Heterocyclic acyldipeptides, processes for the preparation there

Details Heterocyclic acyldipeptides, processes for the preparation there Heterocyclic acyldipeptides, processes for the preparation there

1996-01-04

1998-10-20

Tsang, Cecilia J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514307, 546113, 546114, 546115, 546116, 560 39, 562563, 562575, A61K 3800, C07D47102

Patent

active

058246525

DESCRIPTION:

BRIEF SUMMARY
This Application is a 371 of PCT/SI94/00003 filed Apr. 21, 1994.


TECHNICAL FILED OF THE INVENTION



(IPC C 07D)

The invention belongs to the field of pharmaceutical industry and concerns novel heterocyclic acyldipeptides, processes for the preparation thereof and pharmaceutical compositions containing the same. Novel peptides of the present invention possess an immunostimulatory and antiumor activity.


BACKGROUND OF THE INVENTION

There exists a continuing need for novel medicaments having strong immunostimulatory and antitumor activity and as few side effects as possible. Recently, peptides having biological activity have been acquiring increasing significance in this field, including also muramyl dipeptide derivatives and analogues. G. Baschang, in Tetrahedron 45, 6331 (1989)! are components of bacterial cell walls having therapeutically interesting effects upon the immunological system. N-Acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide, MDP) is the smallest essential structural element of bacterial cell wall having retained immunomodulatory activity. MDP has several undesired side effects such as pyrogenous and somnogenous activity, and it can also cause acute arthritis and anaphylactic reaction.
The synthesis of muramyl peptides is described in the articles by P. Lefrancier and E. Lederer, in Fortschr. Chemie Org. Naturstoffe 40, 1 (1981) and G. Baschang, in Tetrahedron 22, 6331 (1989).
Quite a few things are known about the relation between the structure of Pure Appl. Chem. 59, 449 (1987)! and especially in the recent years it has become clear that the immunomodulatory activity of MDP analogues is not conditioned by an intact N-acetylmuramyl fragment. Muramyl dipeptide analogues having the N-acetylmuramyl moiety of the molecule derived or substituted by groups having preserved only some elements of the N-acetylmuramyl fragment are described e.g. in articles by I. Azuma et al., in Infect. Immun. 20, 600 (1987); T. Shiba et al., in Bull. Chem. Soc. Jpn. 51, 3307 (1978); M. Uemiya et al, in Infect. Immun. 24, 83 (1979); M. Inage et al., in Tetrahedron Lett. 21, 3767 (1980); K. Hemmi et al., in J. Am. Chem. Soc. 103, 7026 (1981); K. Hemmi et al., in Tetrahedron Lett. 23, 693 (1982); T. Gotoh et al., in J. Antibiot. 35, 1280 (1982); F. Floc'h et al., in Drugs of the Future 9, 763 (1984); G. H. Werner et al., in Experientia 42, 521 (1986); J. Danklmeier et al., in Liebigs Ann. Chem. 1990, 145; A. Hasegawa et al., in Gifu Daigaku Nogakubu Kenkyu Hokoku 42, 169 (1979); L. Azuma et al., in Infect. Immun. 33, 834 (1981); D. H. R. Barton et al., in J. Org. Chem. 54, 3764 (1989) as well as in the patents DE 36 34 013, U.S. Pat. No. 5,231,216 and EP 477 912. In the U.S. Pat. No. 4,322,341 hetercrocyclic acytetrapeptides having immunomodulatory properties are disclosed.
The present invention concerns novel heterocyclic acyldipeptides of the formula I ##STR3## wherein Z represents an oxygen or sulphur atom or a --CH.sub.2 -- group; cycloalkyl, cycloalkylalkyl, trifluoromethyl or benzyl group; cycloalkyl, alkylcycloalkyl, dialkylaminoalkyl, acylaminoalkyl or benzyl group; tri-fluoromethyl group; OR.sub.6 or NHR.sub.6 group, wherein R.sub.6 is hydrogen, a straight or branched chain 1-18C alkyl or benzyl group; rings being transcondensed, or a ##STR4## group, wherein R.sub.7 represents H, F, Br, Cl, a straight or branched chain 1-4C alkyl, 1-4C alkoxy, trifluoromethyl, nitro, amino, alkylamino or dialkylamino group, when Y is .dbd.CH-- or .dbd.N--; pharmaceutically acceptable salts of the compounds of formula I and of optically pure diastereomers thereof having immunostimulatory and antitumor activity as well as pharmaceutical compositions containing the same.
The present invention is also is also concerned with an economical process for the preparation of heterocyclic acyldipeptides of formula I.


BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION

The heterocyclic acyldipeptides of formula I are rigid analogues of carbocyclic MDP analogues described in U.S. Pat. No. 5,231,216. Therein, the acetamide gro

REFERENCES:
patent: 5321216 (1994-06-01), Pecar et al.
Goodman & Cilman's "The Pharmacological Basis of Therapeutics" 6th Ed. (MacMillan Publishing 1980) pp. 1249-1255.
Hasegawa et al. Chemical Abstract No. 93:239878z.

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