Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1996-02-20
1998-11-03
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
514307, 514314, 514357, 514466, 514486, 514619, 514620, 544 78, 544 82, 544162, 544168, 546145, 546170, 546335, 546337, 560 27, 564157, 564158, 564165, 549441, A61K 3121, C07D29518
Patent
active
058310940
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel statone antiviral analogs, to the processes and intermediates useful for their preparation and to their use as anti-viral agents.
BACKGROUND OF THE PRESENT INVENTION
Retroviruses are a class of viruses which transport their genetic material as ribonucleic acid rather than as deoxyribonucleic acid. Retroviruses are associated with a wide variety of diseases in man, one of which is AIDS. Although there have been disclosures of other anti-viral agents useful in the treatment of AIDS, for example see patent applications EP 0 218 688, EP 0 352 000 and PCT/US 91/09741, the compounds of the present invention have not been previously disclosed. PCT/US 91/09741 is hereby incorporated by reference.
DESCRIPTION OF THE PRESENT INVENTION
More specifically this invention relates to novel difluoro statone analogs of Formula 1 ##STR1## and the stereoisomers, hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein ##STR2## wherein each of W and W' are independently C.sub.1-6 alkylene or nothing, nitrogen atom in R, provided that W' is C.sub.2-6 alkylene when W' is directly attached to a nitrogen atom in R'; benzyl or 3-tetrahydrofuryl; substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, or pyrimidinyl, wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(O)NHR.sub.4, C.sub.1-4 alkyl or CO.sub.2 R.sub.4 ; phenethyl, fluorenylmethylenoxy, 2-quinolinyl, PDL, ##STR3## NHSO.sub.2 R.sub.4, N(R.sub.4) (benzyl), or N(R.sub.4)(PDL); PDL is --(CH.sub.2).sub.a -2-,3-, or 4-pyridyl, or p-substituted benzyloxy, wherein the substitution is with a nitro, OH, amino, C.sub.1-6 alkoxy, hydroxy C.sub.1-6 alkylene, or halogeno; C.sub.1-6 alkyl, or OH; ##STR4## Y being C.sub.1-6 hydroxy alkylene, C.sub.1-6 alkyl, or ##STR5## and Z being CHO, CO.sub.2 R.sub.4, CO.sub.2 NHR.sub.4 or ##STR6## and V being OR.sub.4 or hydroxy C.sub.1-6 alkylene; than H when R.sub.5 is H, and when R.sub.5 and R.sub.6 are taken together with nitrogen atom to which they are attached form a heterocyclic moiety of the formulae ##STR7## R.sub.7 is CH.sub.2 OR.sub.4 or C(O)NHR.sub.4, CHO, R.sub.8 is (H,OH) or =O;
Isosteres of the compounds of Formula I include those wherein (a) the .alpha.-amino acid residues of the P.sub.1 and P.sub.2 substituents are in their unnatural configuration (when there is a natural configuration) or (b) when the normal peptidic carbamoyl linkage is modified, such as for example, to form ##STR8## (N-methylamide), --COCH.sub.2 -- (keto), --CH(OH)CH.sub.2 -- (hydroxy), --CH(NH.sub.2)CH.sub.2 -- (amino), --CH.sub.2 CH.sub.2 -- (hydrocarbon). Preferably a compound of the invention should not be in an isosteric form. Unless otherwise stated the .alpha.-amino acids are preferably in their L-configuration.
A compound of the invention may be in free form, e.g., amphoteric form, or in salt, e.g., acid addition or anionic salt, form. A compound in free form may be converted into a salt form in an art-known manner and vice-versa.
The pharmaceutically acceptable salts of the peptide of Formula I (in the form of water, or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts of these peptides, which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, paemoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, alkaline earth metal salts suc
REFERENCES:
patent: 5066643 (1991-11-01), Abeles et al.
patent: 5559140 (1996-09-01), Schirlin et al.
Journ. of Med. Chem. vol. 29, No. 10, pp. 2080-2087 (1986) -S. Thaisrivongs et al. "Design and synthesis of potent and specific renin inhibitors containing difluorostatine, difluorostatone and related analoges".
Journ. of Med. Chem. vol. 35, No. 1, pp. 2-14 (1992) --A.M. Doherty et al. "Design and synthesis of potent, selective and orally active fluorine containing renin inhibitors".
Dorsselaer Viviane Van
Schirlin Daniel
Tarnus Celine
Bond Robert T.
Merrell Pharamceuticals Inc.
Nelligan Mark C.
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