Compounds, method for their preparing, pharmaceutical composition, selective antagonists of 5-ht2a -receptor

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) wherein radicals R1, R2 and alk have values given in claim 1 of the invention claim. Compounds prepared by a method by claim 6 are important antagonists of 5-HT2A-receptors and can be sued in treatment psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea, nutritional disturbances, such as bulimia, nervous-psychic anorexia, premenstrual syndrome and/or for the positive effect on obsessive-compulsive disorder.

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

12 cl, 12 ex

 

The invention relates to compounds of formula I

in which

R1denotes phenyl or nattily radical, which is unsubstituted or substituted by the radicals R3and/or R4or denotes Het1,

R2denotes chinoline-radical or ethenolysis-radical, which is unsubstituted or substituted by the radicals R5and/or R6,

R3and R4each, independently of one another, denotes H, Hal, A, OA, HE or CN,

R5and R6each, independently of one another, denotes H, CN, acyl, Hal, A, OA, HE CONH2, CONHA or CONA2,

Het1denotes a monocyclic or bicyclic unsaturated heterocyclic ring system which is unsubstituted or monosubstituted or disubstituted by the group of Hal, A, OA or HE and which contains one, two or three identical or different heteroatoms, such as nitrogen, oxygen and sulphur,

And denotes an alkyl group which has 1-6 carbon atoms,

alk denotes alkylenes group which has 1-6 carbon atoms,

Hal denotes F, Cl, Br or I,

and their physiologically acceptable salt and solvate.

The aim of the invention is the search for new compounds which have valuable properties, in particular those that can be used for the manufacture of medicines.

Found that soy is inane formula I and their physiologically acceptable salt and solvate are good tolerability and valuable pharmacological properties, as they act on the Central nervous system. It has been unexpectedly found that the compounds exhibit selective affinity for 5-HT2A-receptors. In particular, they are selective antagonists of 5-HT2A-.

Substances listed in this application are selective antagonists of 5-HT2A.Antagonists of 5-HT2Amanifest clinically antipsychotic activity without or with minimal side effects. Accordingly, the substance of this proposal should be considered as antipsychotics, which have a small number of side effects. In particular, they can be used in the treatment of neurological disorders, which are disorders of the serotonergic transmission, such as dipressija, state anxiety, state reaction of panic, obsessive-compulsive disorder, pain, sleep disorders, insomnia, appetite disorders, such as anorexia, bulimia, behavior, detecting a propensity for drug use, dependence on certain substances, addictive, such as LSD and MDMA, cardiovascular disorders, such as various hypertension, Raynaud's disease, intermittent claudication, cardiac or peripheral vascular spasms, fibromyalgia, cardiac arrhythmia and thrombotic bolezn is, because these substances inhibit the aggregation of platelets. In combination with classical or atypical neuroleptic means the side effects can be eliminated. Due to the property to lower eye pressure substances can also be used in the treatment of glaucoma. Using these substances, it is possible to eliminate toxic symptoms caused by poisoning, for example, ergovaline.

For in vitro determination of binding affinity to C-HT2A-repertorium, for example, you can use the following test (Example A1). 5-HT2Areceptors are exposed to as a [3N]ketanserina (a substance that is known for its affinity to the receptor), and test the connection. Reducing the affinity of [3N]ketanserina to the receptor is indicative of the affinity of test compounds for 5-HT2Athe receptor. The definition of a perform similarly to the description J..Leysen and other Molecular Pharmacology, 1982, 21: 301-314 or as described, for example, in EP 0320983.

The effectiveness of the compounds according to the invention as antagonists of 5-HT2Athe receptor can be measured in vitro similarly W. Feniuk and other Mechanisms of 5-hydroxytryptamine-induced vasoconstriction in The Peripheral Actions of 5-Hydroxytryptamine ed. J.R. Fozard, Oxford University Press, New York, 1989, p.110. So, the contractility of rat tail artery, caused by 5-hydroxytryptamine, mediated 6-HT2A-receptors. For the test system vascular ring, p is gotovlenie of the ventral caudal artery of the rat, subjected to perfusion in the cell bodies containing oxygenated solution. Introduction increasing concentrations of 5-hydroxytryptamine into solution get a response to cumulative concentrations of 5-HT. Then in the camera bodies add a test compound with a suitable concentration and measuring a second concentration curve for 5-HT. The power of the test compounds at offset 5-HT induced a concentration curve to higher concentrations of 5-HT is a measure of the antagonistic properties of 5-HT2A-receptor in vitro.

5-HT2Aantagonistic properties in vivo can be defined similarly .D.Serdar and other Psychopharmacology, 1996, 128: 198-205.

Other compounds that also show the 5-HT2A-antagonistic action, described for example in EP 0320983.

Such derivatives of piperazine with antiarrhythmic properties are disclosed, for example, in EP 0431944 and EP 0431945.

5-ethynodiolthinyl described A. Morikawa, etc. in Chem. Pharm. Bull. 1992, 40, 770-3 or in EP 61673 as a vasodilator.

M. Ohashi, and others in JP 631761177 describe derivatives piperazineethanol as coloring agents.

Selective antagonists of 5-HT2Athe receptor can preferably be used instead of antagonists of 5-HT2-receptor. As antagonists of 5-HT2-the receptor is also associated with other p is dipali receptors 5-HT 2-group, such as, for example, 5-HT2Cthe receptor. At that time, as described, that the antagonism of 5-HT2C-receptor can lead to unwanted mass gain (E. Richelson, and So Souder, Life Sci. 2000, 68, 29-39), selective antagonists of 5-HT2Areceptors do not cause this effect.

The compounds of formula I are suitable both for veterinary and for medicine for the treatment of dysfunctions of the Central nervous system and inflammation. They can be used for the prevention and combat the effects of ischemic stroke (apoplexia cerebri), such as apoplectically shock and cerebral ischemia, as well as for the treatment of extrapyramidal motor and mental side effects neuroleptic funds, as well as Parkinson's disease, for treating Parkinson's disease in General, for acute and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. They are also suitable as a therapeutic agent for the treatment of brain and spinal cord injuries. In particular, however, they are suitable as pharmaceutical active ingredients for tranquilizers, antidepressants, antipsychotic drugs, neuroleptic funds antihyperuricemic funds, and/or for positively influencing obsessive-compulsive disorder (OCD), state of fear, psihologicheskie the e changes associated with States of anxiety, such as, for example, tachycardia, tremor or sweating, panic attacks, psychosis, schizophrenia, inclusive of shizophrenia-like personality disorders, for the prevention of schizophrenia in relatives of the first generation and schizophrenia resistant to treatment, anorexia, delusional obsessions, agoraphobia, migraines, cognitive deficits, Alzheimer's disease and other forms of dementia such as multi-infarct dementia, Lewy body dementia and dementia in Parkinson's disease, behavioral disorders in dementia, particularly in the elderly, sleep disorders, including sleep apnea, tardive dyskinesia and psychosis in tardive dyskinesia, learning disorders, memory disorders, age-related disorders attention deficit hyperactivity disorder and behavioral disorders, disorders of appetite, such as bulimia, abuse of drugs, such as alcohol, sleeping pills, nicotine, psychostimulatory means, such as, for example, cocaine and amphetamines, disorders of sexual function, disorders associated with aggression in young and adult people, States of pain of all types and fibromyalgia.

The compounds of formula I are suitable for the treatment of extrapyramidal side effects (EPS) neuroleptic funds. EPS is characterized Parkinson-the one with syndromic the akathisia and dystonic reactions (for example, described in EP 337136 for antagonists of 5-HT2).

In addition, they are suitable for the treatment of neuro-psychiatric anorexia (anorexia nervosa), angina, disease, Raynaud's disease, coronelismo, for the prevention of migraine headaches (for example, described in EP 208235 for antagonists of 5-HT2), pain and neuralgia (for example, described in EP 320983 for antagonists of 5-HT2), for the treatment of rett syndrome (Rett) with autism, Asperger's syndrome (Asperger, autism and autistic spectrum disorders, state of distraction, developmental disorders, States of Hyper-activity with mental underdevelopment and state stereotypical behaviour (for example, described in WO 9524194 for antagonists of 5-HT2).

Compounds according to the invention, in particular suitable for the treatment of schizophrenia.

In addition, they are suitable for the treatment of endocrine disorders such as hyperprolactinaemia, moreover, vascular spasm, thrombotic diseases (for example, described in WO 9524194 for antagonists of 5-HT2), hypertension and gastro-intestinal diseases.

In addition, they are suitable for the treatment of cardiovascular diseases, as well as extrapyramidal symptoms, as described in WO 99/11641 on page 2, lines 24-30, antagonists of 5-HT2.

Moreover, they can be used as intermediate products PR is the manufacture of other pharmaceutical active ingredients.

The invention concerns piperazinylcarbonyl and-isoquinolines of the formula I and their physiologically acceptable salts accession acids. The invention also concerns the solvate such as a hydrate or alcoholate of these compounds.

The term solvate of the compounds of formulas I understand the value of adducts of inert solvent molecules onto the compounds of the formula I, which are formed by the force of their mutual attraction. The solvate are, for example, mono - or dihydrate or connection joining with alcohols, such as methanol or ethanol.

The invention relates to compounds of formula I and their salts and solvate according to claim 1 of the formula of the invention and the method of obtaining compounds of formula I and their salts and solvate, which is characterized by the fact that

a) compound of formula II

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

and R2takes the values specified in claim 1 of the claims,

enter into reaction with the compound of the formula III

in which R1and alk take the values specified in claim 1 of the claims, or

b) the compound of formula IV

in which R2takes the values specified in claim 1 of the formula the image is to be placed, enter into reaction with the compound of the formula V

in which L denotes Cl, Br, I or a free or reactive functionally modified Oh group, and R and alk take the values specified in claim 1 of the claims,

or

C) if desired, one of the radicals R2, R3, R4and/or R5converted into another radical R2, R3, R4and/or R5for example, splitting the OA group with the formation of Oh groups and/or turning the group Cho group CN

and/or

received under formula I, treating acid into one of its salts.

The invention also relates to compounds of the formula I according to claim 1 of the formula of the invention and their physiologically acceptable salt or solvate, as pharmaceutical active ingredients.

In addition, the invention relates to compounds of the formula I according to claim 1 of the formula of the invention and their physiologically acceptable salt or solvate, as inhibitors of 5-HT2Athe receptor.

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

For all radicals which occur more than once, such as, for example, a or Hal, their values are independent of each other.

Radical And denotes alkyl has from 1 to 6, preferably 1, 2, 3 or 4, in particular 1 or 2 atom ug is erode. Therefore, alkyl denotes, in particular, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also 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, in addition, trifluoromethyl or pentafluoroethyl.

Acyl is preferably 1-6 carbon atoms and represents, for example, formyl, acetyl, propionyl, butyryl, in addition, TRIFLUOROACETYL or pentafluoropropionic. In particular, the acyl preferably denotes acetyl.

alk denotes alkylene, which has 1, 2, 3, 4, 5 or 6 carbon atoms, a is unbranched or branched and preferably represents methylene, ethylene, propylene, butylene or pentile. In particular, alk preferably represents ethylene.

OA preferably represents a methoxy group, cryptometer, in addition, also ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl or tert-butoxypropan.

Het1denotes a monocyclic or bicyclic unsaturated heterocyclic ring system consisting of 5 to 10 ring members, which is unsubstituted or monosubstituted or disubstituted by which the group of Hal, A, OA or HE and which contains one, two or three identical or different heteroatoms, such as nitrogen, oxygen or sulphur.

Het1preferably denotes 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-, 4Or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, in addition, 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 4-4H-dipiradol, 3 - or 5-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-cinnolin, or 2-, 4-, 5-, 6-, 7 - or 8-hintline.

Hal represents fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. Most preferred for Hal is fluorine.

R1denotes phenyl or naphthyl radical, each of which is unsubstituted or substituted group and R 3and/or R4or Het1where Het1takes one of the values listed above, and R3and R4take one of the values listed below.

R1means are preferably unsubstituted or monosubstituted phenyl or naftalina group, 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-(triptoreline)-phenyl, 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-(deformedarse)-phenyl, o-, m - or p-(formatosi)-phenyl in addition, preferably 2,3-, 2,4-, 2,5-, 2,6-, 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-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl - or 3-methyl-4-bromophenyl, 2,4 - or 2,5-dinitrophenyl, 2,4 - 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-butyl is Anil, in addition, preferably 2-nitro-4-(trifluoromethyl)phenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-dimetilfenil, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5 - or 4-fluoro-3-(trifluoromethyl)-phenyl, 4-chloro-2 or 4-chloro-3-(trifluoromethyl)-, 2-chloro-4 - or 2-chloro-5-(trifluoromethyl)-phenyl, 4-bromo-2 - or 4-bromo-3-(trifluoromethyl)-phenyl, p-iopener, 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.

In particular, R1means preferably 4-forfinal.

R2denotes chinoline or ethenolysis radical, which is unsubstituted or substituted by the radicals R5and/or R6where the radicals R5and R6can take one of the above values, and linking chinoline radical can occur in 2-, 3-, 4-, 5-, 6-, 7 - or 8-position, and link ethenolysis radical can occur in 1-, 3-, 4-, 5-, 6-, 7-or 8-position.

In particular, R2preferably indicates isoquinoline-1-yl, isoquinoline-3-yl, quinoline-2-yl or quinoline-8-yl.

R3and R4each, independently of one another, preferably denote H, Hal, alkyl containing 1-6 carbon atoms, alkoxygroup containing 1-6 atoms in which laroda, or hydroxyl group, in addition, cyano or acyl group.

R3means preferably H, Hal, A, OA, HE, CN or acyl group. R4preferably denotes H. In particular, R3preferably denotes Hal.

R5and R6each, independently of one another, preferably denote H, CN, acyl, Hal, A, OA, HE CONH2, CONHA or CONA2groups in which a and acyl take one of the values specified above.

R5preferably denotes H. R6preferably denotes N.

Accordingly, the invention particularly relates to compounds of the formula I, in which at least one of these radicals is one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the following subformulas from Ia through Ie, which correspond to the formula I and in which the radicals not designated in greater detail than is definitely in the formula I, but in which

in Ia R1denotes a phenyl radical which is unsubstituted or substituted by the radicals R3and/or R4;

in Ib alk represents ethylene;

in Ic R1denotes a phenyl radical which is unsubstituted or substituted by the radicals R3and/or R4and

alk represents ethylene;

in Id R3denotes Hal, and

R4denotes N;

in Ie R 1denotes a phenyl radical which is unsubstituted or substituted by the radicals R3and/or R4,

alk represents ethylene;

R3denotes Hal and

R4denotes N.

The compounds of formula I, as well as source materials for their production, in addition, be made by methods known per se, such as described in the literature (for example in standard works such as Houben-Weyl, Methods der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), more specifically, when the reaction conditions which are known and are suitable for the said reactions. It is also possible to use variants which are known per se but not mentioned here in more detail.

If desired, the initial substance for the desired method can be also obtained in situ without isolating them from the reaction mixture, but instead immediately converted further into the compounds of formula I.

On the other hand, you can perform reactions Paladino.

In the compounds of formulas II and V, the radical L preferably denotes Cl or Br; however, it can refer also I IT or also preferably reactive functionally modified Oh group, in particular alkylsulfonates, which has 1-6 carbon atoms (for example, methanesulfonamido) or arylsulfonate, which has 6 to 10 carbon atoms (the example benzolsulfonate, p-toluensulfonate, 1 - or 2-naphthalenesulfonate) or alternative trichlormethane group, alkoxygroup, such as, for example, methoxy, ethoxy, propoxy or butoxy, in addition, also fenoxaprop.

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

The initial compounds of formulas II and III mainly known; the unknown compounds of formulas II and III can be easily obtained analogously to the methods of obtaining the known compounds.

The reaction of compounds II and III is carried out by methods known from the literature, alkylation or acylation of amines. However, it is possible to conduct the reaction of these compounds in the presence of an inert solvent. Examples of suitable solvents are hydrocarbons, such as benzene, toluene or xylene; ketones, such as acetone or butanone; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol or n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-organic; NITRILES, such as acetonitrile, and, if desired, mixtures of these solvents with one another or mixtures with water. Can be beneficial adding acid binding substances, for example alkali or alkali earth metal hydroxide, to the of rbonate 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 piperazine derivative of the formula II. Depending on conditions, the reaction time ranges from several minutes to 14 days, and the reaction temperature is between about 0 and 150°mostly between 20 and 130°.

In addition, the compounds of formula I can be obtained by reaction of amines of formula IV with a component of the formula V containing the radical R1. The corresponding components in generally known or can be obtained by methods as already described.

The obtained base of formula I can be converted into salt accession acid using acid. Suitable acids for this reaction are those which give physiologically acceptable salts. Thus it is possible to use inorganic acids, for example sulfuric acid, halogen acids, such as chloride-hydrogen acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic, monoo the main or politonalnye carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, Pavlovo acid, deathlessnoob acid, malonic acid, succinic acid, timelineview acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinoyl acid, methane - or econsultancy acid, etanislao acid, 2-hydroxyethanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid, naphthalenamine - and-disulfonate acid and lauridsen acid.

Free base of formula I, if desired, can be distinguished from their salts by treatment of strong bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, provided that the molecule does not contain more acid groups. In those cases where the compounds of formula I have a free acid group, a salt can also be achieved by treatment with bases. Suitable bases are hydroxides of alkali metals, hydroxides of alkaline earth metals or organic base in the form of primary, secondary, or tertiary amines.

In addition, the invention apply is to medicines, which according to the invention are 5-HT2A-receptor antagonistic action 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 bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

In addition, the invention relates to pharmaceutical compositions obtained, in particular, non-chemical methods, which contain at least one compound of the formula I and/or one of its physiologically acceptable salt or solvate and at least one pharmaceutically acceptable excipient. Thus the compounds of formula I lead into a suitable dosage form together with at least one solid, liquid and/or semi excipient or auxiliary substance and, if desired, in combination with one or more additional active ingredient(s).

These compositions can be used as drugs in medicine and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or local applications to the deposits and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, triacetyluridine, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal injection are suppositories, suitable for parenteral administration are solutions, preferably solutions of oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilizate used, for example, to get injectables. These preparations can be sterilized and/or may include excipients, such as sliding substances, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colorants, flavorings and/or a variety of other active ingredients, for example one or more vitamins.

The substances according to the invention mainly designate similar to the use of known compositions, preferably in doses from about 0.1 to 500 mg, in cast the STI from 5 to 300 mg per unit dose. The daily dose is preferably from about 0.01 to 250 mg/kg body weight, in particular from 0.02 to 100 mg/kg body weight. However, the specific dose for each patient depends on very many factors, such as the effectiveness of certain connections in use, the age, body weight, General health, sex, diet, time and method of application, the excretion rate, pharmaceutical combination of substances and the severity of the specific disorder, belongs to therapy. Oral administration is preferred.

In addition, the invention concerns the use of compounds according to the invention and/or their physiologically acceptable salts and solvate for the manufacture of drugs, in particular drugs with 5-HT2Areceptor antagonistic action.

The invention also concerns the use of compounds according to the invention and/or their physiologically acceptable salts and solvate for the manufacture of a medicinal product with 5-HT2Areceptor antagonistic action, for the treatment of schizophrenia.

The invention also concerns the use of compounds according to the invention and/or their physiologically acceptable salts and solvate for the manufacture of a medicinal product with 5-HT2Areceptor antagonistic action is, for the treatment of psychosis, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders such as bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

In addition, the invention relates to selective antagonists of 5-HT2Areceptor 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 bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

In addition, the invention relates to selective antagonists of 5-HT2Areceptor 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 bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD), characterized in that the ant is honesty not associated with other related receptors.

Since the IC50receptor 5-HT2Aequal to 1 nm, for example, the substances described in Example 1, this value is more than 1 μM for 5-HT2C-receptor, 5-HT1A-receptor, 5-HT1B-receptor, 5-HT1D-receptor and D2-receptor, i.e. the affinity coefficients differ by more than 1000. In the class described substances found selectivity relative to other G-proteinsathome receptors from 10 to more than 1000.

The invention also concerns the use of a selective antagonist of 5-HT2A-receptor for the manufacture of a medicine for the treatment of schizophrenia.

The invention also concerns the use of a selective antagonist of 5-HT2A-receptor for the manufacture of a medicine for the treatment of psychosis, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders such as bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

Above and below, all temperatures are given in °C. In the following examples, "conventional treatment" means that, if necessary, removing the solvent, if necessary add water, if necessary, adjusted pH to values of the 2 to 10, depending on the structure of the final product mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated and the product purified by chromatographytandem on silica gel and/or crystallization. Purified compounds, if necessary, is dried by freezing.

Example A1

Preparation of a suspension of 5-HT2Areceptors:

Frontal cortical layer rats are homogenized in ice-cold buffer. The homogenate was centrifuged at 4°and 50000 × within 10 minutes. Tablet resuspended in 2.5 ml ice-cold tris buffer, adjusted to 10 ml with additional buffer and centrifuged as described. The tablet again resuspended in the buffer and diluted to obtain a homogenate, which contains 60 mg of material/ml 0.1 ml of suspension, 100 μl 5 nm solution of [3N]ketanserina, 100 μl of a solution of test compound (concentration of 10-5up to 10-10mol/l) was injected into the incubation tube and the volume was adjusted to 1 ml with buffer. The tubes are incubated at 37°C for 15 minutes. After termination of the incubation by immersing the tubes in a bath of ice cooled suspension is filtered through a glass filter under vacuum. The filters are washed 3 times with 5 ml of cold buffer and then transferred to scintillation tubes. Filters analyze liquid scintillation what spectrometries in 8 ml of scintillation solution of Triton-X.

Example 1

0.9 g of 1,1'-carbonyldiimidazole added to a solution of 1 g of isoquinoline-1-carboxylic acid in 100 ml of tetrahydrofuran (THF) and the mixture is stirred at room temperature for 2 hours. 1.6 g of 1-[2-(4-forfinal)ethyl]piperazine and 2.4 ml of triethylamine are added to this mixture which is then stirred for a further 80 hours. Conventional treatment leads to the production of {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-1-ylmethanone.

To obtain salt 1 N hydrochloric acid is added to a solution of {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-1-ylmethanone in 60 ml of acetone and 50 ml of ether until crystals form. When crystallization is complete, the mother liquor is filtered, the precipitate washed with ether and dried to obtain hydrochloride {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-1-ylmethanone; T square 238-240°.

Example 2

Analogously to Example 1 heroldova acid is reacted with 1-[2-(4-forfinal)ethyl]piperazine to obtain {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-2-ylmethanone,

Crystallization using 1 N hydrochloric acid analogously to Example 1 yields a hydrochloride {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-2-ylmethanone; T square 221-222°.

Example 3

0,34 ml of thionyl chloride are added to a suspension of 0.4 g of the quinoline-8-Carbo new acid in THF and the mixture is heated under reflux for 1 hour is. The mixture is then freed from solvent and the residue (quinoline-8-carbonylchloride) is transferred into a 50 ml dichloromethane. To this solution was added 2.1 g of polymer DMAP (Aldrich, Article No. 35, 998-2), 0.6 ml of triethylamine and 0.6 g of 1-[2-(4-forfinal)ethyl]piperazine and the mixture is stirred at room temperature for 5 days. Conventional treatment leads to the production of {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-8-ylmethanone.

The salt formation reaction of {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-8-ylmethanone in 30 ml of acetone and 0.2 ml of ethanolic hydrochloric acid yields a hydrochloride {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-8-ylmethanone; T square 219-220,5°.

Example 4

Analogously to Example 3 first isoquinoline-3-carboxylic acid is administered in cooperation with thionyl chloride and the resulting isoquinoline-3-carbonylchloride enter into interaction with 1-[2-(4-forfinal)ethyl]piperazine to obtain {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-3-ylmethanone.

Education salt analogously to Example 3 results in amorphous hydrochloride {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-3-ylmethanone; T square 163-170°.

The following examples relate to pharmaceutical compositions.

Example: Ampoules for injection

the pH of a solution prepared from 100 g of the active substance of the formula I and 5 g of sodium hydrogen phosphate in 3 l of bidistilled water on the lead up to 6.5, using 2N hydrochloric acid, the resulting solution is filtered under sterile conditions, distributed in injectable ampoules, lyophilizers and sealed under sterile conditions. Each injection vial contains 5 mg of active compound.

Example: Candles

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

Example: Solution

A solution is prepared from 1 g of the active substance of the formula I, 9,38 g NaH2PO4·2H2O, 28,48 g Na2HPO4·12H2O and 0.1 g benzalkonium chloride in 940 ml of bidistilled water. the pH of the mixture was adjusted to 6.8, and the solution volume was adjusted to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

500 mg of the active substance of the formula I are mixed with 99.5 g of vaseline under sterile conditions.

Example: 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 is pressed accepted way to obtain tablets each containing 10 mg of active compound.

Example F: coated Tablets

Analogously to Example E tablets pressed, and then they accepted way put a coating of sucrose, potato starch, talc, trag what Kant and dye.

Example G: Capsules

2 kg of active substance of the formula I distribute an accepted way into hard gelatin capsules so that each capsule contains 20 mg of active compound.

Example N: ampoules

A solution of 1 kg of active substance of the formula I in 60 l of bidistilled water is distributed in ampoules, lyophilizer in sterile sterile conditions and sealed. Each ampoule contains 10 mg of active compound.

1. The compounds of formula I

in which R1denotes phenyl or nattily radical, which is unsubstituted or substituted by the radicals R3and/or R4;

R2denotes chinoline radical or ethenolysis radical, which is unsubstituted or substituted by the radicals R5and/or R6;

R3and R4each, independently of one another, denotes H, Hal;

R5and R6each denotes H;

alk denotes alkylenes group which has 1-6 carbon atoms;

Hal denotes F, Cl, Br or I, and their physiologically acceptable salt and solvate.

2. The compounds of formula I according to claim 1, wherein R1denotes a phenyl radical which is unsubstituted or substituted by the radicals R3and/or R4.

3. The compounds of formula I according to claim 1 or 2, wherein alk represents ethylene.

4. Soy is inane formula I according to claims 1, 2 or 3, wherein R3denotes halogen and R4denotes hydrogen.

5. Compounds according to claim 1, which represents the

a) {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-1-ylmethanone,

b) {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-2-ylmethanol,

C) {4-[2-(4-forfinal)ethyl]piperazine-1-yl}quinoline-8-ylmethanol,

g) {4-[2-(4-forfinal)ethyl]piperazine-1-yl}isoquinoline-3-ylmethanol, and their physiologically acceptable salt and solvate.

6. Method of producing compounds of the formula I according to claim 1, characterized in that a) a compound of formula II

in which L denotes Cl, Br, I or a free or reactive functionally modified Oh group, and R2takes the values specified in claim 1, is introduced into reaction with the compound of the formula III

in which R1and alk take the values specified in claim 1, or

b) if desired, one of the radicals R2, R3, R4and/or R5converted into another radical R2, R3, R4and/or R5,

and/or received under formula I by treatment with an acid converted into one of its salts.

7. The compounds of formula I according to claim 1 and their physiologically acceptable salt and solvate as a medicinal active ingredients.

8. The compounds of formula I is about to claim 1 and their physiologically acceptable salt and solvate as inhibitors of 5-HT 2Athe receptor.

9. The compound according to claim 1, which is the medicinal active ingredient 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 bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

10. Pharmaceutical composition having antagonistic activity against 5-HT2Areceptor, characterized in that it contains at least one compound of formula I according to claim 1 and/or one of its physiologically acceptable salt or solvate and at least one pharmaceutically acceptable auxiliary substance.

11. Selective antagonists of 5-HT2Areceptor of the formula I according to claim 1 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 bulimia, anorexia nervosa, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

12. Selective antagonists of 5-HT2Areceptor formula I in P1 for the treatment of psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders such as bulimia, mental anorexia, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD), characterized in that the antagonists are not associated with 5-HT2C, 5-HT1A, 5-HT1Band 5-HT1Dthe receptors.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperazine oxime of the general formula (I): wherein X means phenyl or pyridyl substituted with 1 or 2 substitutes; Y means 2- or 3-indolyl, phenyl, 7-azaindole-3-yl, 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl that can be substituted; n = 0-3; m = 0-2; R1 means -NH2, morpholino-, thiomorpholino-group, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl. Compounds possess antagonistic activity with respect to neurokinine receptors and can be used in treatment of anxiety states. Also, invention describes a pharmaceutical composition based on compounds of the formula (I), method for its preparing and using.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

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

4 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to the improved formulation of aripiprazole showing the reduced hygroscopicity. These formulations are not converted to hydrate and not loss the initial solubility being even the medicinal preparation comprising anhydrous apipiprazole crystals are stored for a long time. Also, invention describes method for preparing these formulation and pharmaceutical composition based on thereof.

EFFECT: improved and valuable pharmaceutical properties of agent.

22 cl, 32 dwg, 7 tbl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperazine oxime of the general formula (I): wherein X means phenyl or pyridyl substituted with 1 or 2 substitutes; Y means 2- or 3-indolyl, phenyl, 7-azaindole-3-yl, 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl that can be substituted; n = 0-3; m = 0-2; R1 means -NH2, morpholino-, thiomorpholino-group, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl. Compounds possess antagonistic activity with respect to neurokinine receptors and can be used in treatment of anxiety states. Also, invention describes a pharmaceutical composition based on compounds of the formula (I), method for its preparing and using.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0°, 16.6°, 19.3°, 20.3° and 22.1°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 in IR-spectrum, endothermic peak at 141.5° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to granulated composition containing 11-[4-[2-(2-hydroxyethyl)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine (quetiapine) or its pharmaceutically acceptable salt, preferably quetiapine fumarate, as an active substance and a water-soluble binding agent. Invention relates to a method for preparing this composition and to a method for treatment of patients with nervous system diseases such as psychotic states including schizophrenia. Invention alleviates dosing of drugs by patients in required dose and solves problem concerning maintenance of regimen and schedule of treatment.

EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

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