N-(indolcarbonyl)piperazine derivatives, methods for production the same, pharmaceutical composition, and compounds

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

 

The invention relates to compounds with formula I

in which R1denotes phenyl or nattily radical, which may be unsubstituted or substituted, R2and/or R3or represents Het1,

R2, R3in each case, independently of one another, denotes Hal, A, OA, HE or CN,

R4, R5in each case, independently of one another, denote H, CN, acyl, Hal, A, OA, HE CONH2, CONHA or CONA2,

R4and R5together represent alkylene, including 3-5 atoms,

Het1denotes a single or dual unsaturated heterocyclic structure which is unsubstituted or mono - or disubstituted by Hal, A, OA or HE has one, two or three identical or different heteroatoms, such as nitrogen, oxygen and sulphur,

And denotes alkyl containing 1-6 atoms,

Hal denotes F, Cl, Br or I,

and where the indole ring may also be substituted isatin,

and to their physiologically acceptable salts and solvate, except (1H-indol-5-yl)-(4-feiticeira-1-yl)methanone.

The object of the invention lies in finding new compounds having valuable properties, in particular those that can be used in the manufacture of medical products.

Found that the compounds with formula is y I, and their physiologically acceptable salt and solvate have valuable pharmacological properties, if tolerated, because they affect the Central nervous system. For these compounds are characterized by high affinity receptors 5-HT2A; in addition, they possess antagonistic properties with respect to the receptor 5-HT2A.

To determine the in vitro affinity to the receptors 5-HT2Ayou can use, for example, the following test (example A1). Receptors 5-HT2Aat the same time expose [3N]ketanserina (a substance with a known affinity for the receptor) and the test compounds. Reducing the affinity of [3N]ketanserina to the receptor is indicative of the affinity to the receptor 5-HT2A. among the tested compounds. Definition produced by the method described in J.E.Leysen et al., Molecular Pharmacology, 1982, 21: 301-314, or according to the method described, for example, in EP 0320983.

The effectiveness of the compounds according to this invention as antagonists of the receptor 5-HT2Acan be measured in vitro by the method of W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction in The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard JR, Oxford University Press, New York, 1989, p. 110. Receptors 5-HT2Aare intermediaries depends on the contractility of rat tail artery under the influence of 5-hydroxytryptamine. In ispytatelei the th ring system of the vessel, prepared from the ventral artery of rat tail, is subjected to the irrigation solution, saturated with oxygen, in the environment of the body. By introducing into the solution concentrations of 5-hydroxytryptamine receive the response to cumulative concentrations of 5-HT. Then on Wednesday, the body type of the tested compound in suitable concentrations and measurements to build a second curve concentrations of 5-HT. The effect of the test compound on the amount of shift of the concentration curve of 5-HT in the direction of large concentrations of 5-HT is a measure of the antagonistic properties to the receptor 5-HT2Ain vitro.

To determine the in vivo antagonistic properties against 5-HT2Ait is possible according to the method described in M.D.Serdar et ai., Psychopharmacology, 1996, 128: 198-205.

Other compounds which also exhibit antagonistic properties against 5-HT2Adescribed, for example, in EP 0320983. Similar to piperazine derivatives having anti-arrhythmic properties, are disclosed, for example, in EP 0431945. Other derivatives indolocarbazole with analgesic properties are described in EP 0599240. In the application WO 99/11641 described derivatives phenylindole which exhibit antagonistic properties against 5-HT2A.

Connection with formula I suitable for use both in veterinary and in human medicine for the treatment of functional RA is disorders of the Central nervous system and inflammatory processes. They can be used to prevent and treat complications of cerebral infarcts (cerebral palsy), such as stroke and cerebral ischemia, as well as for treatment of side effects that neuroleptics have on extrapyramidal motor nerves, Parkinson's disease, for urgent and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. These compounds can be used as therapeutic drugs for the treatment of injuries of the brain and spinal cord. However, the special value they represent as pharmaceutical active compounds for the production of tranquilizers, antidepressants, antipsychotics, neuroleptics, protivogipertonicheskoe funds and/or compositions having a positive impact on manic state (manic-compulsive disorder, OCD; for example, WO 9524194), anxiety and physiological changes that accompany such anxiety, such as palpitations, tremors or sweating (for example, EP 319962), panic, psychosis, schizophrenia, loss of appetite, delusional obsessions, fear of open space, migraine, Alzheimer's disease, sleep disorders and apnea in the dream, late dyskinesia, a disorder learning ability, age-related memory disorders, pexeva the disorder, such as abnormally increased hunger, substance abuse, such as alcohol, drugs, nicotine, psychostimulants, such as cocaine or amphetamines (for example, US 6004980), functional sexual disorders, pain of all types and fibromyalgia (for example, WO 9946245). Compounds with formula (I) are suitable for the treatment of extrapyramidal side effects (EPS), which are manifested in the appointment of antipsychotic drugs. For EPS characteristic syndromes type, Parkinson's disease, akathisia and dystonic reactions (for example, EP 337136). In addition, these compounds are suitable for treating loss of appetite for nervous, angina, syndrome Raynaud, spasms of the coronary vessels, for the prevention of migraine headaches (e.g., EP 208235), pain and neuralgia (for example, EP 320983), for the treatment of rett syndrome with autistic symptoms, Asperger's syndrome, autism and autistic disorders, concentration deficits, developmental disorders, hyperactive state with mental underdevelopment and stereotypical behavioral States (e.g., WO 9524194).

In addition, these compounds are suitable for treatment of endocrine disorders such as hyperprolactinaemia, it is useful to apply when blood vessels spasm, thrombotic disorders (e.g., WO 9946245), hypertension and gastro-Kish is cnyh disorders.

Moreover, they are suitable for the treatment of cardiovascular disorders and extrapyramidal symptoms, such as described in WO 99/11641 on page 2, lines 24-30.

Compounds according to this invention is also suitable for the reduction of intraocular pressure and to treat glaucoma. In addition, they are suitable for the prevention and treatment of symptoms of intoxication in animals that appear in the appointment ergovaline. Compounds suitable for treating disorders of the cardiovascular system (WO 99/11641, page 3, lines 14-15). Compounds according to this invention can also be applied in conjunction with other active substances for the treatment of schizophrenia. Possible other active agents mentioned in WO 99/11641 on page 13, lines 20-26.

In addition, they can be used as intermediates for the production of the final pharmaceutically active compounds.

The invention relates to N-(indolocarbazole)-piperazine derivatives with formula I and to their salts with physiologically acceptable acid residues. The invention relates also to a solvate such as hydrate or alcoholate of these compounds.

Accordingly, the invention relates to compounds with formula I and to a process for the preparation of compounds with formula I, paragraph 1 of the claims.

The method of obtaining compounds of formula I by the dotted line is the 1, except (1H-indol-5-yl)-(4-feiticeira-1-yl)methanone, characterized in that

a) conducting a reaction of the compound with formula II

in which L denotes CL, Br, I or a free or reactive functionally modified group HE,

a R4and R5take the values specified in paragraph 1

and connection with formula III

in which R1is referred to in paragraph 1 is,

or

b) conducting a reaction of the compound with formula IV

in which R4and R5have the meanings specified in paragraph 1

and compounds of formula V

in which L denotes CL, Br, I or a free or reactive functionally modified group HE and R1has the meaning specified in paragraph 1

or

C)* if necessary, one of the radicals R1, R4and/or R5converted into another radical, the radical R1, R4and/or R5by splitting, for example, the OA group with the formation of the group, HE and/or group conversion SNO group CN

and/or received base with the formula I is converted into one of its salts by treatment with acid.

The invention also relates to compounds with formula I, paragraph 1, as well as to their Phi is Biologicheskie acceptable salts and solvate as medications, except (1H-indol-5-yl)-(4-feiticeira-1-yl)methanone.

The invention relates especially to compounds with formula I in claim 1 and their physiologically acceptable salts and solvate as medical drugs that have antagonistic effects on the receptor 5-HT2A.

The invention also relates to compounds with formula I, their enantiomers and diastereoisomers, and also their salts.

The indole ring may also be substituted isatin. Isatin is Isola, which is replaced by oxopropoxy at positions 2 - and 3- = indole-2,3-dione.

For all radicals which occur repeatedly, such as a or Hal, rightly, that values do not depend on each other.

Radical And denotes alkyl and contains from 1 to 6, preferably 1, 2, 3 or 4, in particular 1 or 2, atoms, n represents an Alkyl, therefore, especially, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and 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 trifluoromethyl, or pentafluoroethyl.

Acyl preferably contains 1 to 6 C atoms and represents, for example,formyl, acetyl, propionyl, butyryl and tricorder or pentafluoropropionic.

Alkylen is a propylene, butylene or pentile.

OA means preferably methoxy-, and ethoxy-, n-propoxy, isopropoxy-, n-butoxy, isobutoxy-, second -, butoxy - or tert-butoxypropan.

Hal represents fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

R1represents unsubstituted, preferably as indicated - monosubstituted phenyl or naphthyl, particularly preferably phenyl, o-, m - or p - tolyl, o-, m - or p-ethylphenyl, o-, m - or p-propylphenyl, o-, m - or p-isopropylphenyl, o-, m - or p-tert-butylphenyl, o-, m - or p-triptoreline, o-, m - or p-hydroxyphenyl, o-, m - or p-nitrophenyl, o-, m - or p-trifloromethyl, o-, m - or p-cyanophenyl, o-, m - or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m - or p-forfinal, o-, m - or p-bromophenyl, o-, m - or p-chlorophenyl, o-, m - or p-deformational, o-, m - or p-formatexception, and preferably 2,3-, 2,4-, 2,5-, 2,6- and 3,4 - or 3,5-differenl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl - or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo, 2-methyl-5-bromo-, 2-methyl-6-b is ω-, 3-bromo-4-methyl, 3-bromo-5-methyl - or 3-methyl-4-bromophenyl, 2,4 - or 2,5-dinitrophenyl, 2,5 - or 3,4-acid, 3-nitro-4-chlorophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, also preferably 2-nitro-4-triptoreline, 3,5-dateformatitem, 2,5-dimetilfenil, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5 - or 4-fluoro-3-triptoreline, 4-chloro-2 - or 4-chloro-3-trifluoromethyl-, 2-chloro-4 - or 2-chloro-5-triptoreline, 4-bromo-2 - or 4-bromo-3-triptoreline, p-iodophenyl, 2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3, 5dimethylphenyl, 2-fluoro-4-bromophenyl, 2.5-debtor-4-bromophenyl, 2,4-dichloro-5-were, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-were or 2,4,6-triisopropylphenyl.

R1means are also Het1.

Het1means preferably 2 - or 3-furyl, 2 - or 3-thienyl, 1-,2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, moreover, preferably 1,2,3-triazole-1-, - 4 - or - 5-yl, 1,2,4-triazole-1-, -3 - or-5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3- or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3-, 4-, 5 - or 6-2H-dipiradol, 2-, 3 - or 4H-dipiradol, 3 - and 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 - or 7-benzofuran, 2-, 3-, 4-, 5-, 6 - or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 2-, 4-, 5-, 6 - or 7-benzoxazolyl, 3-, 4-, 5-, 6 - or 7-benzisoxazole, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6 - or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 3-, 4-, 5-, 6-, 7 - or 8-indolinyl, 2-, 4-, 5-, 6-, 7 - or 8-hintline.

R1most preferably denotes phenyl, p-chlorophenyl, p-forfinal, thiophene-2-yl, 5-chlorothiophene-2-yl, 2,5-dichlorothiophene-3-yl and 2 - or 3-furyl.

R4, R5represent in each case, independently of one another, preferably H, Hal, alkyl containing 1-6 atoms, alkoxygroup containing 1-6 atoms or hydroxyl group, and moreover, cyano - or Alloway group.

R4means preferably H, Hal, A, OA, HE, CN or acyl group,

R5preferably denotes N.

Preferred are such compounds with formula I, in which R1-CH2-CH2-piperidinecarboxylic radical replaces the 4-, 5-, 6 - or 7-position in the indole ring.

Accordingly, the invention relates in particular to such compounds with formula I, in which at least one of the said radicals has one of the above preferred values. Some is that the preferred groups of compounds can be described by the following subformulas from Ia to Ii, which correspond to the formula I and in which the radicals not defined in detail, taking the values specified in the formula I, but in which

in IaR1denotes phenyl;
in IbR1denotes phenyl which is not substituted or monogamist Hal;
in IcR1denotes phenyl, which monogamist l, or Het1;
in IdR1denotes phenyl, which is unsubstituted or monogamist Hal, or Het1;
in IeR1denotes phenyl, which is unsubstituted or monogamist Hal, or Het1,
Het1denotes unsaturated heterocyclic

the structure, which is unsubstituted,

or mono - or disubstituted by Hal

or And and contains one or two identical or

different heteroatoms, such as nitrogen, oxygen or sulfur;
IfR1denotes phenyl, which is unsubstituted or monogamist Hal or Het1,
R4and R5in each case, independently of one another, are H, Hal or A,
ÈA; Het1denotes unsaturated heterocyclic structure,

which is unsubstituted or mono - or disubstituted l or And and

contains one or two identical or different heteroatoms, such as nitrogen, oxygen or sulfur;
in IgR1denotes phenyl, which is unsubstituted or monoparesis Hal or Het1,
R4and R5in each case, independently of one another, are H, Hal or A,
R4and R5together represent alkylene containing 3-5 atoms,
Het1denotes thienyl or furyl, which are

unsubstituted; or mono - or disubstituted by Hal or A,
in IhR1denotes phenyl which is unsubstituted or

monosubstituted Hal, or Het1,
R4denotes H, Hal, CN, acyl or A,
R5denotes N
R4and R5together also represent alkylene containing 3-5 atoms,
Het1 denotes thienyl or furyl, which are

unsubstituted or mono - or disubstituted al or A;
in IiR1denotes phenyl or naphthyl, which are unsubstituted

or monosubstituted al or Het1,
R4denotes H, Hal, CN, acyl, or CNH2,
R5denotes N
R4and R5together are also alkylene, which contains 3-5 atoms;
Het1denotes thienyl or furyl, which are

unsubstituted or mono - or disubstituted by Hal

or Rather,
and where the indole ring may also be substituted isatin.

Connection with formula I, as well as source materials for their production can be prepared by known methods described in the literature (for example, in the classical works of Houben-Weyl, Methods der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart-Organic Reactions, John Wiley & Sons, Inc., New York), namely under reaction conditions which are known and suitable for the said reactions. In this case you can also use options, which in itself known yet about isany here in more detail.

If necessary, the starting materials for the claimed process can also be formed in place so as not to separate them from the reaction mixture, and immediately used for the next reaction, in which the connection with formula I. on the other hand, the reaction can be conducted in stages.

In the compounds of formulas III and V, the radical L preferably denotes CL or Br; however, it can also be I, HE, or, in other circumstances, preferably reactive functionally modified group IT, especially alkylsulfonates containing 1-6 atoms (for example, methanesulfonamido) or arylsulfonate, including 6-10 atoms (for example, benzolsulfonate, p toluensulfonate, 1 - or 2-naphthalenesulfonate) or, otherwise, trichlormethane, alkoxygroup, such as, for example, methoxy, ethoxy-, propoxy- or butoxy is, moreover, also fenoxaprop.

Compounds with the formula I can preferably be obtained in the reaction of compounds of formula II and compounds of formula III.

As a rule, the starting materials of formulas II and III are known; the unknown compounds of formulas II and III can be easily prepared in the same manner as the known compounds.

The reaction between compounds II and III is carried out by the method to is that described in the literature for the alkylation or acylation of amines. However, you can also perform the reaction compounds in the presence of an indifferent solvent. Suitable solvents are, for example, hydrocarbons, such as benzene, toluene, xylene; ketones such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides such as dimethylformamide (DMF) or N-organic; NITRILES, such as acetonitrile, and suitable mixtures of these solvents with each other or with water. Can have a positive impact of adding the agent linking the acid, for example an alkali metal or alkali earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium or calcium, or the addition of organic bases such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of a derivative of piperazine compounds of the formula II. Depending on the selected conditions, the time of reaction may vary from a few minutes up to 14 days; the temperature of the reaction can be varied in the range from approximately 0 to 150° C, it is usually chosen in the range from 20 to 130° C.

In addition, the compounds of formula I can be obtained in the reaction of amines with formula IV and components with the formula V, including the non radical R 1.

As a rule, the corresponding components are known or can be obtained by known methods, as already described.

The obtained base of the formula I can, with the help of acid, to convert associated with acidic residues of salt. Suitable for this reaction are those acids which lead to physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, vtoroplanovye acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic mono - or politonalnye carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, malonic acid, succinic acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, atantis Ivanova acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluensulfonate acid, naphthalenamine - and-disulfonate acid, and laurylsulphate acid.

The free base of formula I can, if necessary, to obtain from their salts by treatment with strong bases such as sodium hydroxide or potassium hydroxide, or carbonates of sodium or potassium, if the molecule is not present in any other acidic groups. In cases where compounds with the formula I have free acid groups to form salts similarly, by treatment with bases. Suitable bases are hydroxides of alkali metals or organic bases in the form of primary, secondary, or tertiary amines.

In addition, the invention relates to medical preparations according to the invention which exhibit an antagonistic action to the receptors 5-HT2Afor the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, such as abnormally increased hunger and neurotic loss of appetite, premenstrual syndrome and/or to facilitate manic States (manic-compulsive disorder, OCD).

Invented the e also relates to a pharmaceutical preparation drugs including at least one medical drug according to this invention, as well as, if required, carriers and/or excipients and, if desired, other active compounds. In this case, medicines can be molded in a suitable dosage together with at least one solid, liquid and/or semi-liquid media or excipients and, if required, in combination with one or more other active compounds.

The invention also relates to the use of compounds according to this invention and/or their physiologically acceptable salts and solvate for the manufacture of medicines, providing an antagonistic effect on the receptor 5-HT2A.

The invention also relates to the use of compounds according to this invention and/or their physiologically acceptable salts and solvate in the production of medicines, providing an antagonistic effect on the receptor 5-HT2Aintended for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, such as abnormally increased hunger and neurotic loss of appetite, premenstrual syndrome and/or to facilitate manic States (manic-obsessive resstr ustwo, CD).

The pharmaceutical compositions can be used in human medicine and veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral assignments, or for local use, and do not enter into reaction with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc and petroleum jelly. For enteral purpose are used, in particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories; for parenteral purposes apply solutions, preferably oil or water, and also suspensions, emulsions or implants, for local assignments apply ointments, creams or powders. Furthermore, the new compounds can be liofilizirovanny, and received lyophilizate used, for example, in the manufacture of drugs for injection.

These preparations can be sterilized; they can include excipients, as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants, odorants and/or flavorings. In addition, if required, they can also contain one or more other act of the main compounds, for example one or more vitamins.

In this case, the substances according to this invention assigns, as a rule, by analogy with the previously known preparations, preferably in doses of between approximately 0.1 and 500 mg, in particular between 5 and 300 mg per dose. The dose should preferably contain the active substance is from about 0.01 to 250 mg/kg body weight, in particular from 0.02 to 100 mg/kg body weight.

In this case, the substances according to this invention, as a rule, appoint preferably in doses from about 1 to 500 mg, in particular from 5 to 100 mg per dose. The dose should preferably be in the approximate range from 0.02 to 10 mg/kg of body weight. Individual dose for each particular patient depends, however, on all types of factors, such as the efficacy of the specific compound, the age, body weight, General health, sex, diet, duration of appointment and the applied treatment, as well as from the excretion rate, pharmaceutical combination and severity of the particular disorder, against which is applied therapy. Oral appointment is preferred.

Throughout the text of this invention, all temperatures are in ° C. In the examples below, the expression "customary treatment" means: if necessary, UDA is Aut solvent, if necessary, add water, if necessary, the mixture adjust depending on the desired composition of the final product to a pH between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulfate, filtered and concentrated, followed by purification of the residue by chromatography on silica gel and/or by recrystallization.

Example A1

Preparation of suspension receptors 5-HT2A

The frontal area of the cerebral cortex of the rat homogenized in ice-cold buffer. Homogeneous mixture was centrifuged for 10 minutes at 4° and 50,000 x g. Pill again was suspensively in 2.5 ml ice-cold Tris-buffer, using additional buffer reduced to 10 ml and centrifuged, as already described. Then the tablet was re suspensively in the buffer and dissolved, the result was obtained homogenized, which contained 60 mg/ml 0.1 ml of suspension, 100 μl of 5 nm solution of [3N] ketanserina, 100 μl of a solution of test compounds (concentration in the range of 10-5up to 10-10mol/l) added to the incubation tube and, using a buffer, brought the volume up to 1 ml Tubes were incubated for 15 minutes at 37° C. After stopping the incubation using the immersion of the tubes in the bath with ice cooled suspension was filtered through a glass filter under vacuum. Phi is try washed three times using 5 ml of cold buffer, then was transferred to a scintillation tube. The filters were analyzed using liquid scintillation spectrometry in 8 ml of scintillator Triton X.

Example 1

A solution of 2.0 g of 4-carboximide and 8.1 g of 2-chloro-1-methylpyridine iodide in 60 ml of N-methylpyrrolidone (NMP) was treated with a solution of 2.36 g of 4-geneticdiversity and 8.2 g of ethyldiethanolamine (EDIPA) in 20 ml of NMP, followed by stirring at room temperature for 3 hours. The mixture was subjected to conventional processing and obtained the crude product. It was dissolved in acetone and besieged hydrochloride using an aqueous solution of hydrochloric acid. After drying obtained 4.59 (1H-indol-4-yl)-(4-feiticeira-1-yl)methanon, hydrochloride, TPL 289,3° .

Similarly the following compounds:

(1H-indol-4-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL°,

(1H-indol-4-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano,

(1H-indol-4-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano,

(1H-indol-4-yl)-[4-(thiophene-3-yl)piperazine-1-yl]metano,

(1H-indol-4-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazine-1-yl]metano, hydrochloride, TP-168° ,

(1H-indol-5-yl)-[4-(4-florfenicol)piperazine-1-yl]metano,

(1H-indol-5-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano,

(1H-indol-5-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano,

(1H-indol-5-yl)-[4-(thiophen-yl)piperazine-1-yl]metano,

(1H-indol-5-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazine-1-yl]metano,

(3-formyl-1H-indol-5-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL,9° ,

(1H-indol-6-yl)-[4-feiticeira-1-yl)methanon,

(1H-indol-6-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL,0-284,4° ,

(1H-indol-6-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL,2-205,7° ,

(1H-indol-6-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL,0-252,5° ,

(1H-indol-6-yl)-[4-(thiophene-3-yl)piperazine-1-yl]metano,

(1H-indol-6-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazine-1-yl]metano, hydrochloride, TPL-241° ,

(3-formyl-(1H-indol-6-yl)-[4-(4-florfenicol)piperazine-1-yl]metano,

(3-cyano-1H-indol-6-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL° ,

(1H-indol-7-yl)-(4-feiticeira-1-yl)methanon, hydrochloride, TPL° ,

(1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL° ,

(1H-indol-7-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano,

(1H-indol-7-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL,0-252,5° ,

(1H-indol-7-yl)-[4-(thiophene-3-yl)piperazine-1-yl]metano,

(1H-indol-7-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazine-1-yl]metano,

(3-formyl-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL° ,

(3-cyano-1H-indol-7-yl)-[4-(4-florfenicol)piperazin the-1-yl]metano, hydrochloride, TPL>300° ,

(2,3-dimethyl-1H-indol-7-yl)-(4-feiticeira-1-yl)methanon,

(2,3-dimethyl-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, TPL,5-89° ,

(2,3-dimethyl-1H-indol-7-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano,

(2,3-dimethyl-1H-indol-7-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano,

(2,3-dimethyl-1H-indol-7-yl)-[4-(thiophene-3-yl)piperazine-1-yl]metano,

(2,3-dimethyl-1H-indol-7-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazin-1-yl]metano,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-(4-feiticeira-1-yl)methanon, hydrochloride, TPL-237° ,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-[4-(4-florfenicol)piperazine-1-yl]metano,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-[4-(thiophene-2-yl)piperazine-1-yl]metano,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-[4-(thiophene-3-yl)piperazine-1-yl]metano,

(6,7,8,9-tetrahydro-5H-carbazole-3-yl)-[4-(2,5-dichlorothiophene-3-yl)piperazine-1-yl]metano,

(3-formyl-(1H-indol-6-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL,3° ,

(1H-indol-6-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL,5-259,0° ,

(1H-indol-4-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL-267° ,

(3-cyano-1H-indol-5-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL° ,

(3-cyano-1H-indol-7-yl)-[4-(naphthas-2-ileti is)piperazine-1-yl]metano, hydrochloride, TPL,0-285,5° ,

(3-cyano-1H-indol-4-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL,0-285,5° ,

(3-cyano-1H-indol-4-yl)-[4-(2-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL-215,5° ,

(3-cyano-1H-indol-7-yl)-[4-(2-florfenicol)piperazine-1-yl]methane hydrochloride, TPL,5-214° ,

(3-aminocarbonyl-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, hydrochloride, TPL-281° ,

(3-cyano-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano, methanesulfonate, TPL,5-214° ,

(3-cyano-1H-indol-7-yl)-[4-(5-chlorothiophene-2-yl)piperazine-1-yl]metano, hydrochloride, TPL,5-303,0° ,

(3-cyano-1H-indol-7-yl)-(4-feiticeira-1-yl)methanon, methanesulfonate, TPL,7-297° ,

(3-cyano-1H-indol-7-yl)-[4-(2,4-divertenti)piperazine-1-yl]metano, hydrochloride, TPL,6-297,0° ,

7-{4-[2-(4-forfinal)ethyl]piperazine-1-carbonyl}-1H-indole-2,3-dione.

The following examples relate to pharmaceutical preparations.

Example A.

Vials for injection

A solution of 100 g of the active compound with the formula I and 5 g of distributionformat in 3 l of double-distilled water, brought to pH 6.5 using 2 N. hydrochloric acid, sterilized by filtration, filled into injection vials, liofilizirovanny and filled corked. Each vial contains 5 mg of active compound.

Example Century.

Suppositories

A mixture of 2 g of the active compound with the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C.

Solution

The solution is prepared from 1 g of the active compound with formula I, 9,38 g NaH2PO4×2H2O, 28,48 g NaH2PO4×12H2O and 0.1 g benzalkonium chloride in 940 ml of double-distilled water. The solution is brought to pH 6.8, the volume brought up to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D. Ointment

500 mg of active compound with the formula I mixed with 99.5 g of vaseline under aseptic conditions.

Example E. Tablets

A mixture of 1 kg of active compound with formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate extruded in the usual way so that each tablet contained 10 mg of active compound.

Example F. the coated Tablets

In the same way as in example E, the tablets were pressed, then the usual method was applied coating of sucrose, potato starch, talc, tragakant and dye.

Example G. Capsules

2 kg of active compound with the formula 1 was Packed up in hard gelatin capsules by a standard method so that each capsule contains 20 mg of active compound.

Example N. Ampoules

A solution of 1 kg of active compound with the formula I in 60 l of double-distilled in the s was poured into the vials, liofilizirovanny under aseptic conditions and aseptically corked. Each ampoule contains 10 mg of active compound.

APPLICATION

TOXICOLOGICAL REPORT

After a single dose (oral and vnutribruchinno) to rats and mice hydrochloride (3-cyan-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]methanone showed low systemic toxic effects. The specified connection did not affect the ability to procreate and therefore did not teratogenic nor genotoksicheskogo impact. The compound did not cause irritation to skin or eyes and did not affect the sensitivity of animals. Studies of functional and non-functional parameters of the immune system, and tests that verify the safety effects of the compounds on the Central nervous system and respiratory function showed no harmful effects hydrochloride (3-cyan-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]methanone.

Important Toxicological information were obtained by conducting numerous toxicity tests with rats, dogs and monkeys, and in two in vitro tests that check the security of the effects of the compounds on the cardiovascular system.

Numerous toxicity tests were conducted after the influence of the investigated compounds in various species of animals during the period of time more than 4 weeks. It was noted that the impact of the compounds varies considerably depending on the type of the test animals (dog > monkey > rat). Phenomena such as reduced food consumption, body weight loss and weight gain liver most frequently observed at high levels of exposure to the compounds. Less frequently observed damage of the gastric mucosa in dogs (ambiguous data, which are not supported with repeated testing) and marginal stimulation of the thyroid gland in monkeys. I believe that most of the damage can be caused thiocyanate the metabolites of the compounds, which are formed in dogs to a much greater extent than in other animals. While the Toxicological significance of the phenomenon of the increased weight of the liver in dogs remains in question.

To study the pharmacological safety of investigational compounds in relation to cardiovascular function tests were performed in vitro, in vivo, as well as a series of tests to determine the toxic dose. The index value IC50equal to 240 ng/ml, was determined by the method of HERG in Cho cells. Duration effects on isolated cells of the dog Purkinje increased at a concentration of 3000 nm. When tested in vitro concentrat what I tested compound in plasma was much higher, than the maximum concentration in plasma when conducting research on human volunteers. Moreover, tests conducted in vivo on the breed of short-legged hound and monkeys showed that repeated introduction of the investigated compounds in doses, comprising up to 45 mg/kg/dose (for dogs) and up to 135 mg/kg/dose (for monkeys), for 6 weeks no adverse effects on the cardiovascular system.

Indicators of biological activity
  The binding IC50(nm)Antagonism (mg/kg) in vivo
Connection nameEMDNTANTSD21Ascro
Hydrochloride (1H-indol-4-yl)-

(4-penetentiary-1-yl)methanone
25240842000>1000>1000  
Hydrochloride (1H-indol-4-yl)-

[4-(2,5-dichlorothiophene-3-retil)piperazine-1-yl]methanone
27370229     
Hydrochloride (H-indol-4-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
2729064>1000>1000>1000  
Hydrochloride (1H-indol-4-yl)-

[4-(5-chlorothiophene-2-retil)piperazine-1-yl]methanone
30412310     
Hydrochloride (1H-indol-5-yl)-[4-(4-phenethyl)piperazine-1-yl]methanone5-53153>1000    
Hydrochloride (1H-indol-6-yl)-

[4-(2,5-dichlorothiophene-3-retil)piperazine-1-yl]methanone
273701140     
Hydrochloride (1H-indol-6-yl)-

[4-(4-phenethyl)Sarasin-1-yl]methanone
27353881000>1000>1000  
Hydrochloride (1H-indol-6-yl)-[4-(5-chlorothiophene-2-retil)piperazine-1-yl]methanone28107938     
(1H-Indol-6-yl)-[4-(thiophene-3-retil)piperazine-1-yl]metano 273540120     
Hydrochloride (1H-indol-7-yl)-

(4-penetentiary-1-yl)methanone
2697514>1000>1000>10000,32
Hydrochloride (1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
2735480,6800>10006200,10,3
Hydrochloride (1H-indol-7-yl)-

[4-(5-chlorothiophene-2-retil)piperazine-1-yl]methanone
28107863000>1000   
(2,3-Dimethyl-1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]metano
27147831000>1000>1000  
Hydrochloride (3-aminocarbonyl-1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
3269481>1000>1000>1000  
Hydrochloride (3-cyano-1H-indol-4-yl)-

[4-(2-florfenicol)piperazine-1-yl]methanone
3229522 400>1000>1000  
Hydrochloride (3-cyano-1H-indol-4-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
3198317370 >1000  
Hydrochloride (3-cyano-1H-indol-5-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
3097463300>100030  
Hydrochloride (3-cyano-1H-indol-6-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
28101614>1000 >1000  
Hydrochloride (3-cyano-1H-indol-7-yl)-

(4-penetentiary-1-yl)methanone
3289502>1000>1000>1000  
Hydrochloride (3-cyano-1H-indol-7-yl)-

[4-(2,4-divertenti)piperazine-1-yl]methanone
3293410,7800>1000>1000  
Hydrochloride (3-cyano-1H-indol-7-yl)-

[4-(2-florfenicol)piperazine-1-yl]methanone
3229541>100 >1000>1000  
Hydrochloride (3-cyano-1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
2810141>1000>1000>10000,010,06
Methanesulfonate(3-cyano-1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
3269502>1000>100066  
Hydrochloride (3-cyano-1H-indol-7-yl)-

[4-(5-chlorothiophene-2-retil)piperazine-1-yl]methanone
3270294>1000>1000>1000  
Hydrochloride (3-cyano-1H-indol-7-yl)-

[4-(naphthas-2-retil)piperazine-1-yl]methanone
31983069>1000 >1000  
Hydrochloride (3-formyl-1H-indol-5-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
2805984900>1000>1000  
Hydrochloride (3-formyl-1H-indol-6-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
2804738 >1000    
Hydrochloride (3-formyl-1H-indol-7-yl)-

[4-(4-florfenicol)piperazine-1-yl]methanone
28047241000 >1000 3
Hydrochloride (6,7,8,9-tetrahydro-5H-carbazole-3-yl)-(4-penetentiary-1-yl)methanone249001292000>1000>1000  
1-(1H-indol-4-yl)-1-[4-(1-methyl-2-phenylethyl)

piperazine-1-yl]metano
51310615     
1-(1H-indol-4-yl)-1-{4-[2-(4-methoxyphenyl)ethyl]piperazine-1-yl}metano505465>10>1000    
1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-1-(1H-indol-4-yl)methanon
5054341>1000    
1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-1-(1H-indol-6-yl)methanon
51310913   �A0;  
1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-1-(1H-indol-7-yl)methanon
5131073     
2-Chloro-7-(1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-methanol)-1H-indol-3-carbonitril
510713      
7-(1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-methanol)-1H-indol-3-carbonitril
41344631>1000>1000>1000  
7-(1-{4-[2-(4-cyanophenyl)ethyl]piperazine-1-yl}-methanol)-1H-indol-3-carbonitril39288728>1000>1000>1000  
7-(1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-methanol)-1H-indol-3-carbonitril
3909204>1000>1000>1000  
Amide 7-(1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-methanol)-1H-indole-3-carboxylic acid
513246      
Methylamide 7-(1-{4-[2-(4-forfinal)ethyl]

piperazine-1-yl}-methanol)-1H-indole-3-carboxylic acid
50528710>1000    
7-{4-[2-(4-forfinal)ethyl]piperazine-1-carbonyl)

-1H-indole-2,3-dione
33010040>1000    

1. Derivatives of N-(indolocarbazole)piperazine of the formula I

in which R1denotes phenyl or nattily radical, each of which is unsubstituted or substituted R2and/or R3or represents Het1,

R2and R3each independently of one another denotes Hal, A, OA or CN,

R4denotes H, CN, acyl, Hal, CONH2, CONHA or CONA2,

R5denotes H,

R4and R5together alternative are alkylene containing 3-5 carbon atoms,

Het1denotes an aromatic heterocyclic ring system, optionally substituted by one or two halogen atoms and containing one, two or three identical or different heteroatoms, such as nitrogen, oxygen and sulphur,

And denotes alkyl, containing 1-6 carbon atoms,

Hal denotes F, Cl, Br or I,

and where the indole ring may also be substituted isatin,

and their physiologically acceptable salt and solvate,

except (1H-indol-5-yl)-(4-feiticeira-1-yl)methanone and 1-((5-methoxy-1H-indol-7-yl)carbonyl)-4-(2-phenylethyl)piperazine.

2. The compounds of formula I according to claim 1, selected from the group including

(a) (3-cyano-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano,

(b) (3-aminocarbonyl-1H-indol-7-yl)-[4-(4-florfenicol)piperazine-1-yl]metano

and their physiologically acceptable salt and solvate.

3. Method of producing compounds of the formula I according to claim 1, with the exception of [1H-indol-5-yl)-(4-feiticeira-1-yl)methanone and 1-((5-methoxy-1H-indol-7-yl)carbonyl)-4-(2-phenylethyl) piperazine, wherein spend the interaction between a compound of formula II

in which L denotes Cl, Br, I or a free or reactive functionally modified group HE,

R4and R5have the meanings indicated in claim 1,

and the compound of the formula III

in which R1has the meaning specified in claim 1,

and if you want one of the radicals R1, R4and/or R5is converted into another radical R1 , R4and/or R5through, for example, conversion of the group Cho group CN, and/or received base with the formula I is converted into one of its salts by treatment with acid.

4. Method of producing compounds of the formula I according to claim 1, with the exception of [1H-indol-5-yl)-(4-feiticeira-1-yl)methanone and 1-((5-methoxy-1H-indol-7-yl)carbonyl)-4-(2-phenylethyl)piperazine, wherein spend the interaction between a compound of formula IV

in which R4and R5take the values defined in claim 1,

and the compound of the formula V

in which L denotes CL, Br, I or a free or reactive functionally modified group HE,

R1has the meaning specified in claim 1,

and if you want one of the radicals R1, R4and/or R5is converted into another radical R1, R4and/or R5through, for example, conversion of the group Cho group CN and/or received base with the formula I is converted into one of its salts by treatment with acid.

5. The compounds of formula I according to claim 1 or 2, and their physiologically acceptable salt and solvate as a drug exerting an antagonistic effect on the receptor 5-HT2A.

6. Compounds of formulas is I according to claim 1 or 2, their physiologically acceptable salt and solvate as a medicinal product intended for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, such as abnormally increased hunger and neurotic loss of appetite, premenstrual syndrome and/or to facilitate manic States (manic-compulsive disorder, OCD).

7. Pharmaceutical drug that has an antagonistic effect against the receptors 5-HT2Acomprising at least one compound according to claim 6, and, if necessary, excipients and/or auxiliaries and, if desired, other active compounds.

8. The compounds of formula I, characterized in claim 1 or 2, and/or their physiologically acceptable salt and solvate designed to obtain medicines, providing an antagonistic effect on the receptor 5-HT2A.

9. Connection of claim 8, designed to obtain drugs for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, disease Ha is tingtone, eating disorders, such as abnormally increased hunger and neurotic loss of appetite, premenstrual syndrome and/or to facilitate manic States (manic-compulsive disorder, OCD).



 

Same patents:

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 4-(heteroarylmethyl)halo-1-(2H)-phthalazinones, particularly 4-(4-pyridylmethyl)-1-(2H)-phthalazinone. Claimed method includes interaction between substituted phthalidyl-3-triphenylphosphonium and aldehyde of formula Ar-CHO, wherein Ar is pyridine, pyrazine, or pyrimidine, in presence of base followed by reaction with hydrazine hydrate optionally under acidic conditions.

EFFECT: environmental friendly and safe method.

4 cl, 1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted 1-pyridyl-2-azolyl-1-(2-phenylethenyl)ethan-1-ols having general formula I:

where Py denotes 2-, 3-, or 4-pyridyl, Z nitrogen atom or CH group, and R1 and R2, independently from each other, are hydrogen or halogen atom, or trifluoromethyl group. Claimed compounds are applied as agricultural, industrial, medical, or veterinarian fungicides for controlling harmful fungi.

EFFECT: enhanced fungi control efficiency.

2 cl, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

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 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 thiazole derivative of the formula I, where R1denotes a group of formula (a), (b), (C), R2denotes a group of formula (d), where Het represents a five - or six-membered heterocyclic group which is substituted by9and in the loop which, in addition to the nitrogen atom, can optionally contain an oxygen atom, R3denotes hydrogen, alkyl, cycloalkyl, phenyl, R4denotes hydrogen, phenyl, R5- R8independently of one another denotes hydrogen, R9denotes a group of formula (e) and (f), R10denotes phenyl, a-i denotes 0 or a positive integer, i.e
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to the derivatives of diphenyl, in particular, it relates to derivatives of diphenyl who are antagonistic towards 2-defeminization and/or 2-serotoninreuptake and which is clinically used as a therapeutic-help tools for mental disorders, such as vascular dysfunction brain, aggressive behavior due to senile dementia, mental arousal, pornomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disorder, depression, neurosis, psycho-physiological disorder and neurosis of fear

The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to heterocyclic compounds, specifically to piperazine derivatives, in which the piperazine one nitrogen atom is linked to a fragment of aryloxy or aaltio link oxypropylene or alkanoyloxy, and through another nitrogen atom with the rest of acetanilide

The invention relates to new indole derivative of the formula I

< / BR>
where R denotes ethyl or 2,2,2-triptorelin group; Y is hydroxy or pivaloyloxy; the carbon atom marked with the symbol (R) is the carbon atom in (R)-configuration, or its pharmaceutically acceptable salts
Up!