Nova- and decapeptides in the preparation of a drug for the trea

Details Nova- and decapeptides in the preparation of a drug for the trea Nova- and decapeptides in the preparation of a drug for the trea

1995-12-18

1999-11-16

Tsang, Cecilla J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514800, 530313, 530328, 930130, A61K 3800

Patent

active

059858346

DESCRIPTION:

BRIEF SUMMARY
This application claims benefit of international application PCT/EP94/01037 filed Apr. 2, 1994


DESCRIPTION

Commencing in 1981, a growing incidence of hitherto rare, incurable infections was observed in homosexual men in New York and San Francisco. Severe defects in immune resistance were found in all patients. Soon afterwards, Luc Montagnier at the Institut Pasteur discovered a new virus, the human immunodeficiency virus, HIV).
Currently, only the didesoxynucleoside analog 3'-azido-3'-desoxythymidine (AZT) or Zidovudine (INN) is registered for the treatment of AIDS. It relieves the symptoms and prolongs the mean survival time of AIDS patients (EP-A 206 497). AZT therapy is associated with the development of resistant virus strains and serious bone marrow side effects. Further medicaments are currently undergoing clinical trials. Thus, for example, German published patent 39 35 580 describes the use of 1-octadecyl-2-methyl-glycero-3-phosphocholine for the preparation of medicaments for combating HIV infections. EP-A 493 378 describes the use of 2'-3'-dedeoxyguanosin or of mono or triphosphates of 2'-3'-dedeoxyguanosin for the same purpose. All these substances are still undergoing clinical trials and are not yet ready to be marketed.
Medicaments currently used as antiviral chemotherapy do not display the desired selectivity. There is consequently a great need for well tolerated, highly effective medicaments which not only delay the course of the illness, but also repress proliferation of the viruses and are, in addition, able to stabilise the weakened immune system of the patients.
It has now surprisingly been found in an AIDS screening trial on CEM-IW cells that the LHRH-analog decapeptides of formulae II-VIII display an anti-HIV and a growth stimulating effect on cell cultures.
The object of the invention is the preparation of a medicament based on peptide LHRH antagonists. The compounds show little toxicity, even in the highest dosages used.
The amino acid sequence of LHRH is:


______________________________________ LHRH = p-Glu.sup.1 -His.sup.2 -Trp.sup.3 -Ser.sup.4 -Tyr.sup.5 -Gly.sup.6 -Leu.sup.7 -Arg.sup.8 Pro.sup.9 -Gly.sup.10 -NH.sub.2 General formula I describes the peptides of the invention: Ac-D-Nal(2)-D-Phe(4Cl)-xxx-A- B-yyy-zzz-Arg-Pro-D-Ala-NH.sub.2 Formula I where: xxx = D-Pal(3), D-Phe(4Cl) yyy = D-Cit, D-Lys (R), D-Arg, D-Hci R may have the meanings (C.sub.1 -C.sub.4)-acyl or (C.sub.1 -C.sub.10)-alkyl. zzz = L-Leu, NLe, Nva, t-Leu A = Ser, Ser(sugar) sugar may have the meanings glucose, galactose, allose, altrose, mannose, gulose, idose or talose B = Tyr, Lys(Nic), Mop and the pharmaceutically acceptable salts of the peptides such as for example hydrochloride, trifluoroacetate, acetate, sulfate, phosphate, mesylate or tosylate. ______________________________________
The appropriate abbreviations for amino acids, peptides and their derivatives are recommended by the IUPAC-IUB Commission for Biochemical Nomenclature. (European J. Biochem, 1984, 138, 9-37)
Abbreviations for less common amino acids:
Particularly preferred compounds according to general Formula I constitute the following amino acid sequences:


______________________________________ Formula II = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal(3).sup.3, D-Cit.sup.6, Nle.sup.7, D-Ala.sup.10 ]-LHRH Formula III = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal(3).sup.3, D-Cit.sup.6, Nva.sup.7, D-Ala.sup.10 ]-LHRH Formula IV = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Trp.sup.3, D-Cit.sup.6, D Ala.sup.10)-LHRH Formula V = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal(3).sup.3, D-Cit.sup.6, D-Ala.sup.10 ]-LHRH Formula VI = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal(3).sup.3, D-HCi.sup.6, D-Ala.sup.10 ]-LHRH Formula VII = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal.sup.3, D-Cit.sup.6, t-Leu.sup.7, D-Ala.sup.10 ]-LHRH Formula VIII = [Ac-DNal(2).sup.1, D-Phe(pCl).sup.2, D-Pal(3).sup.3, D-Cit.sup.6, Ala.sup.9, D-Ala.sup.10 ]-LHRH ______________________________________
The oligope

REFERENCES:
patent: 5068222 (1991-11-01), Camble et al.
patent: 5073624 (1991-12-01), Coy et al.
patent: 5198533 (1993-03-01), Schally et al.
Dialog, File 157: Aidsline, No. 93333809, Int.Conf. AIDS (Germany), Jun. 6-11, 1993, 9(1), p. 195 (Abstr.No.PO-A18-0362) see the whole document.
Dayhoff, Atlas of Protein Sequence and Structure, vol. 5, 1972, p. 96.

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