Claims for Patent: 5,760,019

Summary for Patent: 5,760,019

Title:	Silanol enzyme inhibitors
Abstract:	Compounds of formula I ##STR1## in which X is OH Y is H, OH methyl or F, A and B are independently a) alkyl of one to ten carbons or heteroatoms, b) aryl of four to seven carbons or heteroatoms, c) cyclic of three to ten carbons or heteroatoms, or moieties of the formulas ##STR2## in a), b), c), d), e) and f), CH is bonded to silicon; R.sup.1 to R.sup.11 are independently hydrogen, alkyl of 1 to 10 carbons or heteroatoms, aryl of 4 to 14 carbons or heteroatoms, arylalkyl of 5 to 20 carbons or heteroatoms, substituted carbonyl or unsubstituted carbonyl; heteroatoms are nitrogen, oxygen, silicon or sulfur; and at least one of A and B is independently moieties d, e or f. The compounds of formula I inhibit protease enzymes and can be used as pharmaceuticals.
Inventor(s):	Sieburth; Scott McN. (Coram, NY), Mutahi; Alfred M. (Edison, NJ)
Assignee:	The Research Foundation of State University of New York (Albany, NY)
Application Number:	08/680,330
Patent Claims:	1. A compounid of formula I ##STR47## in which X is OH Y is H, OH, methyl or F; A and B are independently a) alkyl of one to ten carbons of heteroatoms, b) aryl of four to seven carbons or heteroatoms, c) cyclic of three to ten carbons or heteroatoms, or moieties of the formulas ##STR48## in a), b), c), d), e) and f), CH is bonded to silicon; R.sup.1 to R.sup.11 are independently hydrogen, alkyl of 1 to 10 carbons or heteroatoms, aryl of 4 to 14 carbons or heteroatoms, arylalkyl of 5 to 20 carbons or heteroatoms, substituted carbonyl or unsubstituted carbonyl; heteroatoms are nitrogen, oxygen, silicon or sulfur; and at least one of A and B is independently moieties d, e or f. 2. A compound according to claim 1 wherein moieties for R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.10 and R.sup.11 include at least one amino acid. 3. A compound according to claim 1, wherein Y is OH or OCH.sub.3. 4. A compound according to claim 1 which is Benzyl 5-(benzoylamino)-4,4-dihydroxy-7-methyl-4-sila-octanamide, Benzyl 5-(benzoylamino)-4,7-dimethyl-4-hydroxy-4-sila-octanamide, Butyl 6-cyclohexyl-4,4-dihydroxy-2-(S)-isopropyl-5-(S)-[2-(S)-(2-(S)-1-oxo-1-(4- methoxymethyl-1piperidinyl)-3-phenyl-propanoxy)-hexanoyl-amino)]-4-sila-hex anamide, [5-(R)-((t-butoxycarbonyl)amino)-2-(S)-benzyl-4,4-dihydroxy-6-phenyl-4-sila -hexanoyl]-L-leucyl]-L phenylalanamide [[5-(R)-([Acetyl-L-prolinyl]-L-alaninyl)-amino-4,4-dihydroxy-2-(S)-(2-pheny lethyl)-4-sila-hexanoyl]L-leucyl]-aniline, Benzyl [4,4-dihydroxy-2-(S)-isobutyl-5-(N-phthalamido)-4-sila-pentanoyl]-L-trypta mide [[[2-(R)-[(1-(R)-[[L-Alaninoyl]-L-argininoyl]-L-valinoyl]-amino]-2-phenyl-e thyl)-dihydroxysilyl)(R)-cyclopentane carboxoyl]-L- glutamoyl]-L- alaninoyl]-L-methionine, 3-(R)-([1-((R)-[[t-Butoxycarbonyl)-L-phenyl-alanoyl]-L-histidinyl]-amino)-2 -cyclohexylethyl]dihydroxysilyl) 1,5,5-trimethyl-2-pyrrolidinone, Di-[1-(S)-(2-(R)-hydroxyindanyl)]2-(S)-6-(S)-dibenzyl-4,4-dihydroxy-4-sila- heptanediamide, Di-benzyl 2-(S)-6-(S)-dibenzyl-4,4-dihydroxy-4-sila-heptanediamide, 2-(R),4-(R)-Bis-([benzyloxycarbonyl)-L-valinyl]-amino)-3,3-dihydroxy-1,5-di phenyl-3-sila-pentane, [5-(R)-[[[Morpholinosulfonyl]-L-phenyl-alaninoyl]-L-allylglycinoyl]amino]-6 -cyclohexyl-4,4 dihydroxy-2-methyl-4-sila-pentane, [5-(R)- [[[Morpholinosulfonyl]-L-phenyl-alaninoyl]-L-allylglycinoyl]amino]-7-cyclo hexyl-5,5 dihydroxy-2-methyl-5-sila-pentane, [[6-(R)-Benzoylamino]-3-aza-5,5-dihydroxy-3-methyl-7-phenyl-5-sila-heptanoy l]-L-4-dithianylproline N-t-Butyl-N'-isobutyl-N'-[3-(R)-([[2-quinolinoyl]-L-asparinoyl]-amino)-4-ph enyl-2,2-dihydroxy-2 sila-butyl]urea, t-Butyl N-[3-(R)-([[2-quinolinoyl]-L-asparinoyl]-amino)-4-phenyl-2,2-dihydroxy-2-s ila-butyl]-L pipecolinamide, N-[3,3-Dihydroxy-4-(R)-([[(p-methoxy-benzoyl)-L-valinoyl]-L-prolinoyl]-amin o)-5-methyl-3-sila hexyl]benzylamine, N-(2,2-Dihydroxy-6-guanidino-(3-(R)-[[[-2-n-propylpentanoyl]-L-aspartoyl]-L -prolinoyl]-amino)-2sila-n-hexyl) N-2-phenylethyl amine, 3,5-Bis-(p-hydroxymethyl benzyl)-3,5-diaza-2-(S)-6-(R)-dibenzyl- 1,1 -dihydroxy-1-sila-cyclohexan-4-one, (1-(R)-[[(t-Butoxycarbonyl)-L-valinoyl]-L-prolinoyl]-amino-2-methyl) 2-benzoxazole silanediol, [1-(R)-(3-(S)-Tetrahydrofuranoxycarbonyl)-amino-2-phenylethyl]-(3-[3-(1,2-d ioxo-2-aminoethyl)-5'isobutyl-5'-(S)-pyrrolin-4'-one]-5-(R)-5-benzyl-pyrrol in-4-one) methyl silanediol, 6-Cyclohexyl-4,4-dihydroxy-3-(R)-[5'-(S)-5'isobutyl-5- [5"-(S)-5"-(3-methyl-2-butenyl)-5"-benzyl 3"-pyrrolin-4"one]-3'-pyrrolin-4'-one]-4-sila-hexane, or 7-Cyclohexyl-5,5-dihydroxy-3-(R)-[5'-(S)-5'isobutyl-5-[5"-(S)-5"-(3-methyl- 2-butenyl)-5"-benzyl 3"-pyrrolin-4"-one]-3'-pyrrolin-4'-one]-5-sila-hexane. 5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 6. A method of inhibiting a protease enzyme comprising applying a compound of claim 1 to an enzyme-substrate system which comprises the protease enzyme and its substrate, said compound in an inhibiting amount for the protease enzyme. 7. A method of treating a pathological condition associated with a protease comprising administering a compound of claim 1 to a subject having said pathological condition said compound in an amount to alleviate the pathological condition. 8. The method of claim 7 wherein the protease is serine protease, metalloprotease or aspartic protease. 9. The method of claim 8 wherein the serine protease is plasmin, plasminogen activator, elastase, cathepsin G, mast-cell protease, prolyl endopeptidase, thrombin or factor Xa. 10. The method of claim 8 wherein the metalloprotease is angiotensin-converting enzyme, collagenase, enkephalinase, stromelysin, endothelin converting enzyme or neutral endopeptidase. 11. The method of claim 8 wherein the aspartic protease is renin or HIV protease. 12. The method of claim 9 wherein the serine protease is elastase and the compound is N-[3,3-Dihydroxy-4-(R)-([[(p-methoxy-benzoyl)-L-valinoyl]-L-prolinoyl]-amin o)-5-methyl-3-sila-hexyl]benzylamine or (1-(R)-[[t-Butoxycarbonyl)-L-valinoyl]-L-prolinoyl]-amino-2-methyl) 2-benzoxazole silanediol. 13. The method of claim 9 wherein the serine protease is thrombin and the compound is N-(2,2-Dihydroxy-6-guanidino-(3-(R) -[[[2-n-propylpentanoyl]-L-aspartoyl]-L-prolinoyl]-amino)-2-sila-n-hexyl) N-2-phenylethyl amine. 14. The method of claim 10 wherein the metalloprotease is stromelysin and the compound is [[5-(R)-([Acetyl-L-prolinyl]-L-alaninyl)-amino-4,4-dihydroxy-2-(S)-(2-pheny lethyl)-4-sila-hexanoyl]-L-leucyl]-aniline. 15. The method of claim 10 wherein the metalloprotease is angiotensin-converting enzyme and the compound is Benzyl 5-(benzoylamino)-4,4-dihydroxy-7-methyl-4-sila-octanamide, Benzyl 5-(benzoylamino)-4,7-dimethyl 4-hydroxy-4-sila-octanamide, or [[6-(R)-Benzoylamino]-3-aza 5,5-dihydroxy-3-methyl-7-phenyl-5-sila-heptanoyl]-L-4-dithianylproline. 16. The method of claim 10 wherein the metalloprotease is collagenase and the compound is Benzyl [4,4-dihydroxy-2-(S)-isobutyl-5-(N-phthalamido)-4-sila-pentanoyl]-L-trypam ide. 17. The method of claim 1 wherein the aspartic protease is renin and the compound is Butyl 6-cyclohexyl-4,4-dihydroxy-2-(S)-isopropyl-5-(S)-[2-(S)-(2-(S)- 1-oxo-1-(4-methoxymethyl-1-piperidinyl)-3-phenyl-propanoxy)-hexanoyl-amino )]-4-sila-hexanamide, 3-(R)-([1-((R)-[[t-Butoxycarbonyl)-L-phenyl-alanoyl]-L-histidinyl]-amino)-2 -cyclohexylethyl]-dihydroxysilyl) 1,5,5-trimethyl-2-pyrrolidinone, [5-(R)-[[[Morpholinosulfonyl]-L-phenyl-alaninoyl]-L-allylglycinoyl]amino]-6 -cyclohexyl-4,4-dihydroxy-2-methyl-4-sila-pentane, [5-(R)-[[[Morpholinosulfonyl]-L-phenyl-alaninoyl]-L-allylglycinoyl]amino]-7 -cyclohexyl-5,5-dihydroxy-2-methyl-5-sila-pentane, 6-Cyclohexyl-4,4-dihydroxy-3-(R)-[5'-(S)-5'isobutyl-5-[5"-(S)-5"-(3-methyl- 2-butenyl)-5"-benzyl 3"-pyrrolin-4'one]-3'-pyrrolin-4'-one]-4-sila-hexane, or 7-Cyclohexyl-5,5-dihydroxy-3-(R)-[5'-(S)-5'isobutyl-5-[5"-(S)-5"-(3-methyl- 2-butenyl)-5"-benzyl-3"-pyrrolin-4"-one]-3'-pyrrolin-4'-one]-5-sila-hexane. 18. The method of claim 11 wherein the aspartic protease is HIV protease and the compound is [5-(R)-((t-butoxycarbonyl)amino)-2-(S)-benzyl-4,4-dihydroxy-6-phenyl-4-sila -hexanoyl]-L-leucyl]-L-phenylalanamide, [[[2-(R)-[1-(R)-[[L-Alaninoyl]-L-argininoyl]-L-valinoyl]-amino]-2-phenyl-et hyl)-dihydroxysilyl)-(R)-cyclopentane carboxoyl]-L-glutamoyl]-L-alaninoyl]-L-methionine, Di-benzyl 2-(S)-6-(S)-dibenzyl-4,4-dihydroxy-4-sila-heptanediamide Di-[1-(S)-(2-(R)-hydroxyindanyl)]2-(S)-6-(S)-dibenzyl-4,4-dihydroxy-4-sila- heptanediamide, 2-(R), 4-(R)-Bis-([benzyloxycarbonyl)-L-valinyl]-amino)-3,3 dihydroxy-1,5 -diphenyl-3-sila-pentane, N-t-Butyl-N'-isobutyl-N'-[3-(R)-([[2-quinolinoyl]-L-asparinoyl]-amino)-4-ph enyl-2,2-dihydroxy-2-sila-butyl]urea, t-Butyl N-[3-(R)-([[2-quinolinoyl]-L-asparinoyl]-amino)-4-phenyl-2,2-dihydroxy-2-s ila-butyl]-L-pipecolinamide, 3,5 Bis-(p-hydroxymethyl benzyl)-3,5-diaza 2-(S)-6-(R)-dibenzyl-1,1-dihydroxy-1-sila-cyclohexan-4-one, or 1-(R)-(3-(S)-Tetrahydrofuranoxycarbonyl)-amino-2-phenylethyl]-(3-[3-(1,2-di oxo-2-aminoethyl)-5'-isobutyl-5'-(S)-pyrrolin-4'-one]-5-(R)-5-benzyl pyrrolin-4-one) methyl silanediol.

Details for Patent 5,760,019

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2039-03-29