US 2003/0144175 A1Published application

Protease inhibitors

AssigneeSmithKline Beecham Corporation

InventorsRobert Wells Marquis JR., Yu Ru, Daniel Frank Veber, Maxwell David Cummings, Scott Kevin Thompson, Dennis Shinji Yamashita

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Abstract

The present invention provides 4-amino-azepan-3-one 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.

Claims61

Dependent claims

A compound of Formula I:

37
wherein:
R1 is selected from the group consisting of:
38
R2 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R9C(O)—, R9C(S)—, R9SO2—, R9OC(O)—,
R9R11NC(O)—, R9R11NC(S)—, R9(R11)NSO2—
39
, and R9SO2R11NC(O)—;
R3 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
R3 and R′ may be connected to form a pyrrolidine, piperidine or morpholine ring;
R4 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R5C(O)—, R5C(S)—, R5SO2—, R5OC(O)—, R5R12NC(O)—, and R5R12NC(S)—;
R5 is selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R6 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R7 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R10C(O)—, R10C(S)—, R10SO2—, R10OC(O)—, R10R13NC(O)—, and R10R13NC(S)—;
R8 is selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
R9 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R10 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R11 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R12 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R13 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R′ is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and 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, and Het—C0-6alkyl;
R″″ is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
X is selected from the group consisting of:
CH2, S, and O;
Z is selected from the group consisting of:
C(O) and CH2;
n is an integer from 1 to 5;
and pharmaceutically acceptable salts, hydrates and solvates thereof.

43 more elements

A compound of Formula I

46
wherein:
R1 is selected from the group consisting of:
47
R2 is selected from the group consisting of:
C1-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R9C(O)—, R9SO2—, R9R11NC(O)—, and R9SO2R11NC(O)—;
R3 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, C2-6alkenyl, C2-6alkynyl, Het—C0-6alkyl and Ar—C0-6alkyl;
R3 and R′ may be connected to form a pyrrolidine, piperidine or morpholine ring;
R4 is R5C(O)—;
R5 is slected from the group consisting of:
C1-6alkyl and Het—C0-6alkyl;
R9 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R11 is H;
R′ is H;
R″ is H;
R′″ is selected from the group consisting of:
H and C1-6alkyl;
R″″ is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
and
n is an integer from 1 to 5;
and pharmaceutically acceptable salts, hydrates and solvates thereof.

21 more elements

A compound of Formula II:

48
wherein:
R1 is selected from the group consisting of:
49
R2 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R9C(O)—, R9C(S)—, R9SO2-, R9OC(O)—,
R9R11NC(O)—, R9R11NC(S)—, R9(R11)NSO213
50
and R9SO2R11NC(O)—;
R3 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
R3 and R′ may be connected to form a pyrrolidine, piperidine or morpholine ring;
R4 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R5C(O)—, R5C(S)—, R5SO2—, R5OC(O)—, R5R12NC(O)—, and R5R12NC(S)—;
R5 is selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R6 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, or Het—C0-6alkyl;
R7 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl, Het—C0-6alkyl, R10C(O)—, R10C(S)—, R10SO2—, R10OC(O)—, R10R13NC(O)—, and R10R13NC(S)—;
R8 is selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
R9 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R10 is independently selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar—C0-6alkyl and Het—C0-6alkyl;
R11 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R12 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R13 is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and Het—C0-6alkyl;
R′ is selected from the group consisting of:
H, C1-6alkyl, Ar—C0-6alkyl, and 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, and Het—C0-6alkyl;
R″″ is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl and ArC0-6alkyl;
X is selected from the group consisting of:
CH2, S, and O;
Z is selected from the group consisting of:
C(O) and CH2;
n is an integer of from 1 to 5;
and pharmaceutically acceptable salts, hydrates and solvates thereof.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/881,334Filed 14 Jun 2001
Priority: 23 Dec 1998
Published: 31 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
A61P 19/00
Drugs for skeletal disorders
C07D 223/12
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings

Family

Application60/113,636Us provisional application · filed 23 Dec 1998
Application60/164,581Us provisional application · filed 10 Nov 1999
Application09/593,845Continuation in part · filed 14 Jun 2000
Application09/881,334Continuation in part · filed 14 Jun 2001
US 2003/0144175 A1This patent

From the US filing history. Foreign family members aren’t listed.