IP Library › Granted Patent US 7,491,728

Granted Patent B2

US 7,491,728 · App. 10/552,363 · Granted Feb 17, 2009

Pyrimidinone compounds as calcilytics

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Quick Facts

Patent No.: US 7,491,728
App. No.: 10/552,363
Granted: Feb 17, 2009
Kind: B2

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Abstract

The pyrimidinone compounds are disclosed. Methods of preparing the pyrimidinone compounds are also disclosed.

Claims (136)

1. A compound having the chemical formula:

wherein:

R 1 and R 2 are independently H, halogen, CN, CF 3 , lower alkyl, cycloalk, or aryl; or R 1 and R 2 are together —(CH 2 ) n — and n is 5, 4, or 3;

R 3 is aryl, which is optionally substituted by 1 to 4 substitutents on the aryl and each substitutent independently is H, halogen, CN, CF 3 , OCF 3 , lower alkyl, N(lower alkyl) 2 , lower alkoxy, OH, OC(O)-lower alkyl, OC(O)-lower alkylamino or OC(O)-lower alkyl-N(lower alkyl) 2 ; and

R 4 is —(CH 2 ) n —R 5 wherein n is 2, and R 5 is aryl, which is optionally substituted by 1 to 3 substitutents on the aryl and each substitutent is independently H, halogen, lower alkyl or lower alkoxy;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 and R 2 are independently hydrogen or lower alkyl.

3. The compound according to claim 1 , wherein R 1 and R 2 are together —(CH 2 ) n — and n is 4 or 3.

4. The compound according to claim 2 , wherein said lower alkyl is independently methyl, ethyl or isopropyl.

5. The compound according to claim 1 , wherein R 1 is ethyl or isopropyl.

6. The compound according to claim 1 , wherein R 2 is methyl.

7. The compound according to claim 3 , wherein R 1 and R 2 together are —(CH 2 ) 4 —.

8. The compound according to claim 1 , wherein R 3 is phenyl optionally substituted by hydroxy or hydroxy and fluorine.

9. The compound according to claim 1 , wherein R 5 is phenyl optionally substituted by 1 or 2 halogens.

10. The compound according to claim 9 , wherein said halogens are independently fluorine or chlorine.

11. The compound according to claim 1 , wherein the compound is:

2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-5,6-dimethyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(4-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

5-ethyl-2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(4-fluoro-phenyl)ethyl]-2-(2-hydroxy-phenyl-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-5-propyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-5-isopropyl-6-methyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-5-isopropyl-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-5-methyl-3-phenethyl-6-trifluoromethyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-3-phenethyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one;

3[2-(3-fluoro-phenyl)ethyl]-2-(2-hydroxy-phenyl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one;

5-cyclopropyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-3-phenethyl-3,5,6,7-tetrahydro-cyclopentapyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-3,5,6,7-tetrahydro-cyclopentapyrimidin-4-one;

5-ethyl-2-(2-methoxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl ethyl]-5-isopropyl-2-(2-methoxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(5-chloro-2-hydroxy-pyridin-3-yl)-5-ethyl-3-[2-(3-fluoro-phenylyethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(3-fluoro-2-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(5-fluoro-2-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(2-fluoro-6-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

2-(5-chloro-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

2-(5-bromo-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenylyethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-3-isopropyl-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(3,5-dibromo-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(3-chloro-2-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-3-methyl-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(4-chloro-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one; or

5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-4-methoxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein the compound is:

2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-5,6-dimethyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(4-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

5-ethyl-2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(4-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-6-methyl-5-propyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-5-isopropyl-6-methyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5-isopropyl-6-methyl-3-H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-5-methyl-3-phenethyl-6-trifluoromethyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-3-phenethyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one;

5-cyclopropyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-3-phenethyl-3,5,6,7-tetrahydro-cyclopentapyrimidin-4-one;

3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-3,5,6,7-tetrahydro-cyclopentapyrimidin-4-one;

5-ethyl-2-(2-methoxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

2-(5-chloro-2-hydroxy-pyridin-3-yl)-5-ethyl-3-[2-(3-fluoro-phenyl)ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(3-fluoro-2-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(5-fluoro-2-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-2-(2-fluoro-6-hydroxy-phenyl)-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

2-(5-bromo-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-3-isopropyl-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(3,5-dibromo-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-methyl-3H-pyrimidin-4-one;

2-(4-chloro-2-hydroxy-phenyl)-5-ethyl-3-[2-(3-fluoro-phenyl)-ethyl]-6-met-hyl-3H-pyrimidin-4-one;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein the compound is:

2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

2-(2-hydroxy-phenyl)-5,6-dimethyl-3-phenethyl-3H-pyrimidin-4-one;

3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

3-[2-(4-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-5,6-dimethyl-3H-pyrimidin-4-one;

5-ethyl-2-(2-hydroxy-phenyl)-6-methyl-3-phenethyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(2-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

5-ethyl-3-[2-(4-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-6-methyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenylyethyl]-2-(2-hydroxy-phenyl)-6-methyl-5-propyl-3H-pyrimidin-4-one;

3-[2-(3-fluoro-phenyl)-ethyl]-2-(2-hydroxy-phenyl)-5-isopropyl-6-methyl-3-H-pyrimidin-4-one;