IE47930B1

IE47930B1 - Benzylidene derivatives

Info

Publication number: IE47930B1
Application number: IE556/79A
Authority: IE
Original assignee: Synthelabo
Priority date: 1978-02-27
Filing date: 1979-08-08
Publication date: 1984-07-25
Also published as: NL7901474A; NO790646L; GB2021559B; ES478070A1; DE2907379A1; PT69288A; JPS54125644A; CA1119613A; IT1113010B; LU80974A1; IT7920543A0; BE874488A; NZ189769A; GR66971B; CH637112A5; FI790656A; ATA149179A; AU520618B2; SE7901706L; DK82079A

Abstract

Compounds corresponding to the formula (I> in which X1, X2, X3 and X4 each represent, independently of one another, a hydrogen or halogen atom or a radical CH3, CH3O, NO2, CF3, C(CH3)3 or CH3CONH, n represents an integer ranging 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 or N-(alkyl)- (benzyl), and R' represents a hydrogen atom or an alkyl, the alkyls having from 1 to 4 carbon atoms, with the exception of the compounds in which R'=H when X1, X2 and X3 are each, independently of one another, H, Hal, CH3 or CH3O and X4=H and with the exception of the compound in which R'=H, X1=X3=X4=H, X2=5-Cl, n=1 and R=OH. The compounds are anti- convulsants and are useful in treating disorders of the central nervous system, e.g. epilepsy. Processes for preparing them and pharmaceutical compositions containing them are also claimed.

Description

The present invention relates to benzylidene derivatives, their preparation and their application in therapy.

Patent No. 43143 describes and claims the compounds corresponding to the formula: in which X1, X2 and X.j, which are identical or different, each represent, independently of one another, a hydrogen or halogen atom, especially chlorine or fluorine, or a methyl or methoxy radical, n represents an integer equal to at least 1 and at most 10 and R represents a hydroxyl radical or a radical 0M, NH2> NHCCH^^-COOH, NH(CH2)2-COOM (M representing an alkali metal atom, in particular sodium), NH(CH2)^-C00C2Hg, NH-cycloalkyl, NH-phenyl, NH-benzyl (it being possible for the benzyl radical to carry a substituent chosen from amongst halogen atoms and the trifluoromethyl radical), NH-alkyl, N-(alkyl)2 or N-(alkyl)-(benzyl), the linear or branched alkyl radicals having from 1 to 4 carbon atoms and the cycloalkyl radicals having from 3 to 6 carbon atoms, with the exception of the compound in which X^ = Xj = H, X2 = 5-C1, n = 1 and R = OH.

The compounds of the present application correspond to the formula (I) in which X^, X2< X3 and X4 each represent, independently of one another, a hydrogen or halogen atom or a radical CHj, CHjO, NOj, CF^, 0(ΟΗ2)3 or CH3C0NH, n represents an integer ranging from 1 to 10, R is a radical OH, 0M (M = alkali metal), NH,,, NH-cycloalkyl, NH-phenyl, NHbenzyl, NH-alkyl, N-(alkylor N-(alkyl)-(benzyl), and R1 represents a hydrogen atom or an alkyl, the alkyls 479 30 having from 1 to 4 carbon atoms, with the exception of the compounds in which R' = H when X^, Xg and X3 are each, independently of one another, H, Hal, CH^ or CH30 and X4 = H„ A group of preferred compounds comprises those in which R = OH, OM or HHg when n is According to the invention, the compounds are prepared by reacting a ketone of the formula (II) with a compound of the formula (III) NH2 - CnH2n - CO-R (III) in the form of the base or the hydrochloride, and, if desired, the resulting compounds (I) in which R' = H are then alkylated.

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

A variant of the preparation of the compounds (I) in which R‘ = H and R is NH2 consists in reacting a hydroxybenzophenone of the formula (II) with a compound H2N(CH2)n-CN.HCl (the intermediate obtained during the preparation of the compound (III) of the formula (CH2)n-CO-NH2) and then in carrying out a solvolysis of the nitrile (IV) obtained by condensation, in accordance with the following reaction scheme: The starting compounds (III) and their preparation are already described in the literature.

The starting ketones (II) are prepared 1) either from the compounds ρθϊ3 by reaction with a compound: CO Cl followed by dsmsthylation of the resulting intermediate with aluminium chloride or boron trichloride, 2) or from the compounds which are reacted with a compound .Mg Br and the intermediate is hydrolysed in order to obtain a compound 7 0 3 0 which is demethylated using aluminium chloride or boron trichloride to give the compound (II).

The ketones (II) are new with the exception of those in which X^, X2 and X3 are each, independently of one another, H, Hal, CH3, CH30 or (CHj)^ 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.

The analyses and the IR and NMR spectra confirm the structure of the compounds.

EXAMPLE 1 Sodium 4-N-[a-phenyl-2-hydroxy-5-trifluoro15 methyIbenzylidenyl]-aminobutyrate. [Χχ = 5-CP3, X2 = X3 = X4 = H, R'= H, R = ONa, n = 3] 1. 2-Hydroxy-5-trifluoromethyldiphenylmethanone. 1.1 1.68 g (0.0691 mol) of magnesium, 25 ml of anhydrous ether and 1 crystal of iodine are introduced into a 250 ml three-necked flask equipped with a reflux condenser and a dropping funnel. The mixture is heated to the reflux temperature and about 10 % of a solution of 19.52 g (0.1243 mol) of bromobenzene in 30 ml of anhydrous ether is introduced. When the reaction is well established, the remainder is introduced in such a way as to maintain reflux.

After the introduction, the mixture is heated under reflux until all the magnesium disappears. 9.5 g (0.0472 mol) of 2-methoxy-5-trifluoromethylbenzonitrile in 80 ml of anhydrous ether are then introduced in such a way as to maintain reflux and the mixture is subsequently heated at the reflux temperature for 4 hours. It is then hydrolysed, in the cold and under nitrogen, with 40 ml of 2N HC1. A precipitate forms which is filtered off, washed with ether and dried. The product is the imine hydrochloride OCH.

.NH . HC1 CF. 7 9 3 0 This hydrochloride is taken up in 50 ml of toluene and 50 ml of 25 % strength H?S0^ and the mixture is heated at the reflux temperature for 8 hours. The organic phase is then decanted, washed several times with water, dried over MgSO^ and filtered, and the toluene is evaporated off. 2Methoxy-5-trifluotomethyldiphenylmethanone is obtained.

Boiling point (0,07 mm tig 1 = .170^0. 1.2 2.8 g (1/100 mol) of 2-methoxy-5-trifluoromethyl10 diphenyImethanone and 100 ml of methylene chloride are introduced into a 250 ml reaction flask and the mixture is cooled to -60C. 10 g of boron trichloride are then introduced and the mixture is subsequently stirred at ambient temperature for 1 hour. It is poured into 1.6 litres of ice-cooled water, 250 ml of methylene -hloide ate added, the mixture is stirred, the organic chase is decanted, washed twice with water, dritd cor and filtered, and the solvent is >’’.ipiu al »’d off.

This yields pale yellow crystals which are recr yst a J ! i .· d if·.·»» pet! oleum cth»>i with vegetable char'Otil ti >· ιΐ merit . This yield.- hydroxy-5-trifluoromethyldi|ih< t·, lim tliirr-ne which melts at 84-35^0. η 2. 1.15 g of 97 % pure 4-aminobutyric acid, 300 ml of methanol and 0.62 g of sodium methylate are introduced into a 1 litre round-bottomed flask and the mixture is stirred for 2 to 3 minutes. 2.8 g of 2-hydroxy-5-trifluoro5 methyldiphenylmethanone and 300 ml of ethanol are then introduced. The mixture is evaporated at atmospheric pressure (100°C5. Finally, all the solvent is evaporated off (in vacuo) and the residue is cooled and dissolved in 1 litre of cold water. The solution is acidified to pH =4 with citric acid and extracted with chloroform, the chloroform phase is dried over MgSO^ and filtered, and the chloroform is evaporated off. This yields an oil which crystallises in petroleum ether. The crystals are filtered off, drained, washed with petroleum ether, drained and recrystallised from ether with vegetable charcoal treatment. This yields the acid which melts at 154-155°C. 2.5 g of the acid are dissolved in 150 ml of methanol, and 0.38 g of sodium methylate is added. The mixture is evaporated to dryness to yield the sodium salt which is dried in a desiccator for 1 hour at 80°C.

Melting point = 216-217°C.

Example 2 4-N-[a-(2’,4'-Dichlorophenyl)-5-chloro-2-hydroxybenzylidenylj-aminobutyramide.

[X-j. = 5-C1, X2 = H, X3 = 2’-Cl, X4 = 4'-Cl, R = NH2, R' = Η, n = 3] 1. 2-Hydroxy-2',4 *,5-trichlorodiphenylmethanone. 1.1 A solution of 2,4-dichlorobenzoyl chloride in ether is added slowly to a stirred solution, which has been heated to the reflux temperature, of 25.7 g of p-chlorophenol and 50.5 g of triethylamine in 1.2 litres of ether. The mixture is then heated at the reflux temperature for 5 hours, whilst stirring, and the products are left in contact overnight. The precipitate of Et^N.HCl is filtered off and washed with ether. The organic phase is washed with io water, bicarbonate solution and water. It is dried over MgSO^ and filtered^and the filtrate is concentrated to about 3/4 of its original volume. p-Chlorophenyl 2,4dichlorobenzoate precipitates. The mixture is cooled and the precipitate is filtered off, drained and dried in a heated desiccator at 60°C.

Melting point = 124-125°C. 1.2 55.5 g of the above ester are heated to the melting point. The liquid is stirred and 55.5 g of AlCl^ are added. The mixture is then heated to 190° and stirred for 15 minutes at this temperature. After cooling, the residue is ground and hydrolysed. It is poured into 800 g of a mixture of water + ice + 100 ml of concentrated hydrochloric acid, whilst stirring. The mixture is then extracted with chloroform, the extract is dried over MgSO^ and filteredjand the filtrate is evaporated to dryness.

The residue is recrystallised from petroleum ether, filtered off and dried in a desiccator. The product melts at 47830 96-97°C. 2. 4-N-[a-(2',4'-Dichlorophenyl)-5-chloro-2-hydroxybenzylidenyl]-aminobutyramide.

A solution of 12.8 g of the ketone obtained under 1, 5 5.8 g of Y-aminobutyramide in the form of the hydrochloride and 2.4 g of MeONa in 500 ml of methanol is evaporated to dryness.

Thereafter, 350 ml of alcohol are added to the residue and evaporated off; this is performed 4 times in succession and the last 2 evaporations are completed under reduced pressure. The residue is dissolved in CHCl^.

The solution is washed with water, dried over MgSO^ and filtered}and the filtrate is evaporated to dryness. The residue crystallises in ether. The crystals are filtered off on a frit and drained. The product is then treated with charcoal in methanol, the mixture is filtered and the filtrate is evaporated to dryness. The residue is recrystallised from alcohol and the crystals are filtered off, washed with ether, drained and dried in a heated desiccator.

Melting point = 141-l42°C, example 3 4-N-[a-(4'-Chlorophenyl)-5-tert.-butyl-2-hydroxybenzylidenyl]-aminobutyric acid.

[X-L = 5-C(CH3)3, X2 = H, X3 = 4'-Cl, X^ = Η, n = 3, R' = H, R = OH] 1. 5-Tert.-buty1-4*-chloro-2-hydroxydiphenylmethanone. 1.1 128 g of p-chlorobenzoyl chloride and 0.25 g of freshly melted and ground ZnClg are added, whilst stirring, to 120 g 479 30 of p-tert.-butylanisole in 180 ml of tetrachloroethane.

The mixture is then heated at 14O°C for 40 hours, whilst stirring. The solvent is then evaporated off and the residue is distilled under reduced pressure. The distil5 late crystallises in petroleum ether. The 5-t-butyl-4'chloro-2-methoxydiphenylmethanone is recrystallised from petroleum ether with vegetable charcoal treatment.

Melting point = 46-47°C, 1.2 46.3 g of AlClj are added, whilst stirring, to 88 g of 10 the previously obtained compound in 150 ml of benzene and the mixture is heated at 70° for 12 hours. After cooling, it is then hydrolysed by pouring it onto ice and concentrated hydrochloric acid and stirring. The organic phase is decanted, washed with water, dried over MgSO^ and filtered?and the filtrate is evaporated to dryness. The residue crystallises in petroleum ether. The crystals are filtered off on a frit, drained and recrystallised from methanol with vegetable charcoal treatment. The product is dried in a desiccator.

Melting point = 64-65°C 2. 4-N-[a-(41-Chlorophenyl)-5-tert.-butyl-2-hydroxybenzylidenyl]-aminobutyric acid.

A solution of 5.4 g of 4-aminobutyric acid, 3 g of MeONa and 15.4 g of the previously obtained ketone in 500 ml of methanol and 300 ml of alcohol is evaporated to dryness. 600 ml of alcohol are added and the mixture is evaporated to dryness, ultimately under reduced pressure. This oper15 ation is repeated twice, The residue is dissolved in water which has been acidified to pit 4 with citric acid.

The solution is extracted with chloroform, the extract is dried over MgSO^ and filtered,and the filtrate is evaporated to dryness. The precipitate obtained is transferred onto a frit with petroleum ether. It is recrystallised from ethyl ac-cate with vegetable charcoal treatment. The product is dried in a heated desiccator.

Melting point = 't./iO-l4loC example 4 4-N-[a-(4'-Chlorophenyl)-5-fluoro~2-methoxybenzylidonyll-amitiobutyramide, [Xx = 5-F, X3 = 4'-Cl, X? = X4 --- H, R = NH2, Ft' = CH,., n = 3] A solution of 3.4 g of 4-M-[a-(4'-chlorophenyl)15 5-f3,uoro-2-hydroxytencjlid7Hyl]-amin9butyraiaide and 0.55 g of sodium methylate in 150 ml of methanol is evaporated to dryness. The residue is then dried in a heated desiccator at 120°.

After cooling, the residue is dissolved in 100 ml of DMSO (dimethylsuiph ide), The solution is stirred and 3 g of methyl iodide in ml of DMSO are introduced dropwise into the stirred solution. The mixture is then stirred at ambient temperature for 30 minutes, The mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 200 ml of chloroform and the solution is washed wit-h water, dried and evaporated 47980 to dryness. The residue is transferred onto a frit with ether. The product is recrystallised from alcohol and the crystals are washed with .acetone and ether, drained and dried in a heated desiccator.

Melting point = 154.5 - 155.5°C.

The following table shows the compounds which have been prepared by way of examples and illustrate the formula (I).

TABLE I Com- poundX1 x2 x3X4 n R R' Melting point (¾) 1 ' 5-N02 H 4'-Cl H 3 OH H 240 (dec/ 2 5-CHjCONH H H H 3 nh2 H 240 (dec/ 3 5-CF3 H 4'-CF3 H 3 ONa H 238 (dec.; 4 5-CF3 H 3'-CF3 H 3 ONa H 218 (dec.; 5 5-CF3 H 4'-CF3 H 3 nh2 H 119.6 6 5-CFj H 3'-CF3 H 3 nh2 H 98.7 7 5-CF3 H 4'-F H 3 OH ONa H H 173.5 >250 8 5-N02 H 4'-Cl H 3 nh2 H 172.5 9 5-CF3 H 4'-F H 3 nh2 H 120.6 10 5-F H 4'-N02 H 3 OH ONa H H 169-70 180 (dec/ 11 5-F H 4'-N02 H 3 nh2 H 190-1 12 5-CF3 H H H 3 OH ONa II H 154-5 216 (dec.; 13 5-CF3 H H H 3 nh2 H 93-4 14 5-C(CH3)3 H 4'-Cl II 3 OH H 140-1 15 5-C(CH3)3 H 4'-Cl H 3 nh2 H 121-2 16 5-NO2 H H H 3 OH ONa H H 177-8 227 (dec.) 17 5-N02 H II H 3 nh2 H 185-6 18 5-C(CH3)3 H E H 3 nh2 H 135-6 19 5-C(CH3)3 H H H 3 oh H 131-2 20 5-C1 H 4'-Cl 2-C1 3 nh2 H 141-2 21 5-C1 H 4'-Cl 2-C1 3 J OH ONa H H 172-4 245 (dec.) 7 9 3 0 TABLE 1 (Continued) Com- poundX1x2X3 X4 n R R' Melting point °C 22 5-F H 4'-CF3 H 3 OH nh2 140-1 151-2 23 5-F H 4'-Cl H 3 nh2 CH3 155 24 5-F H 4'-CF3 H 3 ON a H > 250 25 5-Br H 2'-Cl 4'- C1 3 OH H 118-119 26 5-Br H 2'-Cl 4'- C1 3 nh2 H 131-132 47030 The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.

The acute toxicity was determined in mice by intra5 peritoneal administration. The LD 50 (50 % lethal dose), namely the dose which causes death in 50 % of the animals, varies from 700 to more than 1,000 mg/kg.

The activity of the compounds was shown by the antagonism towards the mortality induced by bicucullinein io mice.

Bicuculline is a relatively selective blocking agent for GABA-ergic post-synaptic receptors and its convulsive and lethal effects are antagonised by compounds which raise the cerebral concentration of GABA or possess a GABA15 mimetio activity'.

The 50 % active dose (AD 50), namely the dose which protects 50 % of the animals against the effect of bicuculline, was evaluated for the substances studied.

The AD 50 of the compounds of the invention varies 2o from 20 to 80 mg/kg, administered intraperitoneally.

The compounds of the invention are active as anticonvulsive agents. They can be used in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of psychoses and certain neurological diseases such as epikpsy.

The invention consequently comprises all pharmaceutical compositions which contain the compounds (I) as active principles, in association with any excipients suit able for their administration, in particular their oral administration (tablets, dragees, sugar-coated pills, capsules, cachets and solutions or suspensions which can be taken orally), or parenteral administration.

The daily dosage can range from 100 to 1,500 mg.

Claims

CLAIMS:

1. Compouhii?cotitf.ponU!.u·ι tc th·? formula (I) OP. ‘ in which Xj , X.., X- ( and X^ t a-.-h r· μι . sent, independently 5 of one another , a hydrogen η» 1ι.ιΙο.|.·η atom or a radical CHy CH, N0 ? . CF, , C(CJI 3 ) 3 or CH-jCONH, n represents an Integer ranging from J to lo, R is a radical OH, OM (M = alkali metal), NH 3 , NH-cycloalkyl, NH-phenyl, L’H-borizyl, NH-alkyl, N- (a lkyl 1 2 or N-(alkyl)10 (benzyl), and R‘ represents a hydronen atom or an alkyl, the alkyls having from 1 to 4 carbon atoms, with the exception of the compounds in which R' - II when X^, X 2 and X^ are e.icli, independently ο), ,ηο another, II, Hal, CH 3 or CH 3 O and X 4 = 11,

2. Compounds according to claim 1, in which R = OH, OM (M = alkali metal) or ΝΗ 2 ·

3. Compounds according to claim 2, in which

4. Any one of the compounds 1 to 26 hereinbefore 5. Process for the preparation of the compounds according to claim 1, which process comprises reacting a ketone of the formula (II) with a compound of the formula NH O -C -COR 2 n 2n (III) in the form of the base or the hydrochloride, and, if desired, then alkylating the resulting compounds (I) in which R' = H, in order to prepare the compounds (I) in which R' = alkyl, the radicals having the meanings given in claim 1. 6. A process according to claim 5 substantially as described in any one of the foregoing Examples 1 to 4. 7. A compound (I) when prepared by a process according to claim 5 or 6. 4 7S30 R' = H. listed.

5. 8. A pharmaceutical composition comprising a compound according to any of claims 1 to 4 and 7 together with a pharmaceutically acceptable excipient or diluent.