(1H-imidazol-1-ylmethyl) substituted benzimidazole derivatives and use thereof in treating androgen dependent disorders

Claim 1

A chemical compound having the formula ##STR39## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR40## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 15

A method of treating mammals suffering from androgen dependent disorders, said method comprising the systemic administration to said mammals of an amount effective to treat androgen dependent disorders of a compound having the formula ##STR43## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR44## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 16

A method of treating mammals suffering from androgen dependent disorders, said method comprising the systemic administration to said mammals of an amount effective to treat androgen dependent disorders of a compound having the formula ##STR43## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR44## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 21

A method of inhibiting androgen synthesis in mammals, said method comprising the systemic administration to said mammals of an androgen synthesis inhibitory amount of a compound having the formula ##STR45## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR46## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 22

A method of inhibiting androgen synthesis in mammals, said method comprising the systemic administration to said mammals of an androgen synthesis inhibitory amount of a compound having the formula ##STR45## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR46## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 23

A method of inhibiting the androgen formation from C 21 steroids in mammals, said method comprising the systemic administration to said mammals of an androgen synthesis inhibitory amount of a compound having the formula ##STR47## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-1 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR48## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 24

A method of inhibiting the androgen formation from C 21 steroids in mammals, said method comprising the systemic administration to said mammals of an androgen synthesis inhibitory amount of a compound having the formula ##STR47## or pharmaceutically acceptable acid addition, metal or amine substitution salt or a stereochemically isomeric form thereof, wherein R is hydrogen; C 1-10 alkyl; C 3-7 cycloalkyl; Ar 1 or Ar 1 -C 1-6 alkyl; R 1 is hydrogen; C 3-7 cycloalkyl; Ar 1 ; C 1-1 alkyl; C 1-6 alkyl substituted with Ar 1 or C 3-7 cycloalkyl; hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyloxy optionally substituted with Ar 2 ; C 3-6 alkynyloxy optionally substituted with Ar 2 ; or Ar 1 -oxy; A is a bivalent radical having the formula ##STR48## wherein the carbon atom in the bivalent radical (a) or (b) is connected to --NR 1 ; said R 2 being hydrogen; halo; C 1-4 alkyl substituted with up to 4 halo atoms; C 3-7 cycloalkyl; Ar 1 ; quinolinyl; indolinyl; C 1-10 alkyl; C 1-6 alkyl substituted with Ar 1 , C 3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C 1-10 alkyloxy; C 1-6 alkyloxy substituted with Ar 1 or C 3-7 cycloalkyl; C 3-6 alkenyl optionally substituted with Ar 1 ; Ar 2 -oxy; C 1-6 alkyloxycarbonyl; carboxyl; C 1-6 alkylcarbonyl; Ar 1 -carbonyl or Ar 1 --(CHOH)--; said X being O or S; said R 3 being hydrogen, C 1-6 alkyl or Ar 2 -C 1-6 alkyl; Ar 1 is phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; Ar 2 is phenyl or substituted phenyl; in Ar 1 and Ar 2 said substituted phenyl being phenyl substituted with 1 or 2 substituents each independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl, C 1-6 alkyloxy, cyano, amino, mono- and di(C 1-6 alkyl)amino, nitro, carboxyl, formyl and C 1-6 alkyloxycarbonyl.

Claim 25

A method of treating mammals suffering from increased levels of ureic acid, said method comprising the systemic administration to said mammals of an amount effective to treat increased levels of ureic acid of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazole, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

Claim 26

A method of treating mammals suffering from increased levels of ureic acid, said method comprising the systemic administration to said mammals of an amount effective to treat increased levels of ureic acid of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazole, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.