FI62058C - FOERFARANDE FOER FRAMSTAELLNING AV SUBSTITUERAD ISOBUTYRANILIDINNEHAOLLANDE KOMPOSITION MED ANTIANDROGEN AKTIVITET - Google Patents

Description

ΓΒΐ f11x ^ WULUTUSjULKAISU / Τ nn C o ^ 5 | Γα (11) PUBLISHING WRITTEN 62 05 8 (45) Patentti myönnetty 10 II 1902 ^ v ^ (51) K ».ik? /Int.ci.3 C 07 C 103 / 375 SUO MI - Fl N LAN D (21) Pitenttlhekumu · - Paunnrtfcnlng 1693/71 (22) Hak «ml» p (lvi - AntSknlngttltg 16.06.71 ^^ (23) Alkpllvt — GIMchtcsdtg l6.06.71 (41) Tullut | ulklMktl - kllvlt effumllg 17.12.72 j »reklrt.rih.Mltu. NthUvikslp ™ ** kuulju.lutoun pvm.- ''

Patent and registration officeMn 'Amftkan taken out «di uti. * Krtft * o publicund au.u [. od (32) (33) (31) Pyydetty etuolkeut — Begird prtorltet (71) Essex Lääkkeet Oy, Kuunkehräk C, 02210 Espoo 21, Suomi-Finland (FI) (72) Rudolph 0. Neri, Passaic, NJ, John G Topliss, Essex, NJ, USA (US) (7) Leitzinger Oy (5U) Procedure for Preparation of Substituted Isobutyranilide Containing Compounded Antiandrogenic Activity - Menetelmä valmistaa

The present invention relates to a process for the preparation of pharmaceutical compositions comprising, inter alia, anti-androgenic activity containing a compound or its pharmaceutically acceptable salt of formula I

H O CH3 Y - N - C - CH ™

- AjT

where X is nitro and Y is chlorine, bromine or trifluoromethyl, or X is chlorine and Y is trifluoromethyl.

The substituted anilides of formula I according to the invention can be prepared as follows:

(a) reacting an aniline derivative having the general formula II H

Y - N Z

- AJ

Wherein X and Y are as defined above and 7, denotes hydrogen or isobutyryl divergent acyl, with isoic acid or its reactive derivatives, preferably halide or anhydride.

Reaction is preferably carried out by heating the reactants in the presence of an acid acceptor. The reactants are conveniently heated in a solvent at elevated temperatures up to about the reaction flow temperature of the reaction mixture. Suitable solvents include aromatic hydrocarbons, ethers and tertiary organic amines such as benzene, xylene, diethyl ether, pyridine and triethylamine. Particularly suitable acid acceptors include tertiary, organic amines and basic inorganic salts, such as triethylamine, pyridine and alkali metal salts of weak acids, such as sodium and potassium carbonates.

If desired, a tertiary organic amine, such as pyridine or triethylamine, may have the function of both solvent and acid acceptor.

It is also possible to use an excess of the aniline s 2 as an acid acceptor. The condensation reaction proceeds rapidly and at the end thereof the reaction mixture is worked up according to standard methods: for example the reaction mixture can be mixed with a dilute mineral acid and cooled. the desired product is then extracted from the water mixture with a water-immiscible solvent, such as diethyl ether, and, after appropriate rinsing, the product is isolated by evaporation of the solvent, after which it is further purified by conventional techniques, sludge on crystallization.

A further possibility is to prepare the carboxanilides of formula I by a suitable method, selected from the following known reactions for the preparation of amides:

Pyrolysis of a site derived from an amine of formula II and isobutyric acid, whereby the anion of the salt is used as an acylating agent.

Condensation of the substituted aniline of formula II with a trisubstituted acyloxyphosphonium halide, preferably triphenylacyl oxyphosphonium chloride or bromide. The acyloxyphosphonium halide can be prepared separately and then condensed with the aniline or also all reactants can be condensed together in one step, the acyloxyphosphonium halide being the intermediate. Examples of these reactions are the following: cci4 + 03p -> 03PCCI3 ci "-> 03pocor ci" 0

II

Y NHo Y yv NH - C - R

yy + 03ioc ° R ci_ -> yy 0 or Y Y. * νΝΗ "^" r

03P + BrCCl3 + RCOOH + T -> | | T

- + - + 03POCOR Br where X and Y have the meaning given and R is isopropyl.

Amide exchange reaction can be carried out, for example, by iterative heating of a large excess of isobutyric acid. The starting anilide may be selected to provide an acid which is removed from the reaction mixture and promotes formation of the desired anilide. A volatile acid (such as acetic or formic acid) can be distilled off from the reaction mixture; when the starting anilide is a urethane, the acid obtained is unstable, which is why it is decomposed and thus removed;

(b) a ketoxime of formula III

.N - OH

^ S

Y _ / CH III

xl where Y and X are as defined above are subject to conditions for a Beckmann rearrangement, (c) reacting a ketone having the formula iv, with hydrazoic acid in the presence of a strong acid yeast

(d) elimination of an NH 2 group by diazotization and reduction of a substituted anilide having the formula V

f H CH - Y - - N - C - CH 2 x ^ Ljr XCH 3 (v) ^ Sjh 2 where X and Y are as defined above.

The reduction can be carried out, for example, with alcohol, hypophosphoric acid or formaldehyde, the latter under alkaline conditions.

(e) for the preparation of a compound of formula I wherein X is nitro and Y is as defined above, a substituted anilide having formula VI is reacted

H O CH, 11 X 1 X, where Y is as defined above, with a mixture of sulfuric and nitric acid.

(f) to prepare a compound of formula I wherein Y is trifluoromethyl and X is chlorine, a substituted anilide having formula VII is diazotized

H / ch3

* YyN.c.cH

H 2 N-CH 3 62058 wherein Y is as defined above, and the thus obtained diazo compound is reacted with a chlorinating agent, preferably in the presence of a catalytic converter;

(g) to prepare a compound of formula I wherein X is chlorine and Y is trifluoromethyl, a nitrobenzene derivative having the formula VIII is reacted

Y N ° 2

"AJ

wherein X and Y are as defined above, with isobutyric acid and / or isobutyric anhydride in the presence of a reducing metal, e.g. zinc.

(h) for the preparation of a compound of formula I wherein X is nitro

and Y is as defined above, a substituted anilide having the formula IX HO CH is reacted

In N / 3

- c - CH

oXJ

where Y is as defined above and Q is -NH 2 r -NHOH or -NO, with oxidizing agent. The oxidation is preferably carried out with the aid of a peroxide, such as hydrogen peroxide or persulfuric acid, although other oxidizing agents, such as permanganates and nitric acid, can be used when Q is -NO.

(i) for the preparation of a compound of formula I wherein X is chlorine and Y is trifluoromethyl, an anilide having formula X

? S 2 CH 2

C

"XT

where X and Y are as defined above, are catalytically hydrogenated, e.g. with palladium.

(j) an isocyanate having the formula XI

ϊ = c = o

XX

r Ο Γ: tr o

g o ^ O O O

where X and Y are as defined above, they are reacted with isopropyl-magnesium halide. This process is not recordered for those compounds where Y or X are nitro.

(k) to prepare a compound of formula I wherein Y is trifluoromethyl and X is chlorine, an N-chloro anilide derivative having the formula XII isomerized

O CH., CF

(l) for the preparation of a compound of formula I wherein X is nitro and Y is as defined above, a substituted benzene having formula XIII is reacted

γ -Hai ° 2N- (XIII) wherein Y is as defined above and Hai refers to a halogen atom, with isobutyramide in the presence of a strong base such as sodium hydride or sodium amide, and an inert solvent such as dimethylformamide or dimethyl sulfoxide. Y is preferably trifluoromethyl and the halogen atom is preferably chlorine, bromine or fluorine.

The anilides of formula I are usually colorless and crystalline, exhibit moderately high melting points and are essentially insoluble in water but soluble in common organic solvents such as aromatic hydrocarbons, halogenated hydrocarbons and the like.

The compounds of formula I exhibit an anti-androgenic effect upon administration within a dosage range of about 0.1 - 50 mg per body weight per day. They are thus useful in treating and relieving androgen-induced and androgen-dependent conditions, such as prostatic hypertrophy, Rtein-Leventhal syndrome, idiopathic hirsutism, and acne.

It is known that a number of steroids and non-steroids have anti-androgenic action, e.g. through:

Byrnes, W.W., R.O. Stafford, and H.J. Olson, Proc. Roc.

Exp. Biol. With. 82: 243, 1953?

Lerner, L.L., A. Bianchi, and A. Borman, Proc. Soc. Exp.

Biol. With. 103: 173, 1960?

Junkman, K., and F. Neumann, Acta Endocrinol. Suppl. 90? 139, 1964? Neri, R.0., M. Monahan, J. Meyer, B. Afonso, and I.I.A.

Tabachnick, Eur. J. Pharmacol. 1: 438, 1967?

Rocky, S., and R. Neri, Fed. Proc. 27: 624, 1968 (Abstract)?

Dorfman, R.I., and W.R. Nes, Endocrinology 67: 282, 1960?

Dorfman, R.I., Endocrinology 64: 465, 1959?

Hertz, R., and W.W. Tullner, J. Natl. Cancer Inst. 8: 121, 1947? Cantarow, A., and A.J. Zagerman, Proc. Soc. Exp.

Biol. With. 115: 1052, 1964?

Dorfman, R.I., and D. Stevens, Endocrinology 67: 304, 1960?

Randall, L.O., and J.J. Selitto, Endocrinology 62: 694, 1958?

Neri, R.O., Excerpta Medica Third Int. Cong, on Horm Steroids 210: 69, 1970?

Boris, A., L. Demartino, and T: Trmal, Endocrinology 88: 1086, 1971.

In general, however, these compounds exhibit other hormonal effects that contradict their use to humans (see, in particular, Neri, R.O., Excerpta Medica Third Int. Cong. On Horm. Steroids 210: 69, item 415, 1970). As examples of known antiandrogens, diprotrone acetate may be mentioned. This is one of the most effective known anti-androgens, but nevertheless exhibits undesirable side effects.

In species that are haunted by prostatic hypertrophy, the frequency of the hypertrophic state appears to increase with increasing age and thus poses a serious problem (even in older dogs). In general, hormone therapy, for example administration of estrogenic substances, has not been found to be a particularly desirable treatment, not only because of adverse side effects due to properties built into the oestrogens, but also because such agents have not been shown. themselves to be fully effective in providing meaningful relief and cure. Neither is surgical ablation, although effective, particularly desirable, since one can not only expect a mortality of 2-3%, but also that many individuals may experience such non-fatal complications as epididymitis, pneumonia, pyelone-free, secondary reaction, etc. The chemotherapeutic treatment of prostatic hypertrophy with the absence of side effects caused by the anti-androgenic agent has been a long sought after drug.

By standard laboratory tests, it has been established that the compounds of the invention provide a marked relief of prostatic hyperplasia, thereby reducing or eliminating the undesirable effects that arise from the administration of estrogens or complications in surgical procedures. Depending on the severity of the condition, a satisfactory therapeutic response is usually achieved in such mammals as adults having a body weight of about 70 kg, when 1-4 dosage units of the pharmaceutical compositions hereinafter described are administered to the mammal. A suitable dose for a 70 kg mammal is within a range of about 25 - 100 mg of the most suitable active components per day.

To determine the antiandrogenic activity of the compounds, the following tests were performed with castrated rats:

Male dishes (Charles River DC strain 21-28 days old. Weight 55-60 g) were castrated bilaterally. The following day, treatment was started. The dishes were treated with the test compound in an amount as shown in the following Table I, the test compound being given orally as a suspension in a carboxymethyl cellulose (CMC) aqueous solution. At the same time, the remedies were given 10 µg of testosterone propionate (androgenic stimulant) in sesame oil subcutaneously. This treatment lasted for 7 days.

Twenty-four hours later, the animals were killed and their corn bladder and ventral prostate removed and weighed.

9 62053

Two other groups of laboratory animals were given one testosterone propinate and the other only sesame oil and CMC.

In this test method, the inhibition in the weight gain of the seminal bladder and ventral prostate as measured by the compound's antiandrogenic activity was used as the inhibition. In the following table, the activity has been evaluated with 0-3 for 0 = none, 1 = weak, 2 = moderate and 3 = vigorous activity. The value 3 corresponds to a percentage inhibition of the weight gain of more than 70%, the value 2 corresponds to 45 - 70%, the value 1 corresponds to 20 - 45% and the value 0 corresponds to 20% inhibition.

The comparative compound 4-trifluoromethylisobutyranilide indicated in the table is described in DE-OS 1921841.

Table Cereal bladder Activiventral Activi-X Y R daily dose of prostate _ (mg / kg) _ (mg / kg) _

Cl CF3 -CH (CH3) 2 10 3 10 2 5 2 5 1 2.5 1 2.5 0 NO2 CF3 -CH (CH3) 2 1-5 2 11 10-25 3 5-25 3 NO2 Cl -CH ( CH3) 2 5-15 2 5-15 2 Comparison CF3 H -CH (CH3) 2 15 0 15 0 50 0 50 0

The values shown in the table show that the compositions prepared according to the invention are considerably more effective than the known compound.

Accordingly, the invention provides a method for producing an anti-androgenic effect in an animal, administering a therapeutically effective quantity of a compound of formula I.

In the compositions it is often convenient that: (I) the composition is in the form of a dosage unit, or (II) the composition is in the form of an animal base feed or feed supplement, or the carrier is at least one component selected from ethanol, benzyl alcohol. , glycerol, preservatives, starch, lactose, magnesium stearate and dyes, aromatizers and sweeteners.

Where the carrier in the pharmaceutical compositions comprises a pharmaceutically acceptable organic solvent and / or water, it is usually preferred that the carrier is a sterile, pyrogen-free, injectable liquid or that at least one component is present, selected from benzyl alcohol, glycerol, preservative, buffering agents, thickening agents, suspending agents, stabilizers, wetting agents, dyes, sweeteners and aromatizers.

Certain anilides are known to exhibit undesirable side effects when used as chemotherapeutic agents: for example, at certain doses, certain anilides cause methemoglobin formation and sulfhemoglobinemia? appropriate laboratory tests are readily available for determining the dosage at which these undesirable side effects occur (Goodman and Gilman, "The Pharmacological Basis of Therapeutics", p. 311-316, 2nd edition, 1955, McMillan Company). It has been discovered that the undesirable side effects of the compounds of formula I generally do not occur within the range of effective doses in which the compounds exhibit their favorable anti-androgenic effects, and thus these compounds are highly useful for the purposes described herein. Laboratory standard tests can be used to determine the dosing interval within which the desirable side effects begin to occur.

In general, the undesirable side effects, if caused by the more suitable compounds of the invention, appear at doses well above 50 mg / kg body weight. However, there is a satisfactory difference between the therapeutic dosage and the dosage at which toxic symptoms occur, so the compounds of the invention thus exhibit a suitable therapeutic index.

The substituted anilides of formula I provide an anti-androgenic effect within a range of a daily dosage of 0.1 - 50 mg / kg, depending on the size of the animal and the particular compound being administered.

The substituted anilides of formula I may be administered by oral, parenteral or rectal route. Usually, they may be administered in the form of pharmaceutical compositions containing the active component together with a pharmaceutical carrier or excipient. The compositions for human administration preferably consist of dosage units, such as tablets, capsules, drugs, suppositories or injection solutions or suspensions in ampoules. However, they can also be prepared in the form of preparations that are measured immediately before use, such as suspensions, syrups, tinctures or mixtures, which have the advantage that they can be flavored with a wide variety of naturally occurring or synthetic flavorings.

Particularly suitable solid carriers, especially intended for use in solid dosage units for oral administration, include, for example, binders such as starch, lactose and other sugars, gelatin, plant adhesives and polyethylene glycols, and lubricants, such as talc and magnesium stearate. Particularly suitable carriers for use in liquid compositions for oral administration include water and / or an orally acceptable oil together with at least one component selected from ethanol, benzyl alcohol, glycerol, preservatives, such as the methyl and ethyl esters of p-hydroxybenzoic acid, and buffer agents. , thickeners, suspending agents, stabilizers, wetting agents, emulsifiers, dyes and flavorings. Particularly suitable carriers for use in liquid compositions for injection include sterile, pyrogen-free water, optionally together with at least one additional component, selected from buffer agents, osmotic pressure control agents, suspending agents, preservatives, etc.

It is usually particularly convenient to administer the compounds of formula I orally, although parenteral administration is often very satisfactory.

Compositions for administration to food-producing animals normally contain the active component in combination with an animal feed base or a feed supplement such as carrier. For some end-mAl, dosage units for oral or parenteral administration may be more suitable, especially for the treatment of pets, such as dogs and cats.

Dosage units normally contain from 1 to 100 mg of active component, preferably 5 to 25 mg.

The invention Ash is further illustrated by the following examples, where the temperatures indicated are degrees Celsius.

Example 1 4-Nitro-3-trifluoromethyl-isobutyranilide

A stirred, cooled solution of 100 g of 4-nitro-3-trifluoromethylaniline in 400 ml of pyridine is added dropwise with 54 g of isobutyryl chloride and then the reaction mixture is heated 1.5 hours in an Angbad. The obtained mixture is cooled and poured into ice water, the crude anilide is filtered off and washed with water and the title product is recrystallized from benzene to give an analytically pure material, mp 111.5 - 112.5 °.

Example 2 4-Chloro-3-trifluoromethyl-isobutyranilide

A stirred, cooled solution of 15.0 g of 4-chloro-3-trifluoromethylaniline in 75 ml of dry pyridine is added with 6.8 g of isobutyryl chloride and the resulting mixture is heated for two hours at 70 ° C. The reaction mixture is allowed to cool to room temperature and then poured into ice water, after which the precipitate formed is filtered off, dried and recrystallized from 1: 1 petroleum ether / methylene chloride to give 4-chloro-3-trifluoromethyl-isobutyranilide, sp. 103 - 104 ° C.

4-Nitro-3-trifluoromethyl-isobutyranilide 13

EXAMPLE 3 20.6 g (0.10 mol) of 4-nitro-3-trifluoromethylaniline are mixed with R, 8 g of isobutyric acid and the mixture is heated to give 4-nitro-3-trifluoromethylanilinium isobutyrate. The mixture is continued to heat for about 27 hours at 175 ° C to transfer the intermediate to the title product, which is crystallized from benzene sp. 111.5 - 112.5 ° C.

Example 4 4-Chloro-3-trifluoromethylisobutyranilide 9 g of 4-chloro-3-trifluoromethylisobutyrophenone oxime are heated for ten minutes in 300 g of polyphosphoric acid at 130-140 ° C. The mixture is poured into the ice water to recover the title product, sp. 103 - 104 ° C.

Example 5 3- Chloro-4-nitroisobutyranilide

A mixture of 27 g of 3-chloro-4-nitroisobutyrophenone, 150 ml of benzene and 30 ml of concentrated sulfuric acid is stirred at 40 - 50 ° C and slowly a 5% solution of hydrazoic acid in benzene is added. When the reaction ceases, the sulfuric acid layer is poured into ice water and neutralized with ammonia to give the title product, which can be recrystallized from toluene, sp. 144 - 146 ° C.

Example 6 4- Nitro-3-trifluoromethylisobutyranilide

Method A. A mixture of 13.1 g (0.050 mole) of triphenylphosphine, 50 ml of carbon tetrachloride and 150 ml of tetrahydrofuran reflux was heated for 30 minutes. The mixture was cooled to 5 ° C, added with 4.4 g (0.050 mol) of isobutyric acid and stored for 10 minutes at 5 ° C. 10.3 g of 4-nitro-3-trifluoromethylaniline and 6.7 g (0.052 mol) of diisopropylethylamine are added and refluxed for two hours.

The mixture is cooled to room temperature, the diisopropylethylamine hydrochloride is filtered off, the solvent is removed, washed thoroughly with benzene to eliminate the triphenylphosphine oxide and the title product recrystallized from benzene, m.p. 111.5 - 112.5 ° C.

Method B. A mixture of 13.1 g (0.050 mole) of triphenylphosphine, 20.0 g of bromochloromethane, 4.4 g (0.050 mole) of isobutyric acid, 10.3 g (0.050 mole) of 4-nitro-3-trifluoromethylaniline and 6 7 q (0.052 mole) of diisopropylamine in 150 ml of tetrahydrofuran was refluxed for three hours. The title product is reprocessed in the same way as in Method A.

Example 7 4-Chloro-3-trifluoromethylisobutyranilide 22 g of zinc dust is added in small portions to a stirred solution of 33 g of 2-chloro-5-nitrobenzotrifluoride in 200 ml of isobutyric acid and 60 ml of isobutyric anhydride at 0 ° C. The reaction mixture is stirred for one hour at 0 ° C and three hours at room temperature, then heated to 70 ° C for a period of 15-30 minutes. The suspension is filtered, the majority of the acid and anhydride are removed in vacuo, the ether is dissolved in ether, washed with sodium hydroxide and dried over magnesium sulfate, the solvent removed and the title product recovered, m.p. 103 - 104 ° C.

Example · 4 4-Nitro-3-trifluoromethyl isobutyranilide 0.2 mole of 90% hydrogen peroxide is added to 40 ml of trifluoroacetic acid. This solution is added with 0.05 mole of 4-amino-3-trifluoromethylisobutyranilide in one portion. The temperature of the reaction mixture is maintained for one hour at about 50 ° C and poured into ice water to give the title product, sp. 111.5 - 112.5 ° C.

4-Chloro-3-trifluoromethylisobutyranilide 6 2 0b o 15

Example 9

At 95 ° C and 28 kp / cm 2, 33 g of 4-chloro-1-methyl-3-trifluoromethyl-acrylanilide in 100 ml of ethanol, containing 0.01 morpholine and 3.3 g of 5% platinum / carbon catalyst, are hydrogenated. . After uptake of 0.1 mole of hydrogen, the mixture is filtered, the solvent is removed and the title product, sp. 103 - 104 ° C.

Example 10 4-Chloro-3-trifluoromethyl isobutyranilide In a closed pressure vessel, a mixture of 30 g of 4-chloro-3-trifluoromethylacetanilide and 880 g of isobutyric acid is heated for 8 hours at 250 ° C. The majority of the acids are removed by distillation, the ether is dissolved in ether and the solution is washed with sodium hydroxide solution and dried over magnesium sulfate. The mixture is filtered and the solvent removed to give the title product, sp. 103 - 104 ° C.

Example 11 4- Chloro-3-trifluoromethyl isobutyranilide 0.08 mol of isopropylmagnesium bromide in 200 ml of ether is added with 20 g of 4-chloro-3-trifluoromethylphenyl isocyanate in 50 ml of ether with stirring. After completion of the addition, the mixture is stirred for one hour at 5 ° C, after which it is allowed to rise to ice temperature and poured into ice water, the ether solution is dried over magnesium sulfate and filtered and the solvent removed to give the title product, m.p. 103 - 104 ° c.

4-chloro-3-trifluormetylisobutyranilid

Example 12 16 6 2 C 5 8

A mixture of 14.7 g (0.05 mole) of N-chloro-3-trifluoromethylisobutyranilide in 55 g of 37% hydrochloric acid in acetic acid was heated for 30 minutes in Angbad. The mixture is poured into 250 ml of ice water to give the title product, sp. 103 - 104 ° C.

Example 13 4-Nitro-3-trifluoromethylisobutyranilide

A stirred mixture of 9.6 g (0.20 mol) of sodium hydride (50% in mineral oil) in 150 ml of dry dimethyl sulfoxide in a nitrogen atmosphere is added with 0.20 mol of isobutyramide. When hydrogen is extinct, 0.10 mol of 1-chloro-3-trifluoromethyl-4-nitrobenzene is added dropwise with stirring. Stirring is carried out for 24 hours, after which the mixture is poured into 1 liter of potassium water, extracted with ether, dried over magnesium sulfate and filtered, after which the solvent is removed. The title product is chromatographically isolated on silica gel and recrystallized from carbon tetrachloride, sp. 111.5 - 112.5 ° C.

Example 14 3-Chloro-4-nitroisobutyranilide

A diazotizing solution is prepared by the slow addition of 37.3 g of sodium nitrite to an ice-cold mixture of 1 liter of concentrated sulfuric acid and 0.5 liter of water. The solution is added at -5 ° C with 238 g of potassium 50% hypophosphoric acid. The stirred mixture is added to a solution of 60.4 g of 5-amino-3-chloro-4-nitroisobutyranilide in 1.85 liters of acetic acid, maintained at a temperature of between -10 and -15 ° C. After completion of the addition, the mixture is stirred for 2 hours, after which the temperature is allowed to rise to 5 ° C and maintained for 36 hours at this temperature. The mixture is poured into ice water and the title product is obtained, sp. 144 - 146 ° C.

Example 15 3- Bromo-4-nitro-isobutyranilide 4.9 g of N- (isopropylcarbonyl) -3-bromaniline are dissolved in about 40 ml of sulfuric acid and cooled to about 5 ° C. About 2.1 g of 90% nitric acid, dissolved in about 5.0 ml of concentrated sulfuric acid, are added dropwise. The reaction is allowed to proceed for 2 hours, after which the mixture is poured into 500 ml of ice water with stirring. The product is recovered by filtration, washed with water until it is free of excess acid, to give the title product, sp. 144 - 146 ° C.

Example 16 4- Chloro-3-trifluoromethylisobutyranilide

A solution of 23.0 g of N- (isopropylcarbonyl) -4-amino-3-trifluoromethyl-aniline in 150 ml of glacial acetic acid and 100 ml of water, while maintaining the mixture at a temperature of 10-20 ° C, is slowly added with 17 ml of concentrated sulfuric acid, cool to about 0 ° C and slowly add 8.5 g of sodium nitrite in 15 ml of water, while maintaining the reaction mixture for 30 minutes at about 0 ° C. The diazonium sulfate solution formed for 10 minutes is added to a hot, stirred solution of 7 g of copper (I) chloride in 150 ml of concentrated hydrochloric acid, diluted with 40 ml of water. The mixture is maintained for 10 minutes at 80 - 90 ° C, then cooled. Ice, water and an excess of ammonia are added and the reaction product is extracted with methylene chloride. The organic layer is dried and concentrated in vacuo and the residue is recrystallized from carbon tetrachloride to give the title product, sp. 103 - 104 ° C.

Representative embodiments of compositions containing compounds of the invention are taken into account that instead of the particular active ingredient specified, an equivalent weight of another substituted anilide of formula I may be used:

Example A. Tablet Compositions.

Formula A (5 mg) mg per tablet 4-Nitro-3-trifluoromethylisobutyranilide 5.0

Starch, food quality 5.0

Lactose, U.S.P. (sputum dried) 89.5

Magnesium stearate, U.S.P. 0.5 100.0

Formula B (25 mg) 4-Nitro-3-trifluoromethylisobutyranilide 25.0

Starch, food quality 10.0

Lactose, U.S.P. (sputum dried) 164.0

Magnesium stearate, U.S.P. 1.0 200.0 4-Nitro-3-trifluoromethylisobutyranilide is passed through a high-speed grinder provided with screen No. 100-150. The ground 4-nitro-3-trifluoromethylisobutyranilide is mixed with the starch in a suitable mixing vessel. An equal amount of weight of the sputum-dried lactose is added to the mixture and it is mixed until uniform. The resulting mixture is mixed with the remaining amount of sputum-dried lactose and mixed until a uniform mixture is obtained. The magnesium stearate is mixed with a portion of this mixture and the product is mixed with the remaining amount of mixture. Continue until it is uniform. The material is pressed into tablets of the intended weight (100.0 mg for a 5 mg tablet and 200.0 mg for a 25 mg tablet).

Example B. Capsule Compositions.

Formula mg per capsule! 4-Nitro-3-trifluoromethylisobutyranilide 5.0

Lactose, U.S.P. (sputum dried) 292.0

Magnesium stearate, U.S.P. 3.0 300.0 19 62053

The components are mixed until a uniform mixture is obtained. This is filled into packed gelatin capsules.

Example C. Parenteral suspension.

Formula A (5 mg) mg per ml of 4-nitro-3-trifluoromethylisobutyranilide 5.00

Methyl cellulose, 15 cps, U.S.P. 0.05

Sodium citrate, dihydrate 6.00

Benzyl alcohol, NF 9.00

Methyl p-hydroxybenzoate, U.S.P. 1.80

Propyl p-hydroxybenzoate, U.S.P. 0.20

Injection water, U.S.P. to 1.00

Formula B (25 mg) 4-nitro-3-trifluoromethylisobutyranilide 25.00

Methyl cellulose, 15 cps, U.S.P. 0.25

Sodium citrate, dihydrate 30.00

Benzyl alcohol, NF 9.00

Methyl p-hydroxybenzoate, U.S.P. 1.80

Propyl p-hydroxybenzoate, U.S.P. 0.20

Injection water, U.S.P. to 1.00 45 ml of injection water is charged in a suitable stainless steel vessel and heated to 85 - 90 ° C. With vigorous stirring, methyl cellulose was slowly sprinkled in warm water (500 g for Formula A or 2500 g for Formula B). Stir until the methyl cellulose is thoroughly dispersed and wet. 30 liters of potassium (0.5 ° C) injection water are added. The whole mixture is cooled to 80 ° C. The sodium citrate (600 g for Formula A or 3000 g for Formula B) is dissolved in a sufficient amount of injection water to form 5 liters of solution. Slowly with stirring, this solution is added to the cooled methyl cellulose solution. The p-Hydroxybenzoates (180 g of the methyl ester and 20 g of the propyl ester) are dissolved in 900 g of benzyl alcohol heated to 30 ° C. This solution is immersed in the cooled methyl cellulose solution. The poured solution is immersed in 90 liters of injection water and stirred until the solution is uniform. In a sterile 20 r \ r :, 6 s- v h ...

environment, the kit is passed through a sterile filter.

Aseptically, about 3.5 liters of the sterile methyl cellulose solution is transferred to a separate container, retaining the remaining amount of the batch in a sterile stainless steel mixing tank. 4-Nitro-3-trifluoromethylisobutyranilide is slurried in a steroid colloid mill with approximately 2 liters of the separated methyl cellulose solution and the slurry is added to the solution in the mixing tank. The slurry tank and the mill are rinsed with the remaining 1.5 liters of methyl cellulose solution remaining and the rinses are immersed in the mixing tank. The slurry tank and the mill are rinsed with 2 liters of injection water and these rinse water is drained into the mixing tank. The volume in the mixing tank is adjusted to £ 100 liters with injection water and stirred until the mixture is uniform. The kit provides 100 liters of sterile suspension having the proportions specified in Formula A or B.

Claims (3)

Process for the preparation of novel pharmaceutical compositions, including anti-androgenic activity which contains a compound of formula I or its pharmaceutically acceptable site HO CH - (I) j Y S? N— N - C - CH. , where X is nitro and Y is chloro, bromo or trifluoromethyl, or X is chloro and Y is trifluoromethyl, characterized in that a compound of formula I is prepared according to any of the following processes a) -l): (a) an aniline derivative having the general formula II IXX1 wherein X and Y are as defined above and z represents hydrogen or from isobutyryl deviating acyl # with isobutyric acid or its reactive derivatives, preferably halide or anhydride, (b) a ketoxim of formula III N - OH Y - / ch 3 (iii) x-UJ CH-ch 3 where Y and X are as defined above are subject to conditions for a Beckmann rearrangement, (c) reacting a ketone having the formula iv o ch 3 Y - C - (IV) X NcH 3 6 where Y and X are as defined above with hydrazoic acid in the presence of a strong acid, (d) elimination of the NH 2 group by diazotization and reduction of a substituted anilide having the formula VHO CH, Y - N - C - CH (V) X -% x CH 3 nh 2 where X and Y are as defined above e, (e) for the preparation of a compound of formula I wherein X is nitro and Y is as defined above, a substituted anilide having the formula VI HO CHI'I '/ 3 wherein Y is as defined above is reacted with a mixture of sulfuric and nitric acid} (f) to produce a compound of formula I wherein Y is trifluoromethyl and X is chlorine, a substituted anilide having the formula VII HO CH IH / 3 Y - n - C is diazotized. - Y is CH3 wherein Y is as defined above, and the thus obtained diazo compound is reacted with a chlorinating agent, preferably in the presence of a catalyst, (g) to produce a compound of formula I where X is chlorine and Y is trifluoromethyl, a nitrobenzene derivative having the formula VIII Y ^ NO- (VIII) XX 23 6205 (h) for the preparation of a compound of formula I wherein X is nitro and Y is as defined above a meaning, a substituted anilide is reacted, soin has the formula IX HO CH-1H / 3 ycc \ XX wherein Y is as defined above and Q is -NH 2, -NHOH or -NO, with oxidizing agent, (i) for the preparation of a compound of formula I wherein X is chlorine and Y is trifluoromethyl, an anilide having the formula X HO CH 2 IH 2 VV / N - C - C xXT where X and Y are as defined above are catalytically hydrogenated an isocyanate having the formula XI Ϊ = C = O (XI) wherein X and Y are as defined above is reacted with isopropyl-magnesium halide, (k) to produce a compound of formula I wherein Y is trifluoromethyl and X is chlorine, an N-chloro anilide derivative having the formula XII is 0 CH-II / 3 - C - CH 2 Γ JJ Cl CH 3 (XII) by heating or photolysis, 6205ο 24 (1) to prepare a compound of the formula Where X is nitro and Y is as defined above, a substituted benzene having the formula XIII Y (XIII) ° 2N 'V where Y is as defined above and Hai is a halogen atom, with isobutyramide in the presence of a strong base; and then a compound of formula I prepared according to any of the above-described methods is mixed with a pharmaceutical carrier or excipient. 2. A process according to claim 1, characterized in that the method alternative a) or e) is used and the so obtained compound of formula I is mixed with a pharmaceutical carrier or excipient. 3. A process according to claim 1 or 2, characterized in that the compound of formula I is 4-nitro-3-trifluoromethylisobutyranilide.