SEROTONIN ANTAGONISTS, THEIR PREPARATION AND MEDICINES CONTAINING THEM.
Patent Information
- Authority / Receiving Office
- FR · FR
- Patent Type
- Applications
- Current Assignee / Owner
- RHONE POULENC RORER SA
- Filing Date
- 1990-06-05
- Publication Date
- 1991-12-06
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
Existing treatments for conditions involving serotonin, such as anxiety, depression, and schizophrenia, lack compounds with effective serotonin receptor antagonistic properties and are limited in their therapeutic efficacy.
Development of novel compounds of formula (I), including 1,2,3,6-tetrahydro-pyridyl-1 radicals and their salts, which exhibit potent serotonin 5-HT2 receptor antagonism, prepared through specific chemical reactions and processes, allowing for the creation of pharmaceutically acceptable forms for administration.
The compounds demonstrate high affinity for serotonin receptors with low toxicity, providing effective treatments for conditions like anxiety, depression, schizophrenia, migraine, asthma, hypertension, and hives, with IC50 values less than 25 nM and low oral toxicity in mice.
Abstract
Description
The invention described in the main patent relates to compounds of formula: R 2 N (CH 2)n R 1 I (I) R 3 their salts, their preparation processes and the medicines containing them. In formula (I): R 1 represents a 1,2,3,6-1-tetrahydropyridyl radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or an alkyl, hydroxy, or alkoxy radical, (c) a 3-indolyl radical, (d) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom, or (e) a 5-hydroxyindolyl)-3 radical, a 1-piperazinyl radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by an alkoxy, alkyl, hydroxy, nitro, amino, or halogen atom, (c) a 1,2-benzisothiazol-3-yl radical, (d) a radical benzisoxazol-1,2-yl-3 or (e) a pyridyl-2 radical, a piperidino radical substituted at position 4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or a hydroxy, alkyl or alkoxy radical,(c) two phenyl radicals, (d) a bis(4-fluorophenyl)methylene radical, (e) a 4-fluorobenzoyl radical, (f) a 2-oxo-1-benzimidazolinyl radical, (g) a 2-oxo-1-benzimidazolinyl radical substituted at position -3 by an alkylcarbonyl or benzoyl radical, (h) a hydroxy radical and a phenyl radical possibly substituted by an alkyl, alkoxy, hydroxy radical or a halogen atom, (i) a 3-indolyl radical, (j) a 3-indolyl radical substituted at the nitrogen atom by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom or (k) a 5-hydroxy-3-indolyl radical, -R2 represents a 5O2R4 radical in which R4 represents an alkyl or phenyl radical, -R3 represents a phenyl or naphthyl radical, -or R2 and R3 together with the nitrogen atom to which they are attached form a ring chosen from the following formulas:, 02 S _ N _ / x / R 5-N 502 R 5 represents an alkyl radical or a chain -(CH 2)nR 1, N is equal to 2, 3 or 4. N - 1 1 This addition concerns new compounds of formula (I), their salts, their preparation processes and the medications containing them. According to this addition, -R 1 represents a 1,2,3,6-1-tetrahydropyridyl radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or an alkyl, hydroxy, or alkoxy radical, (c) a 3-indolyl radical, (d) a 3-indolyl radical substituted on the nitrogen atom i Ø by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom, or (e) a 5-hydroxyindolyl)-3 radical, a 1-piperazinyl radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by an i 5 alkoxy, alkyl, hydroxy, nitro, amino, or halogen atom, (c) a 1,2-benzisothiazol-3-yl radical, (d) a benzisoxazol-1,2-yl-3 radical or (e) a pyridyl-2 radical, a piperidino radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or a hydroxy, alkyl or alkoxy radical, (c) two phenyl radicals,(d) a bis(4-fluorophenyl)methylene radical, (e) a 4-fluorobenzoyl radical, (f) a 2-oxo-1-benzimidazolinyl radical, (g) a 2-oxo-1-benzimidazolinyl radical substituted at position -3 by an alkylcarbonyl or benzoyl radical, (h) a hydroxy radical and a phenyl radical optionally substituted by an alkyl, alkoxy, hydroxy radical or a halogen atom, (i) a 3-indolyl radical, (j) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom or (k) a 5-hydroxy-3-indolyl radical, -R2 and R3 together with the nitrogen atom to which they are attached form a ring selected from the formulas:, ONOTN N (G) (H) N is equal to 2, 3 or 4. In the preceding definitions and those cited below, alkyl radicals contain 1 to 4 carbon atoms in a straight or branched chain, and halogen atoms are preferably fluorine, chlorine or bromine atoms. The invention also relates to the salts of compounds of formula (I) with mineral or organic acids. Compounds of formula (I), with the exception of those for which Rl represents a 4-aminophenyl-1-piperazinyl radical, can be prepared by the action of a derivative of formula R 2 NH (II) R3 in which R2 and R3 have the same meanings as in formula (1), on a halogenated derivative of formula Hal(CH2)n, R1 in which Hal represents a halogen atom, N and Rj have the same meanings as in formula (I). This reaction is preferably carried out in the presence of a base such as an alkali metal hydride, an alkali metal hydroxide, or an alkali metal carbonate, in an inert solvent such as dimethylformamide or tetrahydrofuran, at a temperature between 200°C and the boiling point of the solvent. The derivative of formula (II), in which R₂ and R₃ together with the nitrogen atom to which they are attached form a ring of formula (H), can be prepared by the action of amino-8 tetrahydro-1,2,5,6 quinoline on urea. This reaction generally takes place in an inert solvent such as diglyme or toluene, at a temperature between between 100 and 170 C. Halogenated derivatives of formula (III) can be obtained by the action of an amine of formula: HR 1 (IV) in which R1 has the same meanings as in formula (I) on a dihalogenated derivative of formula: Hal(CH2)nX(V) in which Hal and X represent a halogen atom and N is equal to 2 or 3. This reaction generally takes place in an inert solvent such as dimethylformamide or acetonitrile, in the presence of a base such as an alkali metal carbonate, at a temperature between 20°C and the boiling point of the solvent. Amines of formula (IV) are commercially available or can be obtained by application or adaptation of the methods described by RL DUNCAN et al., J Med Chem, 13, 1 (1970); L NEDELEC et al., Eur J Med Chem 22, 33 (1987); DK YUNK et al., J. Med Chem, 21, 1301 (1978); JP YEVICH et al., J Med Chem, 29, 3, 359 (1986); L THUNUS et al., Ann Pharm, 38, 353 (1980); L GOOTES et al., Arzneim Forsch, 17, 1145 (1967); J BERGMAN et al., J HET Chem, 1071 (1970) and in patents DE 2139084, BE 62 630, EP 110 435, US 4 470 989 and US 3 575 990 and methods described in the examples. Compounds of formula (I), with the exception of those in which R1 represents a 4-aminophenyl-1-piperazinyl radical, can also be obtained by the action of a derivative of formula: R2N(CH2)nHal(VI)R3, in which R2, R3, and N have the same meanings as in formula (I), and Hal represents a halogen atom, on a derivative of formula (IV), in which R1 has the same meanings as in formula (I). This reaction is generally carried out in an inert solvent such as tetrahydrofuran or dimethylformamide, in the presence of a base such as an alkali metal bicarbonate or a triethylamine, at the boiling point of the reaction medium. Derivatives of formula (VI) can be obtained by reacting a derivative of formula (II) with a dihalogenated derivative of formula (y). This reaction is carried out in an inert solvent such as dimethylformamide, using sodium hydride at a temperature between 200°C and the boiling point of the solvent. The compounds of formula (I) for which R1 represents a 4-aminophenyl-1-piperazinyl radical can be obtained by reduction of the corresponding compounds of formula (I) for which Rl represents a 4-nitrophenyl-1-piperazinyl radical. This reduction is generally carried out using stannous chloride and sodium borohydride in an alcohol such as methanol or ethanol, at a temperature between 20 and 700°C, or using iron and hydrochloric acid in water or a water-alcohol mixture, at a temperature between 200°C and the reflux temperature of the reaction mixture. The reaction mixtures obtained by the various processes described above are treated according to classical physical methods (evaporation, extraction, distillation, crystallization, chromatography) or chemical (formation of salts,). Compounds of formula (I), in their free base form, can optionally be transformed into addition salts with a mineral or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether, or a chlorinated solvent. The compounds of formula (I) and their salts exhibit interesting properties. These compounds possess serotonin antagonistic properties (5-HT2 receptors) and are therefore useful for treating conditions in which serotonin is involved, particularly disorders of the central nervous system, of the cardiovascular system and gastrointestinal disorders. These compounds are particularly useful for treating anxiety, sleep disorders, depression, psychoses, including schizophrenia, migraines, asthma, hypertension, and urticaria, as well as for their analgesic effects. and as inhibitors of platelet aggregation. The affinity of compounds of formula (I) for central serotonin receptor sites (type 52) was determined according to a technique inspired by that of JE LEYSEN et al, Mol. Pharmacol, 21, 301 (1982) which consists of measuring the affinity of the products for the binding sites of tritiated ketanserin. In this test, the IC50 of compounds of formula (I) is generally less than 25 nM. The compounds of formula (I) exhibit low toxicity. They are generally non-toxic at 300 mg / kg orally in the mouse in single administration. For therapeutic use, compounds of formula (I) may be used either as is or in the form of salts. pharmaceutically acceptable. Pharmaceutically acceptable salts include, in particular, addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic acids such as acetates, propionates, succinates, oxalates, benzoates, fumarates, maleates, methanesulfonates, isothionates, theophilin- acetates, salicylates, phenolphthalinates, methylene-bis-B- oxynaphthoates or substitute derivatives of these derivatives. The following example, given as a non-exhaustive guide, shows how The invention can be put into practice. EXAMPLE 1 A solution of 4.5 g of benzolc, dl indolone-2 in 25 cm³ of dimethylformamide is poured over 30 minutes under an argon current to a mixture of 1.3 g of sodium hydride dispersed in petrolatum and 10 cm³ of dimethylformamide. The reaction mixture is stirred for 30 minutes at 1000°C, then cooled to approximately 20°C. Next, over 10 minutes, 9.3 g of (3-bromopropyl)-1-phenyl-1,2,3,6-tetrahydropyridine in 20 cm³ of dimethylformamide is added. The reaction mixture is stirred. 2 hours at reflux then cooled to a temperature close to 20°C. The residual oil is concentrated to dryness at 40°C under reduced pressure (20 mmHg; 2.7 kPa) and then purified by flash chromatography on a silica column under argon flow at medium pressure (0.5–1.5 bar) with ethyl acetate as the eluent. 7.4 g of Nl(4-phenyl-1,2,3,6-pyridyl)-3-propyllbenzolc,dl-2-indolone is obtained as an oil yellow (acid oxalate; melting point: 138 C). (3-Bromo-1-propyl)-1-phenyl-4-tetrahydro-1,2,3,6-pyridine can be prepared as follows: 8.7 g of (3-hydroxy-1-propyl)-1-phenyl-4-tetrahydro-1,2,3,6-pyridine is dissolved in 100 cm³ of toluene, and 2.7 cm³ of phosphorus tribromide is added. The mixture is heated under reflux for 2 hours and then cooled to a temperature close to 20°C. The precipitate formed is filtered through sintered glass and then taken up by 250 cm3 of dichloromethane and 150 cm3 of distilled water. The organic phase is decanted, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness at 40°C under reduced pressure (20 mmHg; 2.7 kPa). This yields 14 g of (3-bromopropyl)-1-phenyl-1,2,3,6-tetrahydropyridine, in the form of its hydrobromide salt (melting point: 185°C), used in its crude form in subsequent syntheses. (3-Hydroxypropyl)-1-4-phenyl-1,2,3,6-tetrahydropyridine can be prepared as follows: 25 cm³ of 3-bromopropanol, 73.4 cm³ of triethylamine, and 51.5 g of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride in 700 cm³ of toluene are heated to boiling for 16 hours. The mixture is then cooled to approximately 200°C and concentrated to dryness at 40°C under reduced pressure (20 mmHg; 2.7 kPa). This yields 42 g of (3-Hydroxypropyl)-1-phenyl-4-tetrahydropyridine, as a brown oil that crystallizes (melting point < 400 C), used in its raw state in subsequent syntheses. The medicinal products according to the invention consist of a compound of formula (I) in free form or as an addition salt with a pharmaceutically acceptable acid, in its pure form or in a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicinal products according to the invention may be administered orally, parenterally, rectal or topical. Tablets, pills, powders (gelatin capsules, caplets), or granules may be used as solid compositions for oral administration. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose, or silica, under an argon current. These compositions may also include substances other than diluents, for example, one or more lubricants such as magnesium stearate or talc, a colorant, or a coating. (sugared almonds) or a varnish. Liquid compositions for oral administration may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may include substances other than diluents, for example wetting agents, sweeteners, thickeners, flavorings or stabilizers.Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions, or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, injectable organic esters, for example ethyl volate, or other suitable organic solvents may be used as solvents or vehicles. These compositions may also contain adjuvants, in particular wetting, isotonic, emulsifying, dispersing, and stabilizing agents. Sterilization may be achieved in several ways, for example, by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation, or by heating. They may also be prepared as sterile solid compositions that can be dissolved at the time of use in [unclear]. sterile water or any other sterile injectable medium. Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. Compositions for topical administration may include, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols. In human therapy, the compounds according to the invention are particularly useful for the treatment of conditions in which serotonin is involved, and in particular disorders of the central nervous system, the cardiovascular system, and intestinal disorders. They are, in particular, useful for the treatment of anxiety, sleep disorders, depression, psychoses, and in particular schizophrenia, migraine, asthma, hypertension, and urticaria, as analgesics and as platelet aggregation inhibitors. Dosage depends on the desired effect, the duration of treatment, and the route of administration; it generally ranges from 10 to 300 mg daily orally for an adult, with single doses ranging from 5 to 150 mg of the active ingredient. In general, the doctor will determine the appropriate dosage based on age, weight, and all other factors. factors specific to the subject being addressed. The following examples illustrate compositions according to the invention: EXAMPLE A Capsules containing 50 mg of the active ingredient are prepared using the usual technique, with the following composition: 11(4-phenyl-1,2,3,6-pyridyl)-3-propyl benzoyl peroxide, 11-2-indolone 50 mg, cellulose 18 mg, lactose 55 mg, colloidal silica 1 mg, sodium carboxymethylamide 10 mg, talc 10 mg, magnesium stearate 1 mg EXAMPLE B Tablets containing 50 mg of the active ingredient are prepared according to the usual technique, with the following usual composition: 11(4-Inyl-1,2,3,6-Tetrahydropyridyl)-3-propyllbenzolc, dl indolne-2 50 mg, lactose 104 mg, cellulose, povidone, sodium carboxymethyl starch, talc, magnesium stearate, colloidal silica, mixture of hydroxyethylcellulose, glycerin, titanium dioxide (71-3, 5-24, 5) q.s.p. Film-coated tablets containing 22 mg, 2 mg, and 2 mg per tablet (245 mg). EXAMPLE C An injectable solution containing 10 mg of active ingredient is prepared with the following composition: Nl(4-phenyl-1,2,3,6-pyridyl)-3-propyll benzol cdl indolone-2-benzoic acid benzyl alcohol sodium benzoate 95% ethanol sodium hydroxide propylene glycol water qs p. mg mg 0.06 cm³ mg 0.4 cm³ 24 mg 1.6 cm³ 4 ancm³
Claims
CLAIMS 1. Nose of formula: R2N(CH2)nR1l(I)R3 in which -R1 represents a 1,2,3,6-1-tetrahydropyridyl radical substituted at position 4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or an alkyl, hydroxy, or alkoxy radical, (c) a 3-indolyl radical, (d) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom, or (e) a 5-hydroxyindolyl)-3 radical, a 1-piperazinyl radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by an alkoxy, alkyl, hydroxy, nitro, amino radical, or a halogen atom, (c) a (d) a benzisothiazol-1,2-yl-3 radical, (e) a benzisoxazol-1,2-yl-3 radical, or (a) a pyridyl-2 radical, a piperidino radical substituted at position -4 by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or a hydroxy, alkyl, or alkoxy radical, (c) two phenyl radicals,(d) a bis(4-fluorophenyl)methylene radical, (e) a 4-fluorobenzoyl radical, (f) a 2-oxo-1-benzimidazolinyl radical, (g) a 2-oxo-1-benzimidazolinyl radical substituted at position -3 by an alkylcarbonyl or benzoyl radical, (h) a hydroxy radical and a phenyl radical optionally substituted by an alkyl, alkoxy, hydroxy radical or a halogen atom, (i) a 3-indolyl radical, (j) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and / or at position -5 by a chlorine or fluorine atom or (k) a 5-hydroxy-3-indolyl radical, -R2 and R3 together with the nitrogen atom to which they are attached form a ring selected from the formulas:, 0 NNO N- (G) (H) -n is equal to 2, 3 or 4. and their salts with mineral or organic acids.
2. A process for preparing compounds of formula (I) according to claim 1, except for those for which R1 represents a 4-aminophenyl-1-piperazinyl radical characterized in that a derivative of formula is reacted: R 2 NH (II) IR 3, in which R 2 and R 3 have the same meanings as in claim 1, on a halogenated derivative of formula: Hal (CH 2)n R 1 (III), in which Hal represents a halogen atom, N and R 1 have the same meanings as above, isolates the product and optionally transforms it into an addition salt with a mineral acid or organic.
3. A process for preparing the compounds of formula (I) according to claim 1, except for those for which R1 represents a 4-aminophenyl-1-piperazinyl radical characterized in that a derivative of formula R2N(CH2)nHal(VI)IR3 is reacted with a derivative of formula: HR 1 (IV) in which R1 has the same meanings as above, R2, R3 and N have the same meanings as in claim 1, and Hal represents a halogen atom, isolates the product and optionally transforms it into an addition salt with a mineral acid or organic.
4. A process for preparing the compounds of formula (I) according to claim 1, wherein R1 represents a 4-aminophenyl-1-piperazinyl radical, characterized in that the corresponding compound of formula (I), wherein R1 represents a 4-nitrophenyl-1-piperazinyl radical, is reduced, the product is isolated, and optionally transformed into an addition salt with an acid mineral or organic.
5. Medicinal products characterized in that they contain, as an active ingredient, at least one compound of formula (I) according to claim 1.
6. Medicinal products according to claim 5 for the treatment of diseases where serotonin is involved.