Claims
- 1. A compound of the formula IIIB or a pharmaceutically acceptable salt thereof:
- 2. A compound according to claim 1 wherein:
n is 1; R1 and R2 are together unsubstituted alkylene of about 4 to about 6 carbons or alkylene of about 4 to about 6 carbons substituted with —OH or alkoxy; Ar is unsubstituted phenyl or mono-, di-, tri-, or tetra-substituted phenyl, wherein said substituents are independently selected from alkyl; alkoxy; aralkyloxy; alkylene dioxide; —OH; haloalkyl; —NRgRh, in which Rg and Rh are independently selected from hydrogen, alkyl, and —S(O)2Rf; —S(O)2N(Ri)(Rj), where Ri and Rj are each independently selected from hydrogen, alkyl optionally substituted with —CO2Re, and aralkyl; or Ri and Rj together form —(CH2)2X(CH2)2—, where X is a direct bond, —NRe—, S or O; and R is hydrogen, halogen, —OH or alkoxy.
- 3. A compound according to claim 2 wherein:
R1 and R2 are together —(CH2)4— or —CH2CH(OH)(CH2)2—; Ar is unsubstituted phenyl or mono-, di-, tri-, or tetra-substituted phenyl, wherein said substituents are independently selected from lower alkyl; —OCH3; —OCH2C6H5; —OCH2O; —OH; —CF3; —N(SO2CH3)2; —NHSO2CH3; —SO2N(CH3)2; —SO2N(CH3)(CH2CO2H); —SO2NHCH3; —SO2N(CH3)(CH2C6H5); 364where X′ is —N(CH3)— or —O—.
- 4. A compound according to claim 1, with the provisos that:
when n is 1, R1 and R2 are unsubstituted alkylene of 4 carbons, and R is H, then Ar is other than unsubstitued phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-amino-4,5-dichlorophenyl, 3,4-dichlorophenyl, 2-amino-4-trifluoromethylphenyl, 2-N(SO2CH3)2-phenyl, 3-N(SO2CH3)2-phenyl, 4-N(SO2CH3)2-phenyl, 2-NHSO2CH3-phenyl, 3-NHSO2CH3-phenyl, 4-NHSO2CH3-phenyl, 2-N(SO2CH3)2-4,5-dichlorophenyl, 2-N(SO2CH3)2-4-trifluoromethylphenyl, 2-NHSO2CH3-4-trifluoromethylphenyl, 4-SO2CH3-phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4,5-trimethoxyphenyl, 2-NHSO2CH3-4,5-dichlorophenyl, 2-NHCH2CO2H-4-trifluoromethylphenyl, 2-NH(SO2C6H5)-phenyl, 3-SO2NHCH3-4-chlorophenyl, 3-SO2NH2-4-chlorophenyl, 3-SO2NHCH3-4-fluororophenyl, 4-SO2NHCH3-phenyl, 3-SO2NHCH3-phenyl, 2-SO2NHCH3-phenyl, 2-SO2NHCH3-4-bromophenyl, 2-methoxy-3-SO2NHCH3-phenyl, 4-methoxy-3-SO2NHCH3-phenyl, 2-N(CH2CO2H)2-4-trifluoromethylphenyl, 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 2-SO2N(CH3)CH2C6H5-4,5-dimethoxyphenyl, 2-SO2N(CH3)CH2CO2H-3,4-dimethoxyphenol, 2-fluorophenyl, or 4-fluorophenyl; when n is 1, R1 and R2 are unsubstituted alkylene of 4 carbons, and R is NH2, then Ar is other than 3,4-dichlorophenyl, 2-aminophenyl or 4-N(SO2CH3)2-phenyl; when n is 1, R1 and R2 are —CH2CH(OH)(CH2)2—, and R is hydrogen, then Ar is other than 2-amino-4-trifluoromethylphenyl, aminophenyl, 4-SO2CH3-phenyl, 3,4,5-trimethoxyphenyl, 2-SO2NHCH3-phenyl, trifluoromethylphenyl, methylphenyl, halophenyl, methoxyphenyl, unsubstituted phenyl, 3-chloro-4-hydroxyphenyl, 4-benzyloxyphenyl, hydroxyphenyl, aminochlorophenyl, aminobromophenyl, acetamidophenyl, methylsulfonylaminophenyl, formamidophenyl or 3-amino-4-methoxyphenyl; when n is 1, R1 and R2 are —CH2CH(OH)(CH2)2—, and R is hydroxy or amino, then Ar is other than trifluoromethylphenyl; and when n is 1, R1 and R2 are unsubstituted alkylene of 4 carbons, and R is OH or OCH3, then Ar is other than 2-NHSO2CH3-phenyl, 4-trifluoromethyl or 3,4-dichlorophenyl.
- 5. A compound of the formula IIIB-i or a pharmaceutically acceptable salt thereof:
- 6. A compound according to claim 5 wherein:
R3 is independently selected from alkyl; alkoxy; aralkyloxy; alkylene dioxide; —OH; haloalkyl; —NRgRh, in which Rg and Rh are independently selected from hydrogen, alkyl, and —S(O)2Rf; —S(O)2N(Ri)(Rj), in which Ri and Rj are each independently selected from hydrogen, alkyl optionally substituted with —CO2Re, and aralkyl; or Ri and Rj together form —(CH2)2X(CH2)2—, where X is a direct bond, —NRe—, S or O; R is hydrogen, halogen, —OH or alkoxy.
- 7. A compound according to claim 6 wherein:
R3 is independently selected from lower alkyl; —OCH3; —OCH2C6H5; —OCH2O—; —OH; CF3; —N(SO2CH3)2; —NHSO2CH3; —SO2N(CH3)2; —SO2N(CH3)(CH2CO2H); —SO2NHCH3; —SO2N(CH3)(CH2C6H5); 366where X′ is —N(CH3)— or —O—.
- 8. A compound according to claim 5 wherein substituent R″ is in the S configuration.
- 9. A compound according to claim 5 with the provisos that:
when R and R″ are H, then the phenyl ring and (R3)x together are other than unsubstitued phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N(SO2CH3)2-phenyl, 3-N(SO2CH3)2-phenyl 4-N(SO2CH3)2-phenyl, 2-NHSO2CH3-phenyl, 3-NHSO2CH3-phenyl, 4-NHSO2CH3-phenyl, 4-SO2CH3-phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-SO2NHCH3-phenyl, 2-SO2NHCH3-phenyl, 4-SO2NHCH3-phenyl, 2-fluorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 2-amino-4-trifluoromethylphenyl, 2-N(SO2CH3)2-4-trifluoromethylphenyl, 2-NHSO2CH3-4-trifluoromethylphenyl, 2-NHCH2CO2H-4-trifluoromethylphenyl, 3-SO2NHCH3-4-chlorophenyl, 3-SO2NH2-4-chlorophenyl, 3-SO2NHCH3-4-fluororophenyl, 2-SO2NHCH3-4-bromophenyl, 2-methoxy-3-SO2NHCH3-phenyl, 4-methoxy-3-SO2NHCH3-phenyl, 2-N(CH2CO2H)2-4-trifluoromethylphenyl, 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 2-amino-4,5-dichlorophenyl, 2-N(SO2CH3)2-4,5-dichlorophenyl, 3,4,5-trimethoxyphenyl, 2-NHSO2CH3-4,5-dichlorophenyl, or 2-SO2N(CH3)CH2C6H5-4,5-dimethoxyphenyl, 2-SO2N(CH3)CH2CO2H-3,4-dimethoxyphenol; when R″ is H and R is NH2, then the phenyl ring and (R3), together are other than 3,4-dichlorophenyl, 2-aminophenyl or 4-N(SO2CH3)2-phenyl; when R″ is OH, and R is hydrogen, then the phenyl ring and (R3), together are other than unsubstitued phenyl, 2-amino-4-trifluoromethylphenyl, aminophenyl, 4-SO2CH3-phenyl, 3,4,5-trimethoxyphenyl, 2-SO2NHCH3-phenyl, trifluoromethylphenyl, methylphenyl, halophenyl, methoxyphenyl, 3-chloro-4-hydroxyphenyl, 4-benzyloxyphenyl, hydroxyphenyl, aminochlorophenyl, aminobromophenyl, acetamidophenyl, methylsulfonylaminophenyl, formamidophenyl or 3-amino-4-methoxyphenyl when R″ is OH and R is hydroxy or amino, then the phenyl ring and (R3)x together are other than trifluoromethylphenyl; and when R″ is H and R is OH or OCH3, then the phenyl ring and (R3)x together are other than 2-NHSO2CH3-phenyl, 4-trifluoromethylphenyl or 3,4-dichlorophenyl.
- 10. A compound selected from the group consisting of:
2-(3-N-Methylsulfonamido-3-amino-4-methoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide methane sulfonate; 2-(3-N-Methylsulfonamido-3-amino-4-benzyloxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; 2-(3-N-Methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; 2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-(2-N-Methylsulfonamido-2-amino-4-trifluoromethylphenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-(3-N-Methylsulfonamido-3-amino-4-metoxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-methoxyphenyl)-2-(1-pyrrolidinyl) ethyl]acetamide; (R,S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide; (S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide; 2-(3-N-Bis-methylsulfonamido-3-amino-4-hydroxyphenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide; 2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Dimethylsulfamoyl)-4,5-methylenedioxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Pyrrolidinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Dimethylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1l-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamide; 2-[2-[N-(4-Methylpiperazine)]sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamide; 2-[2-N-(Morpholinesulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; N-Methyl-[[2-(N-sulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(pyrrolidinyl)ethyl]]acetamido]glycine; 2-[2-(N-Pyrrolidinesulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-t-Butylsulfamoyl)-3,4,5-trimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Methylsulfamoyl)-4-methoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; 2-[4-N-(Methylsulfamoyl)-phenyl]-N-methyl-N-[(1S)-1-phenyl-2-[1-(3S)-(3-hydroxypyrrolidinyl)ethyl]]acetamide; 2-[2-(N-Methylsulfamoyl)-phenyl]-N-,methyl-N-[1-(2-fluorophenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; and 2-[2-(N-Benzyl-N-methylsulfamoyl)-4,5-dimethoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; or a pharmaceutically acceptable salt thereof.
- 11. A compound according to claim 10 which is selected from the group consisting of
2-[2-(N-Methylsulfamoyl)-4-methoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide; and (S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide; or a pharmaceutically acceptable salt thereof.
- 12. A compound according to claim 11 which is 2-[2-(N-Methylsulfamoyl)-4-methoxyphenyl]-N-methyl-N-[(1S)-1-phenyl-2-[(1-pyrrolidinyl)ethyl]]acetamide or a pharmaceutically acceptable salt thereof.
- 13. A compound according to claim 11 which is (S)-2-(2-N-Methylsulfonamido-2-aminophenyl)-N-methyl-N-1-(4-hydroxyphenyl)-2-(1-pyrrolidinyl)ethyl]acetamide or a pharmaceutically acceptable salt thereof.
- 14. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier.
- 15. A pharmaceutical composition comprising a compound according to claim 5 together with a pharmaceutically acceptable carrier.
- 16. A pharmaceutical composition comprising a compound according to claim 10 together with a pharmaceutically acceptable carrier.
- 17. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound according to claim 1.
- 18. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound according to claim 5.
- 19. A method of treating hyperalgesia in a patient comprising administering to said patient an effective amount of a compound according to claim 10.
Parent Case Info
[0001] This application is a continuation-in-part of application Ser. No. 09/478,482, filed Jan. 6, 2000, now allowed, which in turn is a divisional of application Ser. No. 09/150,369, filed Sep. 9, 1998, now U.S. Pat. No. 6,303,611, which in turn is a continuation-in-part of application Ser. No. 09/034,661 filed Mar. 3, 1998, now U.S. Pat. No. 5,945,443, which in turn is a divisional of application Ser. No. 08/899,086 filed on Jul. 23, 1997, now U.S. Pat. No. 5,744,458, which in turn is a divisional of application Ser. No. 08/796,078, filed on Feb. 5, 1997, now U.S. Pat. No. 5,688,955, which in turn is a continuation-in-part of application Ser. No. 08/612,680, filed on Mar. 8, 1996, now U.S. Pat. No. 5,646,151. The disclosures of each of the foregoing applications is hereby incorporated herein by reference, in their entireties.
Divisions (3)
|
Number |
Date |
Country |
Parent |
09150369 |
Sep 1998 |
US |
Child |
09478482 |
Jan 2000 |
US |
Parent |
08899086 |
Jul 1997 |
US |
Child |
09034661 |
Mar 1998 |
US |
Parent |
08796078 |
Feb 1997 |
US |
Child |
08899086 |
Jul 1997 |
US |
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
09478482 |
Jan 2000 |
US |
Child |
10146693 |
May 2002 |
US |
Parent |
09034661 |
Mar 1998 |
US |
Child |
09150369 |
Sep 1998 |
US |
Parent |
08612680 |
Mar 1996 |
US |
Child |
08796078 |
Feb 1997 |
US |