Cyclic hydrazine compounds

Details Cyclic hydrazine compounds Cyclic hydrazine compounds

1996-01-11

1997-09-23

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540488, 540489, 540492, A01N 4300, A61K 3133

Patent

active

056704976

DESCRIPTION:

BRIEF SUMMARY
THIS IS A 371 OF PCT/EP 94/02235, FILED JUL. 7, 1994.

The invention relates to derivatives of cyclic hydrazincs and salts thereof, to processes for the preparation of those compounds and salts thereof, to pharmaceutical compositions comprising those compounds or salts thereof, and to the use of those compounds or salts thereof in the therapeutic or diagnostic treatment of the human or animal body or in the preparation of pharmaceutical compositions.
According to WHO estimates, more than 12 million people are at present infected with HIV-1 or HIV-2.
Hitherto, the treatment of retroviral diseases, such as AIDS, has involved principally the use of inhibitors of reverse transcriptase, an enzyme active in the conversion of retroviral RNA into DNA, such as 3+-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), and also trisodium phosphonoformate, ammonium 21 -tungsto-9-antimonate, 1-.beta.-D-ribofuran-oxyl-1,2,4-triazole-3-carboxamides and dideoxycytidine as well as adriamycin. Attempts have also been made to introduce into the body, for example in the form of a recombinant molecule or molecule fragment, the T4-cell receptor which is present in certain cells of the defence system of the human body and which is responsible for the anchoring and introduction of infectious virus particles into those cells and thus for their infection. The desired result is that binding sites for the virus would be titrated out and the virions would therefore no longer be able to bind to the cells. Compounds, such as polymannoacetate, that prevent the penetration of the virus through the cell membrane by other methods, are also used.
In addition, reports have been made of first clinical trials with an inhibitor of HIV-protease, l-L-asparaginyl!amino!butyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959) (for example G. J. Muirhead et at., Brit. J. Clin. Pharmacol. 34, 170P-171P (1992)).
In the AIDS viruses, HIV-1 and HIV-2, and other retroviruses, the proteolytic maturation, for example of the core proteins of the virus, is brought about by an aspartate protease, such as HIV-protease. Without that proteolytic maturation, it is not possible for infectious virus particles to be formed. Owing to the central role played by the mentioned aspartate protease, such as HIV-1- and HIV-2-protease, in virus maturation, and on the basis of experimental results, for example using infected cell cultures, it is assumed that effective inhibition of the maturation step effected by that protease in vivo will suppress the assembly of mature virions. Corresponding inhibitors can accordingly be used therapeutically.
The aim of the present invention is to provide a novel class of compounds having favourable pharmacological properties.
The compounds according to the invention are compounds having the formula I ##STR1## wherein R.sub.1 is hydrogen or acyl, unsubstituted or substituted alkyl or alkenyl, and selected from the group consisting of --(C.dbd.O)--, --(C.dbd.S)--, --(S.dbd.O)--, --(S(.dbd.O).sub.2)--, --(P.dbd.O)--, ##STR2## R.sub.6 being unsubstituted or substituted alkyl and R.sub.7 being hydrogen, unsubstituted or substituted alkyl, hydroxy, amino, alkyloxy, cyano or aryloxy,
The carbon atoms carrying the radical R.sub.1 --O-- and the radical R.sub.2 in compounds of formula I may, because they are centres of asymmetry, be in the (R)-, (S)- or (R,S)-configuration, as may any other asymmetrical carbon atoms present in the substituents. Accordingly, the compounds of formula I may be in the form of mixtures of isomers or pure isomers, especially in the form of mixtures of diastereoisomers, mixtures of enantiomers, such as racemates, or pure enantiomers. Preferred are the compounds of formula I wherein the carbon atoms substituted by R.sub.1 --O-- and by R.sub.2 both have the (S)-configuration or both have the (R)-configuration, and any other asymmetrical carbon atoms present are either in the (R)- or (S)-configuration or in the (R,S)-configuration, i.e. compounds of formula Ia falling under formula I ##STR3## or of formula Ib falling under

REFERENCES:
Thornber, C.W., Chem. Soc. Reviews 18, 563-5 (1979).
Derwent abstract 04191v/03 (Corresp. to DE-2230-979).

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