US 2006/0189600 A1Published application

Benodiazepine spirohydantoin cgrp receptor antagonists

AssigneeMerck & Co., Inc.

InventorsIan Bell, Samuel Graham, Theresa Williams, Craig Stump

Life of this patent

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Abstract

The present invention is directed to compounds that are antagonists of CGRP receptors and that are useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

Claims16

Dependent claims

A compound of the formula I:

R1 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9, wherein R9 is independently selected from:
(i) hydrogen,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) —C5-6cycloalkyl,
(iv) benzyl, and
(v) phenyl,
(g) —NR9R10, wherein R10 is independently selected from:
(i) hydrogen,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) —C5-6cycloalkyl,
(iv) benzyl, and
(v) phenyl,
or where R9 and R10 may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(I) —C1-6alkyl,
(II) —O—C1-6alkyl
(III) halo,
(IV) hydroxy,
(V) phenyl, and
(VI) benzyl,
(h) —CONR9R10, and
(i) —SO2R10,
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl,
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
R2a, R2b and R2c are independently selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(3) halo,
(4) hydroxy,
(5) —O—C1-6alkyl which are unsubstituted or substituted with 1-6 fluoro
(6) —OCF3
(7) trifluoromethyl,
(8) —CO2R9,
(9) —CONR9R10, and
(10) —SO2R10;
R3 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10, and
(i) —SO2R10,
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10,
(i) —SO2R10,
(j) —CN, and
(k) —OCF3;
R4 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) C5-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
R6 is selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10,
(i) —SO2R10, and
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
X is a bond or is —N(R4a)—, where R4a is independently selected from the definitions of R4;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

127 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/547,228Filed 10 Mar 2004
Priority: 14 Mar 2003
Published: 24 Aug 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/455,611Us provisional application · filed 14 Mar 2003
US 7,205,293 B2Related patent
US 2006/0189600 A1This patent

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

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Abstract

A compound of the formula I:

R1 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9, wherein R9 is independently selected from:
(i) hydrogen,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) —C5-6cycloalkyl,
(iv) benzyl, and
(v) phenyl,
(g) —NR9R10, wherein R10 is independently selected from:
(i) hydrogen,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) —C5-6cycloalkyl,
(iv) benzyl, and
(v) phenyl,
or where R9 and R10 may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(I) —C1-6alkyl,
(II) —O—C1-6alkyl
(III) halo,
(IV) hydroxy,
(V) phenyl, and
(VI) benzyl,
(h) —CONR9R10, and
(i) —SO2R10,
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl,
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
R2a, R2b and R2c are independently selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(3) halo,
(4) hydroxy,
(5) —O—C1-6alkyl which are unsubstituted or substituted with 1-6 fluoro
(6) —OCF3
(7) trifluoromethyl,
(8) —CO2R9,
(9) —CONR9R10, and
(10) —SO2R10;
R3 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10, and
(i) —SO2R10,
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10,
(i) —SO2R10,
(j) —CN, and
(k) —OCF3;
R4 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) C5-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
R6 is selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR9R10,
(h) —CONR9R10,
(i) —SO2R10, and
(j) trifluoromethyl
(3) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
X is a bond or is —N(R4a)—, where R4a is independently selected from the definitions of R4;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

127 more elements

Facts

Application

10/547,228Filed 10 Mar 2004

Priority

14 Mar 2003

Published

24 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics