Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1997-12-31
1999-09-07
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
530327, 514 9, 514 11, C07K 700
Patent
active
059488840
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND AND PRIOR ART
The present invention relates to novel cyclic peptides from the cyclosporin series which have a strong inhibitory effect on human immunodeficiency virus (HIV) without having any immunosuppressive activity. Such cyclic peptides are claimed, inter alia, in EP 484 281. One of the substances which is specifically claimed in this patent specification is (gamma-hydroxy-N-methylleucine)cyclosporin. While this substance can very readily be prepared from cyclosporin A by means of microbial hydroxylation, EP 484 281 indicates that this substance has an activity against HIV which is some 5-6 times weaker than that of the most strongly active substances, namely MeIle-4-cyclosporin or MeVal-4-cyclosporin. All 3 substances have practically no immunosuppressive activity. Unexpectedly, it has been found that the anti-HIV effect of (gamma-hydroxy-MeLeu-4)cyclosporin can be substantially improved, without giving rise to any immunosuppressive activities, by introducing suitable substituents into the methylene group of the amino acid sarcosine in position 3 of said cyclosporin. Since the therapeutic doses of cyclosporin A which are used after organ transplants in order to prevent rejection of the transplanted organs are very high, and similarly high doses are to be expected for an anti-HIV therapy which uses cyclosporin derivatives, the value of the present invention is that it provides novel cyclosporin derivatives which possess high anti-HIV activity and that these cyclosporin derivatives can be prepared simultaneously, in a few steps, from cyclosporin A, which is a product which is already being prepared by the ton.
BRIEF SUMMARY OF THE INVENTION
The present invention consequently relates to novel cyclic peptides of the general formula ##STR2## in which A to K denote residues of the following amino acids: A is a substituted homothreonine of the general formula trans-configured, these groups can additionally be substituted by hydroxyl, amino, C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 dialkylamino, alkoxy or acyloxy, straight-chain or branched, alkenyl or alkynyl, straight-chain or branched, and where, when X is S, R.sub.3 can also be aryl or heteroaryl, halogen, preferably fluorine, cyano, or R.sub.5 is hydrogen, hydroxyl or halogen, preferably fluorine, and, furthermore, amino, C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 dialkylamino, acyloxy, preferably acetyloxy, and, furthermore, tert-butoxycarbonyl-aminoethoxy-ethoxy-acetyloxy, or alkoxycarbonyl, preferably butoxycarbonyl,
DETAILED DESCRIPTION
An important element in the present invention is the variation of the radical R in formula III of the amino acid C.
Examples of the radical R in formula III are C.sub.1 -C.sub.6 alkyl, alkenyl or alkynyl, straight-chain or branched, where these groups can additionally be substituted by hydroxyl, alkyloxy, acyloxy, C.sub.1 -C.sub.4 alkylamino or C.sub.1 -C.sub.4 dialkylamino. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, cyclopropylmethyl, allyl, butenyl, pentenyl, isopentenyl, propargyl and butynyl. Examples of the alkyloxy and acyloxy substituents in the radical R are methoxy, ethoxy, propyloxy, beta-methoxyethoxy, and also acetoxy or pivaloyloxy. Examples of the C.sub.1 -C.sub.4 alkylamino and C.sub.1 -C.sub.4 dialkylamino substituents in the radical R are methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, dipropylamino, diisopropylamino and tert-butylamino. The radical R.sub.2 in R can have the meaning of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Furthermore, R can also have the meaning of halogen or cyano. The radical R.sub.3 in X--R.sub.3 can be straight-chain or branched C.sub.1 -C.sub.4 alkyl, alkenyl or alkynyl, and, when X is S, can also be aryl or heteroaryl. Examples of aryl are phenyl, 1-naphthyl and 2-naphthyl, and examples of heteroaryl are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrazinyl and benzothiazol-2-yl.
Preferr
REFERENCES:
Billich et al, Journal of Virology, vol. 69, No. 4, pp. 2451-2461, 1995.
Karpas, etal, Proc. Natl. Acad. Sci USA 89(1992) pp. 8351-8355.
C-Chem AG
Delacroix-Muirheid C.
Tsang Cecilia J.
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