Claims
- 1. A compound of Formula (I): wherein:R1 is hydrogen, alkyl, acyl, heteroalkyl, —CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), —COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or —SO2R6 where R6 is alkyl; alk1 is an alkylene chain of 1 to 6 carbon atoms; X is —NHCO— or —CONH—; Y is an alkylene chain of 1 to 3 carbon atoms or an alkylene chain of 2 or 3 carbon atoms wherein one of the carbon atoms is replaced by a heteroatom selected from the group consisting of —O—, —NRb— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} and —S(O)n— wherein n is 0 to 2; Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a group selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino; Ar2 is aryl; alk2 is an alkylene group of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} or —S(O)n1— wherein n1 is 0 to 2; and Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
- 2. A compound of Formula (Ia): whereinR1 is hydrogen, alkyl, acyl, heteroalkyl, —CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), —COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or —SO2R6 where R6 is alkyl; alk1 is an alkylene chain of 1 to 6 carbon atoms; X is —NHCO— or —CONH—; Y is —O—(CH2)—, —O—(CH2)2—, —O—(CHCH3)—, —NRb—(CH2)—, —NRb—(CH2)2—, —NRb—(CHCH3)— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)], —S(O)n—(CH2)—, —S(O)n—(CH2)2—, or —S(O)n—(CHCH3)— where n is 0 to 2; Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino; Ar2 is aryl; alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} or —S(O)n1— wherein n1 is 0 to 2; and Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
- 3. The compound of claim 2 wherein R1 is hydrogen, alkyl, acyl, or —SO2Ra where Ra is alkyl.
- 4. The compound of claim 3 wherein R1 is hydrogen, methyl, acetyl, —COCH2CO2H, —COCH2CO2CH3, or —CO2-tert-butyl.
- 5. The compound of claim 2 wherein Y is —SCH2—, —OCH2— or —NHCH2—.
- 6. The compound of claim 5 wherein X is —CONH—.
- 7. The compound of claim 6 wherein Y is —SCH2—.
- 8. The compound of claim 6 wherein Y is —OCH2—.
- 9. The compound of claim 8 wherein alk1 and alk2 are independently an alkylene chain of 1 or 2 carbon atoms.
- 10. The compound of claim 2 wherein Ar1 is a heteroaryl group.
- 11. The compound of claim 3 wherein Ar1 is pyrimidin-2-yl.
- 12. The compound of claim 11 wherein Y is —SCH2— or —OCH2—.
- 13. The compound of claim 12 wherein Ar2 is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, and halo.
- 14. The compound of claim 13 wherein Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl.
- 15. The compound of claim 12 wherein alk2 is —CH2— and Ar3 is aryl.
- 16. The compound of claim 15 wherein Ar3 is 3,4-dichlorophenyl.
- 17. A compound of Formula (Ib): wherein:R1 is hydrogen, alkyl, acyl, heteroalkyl, —CONR3R4 (where R3 and R4 are independently hydrogen or alkyl), —COOR5 (where R5 is hydrogen, alkyl or heteroalkyl), or —SO2R where R is alkyl; alk1 is an alkylene chain of 1 to 6 carbon atoms; X is —NHCO— or —CONH—; Y is: (i) —(CH2)—, —(CH2)2—, —(CH2)3—, —(CHCH3)—, —(CHCH3)—(CH2)—, or —(CH2)—(CHCH3)—; or (ii) —(CH2)—O—, —(CH2)2—O—, —(CHCH3)—O—, —(CH2)—NRb—, —(CH2)2—NRb—, or —(CHCH3)—NRb— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} when X is —CONH—; Ar1 is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar2 group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino; Ar2 is aryl; alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} or —S(O)n1— wherein n1 is 0 to 2; and Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
- 18. The compound of claim 17 wherein Ar1 is a heteroaryl group and Ar2 is aryl optionally substituted with one or two substituents selected from the group consisting of alkoxy, hydroxy, and halo.
- 19. The compound of claim 18 wherein Ar1 is pyrimidin-2-yl and Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl.
- 20. A compound of Formula (Ib): wherein:R1 is —COCH2CO2H, —COCH2CO2CH3, or —CO2-tert-butyl; alk1 is an alkylene chain of 1 to 6 carbon atoms; X is —CONH—; Y is: (i) —(CH2)—, —(CH2)2—, —(CH2)3—, —(CHCH3)—, —(CHCH3)—(CH2)—, or —(CH2)—(CHCH3)—; or (ii) —(CH2)—O—, —(CH2)2—O—, —(CHCH3)—O—, —(CH2)—NRb—, —(CH2)2—NRb—, or —(CHCH3)—NRb— {where Rb is hydrogen, alkyl, acyl, —CONR7R8 (where R7 and R8 are independently hydrogen or alkyl), —COOR9 (where R9 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)} when X is —CONH—; Ar1 is pyrimidin-2-yl; Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl of Ar1; alk2 is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRc— {where Rc is hydrogen, alkyl, acyl, —CONR10R11 (where R10 and R11 are independently hydrogen or alkyl), —COOR12 (where R12 is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)) or —S(O)n1— wherein n1 is 0 to 2; and Ar3 is cycloalkyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
- 21. A compound of the Formula (Ib): wherein:R1 is —COCH2CO2H, —COCH2CO2CH3, or —CO2-tert-butyl; X is —CONH—; Y and alk1 are independently methylene or ethylene; Ar1 is pyrimidin-2-yl; Ar2 is phenyl or 3,4-dimethoxyphenyl and is at the 5-position of the pyrimidin-2-yl of Ar1; alk2 is methylene; and Ar3 is 3,4-dichiorophenyl; or a pharmaceutically acceptable salt thereof.
- 22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 21 and a pharmaceutically acceptable excipient.
- 23. A method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-21 and a pharmaceutically acceptable excipient.
- 24. The method of claim 23 wherein the disease is asthma.
- 25. A process for preparing a compound as claimed in claim 1, which process comprises:coupling a compound having a formula 7, wherein Pro is a protective group, and alk2 and Ar3 are as defined in claim 1; with a compound of formula 8: Ar1—Ar2—Y—CO2H 8 wherein Ar1, Ar2 and Y are as described in claim 1; removal of the protecting group to provide a compound of Formula (I) wherein R1 is hydrogen, and Ar1, Ar2, alk2 and Ar3 are as defined in claim 1; and conversion to compounds of Formula (I) wherein R1 is acyl or sulfonyl with an acid halide of general formula R1C(O)Hal or a sulfonyl halide of general formula R1SO2Hal, wherein Hal is a halo group.
- 26. A process for preparing a compound as claimed in claim 1, which process comprisesreduction of the cyano group of a compound having formula 10: wherein Pro is a protective group, and alk2 and Ar3 are as defined in claim 1; coupling with a compound of Formula 8: Ar1—Ar2—Y—CO2H 8 wherein Ar1, Ar2 and Y are as described in claim 1; removal of the protecting group to provide a compound of Formula (I): wherein R1 is hydrogen, and Ar1, Ar2, alk2 and Ar3 are as defined in claim 1, and conversion to compounds of Formula (I) wherein R1 is an acyl or sulfonyl group with an acid halide R1C(O)Hal or a sulfonyl halide R1SO2Hal, wherein Hal is a halo group.
- 27. A process for preparing a compound as claimed in claim 1, which process comprises coupling a compound having a formula 15a or 15bwherein R1 is alkyl, and alk2 and Ar3 are as defined in claim 1,with a compound of formula 8Ar1—Ar2—Y—CO2H 8 wherein Ar1, Ar2 and Y are as described in claim 1 to provide a compound of Formula (Ia) or (Ib) wherein R1 is alkyl, Ar1, Ar2, alk2 and Ar3 are as defined in claim 1.
- 28. A process for preparing a compound as claimed in claim 1, which process comprises:mesylating a compound having a formula 16, wherein R1 is alkyl, and alk2 and Ar3 are as defined in claim 1; converting to a cyanide followed by reduction, and coupling with a compound of formula 8 Ar1—Ar2—Y—CO2H wherein Ar1, Ar2 and Y are as described in claim 1, to provide a compound of Formula (I) wherein R1 is alkyl, and Ar1, Ar2, alk2, Ar3, and Y are as described in claim 1.
CROSS REFERENCE TO RELATED APPLICATION
This application claims benefit under Title 35 U.S.C. 119 (e) of U.S. Provisional Application No. 60/256,585 filed Dec. 19, 2000.
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6166015 |
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Provisional Applications (1)
|
Number |
Date |
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|
60/256585 |
Dec 2000 |
US |