Peptide agonists of bradykinin B2 receptor

Details Peptide agonists of bradykinin B2 receptor Peptide agonists of bradykinin B2 receptor

1999-06-04

2001-11-13

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S183000, C530S323000, C530S328000, C544S049000, C544S105000

Reexamination Certificate

active

06316413

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds of the peptide type or an analogous type, to their method of preparation and to their use in therapeutics. These novel compounds, called “pseudopeptides”, have an action of the bradykinin B
2
receptor agonist type and are useful in therapeutics, especially for the treatment of pathological conditions of the cardiovascular system.
PRIOR ART
It is known that, through its action on the B
2
receptor, bradykinin, a peptide composed of 9 amino acids (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), has beneficial effects in the treatment of certain pathological conditions, especially in the cardiovascular system. Thus bradykinin protects the heart from myocardial ischemia and prevents certain deleterious events associated with reperfusion of the ischemic heart (cf. the article by L. E. RUBIN et al., Circ. Res., 76, 434-440, 1995, and the article by T. J. M. TOBE et al., J. Cardiovasc. Pharmacol., 17, 600-607, 1991).
Bradykinin also makes it possible to increase the permeability of the blood-brain barrier and thereby to promote the passage of anti-infectious or antitumoral drugs (T. INAMURA et al., J. Cerebral Blood Flow and Metab., 14, 862-870, 1994; FR-M-7979). Bradykinin has also been described as causing the triggering of uterine contractions (T. ENGSTROM et al., J. Endocr., 118, 81-85, 1988), as being capable of inducing ovulation (Y. YOSHIMURA et al., Endocrinology, 122, 2540-2546, 1988) and as being capable of increasing spermatozoal motility (W. MISKA et al., Arch. Androl., 33, 1-5, 1994).
Bradykinin is of no practical use because its rapid degradation by proteases limits its duration of action. It was therefore desirable to find compounds which were of the bradykinin B
2
receptor agonist type, i.e. had an action similar to that of bradykinin, but which were not susceptible to degradation by proteolytic enzymes. For this purpose WO-A-89/09231 proposed bradykinin derivatives obtained by reduction of one of the amide linkages. Other modified structures derived from bradykinin and again containing reduced amide linkages were proposed in U.S. Pat. No. 5,112,596 and U.S. Pat. No. 5,268,164, which relate to their property of increasing the permeability of the blood-brain barrier; one of these compounds, RMP7, is currently undergoing a clinical trial in order to evaluate its ability to potentiate the action of anticancer drugs in patients suffering from cerebral gliomas.
It is further known that WO-A-95/07294 and WO-A-95/24422 each recommend peptides and pseudopeptides as bradykinin receptor antagonists. Now, these peptides and pseudopeptides happen to be structurally different from the compounds according to the invention of formula I below.
It is also known that EP-A-0322779 proposes 5-oxo-1,5-benzothiazepin-1-acetamide derivatives and 5-oxo-1,5-benzooxazepin-1-acetamide derivatives as antiamnesic agents.
These derivatives are found to be structurally different from the pseudo-peptides of formula I according to the invention.
OBJECT OF THE INVENTION
According to the invention it is proposed to provide a novel technical solution for overcoming the above-mentioned disadvantages associated with the use of bradykinin. This novel solution involves compounds acting as bradykinin B
2
receptor agonists, i.e. having an action similar to that of bradykinin. These compounds have a novel structure which is different from that of bradykinin and the known analogous products of the prior art. These compounds are potentially resistant to the action of proteases and hence have a duration of action compatible with use in therapeutics.
In accordance with this novel technical solution, it is proposed according to a first feature of the invention to provide compounds of the pseudopeptide type as novel industrial products, according to a second feature of the invention to provide a method of preparing these compounds, and according to a third feature of the invention to provide the use of these compounds, especially in therapeutics, for example as active ingredients for increasing the permeability of the blood-brain barrier, improving genital functions and treating myocardial ischemia.
SUBJECT OF THE INVENTION
In accordance with the novel technical solution of the invention, a compound of pseudopeptide structure is recommended as a novel industrial product, said compound being characterized in that it is selected from the group consisting of:
(i) the compounds of formula I:
(cf. SEQ ID No. 1 and 2)
in which:
A
1
is a single bond, D-Arg or L-Lys,
A
2
is L-Pro or trans-4-hydroxy-L-Pro (4Hyp),
A
3
is L-Phe or L-thienylalanine (Thi),
Y is a hydrogen atom or a C
1
-C
3
-alkyl group, and
X is a sulfur or oxygen atom; and
(ii) their addition salts.
In the sequence listing given below, SEQ ID No. 1 relates to the products of structure I in which A
1
is a single bond, and SEQ ID No. 2 relates to those of structure I in which A
1
is D-Arg or L-Lys.
According to the invention a method of preparing a compound of formula I and its addition salts is also recommended. The characteristics of this method are given below.
The use of a compound of formula I or one of its non-toxic addition salts is also recommended for obtaining a drug for use in therapeutics in the treatment of pathological conditions where bradykinin brings a beneficial effect, especially in the cardiovascular system, for example for treating myocardial ischemia or improving the permeability of the blood-brain barrier, or in the genital system, for example for triggering ovulation, improving spermatozoal motility or triggering uterine contractions.
The compounds of formula I and their addition salts are also useful as reagents in biological assays.
Abbreviations
For the sake of convenience, the following abbreviations and acronyms have been used in the present text:
a) for the amino acids and their residues:
Ala alanine
Arg arginine
DBO(Y) is a “pseudo” amino acid of the structural formula
(where Y is as defined above)
DBT(Y) is a “pseudo” amino acid of the structural formula
(where Y is as defined above)
DBZ(Y) is DBO(Y) or DBT(Y), where Y is as defined above
Gly glycine
4Hyp trans-4-hydroxyproline [alternative nomenclature for the product of L configuration: (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid]
Phe phenylalanine
Pro proline
Ser serine
Thi thienylalanine [alternative nomenclatures: 3-(thien-2-yl)alanine or ThAla]
(b) for the other moieties:
Adoc adamantyloxycarbonyl
Aoc t-amyloxycarbonyl
Boc t-butoxycarbonyl (or 1,1-dimethylethoxycarbonyl)
BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate
Bzl benzyl (or phenylmethyl)
DCM dichloromethane
DIEA diisopropylethylamine
DMF N,N-dimethylformamide
Fmoc fluoren-9-ylmethoxycarbonyl
Foc fufuryloxycarbonyl
HTFA trifluoroacetic acid
Iboc isobornyloxycarbonyl
Res resin
RT room temperature (15-20° C.)
THF tetrahydrofuran
Tos p-toluenesulfonyl (or tosyl)
z phenylmethoxycarbonyl (or benzyloxycarbonyl)
Z(p-Cl) p-chlorobenzyloxycarbonyl
Z(p-OMe) p-methoxybenzyloxycarbonyl


REFERENCES:
patent: 4477464 (1984-10-01), Slade
patent: 4512988 (1985-04-01), Weller
patent: 5491084 (1996-02-01), Karanewsky
patent: 3423743 (1995-10-01), None
patent: 0322 779 (1989-05-01), None
patent: 413277 (1990-11-01), None
patent: WO9507294 (1995-03-01), None
patent: WO 9524422 (1995-09-01), None

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