DK166385B - N-acyl-p-substd.-aniline derivs. - useful as antiandrogenic agents - Google Patents

Abstract

Cpds. of formula (I) are new. (R1 is H, CN, CONH2, NO2, F, Cl, Br, I, PhS, PhSO or PhSO2, or alkyl, alkoxy, alkanoyl, perfluoroalkyl, or alkyl- or perfluoroalkyl-thio, sulphinyl or sulphonyl having up to 4C; R2 is CN, CONH2, NO2, F, Cl, Br, I, PhS, PhSO or PhSO2, or alkanoyl, alkyl- or perfluoroalkyl-thin, -sulphinyl or sulphonyl or perfluoroalkyl each having up to 4C; R3 is H or halogen; R4 is H or 1-4C alkyl; R5 is H, OH, or alkoxy or acyloxy each having up to 15C, or R4+R5 form an oxycarbonyl gp. to complete an oxazolidine. dione gp. R6 is 1-4C alkyl or haloalkyl, -A3R8 or -A4-X2-A5-R9; A1 and A4 are 1-6C alkylene; A2, A3 and A5 are direct links or 1-6C alkylene; X1 and X2 are O, S, SO, SO2,NH or NR10; R10 is 1-6C alkyl; R7 and R9 are alkyl, alkenyl, hydroxyalkyl or cycloalkyl each having up to 6C; or R7 or R9 is Ph (ipt. substd. by 1-3 halogen, NO2, COOH, CONH2, CN, Ph, PhS, PhSO, PhSO2, or alkyl, alkoxy, alkanoyl, perfluoroalkyl, alkyl or perfluoroalkyl-thio, sulphinyl or -sulphonyl, alkoxycarbonyl or N-alkylcarbamoyl each having upto 4C), or naphthyl, or 5- or 6-membered satd. or unsatd. heterocyclic gp. contg. 1-3 N, O or S and it is a single ring or is fused to a benzo ring (the heterocyclic gp. being opt. substd. by 1 or 2 halogen, CN, NH2, oxy, OH or alkyl, alkoxy, alkyl-thio,-sulphinyl or -sulphonyl having up to 4C; or if the gp. is sufficiently satd. it may bear 1 or 2 oxo substituents); and R8 is Ph, naphthyl or a heterocyclic gp. as defined above for R7 or R9). Cpds. (I) are antiandrogenic agents and so are useful for treatment of malignant or benign prostatic disease, acne, hinsutism, seborhoea etc. and to improve ovulation in animals.

Description

DK 166385 B

The present invention relates to novel acyl anilides of formula I having anti-androgenic properties. The invention further relates to a process for the preparation of the compounds of formula I and to a pharmaceutical or veterinary agent containing these compounds.

Many acyl anilides are known to have anti-androgenic action. Especially the compound of formula 10 ch3

NO o - (/ \ -NHCO-C-R

3-7! cf3 ch3 15 wherein R is hydrogen, which compound is known as FLUTA-MID, is being developed for use as antiandrogen. It is believed that flutamide is oxidized in vivo to the corresponding compound wherein R is hydroxy.

Other acyl anilides having antiandrogenic action are known from EP Patent Nos. 2309, 2892 and 40932 as well as from JP Patent Nos. 52-128329.

In the compounds of European Patent Specification No. 2309, the substituents on the am * 1 inor in flutamide are replaced by e.g. cyano groups. In the compounds of EP Patent No. 30,2892, one of the methyl groups in the isobutyramide of flutamide has been replaced by a trifluoromethyl (CF3) group. In the compounds of EP Patent No. 40932, one of the methyl groups in the isobutyramide moiety is replaced by an aryl group.

According to the present invention, an acyl anilide of formula (I) is disclosed.

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2

R 1 is R 2 - 2 - -NR 4 -CO-CA 1-X 1 -A 2 -R 7 (I) R 6 R 3 wherein R 1 is cyano, nitro, fluoro, chloro, bromo or iodo or alkyl, alkoxy or perfluoroalkyl each with up to to 4 carbon atoms wherein R 2 is cyano, nitro, fluorine, chlorine, bromine or iodine or perfluoroalkyl having up to 4 carbon atoms, 15 where R 3 is hydrogen, R 4 is hydrogen, 20 where R 5 is hydroxy or acyloxy with up to 15 carbon atoms, wherein R6 is alkyl or haloalkyl with up to 4 carbon atoms, where A1 is alkylene with up to 6 carbon atoms, where A2 is a direct bond or alkylene with up to 6 cow 1 substance atoms where X1 is sulfur, sulfinyl (- SO-) or sulfonyl (-SO2-) where R? is alkyl, alkenyl, hydroxyalkyl or cycloalkyl, each having up to 6 carbon atoms, or R 1 is phenyl bearing one, two or three substituents selected from hydrogen, halogen, nitro and cyano, and alkyl, alkoxy, alkylthio, alkylsulfinyl and alkyl sulphonyl, each having up to 4 ku 1 substance atoms ^ or R? is a 5- or 6-membered, saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic group may be a single ring or may be condensed to a benzene, and which heterocyclic group is unsubstituted or carries one

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3 or two halogen or all refrigerant substituents with up to 4 carbon atoms.

It is seen that the acylanide derivative of the invention has an asymmetric carbon atom, namely the carbon atom which carries the substituents R5 and R6, and therefore it can exist in racially and optically active forms. It is to be understood that the invention encompasses the racemic form of the acyl anilide derivative and any optically active form having anti-androgenic action, as it is common knowledge how a racemic compound can be cleaved to its optically active forms and how any anti-androgenic effect of one of these forms can be determined.

A suitable value for R 1 when it is alkyl or for an alkyl substituent in R 7 when R 7 is phenyl or a heterocyclic group substituted by alkyl is e.g. methyl or ethyl.

A suitable value for R 1 when it is alkoxy or for an alkoxy substituent in R 7 R when R 7 is phenyl substituted by alkoxy is e.g. methoxy or ethoxy.

A suitable value for R 1 or R 2 when perfused with an unoriginal cooler is e.g. trif 1uormethyl or pentafluoroethyl.

25

A suitable value for a halogen substituent in R7 'when R7 is phenyl or a heterocyclic group substituted by halogen is fluorine, chlorine, bromine or iodine.

3Q A suitable value for R5 when acyloxy is e.g. alkanoyloxy or aroyloxy, each having up to 15 carbon atoms, e.g. acetoxy, propionyloxy, decanoyloxy, dedecanoyloxy or benzoyloxy.

Preferably, R 5 is hydroxy.

A suitable value for R 6 when it is alkyl or haloalkyl is e.g. methyl, ethyl, n-propyl, fluoromethyl, difluoromethyl, f 4

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trifluoromethyl, pentafluoroethyl, chloromethyl, dichloromethyl or trichloromethyl.

Preferably R 5 is methyl or trifluoromethyl, especially methyl.

5

A suitable value for or A 2 'when it is alkylene is e.g. methylene, ethylene, ethylidene (CH

C

Methylene, 1-methyl ethyl and {-CH-CH 2 - »CH 3 CH 3 2-methyl ethyl en (-CH 2 CH- or 1,1,3-trimethylpropane-1,3-15 ch 3 CH 2 CH).

A suitable value for R 7 when it is alkyl, alkenyl, hydroxyalkyl or cycloalkyl, is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, 2-methylprop-2-enyl, 2-hydroxyethyl, cyclopentyl or cyclohexyl.

A suitable value for R 7 when heterocyclic is e.g. furyl, thienyl, pyrrolyl, pyridyl, imidazolyl, thiazolyl, pyrimidinyl, thiadiazolyl, triazolyl, benzimidazolyl, benzothiazolyl, indolyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl or 1,2-hydroxy

30 35

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5

A preferred combination of values for R 1 and R 2 is as follows:

Ri R2 5 Trifluoromethyl Nitro

Trifluoromethyl Cyano

Chlorine Chlorine

Chlorine Ni believe

Chlorine Cyano 10 Cyano Cyano

A preferred acyl anilide of the invention has the above formula 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 2 is hydroxy, R6 is methyl or trifluoromethyl, is methylene, ethylene or ethylidene, is sulfur, sulfinyl or sulfonyl, A2 is a direct bond or methylene, and R4 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl, each having up to 6 carbon atoms, or phenyl which is unsubstituted or which carries a fluoro, chloro, cyano, nitro, methoxy or methylthiosubstituent, or thienyl, imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl which is unsubstituted or carrying a chloro, bromo or methyl substituent.

A particularly preferred acyl anilide of the invention has the above formula 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 * is methylene, is sulfur, sulfinyl or sulfonyl, A2 is a direct bond, and R? is all alkyl of up to 3 carbon atoms, especially ethyl, or is allyl, phenyl, p-fluorophenyl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-1,3,4-thiadiazole-35 2-yl or 2-pyridyl.

Concrete acyl anilides of the invention are described below in the Examples.

Beer

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6 Particularly active compounds are 3-chloro-4-cyano-N- (3-ethylthio-2-hydroxy-2-methylpropionyl) aniline, 3-chloro-4-cyano-N- (3-ethylsulfonyl-2-hydroxy) 2-methylpropionyl) aniline, 4-cyano-3-trifluoromethyl-N- (2-hydroxy-2-methyl-3-phenylsulfonyl) propionyl) aniline, 4-cyano-3-trifluoromethyl-N- ( 3-Ethylsulfonyl-2-hydroxy-2-methylpropionylanilane, 4-nitro-3-tri-fluoromethyl-N- (2-hydroxy-3-phenylsulfonyl-2-methylpropionyl) anil in, 4-nitro-3-trifluoromethyl-N- (3-ethylsulfonyl-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] an in 1, 4-nitro trifluoromethyl-N- (3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl) aniline , 4-Nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl-3- (pyrid-2-yl-thio) propionyl] aniline, 4-nitro-3-trifluoromethyl 1-N- [2-hydroxy-2-methyl-3- (5-me thyl-1,3,4-thiadiazol-2-ylthio) propionyl] ananine, 4-nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl-3- -methylthiazol-2-ylthio) propionyl] aniline, 4-nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl-3- (pyrid-2-ylsulfonyl) propionyl] aniline, 4-nitro -3-trifluoromethyl-N- (3-p-fluorophenyl sulfonyl) -2-hydroxy-2-methylpropionyl) ananine, 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-yl-thio) 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-

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7 methylpropionyl) ani 1 in and 4-cyano-3-trifluoromethyl-N- (3-p-fluorophenylsulfony 1-2-hydroxy-2-methylpropionyl) aniline, 5 of which the latter is particularly preferred.

The acylanides of the invention can be prepared by any known method known as suitable for the preparation of chemically analogous compounds.

10

A process (a) for the preparation of an acyl anilide of the invention comprises reacting an amine of the formula R 1 is Y 2 R 2 -V 1 / - NHR 4 R 1 2 wherein R 1, R 2, R 1 and R * have the above meanings, with a acid of the formula H02C-CR3R6-A1-X1-A2-R7 wherein R3, R6, R7, X1, A1 and A2 have the above meanings, or with a reactive derivative of the acid.

A suitable reactive derivative of an acid is e.g. an acid anhydride or an acid tail and also id, e.g. an acyl chloride, or a lower alkyl ester of the acid, e.g. the methyl or ethyl ester. Preferably, the reaction is carried out in N, N-dimethylacetamide solution using acyl chloride (prepared from the acid and thionyl chloride) as the reaction agent.

Another method (b) for the preparation of an acyl analyte ID 2 according to the invention, wherein R 3 is hydroxy and X * is sulfur, if 3 takes the reaction of an epoxide of the formula

DK 166385B

Wherein R1, R2, r3 Qg r4 have <the above meanings and zl has the formula 10 / ° \ -CRO - CHR11 where R® has the above meaning and where RU is Thus, -CHR11- is -A * - as indicated above, with a thiol of the formula

R7-A2-SH

20 where R7 and A2 have the above meanings.

The epoxide used as starting material can be obtained by epoxidation, e.g. with a peracid, of the corresponding unsaturated acylani1 id.

25

A third process (c) for the preparation of an acyl anilide of the invention wherein R * 5 is hydroxy comprises reacting a compound of formula R1 30 \ r2 / r \ - NR4-CO-CO-R6 R3

35 R

wherein R 1, R 2, R 3, R 4 and R 6 have the above meanings, with an organometall 1 in so-called formula

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g

Rf-Z-X-Al-M

where Al, A2, R7 and χΐ have the above meanings and M is j a metal radical, e.g. 1 ithium radical1 et. ! 5

The latter reaction is preferably carried out in an inert solvent, e.g. diethyl ether or tetrahydrofuran, at a low temperature, e.g. between -60 and -100 ° C

An acyl anilide according to the invention wherein R 5 is hydroxy can be prepared by hydrolysis of the corresponding acyl anilide wherein R 5 is acyloxy. j i

An acyl anilide of the invention wherein R 5 is acyloxy can be prepared by acylating the corresponding acyl anilide wherein R * is hydroxy.

An acyl anilide of the invention wherein X * is sulfinyl or ii sulfonyl or wherein a substituent in the phenyl group R7 is alkylsulfinyl or is alkylsulfony 1 can be prepared by oxidation of the corresponding acylanilide wherein χΐ is sulfur or wherein a substituent in the phenyl group R7 is alkylthio. The oxidizing agent and the conditions used will determine whether a sulfinyl or a sulfonyl compound is obtained. Thus, oxidation with 25 Nm in ummetaperiodate in methanol solution at or below laboratory temperature will generally convert a thio compound to the corresponding sulf inyl compound, and oxidation with a peracid, e.g. m-chloroperbenzoic acid, in methylene chloride solution at or above laboratory temperature, will generally convert a thio compound to the corresponding sulfonyl compound.

in

A racemic acyl anilide of the invention wherein R® is hydro-J

xy, can be separated into the optical isomers by forming an ester of! With an optically active acid, e.g. (-) - camp-maleic acid, separating the resulting diastereoisomeric esters by fractional crystallization, or preferably

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10 by flash chromatography, and then hydrolyzing each separate ester to the alcohol. Alternatively, an optically active acyl anilide according to the invention can be obtained by applying any of the methods described above to an optically active starting material.

5

As mentioned above, an acyl anilide of the invention has anti-androgenic properties, demonstrated by its ability to reduce the weight of semen vesicles in adult male rats when administered orally for four consecutive days. An acylanilide of the invention can therefore be used to treat e.g. malignant or benign prostatic diseases or of androgen-dependent disease states, such as acne, hirsutism, or seborrhoea, in warm-blooded vertebrates, including humans. It can also be used to improve ovulation in a domestic animal.

As can be seen from the following comparative experiment, a preferred acyl anilide of the invention is up to 10 times more active as antiandrogen than the known chemically related anti androgens flutamide and hydroxy flutamide. In a dose of an acyl anilide of the invention which produces antiandrogenic effect in rats, no symptoms of toxicity are seen.

The acyl anilide of the invention may be administered to a warm-blooded animal in the form of a pharmaceutical or veterinary agent comprising the acyl anilide together with a pharmaceutically acceptable diluent or carrier.

The agent may be in a form suitable for oral dosing, such as a tablet, capsule, aqueous or oily solution or suspension or emulsion. Alternatively, it may be in the form of a sterile solution or suspension suitable for parenteral administration, or it may be in the form of an ointment or lotion for topical administration, or in the form of a suppository for anal or vaginal administration.

The agent may additionally contain one or more drugs selected from anti-estrogens, e.g. Tamoxifen, aromatase inhibitor

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liers, e.g. Testolactone or ami noglutethamide, progestins, e.g. medroxyprogesterone acetate, inhibitors of gonadrophin secretion, e.g. Danazol, LH-RH analogs, e.g. Buserelin, cytotoxic agents, e.g. cyclophosphamide, antibiotics, e.g.

5 penicillin or oxytetracycline, and anti-inflammatory agents, for example, especially for topical use, fluorcinolone acetonide.

The acylane of the present invention will normally be administered to a warm-blooded animal at a dose between 0.1 mg and 125 mg 10 per day. kg body weight.

The invention is illustrated by the following examples.

EXAMPLE 1.

15 -----------

Thionyl chloride (0.6 ml) was added to a stirred solution of 2-hydroxy-2-methyl-3-phenylthiopropionic acid (1.7 g) in N, N-dimethylacetamide (40 ml) which was cooled to -15 At a rate such that the temperature was maintained and the mixture was stirred at this temperature for 15 minutes. 4-cyclo-3-trifluoromethylanilane (1.5 g) was added, the mixture was stirred at -15 ° C for 30 minutes and then at laboratory temperature for 15 hours and then poured into water (800 ml). The mixture was extracted six times with diethyl ether (80 mL each time) and the combined extracts were washed sequentially (50 mL portions each time), twice with aqueous 3N hydrochloric acid, once with saturated aqueous sodium chloride solution, two times. times with saturated aqueous sodium bicarbonate solution and again once with 30 saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a column of silica gel (Merck 7734) using methylene chloride as eluant. The product was crystallized from a 5: 1 v / v mixture of toluene 35 and petroleum ether (bp 60 - 80 ° C) to give 4- cyano-3-trifluoromethyl-N- (2-hydroxy-2-methyl) -3-phenylthio-propionyl) -aniline, m.p. 81.5 - 83 ° C.

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12% of 2-hydroxy-2-methyl-3-phenylthiopropionic acid used as starting material was prepared as follows:

Method A: 5 ---------

A solution of methyl 2,3-epoxy-2-methylpropionate (4.06 g) in tetrahydrofuran (40 ml) was added over 20 minutes to a stirred suspension of thiophenol (7.7 g) and sodium hydride (2, (10 ml of a 60% dispersion in mineral oil) in tetrahydro uranium (75 ml) which was kept under an atmosphere of nitrogen and the mixture was stirred at room temperature for 15 minutes and then at 60 ° C for 4 hours, cooled and neutralized. by dropwise addition of a solution of concentrated sulfuric acid 15 (0.5 ml) in ethanol (5 ml). A solution of potassium hydroxide (10 g) in a mixture of water (30 ml) and ethanol (150 ml) was added and the mixture was heated under reflux for 22 hours. The organic solvents were removed by evaporation under reduced pressure, water (50 ml) was added and the mixture was washed twice with diethyl ether (25 ml each time). The aqueous solution was then acidified with concentrated aqueous hydrochloric acid and extracted four times with diethyl ether (100 ml each time). The combined extracts were washed with saturated aqueous sodium chloride solution (50 ml), dried over 25 magnesium sulfate and evaporated to dryness, and the residue was crystallized by a 5: 1 v / v mixture of petroleum ether (bp 60-80 ° C) and toluene. There was thus obtained 2-hydroxy-2-methyl-3-phenylthiopropionic acid, mp 95.5 - 97 ° C.

EXAMPLE 2.

The procedure of Example 1 was repeated except that the desired aniline and 2-hydroxy-substituted alkanoic acid were used as starting materials. There were thus obtained the compounds described in the following table.

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13 TABLE 1 R1 \ r2_ ^^ -MHCO-C-A1-X1-A2 3-R7 R6 10 R1 R2 R6 A1 X1 A2 R7 Mp.

(° C) 15 CF3 NO2 CH2 CH2 S - phenyl 105-106 CF3 NO2 CH3 CH2 S - 2-ni trophenyl 52-54 CF3 NO2 CH3 CH2 S - methyl 109-110 CF3 NO2 CH3 CH2 S - ethyl (rubber) CF3 NO2 CH3 CH2 S - n-propyl (rubber) CF3 NO2 CH3 CH2 S - isopropyl 66-68 CF3 CN CH3 CH2 S - ethyl (rubber) CF3 CN CH3 CH2 S - n-propyl (rubber) CF3 CN CH3 CH2 S - isopropyl 98-100 CF3 CN CH3 CH2 S - methyl 108.5-109.5 in 30! 35 2 i 3 in DK 166385 6 14

Ri R2 R6 Al Xl A2 R7 Mp.

(° C) 5 CN CN CH3 CH2 S - phenyl 82-83.5

Cl Cl CH3 CH2 S - methyl 90.5-91.5

Cl CN CH3 CH2 S - phenyl 60-62 Cl Cl CH CH3 CH2 S - ethyl 96-98 NO2 Cl CH3 CH2 S - phenyl 77-78

Cl NO2 CH3 CH2 S - phenyl 88-90

Cl NO2 CH3 CH2 S - ethyl (rubber)

C1 NO2 CH3 CH2 S - n-butyl (rubber) CH30 CN CH3 CH2 S - phenyl (rubber) CH3 CN CH3 CH2 S - phenyl 98-99 CF3 NO2 CH3 CH2 S CH2 phenyl 79-80 CF3 NO2 CH3 CH2CH2 S - phenyl (rubber) CF3 CN CH3 CH2CH2 S - phenyl 115-116.5 CF3 CN CH3 CH2 S CH2 phenyl 105-106

Cl CN CH3 CH2 S CH2 phenyl 123-124 CF3 N02 CF3 CH2 S - phenyl 139-140 CF3 NO2 CF3 CH2 S - 4-Chlorophenyl 147-148 CF3 N02 CF3 CH2 S - 4-nitrophenyl1 145-146 CF3 N02 CF3 CH2 S - methyl 82-85 CF3 NO2 CF3 CH2 S - ethyl 79-81 CF3 NO2 CF3 CH2 S - n-propyl 67-68 CF3 NO2 CF3 CH2 s - isopropyl 88-89 CF3 CN CF3 CH2 S - phenyl 143-144 30 CF3 CN CF3 CH2 S - 4-chlorophenyl 178-179 CF3 CN CF3 CH2 S - methyl 120.5-122 CF3 CN CF3 CH2 S - ethyl 119-120 CF3 CN CF3 CH2 S - n-propyl 88-90 CF3 CN CF3 CH2 S - isopropyl 107-109 35 Cl Cl CF3 CH2 S - phenyl 104

Cl Cl CF3 CH2 S - methyl 84-85

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15 pi p2 r6 A ^ R7 m.p.

(° C) _____

Cl Cl CF 3 CH 2 s ethyl 57'59

Cl Cl CFs CH2 S - n-propyl 60-61 C1 C1 cp3 CH2 s "isopropyl 57-59 Cl Cl CF3 CH2 S - phenyl 152

Cl CN CF3 CH2 s - methyl 121-122.5

Cl CN CF3 CH2 S - ethyl 95-96

Cl CN CF3 CH2 S - n-propyl 89-90

Cl CN CF3 CH2 S - isopropyl 87-88 CF3 NO2 CF3 CH2 s CH2 phenyl 120-121 CF3 CN CF3 CH2 S CH2 phenyl 138-139

Cl Cl CF3 CH2 S CH2 phenyl 145-146 20

All of the alinines used as starting material are known compounds. The 2-hydroxy-substituted alkanoic acids were prepared either by the method described in the second part of Example 1 (Method A) or by the method exemplified below (Method B). These acids, which are novel and which were characterized by melting point, are described in the table below.

Method B: 1,1,1-Trifluoro-3-phenylthiopropan-2-one (13.1 g) was added dropwise to a cooled stirred solution of potassium cyanide (4.4 g) in water (16 ml) at such a rate that the temperature of the mixture was maintained between 0 and 5 ° C. A 4: 1 v / v-b1 breath of water and concentrated sulfuric acid (17.1 ml) was added at a rate such that the above temperature was maintained and the

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The sixteen pieces were then stirred at room temperature for 15 hours and then extracted three times with diethyl ether (25 ml each time). The combined extracts were washed three times with water (25 ml each time), dried over magnesium sulfate and evaporated to dryness under reduced pressure.

A mixture of the cyanhydrin thus obtained (3.0 g) and concentrated aqueous hydrochloric acid (30 ml) was heated in a sealed tube to 110 ° C for 6 hours, cooled and poured on ice. The aqueous mixture was extracted four times with diethyl ether (25 mL each) and the combined ethereal solutions extracted twice with saturated aqueous sodium bicarbonate solution (40 mL each). The combined extracts were acidified with aqueous hydrochloric acid and then extracted with diethyl ether (40 ml each time). The combined extracts were dried over magnesium sulfate and evaporated to dryness and the residue was stirred with petroleum ether (bp 60 - 80 ° C). The mixture was filtered to give solid residue 2-hydroxy-3-phenylthio-2-trifluoromethylpropionic acid, mp 83-84 ° C.

20 25 30 35

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17

TABLE 2 OH

HOCOC-A1-X1-A2-R7 5 r6 r6 ai X1 A2 R7 Method m.p.

ro 10 'CH3 CH2 s "2-nitrophenyl B 85-88 CH3 CH2 S - methyl A 48-52 CH3 CH2 S - isopropyl A 50-52 cH3 CH2 S CH2 phenyl A 62-63 CF3 CH2 S - 4-nitrophenyl B 169-171 x) CF3 CH2 S - methyl B 73-76 CF3 CH2 S - n-propyl B 37-40 CF3 CH2 S - isopropyl B 57-59 20 CF3 CH2 S CH2 phenyl B 91-92 x) Melting point of dicyclohexylamine salt used to characterize in ng.

25

The thiol cannons used in Method B were prepared by reacting the desired thiol with the desired bromocetone in the usual manner (e.g., as described in Zhur.org.Khim. 1971, 72221). Those that are new and that have been characterized are described in the following table.

35

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18 TABLE 3 cf3coch2s-a2-r7 5 _________ A2 R7 Kp. (eC / mm Hg) 10- 4-nitrophenyl 84.5-86 (m.p.) methyl 39-47 / 100 n-propyl 72-82 / 65 isopropyl 75-85 / 87 CH2 phenyl 118-122 / 17 EXAMPLE third

20

A solution of ethanethiol (0.45 ml) in tetrahydrofuran (5 ml) was added dropwise to a stirred suspension of sodium hydride (0.28 g of a 60% dispersion in mineral oil) in tetrahydrofuran (10 ml), which was kept at 0 - 5 ° C and the mixture was then stirred at laboratory temperature for 15 minutes. A solution of 3,4-dichloro-N- (2,3-epoxy-2-methylpropionyl) aniline (1.5 g) in tetrahydrofuran (15 ml) was added dropwise and the mixture was stirred at laboratory temperature for 15 hours. Water (50 ml) was added, the organic layer was separated and the aqueous layer was extracted twice with diet sheathed here (25 ml each time). The combined organic solutions were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel (Merck 9385) using a 1: 1 v / v mixture of ethyl acetate 35 and petroleum ether (bp 60-80 ° C) as eluant. The product was crystallized from a 5: 1 v / v mixture of toluene and petroleum ether (b.p. 60-80 ° C) to give 3,4-dichloromethane.

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19 N- (3-ethyl thio-2-hydroxy-2-methylpropionyl) aniline, m.p. 81-83 ° C.

3,4-Dichloro-N- (2,3-epoxy-2-methylpropionyl) aniline used as starting material was prepared as follows:

A solution of 3,4-dichloroaniline (10 g) in dimethylacetamide (25 ml) was added dropwise to a stirred cooled solution of methacryloyl chloride (10 ml) in dimethylacetamide (50 ml) at a rate such that the internal temperature of the mixture did not exceed 0 ° C, and the mixture was then stirred at laboratory temperature for 16 hours and then poured into cold water (1 liter). The mixture was extracted five times with diethyl ether (100 ml each time) and the combined extracts were dried and evaporated to dryness. The residue was crystallized from a 1: 1 v / v mixture of toluene and petroleum ether (b.p. 60-80 ° C) at -50 ° C to give 3,4-dichloro-N-methacryloylaniline, m.p. 120 - 122 ° C.

20 m-chloroperbenzoic acid (3.4 g) was added portionwise to a boiling solution of 3,4-dichloro-N-methacryloyl chloride (2.2 g) and 4-methyl-2,6-di-t-butylphenol ( 05 g) in 1,1,1-trichloroethane (75 ml) and the mixture was heated under reflux for 4 hours, cooled and washed sequentially (25 ml portions each time), once with saturated aqueous sodium sulfite solution twice, with saturated aqueous sodium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on a silica gel column (Merck 7734) using a 1: 1 v / v mixture of ethyl acetate and petroleum ether (bp 60-80 * 0) as eluant. The product was crystallized from petroleum ether (b.p. 60-80 ° C) to give 3,4-dichloro-N- (2,3-epoxy-2-methylpropionyl) aniline, m.p.

35

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EXAMPLE 4.

The procedure described in Example 3 was repeated using the desired thiol and the desired N- (2,3-epoxy-2-methylpropionyl) an in 1 in as starting materials, thereby yielding the compounds described in the following table. .

TABLE 4 10

R1 OH

R2-1 / y- nhco-c-ch2-s-r7 15 V - - / ch3 R1 R1 R2 R7 m.p.

(° C) 25 C1-Cl thiazol-2-yl 105-107 * C1-C1 pyrimidin-2-yl 103-105 CF3 NO2 2-chlorophenyl 98-100 CF3 NO2 3-chlorophenyl 132-133 CF3 NO2 4-chlorophenyl 101-103 CF3 NO2 4-fluorophenyl 112-113 CF3 NO2 4-cyanophenyl 108-111 35 21

DK 166385 B

R1 R2 R7 - m.p.

(LUL) _ 5 CF3 NO2 4-nitrophenyl 139-141 CF3 NO2 4-methoxyphenyl 120-121 CF3 NO2 4-methylthiophenyl 111-112 CF3 NO2 n-pentyl (oil) CF3 NO2 2-hydroxyethyl (oil) 10 CF3 NO2 allyl 80-81 CF3 NO2 2-methylallyl 78-79 CF3 NO2 cyclopentyl 87-88.5 CF3 NO2 pyrid-2-yl 155-157 CF3 NO2 pyrid-3-yl 149-150 CF3 NO2 pyrid-4-yl 193-195 CF3 NO2 6-chloro 159-162 CF3 NO2 thiazol-2-yl 131-132 CF3 NO2 4-methylthiazol-2-yl 160-162 CF3 NO2 5-methyl-1,3,4-thiadiazole-109-111 2- yl CF3 CN 4-chlorophenyl 137-138

Cf3 CN 4-fluorophenyl 116-117 CF3 CN 4-methylthiophenyl 125-126 CF3 CN pyrid-2-yl 137-139 CF3 CN pyrid-3-yl 135-136 CF3 CN 5-chloropyride 113-115 CF3 CN thien-2 -Y1 101-103 CF3 CN thi azol-2-yl 107-109 CF3 CN 4,5-dihydrothiazol-2-yl 110-111 CF3 CN 1-methylimidazo1-2-y1 112 CF3 CN benzthiazol-2-yl 178- 180 CF3 CN pyrimidin-2-yl 120-121 35

DK 166385 B

22

Similarly, using the desired thiol and the desired N- (2,3-epoxy-2-methylbutyryl) aniline: 4-cyano-3-trifluoromethyl-N - [(2SR, 3RS) -3-p -Fluorophenylthio-2-5 hydroxy-2-methylbutyl] aniline, m.p. 114-116 ° C, and 4-nitro-3-trifluoromethyl-N - [(2SR, 3RS) -2-hydroxy-2-methyl-3 -phenylthiobutyryl] aniline, m.p. 143-145 ° C.

The N - (2,3-epoxy-2-methylpropionyl or butyryl) anilines used as starting material were obtained by epoxidizing the desired N-methacrylic acid or N-methylcrotonoylanil in a similar manner as described in the second part of Example 3. N-methacryloyl-4-nitro-3-trifluoromethylaniline had a melting point of 102-104 ° C and the corresponding epoxy compound had a melting point of 119-121 ° C.

4-cyano-N-methacryloyl-3-trifluoromethylaniline had a melting point of 137-139 ° C and the corresponding epoxy compound had a melting point of 149-150 ° C.

N- (2-methylcrotonoyl) -4-nitro-3-trifluoromethyl-aniline had a melting point of 65-67 ° C and the corresponding epoxy compound had a melting point of 99-102 ° C.

2 4-Cyano-N- (2-methylcrotonoyl) -3-tri fluoromethyl aniline had a melting point of 127-128 ° C and the corresponding epoxy compound had a melting point of 100-103 ° C.

(The last two compounds are derived from trans-tiglinic acid, as opposed to cis-angelic acid 30).

EXAMPLE 5.

A solution of sodium metaperiodate (0.407 g) in water (15 ml) was added dropwise to a stirred solution of 4-cyano-3-tri-fluoromethyl-N- (3-ethyl thio-2-hydroxy-2- trif 1uormethy1 propio- 23

UK IbbJbb B

nil) aniline (0.6 g) in methanol (25 ml), and the mixture was stirred at 1 pore temperature for 48 hours and then filtered. The solid was washed with methanol (25 ml) and the mixture was filtered and the combined filtrates were evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (150 ml) and the solution was washed successively with water (15 ml), saturated aqueous sodium sulfite solution (25 ml) and saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulfate and evaporated to dryness under ref. duced pressure. The residue was chromatographed on silica gel (Merck 7734) using a 1/1 v / v mixture of ethyl acetate and petroleum ether (bp 60-80eC) as eluant, and the two diastereoisomers of 4-cyano-3-trifluoromethyl-N- (3- ethyl sulfinyl-2-hydroxy-2-trifluoromethylpropionyl) aniline was obtained by evaporation of the desired fractions of the eluate. These had mp 141-143 ° C (most polar isomer) and 160-162 ° C (least polar isomer).

The above-described procedure was repeated using the desired thiopropionylanil as starting material, and thus the compounds described in the following table were obtained.

TABLE 5 24

DK 166385 B

R1 OH

5 r2 ^ _HHCO-C-CH2-SO-R7 S6 10

Ri r2 R6 R7 Diastereo- Mp.

isomer (° C) 15 CF3 NO2 CH3 phenyl Horse polar 126.5-127.5 CF3 CN CH3 phenyl Most polar 164-165 CF3 CN CF3 phenyl Mixed 175-176 CF3 CN CH3 ethyl Mixed 110-112 EXAMPLE 6.

A solution of m-chloroperbenzoic acid (0.40 g) in methylene chloride (80 ml) was added to a stirred solution of 4-cyano-3-trifluoromethyl-N- (2-hydroxy-3-phenylthio-2- Trifluoromethylpropionyl) aniline (0.38 g) in methylene chloride (100 ml) over 30 minutes, and the reaction mixture was then stirred at laboratory temperature for 18 hours. Aqueous 10% w / v sodium sulfite-30 gel solution (15 ml) was added, the mixture was stirred and the organic layer was separated, washed sequentially twice with aqueous 10% w / v sodium carbonate solution (15 ml each time) and once with saturated aqueous sodium chloride solution (15 ml), dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was dissolved in a 1: 1 v / v mixture of ethyl acetate and petroleum ether (bp 60-80 ° C) and the solution was chromatographed on a silica gel column (Merck 7734) using a 1: 1 v / v mixture of ethyl acetate and petroleum ether (boiling point 60-80 ° C) as eluant. There was thus obtained 4-cyano-3-trifluoromethyl-N- (2-hydroxy-3-phenylsulfonyl-2-trifluoromethylpropionyl) aniline, mp 175-176 ° C.

5

The above-described procedure was repeated using the desired thiopropionylaniline as starting material, thereby yielding the compounds described in the following table.

10 15 20 25 30 35 TABLE 6 26

DK 166385 B

"1 OH

\ ~ λ J

5 R 2 </ y-nhco- and 2-SO 2 R 7 R 6

Ri R2 R6 R7 Mp.

CC) 15 CF3 NO2 CH3 phenyl 149-151 CF3 NO2 CH3 4-fluorophenyl 188-189 CF3 NO2 CH3 pyrid-2-yl 148-150 CF3 NO2 CH3 ethyl 135-136 CF3 NO2 CH3 n-propyl 118-119 CF3 NO2 CH3 n-pentyl 104-105 CF3 CN CH3 phenyl 172-173.5 CF3 CN CH3 4-fluorophenyl! 189-191 CF3 CN CH3 ethyl 116-118 CF3 CN CH3 n-propyl 117-119 CF3 CN CF3 ethyl 164-165

Cl NO2 CH3 ethyl 145-146

Cl NO2 CH3 n-butyl 116-118

Cl CN CH3 ethyl 135-136 CH3O CN CH3 phenyl 172-173 Example 35.

27

DK 166385 B

(-) - Camphanoyl chloride (4.33 g) was added portionwise over 5 minutes to a solution of 4-cyano-3-tri fluoromethyl-N- (2-hydroxy-3-phenylthio-2-trifluoromethylpropionyl) aniline ( 5.8 g) in pyridine (35 ml) and the mixture was heated to 95 ° C for 150 minutes and then evaporated to dryness. Toluene (50 ml) was added and the mixture was again evaporated to dryness. The residue was dissolved in ethyl acetate (200 ml) and the solution washed with water (30 ml) and then twice with saturated aqueous sodium chloride solution (20 ml each time), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and the solution 15 was flash chromatographed on silica gel (Merck 9385) using methylene chloride as eluant. Thereby the two diastereo in summers of 4-cyano-3-trifluoromethyl-N- [2 - (-) - camphanoyl-oxy-3-phenyl thio-2-trifluoromethylpropionyljan were obtained in 1 in, of which the least polar isomer had a melting point 121 -123 ° C and the most 20 polar isomers had a melting point of 140-143 ° C.

A mixture of a solution of the least polar isomer (2.0 g) in methanol (30 ml) and aqueous 4¾ w / v sodium hydroxide solution (3.5 ml) was stirred at 1 abator temperature for 30 minutes and then evaporated to dryness. dryness under reduced pressure. The residue was dissolved in ethyl acetate (160 ml) and the solution washed successively with water (25 ml), saturated aqueous sodium chloride solution (25 ml), aqueous 2N hydrochloric acid (15 ml), water (25 ml) and saturated aqueous sodium chloride solution ( 25 ml), 30 dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in methylene chloride (5 ml) and chromatographed on silica gel (Merck 9385) using methylene chloride as eluant. The product was crystallized in petroleum ether (boiling point 60-80 ° C) to give (-) - 4-cyano-3-trifluoro-methyl-N- (2-hydroxy-3-phenylthio-2-trifluoromethylpropionyl) ani-1 in,

DK 166385 B

28 mp 156-157 ° C, [α] D = 43.8 ° (c = 1% in methanol).

The procedure described in the previous section was repeated using the most polar isomer of the campanoyl ester and the resulting product was crystallized by a 5: 1 v / v mixture of toluene and petroleum ether (bp 60-80 ° C ). There was thus obtained (+) - 4-cyano-3-trifluoromethyl-N- (2-hydroxy-3-phenylthio-2-trifluoromethyl propionyl) -aniline, mp 159-160 ° C, [a] * 3 = + 45.5 ° (c = 1% in methanol).

EXAMPLE 8.

The procedure described in Example 7 was repeated using 4-cyano-3-trifluoromethyl-N- (3-p-fluorophenylthio-2-hydroxy-2-methylpropionyl) aniline as the compound to be resolved. There was thus obtained the (-) - isomer, m.p. 94-96 ° C, [a] g 4 = -3.06 ° (c = 1% in methanol), and the (+) - isomer, mp 95-97 ° C, [ a] p 4 = + 2.42 ° (c = 1% in methanol).

EXAMPLE 9.

25 n-butyl 1 in thium (4.7 ml of a 1.6 molar solution in hexane) was added over 2 minutes to a stirred solution of methylthiobenzene (0.82 ml) and 1,4-diazabicyclo [2 , 2.2] octane (0.78 g) in tetrahydrofuran (20 ml) which was kept at -2 ° C under an at-mosphere of argon. The mixture was allowed to warm to + 2 ° C, stirred at this temperature for 2 hours, cooled to -65 ° C, and a solution of N- (3,4-dichlorophenyl) pyruvamide (0.81 g) in tetrahydro uranium (5 ml) was added over 5 minutes. The mixture was stirred and allowed to warm to -30 ° C for 90 ml-3 Nuts, aqueous 2N hydrochloric acid (25 ml) was added, the tetrahydrofuran was removed by evaporation under reduced pressure and the residue was extracted three times with diethyl ether (40 ml

DK 166385 B

29 each time). The combined extracts were washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness, and the residue was purified by flash chromatography on a silica gel column (Merck 9385) using a 5: 2 v / v mixture of petroleum ether (boiling point). 60-80 ° C) and ethyl acetate as eluant. The product was crystallized from petroleum ether (b.p. 60-80 ° C) to give 3,4-dichloro-N- (2-hydroxy-2-methyl-3-phenylthiopropionyl) anal., M.p. 85-86 ° C.

The procedure described above was repeated using 4-bromo-2-methylsulfonylthiophene as the starting material in place of methylthiobenzene. There was thus obtained N- [3- (4-bromothien-2-ylsulfonyl) -2-hydroxy-2-methylpropionyl] -3,4-dichloroaniline, m.p. 170-171 ° C.

EXAMPLE 10.

The present example illustrates the measurement of antiandrogenic activity 20 of the compounds of the invention and, by comparison, with flutamide and with a 3-ethoxypropanamide akin to the 3-ethoxypropanamides of JP Patent No. 52-128329.

The method of measuring antiandrogen activity was as follows: 25

The compound being tested was administered orally on each of four consecutive days at a given dose to each animal in a group of 5 male rats weighing between 170 and 190 g. On the 5th day, the animals were sacrificed and the weights of the seminal vesicles was determined. The weights of the seminal vesicles of control rats of the same age and weight, which rats had not been treated with the compound, were also determined. The average weight of the seminal vesicles of the control rats was compared with the average weight of the seminal vesicles of the treated rats, and the percentage inhibition in the treated rats of the control weight was then calculated. A variety of test doses were selected and the dose at which inhibition in the treated rats was 50%

DK 166385B

(ED50) of the mean weight of the seminal vesicles of the control animals was determined. The ED 50 values for a representative range of test compounds of the invention and, by comparison, the known compound flutamide and a 3-ethoxypropanamide are shown in the following tables.

10 15 20 25 30 35 TABLE 7 31

DK Ί66385B

Ri_ OH

5 r2 - ^^^ \ - nhco-c-a1-x1-a2-r7 R -

Example 10 (mg / kg) (Compound No. in Table)> CF3 NO2 Me Me - 2 (ie flutamide) CF3 NO2 Me CH2 S Me 1.7 2 (3) CF3 CN Me CH2 SO Et 1.3 5 (4) CF3 NQ2 Me CH2 S phenyl 1.0 2 (1) CF3 NO2 Me CH2 SO phenyl 1.0 5 (1) CF3 NO2 Me CH2 SO2 phenyl 1.5 6 (1) 20 CF3 CN CF3 CH2 S phenyl 0.7 2 (35) CF3 CN CF3 CH2 SO phenyl 0.3 5 (3) CF3 CN Me CH2 S 4-fluorophenyl! 0.5 4 (23) CF3 NO2 Me CH2 SO2 4-fluorophenyl 0.4 6 (2) CF3 CN Me CH2 SO2 4-fluorophenyl 0.5 6 (8) CF3 NO2 Me CH2 S 4-chlorophenyl 1.6 4 (5) CF3 NO2 Me CH2 S thiazol-2-yl 0.6 4 (19) CF3 NO2 Me CH2 S pyrid-2-yl 0.9 4 (15) CF3 CN Me CH2 S benzothiazol-2-yl 1, 8 4 (32) CF 3 NO 2 Me CH 2 S 5-methyl-1,3,4-thiadiazol-2-yl 1,4 4 (21) all compounds are A 2 a direct bond.

TABLE 8 32

DK 166385 B

R * _ OH

R2 ~~ '{v ^ y nhc ° -c-a1-x1-a2-R7 10 _ R1 R2 R6 A1 X1 R7 ED5 Example (mg / kg) (Compound No. in Table 15) CF3 NO2 Me GH2 0 Et ( Ή 25 CF3 CN Me CH2 S Me 2.5 2 (10) CF3 CN CF3 CH2 S Me <2.5 2 (37) 20 Cl CN CF3 CH2 S Me <2.5 2 (47) CF3 CN CF3 CH2 S Et <2.5 2 (38)

Cl Cl CF3 CH2 S Et <2.5 2 (43) 25 CF3 CN CF3 CH2 S Prn <2.5 2 (39)

Cl Cl CF3 CH2 S Prn <2.5 2 (44)

Cl CN CF3 CH2 S Prn <2.5 2 (49) CF3 CN Me CH2 S Pr1 '<2.5 2 (9) 30 CF3 NO2 CF3 CH2 S Pr1 <2.5 2 (34) CF3 CN Me CH2 SO Et 1.3 5 (4) CF3 NO2 Me CH2 SO2 Et 1.4 6 (4) 35 CF3 CN Me CH2 SO2 Et 1.1 6 (9) CF3 CN CF3 CH2 SO2 Et <2.5 6 (11) 33

DK 166385 B

(i) The first compound is a 3-ethoxypropanamide akin to the 3-ethoxypropanamides of the aforementioned JP Patent No. 52-128329, the only difference being that the 3-ethoxypropanamide examined herein has 3-trifluoromethyl-1 4- Nitrosubstitution rather than 3,4-dichloro-substitution in the phenyl ring.

(ii) In all compounds, A2 is a direct bond.

10 15 20 25 30 35 TABLE 9 34

DK 166385B

5 R1 0B

E2 HHCO-C-41-X1-A2-R7 l6 10 „1 R2 R6 A ^ X * R? ed50 Example

R

(mg / kg) (Compound No. in Table)

Cf3 NO2 Me CH2 S 4-cyanophenyl 10 4 (7) CF3 NO 2 Me ch2 s 4-nitrophenyl 20 4 (8) cp3 NO2 Me CH2 S 4-methoxyphenyl 16 4 (9) 20 CF3 NO0 Me ch2 s 4-methylthiophenyl 5 4 (10) CF 3 CN Me CH 2 S 2-thienyl 4 4 (28) CF 3 NO 2 Me CH 2 S 6-chloropyrid-2-yl 9 4 (18) CF 3 CN Me CH 2 S 2-pyrimidinyl 9 4 (33) qP3 CN Me CH2 S 1-Methylimidazole-7 4 (31) 2-yl 30 CF3 CN Me CH2 S 4,5-dihydrothiazol-6 4 (30) 2-yl In all compounds, A2 is a direct bond.

From the above Table 7, it can be seen that the EDsg value for flutamide is 2 mg / kg, whereas the compounds of the invention have ED 50 values in the range of 0.3-1.8 mg / kg.

Claims (10)

5 Patent claims. 1. Acylanilide of the formula R 1 R 5 R 2 - (H 2 N 4 -Co-c-a 1 -x 1-a 2 -R 7 R 6 R 3 where R 1 is cyano, nitro, fluoro, chloro, bromo or iodo, or alkyl, alkoxy or perfluoroalkyl , each having up to 4 carbon atoms, where R 2 is cyano, nitro, fluoro, chloro, bromo or iodo, or perfluoroalkyl of up to 4 carbon atoms, wherein R 3 is hydrogen, R 4 is hydrogen, R 5 is hydroxy or acyloxy with up to 15 carbon atoms, 30 where R6 is alkyl or haloalkyl with up to 4 carbon atoms, where Al is alkylene with up to 6 carbon atoms, 35 where A2 is a direct bond or alkylene with up to 6 carbon atoms, DK 166385 B where X * is sulfur, sulfinyl (-SO-) or sulfonyl (-SO4 -) wherein R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl, each having up to 6 carbon atoms, or R7 is phenyl bearing one, two or two. or three substituents selected from hydrogen, halogen, nitro and cyano, and alkyl, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl, each with up to 4 carbon atoms, or R7 is a 5- or 6 -saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from oxygen, * 10 nitrogen and sulfur, which heterocyclic group may be a single ring or may be condensed to a benzo ring and which heterocyclic group is unsubstituted or carries one or two halogen substituents or all refrigerant substituents with up to 4 carbon atoms. 15 Acyl anilide according to claim 1, characterized in that R1 is cyano, nitro, trifluoromethyl, chloro, methyl or methoxy, R2 is cyano, nitro, trifluoromethyl or chloro, R3 and R4 are both hydrogen, R5 is hydroxy, R6 is methyl or trifluoromethyl, Al is methylene, ethylene or ethylidene, X1 is sulfur, sulfinyl or sulfonyl, A2 is a direct bond or methylene, and R7 is alkyl, alkenyl, hydroxyalkyl or cycloalkyl, each having up to 6 carbon atoms. or phenyl which is unsubstituted or which carries one fluoro, chloro, cyano, nitro, methoxy or methylthiosubstituent, or thienyl, imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl which is unsubstituted, or carrying one chloro, bromo or methyl substituent. Acyl anilide according to claim 1, characterized in that R 1 is trifluoromethyl, R 2 is cyano or nitro, R 3 and R 4 are both hydrogen, R 1 is hydroxy, R 6 is methyl, A * is methylene, X * is sulfur, sulfinyl or sulfonyl. , A 2 is a direct bond, 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. DK 166385 B The compound according to claim 1 3-chloro-4-cyano-N- (3-ethylthio-2-hydroxy-2-methylpropionyl) aniline, 3-chloro-4-cyano-N- (3-ethylsulfonyl-2-hydroxy) 2-methylpropionyl) aniline, 4-cyano-3-trifluoromethyl-N- (2-hydroxy-2-methyl-3-phenylsulfonylpropionyl) aniline, 4-cyano-3-trifluoromethyl N- (3-ethylsulfonyl-2-hydroxy-2-methyl propionyl) aniline, 4-nitro-3-trifluoromethyl-N- (2-hydroxy-3-phenylsulfonyl-2-methylpropionyl) aniline, 4-Nitro-3-tri-fluoromethyl - N- (3-ethylsulfonyl-2-hydroxy-2-methylpropionyl) aniline, 3-chloro-4-nitro-N- (2-hydroxy-3-phenylthio) 2-Roethyl propionyl) -aniline, 4-nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl-3- (thiazol-2-ylthio] propionyl] aniline, 4-nitro-3-trifluoromethyl-N - [3-Allyl-thio-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-tri-fluoromethyl-N- [2-hydr oxy-2-methyl-3- (5-methyl-1,3,4-thiadiazol-2-ylthio) propionyl] aniline, 4-nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl] 3- (4-methyl-thiazol-2-ylthio) propionyl] aniline, DK-166385B 4-nitro-3-trifluoromethyl-N- [2-hydroxy-2-methyl-3- (pyrid-2-ylsulfonyl) propionyl] aniline, 4-nitro-3-trifluoromethyl-N- (3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl) aniline, 4-cyano-3-trifluoromethyl-N- [2-hydroxy-2- methyl 3- (thiazol-2-ylthio) propionyl] aniline, 4-cyano-3-tri-fluoromethyl-N- [2-hydroxy-2-methyl-3- (pyrid-2-ylthio) propionyl] aniline, 4 -cyano-3-tri-fluoromethyl-N- (2-hydroxy-2-methyl-3-methylthio-propionyl) -anine, 4-cyano-3-tri-fluoromethyl-N- (3-pyluoro-phenyl-thi) o-2-hydroxyzine tyl propionyl) ani 1 i n. 5. The compound 4-cyano-3-trifluoromethyl-N- (3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl) ani 1 i n. Process for the preparation of an acyl anilide according to claim 1, characterized in, (a) reacting an amine of formula R1 R2 - NHR4 R3 wherein R1, R2, R3 and R4 have the meaning of claim 1 with an acid of the formula ho2c-cr5r6-a1-x1-a2-r7 UK 100,380 d wherein R5, R6, R7, X7, A1 and A2 are as defined in claim 1, or with a reactive derivative of this acid, or 5 (b) for the preparation of an acyl anilide wherein R 5 is hydroxy and χΐ is sulfur, reaction of an epoxide of the formula R 1 - R 2 - (N-R 4 -GO-Z1 Rd 15 wherein R 1, R 2, R 3 and R 4 have the above meanings, and wherein Z1 has the formula / O -CR6 THRU 20 where r6 has the above meaning and where RU is such that -CHR11- is -A * -f as indicated above, with a thiol of formula r7_a2-sh 25 where R7 and A2 has the above meanings, or (c) for the preparation of an acyl anilide in which 'R $ is hydroxy, reaction of a compound of formula 30 R 2 - {/ -NR4-CO-CO-R6 5 R3wherein R 1, R 2, R 3, R 4 and R 6 each have the above meanings, with an organometallic compound of formula 10 R1-A2-X1-A1-M wherein Al, A2, R1 and χΐ have the above meanings and M is a metal radical, wherein (i) an acyl anilide wherein R 5 is hydroxy may be prepared by hydrolysis of the corresponding acyl anilide wherein R 5 is acyloxy, or (ii) an acyl anilide wherein R 2 is acyloxy may be prepared by acylation of the corresponding acyl anilide, wherein R 5 is hydroxy, or (iii) an acyl anilide wherein χΐ is sulfinyl or sulfonyl, or wherein a substituent in the phenyl group R 1 is alkylsulfinyl or is alkylsulfonyl, perfluoroalkylsulfonyl or phenylsulfonyl may be prepared by oxidation of the corresponding acylanilide, wherein X * is sulfur or wherein a substituent in the phenyl group R1 is alkylthio or (iv) a racemic acyl anilide wherein R® is hydroxy can be separated into the optical isomers by forming an ester of the hydroxy group R5 with an optically active acid, separation of the resulting diastereoisomeric esters and then hydrolyzing each 35 ester separately to the alcohol. Pharmaceutical or veterinary agent, characterized in that it comprises an acyl anilide according to claim 1 together with a pharmaceutically useful diluent or carrier. An agent according to claim 7, characterized in that it is in a form suitable for oral dosing such as a tablet, capsule, aqueous or oily solution or suspension or emulsion, or in the form of a sterile solution or suspension suitable for use. 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. The agent of claim 7, further comprising one or more drugs selected from anti-estrogens, aromatase inhibitors, progestins, gonadotrophin secretion inhibitors, LH-RH analogs, cytotoxic agents, antibiotics and ant ii nf 1 ammatory funds. 20 25 30 35