IE902551A1 - Substituted 2-imino-3-alkylbenzothiazolines and their preparation and use - Google Patents
Substituted 2-imino-3-alkylbenzothiazolines and their preparation and useInfo
- Publication number
- IE902551A1 IE902551A1 IE255190A IE255190A IE902551A1 IE 902551 A1 IE902551 A1 IE 902551A1 IE 255190 A IE255190 A IE 255190A IE 255190 A IE255190 A IE 255190A IE 902551 A1 IE902551 A1 IE 902551A1
- Authority
- IE
- Ireland
- Prior art keywords
- phenyl
- substituted
- alkyl
- alkoxy
- ethyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Compounds of formula: <IMAGE> in which R1 denotes a substituted 1-piperazinyl, substituted 1,2,3,6-tetrahydro-1-pyridyl or substituted piperidino radical, R2 denotes a polyfluoroalkoxy radical and n is equal to 2 or 3, salts of these compounds with an acid, processes for their preparation and medications containing them.
Description
RHONE-POULENC Raymond Aron , SANTE 92160 a French Body Corporate, Antony, France. of 20 Avenue - 2 The present invention provides compounds of formula: (CH2)n - R1 in which - represents . 1-piperazinyl substituted at the 4-position by (a) phenyl (b) phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy (c) phenylalkyl, (d) pyridyl or (e) pyrimidinyl . 1,2,3,6-tetrahydro-l-pyridyl substituted at the 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, . piperidino substituted at the 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, - R2 represents polyfluoroalkoxy, and - n is 2 or 3, the aforesaid alkyl and alkoxy radicals and alkyl and alkoxy portions (and those mentioned below) containing 1 to 4 carbon atoms each in a straight or branched chain, and their addition salts with inorganic and organic acids.
The polyfluoroalkoxy radicals (R2) are preferably trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy radicals.
The halogen atoms are preferably fluorine, chlorine or bromine atoms.
The compounds of formula (I) may be prepared by the hydrolysis of a compound of formula: (II) in which Rlz R2 and n have the same meanings as in the formula (I).
This hydrolysis is generally performed with a base such as an alkali metal carbonate (preferably sodium or potassium carbonate) or concentrated ammonia solution, in a water/alcohol mixture, at a temperature in the region of °C.
The compounds of formula (II) may be obtained by the action of a derivative of formula: in which R2 and n have the (HI) same meanings as in the formula (I) and R3 represents a reactive group such as a - 4 methanesulphonyl or p-toluenesulphonyl radical, on an amine of formula: HRj (IV) in which R^ has the same meanings as in the formula (I).
This reaction is generally performed in an inert solvent such as an aromatic solvent (e.g. benzene, toluene, or xylene) or dimethylformamide, at a temperature between 20°C and the boiling point of the solvent.
The derivatives of formula (III) may be prepared by 10 the action of a derivative of formula: N - CO - CF3 •N (CH2)n - OH (V) in which R2 and n have the same meanings as in the formula (I), on methanesulphonyl or p-toluenesulphonyl chloride, either in an inert solvent such as an aromatic solvent (e.g. benzene, toluene, xylene) or a chlorinated solvent (e.g. chloroform or methylene chloride), in the presence of a tertiary amine such as triethylamine, at a temperature in the region of 20°C, or in pyridine, at a temperature in the region of 0°C.
The derivatives of formula (V) may be obtained by the action of ethyl trifluoroacetate on a derivative of formula: in which R2 and n have the same meanings as in the formula (I) · This reaction is generally performed in an alcohol 5 (e.g. methanol, ethanol), in the presence of a tertiary base such as triethylamine, at a temperature in the region of °C.
The derivatives of formula (VI) may be prepared by the action of a halogenated derivative of formula: Hal-(CH2)n-OH (VII) in which n has the same meanings as in the formula (I) and Hal represents a halogen atom (preferably bromine or chlorine) on a 2-amino-6-polyfluoroalkoxy-benzothiazole.
This reaction is performed in an alcohol (preferably ethanol or methanol), at the boiling point of the solvent. 2-Amino-6-polyfluoroalkoxybenzothiazoles may be prepared by application or adaptation of the method described by L.M. YAGUPOL'SKII et al., Zh. Obshch. Khim., 33(7), 2301, (1963).
The compounds of formula (I) may also be prepared by the action of bromine and an alkali metal thiocyanate on a compound of formula: *2-> NH - (CH2)n - R1 (VIII) in which R^, R2 and n have the same meanings as in the formula (I).
This reaction is preferably performed in acetic 5 acid, at a temperature in the region of 20°C.
As the alkali metal thiocyanate, potassium thiocyanate is preferably used.
The compounds of formula (VIII) may be obtained by the action of an amine of formula (IV) on a derivative of formula: N - (CH2)n - 0 - R5 | (IX) R4 in which R2 and n have the same meanings as in the formula (I) and R4 and R5 represent a p-toluenesulphonyl radical.
This reaction is preferably performed in the 15 presence of sodium hydrogen carbonate, in an inert solvent such as dimethylformamide, at a temperature of between 506C and 100°C.
The derivatives of formula (IX) may be obtained by the action of p-toluenesulphonyl chloride on a derivative of formula: - (CH2)n - OH (X) in which R2 and n have the same meanings as in the formula (I) · This reaction is generally performed in an inert 5 solvent such as a chlorinated solvent (e.g. chloroform or methylene chloride), at a temperature of between 0°C and °C.
The derivatives of formula (X) may be obtained by the action of a 4-polyfluoroalkoxyaniline on a derivative of formula (VII).
This reaction is generally performed at a temperature of between 100°C and 170°C.
The reaction mixtures obtained by the various processes described above are treated according to conventional physical methods (evaporation, extraction, distillation, crystallization, chromatography, etc.) or chemical methods (salt formation, etc.).
The compounds of formula (I), in free base form, can be optionally converted into addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent.
The compounds of formula (I) and their salts possess advantageous pharmacological properties. These compounds are active in antagonizing glutamate-induced - 8 convulsions, and are hence useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders, and in particular the deficiency forms of schizophrenia, sleep disorders, phenomena linked to cerebral ischaemia and also neurological conditions in which glutamate may be implicated, such as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and olivopontocerebella atrophy.
The activity of the compounds of formula (I) against glutamate-induced convulsions was determined by a technique based on that of I.P. LAPIN, J. Neural. Transmission, vol. 54, 229-238, (1982); intracerebroventricular injection of glutamate being performed according to a technique based on that of R.
CHERMAT and P. SIMON, J. Pharmacol. (Paris), vol. 6, 489-492 (1975). Their ED50 is generally equal to or less than 10 mg/kg.
The compounds of formula (I) possess low toxicity. Their LD50 is more than 15 mg/kg when administered intraperitoneally (I.P.) in mice.
For medicinal use, the compounds of formula (I) may be employed as the bases, or in the state of pharmaceutically acceptable acid addition salts, i.e. salts which are non-toxic at the doses at which they are used.
As examples of pharmaceutically acceptable salts, the addition salts with inorganic or organic acids, such as acetate, propionate, succinate, benzoate, fumarate, maleate, - 9 oxalate, methanesulphonate, isethionate, theophylline acetate, salicylate, phenolphthalinate, methylenebis(βhydroxynaphthoate), hydrochloride, sulphate, nitrate and phosphate, may be mentioned.
The examples which follow illustrate the invention.
EXAMPLE 1 3-{2-[4-(2-Pyridyl)-l-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (1.3 g), dissolved in a mixture of 7 % strength aqueous potassium carbonate solution (19 cc) and methanol (32 cc), is stirred at a temperature in the region of 20°C for 4 hours. The medium is concentrated under reduced pressure (20 mmHg; 2.7 kPa) and the residue is taken up with distilled water (300 cc). The aqueous phase is extracted with ethyl ether (3 x 200 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a silica column with acetone as eluent. After formation of the trihydrochloride by adding 4.2 N ethereal hydrogen chloride in acetone, 2-imino-3-{220 [4-(2-pyridyl)-1-piperazinylJethyl}-6trifluoromethoxybenzothiazoline trihydrochloride (0.73 g), m.p. about 230°C, is obtained. 3-{2-[4-(2-Pyridyl)-l-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline may be prepared according to the following process: a mixture of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene - 10 (100 cc) and 4-(2-pyridyl)piperazine (6.9 g) is heated to reflux for 2 hours, cooled to 4°C and then drained. The toluene filtrate is evaporated under reduced pressure and purified by chromatography on a silica column with dichloromethane as eluent. 3-(2-(4-(2-Pyridyl)-1piperaz iny1]ethyl}-2-trifluoroacetylimino-6trifluoromethoxybenzothiazoline (1.3 g), m.p. 132°C, is obtained. 2—(2-Trifluoroacetylimino—6—trifluoromethoxy—3— benzothiazolinyl)ethyl methanesulphonate may be prepared in the following manner: triethylamine (6.9 g) is added gradually to a mixture of methylene chloride (120 cc), methanesulphonyl chloride (7.34 g) and 2-(2-trifluoroacetylimino-6-trifluoromethoxy-315 benzothiazolinyl)ethanol (12 g). After 1 hour's stirring at a temperature in the region of 20°C, the reaction medium is cooled to 10°C, drained, washed with cold methylene chloride (20 cc) and then dried at 40°C under reduced pressure. 2-(2Trifluoroacetylimino-6-trifluoromethoxy-320 benzothiazolinyl)ethyl methanesulphonate (10 g), m.p. 145°C, is obtained. A 2nd crop (2.7 g) is obtained by washing the filtrate with water (100 cc), drying over magnesium sulphate, concentration to a residual volume of approximately 50 cc, cooling to 5°C and then draining. 2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethanol may be prepared in the following manner: 2-(2-imino-6-trifluoromethoxy-3IE 902551 - 11 benzothiazolinyl)ethanol hydrobromide (20.7 g), ethyl trifluoroacetate (9.8 g) and triethylamine (16.1 cc) are stirred in ethanol (100 cc) for 22 hours at a temperature in the region of 20°C. After concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on a silica column with ethyl acetate as eluent. 2-(2-Trifluoroacety1imino-6-trifluoromethoxy-3benzothiazolinyl)ethanol (19.2 g), m.p. 144°C, is obtained. 2-(2-Imino-6-trifluoromethoxy-310 benzothiazolinyl)ethanol may be prepared according to the following process: 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and 2-bromoethanol (10 g) in absolute ethanol (30 cc) are heated to boiling for 95 hours. The mixture is then cooled to a temperature in the region of 2O’C. The precipitate formed is filtered off and washed with ethyl ether (100 cc). 2-(2-Imino-6-trifluoromethoxy-3benzothiazolinyl)ethanol hydrobromide (6.4 g), m.p. 219°C, is obtained. 2-Amino-6-trifluoromethoxybenzothiazole may be prepared according to the method described by L.M.
YAGUPOL'SKII et al., Zh. Obshch. Khim, 33(7), 2301 (1963).
EXAMPLE 2 Using the procedure described in Example 1, but starting with 3-{2-[4-(4-methylphenyl)-125 piperazinyl]ethyl}-2-trifluoroacetylimino-6trifluoromethoxybenzothiazoline (0.9 g) in methanol (18 cc) and a 7 % strength aqueous-alcoholic solution (14 cc) of - 12 potassium carbonate, 2-imino3 — {2—(4—(4-methylpheny1) -1-piperaziny1]ethyl}-6trifluoromethoxybenzothiazoline (0.7 g), m.p. 120°C, is obtained. 3-{2-[4-(4-Methylphenyl)-1-piperaz iny1]ethyl}-2 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline may be prepared in the following manner: the procedure is as in Example 1, starting with 2-(2-trifluoroacetylimino-6trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (150 cc) and 4-(4methylphenyl)piperazine (5.29 g). After purification by chromatography on a silica column with a mixture of dichloromethane and ethyl acetate (98:2 by volume) as eluent, 3-{-2-[4- (4-methylpheny1)-1-piperaziny1]ethyl}-215 trifluoroacetylimino-6-trifluoromethoxy-benzothiazoline (0.9 g) is obtained.
EXAMPLE 3 Using the procedure described in Example 1, starting with 2-(2-trifluoroacetylimino-6-trifluoromethoxy20 3-benzothiazolinyl)ethyl methanesulphonate (5.88 g) in toluene (200 cc) and 4-(2-methylphenyl)piperazine (6.87 g) and after 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure. To the residue thereby obtained, methanol (100 cc) and a 7 % strength aqueous25 alcoholic solution (20 cc) of potassium carbonate are added and the mixture is stirred for 2 hours at approximately 20°C. The alcohol is evaporated off under reduced pressure - 13 and the residue is purified by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (70:30 by volume) as eluent, and then an ethyl acetatecyclohexane mixture (50:50 by volume) as eluent. 2-Imino-3-{2-[4-(25 methylphenyl)-1-piperazinyl]ethyl}-6trifluoromethoxybenzothiazoline (1.8 g), m.p. 135°C, is thereby obtained.
EXAMPLE 4 Using the procedure described in Example 1, but 10 starting with 3-[2-(4-benzyl-l-piperazinyl)ethyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (3.8 g) in methanol (20 cc) and a 7 % strength aqueous-alcoholic solution (10 cc) of potassium carbonate, and after purification by chromatography on a silica column with an ethyl acetate/cyclohexane mixture (50:50 by volume) as eluent, followed by the addition of 4.2 N ethereal hydrogen chloride, 3-[2-(4-benzyl-1-piperazinyl)ethyl]-2-imino-6trifluoromethoxybenzothiazoline hydrochloride (2.5 g), m.p. about 230°C, is obtained. 3-[2-(4-Benzyl-l-piperazinyl)ethyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline may be prepared in the following manner: the procedure is as in Example 1, starting with 2-(2-trifluoroacetylimino-6trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (120 cc) and 4-benzylpiperazine (7 g).
After purification by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (50:50 by volume) as - 14 eluent, 3-[2-(4-benzyl-l-piperazinyl)ethyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (3.8 g), is obtained.
EXAMPLE 5 Using the procedure described in Example 1, starting with 2-(2-trifluoroacetylimino-6-trifluoromethoxy3-benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (150 cc) and 4-(2-pyrimidinyl)piperazine (6.5 g) and after 4 hours under reflux, the toluene filtrate is evaporated under reduced pressure. Methanol (100 cc) and a 7 % strength aqueous-alcoholic solution (20 cc) of potassium carbonate are added to the toluene residue. After 2 hours' stirring at approximately 20°C, the methanol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a dichloromethane/methanol mixture (90:10 by volume) as eluent. After formation of the trihydrochloride by adding 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(2pyrimidiny1)-1-piperazinyl]ethyl}-620 trifluoromethoxybenzothiazoline trihydrochloride (1.13 g), m.p. about 270°C, is obtained.
EXAMPLE 6 3-[3-(4-Phenyl-l-piperazinyl)propyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (3.6 g), dissolved in a mixture of 7 % strength aqueous potassium carbonate solution (45 cc) and methanol (150 cc), is stirred for 4 hours at a temperature - 15 in the region of 2 0°C. After concentration to dryness, the reaction medium is taken up in distilled water (100 cc) and the organic phase extracted with ethyl acetate (2 x 100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). After formation of the dihydrochloride by adding 4.2 N ethereal hydrogen chloride (4 cc) in ethyl acetate, the precipitate is recrystallized in an absolute ethanol/ethyl ether mixture (50:50 by volume). 2-Imino-3-[3-(4-phenyl-l10 piperazinyl)propyl]-6-trifluoromethoxybenzothiazoline dihydrochloride (1.6 g), m.p. 260°C, is obtained. 3-[3-(4-Phenyl-l-piperazinyl)propyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared according to the following process: 3-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)propyl p-toluenesulphonate (4.4 g), Nphenylpiperazine (1.44 g) and sodium hydrogen carbonate (0.68 g) in dimethylformamide (50 cc) are heated to 80°C for 19 hours. The reaction medium is concentrated to dryness under reduced pressure (7 mmHg; 0.95 kPa), the residue taken up in distilled water (100 cc) and the organic phase extracted with dichloromethane (50 cc). After drying over magnesium sulphate and concentration to dryness under reduced pressure, the oily residue obtained is taken up with IN aqueous hydrochloric acid (15 cc) and the hydrochloride formed precipitated in distilled water (15 cc). 3-(3-(4Pheny1-1-piperazinyl)propyl]-2-trifluoroacetylimino-6IE 902551 - 16 trifluoromethoxybenzothiazoline hydrochloride (4 g), m.p. 238°C, is obtained. 3-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)propyl p-toluenesulphonate may be prepared according to the following process: 3-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)propanol (11 g) is added gradually to ptoluenesulphonyl chloride (10.8 g) dissolved in pyridine (200 cc) cooled to 0°C. The reaction is continued for 1 hour at 5°C and the reaction medium is then kept in the cold (67°C) for 15 hours. After addition to distilled water (2 litres), extraction with ethyl acetate (200 cc), washing with 1 N hydrochloric acid (2 x 50 cc), drying over magnesium sulphate and concentration to dryness under reduced pressure, 3-(2-trifluoroacetylimino-6trifluoromethoxy-3-benzothiazolinyl)propyl ptoluenesulphonate (6.7 g), m.p. 139°C, is obtained. 3-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)propanol may be prepared in the following manner: 3-(2-imino-6-trifluoromethoxy-3benzothiazolinyl)propanol (24.8 g), ethyl trifluoroacetate (14.2 g) and triethylamine (8.6 g) are stirred in absolute ethanol (250 cc) for 24 hours at a temperature in the region of 20°C. The reaction medium is then cooled to 0-5°C and the precipitate formed filtered off and dried. 3-(2Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)propanol (28.2 g) , m.p. 144°C, is obtained. - 17 3-(2-Imino-6-trifluoromethoxy-3benzothiazolinyl)propanol may be prepared according to the following process: 2-amino-6-trifluoromethoxy-benzothiazole (82 g) and 3-bromopropanol (65 cc) in absolute ethanol (25 cc) are heated to boiling for 72 hours. The mixture is then cooled to a temperature in the region of 20°C. The oil obtained is taken up in distilled water (1 litre) and the organic phase extracted with dichloromethane (3 x 200 cc). After drying over magnesium sulphate and concentration to dryness under reduced pressure, the crude product is purified by chromatography on a silica column with ethyl acetate as eluent. 3-(2-Imino-6-trifluoromethoxy-3benzothiazolinyl)propanol (25 g), m.p. 106°C, is obtained.
EXAMPLE 7 Using the procedure described in Example 1, starting with 3-{2-[4-(m-tolyl)-l-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (l g) in methanol (30 cc) and a 7 % strength aqueous-alcoholic solution (15 cc) of potassium carbonate, and after purification by chromatography on a silica column with an ethyl acetate/cyclohexane mixture (50:50 by volume) as eluent, followed by the addition of 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(m-tolyl)-1-piperazinyl]ethyl)-6trifluoromethoxybenzothiazoline hydrochloride (0.6 g), m.p. about 250°C, is obtained. 3-{2-[4-(m-Tolyl)-1-piperazinyl)ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline may - 18 be prepared in the following manner: the procedure is as in Example 1, starting with 2-(2-trifluoroacetylimino-6trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (150 cc) and 4-(35 methylphenyl)piperazine (5.29 g). After purification by chromatography on a silica column with a dichloromethane/ethyl acetate mixture (70:30 by volume) as eluent, 3-{2-[4-(m-tolyl)-l-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (1 g) is obtained.
EXAMPLE 8 Bromine (1.15 g), dissolved in acetic acid (15 cc), is added dropwise at a temperature in the region of 20°C to a mixture of 4-phenyl-l-[2-(415 trifluoromethoxyanilino)ethyl]-1,2,3,6-tetrahydropyridine (2.62 g) and potassium thiocyanate (2.8 g) in acetic acid (50 cc). After the usual treatment, 2-imino-3-[2-(4-phenyl1.2.3.6- tetrahydro-l-pyridyl)ethyl]-6trifluoromethoxybenzothiazoline dihydrochloride (0.67 g), m.p. 256°C, is obtained. 4-Phenyl-1-(2-(4-trifluoromethoxyan ilino)ethy1]1.2.3.6- tetrahydropyridine may be prepared in the following manner: a mixture of N-(p-toluenesulphonyl)-2-(4trifluoromethoxyanilino)ethyl p-toluenesulphonate (5.56 g), 4-phenyl-1,2,3,6-tetrahydropyridine (1.84 g) and sodium hydrogen carbonate (0.97 g) in dimethylformamide (95 cc) is heated to 80°C for 18 hours. After the usual treatment, 4IE 902551 - 19 phenyl-1-[2-(4-trifluoromethoxyanilino)ethyl]-1,2,3,6tetrahydropyridine (2.62 g) is obtained in the form of an oil, which is used without further treatment in the subsequent syntheses.
N-(p-Toluenesulphonyl)-2-(4trifluoromethoxyanilino)ethyl p-toluenesulphonate may be prepared according to the following process: p-toluenesulphonyl chloride (8.6 g) is added gradually to 2(4-trifluoromethoxyanilino)ethanol (5.0 g) and triethylamine (6.35 cc) in dichloromethane (50 cc) at 0°C. Reaction is continued for 2 hours at a temperature in the region of 2 0°C, the reaction medium then washed with distilled water (3 x 50 cc) and the organic phase dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). After the addition of absolute ethanol (50 cc), the precipitate formed is filtered off. N-(pToluenesulphonyl)-2-(4-trifluoromethoxyanilino)ethyl ptoluenesulphonate (7.3 g), m.p. 88°C, is obtained. 2-(4-Trifluoromethoxyanilino)ethanol may be prepared in the following manner: 4-trifluoromethoxyaniline (88.5 g) and 2-bromoethanol (31.2 g) are heated to 160°C for 1.5 hours. After cooling to a temperature in the region of 20°C, the reaction medium is taken up in dichloromethane (200 cc), the insoluble matter filtered off and the filtrate concentrated to dryness under reduced pressure. After purification by chromatography on a silica column with an ethyl acetate/cyclohexane mixture (40:60 by - 20 volume) as eluent, 2-(4-trifluoro-methoxyanilino)ethanol (26.8 g) is obtained in the form of an orange-coloured oil.
EXAMPLE 9 3-(2-(4-Phenylpiperazinyl)ethyl]-25 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.1 g), dissolved in a mixture of 7 % strength aqueous potassium carbonate solution (5 cc) and methanol (100 cc), are stirred at a temperature in the region of 20°C for 5 hours. The reaction medium is added to distilled water (200 cc) and the organic phase extracted with ethyl ether (3 x 150 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). After formation of the hydrochloride by adding 4.2 N ethereal hydrogen chloride (0.45 cc) in ethyl acetate (30 cc), 2-imino-3-[2-(4-phenylpiperazinyl)ethyl]-6trifluoromethoxybenzothiazoline hydrochloride (0.8 g), m.p. 230°C, is obtained. 3-[2-(4-Phenylpiperazinyl)ethyl]-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared according to the following process; 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl p-toluenesulphonate (6.5 g), Nphenylpiperazine (2.2 g) and sodium bicarbonate (1.0 g) in dimethylformamide (80 cc) are heated to 60°C for 19 hours.
The reaction medium is added to distilled water (300 cc) and the organic phase is extracted with dichloromethane (3 x 50 cc). After drying over magnesium sulphate and - 21 concentration to dryness under reduced pressure, the oily residue obtained is taken up with 1 N hydrochloric acid (20 cc) and the hydrochloride formed precipitated in ethanol (20 cc). 3-[2-(4-Phenylpiperazinyl)ethyl]-25 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.1 g), m.p. 204°C, is obtained. 2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl p-toluenesulphonate may be prepared according to the following process: 2-(210 trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethanol (19.3 g) is added gradually to ptoluenesulphonyl chloride (19.7 g) dissolved in pyridine (120 cc) cooled to 0°C. Reaction is continued for 1 hour at 10-15°C. The reaction medium is added to distilled water (500 cc) and the organic phase extracted with dichloromethane (3 x 100 cc). After washing with 1 N hydrochloric acid (2 x 50 cc) and then distilled water (2 x 50 cc), drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mmHg; 2.7 kPa), 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethanol p-toluenesulphonate (14.1 g), m.p. 143°C, is obtained. 2-(2-Tr ifluoroacetylimino-6-tr ifluoromethoxy-3benzothiazolinyl)ethanol may be prepared in the following manner: 2-(2-imino-6-trifluoromethoxy-3benzothiazolinyl)ethanol hydrobromide (20.7 g), ethyl trifluoroacetate (9.8 g) and triethylamine (16.1 cc) are - 22 stirred in ethanol (100 cc) for 22 hours at a temperature in the region of 20°C. After concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on a silica column with ethyl acetate as eluent. 2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethanol (19.2 g), m.p. 144°C, is obtained. 2-(2-Imino-6-trifluoromethoxy-3benzothiazolinyl)ethanol may be prepared according to the following process: 2-amino-6-trifluoromethoxy-benzothiazole (9.4 g) and 2-bromoethanol (10 g) in absolute ethanol (30 cc) are heated to boiling for 95 hours. The mixture is then cooled to a temperature in the region of 20°C. The precipitate formed is filtered off and washed with ethyl ether (100 cc). 2-(2-Imino-6-trifluoromethoxy-315 benzothiazolinyl)ethanol hydrobromide (6.4 g), m.p. 219°C, is obtained. 2- Amino-6-trifluoromethoxybenzothiazole may be prepared according to the method described by L.M. YAGUPOL'SKII et al., Zh. Obshch. Khim, 33(7), 2301 (1963).
EXAMPLE 10 3- {2-[4-(4-Methoxyphenyl)-1-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.53 g), methanol (33 cc) and 7 % strength potassium carbonate solution (21 cc) in a mixture of methanol (2 volumes) and water (5 volumes) are stirred for 4 hours at a temperature in the region of 20°C. The reaction medium is concentrated under reduced pressure and then - 23 extracted with ethereal sulphuric acid. The organic phase is dried over magnesium sulphate and then treated with an excess of alcoholic hydrochloric acid solution. The precipitate is drained, washed with ethereal sulphuric acid and dried at 50°C at 20 mmHg. 2-Imino-3-{2-[4-(4methoxypheny1)-1-piperaz iny1]ethyl}-6trifluoromethoxybenzothiazoline trihydrochloride (1.05 g), m.p. 240°C, is obtained. 3-{2-[4-(4-Methoxyphenyl)-1-piperaz iny1]ethyl}-210 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: a mixture of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g), toluene (120 cc) and the base liberated from 4-(p15 methoxyphenyl)piperazine dihydrochloride (10.56 g) is heated to reflux for 1 hour, cooled to +4°C and then drained. The toluene filtrate is evaporated under reduced pressure and then treated with 1.2 N aqueous hydrochloric acid solution (45 cc). The hydrochloride separates in amorphous form and then crystallizes on grinding with ethanol (50 cc). After draining, washing with ethanol (15 cc) and drying at 50°C at 20 mmHg, 3-{2-[4-(4-methoxyphenyl)-l-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.7 g) is obtained. 2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate may be prepared in the following manner: triethylamine (6.9 g) is added - 24 gradually to a mixture of methylene chloride (120 cc), methanesulphonyl chloride (7.34 g) and 2-(2trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol (12 g). After 1 hour's stirring at a temperature in the region of 20°C, the reaction medium is cooled to 10°C, drained, washed with cold methylene chloride (20 cc) and then dried at 40°C under reduced pressure. 2-(2-Trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (10 g), m.p. 145°C is obtained. A 2nd crop (2.7 g) is obtained by washing the filtrate with water (100 cc), drying over magnesium sulphate, concentration to a residual volume of approximately 50 cc, cooling to 5°C and then draining.
EXAMPLE 11 Using the procedure described in Example 9, but starting with 3-{2-[4-(3,4-dimethoxyphenyl)-1piperazinyl]ethyl}-2-trifluoroacetylimino-6trifluoromethoxybenzothiazoline hydrochloride (1.4 g) in methanol (30 cc) and a 7 % strength aqueous-alcoholic solution (19 cc) of potassium carbonate, 2-imino-3-{2-[4(3,4-dimethoxyphenyl) -1-piperaz inyl]ethyl}-6trifluoromethoxybenzothiazoline trihydrochloride (0.97 g), m.p. 250°C, is obtained. 3-{2-[4-(3,4-dimethoxyphenyl)-12 5 piperazinyl]ethyl}-2-trifluoroacety1imino-6trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: the procedure is as in - 25 Example 9, starting with 2-(2-trifluoroacetylimino-6trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulphonate (4.3 g), toluene (70 cc) and the base liberated from 4-(3,4 dimethoxyphenyl)piperazine dihydrochloride (14 g). The expected hydrochloride (1.45 g), m.p. 260°C, is obtained.
EXAMPLE 12 Using the procedure described in Example 9, but starting with 3-{2-[4-(4-fluorophenyl)-1piperazinyl]ethyl}-2-trifluoroacetylimino-βίο trifluoromethoxybenzothiazoline hydrochloride (1.7 g), methanol (36 cc) and a 7 % strength agueous-methanolic solution (21 cc) of potassium carbonate, 3-{2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl}-2-imino-6trifluoromethoxybenzothiazoline dihydrochloride, m.p. 260°C is obtained. 3-(2-(4-(4-fluorophenyl)-1-piperaz iny1]ethyl} -2 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: the procedure is as in Example 9, starting with 4-(420 fluorophenyl)piperazine (9 g), toluene (70 cc) and 2-(2trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g). The expected product (1.7 g), m.p. 240°C, is obtained.
EXAMPLE 13 Using the procedure described in Example 9, but starting with 3-{2-[4-(4-chlorophenyl)-1piperazinyl]ethyl}-2-trifluoroacetylimino-6IE 902551 - 26 trifluoromethoxybenzothiazoline (1.40 g) , methanol (30 cc) and a 7 % strength aqueous-methanolic solution (19 cc) of potassium carbonate, 3-(2-[4-(4-chlorophenyl)-1piperaz iny1]ethyl}-2-imino-65 trifluoromethoxybenzothiazoline dihydrochloride (0.9 g), m.p. 270°C, is obtained. 3- {2-[4-(4-Chloropheny1)-1-piperaz inyl]ethyl}-2 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline may be prepared in the following manner: a mixture of 2-(210 trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g), toluene (70 cc) and the base liberated from 4-(4chlorophenyl)piperazine dihydrochloride (13.45 g) is heated to reflux for 1 hour 15 minutes. After cooling to 10°C and draining of the precipitate, the toluene filtrate is concentrated and then purified by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent. After recrystallization in ethanol (50 cc), the expected product (1.4 g), m.p. 165°C, is obtained.
EXAMPLE 14 4- Phenyl-1-[2-(4-trifluoromethoxyanilino) ethyl ] piperidine (3.0 g) and potassium thiocyanate (3.2 g) in acetic acid (25 cc) are treated dropwise with bromine (1.3 g) dissolved in acetic acid (15 cc) at a temperature in the region of 20°C. Reaction is continued for 18 hours at this temperature. After the addition of - 27 distilled water (100 cc), the reaction medium is neutralized with 30 % strength sodium hydroxide and the organic phase is extracted with ethyl acetate (3 x 50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2,7 kPa). The residue obtained is purified by chromatography on a silica column with ethyl acetate as eluent. After formation of the dihydrochloride by adding 4.2 N ethereal hydrogen chloride (4 cc) in ethyl acetate (30 cc), 2-imino-3-[2-(4-phenylpiperidino)ethyl]-610 trifluoromethoxybenzothiazoline dihydrochloride (2.4 g), subliming at about 220°C, is obtained. 4-Phenyl-l-[2-(4-trifluoromethoxyanilino)ethyl]piperidine may be prepared in the following manner: a mixture of N-(p-toluenesulphonyl)-2-(415 trifluoromethoxyanilino)ethyl p-toluenesulphonate (7.2 g), 4-phenylpiperidine (4.9 g) and sodium hydrogen carbonate (2.4 g) in dimethylformamide (50 cc) is heated to 80°C for 18 hours. After cooling to a temperature in the region of 20°C, the reaction medium is concentrated to dryness under reduced pressure (7 mmHg; 0.95 kPa). The residue is washed with water (2 x 30 cc), then taken up with ethanol (50 cc) and concentrated to dryness under reduced pressure. The crude product is treated with 37 % strength hydrochloric acid (30 cc) in a mixture of acetic acid (30 cc) and distilled water (20 cc). The mixture is heated to boiling for 3 hours. After cooling to a temperature in the region of 20°C and the addition of distilled water (100 cc), the - 28 aqueous solution is neutralized with 30 % strength sodium hydroxide and the organic phase extracted with ethyl acetate. 4-Phenyl-l-[2-(4trifluoromethoxyanilino)ethyl]piperidine (4.0 g) is obtained 5 in the form of a brown oil, which is used in the crude state in the following reaction.
N-(p-Toluenesulphonyl)-2-(4-trifluoromethoxyanilino) ethyl p-toluenesulphonate may be prepared according to the following process: p-toluenesulphonyl chloride (8.6 g) is added gradually to 2-(4trifluoromethoxyanilino)ethanol (5.0 g) and triethylamine (6.35 cc) in dichloromethane (50 cc) at O’C. Reaction is continued for 2 hours at a temperature in the region of 20°C, the reaction medium then washed with distilled water (3 x 50 cc) and the organic phase dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa). After the addition of absolute ethanol (50 cc), the precipitate formed is filtered off. N-(pToluene-sulphonyl)-2-(4-trifluoromethoxyanilino)ethyl p20 toluenesulphonate (7.3 g), m.p. 88°C, is obtained. 2-(4-Trifluoromethoxyanilino)ethanol may be prepared in the following manner: 4-trifluoromethoxyaniline (88.5 g) and 2-bromoethanol (31.2 g) are heated to 160°C for 1.5 hours. After cooling to a temperature in the region of 20°C, the reaction medium is taken up in dichloromethane (200 cc), the insoluble matter filtered off and the filtrate concentrated to dryness under reduced - 29 pressure. After purification by chromatography on a silica column with a mixture of ethyl acetate and cyclohexane (40:60 by volume) as eluent, 2-(4trifluoromethoxyanilino)ethanol (26.8 g) is obtained in the 5 form of an orange-coloured oil.
EXAMPLE 15 The procedure is as in Example 1, but starting with 3-{2-[4-(2-fluorophenyl)-1-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline (0.6 g), methanol (20 cc) and a 7 % strength aqueous-alcoholic solution (10 cc) of potassium carbonate. After the addition of 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(2fluorophenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline dihydrochloride (0.335 g), m.p. about 260°C, is obtained. 3-{2-[4-(2-Fluorophenyl)-1-piperazinyl]ethyl-2trifluoroacetylimino-6-trifluoromethoxybenzo-thiazoline may be prepared in the following manner: the procedure is as in Example 1 for the preparation of 3-{2-[4-(2-pyridyl)-120 piperazinyl]ethyl}-2-trifluoro-acetylimino-6trifluoromethoxybenzothiazoline, starting with 2-(2trifluoroacetylimino-6-trifluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (70 cc) and 4-(2-fluorophenyl)piperazine (9 g). After purification by chromatography on a silica column with ethyl acetate as eluent, 3-{2-[4-(2-fluorophenyl)-lpiperaz inyl]ethyl}-2-trifluoroacetylimino-6IE 902551 - 30 trifluoromethoxybenzothiazoline (0.6 g), is obtained.
EXAMPLE 16 The procedure is as in Example 1, starting with 2(2-trifluoroacety1imino-6-trifluoromethoxy-35 benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (120 cc) and 4-(3-chlorophenyl)piperazine (7.8 g). After 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure, and methanol (100 cc) and a 7 % strength agueous-alcoholic solution (10 cc) of potassium carbonate are added to the toluene residue. The mixture is stirred at approximately 20°C. The methanol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a mixture of dichloromethane and methanol (95:5 by volume) as eluent, and then with ethyl acetate as eluent. After the addition of 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(3chlorophenyl)-1-piperazinyl]ethyl}-6trifluoromethoxybenzothiazoline trihydrochloride (0.9 g), m.p. about 260°C, is obtained.
EXAMPLE 17 The procedure is as in Example 1, starting with 2(2-tr i fluoroacetylimino-6-tr i fluoromethoxy-3benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (120 cc) and 4-(3-fluorophenyl)piperazine (6.7 g). After 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure, and methanol (100 cc) and a 7 % strength aqueous-alcoholic solution (20 cc) of potassium carbonate - 31 are added to the toluene residue. After 2 hours' stirring at approximately 20°C, the methanol is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column with a mixture of 5 dichloromethane and methanol (98:2 by volume) as eluent, followed by ethyl acetate. After the addition of 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(3fluorophenyl)-1-piperaz iny1]ethyl}-6trifluoromethoxybenzothiazoline dihydrochloride (1 g), m.p. about 270°C, is obtained.
EXAMPLE 18 The procedure is as in Example 1, but starting with 3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-2trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride (1.8 g) in methanol (39 cc) and a 7 % strength aqueous-alcoholic solution (23 cc) of potassium carbonate. After purification by chromatography on a silica column with acetone as eluent, followed by the addition of 4.2 N ethereal hydrogen chloride, 2-imino-3-{2-[4-(220 methoxyphenyl)-1-piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline trihydrochloride (1.2 g), m.p. 210°C, is obtained. 3-{2-[4-(2-Methoxyphenyl) -1-piperaz iny1]ethyl} -2 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride may be prepared in the following manner: the procedure is as in Example 1, starting with 2-(2trifluoroacetylimino-6-trifluoromethoxy-3IE 902551 - 32 benzothiazolinyl)ethyl methanesulphonate (4.52 g) in toluene (120 cc) and 4-(2-methoxyphenyl)piperazine (7.7 g). After the addition of 4.2 N ethereal hydrogen chloride, 3-(2-(4-(2-methoxyphenyl)-1-piperaz inyl]-ethyl}5 2-trifluoro-acetylimino-6-trifluoromethoxy-benzothiazoline hydrochloride (1.8 g), m.p. 230°C, is obtained.
The present invention also provides medicinal agents comprising a compound of formula (I), or a salt of such a compound, in the pure state or in the form of a pharmaceutical composition in which the active ingredient is combined with another pharmaceutically compatible product, which can be inert or physiologically active. The medicinal agents of the invention may be administered orally, parenterally, rectally or topically.
As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, wafer capsules) or granules may be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica.
These compositions can also comprise substances other than diluents, e.g. one or more lubricants such as magnesium stearate or talc, a colouring, a coating (dragees) or a varnish.
As liquid compositions for oral administration, solutions, suspensions, emulsions, syrups and elixirs of a pharmaceutically acceptable nature, containing inert - 33 diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin, may be used. These compositions can comprise substances other than diluents, e.g. wetting products, sweeteners, thickeners, flavourings or stabilizers.
The sterile compositions for parenteral administration can preferably be solutions, aqueous or nonaqueous, suspensions or emulsions. As a solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, e.g. ethyl oleate, or other suitable organic solvents may be employed. These compositions can also contain adjuvants, especially wetting agents, tonicity regulators, emulsifiers, dispersants and stabilizers. The sterilization may be carried out in several ways, e.g. by aseptic filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile distilled water or any other sterile injectable medium.
The compositions for rectal administration are suppositories or rectal capsules which contain, apart from the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
The compositions for topical administration can be, e.g., creams, ointments, lotions, eye washes, mouth washes, nasal drops or aerosols. - 34 In human therapy, the compounds according to the invention are especially useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders, and in particular the deficiency forms of schizophrenia, sleep disorders, phenomena linked to cerebral ischaemia and also neurological conditions in which glutamate may be implicated, such as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and olivopontocerebella atrophy.
The doses depend on the effect sought, the treatment period and the administration route used; they are generally between 30 and 300 mg per day by oral administration for an adult, with unit doses ranging from 10 to 100 mg of active substance.
Generally speaking, the doctor will determine the appropriate dosage in accordance with the age and weight and all other factors characteristic of the subject to be treated.
The examples which follow illustrate pharmaceutical compositions according to the invention.
EXAMPLE A Hard gelatin capsules containing 50 mg of active product and having the following composition are prepared according to the usual technique: 2-Imino-3-{2-[4-(2-pyridyl)-1piperazinyl]ethyl}-6-trifluoromethoxybenzothiazoline ............... mg - 35 Cellulose ............................
Lactose ..............................
Colloidal silica .....................
Carboxymethylstarch sodium ...........
Talc .................................
Magnesium stearate ...................
EXAMPLE B 18 mg 55 mg 1 mg 10 mg 10 mg 1 mg Tablets containing 50 mg of active product and having the following composition are prepared according to the usual technique: 2-Imino-3-{2-[4-(4-methylphenyl)-1piperaziny1]ethyl}-6-trifluoromethoxybenzothiazoline ............... 50 mg Lactose .............................. 104 mg Cellulose ............................ 40 mg Polyvidone ........................... 10 mg Carboxymethylstarch sodium ........... 22 mg Talc ................................. 10 mg Magnesium stearate ................... 2 mg Colloidal silica ..................... 2 mg Mixture of hydroxymethylcellulose, glycerol and titanium oxide (71:3.5:24.5) .................q.s. 1 finished film-coated tablet weighing 245 mg - 36 EXAMPLE C An injectable solution containing 10 mg of active product having the following composition is prepared: 3-[2-(4-Benzy1-l-piperazinyl)ethyl]-2imino-6-trifluoromethoxybenzothiazoline .......................... 10 mg Benzoic acid ........................ 80 mg Benzyl alcohol ...................... 0.06 cc Sodium benzoate ..................... 80 mg Ethanol, 95 % strength .............. 0.4 cc Sodium hydroxide .................... 24 mg Propylene glycol .................... 1.6 cc Water ...........................q.s. 4 cc
Claims (9)
1. A compound of formula: NH (I) 2 ) n - R, in which - Rj represents . 1-piperazinyl substituted at the 4-position by (a) phenyl, (b) phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, (c) phenylalkyl, (d) pyridyl or (e) pyrimidinyl, . 1,2,3,6-tetrahydro-l-pyridyl substituted at the 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, . piperidino substituted at the 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, - R 2 represents polyfluoroalkoxy, and - n is 2 or 3, the aforesaid alkyl and alkoxy radicals and alkyl and alkoxy portions containing 1 to 4 carbon atoms each in a straight or branched chain, and its acid addition salts.
2. A compound according to claim 1 in which R 2 represents trifluoromethoxy, pentafluoroethoxy, 2,2,2IE 902551 - 38 trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy.
3. A compound according to claim 1 or 2 in which Rj represents 1-piperazinyl substituted at the 4-position by phenyl, 2-,3-or 4-methylphenyl, 2-or 4-methylphenyl, 3,45 dimethoxyphenyl, 2-,3-or 4-fluorophenyl, 3- or 4chlorophenyl, benzyl, 2-pyridyl, or 2-pyrimidinyl or R^ represents 4-phenyl-1,2,3,6-tetrahydro-l-pyridyl or 4phenylpiperidino. 4. A process for preparing a compound of formula: NH (I) (CH 2 ) n - R 1 in which - Rj_ represents . 1-piperazinyl substituted at the 4-position by (a) phenyl, (b) phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, (c) phenylalkyl, (d) pyridyl or (e) pyrimidinyl, . 1,2,3,6-tetrahydro-l-pyridyl substituted at the
4.-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, . piperidino substituted at the 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, - 39 - R 2 represents polyfluoroalkoxy, and - n is 2 or 3, the aforesaid alkyl and alkoxy radicals and alkyl and alkoxy portions containing 1 to 4 carbon atoms each in a straight
5. Or branched chain, and its acid addition salts, which comprises hydrolysing a compound of formula: (II) in which Rj, R 2 and n are as hereinbefore defined, isolating the product, and optionally converting it into an addition 10 salt with an inorganic or organic acid. 5. A process for preparing a compound of formula: R 2NH (I) I (CH 2 , n - Rj in which - R^ represents 15 . 1-piperazinyl substituted at the 4-position by (a) phenyl, (b) phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, (c) phenylalkyl, (d) pyridyl or (e) pyrimidinyl, . 1,2,3,
6.-tetrahydro-l-pyridyl substituted at the - 40 4-position by phenyl or phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, . piperidino substituted at the 4-position by phenyl or 5 phenyl substituted by at least one substituent selected from halogen, alkyl and alkoxy, - R 2 represents polyfluoroalkoxy, and - n is 2 or 3, the aforesaid alkyl and alkoxy radicals and alkyl and alkoxy 10 portions containing 1 to 4 carbon atoms each in a straight or branched chain, and its acid addition salts, which comprises reacting bromine and an alkali metal thiocyanate with a compound of formula: f 2 (VIII) NH - (CH 2 ) n - R, 15 in which Rj, R 2 and n are as hereinbefore defined, isolating the product, and optionally converting it into an addition salt with an inorganic or organic acid. 6. A process for the preparation of a compound as claimed in claim 1 substantially as described in any one of 20 Examples 1 to 18.
7. A compound as claimed in claim 1 when produced by a process as claimed in claim 4, 5 or 6.
8. A pharmaceutical composition which comprises, as active principle, at least one compound according to - 41 claim 1, 2, 3 or 7 as base or as a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or coating.
9. A compound as claimed in claim 1, 2, 3 or 7 5 for use in therapy in the treatment of conditions in which glutamate inhibition is desired.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8909483A FR2649704B1 (en) | 1989-07-13 | 1989-07-13 | IMINO-2 ETHYL-3 BENZOTHIAZOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THEM |
| FR9005889A FR2661910B1 (en) | 1990-05-11 | 1990-05-11 | IMINO-2 HETEROCYCLYLALKYL-3 BENZOTHIAZOLINE DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE902551A1 true IE902551A1 (en) | 1991-02-27 |
| IE63318B1 IE63318B1 (en) | 1995-04-05 |
Family
ID=26227474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE255190A IE63318B1 (en) | 1989-07-13 | 1990-07-12 | Substituted 2-imino-3-alkylbenzothiazolines and their preparation and use |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0409692B1 (en) |
| JP (1) | JPH0386871A (en) |
| AT (1) | ATE102612T1 (en) |
| AU (1) | AU624972B2 (en) |
| CA (1) | CA2021031A1 (en) |
| CZ (1) | CZ281164B6 (en) |
| DE (1) | DE69007196T2 (en) |
| DK (1) | DK0409692T3 (en) |
| ES (1) | ES2062445T3 (en) |
| FI (1) | FI93109C (en) |
| HU (1) | HU210827B (en) |
| IE (1) | IE63318B1 (en) |
| IL (1) | IL95053A (en) |
| NO (1) | NO175590C (en) |
| NZ (1) | NZ234487A (en) |
| PL (2) | PL164326B1 (en) |
| PT (1) | PT94701B (en) |
| RU (1) | RU1836368C (en) |
| SK (1) | SK278908B6 (en) |
| YU (1) | YU47723B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2674853B1 (en) * | 1991-04-03 | 1995-01-20 | Synthelabo | PIPERIDINYLGUANIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2678619B1 (en) * | 1991-07-04 | 1993-09-17 | Rhone Poulenc Rorer Sa | DERIVATIVES OF 1,2,4-THIADIAZOLO [3,4-B] BENZOTHIAZOLE, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
| AU3957093A (en) * | 1992-04-15 | 1993-11-18 | Rhone-Poulenc Rorer S.A. | 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxyl ic acid derivatives, preparation thereof and drugs containing same |
| FR2696457B1 (en) * | 1992-10-02 | 1994-11-25 | Rhone Poulenc Rorer Sa | Derivatives of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, their preparation and the medicaments containing them. |
| US5889010A (en) * | 1995-05-18 | 1999-03-30 | Pfizer Inc. | Benzimidazole derivatives having dopaminergic activity |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2631163B2 (en) * | 1976-07-10 | 1978-06-29 | Basf Ag, 6700 Ludwigshafen | Process for the preparation of 2-iminobenzothiazoles |
| FR2492258A1 (en) * | 1980-10-17 | 1982-04-23 | Pharmindustrie | NEW AMINO-2 TRIFLUOROMETHOXY-6 BENZOTHIAZOLE-BASED MEDICINAL PRODUCT |
| EP0375510B1 (en) * | 1988-12-15 | 1992-11-11 | Rhone-Poulenc Sante | 2-imino-6-polyfluoroalcoxy-benzothiazole derivatives, process for their preparation and medicaments containing them |
| FR2649701B2 (en) * | 1988-12-15 | 1991-11-22 | Rhone Poulenc Sante | IMINO-2 BENZOTHIAZOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND MEDICINES CONTAINING THEM |
-
1990
- 1990-07-09 DE DE69007196T patent/DE69007196T2/en not_active Expired - Fee Related
- 1990-07-09 EP EP90401976A patent/EP0409692B1/en not_active Expired - Lifetime
- 1990-07-09 DK DK90401976.7T patent/DK0409692T3/en active
- 1990-07-09 AT AT90401976T patent/ATE102612T1/en not_active IP Right Cessation
- 1990-07-09 ES ES90401976T patent/ES2062445T3/en not_active Expired - Lifetime
- 1990-07-10 AU AU58847/90A patent/AU624972B2/en not_active Ceased
- 1990-07-11 SK SK3425-90A patent/SK278908B6/en unknown
- 1990-07-11 YU YU133990A patent/YU47723B/en unknown
- 1990-07-11 CZ CS903425A patent/CZ281164B6/en unknown
- 1990-07-12 CA CA002021031A patent/CA2021031A1/en not_active Abandoned
- 1990-07-12 IL IL9505390A patent/IL95053A/en not_active IP Right Cessation
- 1990-07-12 PL PL90300986A patent/PL164326B1/en unknown
- 1990-07-12 PL PL90286036A patent/PL164152B1/en unknown
- 1990-07-12 NO NO903113A patent/NO175590C/en unknown
- 1990-07-12 IE IE255190A patent/IE63318B1/en not_active IP Right Cessation
- 1990-07-12 HU HU904189A patent/HU210827B/en not_active IP Right Cessation
- 1990-07-12 NZ NZ234487A patent/NZ234487A/en unknown
- 1990-07-12 FI FI903531A patent/FI93109C/en not_active IP Right Cessation
- 1990-07-12 JP JP2182893A patent/JPH0386871A/en active Pending
- 1990-07-13 PT PT94701A patent/PT94701B/en not_active IP Right Cessation
-
1992
- 1992-01-08 RU SU925010496A patent/RU1836368C/en active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HU209301B (en) | Process for producing serotonine antagonists and pharmaceutical compositions comprising same | |
| CA1338908C (en) | Aminoalkylthio derivatives of triazolopyridine or triazoloquinoline, the processes for their preparation, and drugs, useful especially as analgesics in which they are present | |
| US5008280A (en) | 2-iminobenzothiazoline derivatives, their preparation and pharmaceutical compositions containing them | |
| EP0279598B1 (en) | Arylpiperazinyl-alkylene-phenyl-heterocyclic compounds | |
| IL93760A (en) | N-3(3-aryl (hydroxyimino) methylphenyl-3- (pyridyl)-1h, 3h-pyrrolo (1,2-c)thiazole-7-carboxamide derivatives, their preparation and pharmaceutical compositions containing them | |
| US5026717A (en) | 2-imino-6-polyfluoroalkoxybenzothiazole derivatives, and pharmaceutical compositions containing them | |
| IE902551A1 (en) | Substituted 2-imino-3-alkylbenzothiazolines and their preparation and use | |
| CS259516B2 (en) | Method of new heterocyclic compounds production | |
| US5260297A (en) | 2-imino-3-alkylbenzothiazoline derivatives bearing a heterocyclic substituent on the alkyl group, their preparation and medicinal products containing them. | |
| JPS58128384A (en) | Benzodioxine compound, manufacture and medicinal composition for psychotic trouble treatment | |
| US5340824A (en) | Benzothiazole derivatives and medicinal products containing them | |
| US5234924A (en) | Benzothiazine and benzothiazole compounds useful as analgesics | |
| US4929616A (en) | Novel basic-substituted 5-halo-thienoisothiazol-3(2H)-one 1,1-dioxides, a process for the preparation thereof, and pharmaceutical preparations containing these compounds | |
| PL107647B1 (en) | HOW TO MAKE NEW 1,1-DIOXIDE 4-HYDROXY-2H-NAFTO / 2,1-E / -1.2-Thiazine-3-CARBOXYAMIDE | |
| FI93455C (en) | Process for the preparation of novel therapeutically useful 1-oxa-2-oxo-8-azaspiro / 4,5 / decane derivatives | |
| KR820000600B1 (en) | Process for the preparation of alkylated hydroxylamines | |
| EP0566592B1 (en) | Pyrimido-benzothiazines with lipoxygenase inhibitory action | |
| US5418231A (en) | Pyrimido-benzothiazines | |
| EP0137083B1 (en) | 1,5-benzothiazepine derivatives and production thereof | |
| DK163921B (en) | SUBSTITUTED (PIPERAZINYL OR HOMOPIPERAZINYL) ALKYL THIOLS AND THIOCARBAMATES AND SALTS THEREOF, PROCEDURES FOR THEIR PREPARATION AND IMMUNOLOGICAL, ANTI-ALLERGY, or ANTI-INFREMATORY PATTERN | |
| FR2661910A1 (en) | 2-Imino-3-(heterocyclylalkyl)benzothiazoline derivatives, their preparation and the medicaments containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |