GB2129804A - New therapeutically useful hydroxybenzylidene derivatives - Google Patents

New therapeutically useful hydroxybenzylidene derivatives Download PDF

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GB2129804A
GB2129804A GB08330288A GB8330288A GB2129804A GB 2129804 A GB2129804 A GB 2129804A GB 08330288 A GB08330288 A GB 08330288A GB 8330288 A GB8330288 A GB 8330288A GB 2129804 A GB2129804 A GB 2129804A
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general formula
hydroxybenzylidene
derivatives
chlorophenyl
preparation
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GB8330288D0 (en
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Jean-Pierre Kaplan
Bernard Raizon
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Synthelabo SA
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Synthelabo SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Hydroxybenzylidene derivatives of the general formula: <IMAGE> (wherein n represents an integer from 1 to 12, X1, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom and R represents a primary amino radical, a hydroxy radical, or a group -OM in which M represents an alkali metal or alkaline earth metal) are new therapeutically useful compounds; more particularly as anti-convulsant agents.

Description

SPECIFICATION New therapeutically useful hydroxybenzylidene derivatives The present invention relates to new therapeutically useful hydroxybenzylidene derivatives, to processes for their preparation and their application in therapy such as pharmaceutical compositions containing them.
The hydroxybenzylidene derivatives of this invention are those compounds of the general formula:
wherein n represents an integer from 1 to 1 2 (preferably 1 to 4), X1, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom and R represents a primary amino radical (-N H2), a hydroxy radical (-OH) or a group -OM in which M represents an alkali metal, e.g. sodium, or alkaline earth metal, e.g. calcium or magnesium.
The preferred compounds of the invention are those of the general formula:
wherein R, X1, X2 and X3 are as hereinbefore defined. Preferably R represents an amino or hydroxy radical, X, represents a fluorine or chlorine atom, X2 represents a chlorine atom, and X3 represents a hydrogen atom. Of outstanding importance are 4-((5-fluoro-2, 3-d ihydroxyphenyl)- (4-chlorophenyl)methylene]-am inobutanam ide, 4-((S4luoro-2, 3-dihydroxyphenyl) (4-chlorophenyl)methylene]-aminobutanoic acid and 4-[(5-chloro-2,3-dihydroxyphenyl) (4-chlorophenyl)methylene]-aminobutanamide.
According to a feature of the present invention the hydroxybenzylidene derivatives of general formula I are prepared by the process which comprises reacting a corresponding benzophenone of the general formula:
(wherein X1, X2 and X3 are as hereinbefore defined) with a compound of the general formula: H2N(CH2)nCOR IV (wherein n and R are as hereinbefore defined), optionally in the form of an acid addition salt such as the hydrochloride, at a temperature of from 20 to 1 20 C in an organic solvent medium, such as methanol, ethanol or a methanol/toluene mixture, in the presence of a base, for example an alkali metal alkoxide such as sodium methoxide.
The benzophenone starting materials of general formula Ill can be obtained from benzophenones carrying a methyl radical in the 3-position on the hydroxy-substituted benzene ring according to the following reaction scheme:
CR30113 (1) Br2,(2)3OH \050 X243 $3 H2S04 O%I PIO H2O2 Xr ae x3 3 wherein X1, X2 and X3 are as hereinbefore defined.
According to a further feature of the invention the hydroxybenzylidene derivatives of general formula I wherein R represents an amino or hydroxy radical are obtained by extraction after in vitro metabolism by liver homogenates or in vivo metabolism by animals (e.g. rats) to which a compound of the general formula:
(wherein the various symbols are as hereinbefore defined) is administered.
Compounds of general formula V, e.g. 4-[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methy- lene]-aminobutanamide, have been described in our French Patent 75/24065 and its Patent of Addition 76/21922, and corresponding British Patent 1506808 and United States Patent 4094992.
The compounds of general formula I wherein R represents a group -OM (M being as hereinbefore defined) can be obtained from corresponding compounds wherein R represents the hydroxy radical by methods known per se, viz. methods heretofore used or described in the chemical literature for the preparation of alkali metal and alkaline earth metal salts of carboxylic acids.
The Examples which follow illustrate the invention. The analyses and the IR and NMR spectra confirm the structures of the compounds obtained.
Example 1 4-5-Fluoro-2, 3dih ydroxyphen yl)(4-chlorophen yl)meth ylene]-aminob utanamide.
The animals (rats---Charles River, weighing about 200 g) are treated intravenously with 20 mg/kg of 4-[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]-aminobutanamide.
The bile of these animals is recovered by cannulation of the choledochus for 6 hours.
The bile is hydrolysed with ss-glucuronidase at 37"C for 5 minutes at pH 6.5.
The mixture is extracted with 6 times the volume of n-hexane, which makes it possible to remove the most lipophilic compounds present in the bile.
The aqueous phase is recovered and extracted with ethyl acetate (6 volumes); the organic phase is evaporated and the solids are taken up in hot methanol. The mixture is left to cool. A precipitate of the desired compound forms. The product is recrystallised from hot methanol.
Melting point = 224-230"C (decompositionHmeasured on a Tottoli apparatus.
The compound is in the form of a bright orange crystalline powder.
The IR spectrum measured in KBr has the following characteristics: 3400-3100cm-1 :pNH2 of the amide and vOH with the intramolecular or intermolecular H bond 3000-2900 cm - 1 :vCH2 2800-2200 cam~' : :vOH with the intramolecular H bond (OH... N=C) 1660 cm - 1 : vC = O of the amide 1600 cm : vC = N of the amide 1270-1130 cm-' :vC-O, phenol 840 cm-l : 8, para-disubstituted benzene.
The UV and NMR spectra confirm the structure of the compound.
Example 2 4-[(5-Fluoro-2, 3-dihydroxyphenyl) (4-chlorophenyl)methylene]-aminobutanoic acid This compound passes into the methanol phase during the treatment of the solids with hot methanol, described in Example 1, and remains in this phase. It is extracted from the methanol phase by chromatography on silica (the eluent is a 7/3 benzene/ethanol mixture).
Example 3 4-1(5-Chloro-2, 3dih ydroxyphen yl)(4-chlorophen yl)meth ylene]-am inobutanamide 1. (5-Chloro-2,3-dihydroxyphenyl) (4-chlorophenyl)-methanone.
1.1 28.1 g (0.1 mol) of (5-chloro-2-hydroxy-3-methylphenyl) (4-chlorophenyl)-methanone, 150 ml of chloroform and 0.5 g of benzoyl peroxide are introduced into a 0.5 litre two-necked round-bottomed flask, under a well-ventilated hood.
The reaction medium is heated to the reflux temperature and an ultraviolet lamp is switched on.
25 ml (0.5 mol) of bromine are then introduced all at once and the reaction mixture is heated at the reflux temperature, in the presence of UV, for 1 6 hours.
The reaction is followed by NMR. The solvent is evaporated off and the hydrobromic acid present is driven off by evaporating off 3 times 50 ml of benzene.
The residue is then taken up in 600 ml of methanol and the mixture is heated under reflux for 6 hours. It is left to cool and the crystals which have appeared are filtered off.
After recrystallisation from a diethyl ether/pentane mixture, the benzophenone carrying a dimethylacetal group in the 3-position is obtained.
Melting point = 82-83"C.
1.2 1 7.8 g (52 mmol) of the previously obtained acetal, 50 ml of concentrated sulphuric acid, 200 ml of water and 250 ml of toluene are introduced into a 0.5 litre round-bottomed flask. The reaction mixture is heated for 3 hours at the reflux temperature and then left to return to ambient temperature. The organic phase is decanted, washed until the washings are neutral, dried over Na2SO4 and then filtered, and the filtrate is evaporated to dryness.
After recrystallisation from tert.-butyl methyl ether, (5-chloro-2-hydroxy-3-formylphenyl) (4chlorophenyl)methanone is obtained; this is a polymorphous product which has two melting points: 109.9"C and then 119.8"C.
1.3 800 ml of distilled water and 1.60 g of sodium hydroxide pellets are introduced into a 2 litre three-necked round-bottomed flask. The reaction mixture is heated to the reflux temperature while a stream of argon gas is bubbled through. 12 g (40 mmol) of benzophenone are then introduced and the mixture is heated under reflux until solubilisation is complete.
This gives an orange solution; still under argon, a solution of 16 ml of H202 (110 volumes) in 144 ml of distilled water is introduced all at once.
The solution becomes turbid almost instantaneously and becomes yellow in colour. A precipitate (yellow) forms rapidly. Refluxing is continued for + hour, the mixture is filtered hot and the precipitate is washed 3 times with 100 ml of distilled water.
The filter cake is placed in a 6N solution of HCI (500 ml) and the mixture is stirred overnight.
The precipitate is filtered off and drained, the filter cake is taken up in diethyl ether, the organic phase is decanted, washed with water, aqueous bicarbonate solution and water, dried over Na2SO4 and filtered, and the filtrate is evaporated to dryness.
The crude product is dissolved in 40 ml of boiling toluene, and 60 ml of pentane are added slowly. This gives (5-chloro-2, 3-dihydroxyphenyl)(4-chlorophenyl)-methanone having a melting point of 133-135 C.
2. 4-((5-Chloro-2, 3-dihydroxyphenyl) (4-chlorophenyl)methylene]-aminobutanamide.
A mixture of 1.96 g (14.1 mmol) of gabamide hydrochloride and 0.764 g (14.1 mmol) of sodium methoxide with 4 g (14.1 mmol) of (5-chloro-2,3dihydroxyphenyl)(4-chlorophenyl)- methanone in 400 ml of methanol is heated at the reflux temperature for 10 hours; the reaction mixture is then left in contact for 48 hours. The liquid medium is evaporated off.
The dry residue is taken up in 2 litres of CH2CI2 and the mixture is washed with 500 ml of H20. The organic phase is decanted, dried over MgSO4 and filtered, the filtrate is evaporated to dryness and the residue is then carried onto a frit with 100 ml of petroleum ether.
The product is dissolved in 1 litre of boiling ethyl acetate and treated with charcoal, the mixture is filtered and the filtrate is concentrated to 100 ml. The product crystallises. It is filtered off, drained and washed twice with 50 ml of diethyl ether.
The recrystallised product is analytically pure.
Melting point = 224-225"C.
Table I which follows shows the compounds of the invention which were obtained by way of examples, and Table II shows the starting benzophenones of formula Ill.
Table I
Melting Compound n R Xg X2 X3 point ("C) 1 3 NH2 5-F 4-CI H 224-230 2 3 OH 5-F 4-CI H decompo sition 3 3 NH2 5-CI - 4-CI H 224-225 Table II
Melting point Compound X, X2 X3 ( C) 1 5-F 4-CI H 124-126 2 5-CI 4-CI H 133-135 The compounds of the invention were subjected to pharmacological tests relative to the field of the central nervous system.
The compounds of the invention were studied, in particular, in the test for antagonism towards the mortality caused by bicuculline in mice.
Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its convulsant and lethal effects are antagonised by compounds which increase the level of GABA in the brain or which possess a GABA-mimetic activity.
The dose which protects 50% of the animals against the effect of bicuculline is then measured.
The compounds of the invention are active as anti-convulsants and can therefore be used in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of neurological diseases such as epilepsy.
The invention consequently includes pharmaceutical compositions which contain a compound of general formula I, as active ingredient, in association with any excipient(s) suitable for its administration, in particular oral administration (tablets, coated tablets, gelatin capsules, ordinary capsules, cachets, and solutions or suspensions to be taken orally) or parenteral administration.
The daily dosage can range from 50 to 1000 mg.

Claims (14)

1. Hydroxybenzylidene derivatives of the general formula:
wherein n represents an integer from 1 to 12, X1, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom, and R represents a primary amino radical, a hydroxy radical, or a group -OM in which M represents an alkali metal or alkaline earth metal.
2. Hydroxybenzylidene derivatives according to claim 1 wherein n represents an integer from 1 to 4.
3. Hydroxybenzylidene derivatives according to claim 1 of the general formula:
wherein R, X1, X2 and X3 are as defined in claim 1.
4. Hydroxybenzylidene derivatives according to claim 3 wherein R represents an amino or hydroxy radical, X1 represents a fluorine or chlorine atom, X2 represents a chlorine atom, and X3 represents a hydrogen atom.
5. 4-((5-Fluoro-2, 3-dihydroxyphenyl)(4-chlorophenyl)methylene]-aminobutanamide.
6. 4-[(5-Fluoro-2,3-dihydroxyphenyl)(4-chlorophenyl)methylene]-aminobutanoic acid.
7. 4-((5-Chloro-2, 3-dihydroxyphenyl)(4-chlorophenyl)methylenej-aminobutanamide.
8. A process for the preparation of a hydroxybenzylidene derivative of the general formula depicted in claim 1 which comprises reacting a corresponding benzophenone of the general formula:
(wherein X1, X2 and X3 are as defined in claim 1) with a compound of the general formula: H2N(CH2)nCOR (wherein n and R are as defined in claim 1), optionally in the form of an acid addition salt, at a temperature of from 20 to 120"C in an organic solvent medium in the presence of a base.
9. A process for the preparation of hydroxybenzylidene derivatives of the general formula depicted in claim 1 wherein R represents an amino or hydroxy radical which comprises their extraction after in vitro metabolism by liver homogenates or in vivo metabolism by animals to which a compound of the general formula:
(wherein the various symbols are as defined in claim 1) is administered.
10. A process for the preparation of hydroxybenzylidene derivatives of the general formula depicted in claim 1 substantially as hereinbefore described with especial reference to Example 1, 2 or 3.
11. Hydroxybenzylidene derivatives of the general formula depicted in claim 1 when prepared by a process claimed in claim 8, 9 or 10.
1 2. Pharmaceutical compositions which comprise, as active ingredient, a hydroxybenzyli dene derivative of the general formula depicted in claim 1 in association with a pharmaceuti cally-acceptable excipient.
1 3. Hydroxybenzylidene derivatives of the general formula depicted in claim 1 for use as medicaments, more particularly as anti-convulsant agents.
14. Benzophenones which can be used for the preparation of hydroxybenzylidene derivatives as claimed in claim 1 and which correspond to the general formula:
wherein X1, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom.
GB08330288A 1982-11-15 1983-11-14 New therapeutically useful hydroxybenzylidene derivatives Withdrawn GB2129804A (en)

Applications Claiming Priority (1)

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FR8219078A FR2536070A1 (en) 1982-11-15 1982-11-15 HYDROXYLATED DIPHENYL-AZOMETHINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

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GB2129804A true GB2129804A (en) 1984-05-23

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JP (1) JPS59108755A (en)
BE (1) BE898233A (en)
DE (1) DE3341198A1 (en)
FR (1) FR2536070A1 (en)
GB (1) GB2129804A (en)
IL (1) IL70227A0 (en)
IT (1) IT1170245B (en)
LU (1) LU85090A1 (en)
NL (1) NL8303903A (en)

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Publication number Priority date Publication date Assignee Title
FR2319338A1 (en) * 1975-08-01 1977-02-25 Synthelabo NEW A-PHENYL BENZYLIDENIC DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM

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IT1170245B (en) 1987-06-03
GB8330288D0 (en) 1983-12-21
IL70227A0 (en) 1984-02-29
FR2536070A1 (en) 1984-05-18
DE3341198A1 (en) 1984-05-17
JPS59108755A (en) 1984-06-23
BE898233A (en) 1984-05-16
FR2536070B1 (en) 1985-03-08
LU85090A1 (en) 1985-07-17
NL8303903A (en) 1984-06-01
IT8323700A0 (en) 1983-11-14

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