Difluoro statone analogs

Details Difluoro statone analogs Difluoro statone analogs

1993-06-30

1996-09-24

Barts, Samuel

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514620, 5142375, 514307, 546335, 546170, 546337, 546145, 549441, 556419, 560 27, 564157, 564158, 564165, 544168, 544162, A61K 3144

Patent

active

055591400

DESCRIPTION:

BRIEF SUMMARY
This application was filed under U.S.C. 371 from the application PCT/US 91/096741 filed Dec. 20, 1991.
This invention relates to novel difluoro statone analogs, to the processes and intermediates useful for their preparation and to their use as anti-vital agents.


BACKGROUND INFORMATION

EP 352 000 A3 discloses retrovital protease binding peptides useful in inhibiting protease activity add in treating vital disease which differ structurally from the compounds of the present invention.


DESCRIPTION OF THE PRESENT INVENTION

More specifically this invention relates to novel difluoro statone analogs of the formula ##STR1## and the hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein ##STR2## with the proviso that B is other than p-hydroxybenzyl or p-alkoxybenzyl, a is zero, 1, 2 or 3, ##STR3## P.sub.2 is C.sub.1-6 alkyl, cyclopentyl, cyclohexyl, hydroxy C.sub.1-6 alkylene, or ##STR4## with T being H or C(O)R.sub.4, R is --CH.sub.2 CHO, hydroxy C.sub.1-6 alkylene, C.sub.1-6 alkoxy C.sub.1-6 alkylene, C.sub.1-6 alkyl, phenyl ##STR5## or Q, R.sub.1 is benzyloxy, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, phenyl, benzyl, phenethyl, fluorenylmethylenoxy, 2-isoquinolinyl, PDL, ##STR6## NHSO.sub.2 R.sub.4, N(R.sub.4)(benzyl), and N(R.sub.4)(PDL), with PDL being --(CH.sub.2).sub.a -2-, 3-, or 4-pyridyl, or p-W-substituted benzyloxy with W being nitro, OH amino, C.sub.1-6 alkoxy, hydroxy C.sub.1-6 alkylene, or halogeno, alkylene, hydroxy C.sub.1-6 alkylene, C.sub.1-6 alkyl H or OH, ##STR7## V being OR.sub.4 or hydroxy C.sub.1-6 alkylene, CH.sub.2 Si(CH.sub.3).sub.2 (R.sub.3), --(CH.sub.2 ).sub.d -Q, PDL, ##STR8## .paren open-st.C.sub.1-6 alkylene.paren close-st.OR.sub.4 or --CH(Y)(Z), Y being hydroxy C.sub.1-6 alkylene, C.sub.1-6 alkyl, or (CH.sub.2 .paren close-st..sub.e C.sub.6 H.sub.4 .paren open-st.V).sub.e, and Z being CHO, CO.sub.2 R.sub.4, CO.sub.2 NHR.sub.4 or (CH.sub.2 .paren close-st..sub.e OR.sub.4, 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 ##STR9## R.sub.7 is CH.sub.2 OR.sub.4 or C(O)NHR.sub.4, R.sub.8 is (H,OH) or .dbd.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 --CH.sub.2 NH-- (reduced), ##STR10## (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 a-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. Examples of salt forms are the trifluoroacetate, hydrochloride, sodium, potassium and ammonium forms, although the scope of salts embraced herein is not limited thereto, the scope includes all of the salts known to be useful in the art of peptide chemistry.
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, ox

REFERENCES:
T. W. Graham Solomons, Organic Chemistry, Second Edition, 1980, pp. 657-660 .

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