HU183302B - Process for producing substituted benzonitril derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of substituted benzonitriles of formula (I). In formula (I), X is O or S: R 1 is bromo, chloro, fluoro, phenoxy-C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, C 1 -C 3 alkylamino sulfonyl, di (C 1 -C 3) alkylamino sulfonyl, benzoyl, C 1 -C 3 alkoxy, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; R2 is hydrogen, bromo, chloro, fluoro or trifluoromethyl; and n is 1, 2, 3 or 4. The compounds of formula (I) exhibit excellent antiviral activity and have low toxicity. -1-

Description

The present invention relates to novel substituted benzonitrile derivatives. More particularly, the present invention relates to the preparation of compounds of formula I wherein:

X is oxygen or sulfur,

R 'is bromo, chloro, fluoro, phenoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, benzoyl, alkoxy, alkyl -, halogenated alkyl or acetyl;

^R2 is hydrogen, bromine, chlorine, fluorine atom or trifluoromethyl group, and n · 1, 2, 3 or 4th

Throughout the specification and the claims, "alkyl" means a C 1-3 alkyl group such as methyl, ethyl, propyl or isopropyl; "Halogenated alkyl" is preferably alkyl substituted with 1 to 4 substituents, preferably bromo, chloro or fluoro, such as trifluoromethyl, 2,2-dichloro-1,1-difluoroethyl or 1-chloropropyl. . The term "alkoxy" refers to a C 1-3 alkoxy group such as methoxy, ethoxy, propoxy or isopropoxy. Substituents designated by the term "alkyl" contain from 1 to 3 carbon atoms in the alkyl moiety. For example, "alkylsulfonyl" refers to methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl groups; and the term "dialkylaminosulfonyl" includes, for example, dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, diisopropylaminosulfonyl, and N, N-methylethylaminosulfonyl. designate.

Preferred compounds of formula (I), wherein R ¹ is chlorine or bromine, alkylsulfinyl, alkylsulfonyl, alkyl, halogenated alkyl or alkoxy; R ^{2 is} hydrogen, chloro, bromo or fluoro, or trifluoromethyl; X is O and n is 1 or 2. Particularly preferred are compounds of formula I wherein R ³ is bromo, chloro or haloalkyl; R ^{2 is} hydrogen, bromine, chlorine or trifluoromethyl; X represents an oxygen atom and n is 1 or 2.

For the sake of simplicity, the compounds of the invention will sometimes be referred to hereinafter simply as "substituted benzonitrile derivatives".

The compounds of the present invention are generally crystalline solids which have limited water solubility and varying degrees of solubility in organic solvents such as methylene chloride, methanol and ethanol. The compounds exhibit antiviral activity and are thus useful in preventing the division of viruses by contacting the virus or, preferably, the virus-carrying cells with an effective amount of the compounds of the invention. For treatment, an effective but non-toxic amount of one or more compounds of the invention is used. The present invention also relates to a process for the preparation of a pharmaceutical composition comprising the active compounds in a pharmaceutically acceptable carrier. The formulations may contain from 0.1 pg or less to 99% w / w of active ingredient per ml of vehicle.

According to the invention, the compounds of formula (I), as defined above for X, R ¹ , R ² and na, are prepared by reacting a substituted benzene derivative of formula Bz-A with a substituted benzene derivative of formula Bz'-XY we react - where

A is halogen;

X is O or S;

Y is hydrogen or a cation capable of forming a phenol such as sodium or potassium;

3z is a 2-cyano-4-nitrophenyl group, while Bz 'is a group of the formula (a) wherein n, R ¹ and R ^{2 are} as previously defined.

The reaction is carried out by mixing the reagents in the presence of a metal, such as an alkali metal hydroxide or carbonate, for the metal to be used to form the phenol, in an inert organic solvent such as dimethylsulfoxide, methyl ethyl ketone or acetonitrile. The reaction is carried out in a temperature range of 60 ° C to 100 ° C with excellent yields in 2 to 4 hours. The reagents can be mixed in any order and in various proportions, but are used in equimolar amounts, so preferably in equimolar amounts. we also apply them. Ela Y represents a hydrogen atom, and the base used to form the phenol is used in approximately equimolar amounts. The isolation and purification of the compounds can be carried out by conventional procedures.

In particular, according to the invention, the compounds of formula (I) - X, R ³ , R ² and na - are readily prepared from a compound of formula (II) - η, X, R ¹ and R ² - and By reaction of 2-halo-5-nitrobenzonitrile in an inert organic solvent in the presence of an alkaline reagent under conditions which allow the desired compound to be formed. The alkaline reagent must be appropriately basic and present in sufficient concentration to form a suitable salt of the compound of formula (110) with 2-halo-5-nitrobenzonitrile.

Particularly suitable for the preparation of compounds of formula I is one of the following two processes:

A compound of formula II, R ¹ , R ² , n and X as hereinbefore defined, is reacted with 2-halo-5-nitrobenzonitrile, usually 2-chloro-5-nitrobenzonitrile. The reaction takes place in approximately equimolar amounts of the reagents in an inert solvent, preferably dimethylsulfoxide (DMSO) or acetonitrile, at a temperature between 60 ° C and 100 ° C, in the presence of an alkaline reagent, preferably sodium hydroxide or potassium carbonate. for 1 to 10 hours. The final product can be isolated from the reaction mixture by conventional techniques such as dilution with water and filtration. Purification can be accomplished by conventional methods such as recrystallization from solvents such as alkanols, alkyl alkanol ethers, chloroform, dimethylformamide, methyl ethyl ketone, isopropyl acetate or acetic acid. Compounds wherein R ^{1 is} alkylsulfinyl or alkylsulfonyl and X is oxygen may also be prepared by oxidation of a suitable compound of formula (I) wherein R ¹ is alkylthio and X is oxygen. The oxidation is preferably carried out by oxidizing the sulfur atom of the parent compound with a suitable oxidizing agent, such as hydrogen peroxide, in glacial acetic acid under conditions which allow the alkylsulfinyl or alkylsulfonyl substituents to be formed.

Reagents for the methods described are commercially available compounds or may be prepared by methods known in the art. 2-Chloro-5-nitro-ben-21

Zonitrile 183,302 is commercially available, as are most substituted phenols and substituted thiophenols (Formula II). Substituted phenols having a dialkylaminosulfonyl substituent can be readily prepared by the methods described by Eliel et al., J. Org. Chem., 20, 1657 (1955). .

As used herein, the term "inorganic organic solvent" is used to refer to organic solvents which do not themselves react under the conditions used to produce the desired compounds. Suitable inert organic solvents include dimethylsulfoxide, methyl ethyl ketone, acetonitrile, toluene or dimethylformamide. "Alkaline reagent" refers to bases which are capable of forming salts with phenols. Examples include sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The term "halogen" refers to bromine, chlorine, fluorine and iodine atoms.

Further details of the invention are illustrated by the following examples, without limiting the invention to the examples.

/. example

Preparation of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile

To a solution of 3,4-dichlorophenol (91.3 g, 0.56 mol) in dimethylsulfoxide (500 mL) was added sodium hydroxide (22.4 g, 0.56 mol). The resulting slurry was maintained at 60 ° C for 15 minutes, followed by addition of 100 g (0.55 mol) of 2-chloro-5-nitrobenzonitrile. The mixture was heated at 75 ° C for 3 hours. The reaction mixture was cooled and added to a suspension of 200 ml of 2N aqueous sodium hydroxide and 1800 ml of ice water. The activated product is collected by filtration, washed well with water and dried. 163.3 g (96.4%) of the title compound are obtained, m.p. 154-155 ° C. The product was recrystallized from 3-methoxy-2-propanol to give purified 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, m.p. 155-156 ° C. The typical infrared bands of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile are as follows:

IR spectra (Nujol): 2250, 1620, 1580, 1520, 1465,

1360.1270, 1130, 1040 and 895 cm ^-1 .

Example 2

Preparation of 2- (2,4-Dichlorophenoxy) -5-nitro-benzonitrile

To a solution of 5.0 g (0.0307 mol) of 2,4-dichlorophenol in 150 ml of dimethyl sulfoxide is added 1.23 g (0.0307 mol) of sodium hydroxide. The thick slurry was heated at 60 ° C for 15 minutes and 2-chloro-5-nitrobenzonitrile (5.04 g, 0.0276 mol) was added. The mixture was heated at 75 ° C for 3.25 hours. The reaction mixture was cooled and then poured into water. The product was collected by filtration, washed well with water and dried. 8.1 g (95.3%) of the title compound are obtained. After recrystallization from ethanol, the resulting purified 2- (2,4-dichlorophenoxy) -5-nitrobenzonitrile has a melting point of 153.5-154.5 ° C.

Example 3

Preparation of 2- (4-Bromophenoxy) -5-nitrobenzonitrile

To a solution of 4.31 g (0.0307 mol) of 4-bromophenol in 150 ml of dimethyl sulfoxide is added 1.23 g (0.0307 mol) of sodium hydroxide. The resulting slurry was heated at 60 ° C for 15 minutes and then 2-chloro-5-nitrobenzonitrile (5.04 g, 0.0276 mol) was added. The mixture was heated at 75 ° C for 4 hours. The reaction mixture was cooled and then poured into alkaline water. The precipitated product was collected by filtration, washed well with water and dried. 8.1 g of crude title product are obtained. The crude product was dissolved in dichloromethane and washed with 10% aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 7.5 g (85%) of the title compound. Purified by recrystallization from ethanol, 2- (4-bromophenoxy) -5-nitrobenzonitrile, m.p. 171-172 ° C.

Example 4

Preparation of 2- (4-chlorophenoxy) -5-nitrobenzonitrile

To a solution of 3.95 g (0.037 mol) of 4-chlorophenol in 150 ml of dimethyl sulfoxide is added 1.23 g (0.0307 mol) of sodium hydroxide. After keeping the thick slurry at 60 ° C for 15 minutes, 2-chloro-5-nitrobenzonitrile (5.04 g, 0.0276 mol) was added and the mixture was stirred at 75 ° C for 3 hours. The reaction mixture was cooled and poured into water. The activated product is collected by filtration, washed well with water and dried. 7.0 g (92%) of the title compound are obtained. The product was recrystallized from ethanol to give 2- (4-chlorophenoxy) -5-nitrobenzonitrile, m.p. 163-164 ° C.

Example 5

Preparation of 2- (4-phenoxyphenoxy) -5-nitromobenzomtril

To a solution of 5.71 g (0.0307 mol) of 4-phenoxyphenol in 150 ml of dimethyl sulfoxide is added 1.23 g (0.0307 mol) of sodium hydroxide. The resulting slurry was heated at 75 ° C for 15 minutes and 2-chloro-5-nitrobenzonitrile (5.04 g, 0.027 mole) was added. and maintaining the mixture at? 75 ° C for 4 hours. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried. The crude product was dissolved in dichloromethane and washed with 10% aqueous sodium hydroxide solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo leaving 8.0 g (87%) of the title compound. Recrystallization of the product from ethanol gave 2- (4-phenoxyphenoxy) -5-nitrobenzonitrile, m.p. 150-151,5 ° C.

Example 6

Preparation of 2- [4- (M '-thio-thio] -phenoxy] -5-nitrobenzomitrile

To a solution of 4- (methylthio) phenol (11.55 g, 0.0824 mol) in dimethyl sulfoxide (150 ml) was added sodium hydroxide (3.3 g, 0.0824 mol). The thick slurry was heated to 60 ° C and 13.7 g (0.0730 mol) of 2-chloro-5-nitrobenzonitrile were added and the mixture was heated at 75 ° C for 2.5 hours. The mixture was cooled and added to a mixture of 200 ml of 5N aqueous sodium hydroxide solution and 500 ml of water. The activated product is collected by filtration, washed well with water and dried. 20.3 g (94.6%) of the title compound are obtained, which is recrystallized from methanol to give 2- [4- (methylthio) phenoxy] -5-nitrobenzonitrile, m.p. 124-126 ° C.

183,202

Example 7

Preparation of 2- [4- (Methylsulfmyl) phenoxy] -5-nitrobenzonitrile

To a thick suspension of 10.0 g (0.035 mol) of 2- (4-ethylthio) -phenoxy-5-nitrobenzenitrile in 100 ml of glacial acetic acid was added 4.0 g of 30% aqueous hydrogen peroxide (0%) over 5 minutes. 0350 mol) in 20 ml glacial acetic acid. The reaction mixture was stirred at room temperature for 16 hours and then at 50 ° C for 3 hours. The reaction mixture was poured into water and the product was collected by filtration, washed well with water and dried. 9.8 g (92.8%) of the title compound are obtained. Recrystallization from ethanol gave 2- [4- (methylsulfinyl) phenoxy] -5-nitrobenzonitrile, m.p. 159160 ° C.

& example

Preparation of 2- [4- (methylsulphonyl) phenoxy] -5-nitrobenzonitrile

To a suspension of 10.0 g (0.035 mol) of 2- [4- (methylthio) phenoxy] -5-nitrobenzonitrile in 75 ml glacial acetic acid, maintained at 60 ° C, 15.85 g of 30% aqueous hydrogen peroxide (0.140 mol) was added over 5 minutes. An additional 25 ml of glacial acetic acid was added and the mixture was heated at 75 ° C for 3 hours. The reaction mixture was cooled and then poured into water. The activated product is collected by filtration, washed with water and dried. 10.9 g (98.2%) of product are obtained, m.p. 205-206.5 ° C. Recrystallized from methanol, m.p. 206-207 DEG C. 2- (4-methylsulfonylphenoxy) -5-nitrobenzonitrile.

Example 9

Preparation of N, N-Dimethyl-4- (2-cyano-4-nitrophenoxy) benzenesulfonamide

To a solution of 6.37 g (0.0317 mol) of N, N-dimethyl-4-hydroxybenzenesulfonamide in 150 ml of dimethyl sulfoxide was added 1.27 g (0.0317 mol) of sodium hydroxide. The mixture was heated to 60 ° C and 5.26 g (0.0288 mol) of 2-chloro-5-nitrobenzonitrile was added. The mixture was then heated at 75 ° C for 2.5 hours. The reaction mixture was cooled and poured into a solution of 2N aqueous sodium hydroxide solution (400 mL) in water (300 mL). The mixture was recrystallized from ethanol and dimethylformamide to give purified N, N-dimethyl-4- (2-cyano-4-nitrophenoxy) -benzenesulfonamide, m.p. 221.5-223 ° C.

Example 10

Preparation of N, N-Diethyl-4- (2-cyano-4-nitrophenoxy) benzenesulfonamide

To a solution of 6.73 g (0.0294 mol) of N, N-diethyl-4-hydroxybenzenesulfonamide in 150 ml of dimethyl sulfoxide was added 1.18 g (0.0294 mol) of sodium hydroxide. The mixture was heated to 60 ° C and 4.88 g (0.0267 mol) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75 ° C for 3 hours. The reaction mixture was cooled and poured into a mixture of 400 ml of 2N aqueous sodium hydroxide solution and 300 ml of water. The activated product is collected by filtration, washed well with water and dried. 8.8 g (88%) of the title compound are obtained. The product is recrystallized from ethanol to give purified N, N-diethyl-4- (2-cyano-4-nitrophenoxy) benzenesulfonamide, m.p. 163-164 ° C.

Example 11

Preparation of 2- (4-Benzoyl-phenoxy) -5-nitrobenzonitrile

To a solution of 4-hydroxybenzophenone (11.4 g, 0.0575 mol) in dimethyl sulfoxide (150 mL) was added sodium hydroxide (2.3 g, 0.0575 mol). The mixture was heated to 60 ° C and 10.0 g (0.0548 mol) of 2-chloro-5-nitrobenzonitrile was added. After 3 hours at 75 ° C, the mixture was cooled and poured into a mixture of 100 ml of 2N aqueous sodium hydroxide solution and 700 ml of water. The product was collected by filtration, washed well with water and dried. 17.75 g (89.6%) of crude product are obtained. This was recrystallized from ethanol / dimethylformamide to give 2- (4-benzoyl-phenoxy) -5-nitrobenzonitrile in purified form, m.p. 179.5-180.5 ° C.

Example 12

Preparation of 2 - [(4-chlorophenyl) thio] -5-nitrobenzonitrile

To a solution of 4-chlorothiophenol (15.2 g, 0.105 mol) in dimethylsulfoxide (150 mL) was added sodium hydroxide (4.2 g, 0.105 mol). The mixture was heated to 60 ° C and 18.3 g (0.100 mol) of 2-chloro-5-nitrobenzonitrile was added. After 2.5 hours at 60 ° C, the mixture was cooled and poured into a mixture of 100 ml of 2N aqueous sodium hydroxide solution and 600 ml of water. The product was collected by filtration and dried. 28.8 g (99%) of the title compound are obtained. This was recrystallized from ethanol to give purified 2 - [(4-chlorophenyl) thio-5-nitrobenzonitrile, m.p. 162-164,5 C.

Example 13

Preparation of 2- (3-methoxyphenoxy) -5-nitrobenzonitrile

In a one-necked flask equipped with a 250 ml magnetic stirrer, a reflux condenser and a nitrogen bubbler, 9.13 g (0.050 mole) of 2-chloro-5-nitrobenzonitrile, 6.39 g (0.0515 mole) of 3-methoxyphenol, Anhydrous potassium carbonate (7.10 g, 0.0515 mol) and acetonitrile (75 ml) were charged. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The solid precipitated product was collected by filtration, washed thoroughly with water and air dried. The air-dried solid was recrystallized from about 200 mL of absolute ethanol to give 7.15 g (53%) of purified 2- (3-methoxyphenoxy) -5-nitrobenzonitrile, m.p. 102-103.5 ° C.

Example 14

Preparation of 2 - [(4-Trifluoromethyl) phenoxy] -5-nitrobenzonitrile

In a one-necked flask equipped with a magnetic stirrer, 250 ml, a reflux condenser and a nitrogen bubbler attached thereto, 9.13 g (0.050 mol) of 2-chloro-5-nitrobenzonitrile, 8.35 g (0.0515 mol) of 4- (trifluoro- methylphenol, 7.10 g (0.0515 mol) of anhydrous potassium carbonate and 75 ml of acetonitrile were charged. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The solid precipitated product was collected by filtration, washed thoroughly with water and air dried. The resulting material was 350 ml

Recrystallization from 183,302 absolute ethanol gave 12.35 g (80%) of purified 2 - [(4-trifluoromethyl) phenoxy] -5-nitrobenzonitrile, m.p. 154-155.5 ° C.

Example 15

Preparation of 2- (4-Acetylphenoxy) -5-nitrobenzonitrile in a one-necked flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen bubbler attached thereto, 9.13 g (0.05 mol) of 2-chloro-5 Nitrobenzonitrile, 7.01 g (0.0515 mol) of 4-hydroxyacetophenone, 7.10 g (0.0515 mol) of anhydrous potassium carbonate and 75 ml of acetonitrile were charged. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The solid precipitated product was collected by filtration, washed thoroughly with water and air dried. The dried solid was recrystallized twice from 300 ml of absolute ethanol. 4.95 g (35%) of pure 2- (4-acetylphenoxy) -5-nitrobenzonitrile are obtained, m.p. 135-166.5 ° C.

Example 16

Preparation of 2- (4-Chloro-2-methylphenoxy) -5-nitrobenzomtril in a one-necked flask equipped with a magnetic stirrer, a reflux condenser and an attached nitrogen bubbler, in 250 ml (9.73 g, 0.0533 mol). Chloro-5-nitrobenzonitrile, 7.83 g (0.0549 mol) of 4-chloro-2-methylphenol, 7.56 g (0.0549 mol) of anhydrous potassium carbonate and 75 ml of acetonitrile were charged. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The product is isolated in solid form. The solid is filtered off, rinsed thoroughly with water and air dried. The air-dried solid was recrystallized from 400 ml of absolute ethanol and a little acetone. 9.60 g (62%) of purified 2- (4-chloro-2-methylphenoxy) -5-nitrobenzonitrile are obtained, m.p. 144.5-145.5 ° C.

Example 17

Preparation of 2- (3,4,5-Trichlorophenoxy) -5-nitrobenzonitrile in a 250 ml one-necked flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen bubbler attached thereto 2 .68 g (0.0475 mol). Chloro-5-nitrobenzonitrile, 9.67 g (0.0489 mol) of 3,4,5-trichlorophenol, 6.75 g (0.0489 mol) of anhydrous potassium carbonate and 75 ml of acetonitrile were charged. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with 150 mL of water. The solid product is filtered off, rinsed thoroughly with water and air dried. The air-dried solid was recrystallized from 200 mL absolute ethanol / 100 mL acetone to give 11.62 g (71%) of purified 2- (3,4,5-trichlorophenoxy) -5-nitrobenzonitrile as small white crystals. mp 162-164 ° C.

Example 18

Preparation of 2- (2,3,5,6-Tetrafluorophenoxy) -5-nitrobenzonitrile

In a one-necked flask equipped with a 250 ml magnetic stirrer, a reflux condenser and an attached nitrogen bubbler, 9.13 g (0.050 mol) of 2-chloro-5-nitrobenzonitrile, 8.55 g (0.0515 mol) of 2.3, 5,6-Tetrafluorophenol, 7.10 g (0.0515 mol) of anhydrous potassium carbonate and 75 ml of acetonitrile are added. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with 150 mL of deionized water. The solid product was filtered off, rinsed with water and dried in air. Recrystallization of the solid in air from 300 ml of absolute ethanol afforded 11.36 g (73%) of purified 2- (2,3,5,6-tetrafluorophenoxy) -5-nitrobenzonitrile, m.p. 152.5-154.5 ° C.

Example 19

Preparation of 2- (2,3,4,5,6-Pentafluorophenoxy) -5-nitrobenzonitrile

9.59 g (0.0525 mole) of 2-chloro-5-nitrobenzonitrile, 9.96 g (0.0541 mole) 2.3 in a 250 ml one-necked flask equipped with a magnetic stirrer, a reflux condenser and an attached nitrogen bubbler. 4,5,6-pentafluorophenol, 7.56 g (0.0541 mol) of anhydrous potassium carbonite and 75 ml of acetonitrile are added. The mixture was heated to reflux and maintained at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with 150 mL of deionized water. The solid precipitated was filtered off, rinsed thoroughly with water and air dried. The air-dried solid was recrystallized from 200 ml of absolute ethanol to give 9.91 g (57%) of purified 2- (2,3,4,5,6-pentafluoroph; nooxy) -5-nitrobenzonitrile, m.p. 12 at 29 ° C.

The following 2- (substituted-phenoxy) -5-nitro-1-nitronitrile derivatives are prepared analogously to the methods described previously.

Example 20

2 - [(3,4-dichlorophenyl) thio] -5-nitrobenzonitrile m.p. 137-139 ° C

Example 21

2- (4-Fluorophenoxy) -5-nitro-b-enzonitrile m.p. 132.5-133.5 ° C

Example 22

2- (2,3-Dichlorophenoxy) -5-nitrobenzomtril, m.p. 146-147 ° C

Example 23

2- (2,5-Dichlorophenoxy) -5-nitrobenzonitrile m.p. 167-168,5 ° C

-5183 202

Example 24

2- (2,6-Dichlorophenoxy) -5-nitrobenzonitrile, m.p. 157-159 ° C.

Example 25

2- (2,3-Dichlorophenoxy) -5-nitrobenzonitrile m.p. 196-198 ° C

Example 26

2 - [(2-Trifluoromethyl) phenoxy] -5-mtrobenzonitrile, m.p. 113-115 ° C

Example 27

2 - [(3-Trifluoromethyl) phenoxy] -5-nitrobenzonitrile m.p. 85.5-86.5 ° C

Example 28

2- [3,5-Bis (trifluoromethyl) phenoxy] -5-nitrobenzonitrile m.p. 138-140 ° C

Example 29

2- (2,3,4-Trichlorophenoxy) -5-nitrobenzonitrile m.p. 203-204.5 ° C

Example 30

2- (2,3,5-Trichlorophenoxy (-5-nitrobenzonitrile) m.p. 160-162 ° C

Example 31

2- (2,3,6-Trichlorophenoxy) -5-nitrobenzonitrile m.p. 141-143 ° C.

The physical constants of the above compounds are as follows

Table 1 summarizes this.

Table 1

The number of the example X R ¹ (R ² ) n Mp (° C) % C calculated % H % N % C Found % H % N First 0 4-C1 3-C1 155-156 50.51 1.96 9.06 50.3 1.99 9.17 Second 0 4-C1 2-C1 153,5-154.5 50.51 1.96 9.06 50.7 1.97 9.20 Third 0 4-Br H 171-172 48.93 2.21 8.78 48.9 2.21 9.05 4th 0 4-C1 H 163-164 56.85 2.57 10.20 56.6 2.52 10.29 5th 0 4-O-phenyl H 150-151.5 ° 68.67 3.64 8.43 68.7 3.60 8.44 6th 0 4-SCH ₃ H 124-126 58.73 3.52 9.79 58.5 3.61 9.77 7th 0 4 SCHj 1 H 159-160 55.62 3.33 9.27 55.5 3.38 9.47 8th 0 O 4 -SO ₂ CH ₃ H 206-207 52.82 3.17 8.80 52.9 3.23 8.83 9th 0 4-SO ₂ N (CH ₃ ), H 221.5 to 223 51.87 3.77 12.10 51.6 3.82 12.12 10th 0 4-SO ₂ N (C ₃ H _s ) ₂ H 163-164 54.39 4.56 11.19 54.6 4.55 11.23 11th 0 Carbonyl-4-phenyl H 179.5-180.5 69.76 3.51 8.14 69.7 3.55 8.06 12th 0 4-C1 H 162 to 164.5 53.70 2.43 9.64 53.5 2.52 9.56 13th 0 3-OCH ₃ H 102-103.5 62.22 3.73 10.37 61.94 3.72 10.32 14 0 4-CF ₃ O H 154 to 155.5 54.55 2.29 9.09 54.5 2.38 9.12 15th 0 II 4-CCH H 135 to 136.5 63.83 3.57 9.93 63.8 3.69 9.89 16th 0 2-CH 4-C1 144.5 to 145.5 58.24 3.14 9.70 58.2 3.35 9.68 17th 0 4-C1 3,5-Cl 162-164 45.45 1.47 8.15 45.4 1.64 8.26 18th 0 2-F 3,5,6-F 152.5 to 154.5 50.01 1.29 8.97 50.3 1.53 9.09 19th 0 2-F 3,, 5,6-F 127.5 to 129 47.29 0.92 8.49 47.5 1.20 8.49 20th 0 4-C1 3-C1 137-139 48.01 1.86 8.62 48.1 2.06 8.70 21st 0 4-F H 132.5 to 133.5 60.47 2.73 10.85 60.3 2.87 10.92 22nd 0 2-C1 3-C1 146-147 50.51 1.96 9.06 50.34 2.15 9.09 23rd 0 2-C1 5-Cl 167 to 168.5 50.51 1.96 9.06 50.5 2.17 9.14 24th 0 2-C1 6-Cl 157-159 50.51 1.96 9.06 50.4 2.06 9.03 25th 0 3-C1 5-Cl 196-198 50.51 1.96 9.06 50.3 2.04 9.06 26th 0 2-CF ₃ H 113-115 54.55 2.29 9.09 54.6 2.52 9.12 27th 0 3-CF ₃ H 85.5 to 86.5 54.55 2.29 9.09 54.3 2.56 9.23 28th 0 3-CF ₃ 5-CF ₃ 138-140 47.88 1.61 7.45 47.9 1.73 7.55 29th 0 2-C1 3,4-Cl 203 to 204.5 45.45 1.47 8.15 45.3 1.72 8.10 30th 0 2-C1 3,5-Cl 160-162 45.45 1.47 8.15 45.4 1.69 8.23 31st 0 2-C1 3,6-Cl 141-143 45.45 1.47 8.15 45.4 1.75 8.30

The compounds of the present invention have antiviral activity, and in particular show superior activity against picornaviruses, such as small ribonucleic acid viruses. Picornaviruses include viruses such as Coxsackie viruses, rhinoviruses, and viruses responsible for many plant diseases. The compounds of the present invention are of low toxicity to mammals, with low toxicity, with little or no side effects, when administered at a dose sufficient to produce a good antiviral effect. The degree of toxicity and side effects of the antiviral activity varies from compound to compound, as detailed below.

The antiviral activity of the compounds of the present invention was tested by the following method;

mm cups monolayer HeLa cells were treated with 1 ml of medium (Eagles medium supplemented with calf embryo rabbit) which was either

183,302 contained the desired compound at a suitable concentration or no compound at all. A more detailed description of the media used in this experiment can be found in biochemical reference books, such as Kuchler, Biochemical Methods in Cell Cell and Virology, Dowden, Hutchinson and Ross, Inc., Stroudsberg, Pa. (1977). Subsequently, 0.05 ml of type 1A thinovirus (RV-IA), type 2 rhinovirus (RV-2) or Coxsackie A _2t virus (Cox A ₂ 1) was added to the medium. Some compounds were also tested against rhinovirus type 5 (RV-5), rhinovirus type 8 (RV-8), or rhinovirus type 64 (RV-64). No virus was added to the control cells. Cultures were assayed for compound cytotoxicity and viral cytopathic activity (CPE) at 48 and 72 hours post-treatment. 15

The effects of certain compounds on animal organisms were also tested using the following procedure ("single oral dose" test). Male Swiss mice weighing 10 to 12 g were intraperitoneally (IP) dosed with 20 ml of aqueous saline solution of Cox A ₂ 1 virus phosphate buffered in normal conditions in an amount of 0.2 ml. The solution also contained 1% heat inactivated fetal calf serum. The term lethal dose is used herein to mean a dose that results in 80-100% mortality in infected animals within 10 days of administration. 3 hours later, the mice were treated orally with 0.2 ml of the test compound suspended in 0.5% hydroxypropylmethylcellulose (Methocel ^R ) or 0.5 ml of Methocel ^R containing 0.2 ml of the active ingredient. . The suspension contained 30 mg / ml (600 mg / kg) of active ingredient. Mice were observed daily for 7-10 days and mortality was recorded. A significant difference between the control group and the treated group was determined using a combination of the modified Mantel-Naenzel method and the chi-square method. Chi-square values greater than 3.84 were considered significant (95% confidence level).

The effect of certain compounds on animals was investigated by the following procedure ("continuous oral feeding" method). Mice (10-11 g) were treated with virus grown on Coxsackie A ₂₁ HeLa cells at a concentration that causes 80-100% mortality within 10 days when treated intraperitoneally with 0.2 ml of virus preparation. The mice were on a diet consisting of a rodent commercial diet containing the test compound in dispersed form. At day 0, the concentration of the drug in the feed was 0.06% by weight. On day 1, mice were dosed intraperitoneally with 0.2 ml / mouse of virus. Mortality observed in the control and study groups was recorded for 10 days after treatment and the results obtained were checked using the chi-square test. Chi-square values greater than 3.84 were considered to indicate the activity of the compound (95% confidence level). The results are shown in Table 2.

Table 2

The number of the example Cicotoxicitás * (G / ml) RV-1A RV-2 Tissue Culture Test ** Cox A ₃₁ RV 5 RV-8 RV-64 First > 100 0.5 0.25 0.25 0.5 0.25 0.156 Second > 100 0,625 0,625 1.25 2.5 2.5 Third > 100 1.25 1.25 2.5 4th > 100 <0.625 % 0.625 0,625 <0.3 <6 5th > 100 SO 50 <6.25 6th 100 SO • 6.25 <6.25 7th 50 SO 6.25 <6.25 8th > 100 SO 12.5 <6.25 9th > 100 SO SO <6.25 10th > 100 ± 50 SO <6.25 11th > 100 SO ± 100 12.5 12th 25 ± 3.125 1.6 1.6 13th > 50 6.25 <3.125 <3.125 6.25 .3125 0,625 14th > 50 3,125 .3125 0,625 2.5 .3125 0,625 15th > 50 6.25 3,125 3,125 6.25 3,125 6.25 16th > 50 12.5 3,125 12.5 6.25 3,125 SO 17th 10 2.5 1.25 1.25 18th 12.5 3,125 <3.125 3,125 1.25 1.25 .3125 19th 12.5 6.25 <3.125 6.25 1.25 1.25 .3125 20th 10 SO 2.5 ± 2.5 21st 10 0,625 <0.625 0,625 1.25 0,625 0,625 22nd > 50 <3.125 <3.125 <3.125 3,125 23rd > 50 3,125 <3.125 6.25 <6.25 <6.25 3,125 24th > 50 3,125 <3.125 12.5 3,125 <3.125 3,125 25th > 50 6.25 3,125 SO 6.25 3,125 25 26th > 20 SO 1.25 10 27th 12.5 2.5 0,625 1.25 0,625 1.25 0,625 28th > 20 SO 2.5 10 29th > 20 ± 10 1.25 ± 5 30th > 20 2.5 2.5 SO 31st > 20 2.5 1.25 5 3,125 <3.125 3,125

* Cytotoxicity refers to the concentration of compounds in gg / ml which is toxic to cells. ** Minimum concentration of compounds (Mg / ml) which causes a 50% reduction in cytopathic effect.

*** Concentration of test compound in% by weight of animal feed.

"NA" means that the compound was not active against the virus under the experimental conditions. "<" Means "less than", ">" means "greater than", "means" less than or equal to ","> "means" greater than or equal to "," t "means" approximately ". The locations left in the well indicate that the experiment was not run on vcg.

-7183302

Continuation of Table 2

Animal Experiment, Single Oral Dose Continuous Oral Dose _x Dose (mg / kg) x ² Dose *** x First 600 5.36 0.06% 23.62 Second 600 3.659 0.06% 1.38 Third 600 2,139 0.06% 5.81 4th 600 0.252 0.06% 10.61 5th 600 0.719 0.06% 0.26 6th 600 .609 0.06% 6.21 7th 600 18.94 0.06% 18.82 8th 600 0,095 0.06% 10.45 9th 0.06% 9.03 10th 0.06% 2.84 11th 600 0.64 12th 600 4.805 0.06% 0.215 21st 0.06% 10.513

The data in Table 2 confirm the antiviral activity of the test compounds of the invention.

Szövetkultúrás The experimental data show that all compounds active against these three viruses tested (RV 1, RV-2 and Cox A ₂ 1) at least one of the virus. In addition, certain compounds of the invention were effective against RV-5, RV-8 or RV-64 viruses.

Some of the compounds tested exhibited potent antiviral properties (94% confidence level, i.e., x ² greater than 3.84) in mouse experiments.

Of particular interest is the compound of Example 1, chemically called 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, which exhibited antiviral activity in both the "single oral dose" and "continuous oral nutrition" assays. . Orally administered compounds, which also retain their antiviral activity, are very advantageous in that they can be readily incorporated into the diet of mammals, as evidenced by the "continuous oral nutrition" test, or in the form of various oral formulations containing the active ingredient and appropriate excipients. 2- (3,4-Dichlorophenoxy) -5-nitrobenzonitrile exhibits antiviral activity against a broad spectrum of viruses in other tissue cultures using the following assay:

2- (3,4-Dichlorophenoxy) -5-nitrobenzonitrile (2 mg) is dissolved in 0.1 ml dimethylsulfoxide and incubated for at least 15 minutes at 56 ° C. 0.9 ml of the solution heated to 56 ° C is poured into a maintenance medium containing 49% Eagles, 49% 199 medium, 2% Bouc embryo serum and antibiotics, and the resulting 1 ml solution is added to 9 ml of the maintained medium heated to 56 ° C. This solution is maintained at 100, 50, 25, respectively with the maintenance medium

Dilute to a concentration of 12.5 mg / ml.

To each of three WI-38 human embryonic lung cell culture test tubes, 1 ml of culture medium containing the test compound at a given concentration is added, followed by 3 to 300 TCID ₅₀ ( _{3 to} 300 times, i.e. 3 to 300 times the tissue culture ID ₅₀ ). the dose required to inoculate 50% of the cell cultures tested). At the same time, virus titration is performed. Tissue cultures are supplemented with fresh medium if necessary (after 3-4 days) until viral titration is completed.

Cell culture tubes are assayed daily to determine cytopathic effect. The assay is considered complete when the cell surface is damaged by more than 75% in control virus titration tubes. At this time, test tubes containing control and antiviral compounds of the invention are compared. A difference of 75% or greater is denoted by a "+" sign, a difference of 74-50% is denoted by a "±" sign, or a difference of 50% or less by a sign.

In the above assay, 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile at a concentration of 25 mg / ml inhibited the growth of 20 different commodities, i.e., received a "+" sign when tested against 20 different rhinoviruses. These viruses are the untyped rhinovirus called "Hank's (untyped)" and 4, 6, 8, 10, 13, 17, 19, 21, 29, 39, 56, 58, 59, 60, 64, 69, 74, 75 and 81 rhinoviruses.

In other experiments performed in the same manner but with other media, 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile showed inhibitory activity against Coxsackie B ₂ and Coxsackie B ₄ viruses, but (at least did not affect the growth of the following viruses: influenza A, WSN influenza, PR 8 influenza, parainfluenza 1, parainfluenza NDV (Newcastle disease virus), adenovirus (unspecified type). Herpes simplex virus (type 1) and virus identified as feline calici virus.

The results of the above studies indicate that% (3,4-dichlorophenoxy) -5-nitrobenzonitrile is particularly effective in the treatment of Picornaviruses, such as small ribonucleic acid (rna) viruses such as Coxsackeviruses. These experiments also show that this compound is effective against a large number of Ficornavirus agents.

Standard tissue and animal experiments described above have shown that 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile exhibits significantly better antiviral activity than the comparator 5- (3,4-dichlorophenol). phenoxy) -2-nitrobenzonitrile. During the test the szövetkultúrás (3,4-dichlorophenyl phenoxy) -2-nitrobenzonitrile 5- RV-1A, RV-2 and _two effect tested against 1 viruses had to be applied to a higher concentration that the cytopathic effect is 51% - os. In addition, the reference compound was not effective against RV-1A, RV-2 and CosA ₂ viruses. In addition, at the concentration used, it also showed activity in the reference compound against RV-5, RV-8 and RV-64 viruses. The comparator compound also showed no antiviral activity in the "continuous oral feeding" test.

A further advantage of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile is that it has an oral acute toxicity of 5 g / kg in the rat and greater than 2 g / kg in the intraperitoneal route. In Beagle dogs the oral acute toxicity is greater than 2 g / kg.

Because of the many advantageous properties of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile (e.g., broad-spectrum antiviral activity, low toxicity and antiviral activity when administered orally), the present invention provides a preferred embodiment of this compound.

The compounds of the present invention are used by contacting a virus or virus host cell with a defined amount of one or more antiviral compounds of the invention. While it is not intended to limit the invention to a particular mechanism of action, the compounds appear to act in a

3C2 to inhibit the function of viruses in host cells by physically or chemically inactivating virus cells isolated from the cells. In non-living environments, contact should occur such that an effective amount of the compounds is necessarily present when the host cells are encountered. Preferably, the compound is used by contacting the host cells with an effective amount of one or more compounds which are antiviral (i.e., an amount at which significant inhibition is already present). The contact may be directly, for example, by adding the compound used to tissue culture to inhibit contaminating picornaviruses. The contacting may also be accomplished by administering an antiviral dose of a compound of the invention to an animal. The compounds may be administered parenterally (e.g., intraperitoneally, subcutaneously, or intravenously) or orally, and the fact that certain compounds of the invention also appear to be orally active is a very important feature of the invention. In such use, an effective antiviral dose of one or more compounds of the invention is administered to the animal to be treated. When selecting which compound or compounds to treat with an animal, factors such as toxicity, mutagenicity, ease of administration, antiviral activity (potential), stability, compatibility with suitable carriers, and the like, should be considered.

The precise amount of compound or compounds to be used, i.e. the amount sufficient to achieve the desired effect, will depend on various factors such as the compound to be used, the type of contact and administration, the size, age and species of the animal, the mode, time and route of administration. frequency, the virus or viruses in question and the prophylactic treatment or treatment of an infected animal. The compounds may also be used at doses of 600 mg / kg / day, but preferably at least 0.1 mg / kg / day, most preferably 0.1 to 60 mg / kg / day. In each particular case, the most suitable dosage may be determined by conventional procedures, for example, by examining the effect of using various amounts. The examination and evaluation shall be carried out in accordance with the usual methods.

The compounds are preferably administered in the form of compositions which contain the compounds in association with pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are meant to be substances which are chemically inert to the active ingredient and which do not exhibit deleterious toxicity or side effects under the conditions of use. As can be seen, the compounds exhibit significant antiviral activity at low concentrations when added to tissue culture media, such that 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, at concentrations as low as 0.156 Mg / ml, reduced the cytopathic effect by 50%. When testing the effect on the RV-64 virus.

Such formulations contain from 0.1 micrograms or less to 99% by weight of active ingredient per ml of carrier, with a pharmaceutically acceptable carrier. Preferably, the formulations have an active ingredient concentration of 0.1 to 6.0 mg / ml. The compositions may be in solid form such as tablets, capsules, granules, nutritional mixtures, feed additives and concentrates, powders, granules and the like. Liquid preparations such as sterile injectable solutions, oral suspensions or solutions may be prepared. Pharmaceutically acceptable carriers include binders such as surfactant dispersants, suspending agents, tablet binders; lubricants, flavors and colorings.

Typical formulations contain 0.1 µg of active ingredient per ml of carrier or contain, for example, 0.0025, 0.05, 025, 0.5 1.0, 10, 25 or 50% by weight of active ingredient.

Preferred compositions contain the active ingredient in micronized form, in the case of solid compositions mixed with a water-dispersible pharmaceutically acceptable carrier such as a surfactant dispersant, and in the case of a liquid composition in the form of aqueous suspensions or solutions containing a pharmaceutically acceptable suspension such as methylcellulose or hydroxy cellulose or carboxymethyl cellulose or a pharmaceutically acceptable solvent, such as ethanol.

The following describes some of the aqueous suspensions, tablets and capsules of the present invention.

(A) 50 ml deionized water was mixed with 1.0 g Avicel® RC591 Microcrystalline Cellulose (FMC Corp., Philadelphia, PA, USA) in the following order 0.15 g CMC 7HF Carboxymethyl Cellulose (Hercules Inc., Wilmington) , DE, USA), 0.05 g of Pluronic ^R polyol F68 [polyoxypropylene] poly (ethylene condensate) surfactant (Pechiney, United Kingdom), 0.1 g of potassium sorbate preservative, 60, A solution of 0 g of sucrose in 25-30 ml of deionized water, 2.0 g of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile (preferably in micronized form), preferably with the exclusion of air. The volume is adjusted to 100 ml with deionized water and the resulting suspension is passed through a suitable colloidal mill or homogenizer. For example, the resulting suspension is formulated for oral administration containing 100 mg of active ingredient per 5 ml unit dose or 200 mg of active ingredient per 10 dosage units.

If desired, any of the pharmaceutical excipients known to those skilled in the art, such as flavoring, coloring and preserving agents, may be used. In the form of the described suspension and the like, the compounds can be used in concentrations of less than 1% by volume to 10% by volume.

(B) In a similar procedure, 2g of micronized 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, 0.3 g of SeaSpen ^R PF (calcium carrageenan), Marini Colloids (Div. FMC), Springfield, N , USA] 0.5 g of CMC 7HF carboxymethylcellulose, 30 g of sucrose, 0.1 g of Pluronic ^R polyol F68 surfactant, 0.01 g of sodium lauryl sulfonate are mixed with deionized water to make a final volume of 100 ml. .

(C) Similarly, 2g micronized 2- (3,4-dichlorophenoxy) 5-nitrobenzonitrile, 2g microcrystalline cellulose, 0.1 g Pluronic ^R polyol F68 surfactant, 0.01 g sodium lauryl sulfate, 0.1 g. g of methyl paraben (4-hydroxybenzoic acid methyl ester), -0.01 g of propyl paraben (4-hydroxybenzoic acid propyl ester) are mixed with deionized water to give a final volume of 100 ml.

-9183 302 (D) The following materials are mixed together: 7 g of micronized 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, 228 g of microcrystalline cellulose, 5.5 g of corn starch, 7.5 g of Methocel ^R Ali (methylcellulose) (Dow Chemical Company, Midland, MI, USA), deionized water was added after wet granulation. The resulting wet granulate was sieved and dried. 2.0 g of magnesium stearide are added to the granules, mixed and compressed into tablets weighing 200 mg.

(E) The following materials are mixed with each other: 5 g micronized 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, 230 g StaRx ^R 1500 (modified food starch), (Colorcon, West Point, PA, USA). , 2.5 g of magnesium stearate and 12.5 g of corn starch, and the mixture is compressed into 250 mg tablets.

(F) Dissolve 5 g of 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile in 100 ml of polyethylene glycol 400 and place the solution in soft gelatin capsules at 250 mg per capsule.

(G) The following materials are mixed together: 5 g micronized 2- (3,4-dichlorophenoxy) -5-nitrobenzonitrile, 210 mg microcrystalline cellulose, 25 g lactose and 10 g corn starch. The mixture is filled into a hard gelatin capsule at 250 mg per capsule.

Some tablets or capsules according to the invention correspond to a unit dose of 250 mg. Of course, it is also possible to form units of 50 mg or 100 mg, according to the procedures described above, with appropriate changes in the amounts of the material.

The compositions are preferably formulated in mammalian dosage units for oral administration containing an effective but non-toxic amount of the active ingredient. Preferred compositions are solid dosage units containing a water-dispersible pharmaceutically acceptable carrier in an effective amount of the active ingredient.

Dosage units for oral administration such as tablets, wafers, suspensions and the like preferably contain, for example, 1 mg or less of 5, 10, 25, 50, 100, 250 or 300 mg of active ingredient per unit.

Claims (8)

Patent claims A process for the preparation of substituted benzonyls of the formula I in which X is oxygen or sulfur; R ¹ is bromo, chloro, fluoro, phenoxy, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, C 1-3 alkylaminosulfonyl -, di-, (C 1 -C 3) alkyl-5-amino-sulfonyl, benzoyl, (C 1 -C 3) alkoxy, (C 1 -C 3) alkyl, halogenated, (C 1 -C 3) alkyl or acetyl; ^R2 is hydrogen, bromo, chloro, fluoro or trifluoromethyl group; and 10 n is 1, 2,3 or 4, characterized in that a substituted benzene derivative of the formula Bz-A is reacted with a substituted benzene derivative of the formula Bz ¹ -X-Y, wherein A is halogen, X is Y, is hydrogen or a cation capable of forming a phenolate salt, Bz represents a 2-cyano-4-phenyl group and Bz represents ^one of a group of formula (a) wherein wherein R ^1, R ² and n are as defined above meanings. 2. A process as claimed in claim 1, wherein the reaction is carried out at a temperature of 60 ° C to 100 ° C. 3. The process of claim 2, wherein the reaction is an inert one 25 solvents. 4. The process of claim 3 wherein the reagents are used in an equimolar amount. 5. A process according to any one of claims ¹ to ³ , wherein Bz '-X containing Y is hydrogen, Bz ¹ is a group of formula (a) wherein R ¹ , R ² , n and X are as defined in claim 1. The compound of formula Y is reacted with 2-halo-5-nitrobenzo35-titanium in an inert organic solvent in the presence of an alkaline reagent. 6. A process according to claims 1 to 4 wherein the 3,4-dichlorophenol is reacted with 2-chloro-5-nitrobenzonitrile. 40 7. A process according to any one of claims 1 to 4, wherein the 4- (trifluoromethyl) phenol is reacted with 2-chloro-5-t-nitrobenzonitrile. 8. A process for the preparation of a pharmaceutical composition having an antiviral activity, wherein at least 45 of the compounds of formula I according to claim 1, wherein X, R ¹ , R ² and n are as defined in claim 1, are one or more conventional pharmaceutical compositions. mixed with a carrier and, if appropriate, further excipients, to form a pharmaceutical composition.