Isoxazole and isothiazole derivatives

Claim 2

A compound of the formula wherein: A is S or O; R is pyridyl or Q is hydrogen, hydroxy, halo, or methyl; and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro, or trifluoromethyl, or a salt thereof.

Claim 3

A compound of claim 1 wherein R is

Claim 4

A compound of claim 2 wherein R 1 and R 3 are independently chloro, fluoro, or trifluoromethyl.

Claim 5

The compound of claim 3 which is α,α-bis(4-chlorophenyl)-5-isothiazolemethanol or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of formula I as claimed in any one of claims 1-4 for use as a medicament for inhibiting aromatase or treating or preventing estrogen-dependent disease.

Claim 7

Use of a compound of formula I as defined in any one of claims 1-4 in preparing a medicament for inhibiting aromatase or treating or preventing estrogen-dependent disease.

Claim 8

A pharmaceutical formulation comprising a compound of claim 1 in association with a pharmaceutical carrier, diluent or excipient.

Claim 9

A formulation according to claim 17 employing a compound wherein R is

Claim 10

A formulation according to claim 8 employing a,a-bis(4-chlorophenyl)-5-isothiazolemethanol or a pharmaceutically acceptable salt thereof.

Claim 11

A process for preparing a compound of the formula

Claim 12

A process for preparing a compound of the formula

Claim 13

wherein: A is S or O; R is pyridyl or Q is hydrogen, hydroxy, halo, or methyl; and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C l -C 3 alkyl, C 1 -C 3 alkoxy, nitro, or trifluoromethyl, or a salt thereof; which comprises: (a) reacting the alkali metal salt of pyrazole or isothiazole with a ketone of the formula to provide a compound of formula (I) wherein Q is hydroxy; or (b) reacting a halide of the formula where X is chloro or bromo, with a compound of the formula under Friedel-Crafts conditions to provide a compound of formula (I) wherein Q is chloro or bromo; or (c) reacting a compound of the formula where Z is C 1 -C 3 alkyl, sequentially, in either order, with Grignard reagents of the formulas and RMgX wherein X is chloro or bromo, to provide a compound of formula I wherein Q is OH; or (d) heating a compound of formula I wherein Q is hydroxy in a mixture of glacial acetic acid and aqueous hydroiodic acid to provide a compound of formula I wherein Q is H, or (e) alkylating a compound of formula I wherein Q is hydrogen with a methyl halide to provide a compound of formula I wherein Q is methyl, and (f) optionally salifying the product of formula I.

Claim 14

wherein: A is S or O; R is pyridyl or Q is hydrogen, hydroxy, halo, or methyl; and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C l -C 3 alkyl, C 1 -C 3 alkoxy, nitro, or trifluoromethyl, or a salt thereof; which comprises: (a) reacting the alkali metal salt of pyrazole or isothiazole with a ketone of the formula to provide a compound of formula (I) wherein Q is hydroxy; or (b) reacting a halide of the formula where X is chloro or bromo, with a compound of the formula under Friedel-Crafts conditions to provide a compound of formula (I) wherein Q is chloro or bromo; or (c) reacting a compound of the formula where Z is C 1 -C 3 alkyl, sequentially, in either order, with Grignard reagents of the formulas and RMgX wherein X is chloro or bromo, to provide a compound of formula I wherein Q is OH; or (d) heating a compound of formula I wherein Q is hydroxy in a mixture of glacial acetic acid and aqueous hydroiodic acid to provide a compound of formula I wherein Q is H, or (e) alkylating a compound of formula I wherein Q is hydrogen with a methyl halide to provide a compound of formula I wherein Q is methyl, and (f) optionally salifying the product of formula I.

Claim 15

A process for preparing a compound of the formula wherein: A is S or 0; R is pyridyl or Q is hydrogen, hydroxy, halo, or methyl; and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro, or trifluoromethyl, or a salt thereof; which comprises: (a) reacting the alkali metal salt of pyrazole or isothiazole with a ketone of the formula to provide a compound of formula (I) wherein Q is hydroxy; or (b) reacting a halide of the formula where X is chloro or bromo, with a compound of the formula under Friedel-Crafts conditions to provide a compound of formula (I) wherein Q is chloro or bromo; or (c) reacting a compound of the formula where Z is C 1 -C 3 alkyl, sequentially, in either order, with Grignard reagents of the formulas and RMgX wherein X is chloro or bromo, to provide a compound of formula I wherein Q is OH; or (d) heating a compound of formula I wherein Q is hydroxy in a mixture of glacial acetic acid and aqueous hydroiodic acid to provide a compound of formula I wherein Q is H, or

Claim 16

A process for preparing a compound of the formula wherein: A is S or 0; R is pyridyl or Q is hydrogen, hydroxy, halo, or methyl; and R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro, or trifluoromethyl, or a salt thereof; which comprises: (a) reacting the alkali metal salt of pyrazole or isothiazole with a ketone of the formula to provide a compound of formula (I) wherein Q is hydroxy; or (b) reacting a halide of the formula where X is chloro or bromo, with a compound of the formula under Friedel-Crafts conditions to provide a compound of formula (I) wherein Q is chloro or bromo; or (c) reacting a compound of the formula where Z is C 1 -C 3 alkyl, sequentially, in either order, with Grignard reagents of the formulas and RMgX wherein X is chloro or bromo, to provide a compound of formula I wherein Q is OH; or (d) heating a compound of formula I wherein Q is hydroxy in a mixture of glacial acetic acid and aqueous hydroiodic acid to provide a compound of formula I wherein Q is H, or

Claim 17

A process of claim 1 in which an alkali metal salt of pyrazole or isothiazole is reacted with a compound of formula (II) wherein R 1 is chloro, and the product is optionally salified.

Claim 18

A process of claim 1 in which an alkali metal salt of isothiazole is reacted with a compound of formula (II) wherein R is 4-chlorophenyl, R 1 is chloro, and R 2 is hydrogen to provide α,α-bis(4-chlorophenyl)-5-isothiazole-methanol, and the product is optionally salified.