NO790646L - PROCEDURE FOR THE PREPARATION OF BENZYLIDE DERIVATIVES - Google Patents

Description

Method of manufacture of

benzylidene derivatives.

There are previously known compounds with the general formula

in which

X^, X2 and X^/ which are the same or different, each representing hydrogen or halogen, especially fluorine or chlorine, or methyl or methoxy,

n stands for an integer from 1 to 10/and

R stands for hydroxyl, OM, NH2, NH(CH2)3-C00H, NH(CH2)3-G00M

(M stands for an alkali metal, especially sodium), NH(CH2)3-COOC2H5,

NH - cycloalkyl, NH - phenyl, NH - benzyl (benzyl -

the radical may carry a substituent selected from halogen and trifluoromethyl)

NH - alkyl, N - (alkyl)2, N - (alkyl) - (benzyl),

wherein the alkyl groups are linear or branched and contain i to 4 carbon atoms and the cycloalkyl groups have 3 to 6 carbon atoms,

as well as acid addition salts thereof.

The present invention relates to a method for the preparation of therapeutically active compounds of formula (I)

in which

X^, X2, X^ and X4 each stand for hydrogen or halogen,

a radical CH3, CH3O, NO2, CF3, C(CH3)3 or CH3CO NH,

n stands for an integer from 1 to 10,

R is a radical OH, OM (M = alkali metal), NH2,-NH-cycloalkyl, NH-phenyl, NH-benzyl, NH-alkyl, N-(alkyl)2, N-(alkyl)-(benzyl), and

R' stands for a hydrogen atom or alkyl,

wherein the alkyl groups have 1 to 4 carbon atoms,

with the exception of compounds in which R<1> is H when X^, X2 and X^ are each independently H, Hal, CE^, CH3O and X^=H and the compound in which R'=H, X1=X3=X4= H, X2=Cl-5, n=1 and R=OH,

and the peculiarity of the method according to the invention is that a ketone of formula (II)

wherein X^, X2, X^ and X^ have the above meaning, is reacted with a compound of formula (III)

in which n and R have the above meaning, in the form of base or hydrochloride, and if desired, the obtained compounds of formula (I) in which R'=H are alkylated.

A group of preferred compounds is made up of those in which R=OH, OM or NH2 reaches 3.

The reaction is carried out in an alcoholic solvent such as methanol or ethanol, at a temperature of from 10°C to the boiling temperature of the solvent, in the presence of an alkali metal or an alkali metal alcoholate.

A variant of the method for the preparation of compounds (I) in which R'=H and R=NH2 consists in reacting a hydroxybenzophenone of formula (II) with one compound H2N (CH2)n CN.HC1 in which n has the above meaning (intermediate product obtained in the preparation of the compound (III) with the formula H2N-(CH2)n-CO-NH2 where n has the above meaning.)

To carry out a solvolysis of the nitrile (IV) obtained by condensation according to the following reaction scheme:

The starting compounds (III) and their preparation have already been described in the literature.

The starting ketones (II) are prepared either

1) by proceeding from connections

wherein X₂ and X₂ have the above-mentioned compound, by reaction with a compound

in which X^ and X^ have the above meaning,

after which the intermediate product obtained is demethylated with aluminum chloride or boron trichloride, or

2) by proceeding from the connections

wherein X₂ and X₂ have the above compound

by reaction with a compound

wherein X^ and X^ have the above meaning and hydrolyze the intermediate to obtain a for bond

wherein X^, X^, X 3 and X^ have the above compound

which is demethylated to the compound (II) using aluminum chloride or boron trichloride.

The ketones (II) are new with the exception of those in which X^, X2 and X^ are each independently H, Hal, CH3/^3^' ^^3)3 when X4=H.

The preparation of the ketones (II) is illustrated in the examples for the preparation of the final compounds (I).

The following examples illustrate the invention.

Analysis of the IR and RMN spectra confirms the structure of the compounds.

Several compounds corresponding to the general formula of previously known compounds (compounds 24 to 47) are exemplified below.

sodium

Example 1 N-[α-phenyl-2-hydroxy-5-trifluoromethyl-benzylidene-4-amino-butyrate

1. 2-hydroxy-5-trifluoromethyl-diphenyl-methanone.

1.1 In a 250 ml wooden-necked flask, equipped with a heating attachment and bromine

funnel, introduce 1.68 g of magnesium (0.0691 mol), 25 ml of anhydrous ether and 1 iodine crystal. The mixture is brought to reflux temperature and about 10% of a solution of 19.52 g of bromobenzene (0.1243 mol) in 30 ml of anhydrous ether is introduced. After the reaction is dabbed off, the remainder is introduced so that the reflux is maintained. After the introduction, the mixture is brought to the reflux temperature until the magnesium has completely disappeared. 9.5 g (0.0472 mol) of 2-methoxy-5-trifluoromethyl-benzonitrile in 80 ml of anhydrous ether are then introduced so that the reflux temperature is maintained, after which it is heated for 4 hours at the reflux temperature. It is then hydrolysed in the cold and under nitrogen with 40 ml of 2N HC1. A precipitate is formed which is filtered off, washed with ether and dried. It is the hydrochloride of the imine with formula

The hydrochloride is taken up in 50 ml of toluene and 50 ml of I^SO^2 5% and brought to the reflux temperature for 8 hours. The organic phase is decanted, washed several times with water, dried over MgSO 4 , filtered and the toluene evaporated. 2-ethoxy-5-trifluoromethyl-diphenyl-methanone is obtained.

KP-0.07=170°C-

1.2 2.8 g (1/100 mol) of 2-methoxy-5-trifluoromethyl-diphenyl-methanone, 100 ml of methylene chloride are introduced into a 250 ml reaction flask and it is cooled to -60°C. 10 g of boron trichloride are then introduced and the mixture is stirred for 1 hour at ambient temperature. The mixture is poured into 1.5 l of ice-mixed water, it is added

250 ml methylene chloride, stirred, the organic phase decanted, washed twice with water, dried over MgSO 4 , filtered and the solvent evaporated. Light yellow crystals are obtained which are recrystallized from petroleum ether by treatment with charcoal.,.. 2-hydroxy-5-trifluoromethyl-diphenyl-methanone is obtained as

melts at 84 - 85°C.

2. Sodium N-(oc-phenyl-2-hydroxy-5-trifluoromethyl-benzylideneyl)-4-amino-butyrate.

1.15 g of 4-aminobutyric acid 97%, 300 ml of methanol and 0.62 g of sodium methylate are introduced into a 1 1 flask and the mixture is stirred for 2 to 3 minutes. 2.8 g of 2-hydroxy-5-trifluoromethyl-diphenyl-methanone and 300 ml of ethanol are then introduced. The mixture is evaporated at atmospheric pressure (100°C). The solvent is then completely evaporated (under vacuum), the residue is cooled and dissolved in 1 1 cold water. The mixture is acidified to pH=4 with citric acid, -• extracted with chloroform, the chloroform mixture is dried over MgSO^, filtered and the chloroform is evaporated. An oil is obtained which is crystallized from petroleum ether. It is filtered, filtered off with suction, washed with petroleum ether, filtered off with suction and recrystallized from ether by treatment with charcoal. The acid is obtained which melts at 154 - 155°C.

Dissolve 2.5 g of acid in 150 ml of methanol and add 0.38 g of sodium methylate. It is evaporated to dryness and the sodium salt is obtained, which is dried for 1 hour at 80°C in a drying cabinet.

Mp.= 216 - 217°C.

Example 2 N-[cc-(2•,4'-dichloro-phenyl)-5-chloro-2-hydroxy-benzylideneyl-7-4-amino-butyramide.

/ X^ Cl- 5, X^H, X3=Cl-2', X4=Cl-4', R=NH2, R'=H,

n=37

1. 2-hydroxy-2',4',5-trichloro-diphenyl-methanone.

1.1 To a stirred solution of 25.7 g p-chlorophenol and 30.3 g

triethylamine in 1.2 1 ether brought to the reflux temperature, an ether solution of 2,4-dichloro-benzoyl chloride is added slowly. It is then heated to the reflux temperature and stirred for 3 hours and the products are kept in contact with each other overnight. The precipitate of Et^N.HCl is filtered off and washed with ether. The organic phase is washed with water, bicarbonate water and with water,

dried over MgSO^, filtered and concentrated to about 3/4

volume. The 2,4-dichlorobenzoate of p-chlorophenyl precipitates out. It is cooled, filtered, filtered and dried by heating to 60°C.

Temp. = 124 - 125°C.

1.2 35.5 g of the preceding ester is heated to melting and it is stirred and 35.5 g of AlCl^ is added. It is then heated to 190 C and stirred for 15 min. at this temperature. After cooling, the residue is crushed and hydrolysed. It is brought under stirring into 800 g of a mixture of water+ice+100 ml of concentrated hydrochloric acid. It is extracted with chloroform, dried over MgSO 4 , filtered and evaporated to dryness. It is recrystallized from petroleum ether, filtered off with suction and dried in a drying oven. The product melts at 96 - 97°C. 2. N-[α-(2<1>,4'-dichloro-phenyl)-5-chloro-2-hydroxy-benzylideneyl]-4-amino-butyramide.

A solution of 12.8 g of the ketone obtained under 1 above,

furthermore, 5.8 g of IT-amino-butyramide in the form of hydrochloride and 2.4 g of MeONa in 500 ml of methanol are evaporated to dryness.

Then evaporate four times 3 50 ml of alcohol and finish

the last two evaporations under reduced pressure. The residue is dissolved in CHCl-j. It is washed with water, dried over MgSO^, filtered and evaporated to dryness. The residue is crystallized from ether. It is filtered on a glass filter and treated with carbon in methanol, filtered and evaporated to dryness. It is recrystallized from alcohol, filtered, washed with ether, suction filtered and

dried in a drying oven.

Mp.= 141 - 142°C.

Example 3 N-(4'-Chlorophenyl)-5-tertiobutyl-2-hydroxy-benzylidene[7-4-aminobutyric acid

/k1=C(CH3)3-5/ X^H, X3=Cl-4', X4=H, n=3, R'=H, r=oh/

1. 5-tertiobutyl-4<1->chloro-2-hydroxy-diphenyl-methanone.

1.1 To 120 g of p.tertiobutyl-anisole in 100 ml of tetrachloroethane, add, while stirring, 128 g of p.chloro-benzoyl chloride and 0.25 g of freshly melted and crushed ZnCl2. It is then heated to 140°C with stirring for 40 hours. The solvent is then evaporated and distilled under reduced pressure. The distillate is crystallized from petroleum ether. 5-t-butyl-4'-chloro-2-methoxy-diphenyl-methanone is recrystallized from petroleum ether by treatment with charcoal.

Mp.= 46 - 47°C.

1.2 To 88 g of the compound obtained in the above in 150 ml of benzene, 46.3 g of A1C13 are added while stirring and it is heated at 70°C for 12 hours. Then, after cooling, the product is hydrolysed by pouring over ice and concentrated hydrochloric acid while stirring. Decant, wash with water, dry over MgSO^, filter and evaporate to dryness. The residue is crystallized from petroleum ether, filtered on a glass filter, dried and recrystallized from methanol by treatment with charcoal. One dries in a drying oven.

Temp. = 64 - 65°C.

2. N-(4'-Chloro-phenyl)-5-tertiobutyl-2-hydroxy-benzylideneyl-7-4-amino-butyric acid.

A solution of 5.4 g of 4-aminobutyric acid, 3 g of MeONa and 15.4 g

of the ketone obtained above in 500 ml of methanol and 300 ml of alcohol is evaporated to dryness. 600 ml of alcohol are added and evaporated to dryness, and finally under reduced pressure. This operation is repeated twice. The residue is dissolved in water acidified to pH 4 with citric acid.

It is extracted with chloroform, dried over MgSO^, filtered and evaporated to dryness. The precipitate obtained is treated on a glass filter with petroleum ether. It is recrystallized from ethyl acetate by treatment with charcoal. You dry in a heated drying cabinet.

Temp. = 140 - 141°C.

Example 4 N-[α-(4'-chloro-phenyl)-5-fluoro-2-methoxy-benzylideneyl]

4-amino-butyramide.

/X1=F-5, X3=Cl-4', X2=X4=H, R=NH2, R' =CH3, n=3_7

A solution of 3.4 g of n-(4'-chloro-phenyl)-5-fluoro-2-hydroxy-benzylideneyl-7-4-amino-butyramide and 0.55 g of sodium methylate in 150 ml. methanol is evaporated to dryness and then the residue is heated in a drying cabinet at 120°C.

After cooling, the residue is dissolved in 100 ml of DMSO (dimethylsulfoxide).

Stir and add 3 g of methyl iodide in 25 ml of DMSO drop by drop into the stirred solution. Then stir at ambient temperature for 30 min.

It is evaporated to dryness under reduced pressure, the residue is dissolved in 200 ml of chloroform, washed with water, dried and evaporated to dryness. The residue is washed on a glass filter with ether. The product is recrystallized from alcohol, washed with acetone and ether, dried

and heated in a warming cabinet.

Temp. = 154.5 - 155.5°C.

The following table shows exemplary compounds with formula (I). The compounds are subjected to pharmacological testing which shows their effect on the central nervous system.

Acute toxicity was determined in mice by intraperiteoneal administration. LD 50 (lethal dose 50%) resulted in death in 50% of the animals fed from 700 to more than 1000 mg/kg.

The action of the compounds was demonstrated by antagonism of mortality induced by bicuculline in mice.

Bicuculline is a relatively selective blocking GABA-ergic post-synaptic compound and its convulsive and lethal action is antagonized by compounds that increase the cerebral GABA content or have a GABA-mimetic effect.

Active dose 50% (AD 50) is judged as the dose that protects. -50% of the animals against the impact of bicuculline, for the investigated substances.

AD 50 for: the compounds varies between 20 and 80 mg/kg by intraperitoneal administration.

The compounds are active as anticonvulsants and can be used in human and veterinary therapy for the treatment of various disorders in the central nervous system, e.g. treatment of psychoses and various neurological disorders such as epilepsy.

The compounds can be used as active ingredients either alone or together with usual additives for oral or parenteral administration.

The daily dose amounts to 100 to 1500 mg.

Claims (2)

1. Process for the production of therapeutically active substances compounds with the general formula in which X^ , X2 , X^ and X^ each stand for hydrogen or halogen, CH3 , CH3 0, N02 , CF3 , C(CH3 )3 or CH3 CO NH, n stands for an integer from 1 to iO, R is a radical OH, OM (M=alkali metal), NH2 , NH-cyclo alkyl, NH-phenyl, NH-benzyl, NH-alkyl, N-(alkyl)2 , N-(alkyl)-(benzyl), and R' stands for hydrogen or alkyl, wherein alkyl has 1 to 4 carbon atoms, with the exception of compounds in which R'=H when X^ , X2 and X3 are each independently H, Hal, CH3 , CH3 °°9 X4 = H and the compound in which R <1> =H, X1 =X3 =X4 =H, X2 =Cl-5, n=1 and R=OH, as well as therapeutically tolerable acid addition salts thereof, characterized in that a ketone of formula (II) in which X^ , X^ X^ and X^ have the above meaning, is reacted with a compound of formula (IV) in which R and n have the above-mentioned meaning, in the form of base or hydrochloride, and if desired, compounds obtained with formula (I) in which R<1> =H are alkylated to produce compounds (I) in which R'=alkyl. 2. New ketones, characterized in that they have the formulas (II) in which X^ , X2 , X^ and X^ independently of each other stand for hydrogen or halogen, <C> H3 , CH3 0, N02 , CF3/ C(CHo _) 3 or CH^ CO N■ H-, with the exception of compound wherein X^ , X^ are each independently H, Hal, CH3 , <CH>3 0, when X4 is equal to H.