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Details for Patent: 4,937,250

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Details for Patent: 4,937,250

Title: Alpha-heterocycle substituted tolunitriles
Abstract:The invention is concerned with aromatase inhibiting compounds of formula I ##STR1## wherein R and Ro represent hydrogen or lower alkyl; or R and Ro located on adjacent carbon atoms and together when combined with the benzene ring to which they are attached form a naphthalene or tetrahydronaphthalene ring; R.sub.1 and R.sub.2 independently represent hydrogen, lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio, lower alkenyl, aryl, aryl-lower alkyl, C.sub.3 -C.sub.6 -cycloalkyl, or C.sub.3 -C.sub.6 -cycloalkyl-lower alkyl; or R.sub.1 and R.sub.2 combined represent lower alkylidene, mono- or di-aryl-lower alkylidene; R.sub.1 and R.sub.2 combined also represent C.sub.4 -C.sub.6 -straight chain alkylene, lower alkyl-substituted straight chain alkylene or ortho-phenylene bridged-C.sub.2 -C.sub.4 -straight chain alkylene, each forming with the carbon atom attached thereto a corresponding optionally substituted or benzo-fused 5, 6 or 7-membered ring; W represents 1-imidazolyl, 1-(1,2,4- or 1,3,4)-triazolyl or 3-pyridyl; or W represents 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl or 3-pyridyl substituted by lower alkyl; and pharmaceutically acceptable salts thereof.
Inventor(s): Bowman; Robert M. (Summit, NJ), Steele; Ronald E. (Long Valley, NJ), Browne; Leslie J. (Aesch, CH)
Assignee: Ciba-Geigy Corporation (Ardsley, NY)
Filing Date:Mar 07, 1988
Application Number:07/164,696
Claims:1. A compound of the formula ##STR17## wherein R and Ro represent hydrogen or lower alkyl; or R and Ro located on adjacent carbon atoms and together when combined with the benzene ring to which they are attached form a naphthalene or tetrahydronaphthalene ring; R.sub.1 represent hydrogen; R.sub.2 represents aryl, aryl-lower alkyl, C.sub.3 -C.sub.6 -cycloalkyl, or C.sub.3 -C.sub.6 -cycloalkyl-lower alkyl; or R.sub.1 and R.sub.2 combined represent lower alkylidene, mono- or di-aryl-lower alkylidene; R.sub.1 and R.sub.2 combined also represent C.sub.4 -C.sub.6 -straight chain alkylene, lower alkyl-substituted straight chain alkylene or CH.sub.2 -ortho-phenylene-CH.sub.2 ; W represents 1-imidazolyl or 1-imidazolyl substituted by lower alkyl; aryl within the above definitions represents phenyl or phenyl substituted by one or two substituents selected from lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, aroyloxy, nitro, amino, halogen, trifluoromethyl, cyano, carboxy, carboxy functionalized in form of a pharmaceutically acceptable ester or amide, lower alkanoyl, aroyl, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl or N,N-di-lower alkylsulfamoyl; and aryl within the above definitions also represents 2-, 3-, or 4-pyridyl, or said heterocyclic radical monosubstituted by lower alkyl, lower alkoxy, cyano or halogen; and aroyl within the above definitions represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R and Ro represent hydrogen or lower alkyl; or R and Ro located on adjacent carbon atoms and together when combined with the benzene ring to which they are attached form a naphthalene or tetrahydronaphthalene ring; R.sub.1 represents hydrogen; R.sub.2 represents aryl or aryl-lower alkyl as defined in said claim; or R.sub.1 and R.sub.2 combined represent lower alkylidene or C.sub.4 -C.sub.6 -alkylene; and W and aryl have meaning given in said claim; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 of the formula ##STR18## wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents phenyl, 2-, 3- or 4-pyridyl or benzyl; or R.sub.2 ' represents phenyl or benzyl, each monosubstituted on the phenyl ring by cyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, aroyloxy, nitro, halogen, trifluoromethyl, lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; or R.sub.1 ' and R.sub.2 ' combined represent together lower alkylidene, benzylidene or diphenylmethylidene; or R.sub.1 ' and R.sub.2 ' combined represent together C.sub.4 -C.sub.6 straight chain alkylene; aroyl in the above definitions represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; and R.sub.3 represents hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents 3- or 4-pyridyl, benzyl or phenyl; or R.sub.2 ' represents benzyl or phenyl, each monosubstituted on phenyl by cyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, sulfamoyl, N-mono or N,N-di-lower alkylsulfamoyl; aroyl in the above definition represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; and R.sub.3 represents hydrogen or lower alkyl.

5. A compound according to claim 3 wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents benzyl, phenyl, or 3- or 4-pyridyl; or R.sub.2 ' represents phenyl or benzyl, each monosubstituted on phenyl by cyano, halogen, lower alkoxy, lower alkyl or trifluoromethyl; R.sub.3 represents hydrogen or lower alkyl at the 4 or 5 position; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 3 of the formula ##STR19## wherein R.sub.2 ' represents 3-pyridyl, p-cyanobenzyl or p-cyanophenyl; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 6 being 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

8. A compound of claim 6 being 4-[alpha-(3-pyridyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

9. A compound of claim 6 being 4-[alpha-(4-cyanobenzyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

10. A compound of the formula ##STR20## wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, phenyl, lower alkylthio, phenyl-lower alkylthio, phenylthio, pyridyl or benzyl; or R.sub.2 ' represents phenyl, phenyl-lower alkylthio, phenylthio or benzyl, each monosubstituted on the phenyl ring by cyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, aroyloxy, nitro, halogen, trifluoromethyl, lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; or R.sub.1 ' and R.sub.2 ' combined represent together lower alkylidene, benzylidene or diphenylmethylidene; or R.sub.1 ' and R.sub.2 ' combined represent together C.sub.4 -C.sub.6 straight chain alkylene; R.sub.3 represents hydrogen or lower alkyl; and aroyl within the above definitions represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

11. A compound of claim 10 wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, pyridyl, benzyl or phenyl; or R.sub.2 ' represents benzyl or phenyl, each monosubstituted on phenyl by cyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, sulfamonyl, N-mono or N,N-di-lower alkylsulfamoyl; R.sub.3 represents hydrogen or lower alkyl; and aroyl within the above definitions represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 10 wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, benzyl, phenyl, or 3- or 4-pyridyl; or R.sub.2 ' represents phenyl or benzyl each monosubstituted substituted on phenyl by cyano, halogen, lower alkoxy, lower alkyl or trifluoromethyl; R.sub.3 represents hydrogen or lower alkyl at the 4 or 5 position; or a pharmaceutically acceptable salt thereof.

13. A compound of claim 10 being 4-(1-imidazolylmethyl)-1-naphthonitrile or a pharmaceutically acceptable salt thereof.

14. An aromatase inhibiting pharmaceutical composition comprising an effective aromatase inhibiting amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.
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