IP Library Granted Patent US 7,994,325
Granted Patent B2
US 7,994,325 · App. 11/885,926 · Granted Aug 9, 2011

CGRP receptor antagonists

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Quick Facts
Patent No.
US 7,994,325
App. No.
11/885,926
Granted
Aug 9, 2011
Kind
B2
Abstract

Compounds of Formula I: (where variables R 1 , A, B, W, X, Y and Z are as defined herein) useful as antagonists of CGRP receptors and 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.

Claims (108)

1. A compound of the Formula I:

wherein:

Z is selected from:

A is C(R 2 );

B is O or S;

R 1 is selected from:

1) H, C 1 -C 6 alkyl, C 3-6 cycloalkyl and heterocycle, wherein the heterocyle is selected from azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran wherein said alkyl, cycloalkyl and heterocycle are unsubstituted or substituted with one or more substituents each independently selected from:

a) C 1-6 alkyl,

b) C 3-6 cycloalkyl,

c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,

d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,

and where heteroaryl is selected from:

imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole;

e) heterocycle, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 , and where heterocycle is selected from: azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran;

f) (F) p C 1-3 alkyl,

g) halogen,

h) OR 4 ,

i) O(CH 2 ) s OR 4 ,

j) CO 2 R 4 ,

k) CN,

l) NR 10 R 11 ,

m) O(CO)R 4 ;

2) aryl or heteroaryl, selected from: phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole,

unsubstituted or substituted with one or more substituents each independently selected from:

a) C 1-6 alkyl,

b) C 3-6 cycloalkyl,

c) (F) p C 1-3 alkyl,

d) halogen,

e) OR 4 ,

f) CO 2 R 4 ,

g) (CO)NR 10 R 11 ,

h) SO 2 NR 10 R 11 ,

i) N(R 10 ) SO 2 R 11 ,

j) S(O) m R 4 ,

k) CN,

l) NR 10 R 11 , and

m) O(CO)R 4 ;

R 2 is selected from:

1) H, C 1 -C 6 alkyl, C 3-6 cycloalkyl and heterocycle, wherein the heterocyle is selected from azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and thiazolidine: wherein said alkyl, cycloalkyl and heterocycle are unsubstituted or substituted with one or more substituents each independently selected from:

a) C 1-6 alkyl,

b) C 3-6 cycloalkyl,

c) phenyl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,

d) heteroaryl, unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ,

and where heteroaryl is selected from: benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole;

e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , and where heterocycle is selected from: azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and thiazolidine;

f) (F) p C 1-3 alkyl,

g) halogen,

h) OR 4 ,

i) O(CH 2 ) s OR 4 ,

j) CO 2 R 4 ,

k) CN,

l) NR 10 R 11 , and

m) O(CO)R 4 ; and

2) aryl or heteroaryl, selected from:

phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole, unsubstituted or substituted with one or more substituents each independently selected from:

a) C 1-6 alkyl,

b) C 3-6 cycloalkyl,

c) (F) p C 1-3 alkyl,

d) halogen,

e) OR 4 ,

f) CO 2 R 4 ,

g) (CO)NR 10 R 11 ,

h) SO 2 NR 10 R 11 ,

i) N(R 10 ) SO 2 R 11 ,

j) S(O) m R 4 ,

k) CN,

l) NR 10 R 11 , and

m) O(CO)R 4 ,

where R 1 and R 2 , or any two independent R 2 , on adjacent atoms optionally join to form a ring selected from: C 5-7 cycloalkyl, heterocycle, aryl, and heteroaryl, in which the ring is unsubstituted or substituted with 1-10 substituents each independently selected from R 6 ;

R 10 and R 11 are independently selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, and benzyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and benzyl are unsubstituted or substituted with halogen, hydroxy or C 1 -C 6 alkoxy, where R 10 and R 11 optionally join to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is ring is unsubstituted or substituted with 1-5 substituents each independently selected from R 4 ;

R 4 is independently selected from: H, C 1-6 alkyl, (F) p C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl and benzyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl and benzyl are unsubstituted or substituted with halogen, hydroxy or C 1 -C 6 alkoxy;

W is O, NR 4 or C(R 4 ) 2 ;

X is C or S;

Y is O,(R 4 ) 2 , NCN, NSO 2 CH 3 or NCONH 2 , or Y is O 2 when X is S;

R 6 is H;

Q is independently selected from:

(1) ═C(R 7a )—,

(2) —C(R 7a ) 2 —,

(3) —C(═O)—,

(4) —S(O) m —,

(5) ═N—, and

(6) —N(R 7a )—;

T is independently selected from:

(1) ═C(R 7b )—,

(2) —C(R 7b ) 2 —,

(3) —C(═O)—,

(4) —S(O) m —,

(5) ═N—, and

(6) —N(R 7b )—;

R 7a and R 7b are each independently selected from H and phenyl, and R 7a and R 7b on adjacent caron atoms and the atoms to which they are attached optionally join to form a ring selected from phenyl or pyridine, which ring is unsubstituted;

p is 0 to 2q+1, for a substituent with q carbons;

m is 0, 1 or 2;

n is 0 or 1;

s is 1, 2 or 3;

and pharmaceutically acceptable salts and individual diastereomers thereof.

2. The compound of claim 1 having the Formula Ia:

and pharmaceutically acceptable salts and individual stereoisomers thereof.

3. The compound of claim 1 having the Formula Id:

and pharmaceutically acceptable salts and individual stereoisomers thereof.

4. The compound of claim 1 having the Formula Ie:

and pharmaceutically acceptable salts and individual stereoisomers thereof.

5. A compound of claim 1 of the formula:

wherein:

Z is selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.

6. A compound selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.

7. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .

Assignments (6)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
CHANGE OF NAME Recorded Aug 29, 2012
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 028866/0511 →
MERGER Recorded Aug 27, 2012
From: MERCK SHARP & DOHME CORP.
To: SCHERING CORPORATION
Reel/Frame 028850/0515 →
CHANGE OF NAME Recorded Jan 26, 2010
From: MERCK & CO., INC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 023906/0803 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 3, 2009
From: NGUYEN, DIEM N.
To: MERCK & CO., INC.
Reel/Frame 023459/0109 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 3, 2009
From: PAONE, DANIEL V.; SHAW, ANTHONY W.; BURGEY, CHRISTOPHER S.; TUCKER, THOMAS J.; GRAHAM, SAMUEL L.
To: MERCK & CO., INC.
Reel/Frame 023459/0166 →