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Details for Patent: 4,749,713

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Details for Patent: 4,749,713

Title: Alpha-heterocycle substituted tolunitriles
Abstract:The invention is concerned with aromatase inhibiting compounds of formula I ##STR1## where 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, 1986
Application Number:06/837,489
Claims:1. A method of inhibiting aromatase activity and suppressing estrogen synthesis in mammals which comprises administering to a mammal in need thereof an effective amount of 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 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 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 a heterocyclic aromatic radical selected from 2- or 3-thienyl, 3-indolyl, 2-, 3-, or 4-pyridyl and 2- or 3-furyl, or a said heterocyclic radical monosubstituted by lower alkyl, lower alkoxy, cyano or halogen; and aroyl within the above definitions represents benzoyl or banzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; or a pharmaceutically acceptable salt thereof; or of a pharmaceutical composition comprising a said compound or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers.

2. A method 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 hydrogen, lower alkyl, aryl, aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or lower alkenyl; or R.sub.1 and R.sub.2 combined represent lower alkylidene or C.sub.4 -C.sub.6 -alkylene; W and aryl have meaning given in said claim.

3. A method 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 hydrogen, lower alkyl, 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, or 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; and aryl has meaning as defined in said claim.

4. A method 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 hydrogen, lower alkyl, aryl, aryl-lower alkyl or lower alkenyl; or R.sub.1 and R.sub.2 combined represent lower alkylidene or C.sub.4 -C.sub.6 -alkylene; W represents 1-imidazolyl or 1-imidazolyl substituted by lower alkyl; and aryl within the above definitions has meaning as defined in said claim.

5. A method according to claim 1 of inhibiting aromatase activity and suppressing estrogen synthesis in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of the formula ##STR18## wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl 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 alkylosulfonyl, 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; a pharmaceutically acceptable salt thereof; or of a pharmaceutical composition comprising a said compound of formula II or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers.

6. A method according to claim 5, wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, 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.

7. A method according to claim 5 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 on phenyl by cyano, halogen, lower alkoxy, lower alkyl or trifluoromethyl; and R.sub.3 represents hydrogen or lower alkyl at the 4 or 5 position.

8. A method according to claim 5, the compound being of the formula ##STR19## wherein R.sub.2 ' represents 3-pyridyl, p-cyanobenzyl or p-cyanophenyl, or a pharmaceutically acceptable salt thereof.

9. A method according to claim 1 in which the compound is of the formula ##STR20## wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, phenyl, lower alkylthio, phenyl-lower alkylthio, phenylthio, 2, 3- or 4-pyridyl, 2- or 3-thienyl or benzyl; or R.sub.2 ' represents phenyl, phenyl-lower alkylthio, phenylthio or benzyl, each monosubstituted on the phenyl ring 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; aroyl has meaning as defined in said claim; or R.sub.1 ' and R.sub.2 ' combined represent together lower alkylide,ne, benzylidene or diphenylmethylidene; or R.sub.1 ' and R.sub.2 ' combined represent together C.sub.4 -C.sub.6 straight chain alkylene; and R.sub.3 represents hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9 wherein in formula IV R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, 2-, 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 has meaning as defined in said claim; and R.sub.3 represents hydrogen or lower alkyl.

11. A method according to claim 9 wherein in formula IV R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower akyl, 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; and R.sub.3 represents hydrogen or lower alkyl at the 4 or 5 position.

12. A method according to claim 5, the compound being selected from 4-(1-imidazolylmethyl)-benzonitrile and 4-[alpha-n-butyl-1-imidazolylmethyl]-benzonitrile; or a pharmaceutically acceptable salt thereof.

13. A method according to claim 5, the compound being 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

14. A method according to claim 5, the compound being 4-[alpha-(3-pyridyl)-1-imidazolylmethyl]-benzontrile or a pharmaceutically acceptable salt thereof.

15. A method according to claim 5, the compound being 4-[alpha-(4-cyanobenzyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

16. A method according to claim 9, the compound being 4-(1-imidazolylmethyl)-1-naphthonitrile or a pharmaceutically acceptable salt thereof.

17. A method of treating or suppressing estrogen dependent diseases in mammals which comprises administering to a mammal in need thereof an effective aromatase inhibiting amount of a compound of the formula ##STR21## wherein R.sub.1 ' represents hydrogen; R.sub.2 ' represents hydrogen, lower alkyl, phenyl, pyridyl, thienyl 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; and R.sub.3 represents hydrogen or lower alkyl; or a pharamceutically acceptable salt thereof; or of a pharamceutical composition comprising a said compound of formula II or a pharamceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers.

18. A method according to claim 17, the compound being of the formula III ##STR22## wherein R.sub.2 ' represents 3-pyridyl, p-cyanobenzyl or p-cyanophenyl; or a pharmaceutically acceptable salt thereof.

19. A method according to claim 17, the compound being 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

20. A method according to claim 17, the compound being 4-[alpha-(3-pyridyl)-1-imidazolylemethyl]-benzonitrile or a pharmaceutically acceptable salt thereof.

21. A method of treating or suppressing estrogen dependent tumors in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of the formula ##STR23## wherein R.sub.2 ' represents 3-pyridyl, p-cyanobenzyl or p-cyanophenyl; or a pharmaceutically acceptable salt thereof; or of a pharmaceutical composition comprising a said compound of formula III or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers.

22. A method according to claim 21 of treating or suppressing estrogen dependent tumors in mammals which comprises administering to a mammal in need thereof an effective amount of 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile or a pharmaceutically acceptable salt thereof, or of a pharamceutical composition comprising a said compound in combination with one or more pharmaceutically acceptable carriers.
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