NO841878L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DIFENYLAZOMETIN COMPOUNDS - Google Patents

Abstract

1. Claims (for the contracting states : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) Diphenylazomethines containing an esterified chain and corresponding to the formula (I) see diagramm : EP0125975,P15,F1 in which X1 , X2 and X3 independently of one another each represent a hydrogen or halogen atom or a (C1-6 )alkyl radical, R represents a straight-chain or branched (C1-6 )alkyl radical, n represents an integer from 1 to 10 and R' represents a straight-chain or branched (C1-6 )alkyl radical, a (C3-6 )cycloalkyl(C1-4 )alkyl radical, a (C3-7 )cycloalkyl radical, a (C2-6 )alkenyl radical, a (C3-6 )alkynyl radical, a (C1-4 )alkoxy(C1-4 )alkyl radical, a hydroxy-(C1-4 )alkyl radical, a (C1-4 )alkoxy-[(C1-4 )alkoxy]m -(C1-4 )alkyl radical, in which m is an integer from 1 to 3, a (C1-4 )alkoxycarbonyl(C1-4 )alkyl radical, a tetrahydrofurylmethyl radical, a phenyl-(C1-4 )alkyl radical which can carry a halogen atom, or a (C1-4 )alkoxy radical. 1. Claim (for the contracting state AT) Process for the preparation of diphenylazomethines containing an esterified chain and corresponding to the formula (1) see diagramm : EP0125975,P17,F1 in which X1 , X2 and X3 independently of one another each represent a hydrogen or halogen atom or a (C1-6 )alkyl radical, R represents a straight-chain or branched (C1-6 )alkyl radical, n represents an integer from 1 to 10 and R' represents a straight-chain or branched (C1-6 )alkyl radical, a (C3-6 )cycloalkyl (C1-4 )alkyl radical, a (C3-7 )cycloalkyl radical, a (C2-6 )alkenyl radical, a (C3-6 )alkynyl radical, a (C1-4 )alkoxy-(C1-4 )alkyl radical, a hydroxy-(C1-4 )alkyl radical, a (C1-4 )alkoxy[(C1-4 )alkoxy]m -(C1-4 )alkyl radical, in which m is an integer from 1 to 3, a (C1-4 )alkoxy-carbonyl-(C1-4 )alkyl radical, a tetrahydrofurylmethyl radical, a phenyl-(C1-4 )alkyl radical which can carry a halogen atom, or a (C1-4 )alkoxy radical, process characterised in that either a benzophenone (II) see diagramm : EP0125975,P17,F2 is reacted with the hydrochloride of an ester of an omega-amino-alkanoic acid (III) H2 N-(CH2 )n -COOR', HCl or an acid (IV) see diagramm : EP0125975,P17,F3 is reacted with an alcohol R'OH (V) in the presence of carbonyldiimidazole, or an alkali metal salt of an acid (VI) see diagramm : EP0125975,P18,F1 is reacted with a compound R'Y (VII), in which Y represents a halogen atom or a labil group, such as mesyl or tosyl, the radicals X1 , X2 , X3 , n, R and R' having the meanings given above.

Description

The present invention relates to a method for the production of therapeutically active diphenylazomethine compounds which carry an esterified chain, with the general formula (I)

in which

X^, X£ and X, each independently represent hydro-

gen or halogen or (C1-Cg )-a 1ky 1 ,

R represents straight-chain or branched (C1g)-alkyl,

n represents an integer from 1 to 10, and

R' represents straight chain or branched (C^-Cg)-a 1ky1, (C3-C6)-cycloalkyl - (C1-4)-alkyl , (C3-y)-cycloa 1ky1, (C2-6)<->

alkenyl, (C3_6)-α 1kynyl, (C1_4)-α 1oxy-(C1_4)-α 1ky1, hydroxy-(C1_4)-alkyl, (C1_4)-alkoxy-[(C1_4)<-α>lkoxy]m-( C1_4)-alkyl in which m is an integer from 1 to 3, (C14)-a 1oxycarbonyl1-(C1_4)-a 1ky1, tetrahydrofurylmethyl, phenyl-(C1 4)-alkyl which may bear a halogen atom or (C1_4 )-a 1 coke and the method is characterized by either

a benzophenone (II)

in which

X 1 , X 2 , and R have the above meaning, are reacted with the hydrochloride of a c*j-amino-alkanoic acid (III)

in which

R<1>and n have the above meaning, or

an acid (IV)

in which

X,|, X2, X^, R and n have the above meaning, is reacted with an alcohol R'OH (V) in which R<1> has the above meaning, in the presence of carbonyldiimidazole, or a a 1 ka 1imeta11 sa 11 of the acid (VI)

in which

X,|, X2, X3, R and n have the above meaning and M means a a 1 ka 1imeta11, is reacted with a compound R 1 Y (VII) in which R<1> has the above meaning and Y represents a halogen atom or a labile group such as mesyl or tosyl.

These features of the invention appear in the patent claim.

The preferred compounds are those corresponding to the formula

in which

X.p X2 and X3 independently of each other represent hydrogen,

chlorine or methyl, ethyl or propyl,

n represents an integer 3, 4 or 5,

R' represents methyl, ethyl, n-propyl or isobutyl,

R' represents straight chain or branched (C1 g)-alkyl, cyclopropyl methyl 1, cyc 1 opentyl methyl 1, cyclohexylmethyl, allyl, hydroxyethyl 1, (C1 4)-a 1 oxyethyl 1, ethoxycarbonylmethyl 1, tetrahydrofurylmethyl 1, 2-(2-methoxy-ethoxy -ethyl, 2-[2-(2-methoxy-ethoxy)-ethoxyj-ethyl, cyclohexyl, cyclopentyl, benzyl, pro-pargyl, methoxy-benzyl or iso-penten-2-yl, especially those compounds in which X,j, X2 and X3 independently of each other represent a hydrogen atom, a chlorine atom or the methyl radical,

n is an integer 3, 4 or 5,

R represents methyl, ethyl or n-propyl, and

R' represents methyl, ethyl, propyl, allyl or ethoxyethyl and more particularly the compounds corresponding to the formula

in which

the radicals have the above meanings and among these are

those compounds particularly preferred wherein

X1 is a chlorine atom, X2 is a chlorine atom or the methyl radical and X^ is a hydrogen atom.

The compounds can be produced using the following three methods:

Method A

Method B Method C

M = a 1 ka 1imeta11

Y = halogen or a labile group such as mesyl or tosyl.

According to method A, a ketone (II), described in French patent document 81 21559 or 82 19981, is reacted with hydrochloride in that of an ester of the ^o-amino-alkanoic acid (III) in a solvent such as alcohol (methanol or ethanol) at a temperature from 60 to 100°C.

In method B, an acid (IV), described in French patent document 81 21559 or 82 19981, is reacted with an alcohol R'OH (V) in the presence of carbonyldiimidazole in a solvent such as tetrahydrofuran, at a temperature from 60 to 140°C.

In method C, an alkali met a 11s a 11 of the acid (VI), described in French patent document 81 21559 or 82 19981, is reacted with a compound R<1>Y (VII) in a solvent such as anhydrous dimethyl sulfoxide in the presence of a base as triethylamine at a temperature from 50 to 150°C.

The hydrochlorides of the esters of the o>-amino-alkanoic acid (III) can be prepared from the cu-amino-alkanoic acid by reaction with the corresponding alcohol R'OH in the presence of SOC^-

The alcohols R'OH (V) and the compounds R<1>Y (VII) are described

in the literature.

The following examples illustrate the invention.

Microanalyses and spectra IR, UV and RMN confirm the structure

of the compounds.

EXAMPLE 1 4-[(2-k1or-2-hydroxy-3n-propyl-phenyl)(4-chloro-phenyl)methylene]amino}-butanoic acid ethyl ester. (X1= 5-C1,

<X>2= 4-C1, X3= H, n = 3, R = n-C3H?, R<1>= C2H5)

1. A suspension of 206 g is stirred in an oil bath

(2 mol) 4-amino-butanoic acid and 1200 cm<3>ethanol at 50-60°C. Over the course of 1 hour, 252 ml of SOC12 are added and the temperature is brought to the reflux temperature and held there for 3 hours.

The mixture is brought to dryness and the residue is washed twice with 500 cm<3>ether.

After purification of the solution of the residue in ethanol using vegetable carbon and washing with ether, white hydroscopic crystals 11 are obtained.

Temp. = 72°C

2. A mixture of 6 g (0.0194 mol) of (5-chloro-2-hydroxy-3n-propyl-phenyl)(4-chlorophenyl)methanone, 4.06 g (0.0242 mol) of the hydrochloride of 4- amino-butanoic acid ethyl ester and 4.06 g (0.0483 mol) of sodium bicarbonate in 600 ml of ethanol are evaporated to dryness. The reaction mixture is stirred under reduced pressure at 100°C for 15 minutes.

It is then evaporated 3 times with 500 ml of ethanol. The mixture is taken up in 300 ml CH2C12 and 200 ml water, the reaction mixture is decanted, the organic phase is separated and dried over MgSO4. It is evaporated to dryness and the residue is purified on a sieve 1 ikab 1 onne while eluting the mixture with 2.5 1 C H 2 C12 -

The fractions are dried over MgSO4, filtered and evaporated to dryness. The residue is crystallized in 50 ml of ether. Filter, filter and dry the crystals in a desiccator in the presence of P205-

Srrp. = 57-58°C.

EXAMPLE 2 5-[(5-chloro-2-hydroxy-3-methyl-phenyl)(4-chloro-phenyl)methylene]amino]-pentanoic acid ethyl ester. [X1= 5-C1,

X2=4-C1,<X>3= H, n = 4, R = CH3>R' = C2H5].

15 g (0.0533 mol) (5-chloro-2-hydroxy-3-methylphenyl)(4-chlorophenyl)methanone, 2.96 g (0.0547 mol) sodium methylate and 6.25 g (0.0533 mol) 5-amino-pentanoic acid. 400 ml of toluene and 100 ml of methanol are added and the azeotropic mixture that is mixed is gradually heated and distilled, after which it is heated at the boiling point for toluene using a Dean-Stark apparatus for 6 hours.

Evaporate to dryness, triturate the residue in ether and filter off the solid. This is introduced into water and acidified to pH = 4 with citric acid. The solid is filtered off and dissolved in chloroform, dried over magnesium sulphate and evaporated. The compound recrystallized from 11 is obtained from a cyclohexane/benzene mixture. The solid is re-dissolved in methylene chloride and the solution is passed through a silica column eluting with methylene chloride and then with a mixture of methylene chloride/ethyl acetate 80/20. After evaporation, a solid is obtained which is dried.

Temp. = 110-1110 C.

5 g (0.0131 mol) of 5-|[(5-k 1 or-2-hydroxy-3-methyl-phenyl) (4-chloro-phenyl) methylene]aminoj' pentanoic acid obtained in the preceding is dissolved in 100 ml of tetrahydrofuran. 3.5 g (0.0215 mol) of carbonyldiimidazole are then added and the reaction mixture is stirred at room temperature for 1 hour. 3.5 g (0.0215 mol) of carbonyldiimidazole are added again and stirring is continued

for 1 hour. Evaporate to dryness and take up the residue in 200

ml of ether and 200 ml of water. The reaction mixture is decanted,

the organic phase is separated, dried over MgSO^, MgSO^ is filtered off and the filtrate is evaporated to dryness.

After adding 30 ml of hexane to the residue, the product crystallizes.

After filtration and recrystallisation, the crystals are dried.

Temp. = 73-74°C.

EXAMPLE 3 4 - [[(5-chloro-2-hydroxy-3-methyl-phenyl) (4-chloro-4-phenyl)methyleneamino-butanoic acid cyclohexyl methyl ester. [X, =

5-C<1,>X2= 4-C1, X3=H, n = 3, R = C<H>3>

add 5.8 g (0.0015 mol) of sodium a 1 tet of 4-(5-chloro-2-hydroxy-3-methylphenyl)(4-k1orpheny1)methylone amino-butanoic acid in 100 ml anhydrous DMS0, 2.5 ml (d = 1.27, i.e. 0.018 mol) of cyclohexylmethyl bromide and 2 drops of triethylamine are added. The reaction mixture is heated at 100°C with stirring for 4 hours. The DMS0 is then evaporated under vacuum and the residue is distributed between 100 ml of ether and 100 ml of water. The mixture is decanted, the ether phase is dried over MgSO 4 , filtered and the filtrate is evaporated to dryness. An oil is obtained which is crystallized from 40 ml of pentane. The crystals from raf are filtered, washed with 10 ml of pentane, filtered off with suction and dried in a desiccator heated to 40°C in the presence of P2°5-

Temp. = 53-54°C.

The compounds produced by the invention were subjected to pharmacological tests which show their effect on the central nervous system.

The acute toxicity was determined in mice by oral administration. The LD 50 (50% lethal dose), which causes death for 50% of the animals, is over 1000 mg/kg.

The ant ikonvu1si ve activity of the compounds is shown by antagonism towards mortality induced with bicuculline in mice.

Bicuculline is a relatively selective blocker of GABA-energetic postsynaptic receptors and its convulsive and lethal effects are antagonized by compounds that raise cerebral GABA content and have GABA-mimetic activity.

The 50% active dose (AD 50) is judged as the dose that protects 50% of the animals against the effects of the bicuculline for the investigated substances.

The AD 50 of compounds which can be prepared by the invention is 10 to 200 mg/kg by oral administration.

Those of the invention primarily in 11 only compounds are active

as anticonvulsants and also has antidepressant, anxiolytic, analgesic, anti-inflammatory, antidepressant, antiulcerous and antidyskinetic properties. They can be used in human and veterinary medicine, among other things, for the treatment of various diseases of the central nervous system, e.g. for the treatment of depression, psychosis, certain neurological diseases such as epilepsy, spasticity, dyskinesia.

The compounds can be used as active principle in association with all the usual means for their administration, especially for oral administration (tablets, dragees, gels, capsules, drinkable solutions or suspensions) or for parenteral administration.

The daily dose can range from 100 to 4000 mg.

Claims (1)

Process for the preparation of therapeutically active diphenylazomethine derivatives with an esterified chain, of the general form 1(1) in which X^ , % 2 and X 3 independently of each other represent hydrogen or halogen or (C 1 6 )alkyl, R represents straight chain or branched (C 1 _6)-a 1ky1, n represents an integer from 1 to 10, and R<1> represents straight chain or branched (C^_g)-α 1ky1, (C3_6 )-cycloalkyl-(C1_4 )-alkyl, (C3_?)-cyk1 oa 1ky1, (C2_6 )-alkenyl, (C3_5 ) -a 1 kyny1, (C1_4)-a 1koxy - (C1_4)-a 1ky1, hydroxy-(C1_4 )-alkyl, (C1_4)-a 1kok sy-[(C1_4)-a 1koxy]m-( <C > 1_4 )-alkyl wherein m is an integer from 1 to 3, (C1 _4) <-> a 1 oxycarbonyl -(C1 4)-alkyl, tetrahydrofurylmethyl, phenyl-(C| 4)-alkyl which may bear a halogen atom or (C14 )-Al-Coxy, characterized by either is reacted a benzophenone (II) in which X^ , X2 , X3 and R have the above meaning, with the hydrochloride of an ester of co-amino-a1 can be acid (III) in which R <1> and n have the above meaning, or an acid (IV) in which X.| . ) in which X.p X2> X3> R and n have the above meaning and M means a a 1 ka 1imeta11, is reacted with a compound R'Y (VIII) in which R' has the above meaning and Y represents a halogen atom or a labile group such as mesyl or tocyl.