Monocyclic compounds with four bifunctional residues having...

Details Monocyclic compounds with four bifunctional residues having... Monocyclic compounds with four bifunctional residues having...

2000-07-12

2004-08-24

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S330000, C514S011400, C514S018700

Reexamination Certificate

active

06780968

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention refers to new compounds having the general formula (I):
in which:
X
1
, X
2
, X
3
, X
4
, which may be the same or different from one another, represent a group chosen from among —CONR—, —NRCO—, —OCO—, —COO—, —CH
2
NR—, —NR—CH
2
—, CH
2
—CH
2
, where R is H or a C
1-3
alkyl or benzyl;
f, g, h, m, which may be the same or different from one another, represent a number chosen from among 0, 1 or 2;
R
1
and R
2
, which may be the same or different from one another, represent a —(CH
2
)
r
—Ar group, where r=0, 1, 2 and where Ar is an aromatic group chosen from among: benzene, naphthalene, thiophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar group being possibly substituted with a maximum of 2 residues chosen from among C
1-3
alkyl or halo-alkyl, C
1-3
alkoxyl, C
2-4
amino-alkoxyl, halogen, OH, NH
2
, NR
13
R
14
where R
13
and R
14
, which may be the same or different from one another, represent hydrogen or C
1-3
alkyl;
R
3
represents a group chosen from among:
hydrogen
linear or branched alkyl having the formula C
n
H
2n+1
, with n=1-5, cyclo-alkyl or alkylcyclo-alkyl groups having the formula C
n
H
2n−1
with n=5-9
(CH
2
)
r
—Ar
1
, where r=0, 1, 2 and where Ar
1
is an aromatic group chosen from among: benzene, naphthalene, thlophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar
1
group being possibly substituted with a maximum of 2 residues chosen from among C
1-3
alkyl or halo-alkyl, C
1-3
alkoxyl or amino-alkoxyl, halogen, OH, NH
2
, NR
13
R
14
, where R
13
and R
14
, which may be the same or different from one another, represent hydrogen or C
1-3
alkyl;
R
4
represents a group chosen from among:
hydrogen or C
1-6
alkyl
L-Q, where L is a chemical bond or a linear or branched C
1-6
alkyl residue and Q is a group chosen from among:
i) H, OH, OR
9
, NH
2
, NR
9
R
10
, guanidine, sulphate, phosphonate, phosphate, where R
9
and R
10
, which may be the same or different from one another, represent a hydrogen, C
1-3
alkyl group, C
1-3
hydroxyalkyl, C
1-3
dihydroxyalkyl, C
1-3
alkyl-CONHR
12
, C
1-3
alkyltetrazole, C
1-3
alkyl-COOH or wherein R
9
R
10
joined together form with the N-atom a saturated 4-6 membered heterocycle possibly containing a further heteroatom chosen in the group consisting of N, O, S and wherein R
12
is a mono-, di-, tri-glycosidic group possibly protected with one or more C
1-3
-acyl groups or substituted with amino-groups or C
1-3
acylamino-groups;
ii) COOH, tetrazole, SO
2
NH
2
, SO
2
NHCOOR
8
, CONHR
8
, NHCOR
8
, where R
8
represents a linear or cyclic C
1-6
alkyl chain containing one or more polar groups chosen from among the group: OH, NH
2
, NR
15
R
16
, COOH, CONHR
12
, PO
3
H, SO
3
H, OR
11
and where R
15
and R
16
, which may be the same or different from one another, represent a hydrogen or C
1-3
alkyl group, and where R
11
is a C
1-3
alkyl or C
2-4
amino-alkyl chain, R
12
is a mono-, di-, tri-glycosidic group possibly protected with one or more C
1-3
acyl groups or substituted with amino-groups or C
1-3
acylamino-groups or R
15
R
16
joined together form with the N-atom a saturated 4-6 membered heterocycle possibly substituted with C
1-3
alkyl-groups or with saturated 4-6 membered heterocycle-groups containing at least an N-atom;
iii) COOR
17
, CONHR
12
, OR
12
where R
12
is a mono-, di- or tri-glycoside group possibly protected with one or more C
1-3
acyl groups or substituted with amine or C
1-3
acylamine groups and R
17
is a group R
12
as above definined or a group C
1-3
alkyl, C
1-3
alkylphenyl, wherein the phenyl-group can be substituted with a group OH, NO
2
, NH
2
, CN, CH
3
, Cl, Br;
R
5
, R
6
, R
7
, which may be the same or different from one another, represent a hydrogen or C
1-3
alkyl group; with the proviso that when R
1
and R
2
are benzyl or 4-hydroxybenzyl then R
3
and R
4
are not isopropyl.
Also included in the present invention are the pharmaceutically acceptable salts, the processes for their preparation, and the pharmaceutical compositions containing them.
In view of the presence of chiral centres in the compounds of formula (I), also the individual enantiomers and their mixtures, both in the racemic form and in the non-racemic form, form part of the present invention.
DESCRIPTION OF THE RELATED ART
The NK-2 receptor of tachykinins is widely expressed in the peripheral nervous system of mammals. One of the various effects produced by the selective stimulation of the NK-2 receptor is the contraction of smooth muscle. Hence antagonists of the NK-2 receptor may be considered agents capable of controlling excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins concurs in the genesis of the corresponding disorder.
In particular, the bronchospastic and inflammatory component of asthma, coughing, pulmonary irritation, intestinal spasms, spasms of the biliary tract, local spasms of the bladder and of the ureter during cystitis, kidney infections and colics may be considered conditions in which the administration of NK-2 antagonists may be effective (E. M. Kudlacz et al., Eur. J. Pharmacol., 1993, 241, 17-25).
In addition, a number of NK-2 antagonists capable of surmounting the haemato-encephalic barrier have shown anxiolytic properties (D. M. Walsh et al., Psychopharmacology, 1995, 121, 186-191).
Cyclic compounds, and in particular cyclic hexapeptides (A. T. McKnight et al., Br. J. Pharmacol., 1991, 104, 355) and bicyclic hexapeptides (V. Pavone et al., WO 93/212227) or cyclic hexapseudopeptides (L. Quartara et al., J. Med. Chem., 1994, 37, 3630; S. L. Harbeson et al., Peptides, Chemistry and Biology, Proceedings of the Twelfth American Peptide Symposium, 1992, 124) are known in the literature for their antagonistic activity towards the NK-2 receptor of tachykinins. In EP-A-333174 linear di- and tri-peptide compounds comprising the -D-Trp-Phe-moiety are described; such compounds possess tachykinin antagonism.
It has now surprisingly been found that products of lower molecular weight, monocyclic ones, containing only four bifunctional residues linked together via peptide or pseudopeptide bond, present high pharmacological activity associated to a considerable selectivity for the human NK-2 receptor, and thus are proposed as valid alternatives.


REFERENCES:
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Br. J. Pharmacol. (199

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