US 2003/0114437 A1Published application

Protease inhibitors

OwnerMaxwell D. Cummings, Robert W. Marquis Jr +4inventors

InventorsMaxwell D. Cummings, Robert W. Marquis Jr, Yu Ru, Scott K. Thompson, Daniel F. Veber, Dennis S. Yamashita

Life of this patent

Estimating the term…

Loading patent…

Abstract

The present invention provides methods which use 4-amino-azepan-3-one protease inhibitors of cathepsin S in the treatment of diseases in which cathepsin S is implicated, especially treatment or prevention of autoimmune disease; treatment or prevention of a disease state caused by the formation of atherosclerotic lesions and complications arising therefrom; and diseases requiring inhibition, for therapy, of a class II MHC-restricted immune response, inhibition of an asthmatic response, inhibition of an allergic response, inhibition of immune response against a transplanted organ or tissue, or inhibition of elastase activity in atheroma, and novel compounds for use therewith.

Claims54

Dependent claims

A method of inhibiting cathepsin S, comprising administering to a patient in need thereof an effective amount of a compound of Formula I:

131
wherein:
R1 is selected from the group consisting of:
132
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)—,
133
R3 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, C2-6alkenyl, C2-6alkynyl, HetC0-6alkyl, ArC0-6alkyl, Ar—ArC0-6alkyl, Ar—HetC0-6alkyl, Het-ArC0-6alkyl, and Het-HetC0-6alkyl;
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)—, R5R13NC(O)—, and R5R13NC(S)—;
R5 is selected from the group consisting of:
H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, At—C0-6alkyl and Het-C0-6alkyl;
R6 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
R7 is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, At—C0-6alkyl, Het-C0-6alkyl, R10C(O)—, R10C(S)—, R10SO2—, R10OC(O)—, R10R14NC(O)—, and R10R14NC(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, At—C0-6alkyl and Het-C0-6alkyl;
R10 is selected from the group consisting of:
C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, At—C0-6alkyl and Het-C0-6alkyl;
R11 is selected from the group consisting of:
H, C1-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
R12 is selected from the group consisting of:
H, C1-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
R13 is selected from the group consisting of:
H, C1-6alkyl, At—C-6alkyl, and Het-C0-6alkyl;
R14 is selected from the group consisting of:
H, C1-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
R′ is selected from the group consisting of:
H, C1-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
R″ is selected from the group consisting of:
H, C1-6alkyl, At—C0-6alkyl, or Het-C0-6alkyl;
R′″ is selected from the group consisting of:
H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, At—C0-6alkyl, and Het-C0-6alkyl;
X is selected from the group consisting of:
CH2, S, and O;
Z is selected from the group consisting of:
C(O) and CH2;
and pharmaceutically acceptable salts, hydrates and solvates thereof.

40 more elements

A compound selected from the group consisting of:

183
5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
184
4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
185
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
186
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
187
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
188
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
189
5-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
190
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
191
3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
192
4-bromo-N-{(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-benzamide;
193
cyclobutanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
194
cyclopentanecarboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
195
(S)-tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
196
(R)-tetrahydro-furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
197
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
198
5-pyridin-2-yl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
199
4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
200
5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
201
furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
202
furan-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
203
thiophene-3-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
204
thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
205
5-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
206
3-methyl-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
207
3-ethoxy-thiophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[3-oxo-1-(1-oxy-pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide;
208
selenophene-2-carboxylic acid {(S)-2-cyclohexyl-1-[(R) -7-methyl-3-oxo-1-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-ethyl}-amide;
and
209
2,2,4-trideutero-Furan-2-carboxylic acid {(S)-2-cyclohexyl-1-[(4S,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-ethyl}-amide.

52 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/258,053Filed 17 Oct 2002
Published: 19 Jun 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
C07D 223/08
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,…:…