US 2006/0148779 A1Published application

Monocyclic anilide spirohydantoin cgrp receptor antagonists

AssigneeMerck & Co., Inc.

InventorsIan Bell, Cory Theberge, Theresa Williams, C. Blair Zartman, Xu-Fang Zhang, Steven Gallicchio

Life of this patent

Estimating the term…

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.

Claims17

Dependent claims

A compound of the formula I:

wherein:
B is a heterocycle selected from the group consisting of:
where the dashed line indicates the optional presence of a double bond,
where B is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R1, R2, R3a and R3b, wherein
R1, R2, R3a and R3b are independently selected from:
(1)-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, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, 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) trifluoromethyl, and
(vi) —OCF3,
(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) —CONR10aR11a, wherein R10a and R11a are independently selected from:
(i) hydrogen,
(ii) -C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) -C5-6cycloalkyl,
(iv) benzyl,
(v) phenyl,
or where R10a and R11a may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
(2) —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, and
(e) phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) -C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) -C3-6cycloalkyl,
(f) 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,
(g) —CO2R9,
(h) —NR10R11,
(i)—CONR10R11, and
(j) —SO2R12,
(4) halo,
(5) hydroxy,
(6) —O-C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO2R9;
(9) —NR10R11,
(10) —SO2R12,
(11) —CONR10aR11a,
or where R3a and R3b and the carbon atom(s) to which they are attached may be joined together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) -C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) —O-C1-6alkyl,
(iv) -C3-6cycloalkyl,
(v) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl,
(vi) —CO2R9,
(vii) —NR10R11,
(viii) —SO2R12,
(ix) —CONR10aR11a, and
(b) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
(i)-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv) —O-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —C3-6cycloalkyl,
(c) —SO2R12,
(d) hydroxy,
(e) —O-C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(f) —COR12,
(g) —NR10R11,
A1 and A2 are independently selected from:
(1) a bond,
(2) —CR13R14—, wherein R13 and R14 are independently selected from:
(a) hydrogen,
(b) C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(c) hydroxy,
or wherein one of A1 and A2 is absent;
R4 is selected from:
(1) hydrogen, and
(2) C1-6 alkyl;
which is unsubstituted or substituted with 1-6 fluoro,
R5a, R5b and R5c are independently selected from:
(1) hydrogen,
(2) C1-6 alkyl,
(3) —O—C1-6alkyl,
(4) —OCF3,
(5) trifluoromethyl,
(6) halo,
(7) hydroxy, and
(8) —CN;
R6 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, and
(e) phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, or thienyl, 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;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

121 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/547,082Filed 10 Mar 2004
Priority: 14 Mar 2003
Published: 6 Jul 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 235/02
Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings: condensed with carbocyclic rings or…
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 25/06
Drugs for disorders of the nervous system: antimigraine agents
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…

Family

Application60/454,944Us provisional application · filed 14 Mar 2003
US 7,192,954 B2Related patent
US 2006/0148779 A1This patent

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

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Abstract

A compound of the formula I:

wherein:
B is a heterocycle selected from the group consisting of:
where the dashed line indicates the optional presence of a double bond,
where B is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R1, R2, R3a and R3b, wherein
R1, R2, R3a and R3b are independently selected from:
(1)-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, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, 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) trifluoromethyl, and
(vi) —OCF3,
(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) —CONR10aR11a, wherein R10a and R11a are independently selected from:
(i) hydrogen,
(ii) -C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(iii) -C5-6cycloalkyl,
(iv) benzyl,
(v) phenyl,
or where R10a and R11a may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
(2) —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, and
(e) phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) -C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) -C3-6cycloalkyl,
(f) 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,
(g) —CO2R9,
(h) —NR10R11,
(i)—CONR10R11, and
(j) —SO2R12,
(4) halo,
(5) hydroxy,
(6) —O-C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO2R9;
(9) —NR10R11,
(10) —SO2R12,
(11) —CONR10aR11a,
or where R3a and R3b and the carbon atom(s) to which they are attached may be joined together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) -C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) —O-C1-6alkyl,
(iv) -C3-6cycloalkyl,
(v) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl,
(vi) —CO2R9,
(vii) —NR10R11,
(viii) —SO2R12,
(ix) —CONR10aR11a, and
(b) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
(i)-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv) —O-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —C3-6cycloalkyl,
(c) —SO2R12,
(d) hydroxy,
(e) —O-C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(f) —COR12,
(g) —NR10R11,
A1 and A2 are independently selected from:
(1) a bond,
(2) —CR13R14—, wherein R13 and R14 are independently selected from:
(a) hydrogen,
(b) C1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(c) hydroxy,
or wherein one of A1 and A2 is absent;
R4 is selected from:
(1) hydrogen, and
(2) C1-6 alkyl;
which is unsubstituted or substituted with 1-6 fluoro,
R5a, R5b and R5c are independently selected from:
(1) hydrogen,
(2) C1-6 alkyl,
(3) —O—C1-6alkyl,
(4) —OCF3,
(5) trifluoromethyl,
(6) halo,
(7) hydroxy, and
(8) —CN;
R6 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, and
(e) phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, or thienyl, 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;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

121 more elements

Facts

Application

10/547,082Filed 10 Mar 2004

Priority

14 Mar 2003

Published

6 Jul 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 235/02
Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings: condensed with carbocyclic rings or…
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
A61P 25/06
Drugs for disorders of the nervous system: antimigraine agents
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…