treatment of arthritis, asthma, 
inflammations, tumoral growth, gastro-intestinal hypermotility, 
Huntington's desease, neurites, neuralgia, hemicrania, hypertension, 
urinary incontinence, urticaria, symptoms from carcinoid desease, flu and 
colds. 
The compounds of formula (I) object of the present invention are suitable 
for the parenteral, oral, inhalatory and sublingual administration for 
therapeutical purposes to the superior animals and to the humans, 
achieving pharmacological effects according to the above described 
features. For parenteral administrations (endovenous, intramuscular and 
intradermic) sterile solutions or lyophilized chemical preparations are 
used. For nasal, inhalatory and sublinqual administrations, according to 
the particular instance, aqueous solutions, aereosol preparations or 
capsules are used. 
The doses of active principle in the above compositions can be comprised 
between 0.1 and 10 mg/kg of body weight.