Substituted anilides having antiandrogenic properties

Claim 2

An acylanilide of the formula:- wherein R 1 is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl; wherein R 2 is cyano, carbamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl; wherein R 3 is hydrogen or halogen; wherein R4 is hydrogen or alkyl of up to 4 carbon atoms, or is joined to R 5 as stated below; wherein R 5 is hydrogen, hydroxy or alkoxy or acyloxy each of up to 15 carbon atoms, or is joined to R 4 to form an oxycarbonyl group such that together with the -N-CO-C-part of the molecule it forms an oxazolidinedione group; wherein R6 is alkyl or halogenoalkyl each of up to 4 carbon atoms, or has the formula -R 8 or -A 2- R 8 ; wherein A is straight-chain alkylene of up to 10 carbon atoms, or alkenylene or alkynylene each of 2 to 10 carbon atoms; wherein A 2 is alkylene of up to 10 carbon atoms, or alkenylene or alkynylene each of 2 to 10 carbon atoms; and wherein R 7 and R 8 , which may be the same or different, each is selected from phenyl which bears one, two or three substituents selected from hydrogen, halogen, nitro, hydroxy, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N -alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; naphthyl; 5-or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulphur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy. or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents.

Claim 3

An acylanilide as claimed in claim 1, wherein R 1 and R 2 , which may be the same or different, each is cyano, nitro, trifluoromethyl, methylthio, methylsulphinyl, methylsulphonyl or chloro, R 3 and R 4 are both hydrogen, R 5 is hydroxy, R 6 is methyl or trifluoromethyl, A 1 is methylene, ethylene, trimethylene or tetramethylene and R 7 is phenyl which is unsubstituted or which bears one fluoro, chloro, hydroxy, methyl, methylthio, methylsulphinyl or melthylsulphonyl substitutent.

Claim 4

An acylanilide as claimed in claim 1, wherein R 1 is cyano, fluoro, hydrogen, ethoxy, methylsulphonyl or trifluoromethyl, wherein R 2 is cyano or nitro, wherein R 3 and R 4 are both hydrogen and R 5 is hydroxy, wherein R 6 is trifluoromethyl, wherein A 1 is methylene, ethylene, trimethylene or tetramethylene and wherein R 7 is phenyl which is unsubstituted or bears one substituent selected from fluoro, chloro and methyl.

Claim 5

An acylanilide selected from the group of compounds of the formula:- wherein the specific values of R 1 , R 2 , A 1 and R 9 are shown in the following table:-

Claim 6

An acylanilide selected from the group of compounds of the formula:- wherein the specific values of R 1 , R 2 , A 1 and R 9 are shown in the following table:-

Claim 7

An acylanilide selected from the group of compounds of the formula:-

Claim 8

An acylanilide selected from the group of compounds of the formula:-

Claim 9

The compound 3-chloro-4-cyano-N-(2-hydroxy-3-p-methanesulphonylphenyl-2-trifluoromethyl- propionyl)aniline; 3-chloro-4-cyano-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-cyano-3-tritluoromethyl-N-(3-p-chlorophenyl-2-hydroxy-2-trifluoromethytpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-3-phenyl-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenyl-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-chlorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-cyano-N-(2-hydroxy-2-trifluoromethyl-4-phenylbutyryl)aniline; 4-rtitro-3-trifluoromethyl-N-(3-o-chlorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-m-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline or 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline.

Claim 10

The compound 3-chloro-4-cyano-N-(2-hydroxy-3-p-methanesulphonylphenyl-2-trifluoromethyl- propionyl)aniline; 3-chloro-4-cyano-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-cyano-3-tritluoromethyl-N-(3-p-chlorophenyl-2-hydroxy-2-trifluoromethytpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-3-phenyl-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenyl-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-chlorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-cyano-N-(2-hydroxy-2-trifluoromethyl-4-phenylbutyryl)aniline; 4-rtitro-3-trifluoromethyl-N-(3-o-chlorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-m-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline or 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenyl-2-hydroxy-2-trifluoromethylpropionyl)aniline.

Claim 11

A process for the manufacture of an acylanilide claimed in claim 1 which comprises:- (a) the reaction of an amine of the formula wherein R 1 , R 2 , R 3 and R 4 have the meanings stated in claim 1, with an acid of the formula:-HO 2 C-CR 5 R 6 -A 1 -R 7 wherein R 5 , R 6 , R 7 and A 1 have the meanings stated in claim 1 or with a reactive derivative of said acid; (b) for the manufacture of an acylanilide of the invention wherein R 4 and R 5 are joined together to form a carbonyl-oxy group, that is, an oxazolidinedione, the reaction of an isocyanate of the formula:- wherein R i , R 2 and R 3 have the meanings stated in claim 1, with an ester of the formula:- wherein R 6 , R 7 and A have the meanings stated in claim 1 and wherein R is alkyl of up to 6 carbon atoms; (c) for the manufacture of an acylanilide of the invention wherein R 7 is heterocylic and A' is methylene, the reaction of an epoxide of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated in claim 1 and wherein Z' has the formula:- wherein R 6 has the meaning stated in claim 1, with a heterocycle or a reactive derivative thereof of the formula R 7- M wherein R 7 has the meaning stated immediately above and M is a metal radical; (d) for the manufacture of an acylanilide of the invention wherein R 5 is hydroxy, the hydrolysis of the corresponding acylanilide wherein R 5 is acyloxy; (e) for the manufacture of an acylanilide of the invention wherein R 5 is hydroxy and R 4 is hydrogen, the hydrolysis of the corresponding oxazolidinedione; (f) for the manufacture of an acylanilide of the invention wherein R 4 is alkyl, the alkylation of the corresponding acylanilide wherein R 4 is hydrogen; (g) for the manufacture of an acylanilide of the invention wherein R 5 is acyloxy, the acylation of the corresponding acylanilide wherein R 5 is hydroxy; (h) for the manufacture of an acylanilide of the invention wherein R 4 and R 5 are joined together to form a carbonyl-oxy group, the reaction of the corresponding acylanilide wherein R 4 is hydrogen and R 5 is hydroxy with phosgene (COCI 2 ); (i) for the manufacture of an acylanilide of the invention wherein one or more of R 1 , R 2 and a substituent in the phenyl or heterocyclic group R 7 or R 8 is alkylsulphinyl, perfluoroalkylsulphinyl or phenylsulphinyl, or is alkylsulphonyl, perfluoroalkylsulphonyl or phenylsulphonyl, the oxidation of the corresponding acylanilide wherein one or more of R 1 , R 2 and a substituent in the phenyl or heterocyclic group R 7 or R 8 is alkylthio, perfluoroalkylthio or phenylthio, respectively; or (j) for the separation into its optical isomers of an acylanilide of the invention wherein R 5 is hydroxy, the formation of an ester of the hydroxy group R 5 with an optically-active acid, the separation of the diastereoisomeric esters thus obtained, by fractional cystallisation or by flash-chromatography, and then the hydrolysis of each separate ester to the alcohol.

Claim 12

A pharmaceutical composition comprising an acylanilide as claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier; the composition optionally containing one or more drugs selected from anti-oestrogens, progestins, inhibitors of gonodotrophin secretion, cytotoxic agents, antibiotics and anti-inflammatory agents.

Claim 13

The use of an acylanilide as claimed in claim 1 for the manufacture of a medicament for producing an antiandrogenic effect in a warm-blooded animal.

Claim 14

The use of an acylanilide as claimed in claim 4 for the manufacture of a medicament for producing a progestational effect in a warm-blooded animal.

Claim 15

The use of an acylanilide as claimed in claim 5 for the manufacture of a medicament for producing an antiprogestational effect in a warm-blooded animal.