Cyanoamidine P2X
View Patent ↗Novel cyanoamidines compounds of formula (I) and (II) and their derivatives wherein R 1 -R 12 are as defined in the specification act as antagonists of the P2X 7 receptor. These compounds are particularly useful in the treatment of pain, inflammation and neurodegeneration states.
1. A compound of formula (I)
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is a bond or a chain selected from the group consisting of alkyl, alkenyl, and alkynyl,
R 2 is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be independently substituted with 0, 1, 2, or 3 alkenyl, alkyl, alkynyl, halo, haloalkyl, nitro, —C(O)—N—RaRb, —C(O)O—Ra, —C(O)—Ra, —N—RaRb, alkyl-N—RaRb, —O—Ra, —OC(O)—Ra, alkyl-O—Ra, —N—(Ra)—C(O)O—Rb, —N—(Ra)—C(O)N—RaRb, S—Ra, —S(O)—Ra, —S(O) 2 —Ra, S(O) 2 —RaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl;
R 3 is selected from the group consisting of alkyl and haloalkyl,
R 4 is alkyl, and
R 5 is selected from the group consisting of halogen, aryl, and heteroaryl, wherein aryl, and heteroaryl can be independently substituted with 0, 1, 2, 3 or 4 substituents independently selected from alkenyl, alkyl, alkynyl, cyano, halo, haloalkyl, nitro, ethylenedioxy, methylenedioxy, —C(O)NRaRb, —C(O)ORa; —C(O)Ra, —NRaRb, alkylNRaRb, —ORa, —OC(O)Ra, alkylORa, —N(Ra)C(O)ORb, —N(Ra)C(O)NRaRb, SRa, —S(O)Ra, —S(O) 2 Ra, S(O) 2 RaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl and arylalkyl; and
R 6 and R 7 are independently selected from the group consisting of hydrogen and alkyl.
2. The compound of claim 1 , wherein
R 2 is aryl and
R 5 is aryl.
3. The compound of claim 2 , wherein
R 2 is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of alkyl, halo, and haloalkyl, and
R 5 is selected from the group consisting of naphthyl, phenyl, 1,3-benzodioxolyl and 2,3-dihydro-1,4-benzodioxinyl, wherein R 5 can be independently substituted with 0, 1, 2, or 3 halo, —ORa, methylenedioxy, ethylenedioxy, cyano, and —SRa.
4. The compound of claim 3 , wherein the compound is selected from the group consisting of
N-2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylphenyl) ethanimidoyl]amino}-2,2-dimethylpropyl)acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(4-methoxyphenyl)acetamide,
2-(1,3-benzodioxol-5-yl)-N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)acetamide
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(4-cyanophenyl)acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(1-naphthyl)acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(3,4-difluorophenyl)acetamide
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-[4-(ethylthio)phenyl]acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-[4-(methylthio)phenyl]acetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-(4-methoxyphenyl)butanamide, and
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-5-phenylpentanamide.
5. The compound of claim 3 , wherein
R 1 is a bond,
R 2 is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of alkyl, halo, and haloalkyl, and
R 5 is selected from the group consisting of naphthyl and phenyl and wherein naphthyl and phenyl are independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, halo, —ORa, —SRa and cyano.
6. The compound of claim 5 that is 2-(4-chlorophenyl)-N-(1-{[(cyanoimino)(2-methylphenyl)methyl]amino}-2,2-dimethylpropyl)acetamide.
7. The compound of claim 1 wherein
R 1 is alkyl,
R 2 is aryl and,
R 5 is heteroaryl.
8. The compound of claim 7 wherein,
R 2 is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of alkyl, halo, and haloalkyl, and
R 5 is selected from the group consisting of quinolinyl, thienyl, and pyridinyl.
9. The compound of claim 8 , wherein the compound is selected from the group consisting of
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-quinolin-6-ylacetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-quinolin-7-ylacetamide,
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-4-thien-2-ylbutanamide, and
N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-pyridin-3-ylacetamide.
10. The compound of claim 1 , wherein
R 1 is alkyl,
R 2 is aryl, wherein aryl is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of alkyl, halo, and haloalkyl,
R 4 is alkyl and,
R 5 is halogen.
11. The compound of claim 10 that is N-(1-{[N-cyano-2-(2-methylphenyl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-fluoroacetamide.
12. The compound of claim 1 , wherein
R 2 is heteroaryl and,
R 5 is aryl.
13. The compound of claim 12 , wherein R 2 is selected from the group consisting of pyridinyl and quinolinyl.
14. The compound of claim 13 , wherein
R 1 is alkyl,
R 2 is pyridinyl substituted with 0, 1, 2, or 3 substituents independently selected from the group comprising alkyl, halo, and haloalkyl, and,
R 5 is phenyl substituted with 0, 1, 2, 3 or 4 substituent independently selected from the group consisting of halogen and alkoxy.
15. The compound of claim 14 , wherein the compound is selected from the group consisting of
2-(4-chlorophenyl)-N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]amino}-2,2-dimethylpropyl)acetamide and,
N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide.
16. The compound of claim 1 wherein
R 2 is heteroaryl and,
R 5 is heteroaryl.
17. The compound of claim 16 , wherein
R 1 is alkyl,
R 2 is pyridinyl and,
R 5 is quinolinyl.
18. The compound of claim 17 that is N-(1-{[N-cyano-2-(2-methylpyridin-3-yl)ethanimidoyl]amino}-2,2-dimethylpropyl)-2-quinolin-6-ylacetamide.
19. The compound of claim 13 , wherein
R 1 is alkyl,
R 2 is quinolinyl and,
R 5 is phenyl.
20. The compound of claim 19 that is 2-(4-chlorophenyl)-N-(1-{[N-cyano-2-quinolin-5-ylethanimidoyl]amino}-2,2-dimethylpropyl)acetamide.
21. The compound of claim 13 wherein
R 1 is a bond,
R 2 is quinolinyl and,
R 5 is phenyl.
22. The compound of claim 2 that is selected from the group consisting of
N-(1-{[(cyanoimino)(quinolin-5-yl)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide, and
2-(4-chlorophenyl)-N-(1-{[(cyanoimino)(quinolin-5-yl)methyl]amino}-2,2-dimethylpropyl)acetamide.