Amide derivatives

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, perfluoroalkyl, 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 R 4 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 R 6 is alkyl or halogenoalkyl of up to 4 carbon atoms, or has the formula -A 3- R 8 or -A 4- X 2- A 5- R 9 ; wherein A l and A 4 , which may be the same or different, each is alkylene of up to 6 carbon atoms; wherein A 2 , A3 and A 5 , which may be the same or different, each is a direct link or alkylene of up to 6 carbon atoms; wherein X 1 and X 2 , which may be the same or different, each is oxygen, sulphur, sulphinyl (-SO-), sulphonyl (-S0 2 -), imino (-NH-) or alkylimino (-NR 10 - wherein R 10 is alkyl of up to 6 carbon atoms); wherein R and R 9 , which may be the same or different, each is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbon atoms, or R 7 or R 9 is phenyl which bears one, two or three substituents selected from hydrogen, halogen, nitro, 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; or R 7 or. R 9 is naphthyl; or R 7 or R 9 is 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; and wherein R 8 is phenyl, naphthyl or heterocyclic as defined above for R 7 or R 9 .

Claim 3

An acylanilide as claimed in claim 1 wherein R l is cyano, nitro, trifluoromethyl, chloro, methyl or methoxy, R 2 is cyano, nitro, trifluoromethyl 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 or ethylidene, X l is oxygen, sulphur, sulphinyl, sulphonyl, imino or methylimino, A 2 is a direct link or methylene and R 7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbon atoms, or phenyl which is unsubstituted or which bears one fluoro, chloro, cyano, nitro, methoxy or methylthio substituent, or thienyl, imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl which is unsubstituted or which bears one chloro, bromo or methyl substituent.

Claim 4

An acylanilide as claimed in claim 1 wherein R 1 is trifluoromethyl, R 2 is cyano or nitro, R 3 and R 4 are both hydrogen, R 5 is hydroxy, R 6 is methyl, A l is methylene, X l is sulphur, sulphinyl or sulphonyl, A 2 is a direct link and R 7 is alkyl of up to 3 carbon atoms, or is allyl, phenyl, p-fluorophenyl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 2-pyridyl.

Claim 5

The compound 3-chloro-4-cyano-N-(3-ethylthio-2-hydroxy-2-methylpropionyl)-aniline; 3-chloro-4-cyano-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-phenylsulphonylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenylsulphonyl-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 3-chloro-4-nitro-N-(2-hydroxy-3-phenylthio-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[3-allylthio-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(4-methylthiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylsulphonyl)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline; 4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-methylthiopropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline.

Claim 6

The compound 3-chloro-4-cyano-N-(3-ethylthio-2-hydroxy-2-methylpropionyl)-aniline; 3-chloro-4-cyano-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-phenylsulphonylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenylsulphonyl-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 3-chloro-4-nitro-N-(2-hydroxy-3-phenylthio-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[3-allylthio-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(4-methylthiazol-2-ylthio)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylsulphonyl)propionyl]aniline; 4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylsulphonyl-2-hydroxy-2-methylpropionyl)aniline; 4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propionyl]aniline; 4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl]aniline; 4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-methylthiopropionyl)aniline; 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl)aniline.

Claim 7

The compound 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulphonyl-2-hydroxy-2-methylpropionyl)-aniline.

Claim 8

The compound 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulphonyl-2-hydroxy-2-methylpropionyl)-aniline.

Claim 9

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:- wherein R 5 , R 6 , R 7 , X l , A 1 and A 2 have the meanings stated in claim 1, or with a reactive derivative of said acid; or (b) for the manufacture of an acylanilide wherein R 5 is hydroxy and X 1 is sulphur or alkylimino, the reaction of an epoxide of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated above and wherein Z 1 has the formula wherein R 6 has the meaning stated above, wherein Z 2 is a displaceable group and wherein R 11 is such that - CHR 11- is -A 1 - as stated above, with a thiol or amine of the formula:- wherein R 7 and A 2 have the meanings stated above and wherein R 10 has the meaning stated in claim 1; or (c) for the manufacture of an acylanilide wherein R 5 is hydroxy, the reaction of a compound of the formula:- wherein R 1 , R 2 , R 3 , R 4 and R 6 have the meanings stated above, with an organometallic compound of the formula - wherein A 1 . A 2 , R 7 and X 1 have the meanings stated above and M is a metal radical; or (d) for the manufacture of an acylanilide of the invention wherein R 4 and R 5 are joined together to form a carbonyloxy group, the reaction of an isocyanate of the formula:- wherein R 1 , R 2 and R 3 have the meanings stated above, with an ester of the formula:- wherein R 6 , R 7 , X l , A l and A 2 have the meanings stated above, and wherein R is alkyl of up to 6 carbon atoms: whereafter (i) an acylanilide wherein R 5 is hydroxy may be prepared by the hydrolysis of the corresponding acylanilide wherein R 5 is acyloxy; or (ii) an acylanilide wherein R 5 is hydroxy and R 4 is hydrogen may be prepared by the hydrolysis of the corresponding oxazolidinedione, which may be prepared as described in paragraph (d) above; or (iii) an acylanilide wherein R 4 is alkyl may be prepared by the alkylation of the corresponding acylanilide wherein R 4 is hydrogen; or (iv) an acylanilide wherein R S is acyloxy may be prepared by the acylation of the corresponding acylanilide wherein R 5 is hydroxy; or (v) an oxazolidinedione wherein R 4 and R 5 are joined together to form a carbonyloxy group may be prepared by the reaction of the corresponding acylanilide wherein R 4 is hydrogen and R 5 is hydroxy with phosgene (COC1 2 ); or (vi) an acylanilide wherein X 1 or X 2 is sulphinyl or sulphonyl or wherein one or more of R 1 , R 2 and a substituent in the phenyl or heterocyclic group R , R 8 or R 9 is alkylsulphinyl, perfluoroalkylsulphinyl or phenylsulphinyl, or is alkylsulphonyl, perfluoroalkylsulphonyl or phenylsulphonyl, may be prepared by the oxidation of the corresponding acylanilide wherein X 1 or X 2 is sulphur or wherein one or more of R 1 , R 2 and a substituent in the phenyl or 7 heterocyclic group R 7 , R 8 or R 9 is alkylthio, perfluoroalkylthio or phenylthio, respectively; or (vi) a racemic acylanilide wherein R 5 is hydroxy may be separated into its optical isomers by forming an ester of the hydroxy group R 5 with an optically-active acid, separating the diastereoisomeric esters thus obtained, and then hydrolysing each separate ester to the alcohol.

Claim 10

A pharmaceutical or veterinary composition which comprises an acylanilide, claimed in claim 1, in association with a pharmaceutically-acceptable diluent or carrier.

Claim 11

A composition as claimed in claim 7 which is in a form suitable for oral dosage, as a tablet, capsule, aqueous or oily solution or suspension or emulsion; or in the form of a sterile solution or suspension suitable for parenteral administration; or in the form of an ointment or lotion for topical administration, or in the form of a suppository for anal or vaginal administration.

Claim 12

A composition as claimed in claim 7 which additionally contains one or more drugs selected from anti-oestrogens, aromatase inhibitors, progestins, inhibitors of gonadotrophin secretion, LH-RH- analogues, cytotoxic agents, antibiotics and anti-inflammatory agents.

Claim 13

A method for producing an antiandrogenic effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of acylanilide claimed in claim 1.

Claim 14

What we claim is:-

Claim 15

A process for the manufacture of 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, perfluoroalkyl, 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 R 4 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 R 6 is alkyl or halogenoalkyl of up to 4 carbon atoms, or has the formula -A 3 -R 8 or -A 4- X 2- A 5 -R 9 ; wherein A 1 and A4, which may be the same or different, ' each is alkylene of up to 6 carbon atoms; wherein A 2 , A3 and A 5 , which may be the same or different, each is a direct link or alkylene of up to 6 carbon atoms; wherein X 1 and X 2 , which may be the same or different, each is oxygen, sulphur, sulphinyl (-SO-), sulphonyl (-S0 2 -), imino (-NH-) or alkylimino (-NR 10 - wherein R 10 is alkyl of up to 6 carbon atoms); wherein R 7 and R 9 , which may be the same or different, each is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbon atoms, or R 7 or R 9 is phenyl which bears one, two or three substituents selected from hydrogen, halogen, nitro, 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; or R 7 or R 9 is naphthyl; or R 7 or R 9 is 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; and wherein R 8 is phenyl, naphthyl or heterocyclic as defined above for R 7 or R 9 , characterised by:- (a) the reaction of an amine of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated above, with an acid of the formula:- wherein R 5, R 6 , R 7 , X 1 , A l and A 2 have the meanings stated above or with a reactive derivative of said acid; or (b) for the manufacture of an acylanilide wherein R 5 is hydroxy and X l is sulphur or alkylimino, the reaction of an epoxide of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated above and wherein Z1 has the formula wherein R 6 has the meaning stated above, wherein Z 2 is a displaceable group and wherein R11 is such that -CHR 11 - is -A 1 - as stated above, with a thiol or amine of the formula:- wherein R 7 , R 10 and A 2 have the meanings stated above; or (c) for the manufacture of an acylanilide wherein R 5 is hydroxy, the reaction of a compound of the formula:- wherein R 1 , R 2 , R 3 , R 4 and R 6 have the meanings stated above, with an organometallic compound of the formula - wherein A 1 , A 2 , R 7 and X 1 have the meanings stated above and M is a metal radical; or (d) for the manufacture of an acylanilide of the invention wherein R 4 and R 5 are joined together to form a carbonyloxy group, the reaction of an isocyanate of the formula:- wherein R 1 , R 2 and R 3 have the meanings stated above, with an ester of the formula:- wherein R 6 , R 7 , X l , A l and A 2 have the meanings stated above, and wherein R is alkyl of up to 6 carbon atoms: whereafter (i) an acylanilide wherein R 5 is hydroxy may be prepared by the hydrolysis of the corresponding acylanilide wherein R 5 is acyloxy; or iii) an acylanilide wherein R 5 is hydroxy and R 4 is hydrogen may be prepared by the hydrolysis of the corresponding oxazolidinedione, which may be prepared as described in paragraph (d) above; or (iii) an acylanilide wherein R 4 is alkyl may be prepared by the alkylation of the corresponding acylanilide wherein R 4 is hydrogen; or (ivj an acylanilide wherein R 5 is acyloxy may be prepared by the acylation of the corresponding acylanilide wherein R 5 is hydroxy; or (v) an oxazolidinedione wherein R 4 and R 5 are joined together to form a carbonyloxy group may be prepared by the reaction of the corresponding acylanilide wherein R 4 is hydrogen and R 5 is hydroxy with phosgene (COCl 2 ); or (vi) an acylanilide wherein X 1 or X 2 is sulphinyl or sulphonyl, or wherein one or more of R 1 , R 2 and a substituent in the phenyl or heterocyclic group R 7 , R 8 or R 9 is alkylsulphinyl, perfluoroalkylsulphinyl or phenylsulphinyl, or is alkylsulphonyl, perfluoroalkylsulphonyl or phenylsulphonyl, may be prepared by the oxidation of the corresponding acylanilide wherein X l or X 2 is sulphur, or wherein more of R l , R 2 , and a substituent in the phenyl or heterocyclic group R 7 , R 8 or R 9 is alkylthio, perfluoroalkylthio or phenylthio, respectively; or (vi) a racemic acylanilide wherein R 5 is hydroxy may be separated into its optical isomers by forming an ester of the hydroxy group R 5 with an optically-active acid, separating the diastereoisomeric esters thus obtained, and then hydrolysing each separate ester to the alcohol.

Claim 16

A process for the manufacture of 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, perfluoroalkyl, 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 R 4 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 R 6 is alkyl or halogenoalkyl of up to 4 carbon atoms, or has the formula -A 3 -R 8 or -A 4- X 2- A 5 -R 9 ; wherein A 1 and A4, which may be the same or different, ' each is alkylene of up to 6 carbon atoms; wherein A 2 , A3 and A 5 , which may be the same or different, each is a direct link or alkylene of up to 6 carbon atoms; wherein X 1 and X 2 , which may be the same or different, each is oxygen, sulphur, sulphinyl (-SO-), sulphonyl (-S0 2 -), imino (-NH-) or alkylimino (-NR 10 - wherein R 10 is alkyl of up to 6 carbon atoms); wherein R 7 and R 9 , which may be the same or different, each is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbon atoms, or R 7 or R 9 is phenyl which bears one, two or three substituents selected from hydrogen, halogen, nitro, 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; or R 7 or R 9 is naphthyl; or R 7 or R 9 is 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; and wherein R 8 is phenyl, naphthyl or heterocyclic as defined above for R 7 or R 9 , characterised by:- (a) the reaction of an amine of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated above, with an acid of the formula:- wherein R 5, R 6 , R 7 , X 1 , A l and A 2 have the meanings stated above or with a reactive derivative of said acid; or (b) for the manufacture of an acylanilide wherein R 5 is hydroxy and X l is sulphur or alkylimino, the reaction of an epoxide of the formula:- wherein R 1 , R 2 , R 3 and R 4 have the meanings stated above and wherein Z1 has the formula wherein R 6 has the meaning stated above, wherein Z 2 is a displaceable group and wherein R11 is such that -CHR 11 - is -A 1 - as stated above, with a thiol or amine of the formula:- wherein R 7 , R 10 and A 2 have the meanings stated above; or (c) for the manufacture of an acylanilide wherein R 5 is hydroxy, the reaction of a compound of the formula:- wherein R 1 , R 2 , R 3 , R 4 and R 6 have the meanings stated above, with an organometallic compound of the formula - wherein A 1 , A 2 , R 7 and X 1 have the meanings stated above and M is a metal radical; or (d) for the manufacture of an acylanilide of the invention wherein R 4 and R 5 are joined together to form a carbonyloxy group, the reaction of an isocyanate of the formula:- wherein R 1 , R 2 and R 3 have the meanings stated above, with an ester of the formula:- wherein R 6 , R 7 , X l , A l and A 2 have the meanings stated above, and wherein R is alkyl of up to 6 carbon atoms: whereafter (i) an acylanilide wherein R 5 is hydroxy may be prepared by the hydrolysis of the corresponding acylanilide wherein R 5 is acyloxy; or iii) an acylanilide wherein R 5 is hydroxy and R 4 is hydrogen may be prepared by the hydrolysis of the corresponding oxazolidinedione, which may be prepared as described in paragraph (d) above; or (iii) an acylanilide wherein R 4 is alkyl may be prepared by the alkylation of the corresponding acylanilide wherein R 4 is hydrogen; or (ivj an acylanilide wherein R 5 is acyloxy may be prepared by the acylation of the corresponding acylanilide wherein R 5 is hydroxy; or (v) an oxazolidinedione wherein R 4 and R 5 are joined together to form a carbonyloxy group may be prepared by the reaction of the corresponding acylanilide wherein R 4 is hydrogen and R 5 is hydroxy with phosgene (COCl 2 ); or (vi) an acylanilide wherein X 1 or X 2 is sulphinyl or sulphonyl, or wherein one or more of R 1 , R 2 and a substituent in the phenyl or heterocyclic group R 7 , R 8 or R 9 is alkylsulphinyl, perfluoroalkylsulphinyl or phenylsulphinyl, or is alkylsulphonyl, perfluoroalkylsulphonyl or phenylsulphonyl, may be prepared by the oxidation of the corresponding acylanilide wherein X l or X 2 is sulphur, or wherein more of R l , R 2 , and a substituent in the phenyl or heterocyclic group R 7 , R 8 or R 9 is alkylthio, perfluoroalkylthio or phenylthio, respectively; or (vi) a racemic acylanilide wherein R 5 is hydroxy may be separated into its optical isomers by forming an ester of the hydroxy group R 5 with an optically-active acid, separating the diastereoisomeric esters thus obtained, and then hydrolysing each separate ester to the alcohol.

Claim 17

A process for the manufacture of an acylanilide of the formula stated in claim 1 wherein R 1 is cyano, nitro, trifluoromethyl, chloro, methyl or methoxy, R 2 is cyano, nitro, trifluoromethyl or chloro, R 3 and R 4 are both hydrogen, R 5 is hydroxy, R 6 is methyl or trifluoromethyl, A l is methylene, ethylene or ethylidene, X l is oxygen, sulphur, sulphinyl, sulphonyl, imino or methylimino, A 2 is a direct link or methylene and R 7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbon atoms, or phenyl which is unsubstituted or which bears one fluoro, chloro, cyano, nitro; methoxy or methylthio substituent, or thienyl, imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl which is unsubstituted or which bears one chloro, bromo or methyl substituent, characterised by :- (a) the reaction of an amine of the formula:- wherein R 1 and R 2 have the meanings stated above, with an acid of the formula:- wherein R 6 , R 7 , X 1 , A 1 and A 2 have the meanings stated above and R 5 is hydroxy or acyloxy as stated in claim 1, or with a reactive derivative of said acid; or (b) for the manufacture of an acylanilide wherein X 1 is sulphur or alkylimino, the reaction of an epoxide of the formula:- wherein R 1 and R 2 have the meanings stated above and wherein Z 1 has the formula wherein R 6 has the meaning stated above, wherein Z 2 is a displaceable group and wherein R 11 is such that -CHR 11- is -A 1 - as stated above, with a thiol or amine of the formula:- wherein R 7 and A 2 have the meanings stated above and wherein R 10 is hydrogen or methyl; or (c) the reaction of a compound of the formula:- wherein R 1 , R 2 and R 6 have the meanings stated above, with an organometallic compound of the formula - wherein A 1 , A 2 , R 7 and X 1 have the meanings stated above and M is a metal radical; or (d) the reaction of an isocyanate of the formula:- wherein R l and R 2 have the meanings stated above, with an ester of the formula:- wherein R 6 , R 7 , X l , A l and A 2 have the meanings stated above, and wherein R is alkyl of up to 6 carbon atoms, followed by hydrolysis of the oxazolidinedione thus obtained; whereafter (i) an acylanilide wherein R 5 is hydroxy may be prepared by the hydrolysis of the corresponding acylanilide wherein R 5 is acyloxy; or (ii) an acylanilide wherein X 1 is sulphinyl or sulphonyl may be prepared by the oxidation of the corresponding acylanilide wherein X l is sulphur; or (iii) a racemic acylanilide may be separated into its optical isomers by forming an ester of the hydroxy group R 5 with an optically-active acid, separating the diastereoisomeric esters thus obtained, and then hydrolysing each separate ester to the alcohol.

Claim 18

A process for the manufacture of an acylanilide of the formula stated in claim 1 wherein R 1 is trifluormethyl, R 2 is cyano or nitro, R 3 and R 4 are both hydrogen, R 5 is hydroxy, R 6 is methyl, A l is methylene, X 1 is sulphur, sulphinyl or sulphonyl, A 2 is a direct link and R 7 is alkyl of up to 3 carbon atoms or is allyl, phenyl, p-fluorophenyl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl or 2-pyridyl, characterised by:- (a) the reaction of an amine of the formula:- wherein R 2 has the meaning stated above, with an acid of the formula:- wherein R 7 and X 1 have the meanings stated above and R 5 is hydroxy or acyloxy as stated in claim 1, or with a reactive derivative of said acid; or (b) for the manufacture of an acylanilide wherein X 1 is sulphur, the reaction of an epoxide of the formula:- wherein R 2 has the meaning stated above and wherein Z 1 has the formula wherein Z 2 is a displaceable group, with a thiol of the formula:- wherein R 7 .has the meaning stated above; or (c) reaction of a compound of the formula:- wherein R 2 has the meaning stated above, with an organometallic compound of the formula - wherein R 7 and X 1 have the meanings stated above and M is a metal radical; Whereafter (i) an acylanilide wherein R 5 is hydroxy may be prepared by the hydrolysis of the corresponding agylanilide wherein R 5 is acyloxy; or (ii) an acylanilide wherein X 1 is sulphinyl or sulphonyl may be prepared by the oxidation of the corresponding acylanilide wherein X l is sulphur; or (iii) a racemic acylanilide may be separated into its optical isomers by forming an ester of the hydroxy group R 5 with an optically-active acid, separating the diactereoisomeric esters thus obtained, and then hydrolysing each separate ester to the alcohol.

Claim 19

A process as claimed in claim 1, 2 or 3 wherein in the starting materials R l is trifluoromethyl, R 2 is cyano, R 3 and R 4 are both hydrogen, R 5 is hydroxy or acyloxy, R 6 is methyl, A 1 is methylene, X l is sulphur or sulphonyl, A 2 is a direct link and R 7 is p-fluorophenyl, whereafter if R 5 is acyloxy the compound is hydrolysed to the corresponding compound wherein R 5 is hydroxy, and if X 1 is sulphur the compound is oxidised to the corresponding compound wherein X 1 is sulphonyl.