KR100211480B1 - 3-cycloalkylpropanamides, their tautomers and salts, process for their preparation, their use as medicaments and composition thereof - Google Patents

Abstract

The present invention relates to compounds of the general formula (I) and tautomers thereof, salts with bases thereof, methods for their preparation, novel intermediates and their use as pharmaceuticals, in particular anti-inflammatory agents, and pharmaceutical compositions containing them.

In the above formula,

-R ₁ is cycloalkyl,

-R ₂ is hydrogen or alkyl,

-R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are halogen, alkyl, alkoxy, alkylthio,

-(CH ₂ ) m-CF ₃ , -O- (CH ₂ ) m-CF ₃ , -S- (CH ₂ ) m-CF ₃ , -CF ₂ -Hal, -OCF ₂ -Hal, Or -O (CF ₂ ) n-CF-Hal ₃ -CF ₃ , nitro, azido, nitrile, -CO-R 'wherein m is 0-3, n is 1-3, Hal, Hal ₁ , Hal ₂ and Hal ₃ are halogen and R 'is OH, alkyl, alkoxy), or R ₃ and R ₄ together form -O-CH ₂ -O-.

Description

3-cycloalkyl-propanamide, tautomers thereof and salts thereof, methods for their preparation, their use as medicaments and compositions containing them

The present invention relates to novel 3-cycloalkyl-propanamides, tautomers thereof and salts thereof and processes for their preparation, the use of these novel compounds as medicaments and compositions containing them.

The present invention relates to novel 3-cycloalkyl-propanamides of the general formula (I), tautomers thereof and addition salts with inorganic or organic bases thereof.

In the above formula,

-R ₁ represents a cycloalkyl group having 3 to 6 carbon atoms,

-R ₂ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms,

—R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different and are a hydrogen atom, a halogen atom, a straight or branched chain alkyl radical having 1 to 6 carbon atoms, a straight or branched chain alkoxy having 1 to 6 carbon atoms A radical, an alkylthio radical having 1 to 6 carbon atoms,-(CH ₂ ) m-CF ₃ , -O- (CH ₂ ) m-CF ₃ , -S- (CH ₂ ) m-CF ₃ radicals, where m is An integer from 0 to 3), -CF ₂ -Hal, -OCF ₂ -Hal, Or -O (CF ₂ ) n-CF-Hal ₃ -CF ₃ radicals where n is an integer from 1 to 3, the same or different Hal ₁ and Hal ₂ , Hal and Hal ₃ are halogen atoms, Or R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different and are a nitro group, an azido group, a nitrile group, a -CO-R 'group where R' is hydroxy and 1 to 3 carbon atoms R ₄ and R ₅ together form an —O—CH ₂ —O— group.

In general formula (I),

A cycloalkyl group having 3 to 6 carbon atoms means a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical,

Alkyl radicals of 1 to 3 carbon atoms means methyl, ethyl, propyl, isopropyl radicals,

An alkyl radical having 1 to 6 carbon atoms preferably means methyl, ethyl, propyl, isopropyl, straight or branched butyl, straight or branched pentyl, straight or branched hexyl radicals,

-Alkoxy radicals having 1 to 6 carbon atoms means, for example, methoxy, ethoxy, propoxy, isopropoxy, straight or branched butoxy, straight or branched pentyloxy, straight or branched hexyloxy radicals. and,

An alkylthio radical having 1 to 6 carbon atoms means, for example, methylthio, ethylthio, propylthio, isopropylthio, straight or branched butylthio, straight or branched pentylthio, straight or branched hexylthio radicals; and,

Halogen atoms preferably mean fluorine, chlorine, bromine or iodine atoms.

Addition salts with inorganic or organic bases may be salts formed with inorganic bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium salts. Examples of the organic base include methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N'-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexyl Amine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

Among the compounds of the present invention, R ₃ , R ₄ , R ₅ , R ₆ and R ₇ of the general formula (I) are the same or different, hydrogen atom, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, Terbutyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, pentafluoroethyl, bromodifluoromethoxy, acetyl, hydroxycarbonyl, methoxycarbonyl, nitro, Azido, a nitrile radical, or R ₄ or R ₅ together form a —O—CH ₂ —O— group, R ₂ represents a hydrogen atom or a methyl radical, and R ₁ represents the general formula (I) as defined above Particular preference is given to derivatives of and addition salts with inorganic or organic bases thereof.

Among them, R ₁ of the general formula (I) is a cyclopropyl group, R ₂ is a hydrogen atom or a methyl radical, R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different, hydrogen, Particular preference is given to derivatives of formula (I) which are fluorine, chlorine or iodine atoms, methyl, trifluoromethyl or nitro radicals and addition salts with inorganic or organic bases thereof.

Particularly preferred derivatives of formula (I) are

-1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (4-chloro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (3-methyl-4-trifluoromethylphenylcarbamoyl) -2-cyclobutyl-2-oxopropionitrile,

-1- (4-cyano-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile and addition salts with inorganic or organic bases thereof.

In addition, the present invention reacts a compound of the general formula (II) with an acid of the general formula (III) or a functional derivative of this acid to obtain a compound of the general formula (IV), followed by any optional catalyst such as imidazole. After reacting with sodium hydride in the presence, it is reacted with a compound of the general formula (V) to obtain a corresponding compound of the general formula (I), which is isolated and chlorinated if necessary, A method for preparing 3-cycloalkyl-propanamide and salts thereof.

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined above and Hal represents a halogen atom)

Features of the preferred conditions of the production method for carrying out the present invention are as follows.

The reaction of the compound of formula (II) with an acid of formula (III) or a functional derivative of this acid is diisopropylcarbodiimide or dicyclohexylcar in anhydrous organic solvent such as tetrahydrofuran or dichloromethane. It is carried out in the presence of a bodyimide.

The functional derivative of the acid of general formula (III) may be cyanoacetylchloride prepared in situ, for example by the action of cyanoacetic acid on phosphorus pentachloride.

The reaction of sodium hydride with the compound of general formula (IV) is carried out in anhydrous organic solvent such as tetrahydrofuran.

The compound of general formula (I) has an acid characteristic. Addition salts of compounds of formula (I) may be advantageously prepared by reacting the compounds of formula (I) with inorganic or organic bases in a stoichiometric ratio. Salts can be prepared without isolating the corresponding acid.

The compounds according to the invention have very useful pharmacological properties, in particular good anti-inflammatory properties. On the other hand, the product of the present invention inhibits the inflammatory phenomenon caused by the stimulant, and suppresses the hypersensitivity reaction by inhibiting the activity of immune cells by the specific antigen.

This property is also illustrated in the experimental section.

This property justifies the use of the novel 3-cycloalkyl-propanamides of formula (I) and their addition salts with pharmaceutically acceptable bases as medicaments.

The invention also relates to the use of the novel 3-cycloalkyl-propanamides defined by formula (I) and their addition salts with pharmaceutically acceptable inorganic or organic bases as medicaments.

In formula (I), R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different and are hydrogen, fluorine, chlorine, bromine or iodine atoms, methyl, ethyl, terbutyl, methoxy, methyl Thio, trifluoromethyl, trifluoro methoxy, trifluoromethylthio, pentafluoroethyl, bromodifluoro methoxy, acetyl, hydroxycarbonyl, methoxycarbonyl, nitro, azido or nitrile radicals Or R ₄ or R ₅ together form a —O—CH ₂ —O— group, R ₂ represents a hydrogen atom or a methyl radical, and R ₁ is a novel 7-cycloalkyl-propanamide as defined above and pharmaceuticals thereof Addition salts with academically acceptable inorganic or organic bases are preferred for use as medicaments for the purposes of the present invention.

In formula (I), R ₁ represents a cyclopropyl group, R ₂ represents a hydrogen atom or a methyl radical, R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different and are hydrogen, fluorine Particularly preferred for use as a medicament of the invention are compounds which are chlorine or iodine atoms, methyl, trifluoromethyl or nitro radicals and their addition salts with pharmaceutically acceptable inorganic or organic bases.

Examples of particularly preferred medicaments according to the invention are as follows.

-1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (4-chloro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

-1- (3-methyl-4-trifluoromethylphenylcarbamoyl) -2-cyclobutyl-2-oxopropionitrile,

-1- (4-cyano-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile and addition salts with pharmaceutically acceptable inorganic or organic bases thereof.

These agents have been found to be useful for the treatment of rheumatoid arthritis and chronic inflammation of immune or non-immune pathogens (eg, graft versus host response disease, transplantation, uveitis, etc.).

The amount varies depending on the compound used, the subject to be treated and the type of disease, for example, the dosage by the oral route is 0.1 mg to 200 mg per day.

The invention also relates to pharmaceutical compositions containing as active ingredient at least one of at least one of the above derivatives or addition salts with pharmaceutically acceptable bases thereof.

Derivatives corresponding to formula (I) as medicaments and addition salts with pharmaceutically acceptable bases thereof may be incorporated into pharmaceutical compositions for the purpose of oral or parenteral administration.

These pharmaceutical compositions may be, for example, solid or liquid, and are in the form of pharmaceuticals commonly used as pharmaceuticals for humans, such as plain or sugar or plain tablets, gelatin capsules, capsules, granules, suppositories, It may be prepared as an injectable preparation, which may be prepared according to conventional methods. The active ingredient may be used in pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, water soluble or water insoluble vehicles, animal or vegetable fats, paraffin derivatives, glycols, various humectants, dispersants, emulsifiers or preservatives, and the like. It may be incorporated with excipients which are commonly used.

The invention also relates to industrial compounds, in particular the industrial compounds of the general formula (IV)

In the above formula, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined above. Especially among these, R ₃ , R ₆ and R ₇ are hydrogen atoms, R ₄ represents a methyl radical, and R ₅ is preferably a compound as defined above except for a chlorine atom or a methyl radical.

These are described by A. Nohara, T. Ishiguro et al., J. Med. Chem. (1985) 28 (5), pp. 559-566).

The compounds of formula (II) used as starting materials in the production process are generally known compounds and can also be prepared by diazotizing and subsequently reducing the corresponding nitroaniline by methods known to those skilled in the art.

The nitroaniline used can be prepared, for example, as described in Synthetic communications (1988) 18 (16-17) page 2161-2165, TP. Sura et al.

The aniline of formula (II) may be prepared according to European Patent No. 206031 or by reduction of the corresponding nitrobenzene known in the general form.

Some nitrobenzenes are novel and can be prepared as shown in the examples below.

The following examples are non-limiting examples for carrying out the invention.

Example 1

1- (4-trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Step A: 4-trifluoromethyl cyanoacetanilide

8.6 g of cyanoacetic acid and 13.5 cm 3 of 4- (trifluoromethyl) aniline were dissolved in 100 cm 3 of tetrahydrofuran and 16.4 cm 2 of diisopropylcarbodiimide was added over 10 minutes with stirring without cooling. The temperature during the addition was changed to 20 to 60 ° C. The mixture is stirred at ambient temperature for 16 hours, then filtered, the solvent is evaporated and the residue is dissolved in 100 cm 3 of ethanol, stirred at ambient temperature for 1 hour, filtered and ethanol then methylene chloride and hexane Washed. Drying under reduced pressure at 60 ° C. for 3 hours gave 18.85 g of the desired product.

Melting Point: 195-196 ℃

Step B: 1- (4-Trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

3 g of the compound obtained in Step A was suspended in 100 cm 3 of tetrahydrofuran, and 0.88 g of sodium hydride was added and stirred at ambient temperature for 30 minutes. 1.30 cm 3 of cyclopropanecarbonyl chloride was added over 10 minutes and the mixture was stirred at ambient temperature for 16 hours. 1 cm 3 of water was added and stirred for 10 minutes, then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated. The residue was heated at 15 cm 3 of methylene chloride and diluted with ether to give 2.72 g of the desired product.

Melting Point: 212-213 ℃

The compounds of the following examples were prepared according to the methods given above with the appropriate compounds as starting materials.

Example 2

1- (3-chlorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 3

1- (4-trifluoromethylphenylcarbamoyl) -2-cyclobutyl-2-oxopropionitrile

Example 4

1- (4-trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 5

1- (4-fluorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 6

1- (4-chlorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 7

1- (4-bromophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 9

1- (4-trifluoromethoxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 10

1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 11

1- (3,4-dichlorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 8

1- (4-iodophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Step A: 4'-iodocyanoacetanilide

Suspended 35.25 g of phosphorus pentachloride in 250 cm 3 of methylene chloride and 14.41 g of cyanoacetic acid were added over 2 minutes while maintaining the ambient temperature under stirring. The mixture was heated at reflux for 30 minutes, stirred for 2 minutes under nitrogen stream, 24.75 g of 4-iodoaniline was added and continued to heat for 2 hours under reflux, cooled and poured into 300 cm 3 of water. Stir for 1 hour, then filter, residue is dissolved in aqueous solution of sodium bicarbonate, filtered, solid residue is washed with water and ethanol and dried at 60 ° C. under reduced pressure. 29.51 g of the desired product were obtained.

Melting Point: 216-218 ℃

Step B: 1- (4-iodophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

The desired product was obtained as shown in Step B of Example 1 using the 4'-iodo cyanoacetanilide prepared in Step A.

Example 12

1- (4-bromo-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Step A: 4-Bromo-3-methyl cyanoacetanilide

0.457 g of cyanoacetic acid and 1 g of 4-bromo-3-methyl-aniline are dissolved in 30 cm 3 of methylene chloride, and 1.135 g of dicyclohexylcarbodiimide in 5 cm 3 of methylene chloride is added at 40 ° C. over 2 minutes with stirring. It was. Maintain a temperature above 40 ° C. during the addition, stir the mixture at ambient temperature for 1 hour, filter the dicyclohexylurea, evaporate the solvent, and chromatrate the residue with methylene chloride containing an increased amount of ethyl acetate. It was grafted. The desired product was obtained in 87% yield.

Step B: 1- (4-Bromo-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

300 mg of the product obtained above was dissolved in 12 cm 3 of tetrahydrofuran, stirred under nitrogen atmosphere, and the amount of imidazole catalyst was added. 626 mg sodium hydride was added and stirred at ambient temperature for 15 minutes. 124 mg of cyclopropane carbonyl chloride was added over 3 minutes and stirred at ambient temperature for 2 hours. The reaction medium was poured into ice cold water, acidified to pH 2 with 1M hydrochloric acid, stirred for 1 minute, the formed precipitate was filtered off, washed with water and then ether to give the desired product in 88.3% yield.

Example 13

1- (3,4-methylenedioxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Step A: 3,4-methylenedioxy cyanoacetanilide

279 mg of cyanoacetic acid was added to the suspension containing 685 mg of phosphorus pentachloride in 10 cm 3 of methylene chloride over 1 minute while maintaining the ambient temperature. The mixture was heated under reflux for 30 minutes, stirred under nitrogen stream for 2 minutes, 300 mg of 3,4-methylene dioxyaniline was added and heated under reflux for 10 minutes, cooled to ambient temperature, and then the mixture was water 10 Poured into cm 3. Stir for 30 minutes, filter, wash with water then ether and ethyl acetate. 330 mg of the desired product were obtained.

Step B: 1- (3,4-methylenedioxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

The desired product was obtained using the 3,4-methylenedioxy-cyanoacetanilide obtained in Step A and shown in Step B of Example 1.

The compounds of the following examples were prepared according to the methods given above with the appropriate compounds as starting materials.

Example 14

2-cyano-3-cyclopropyl-3-oxo-N-methyl-N- (4-chlorophenyl) propionamide

Example 15

1- (4-chloro-2-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 16

1- (3,4-difluorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 17

1- (4-methoxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 18

1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 19

1- (3,5-dichlorophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 20

1- (4-chloro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 21

1- (3-trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 22

1- (4-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 23

1- (4-chloro-3-trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 24

1- (phenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 25

1- (3-methyl-4-trifluoromethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 26

1- (4-iodo-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 27

1- (4-fluoro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 28

1- (4-cyano-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 29

1- (4- (2,2,2-trifluoroethoxy) -phenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 30

1- (3-methyl-4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 31

1- (4-t-butylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 32

1- (3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 33

1- (4-trifluoromethylthiophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 34

1- (4-methoxycarbanylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 35

1- (4-acetylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 36

1- (3,4-dimethoxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 37

1- (3-chloro-4-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 38

1- (4-methylthiophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 39

1- (3-ethyl-4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 40

2-cyano-3-cyclopropyl-3-oxo-N-methyl-N- (3-methyl-4-trifluoromethylphenyl) propionamide

Example 41

1- (4-bromodifluoromethoxy-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 42

2-cyano-3-cyclopropyl-3-oxo-N-methyl-N- (4-cyanophenyl) propionamide

Example 43

2-cyano-3-cyclopropyl-3-oxo-N-methyl-N- (4-nitrophenyl) propionamide

Example 44

1- (3-methyl-4-trifluoromethoxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 45

1- (3-methyl-4-pentafluoroethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 46

2-cyano-3-cyclopropyl-3-oxo-N-methyl-N- (4-bromo-3-methylphenyl) propionamide

Example 47

1- (4-chloro-3-ethylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Example 48

1- (4-carboxyphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Preparation of 1- (bromodifluoromethoxy) -2-methyl-4-aminobenzene used as starting material in the preparation of Example 41

0.92 g of sodium was dissolved in 30 cm 3 of ethanol and 6 g of 2-methyl-4-nitrophenyl was added. After evaporation of the solvent under reduced pressure, benzene was added. This sodium salt was added to a mixture containing 24 cm 3 of dimethylformamide, 30 cm 3 of dibromodifluoromethane and a small amount of ethanediol as catalyst. The mixture was heated at 70 ° C. for 10 hours, then poured onto ice and extracted with ethyl acetate. The extract was washed with 0.5M aqueous sodium hydroxide solution followed by water, dried and the solvent was evaporated under reduced pressure. Chromatography on silica gel (using ethyl acetate: hexane = 4:96 as eluent), 0.20 g of 1- (difluoromethoxy) -2-methyl-4-nitrobenzene and 1- (bromodifluoromethoxy) 3.35 g of 2-methyl-4-aminobenzene were obtained and hydrogenated on activated charcoal in the presence of palladium to obtain the desired product.

[Preparation of 2-methyl-4-amino-1-trifluoromethoxybenzene used as starting material in the preparation of Example 44]

0.3 g of 1- (bromodifluoromethoxy) -2-methyl-4-nitrobenzene, 0.120 g of antimony trifluorolide and 0.02 g of antimony pentachloride as catalyst were heated in a sealed flask at 175 ° C. for 4 hours. The mixture is diluted with ether, washed with water, dried and the solvent is evaporated under reduced pressure to give 0.13 g of 2-methyl-4-nitro-1-trifluoro-methoxy-benzene to give hydrogen in the presence of palladium on activated charcoal. The addition reaction was carried out to obtain the desired product.

[Preparation of 2-methyl-4-amino-1-pentafluoroethylbenzene used as starting material in the preparation of Example 45]

2.36 g of 1-iodo-2-methyl-4-nitrobenzene and 2.2 g of copper powder (Org. Synthesis Coll. Vol. II (1948) 445, washed with water, followed by acetone and dried under reduced pressure) Were mixed together in 10 cm 3 of dimethylformamide under argon atmosphere. The mixture was cooled to -60 ° C and 11.5 g of pentafluoroethyl iodide was added. After stirring for 16 h at 160 ° C. under a pressure of 3.5 bar, it was cooled with ice and returned to ambient temperature. The mixture was poured on ice, extracted with ethyl acetate, washed with water, dried and the solvent was evaporated under reduced pressure. Chromatography on silica (using pentane with 2-3% difluoromethane as eluent) afforded 1.5 g of 2-methyl-4-nitro-1-pentafluoroethylbenzene, which was hydrogenated in the presence of palladium. Reaction gave the desired product.

Example 49

1- (4-cyano-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile

Spectrophotometric analysis, microanalysis results, yields and melting points are shown in the table below.

Example 50

Tablets were prepared according to the following recipe.

Compound of Example 1 ... 20 mg

Sufficient excipient for compressed tablets ........... 150 mg

(Excipient: lactose, starch, talc, magnesium stearate)

Example 51

Tablets were prepared according to the following recipe.

Compound of Example 2 ... 20 mg

Sufficient excipient for compressed tablets ........... 150 mg

(Excipient: lactose, starch, talc, magnesium stearate)

Pharmacological activity

[Biochemical Test Method]

[Exam 1]

Carrageenan Rat Foot Edema (PO-R)

Test compounds or control vehicles were orally administered to rat groups (n = 6-12, male CFHB, body weight range 160-180 g) and 1 hour later, 1 mg of carrageenan dissolved in 0.2 ml of saline was injected into the right heel of the rat. Control saline was injected to the side of the foot. Paw edema response was assessed after 3 hours.

[Exam 2]

Delayed Hypersensitized Mouse Foot Edema (DTH-M)

Mouse groups (n = 8-10, male CD-1, body weight range 25-30 g) were sensitized by subcutaneous injection of 1 mg of methylated serum albumin (MBSA) in 0.2 ml of saline / frin complete adjuvant (FCA) emulsion. Negative controls were injected with saline / FCA fluid. Seven days after sensitization, 0.1 mg of MBSA in 0.5 ml of saline was injected into the right heel and DTH foot edema response was assessed 24 hours later. Control saline was injected to the side of the foot. Test compounds or control vehicles were administered orally once daily on days 4, 5 and 6, and twice daily 1 hour before and 6 hours after MBSA induction on day 7.

[Exam 3]

Delayed Hypersensitivity Rat Foot Edema (DTH-R)

Rats (n = 8-12, male CFHB, body weight range 160-180 g) were sensitized by subcutaneous injection of 0.1 ml of FCA. Freund's incomplete supplement was injected into the negative control. Seven days after sensitization of the DTH foot edema response, rat right heel was induced with 0.4 mg of Mycobacterium tuberculosis extract antigen in 0.2 ml of saline and evaluated 24 hours later. Control saline was injected to the side of the foot.

Test compounds were administered orally once a day on days 4, 5 and 6, and twice a day before and 6 hours after antigen induction on day 7.

The results of this test are shown in Table 2.

Dosage is mg / kg p.o. It is expressed in units.

Claims (10)

3-cycloalkyl-propanamides of formula (I), tautomers thereof, and addition salts with inorganic or organic bases thereof. In the formula, -R ₁ represents a cycloalkyl group having 3 to 6 carbon atoms, -R ₂ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, -R ₃ , R ₄ , R ₅ , R ₆ and R ₇ Is the same or different and is a hydrogen atom, a halogen atom, a straight or branched chain alkyl radical having 1 to 6 carbon atoms, a straight or branched chain alkoxy radical having 1 to 6 carbon atoms, an alkylthio radical having 1 to 6 carbon atoms,-(CH ₂ m-CF ₃ , -O- (CH ₂ ) m-CF ₃ , -S- (CH ₂ ) m-CF ₃ radicals, where m is an integer from 0 to 3, -CF ₂ -Hal, -OCF ₂ -Hal, Or -O (CF ₂ ) n-CF-Hal ₃ -CF ₃ radicals where n is an integer from 1 to 3, the same or different Hal ₁ and Hal ₂ , Hal and Hal ₃ are halogen atoms, Or R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different and are a nitro group, an azido group, a nitrile group, a -CO-R 'group where R' is hydroxy and 1 to 3 carbon atoms R ₄ and R ₅ together form an —O—CH ₂ —O— group. The compound of claim 1, wherein R ₃ , R ₄ , R ₅ , R _6, and R ₇ are the same or different and each hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, terbutyl, methoxy, methylthio , Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, pentafluoroethyl, bromodifluoromethoxy, acetyl, hydroxycarbonyl, methoxycarbonyl, nitro, azido, nitrile radicals, Or R ₄ or R ₅ together form a —O—CH ₂ —O— group, R ₂ represents a hydrogen atom or a methyl radical, and R ₁ is as defined in claim 1 3-cycloalkyl-propanamide and addition salts thereof with inorganic or organic bases. The compound of claim 1 or 2, wherein R ₁ represents a cyclopropyl group, R ₂ represents a hydrogen atom or a methyl radical, and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are the same or different, Addition salts with 3-cycloalkyl-propanamides of general formula (I) and their inorganic or organic bases, characterized in that they are hydrogen, fluorine, chlorine or iodine atoms, methyl, trifluoromethyl or nitro radicals. The method of claim 1, wherein 1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile, 1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2- Oxopropionitrile, 1- (4-chloro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile, 1- (3-methyl-4-trifluoromethylphenylcarbamoyl)- 2-cyclobutyl-2-oxopropionitrile, 1- (4-cyano-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile, and a compound thereof Or addition salts with organic bases. The compound of formula (II) is reacted with an acid of formula (III) or a functional derivative of this acid to give a compound of formula (IV), followed by sodium hydride in the presence of a catalyst such as imidazole After reacting with the compound of formula (V) to give the corresponding compound of formula (I), which is isolated and chlorinated if necessary, according to formula (I) Of 3-cycloalkyl-propanamide and salts thereof. (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined in claim 1 and Hal represents a halogen atom) A reaction according to claim 5, wherein the reaction of the compound of formula (II) with an acid of formula (III) or a functional derivative of this acid is carried out in anhydrous organic solvent such as tetrahydrofuran or dichloromethane. Or in the presence of dicyclohexylcarbodiimide, the functional derivative of the acid of general formula (III) may be cyanoacetylchloride prepared in situ, for example by the action of cyanoacetic acid on phosphorus pentachloride , Wherein the reaction of sodium hydride with the compound of formula IV is carried out in anhydrous organic solvent such as tetrahydrofuran. A pharmaceutical having anti-inflammatory activity, characterized in that it consists of 3-cycloalkyl-propanamide of formula (I) according to claim 1 and a pharmaceutically acceptable acid addition salt thereof. A drug having anti-inflammatory activity, characterized in that it consists of the 3-cycloalkyl-propanamide according to any one of claims 2 to 4 and pharmaceutically acceptable acid addition salts thereof. A compound of formula (IV) Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined in claim 1 R ₃ , R ₆ and R ₇ are hydrogen atoms, R ₄ represents a methyl radical and R ₅ is a compound of formula (IV) as defined in claim 1 except for a chlorine atom or a methyl radical.