Protease inhibitors
AssigneeSmithKline Beecham Corporation
InventorsRobert Wells Marquis JR., Daniel Frank Veber
Life of this patent
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Abstract
The present invention provides 7-14 membered ring ether protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.
Claims41
A compound of Formula I:
- 6
- wherein:
- A is C(O) or CH(OH);
- R1 is
- 7
- R1 is selected from the group consisting of:
- H, C1-6alkyl, Ar—C0-6alkyl, or Het—C0-6alkyl;
- R″ is selected from the group consisting of:
- H, C1-6alkyl, Ar—C0-6alkyl, or Het-C0-6alkyl;
- R′″ is selected from the group consisting of:
- H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, or Het—C0-6alkyl;
- R2 is selected from the group consisting of:
- H, C2-6alkenyl, C2-6alkynyl, Het, Ar or C1-6alkyl optionally substituted by OR6, SR6, NR62, R6NC(O)OR5, CO2R6, CO2NR62, N(C═NH)NH2, Het or Ar;
- R3 is selected from the group consisting of:
- H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R4C(O)—, R4C(S)—, R4SO2—, R4OC(O)—, R4R7NC(O)—, R4R7NC(S)—, R7HNCH(R7)C(O)—, or R4OC(O)NR7CH(R7)C(O)—;
- R4 is selected from the group consisting of:
- C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl or Het—C0-6alkyl;
- R5 is selected from the group consisting of:
- H, C1-6alkyl, Ar—C0-6alkyl, or Het—C0-6alkyl;
- R6 and R7 are selected from the group consisting of:
- H, C1-6alkyl, Ar—C0-6alkyl, or Het—C0-6alkyl;
- M is selected from the group consisting of:
- HC═CH, H2C—CH2;
- H(OR2)C—C(OR2)H;
- H(OR2)C—CH2;
- H(NR2H)C—C(NR2H)H;
- H(OR2)C—C(NR2H)H;
- and H(NR2H)C—CH2;
- n is 1-7;
- L is 0-1;
- and pharmaceutically acceptable salts, hydrates and solvates thereof.
A compound selected from the group consisting of:
- 2,2-Dimethyl-3a,6,9,9a-4H-3,5dioxa-1-azacyclopentacyclooctene-1-carboxylic acid tert-butyl ester;
- (S)-2,2-Dimethyl-3a,6,9,9a-4H-3,5dioxa-1-azacyclopentacyclooctene-1-carboxylic acid tert-butyl ester;
- 4-Amino-3,4,5,8-tetrahydro-2H-oxocin-3-ol;
- (S)-4-Amino-3,4,5,8-tetrahydro-2H-oxocin-3-ol;
- [(S)-1-(3-Hydroxy-3,4,5,8-tetrahydro-2H-oxocin-4-ylcarbamoyl)-3-butyl]carbamic acid tert-butyl ester;
- [(S)-1-((S)-3-Hydroxy-3,4,5,8-tetrahydro-2H-oxocin-4-ylcarbamoyl)-3-butyl]carbamic acid tert-butyl ester;
- and
- (S)-2-Amino-4-methyl-pentanoic acid (3-hydroxy-3,4,5,8-tetrahydro-2H-oxocin-4-yl) amide;
- (S)-2-Amino-4-methyl-pentanoic acid ((S)-3-hydroxy-oxocan-4-yl) amide;
- (3S, 4R)-4-Amino-oxepan-3-ol;
- and
- (S)-2-Amino-4-methyl-pentanoic acid ((3S, 4R)-3-hydroxy-oxepan-4-yl) amide.
Dependencies are inferred from the claim text.