Derivatives oxazolidinones as antagonists of 5-ht2athe method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of oxazolidinones General formula I, where R' denotes H, CN, Hal, or OA; R2, R3each independently of one another denotes H, CN, Hal, or2and R3together form methylenedioxy; And denotes alkyl with 1-6 C-atoms; Hal denotes F, Cl, Br, J; as well as their enantiomers and physiologically acceptable salts. The method of obtaining the compounds of formula I by reacting the compounds of formula II in which L denotes Cl, Br, J, or a free or reactive functionally modified IT group, with a compound of formula III. Pharmaceutical composition having antagonistic against 5-HT2A-receptor activity and inhibitory activity against reverse grip 5-HT, the compound of the formula I and/or its physiologically acceptable salt and carrier. The compounds of formula I are antagonistic against 5-HT2A-receptor action and inhibitory action against reverse grip 5-HT and can be used to obtain drugs. Technical result: accepting new connections. 4 C. and 3 h.p. f-crystals, 1 PL.

< / BR>
< / BR>

The invention is of IDY independently of each other denotes H, CN, Hal, or OA,

R2and R3together represent methylenedioxy,

And denotes H, CF3or alkyl with 1-6 C-atoms and

Hal denotes F, Cl, Br, I,

and their salts.

5-[(2-oxopentanoate-1-yl)piperidinomethyl] oxazolidin-2-ones possessing the ability to affect the Central nervous system, are known, for example, from EP 0443197.

N-alkylated indolalkylamine remnants of indolepropionic described, for example, in EP 0683166.

Derivatives of 3-phenyl-5- [(4-R-X-piperidino)alkyl] oxazolidin-2-it, where R denotes phenyl, and X denotes-O-,-S-,-SO - or-SO2- having the ability to affect the Central nervous system, are known, for example, from EP 0635505.

Derivatives indometacina with tricyclic residue and can affect the Central nervous system is described, for example, in EP 0722942.

Derivatives of 4-aryl-1-(indan-dihydrobenzofuran or dihydrobenzofuranyl) piperidine having the ability to affect serotonergic and dopaminergic transmission, as well as having inhibitory action on the reuptake of 5-HT (5-hydroxytryptamine) is described, for example, in the international is to teach new compounds with valuable properties, first of all such compounds, which could be used to manufacture the drugs.

It has been found that the compounds of formula I and their salts along with good compatibility possess valuable pharmacological properties, as they can affect the Central nervous system and primarily antagonistic in relation to dopamine and inhibition in relation to the reuptake of 5-HT the effect that they are both in relation to serotonergic and dopaminergic transmission. They have, in particular, affinity to 5-HT1A- and/or 5-HT2A-receptors.

The compounds of formula I inhibit the binding of treated ligands serotonin receptors with hippocampi receptors (Cossery and other European Journ. Pharmacol. 140 (1987), 143-155) and inhibit the synaptic reuptake of serotonin (Sherman and others, Life Sci. 23 (1978), 1863-1870). First of all, they are associated with 5-HT2Aand D2-receptors. In addition, there have been changes in the accumulation of DOPA in the striatum and in the accumulation of STD in the N-line" connections tissues (joint) (Seyfried and others, European Journ. Pharmacol. 160 (1989), 31-41). Antagonistically activity against 5-HT1A-receptor podtverzhdaya ileum from Guinea pigs (Fozard and Kibinger, Br. Journ. Pharmacol. 86 (1985) 601 P). Confirmation antagonistic action against 5-HT1Areceptors ex vivo suppression is reduced under the action of 8-OH-DPAT to the accumulation of 5-NTR (Seyfried and others, European Journ. Pharmacol. 160 (1989), 31-41). To confirm the inhibitory effect against serotonin reuptake ex vivo method is used synaptic suppression of capture (Wong and others , Neuropsychophamacol. 8 (1993), 23-33) and antagonism towards p-chloroamphetamine (Fuller and others, Journ. Pharmacol. Exp. Ther. 212 (1980), 115-119). In the rest of the pharmacological testing can be carried out analogously to the methods described, in particular, in the international application WO 95/33721.

In accordance with the above compounds of formula I suitable for use in both veterinary and medicine to fight with functional disorders of the Central nervous system. They can be used for the prevention and treatment of stroke (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for treatment extrapyramidal-motor side effects of antipsychotic drugs (tranquilizers) and Parkinson's disease. But first and foremost they can be used as active substances in such medicines as anxiolytics, antani (obsessive-compulsive disorder, ROC), state of fear, panic attacks, depression, psychosis, schizophrenia, conditions associated with delusional, obsessive, Alzheimer's, migraines, anorexia, sleep disorders, delayed psoriasis, disorders in the learning process, age-related memory disorders, disorders in feeding behavior, such as bulimia, abuse of drugs (abusus) and/or sexual disorders.

The compounds of formula I and their physiologically acceptable salts can therefore be used as active substances in drugs such as anxiolytics, antidepressants, tools, warning psychotic state and/or antihypertensives, as well as for positive effects on obsessive-compulsive disorder, eating disorders such as bulimia, retarded dyskinesia, a disorder in the learning process and age-related memory impairment. In addition, they can be used as intermediate products for other active substances used in medicinal products.

The object of the invention is thus the compounds of formula I and their physiologically acceptable acid additive salt.

The object of the invention in accordance with e the>/BR>a) compound of formula II

< / BR>
where R1has the meaning specified in paragraph 1, a, L denotes C1, Br, I or a free or reactive functionally modified IT group, is subjected to the interaction with the compound of the formula III

< / BR>
where R2and R3shall have the meaning specified in paragraph 1, or

b) the compound of formula IV

< / BR>
where R1, R2and R3have the values listed in paragraph 1, is subjected to the interaction with the compound of the formula V

< / BR>
where L and L,each independently of one another denotes C1, Br, I or a free or reactive modified IT a group, or

C) the compound of formula VI

< / BR>
where R1, R2and R3have the values listed in paragraph 1, gererous, and/or a basic compound of formula I by treatment with acid is transferred into one of its salts.

Unless otherwise noted, above and beyond the remains of R1, R2, R3and L have the values listed in the interpretation of formulas I, II, III, IV and V

The object of the present invention are also drugs of formula I and their physiologically acceptable salts with antagonistic against 5-HT1A-, 5-HT2Areceptors and ingibiruet I according to p. 1, as well as their enantiomers and their salts.

On all balances presented in various ways, as, for example, And, the following applies: they are set independently from each other.

Alkyl has 1-10, preferably 1, 2, 3, 4, 5 or 6 C-atoms and represents, in accordance with this first of all, for example, methyl, and ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore, pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl and vermeil, deformity, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoroethyl.

And-Oh represents hydroxy or alkoxy, especially, for example, methoxy, ethoxy, propoxy or butylochki.

The compounds of formula I, as well as source materials for their production in the rest get by known methods described in the literature (for example, in such fundamental publications, as Houben-Weyl, Methods der organischen Chemie, published by Georg-Thieme-Verlag, Stuttgart), namely under conditions known and suitable for the implementation of these reactions. This could is the joining of the formula II, respectively, L and L' in the compounds of formula V are each independently of one another denotes C1, Br, I or a free or reactive esterified HE group. If L represents a reactive esterified HE group, the latter is a preferable trichlormethane, alkoxy, such as methoxy, ethoxy, propoxy or butoxy and phenoxy, alkylsulfonate with 1-6 C-atoms (preferably, methylsulfonylamino) or arylsulfonate with 6-10 C-atoms (preferably phenyl - or p-tolilsulfonil, and 2-naphthalenesulfonate). L in compounds of formula V, preferably denotes a C1, 1-imidazolyl, ethoxy, trichlormethane, phenoxy or nitrophenoxy.

The source of the substance, if necessary, can also be formed in situ, eliminating the necessity of their separation from the reaction mixture and allows their immediate subsequent conversion into the compounds of formula I. At the same time, this reaction can be carried out by step-wise mechanism.

The compounds of formula I can be obtained preferably by the interaction of the compounds of the formula II with compounds of formula III.

Source materials of formulas II and III are partially known. If he is to obtain recovery of the corresponding carboxylic acids or their esters. By treatment with thionyl chloride, hydrogen bromide, tribromide phosphorus or similar halogenosilanes receive the corresponding halides of the formula II.

3-(4-piperidyl) indoles of formula III can be obtained, for example, by interaction of 4-piperidones. with indole or with the appropriate substituted R2and/or R3derivatives and subsequent treatment with acid and hydrogenation.

The interaction of compounds of the formula II with compounds of the formula III is carried out usually in an inert solvent in the presence of an acid binding agent, preferably a hydroxide, carbonate or bicarbonate of alkali or alkaline earth metal or any other melodramatically or deletepersistentall salts of weak acids, preferably of potassium, sodium, calcium or caesium. It may be appropriate to add an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. The reaction time depending on the environment ranges from a few minutes up to 14 days, and the reaction temperature is in the range from approximately 0 to 150oC, usually from 20 to 130oC.

As inert solvents is consistent hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, such as onomatology or monotropy ether of ethylene glycol (methylglycol or ethylglycol), dimethyl ether of ethylene glycol (diglyme); ketones, such as acetone or butanone; amides, such as ndimethylacetamide, dimethylacetamide or dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of these solvents.

Another preferred possibility of obtaining compounds of formula I consists in the fact that compounds of the formula IV is subjected to interaction with compounds of the formula V. the compounds of formula V can be used preferably diallylmalonate, such as dimethyl-, detriorated or diethylcarbamyl, the esters of Harborview acid, such as marked the substances of formulas IV and V partially known. If they are not known, they can be obtained by known methods. Their interaction is carried out in solvents and at temperatures specified above.

The compounds of formula VI can also be started by recovery to translate into compounds of formula I. Preferably, in this order to carry out catalytic hydrogenation using, for example, palladium on charcoal and hydrogen.

Educt of the formula VI partially known. If they are not known, they can be obtained by known methods. The recovery is carried out in solvents and at temperatures specified above.

You can further compound of formula I, where R1IT denotes, by alkylation to turn in the ether compound of the formula I, in which R1denotes alkoxygroup.

The basis of the formula I can be translated using acid to the corresponding acid additive salt, for example, the interaction of equivalent amounts of base and acid in an inert solvent, such as ethanol and subsequent evaporation. For such a reaction is primarily suitable acids that can form physiologically acceptable salts. Thus, in particular, can be used such neo is native acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, aminosalicylate, and also organic acids, especially aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine and dissolvability, louisanna acid. About salts with physiologically unacceptable acids, for example, picrate, it should be noted that they can be used for isolating and/or purifying compounds of formula I.

Proposed in the invention the compounds of formula I, thanks to the structure of their molecules can be chiral and in accordance with this can be presented in two enantiomeric forms and the property named is responsible stereoisomers of the compounds according to the invention may be different, it may be appropriate to use the enantiomers. In these cases, the final product or even intermediate products using well-known specialist in this field of technology chemical or physical operations can be divided into enantiomeric compounds, either directly without such a separation be used in the synthesis process.

In the case of racemic amines of the mixture by reacting with an optically active separating agent form diastereoisomers. As separating agents are suitable, for example, optically active acids, such as R-and S-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid, are suitable next N-protected amino acids (for example, N-benzoylpyridine or N-benzosulfonazole) or the various optically active camphor sulphonic acids. My favorite is also the chromatographic separation of enantiomers using optically active separating agent (for example, dinitrobenzophenone, cellulose triacetate or other derivatives of carbohydrates or fixed on silica gel chiral derivatizing methacrylate polymers). As luitprand/acetonitrile, for example, in the ratio 82:15:3.

As mentioned above, salts with physiologically unacceptable acids, for example, the picrate can be used for isolating and/or purifying compounds of formula I.

Another object of the invention is the use of compounds of the formula I and/or their physiologically acceptable salts for pharmaceutical compositions, primarily non-chemical way. Thus they can be used in conjunction with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance, and optionally in combination with one or more other active substances for the manufacture of appropriate dosage forms.

The object of the invention are hereinafter pharmaceutical composition containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These compositions can be used as drugs in medicine and veterinary medicine. As carriers for these compositions can be considered organic or inorganic substances suitable for enteral (for example oral), parenteral or topical administration and do not react with the new compounds, for example, acerina, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, vaseline. For oral assignments are designed primarily for tablets, pills, coated tablets, capsules, powders, granules, syrups, medicine or drops for rectal use - suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical application suitable ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilizate be used, for example, for the preparation of injection preparations. These compositions can be sterilized and/or they may contain auxiliary substances, such as oil, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or one or more other active substances, for example one or more vitamins.

Above and beyond all temperatures are in degrees Celsius. Under used in the following examples, the term "normal processing" we mean the following: if necessary, water is added, depending on irout with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, evaporated, purified by chromatography on silica gel, but also the following isomers, and/or by crystallization. The Rf values represent the retention time on silica gel; solvent system: ethyl acetate/ethanol in a ratio of 9:1.

Mass spectrometry (MS): EI (ionization by electron impact) M+; FAB (bombardment with accelerated atoms) (M+N)+.

Example 1

A solution of 5-(methanesulfonylaminoethyl)-3-p-methoxyphenylacetamide-2-[obtained by the interaction of 2,3-epoxypropanol with N-benzyl-p-methoxyaniline with the formation of 1-(M-benzyl-p-methoxyaniline)propane-2,3-diol, followed by hydrogenolysis to obtain 1-p-methoxyaniline-2,3-diol, followed by interaction with diethylmalonate obtaining 5-hydroxymethyl-3-p-methoxyphenylacetamide-2-she and reaction with CH2SO2Cl] in acetonitrile is mixed with equimolar amounts of 4-(3-indolyl) piperidine (compound a"), of potassium iodide and potassium carbonate, for 16 h, refluxed, and then subjected to conventional processing. Thus obtained 3-(4-methoxyphenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-it, tPL151-153oPL234-236o,20D-56(C=1, methanol);

with (5S)-5-(methanesulfonylaminoethyl)-3-p-chlorophenylacetic-2-one receive (5S)-(-) -3- (4-chlorophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-it, tPL188-189o,20D-28(C=1, DMSO); hydrochloride, tPL260-263o;

5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one obtained 3- (4-tianfeng) -5-[4-(3-indolyl) -1-piperidinylmethyl] oxazolidin-2-he;

5-(methanesulfonylaminoethyl)-3-phenyloxazolidine-2-one obtained 3-phenyl-5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-he;

5- (methanesulfonylaminoethyl) -3-p-tortenelmietlen-2-one obtained 3-(4-forfinal)-5- [4-(3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it.

Similar by interaction of 4-(5H-1,3-dioxolo[4,5-f] indol-7-yl) piperidine (compound B")

with (5S)-5-(methanesulfonylaminoethyl)-3-p-methoxyphenylacetamide-2-one receive (5S)-(-)-3-(4-methoxyphenyl)-5-[4-(5H-1,3-dioxolo[4,5-f]indol-7-yl)-1-piperidinylmethyl] oxazolidin-2-he hydrochloridePL232-234o,20D-50,5(C=1, methanol);

with (5S)-5-(methanesulfonylaminoethyl) -3-p-chlorophenylacetic-2-one receive (5S)-(-)-3-(4-chlorophenyl) -5-[4-(5�m 4-(5-fluoro-3-indolyl)piperidine (compound B")

with (5S) -5- (methanesulfonylaminoethyl) -3-p-methoxyphenylacetamide-2-one receive (5S)-(-)-3-(4-methoxyphenyl)-5- [4-(5-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL233-234o,20D-58,5(C=1, DMSO);

5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one obtained 3-(4-tianfeng)-5- [4-(5-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL290-292o;

with (5S) -5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one receive (5S)-(-)-3-(4-tianfeng)-5- [4-(5-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL203-204o,20D-36,5(C=1, DMSO);

with (5R)-5-(methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one receive (5R)-(+)-3- (4-tianfeng) -5-[4-(5-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL286 and 287o,20D+41,5(C=1, DMSO).

In a similar way interactions 4-(5-cyan-3-indolyl)piperidine (compound G")

5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one obtained 3-(4-tianfeng)-5-[4-(5-cyan-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL290o;

with (5S)-5-(methanesulfonylaminoethyl)-3-p-FPO is drochloride, tPL252-253o;

with (5S) -5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one receive (5S)-(-)-3-(4-tianfeng)-5- [4-(5-cyan-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-it, hydrochloride, tPL270-271o,20D-38,7(C=1, DMSO);

with (5R) -5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one receive (5R)-(+)-3- (4-tianfeng) -5- [4- (5-cyan-3-indolyl)-1-serienummer]oxazolidin-2-it, hydrochloride, tPL270-272o,20D+37,7(C=1, DMSO);

5- (methanesulfonylaminoethyl) -3-p-tortenelmietlen-2-one obtained 3-(4-forfinal)-5- [4-(5-cyan-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-it, hydrochloride, tPL264-268o;

5- (methanesulfonylaminoethyl) -3-phenyloxazolidine-2-one obtained 3-phenyl-5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-he, hydrate hydrochloride,PL183-185o;

with (5R) -5- (methanesulfonylaminoethyl) -3-p-tortenelmietlen - 2-one receive (5R)-(+) -3-(4-forfinal) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL184-188o; 20D/+27,2(C=1, DMSO).

In a similar way interactions 4-(6-fluoro-3-indolyl)piperidine (compound D")

with (5S) -5- (metanormal] oxazolidin-2-it, hydrochloride, tPL287-288o; 20D-38,4(C=1, DMSO);

5- (methanesulfonylaminoethyl) -3-p-tortenelmietlen-2-one obtained 3- (4-forfinal) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL257-259o;

with (5R) -5- (methanesulfonylaminoethyl) -3-p-langenlonsheim-2-one receive (5R)-(+)-3- (4-tianfeng) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL288-290o,20D+38,8(C=1, DMSO);

5-(methanesulfonylaminoethyl)-3-phenyloxazolidine-2-one obtained 3-phenyl-5- [4- (6-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, hydrochloride, tPL234-236o.

Example 2

A solution of 1- [4 -(3-indolyl) piperidine-1-yl] -3-(4-methoxyaniline)propan-2-ol in dichloromethane is mixed with equimolar quantities of detrioration and stirred for 5 hours After the usual processing gain 3-(4-methoxyphenyl)-5- [4-(3-indolyl)-1 - piperidinylmethyl] oxazolidin-2-it, tPL151-153o.

Example 3

Through a solution of 5-[4-(3-indolyl)-3,6-dihydro-2H-pyridine-1-ylmethyl]-3-(4-methoxyphenyl)oxazolidin-2-[received by digitalizacie 3-(4-methoxyphenyl) -5- [4-(3-indolyl)-4-hydroxy-1-piperidin the Teal] oxazolidin-2-it indol] in methanol for 1 h in the presence of palladium (10% on charcoal) miss hydrogen. After separation of the catalyst and conventional processing gain 3-(4-methoxyphenyl)-5- [4-(3-indolyl)-1-piperidinylmethyl] oxazolidin-2-it, tPL151-153o.

The following are examples of pharmaceutical compositions and technology of their preparation in the appropriate dosage forms.

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water using 2 N. hydrochloric acid set at pH 6.5, sterile filtered, filled flask, lyophilized in sterile sterile conditions and sealed. Each vial contains 5 mg of active substance.

Example B: Suppositories

A mixture of 20 g of the active substance of the formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to harden. Each suppository contains 20 mg of active substance.

Example: Solution

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NaH2PO42H2O, 28,48 g Na2HPO412H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, adjusted to a volume of 1 l and sterilized by irradiation. This solution morepotential a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Tablets

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate tabletirujut by the conventional methods, receiving tablets, each containing 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then according to standard technology is covered by a shell of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of active substance of the formula I according to standard technology to produce capsules with terrorisation coating, each of which contains 20 mg of active substance.

Example 3: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules under sterile conditions lyophilized sealed and sterile. Each ampoule contains 10 mg of active substance.

Data pharmacological tests

The data values IC50for a number of compounds of the present invention with their indices of 5-HT1Ainhibition of.

Pharmacological data were obtained by analogy with Kasseri with al., European J. Pharmacol., 140 (1987), 143-155 given in picomoles/liter.

The compounds taken from example 1 (pages 12-15) and represented by the structural formulas (table).

The test results clearly show a pronounced affinity of the compounds of the present invention to 5-HT1A-receptors.

1. Derivative oxazolidinone formula I

< / BR>
where R1denotes H, CN, Hal, or OA,

R2, R3each independently of one another denotes H, CN, Hal, or

R2and R3together form methylenedioxy,

And denotes alkyl with 1-6 C-atoms and

Hal denotes F, C1, Br, I, their enantiomers, as well as their physiologically acceptable salts.

2. The enantiomers of compounds of formula I under item 1.

3. The compounds of formula I under item 1 or 2:

a) (5S)-(-)-3-(4-chlorophenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl] oxazolidin-2-he;

b) 3-(4-tianfeng)-5-[4-(5-cyan-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-he;

in) (5S)-(-)-3-(4-tianfeng)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-he;

g) (5R)-(+)-3-(4-tianfeng)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-he;

d) (5R)-(+)-3-(4-tianfeng)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl] oxazolidin-2-he;

e) 3-phenyl-5-[4-(5-cyan-3-indolyl)-1-piperidinylmethyl] oxazol the Ki acceptable salt.

4. The compounds of formula I under item 1, which has antagonistic activity against dopamine and inhibitory action on the reuptake of 5-HT.

5. The method of obtaining derivatives oxazolidinone formula I under item 1, characterized in that the compound of formula II

< / BR>
where R1has the meaning specified in paragraph 1;

L denotes CL, Br, I or a free or reactive functionally modified IT group, is subjected to the interaction with the compound of the formula III

< / BR>
where R2and R3shall have the meaning specified in paragraph 1, and/or received in the form of a base compound of formula I by treatment with acid is transferred into one of its salts.

6. Pharmaceutical composition having inhibitory against reuptake of 5-HT action, in particular antagonistic against 5-HT2A-reception effect, containing a derivative oxazolidin-2-it, characterized in that as a derivative oxazolidin-2-it contains a compound of formula I under item 1 and/or one of its physiologically acceptable salts.

7. Drugs of formula I under item 1 and their physiologically acceptable salts as antagonists of 5-HT1A, 5-HT2Areceptors

 

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The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to 1,4-disubstituted the piperazines of General formula I, the method of production thereof, containing compositions and their use for the clinical treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation

The invention relates to new derivatives of spirobiindane General formula (I), where R1represents a phenyl group which may be optionally substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, halogenized alkyl groups, lower alkoxygroup, lower alkoxycarbonyl groups, hydroxyl groups, lower aliphatic acylamino, cyano groups, or a 5 - or 6-membered heterocyclic group containing 1-3 oxygen atom, sulfur and/or nitrogen, which may be optionally condensed with a phenyl group; R2represents a phenyl group which is substituted by 1-3 fluorine atoms or chlorine; a represents a carbonyl group; represents a simple bond; D represents an oxygen atom or sulfur; E represents C1-4Allenova group;represents a group of formula (II), where G represents C5-8alonovoa ring, which is substituted by hydroxyl group; Ar represents a phenyl ring; n represents the integer 1 or 2, or a pharmacologically acceptable salt

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to new derivatives 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -chromen-4-it formula I, where R is hydrogen, Cho, CH2OR2or COOH; R1means alkyl containing from 1 to 4 carbon atoms, provided that one of substituents R and R1is hydrogen, and their pharmaceutically acceptable salts, intended for use in the treatment of psychosis and schizophrenia, as well as to a method for producing these compounds, pharmaceutical compositions and method of inhibiting D2-, 5-HT2aand H1receptors in the treatment of psychosis and schizophrenia

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to new derivatives naphthiridine formula I, where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl; R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, elcamino, Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing ether and/or ester bond, or its N-oxide in free form or in the form of a pharmaceutically acceptable salt

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

New ketoenamine // 2190599
The invention relates to new ketoenamine formula (1), where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, which may be unsubstituted or substituted, R2means hydrogen or alkyl, R3means alkyl, which may carry phenyl ring, X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)0-, -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH=CH-, -(CH2)m-NHCO-(CH2)0-, -(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-; R4means group OR6, NR7R8; n is a number from 0 to 2

New ketoenamine // 2190599
The invention relates to new ketoenamine formula (1), where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, which may be unsubstituted or substituted, R2means hydrogen or alkyl, R3means alkyl, which may carry phenyl ring, X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)0-, -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH=CH-, -(CH2)m-NHCO-(CH2)0-, -(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-; R4means group OR6, NR7R8; n is a number from 0 to 2

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new pseudopolymorphs the form of the dihydrochloride of 2-[2-[4-[bis(4-forfinal)methyl] -1-piperazinil] ethoxy] acetic acid, namely the anhydrous dihydrochloride of 2-[2-[4-[bis-(4-forfinal)methyl]-1-piperazinil] ethoxy] acetic acid and the dihydrochloride monohydrate 2-[2-[4-[bis(4-forfinal)methyl] -1-piperazinil] ethoxy] acetic acid

The invention relates to a new derivative of 2-(3H)-oxazolone formula I, where R1is an alkyl group or a group-NR4R5where each R4and R5independently are hydrogen, alkyl or benzyl group, R2is naftilos, unsubstituted phenyl or a phenyl group substituted by 1 to 3 halogen atoms, alkyl groups, hydroxy, alkoxy or triptorelin group, R3is hydrogen or alkyl group
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