GB2138000A - Hydroxylated Diphenylazomethines, their Preparation and Pharmaceutical Compositions Containing Them - Google Patents

Hydroxylated Diphenylazomethines, their Preparation and Pharmaceutical Compositions Containing Them Download PDF

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GB2138000A
GB2138000A GB08409686A GB8409686A GB2138000A GB 2138000 A GB2138000 A GB 2138000A GB 08409686 A GB08409686 A GB 08409686A GB 8409686 A GB8409686 A GB 8409686A GB 2138000 A GB2138000 A GB 2138000A
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formula
hydroxylated
alkyl
halogen atom
diphenylazomethine
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Jean-Pierre Kaplan
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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
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing 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
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • 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
    • 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
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

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

Abstract

Hydroxylated diphenylazomethine of the formula (I> <IMAGE> in which n is an integer from 1 to 4, X1, X2 and X3, which may be the same or different, each represent a hydrogen atom, a halogen atom, -OCH3 or a straight-chain or branched C1-4-alkyl group, R represents NH2, -OH or -OM/p (wherein M represents an alkali metal or alkaline earth metal of valency p) and Z represents -COOH, -COOalkyl, -CONH2, -CONHalkyl, -CON(alkyl)2, -CH2OH, -CH2Oalkyl, -Oalkyl, -NO2,- -NH2, -NHalkyl or -N(alkyl)2, each alkyl moiety having 1 to 4 carbon atoms act on the central nervous system and find use as antidepressants and anticonvulsants.

Description

SPECIFICATION Hydroxylated Diphenylazomethines, Their Preparation and Pharmaceutical Compositions Containing Them The present invention relates to hydroxylated diphenylazomethines, their preparation and their use in therapy.
The hydroxylated diphenylazomethines according to the invention correspond to the formula (I):
in which n is an integer from 1 to 4, X1, X2 and X3, which may be the same or different, each represent a hydrogen atom, a halogen atom, -OCH3 or a straight-chain or branched C,~4-alkyl group, R represents -N H2, -OH or -OM p (wherein M represents an alkali metal or alkaline earth metal of valency p) and Z represents -COOH, -COOalkyl, -CONH2, -CONHalkyl, -CON(alkyl)2, -CH2OH, -CH2Oalkyl, -Oalkyl, -NO2, -NH2, -NHalkyl or-N(alkyl)2, each alkyl moiety having 1 to 4 carbon atoms.
Preferred compounds according to the invention are those of the formula
wherein the various symbols are as defined above, and more particularly those in which n is 2 or 3, X1 is a halogen atom or methyl, X2 is a halogen atom or methyl, R is-NH2, -OH or-ONa and Z is -CH2OCH3, -N(CH3)2 or -N H2.
According to the invention, the compounds of formula (I) can be prepared by reacting a benzophenone of the formula (II)
with a compound of the formula H2N(CH2)nCOR if appropriate in the form of a salt, such as the hydrochloride. The reaction can be carried out at a temperature of 20 to 800C and in a solvent, such as methanol.
The starting benzophenones (II) can be prepared by methods described in the literature.
Thus benzophenones of formula (II) in which Z is-COOalkyl, -COOH, -CONH2, -CONHalkyl or-CON(alkyl)2 can be prepared by reacting a compound of formula (III)
with a compound of formula (IV)
in the presence of AICI3 and in the solvent CH3NO2 to provide a compound of formula (V)
and, if desired, converting the -COOaIkyl group into -COOH (as by treatment with NaOH), -CON H2 (as by treatment with ammonium hydroxide in acetone) or into-CONHalkyl or -cON(alkyl)2 (as by treatment with, say, CH3NH2 in methanol).
Those benzophenones of formula (II) in which Z is -CH2OH or -CH2OaIkyI can be prepared byreacting a compound of formula (VI)
with bromine in dichloromethane solvent in the presence of benzoyl peroxide, under reflux conditions, to provide a compound of formula (VII)
and converting the -CH2Br group of the compound of formula (VII) into the group Z by treatment with water (Z=-CH2OH) or an alcohol such as methanol (Z=-CH2OalkyI), under reflux conditions.
Benzophenones of formula (II) in which Z is --Oalkyl may be prepared by reacting a compound of formula (IV) above with a compound of formula (VIII)
in chloroform in the presence of triethylamine to provide a compound of formula (IX)
the compound of formula (IX) is introduced into a photochemical reactor with a benzene compound of formula (X)
and the mixture is irradiated for 20 hours in a nitrogen atmosphere.
Finally, benzophenones of formula (II) in which Z is -NO2, -NH2, -NHaIkyI or -N(alkyl)2 can be prepared by reacting a compound of formula (Xl)
in acetic acid with KNO3 dissolved in H2SO4 and, if desired, converting the resulting benzophenone of formula (II) in which Z is -NO2 into a benzophenone of formula (II) in which Z is -NH2, -NHaIkyI or -N(alkyl)2 in known manner (as by reducing the -NO2 group to -NH2 with hydrogen in the presence of Raney nickel, using a solvent such as ethanol).
The following Examples illustrate the invention. The structure of the compounds are confirmed by analyses and IR and NMR spectra.
EXAMPLE 1 4-f [(4-Chlorophenyl)-(5-Chloro-2-Hydroxy-3-Methoxyphenyl)methylene]aminolbutanamide 10.4 cm3 of an ethanolic 0.27 N solution of sodium ethylate (that is to say 2.8 mmol) and 0.8 g (2.69 mmol) of 4',5-dichloro-2-hydroxy-3-methoxybenzophenone are added to a suspension of 0.37 g (2.69 mmol) of y-aminobutyramide hydrochloride in 20 cm3 of absolute ethanol.
The mixture is heated to the reflux temperature for 1 hour and 20 cm3 of alcohol are distilled off.
200 cm3 of absolute alcohol are added and the same volume is distilled off again.
After evaporation to dryness, 20 cm3 of watei are added to the residue and the mixture is extracted with methylene chloride.
The extract is washed with water and dried over MgSO4 to give, on evaporation, a residue, which is recrystallised from absolute ethanol. After washing with petroleum ether and drying at 1 00 C in vacuo for 8 hours, the product, of melting point 209-1 OOC, is obtained.
EXAMPLE 2 4-{[4-Chlorophenyl)-(5-Chloro-2-Hydroxy-3-Methoxymethylphenyl)methylene]amino}butanoic acid and its Sodium Salt 1. 5 g (1.61 x 10-2 mol) of (4-chlorophenyl)-(5-chloro-2-hydroxy-3-methoxymethylphenyl)methanone, 300 ml of methanol, 3.1 g (3x 10-2 mol) of y-aminobutyric acid and 1.6 g (3x 1 of2 mol) of sodium methylate are introduced into a 1 litre flask.
The reaction mixture is brought to the reflux temperature for 8 hours and is evaporated to dryness, the residue is taken up in 1.8 litres of distilled water and the mixture is acidified to pH 4:5 by addition of citric acid. The mixture is extracted with two 400 ml portions of methylene chloride, the organic phases are combined, washed with 500 ml of water, dried over Na2SO4 and filtered and the filtrate is evaporated to dryness.
The acid obtained is recrystallised from 25 ml of methanol.
Melting point=104--1050C.
2. 4.7 g (1.1 9x 10-2 mol) of the acid obtained above, 100 ml of methanol and 9.7 ml of sodium methylate solution (1.22 N) are introduced into a 500 ml flask. The reaction mixture is evaporated at 600C, 200 ml of pentane are introduced and the mixture is stirred for 10 minutes.
After filtration, draining and drying in a desiccator at 600C in the presence of P205, the sodium salt is obtained.
Melting point=1360C.
EXAMPLE 3 4-{[(4-Chlorophenyl)-(5-Chloro-2-Hydroxy-3-Dimethylaminophenyl)methylene]amino}butanamide 2.35 g (0.017 mol) of y-aminobutyramide hydrochloride, 500 ml of ethanol, 17 ml of a molar solution of sodium methylate and 5.3 g (0.017 mol) of (4-chlorophenyl)-(5-chloro-2-hydroxy-3dimethylaminophenyl)methanone are introduced into a flask.
The reaction mixture is heated to the reflux temperature and the ethanol is distilled off.
The mixture is evaporated to dryness, the residue is taken up in water and chloroform and the organic phase is decanted, dried over magnesium sulphate and evaporated.
The residue is triturated in pentane, filtered off and recrystallised from a mixture of ethyl acetate/isopropyl ether.
Melting point=1 44.5-1 450C.
The structure and properties of compounds of formula (I) are summarised in Table I.
TABLE I
Compounds n X, X2 X, Z R Melting Point ( C) 1 3 5-Cl 4-Cl H COOCH3 NH2 168-169 2 3 5-Cl 4-Cl H COOCH3 OH 141-142 3 3 5-Cl 4-Cl H CONH2 NH2 143-144 4 3 5-Cl 4-Cl H COOH OH 235-236 5 3 5-Cl 4-Cl H CH2OCH3 NH2 107-8 6 3 5-Cl 4-Cl H CH2OH NH2 158.5-9.5 7 3 5-Cl 4-Cl H CH2OCH3 OH 104-5 8 3 5-Cl 4-Cl H CH2OCH3 ONa 136 (decomposition) 9 | 3 | 5-Cl | 4-Cl | H | CONH2 | OH | 214-5 10 3 5-CI 4-Cl H CONHC3H7 NH2 202-3 11 | 3 | 5-Cl | 4-Cl | H | CONHCH3 | NH2 | 242-3 12 3 5-CI 4-Cl H OCH3 OH 153-4 13 | 3 | 5-Cl | 4-Cl | H | CONHC3H7 | ONa | 160-1 14 3 5-CI 4-Cl H CONHCH3 ONa > 250 (decomposition) 15 3 5-CI 4-CI H OCH3 NH2 209-210 16 | 3 | 5-Cl | 4-Cl | H | NO2 | NH2 | 166-7 17 3 5-CI 4-CI H N(CH3)2 ONa 1 53-1 58 18 3 5-Cl 4-Cl H N(CH3)2 NH2 144.5-5 19 3 5-Cl 4-Cl H NO2 ONa 163-165 20 3 5-Cl 4-Cl H NH2 ONa 257-9 21 3 5-Cl 4-Cl H NH2 NH2 219-220 22 3 5-Cl 4-Cl H CONHC3H7 OH 216-7 23 3 5-Cl 4-Cl H CONHCH3 OH 218-9 24 3 5-CI 4-Cl H N(CH3)2 OH 159-160 25 3 5-Cl 4-Cl H NO2 OH 206-208 26 3 3-Cl 4-Cl H NH2 OH 169-170 The structure and properties of starting benzophenones of formula (II) are summarised in Table II.
TABLE II
Compounds X1 X2 X3 Z Melting Point ( C) 1 5-Cl 4-Cl H CO2CH3 114-115 2 5-CI 4-CI H CONH2 205-206 3 5-CI 4-CI H CO2H 198199 4 5-CI 4vCl H CH2OCH3 95-97 5 5-CI 4-CI H CH2OH 102-103 6 5-CI 4-CI H CONHC3H7 103-104 7 5-CI 4-CI H CONHCH3 169-170 8 5-CI 4-CI H OCH3 140.5-143 9 5-CI 4-CI H NO2 112-112.5 0 10 5-CI 4-CI H N(CHa)2, Cl 164-166 H 11 5-CI 4-CI H NH2 94.5-95 Hydroxylated diphenylazomethines according to the invention have been subjected to tests on mice demonstrating their action on the central nervous system.
The antidepressive activity of the compounds was demonstrated by antagonism to head twitches caused by L-5-hydroxytriptophan (L-5-HTP) in mice.
The mice (CDI males, Charles River France; 1 8-22 g body weight) received increasing doses of the products to be studied, or the solvent, subcutaneously, together with L-5-HTP in a dose of 250 mg/kg. 45 minutes after this injection of L-5-HTP, the number of head twitches of each mouse is counted for one minute.
For each treatment, the average number of head twitches and the percentage variation relative to a control group are calculated.
AD50 (50% dose or dose which reduces the average number of head twitches by 50%) is determined from the dose-effect curve by the graphical method of Miller and Tainter (1944).
AD50 on interperitoneal administration of the compounds according to the invention varies from 40 to 60 mg/kg.
The anticonvulsive activity of the compounds was demonstrated by antagonism to the mortality induced by bicuculline in mice.
Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its convulsive and lethal effects are antagonised by the compounds which increase the levei of cerebral GABA or have a GABA-mimetic activity.
The 50% active dose (AD50), that is to say the dose which protects 50% of the animals from the effect of bicuculline, of the substances studied was evaluated.
ADso on intraperitoneal administration of the compounds according to the invention varies from 10 to 100 mg/kg.
The compounds according to the invention are active antidepressants and anticonvulsants and also have anti ulcer, anxiolytic, analgesic and antiinflammatory properties. They can be used in human and verterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of depressions, psychoses and some neurological diseases, such as epilepsy, spasticity and dyskinesia.
The invention accordingly relates to all pharmaceutical compositions containing the compunds (I) as active principles together with any excipients suitable for their administration, in particular oral (tablets, coated tablets, gelatine capsules, capsules, cachets and solutions or suspensions for oral use) or parenteral administration.
The daily posology may be from 100 to 3000 mg.

Claims (7)

1. A hydroxylated diphenylazomethine of the formula (I)
in which n is an integer from 1 to 4, X1, X2 and X3, which may be the same or different, each represent a hydrogen atom, a halogen atom, -OCH3 or a straight-chain or branched C1~4-alkyl group, R represents -NH2, -OH or -OM p (wherein M represents an alkali metal or alkaline earth metal of valency p) and Z represents -COOH, -COOalkyl. -CONH2, -CONHalkyl, -CON(alkyl)2, -CH2OH, -CH2Oalkyl, -Oalkyl, -NO2, -NH2, -NHalkyl or -N(alkyl)2, each alkyl moiety having 1 to 4 carbon atoms.
2. A compound according to claim 1, of the formula
wherein the various symbols are as defined in claim 1.
3. A compound according to claim 1 or 2, in which n is 2 or 3, X, is a halogen atom or methyl, X2 is a halogen atom or methyl, R is -NH2, -OH or-ONa and Z is -CH2OCH3,-N(CH3)2 or-NH2.
4. A hydroxylated diphenyiazomethine according to claim 1 substantially as described with reference to any one of Compounds 1 to 28 in Table I.
5. A process for the preparation of a hydroxylated diphenylazomethine as claimed in claim 1, which comprises reacting a benzophenone of the formula (II)
with a compound of the formula H2N-(CH2)n-COR, the various symbols being as defined in claim 1.
6. A process according to claim 5 substantially as described with reference to Example 1,2 or 3.
7. A pharmaceutical composition which comprises as active ingredient at least one hydroxylated diphenylazomethine as claimed in any one of.claims 1 to 4, together with a pharmaceutically acceptable excipient.
GB08409686A 1983-04-14 1984-04-13 Hydroxylated Diphenylazomethines, their Preparation and Pharmaceutical Compositions Containing Them Withdrawn GB2138000A (en)

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FR8306082A FR2544309B1 (en) 1983-04-14 1983-04-14 HYDROXYLATED DIPHENYLAZOMETHINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

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FR (1) FR2544309B1 (en)
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GR (1) GR79857B (en)
HU (1) HUT34153A (en)
IL (1) IL71540A0 (en)
IT (1) IT1176042B (en)
LU (1) LU85311A1 (en)
NL (1) NL8401189A (en)
NO (1) NO841486L (en)
NZ (1) NZ207840A (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323416A2 (en) * 1987-12-24 1989-07-05 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Phenylbenzylidene derivatives of 3-aminopropanesulfonic acid having anticonvulsant activity and pharmaceutical compositions containing same for the therapeutical treatment of epilepsy

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
FR2788691B1 (en) 1999-01-21 2002-06-14 Oreal COMPOSITIONS FOR OXIDATION DYEING OF KERATINIC FIBERS COMPRISING A CATIONIC COUPLER, NOVEL CATIONIC COUPLERS, THEIR USE FOR OXIDATION DYEING, AND DYEING METHODS
FR2788768B1 (en) 1999-01-21 2001-02-16 Oreal NEW CATIONIC 2-ACYLAMINOPHENOLS, THEIR USE AS COUPLER FOR OXIDATION DYEING, COMPOSITIONS COMPRISING THEM, AND DYEING METHODS

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2111051A (en) * 1981-11-18 1983-06-29 Synthelabo Therapeutically useful benzylidene derivatives

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* Cited by examiner, † Cited by third party
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
FR2430936A1 (en) * 1978-07-13 1980-02-08 Synthelabo Alpha-phenyl 2-hydroxy-benzylidene amino-alkanoic acid derivs. - and novel di:phenyl-ketone intermediates, useful as anticonvulsants for treating epilepsy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2111051A (en) * 1981-11-18 1983-06-29 Synthelabo Therapeutically useful benzylidene derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323416A2 (en) * 1987-12-24 1989-07-05 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Phenylbenzylidene derivatives of 3-aminopropanesulfonic acid having anticonvulsant activity and pharmaceutical compositions containing same for the therapeutical treatment of epilepsy
EP0323416A3 (en) * 1987-12-24 1990-09-12 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Phenylbenzylidene derivatives of 3-aminopropanesulfonic acid having anticonvulsant activity and pharmaceutical compositions containing same for the therapeutical treatment of epilepsy

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PT78429A (en) 1984-05-01
PT78429B (en) 1986-08-22
ES8502677A1 (en) 1985-01-16
DE3414051A1 (en) 1984-10-18
FR2544309B1 (en) 1986-01-10
ZA842798B (en) 1984-11-28
AU2682584A (en) 1984-10-18
DK191684D0 (en) 1984-04-13
FR2544309A1 (en) 1984-10-19
JPS59199665A (en) 1984-11-12
ES531605A0 (en) 1985-01-16
SE8402082D0 (en) 1984-04-13
IT8420528A0 (en) 1984-04-13
NZ207840A (en) 1986-02-21
HUT34153A (en) 1985-02-28
FI841484A0 (en) 1984-04-13
NO841486L (en) 1984-10-15
IT1176042B (en) 1987-08-12
IL71540A0 (en) 1984-07-31
DK191684A (en) 1984-10-15
BE899423A (en) 1984-10-15
NL8401189A (en) 1984-11-01
FI841484A (en) 1984-10-15
LU85311A1 (en) 1985-11-27
SE8402082L (en) 1984-10-15

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