Alkyl-piperazinil benzoxazolinone and alkyl-piperidinyl benzoxazolinone derivatives, method for their production and method of treatment

 

The invention relates to novel alkyl-piperazinil benzoxazolinone and alkyl-piperidinyl benzoxazolinone derivative of the formula (I), where S1is hydrogen; Z is =C or N; R1, R2and R4independently represent hydrogen, Q is methyl, ethyl or cyclopropylmethyl, and their salts and prodrugs. The method of obtaining compounds of formula (I) by reaction of compounds of formula (I), where Q represents hydrogen, with a compound Q-Hal, where Q is methyl, ethyl or cyclopropylmethyl and Hal represents halogen. The method of obtaining compounds of formula (I), where Z is N, the reaction of the compound of formula (II) with the compound of the formula (III). The method of obtaining compounds of formula (I), where Z is =C, the reaction of the compound of formula (IV) with a derivative of piperidine, with subsequent de-hydration and removing the protection. A method of treatment of CNS disorders, anxiety and/or depression, Parkinson's disease. The technical result is to provide new compounds. 7 C. and 3 h. p. F.-ly, 1 PL.

The present invention relates to a new group of piperazine derivatives and di-dihydropyridine,published as partial agonism in relation to the dopamine receptor D2and partial agonism in relation to serotonin receptor 5-HT1A.

In addition, there is an affinity for adrenergic receptors1. From EP 0189612 it is known that derivatives of piperazine, substituted on one nitrogen atom phenyl-heterocyclic group and not replaced by another nitrogen atom, possess psychotropic activity.

Furthermore, from EP 0190472 known that benzofuranol and benzodioxole derivatives of piperazine, substituted on the other nitrogen atom of piperazino group, also possess psychotropic activity.

Finally, from EP 0169148 it is known that 1,3-dihydro-4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-2H-indol-2-he's such compounds possess analgesic properties.

Surprisingly it was found that a small group of derivatives of piperazine and piperidine derivatives having the formula (I)where S1represents hydrogen, halogen, alkyl(1-3C), CN, CF3, F3SCF3, alkoxy(1-3C), amino or mono - or dialkyl(1-3C)substituted amino, or hydroxy; X is NR3, S, CH2Oh , SO or SO2where R3represents H or alkyl(1-3C); ...Z is =C or N; R1and R2independently represent H or possessing hydrogen or alkyl(1-3C); Q represents methyl, ethyl, ethyl, substituted by one or more fluorine atoms, cyclopropylmethyl, optionally substituted by one or more fluorine atoms;
provided that when S1, R1, R2and R4represent hydrogen, ...Z is =C and Q is ethyl, then X cannot represent CH2,
and their salts and prodrugs possess a combination of activities partial agonist dopamine receptor D2and a partial agonist of serotonin receptor S-HT1A.

Preferred compounds of the present invention are the compounds of formula (I), where S1, R1, R2and R4represent hydrogen, X represents oxygen and a ...Z and Q are as defined above values, and their salts.

Especially preferred are compounds where S1, R1, R2and R4represent hydrogen, X represents oxygen and -- Z is N and Q is methyl or ethyl, and their salts. The most preferred compound is a compound where Q is methyl.

Compounds of the present invention show affinity in relation to the dopamine receptor D2(in the range of pKi 7.5 to 8.5), and in respect of serotoninovogo the ese I, Schneider R. and Snyder S. H., [3H]-Spiroperidol labels dopamine receptors in rat pituitary and brain, Eur. J. Pharmacol. 1997, 46: 377-381 and Gozian H. EI Mestikawy S. , L. Pichat , Glowinsky J. and Harmon M., 1983, Identification of presynaptic serotonin autoreceptors using a new ligand3H-PAT, Nature 1983, 305: 140-142).

These compounds show different activity as a partial agonist at the dopamine receptor D2and, surprisingly, on 5-HT1Athe receptor. This activity was measured by the formation of adenylate cyclase in cell lines expressing these cloned receptors (e.g., human receptors D2and 5-HT1Areceptors expressed in the cell line Cho, in accordance with the methods described Solomon Y., Landos S., Rodbell M., 1974. A highly selective adenylyl cyclase assay. Anal Biochem 1974, 58:541-548 and Weiss , S., Sebben M. and Bockaert J. J., 1985, Corticotropin-peptide regulation of intracellular cyclic AMP production in cortical neurons in primary culture, J. Neurochem 1985, 45:869-874).

A unique combination of partial agonism in relation to the dopamine receptor D2and partial agonism in relation to serotonin receptor 5-HT1Aprovides a surprisingly wide range of activity in some animal models of resilience and mental and/or neurological disorders.

These compounds exhibit surprisingly high efficacy in therapeutic model anxirid the R, Molewijk H. E. , Van der Poel, A. M., Mos j, Van der Heyden J. A. M. and Oliver C. (1995). Conditioned ultrasonic vocalizations in adult male rats as a paradigm for screening anti-panic drugs, Psychopharmacology 1995, 117:32-40). Activity of compounds in this model was in the low range micrograms/kg, which is much more active (on the order of 100 or 3000) in comparison with compounds previously described in EP 0190472 and EP 0398413.

In addition, these compounds also demonstrate the effect in models of predestination antidepressant activity at higher doses (the forced swimming test, for example: Porsolt R. D., Anton g, Blavet n and Jalfre M., 1978, Behavioural Despair in rats: A new model sensitive to antidepressant treatments, Eur J. Pharmacol 1978, 47:379-391 and differential reinforcement of low doses in the model reaction to irritation in rats, for example, McGuire P. S. and Seiden L. S., The effects of tricyclic antidepressants on performance under a differential-reinforcement-of-low-rate schedule in rats, J. Pharmacol Exp Ther 1980, 214:635-641).

At higher doses was also observed effects similar to dopamine antagonist (the antagonism of apomorphine-induced behavior in mice, expressed in clambers up, (A), for example: Costall, B., Naylor, R. J. and Nohria V, Differential actions of typical and atypical agents on two behavioral effects of apomorfine in the mouse, (B), Brit J. Pharmacol 1978, 63: 381-382; suppression of locomotor activity, for example: File S. E. and Hyde J. R. G., A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor treyden J. A. M., Bradford L. D., A rapidly acquired one-way conditioned avoidance procedure in rats as a primary screening test for antipsychotics: influence of shock intensity on avoidance performance, Behav Brain Res 1988, 31:61-67). The first two activities, a and b, have been previously described in the literature on partial agonists dopamine Da receptor (Mewshaw et al., Bioorg. The Meet. Chem. Lett. 8 (1998) 2675).

These compounds apparently are valuable for the treatment of lesions or diseases of the Central nervous system, caused by a disorder of the dopaminergic and/or serotonergic systems, such as disorders associated with anxiety (including, for example, General anxiety, anxiety, obsessive-compulsive disorder), depression, autism, schizophrenia, Parkinson's disease, cognitive disorders and memory disorders.

Suitable acids with which the compounds of the present invention can form acceptable acid additive salts are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluensulfonate, methanesulfonate and naphthalenesulfonate.

Prodrugs are derivatives of the of karst. Suitable prodrugs are, for example, compounds where N-R4represents one of the following groups: amidon, enamine, the basis of manniche, hydroxymethylene derived derived O-(acetoxymethyl carbamate)and, carbamate or enamine.

These compounds or their salts can be brought into forms suitable for injection using conventional methods with the use of auxiliary substances, such as materials, solid or liquid media.

Compounds according to the invention can be obtained by methods known for the synthesis of such compounds.

The compounds of formula (I) can be obtained by interaction of the corresponding compounds where Q represents hydrogen, with a compound Q-Hal, where Q is methyl, (optional fluorinated)ethyl or (optional fluorinated) cyclopropylmethyl, and Hal represents halogen, preferably iodine. This reaction can be performed in a solvent such as acetonitrile, in the presence of a base, such as ethyldiethanolamine or triethylamine.

The parent compound, where Q is hydrogen and -- Z represents-N, are known or can be obtained as described in EP 0189612. The parent compound, where Q is hydrogen and Z ...the e ...Z represents-N, can also be obtained by the coupling of compounds of formula (II)

with the compound of the formula (III)

in the above formulas, the symbols have the above specified values. This reaction can be performed in an organic solvent such as chlorobenzene.

The compounds of formula (I), ...where Z is =S, can also be obtained in the manner indicated in the diagram below:


The original connection for stage (i) can be obtained according to the procedure described in J. Org. Chem. 45 (1980), 4789, and the stage (i) is carried out, as described in J. Org.Chem. 47, (1982), 2804.

Stage (ii) is performed by the method known for this type of chemical reactions as described in example 3.

Further, the invention is illustrated by the following examples.

Example 1.

1.28 g (5 mmol) of 1H. HCl suspended in 25 ml of acetonitrile and added to 0.34 ml (4.4 mmol) of ethyliodide together with 5 ml of diisopropylethylamine. The resulting reaction mixture is stirred and refluxed for 18 hours under nitrogen atmosphere. The reaction mixture was left to reach room temperature, after which it is time to relax is to, which is placed in the upper part of the chromatographic column and perform chromatography (SiO2, eluent CH2Cl2/MeOH 95/5) to give 0.55 g of a white solid. This substance is crystallized from a mixture of EtOAc/EtOH (approx. 1/1), which is added 1.1 equivalent of 1M HCl/EtOH. The crystals are collected by filtration, washed with respectively EtOAc and diethyl ether to obtain after drying, 0.5 g (42%) of the desired Hcl salt of the compound, where S1, R1, R2and R4represent hydrogen, X represents oxygen, ...Z is N and Q is ethyl, T. pl. 280-2oC (decomp.).

Example 2.

6.0 g (40 mmol) of the compound of formula (II) (where S1and R4represent hydrogen, and X is oxygen) dissolved in 150 ml of chlorobenzene, and then add of 8.47 g (44 mmol) of monohydrochloride N-methyl-bis(chloroethyl)amine. The resulting reaction mixture is stirred and brought to a boil under reflux. Present in the source material the water is separated by means of the device of Dean-stark. After 44 hours, a solid material, and the reaction mixture is allowed to cool to room temperature. The liquid is separated, the residue is washed with toluene, after which it is refluxed in ethanol. After ohlazhdennim4HE=97/2,5/0,5). In the result of implementation of this procedure is to obtain 4.5 g of solid material which is dissolved in 96% EtOH (approx. 300 ml), then with stirring, add 2 equivalents of 1M HCl/MeOH. Carry out crystallization and eventually after filtration and drying can be selected 4.15 g (38%) of the hydrochloride of the desired compound, where S1, R1and R2represent hydrogen, X represents oxygen, ...Z is N and Q is methyl, T. pl. 301,5-302,5oC.

Example 3
16.5 g (78.2 mmol) of N-(tert-butoxycarbonyl)metfornin dissolved in 230 ml of anhydrous tetrahydrofuran (THF) under inert atmosphere, after which the solution is cooled to -75oC (dry ice-acetone). While mixing, slowly add commercially available solution of 1.5 M tert-utility in heptane (approx. 156 mmol, 2 molar equivalents), after which the reaction mixture is stirred for 0.5 h at -70oAnd then 2 hours at -25oC. the Reaction mixture is again brought to -75oAnd add a solution of 9.6 ml of N-methylpiperidine (78.2 mmol, 1 molar equivalent) in approx. 25 ml of THF. The reaction mixture is allowed to reach room temperature and stirred for 16 hours. Then to the reaction mixture add a solution of 1.5 ml (ucanny powdery residue is placed in the upper part of the chromatographic column and perform flash chromatography (SiO2the first eluent; EtOAc second eluent: MeOH/EtOAc/triethylamine 15/85/1) to give 12.4 g of the oil is dark yellow. 4.7 grams (approx. of 15.5 mmol) of the obtained product is dissolved in 100 ml of dioxane, then add 100 ml of concentrated Hcl, the mixture is refluxed for 1 hour. The reaction mixture is allowed to cool to room temperature, after which it was concentrated in vacuo, obtaining a solid residue. The resulting residue is suspended in mixed isopropanol, after which the solid material is filtered and then washed with respectively EtOAc, diethyl ether and hexane. After drying remains 3.1 g of residue, of which 1.5 g suspended in EtOH, the rest of the suspension is refluxed for 1 hour. Mixture is allowed to cool to room temperature, then filtered to obtain a residue, which is washed with absolute EtOH and di(isopropyl)ether, respectively. After drying obtain 1.1 g (53%) of the desired compound, where1, R1, R2and R4represent hydrogen, X is oxygen, Z ...is =C and Q is methyl.1H-NMR (400 MHz, D2O):2,96 (broad, 2H, H-5); 3.04 from(C, MN, H-7); 3,3-4,3(broad, 4H, H-2, H-6); 6.4(m, 1H, H-3); 7,14(d, 1H, on the formula below:
7


Claims

1. Alkyl-piperazinil benzoxazolinone and alkyl-piperidinyl benzoxazolinone derivatives of the formula (I)

where S1represents hydrogen;

...Z is =or-N;

R1, R2and R4represent H;

Q represents methyl, ethyl or cyclopropylmethyl,

and their salts and prodrugs.

2. Connection on p. 1, where Q is methyl or ethyl and -- Z has the meaning given in paragraph 1.

3. Connection on p. 2, ...where Z is-n

4. Connection on p. 3, where Q is methyl.

5. A method of obtaining a connection on p. 1 by reaction of compounds of formula (I), where Q represents hydrogen, with a compound of formula Q-Hal, where Q is methyl, ethyl or cyclopropylmethyl and Hal represents halogen.

6. The method of obtaining compounds on p. 1, ...Z represents-N, the reaction of the compound of formula (II)

with the compound of the formula (III)

in which Q has the meaning given in paragraph 1.

7. The method of obtaining compounds of formula (I), ...where Z is =C, the reaction of the compound of formula (IV)

9. The method of treatment of anxiety and/or depression, characterized in that the connection is used for PP.1-4.

A method of treating Parkinson's disease, wherein the connection is used for PP.1-4.

 

Same patents:

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new biologically active compounds - substituted 3-methyl-4,5-dihydro-1,2-benzisoxazole formula I, where I

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to a new derived benzoxazole General formula (1) or salts thereof, R1represents a chlorine atom, R2is hydrogen, R3represents a methyl group

-acetylthio)-1,3,5-triazine as an antioxidant" target="_blank">

The invention relates to the field of organic chemistry and oil industry, specifically to the new derived contrasena - 2-methoxy-4-morpholin-6-(-acetylthio)-1,3,5-triazine (OATT), which is active additive, inhibiting the oxidation of vegetable oils (antioxidant)

The invention relates to a new-aryl-N-alkylsilanes formula I or II, pharmaceutical compositions based on them, the method of inhibiting neurodegenerative diseases, in particular diseases such as Alzheimer's disease, methods of treatment of autoimmune diseases and ways to prevent the occurrence of autoimmune and inflammatory conditions of the nervous system in mammals using the compounds I or II

The invention relates to a new-aryl-N-alkylsilanes formula I or II, pharmaceutical compositions based on them, the method of inhibiting neurodegenerative diseases, in particular diseases such as Alzheimer's disease, methods of treatment of autoimmune diseases and ways to prevent the occurrence of autoimmune and inflammatory conditions of the nervous system in mammals using the compounds I or II

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

The invention relates to a crystalline derivative dibenzothiazepine formula (1) having a melting point of 83 to 86oWith
The invention relates to methods for treating diseases physiotherapy, in particular, by using natural minerals
The invention relates to medicine, namely to psychiatry and pharmacology

The invention relates to medicine, in particular to pharmacy

The invention relates to medicine, in particular to pharmacy
The invention relates to medicine and AIDS, based on piracetam, affect the Central nervous system

The invention relates to the field of medicine and relates to antiviral agents, including nitrogen-containing heterocyclic carboxamide derivatives of General formula I, in which And indicates pyrazinone, pyrimidine, pyridazine or triazine ring which may be substituted with halogen or hydroxy, R1stands About or HE; R2denotes a hydrogen atom, acyl group, or a substituted or unsubstituted carbamylcholine or carboxialkilnuyu group; dashed line indicates a single or double bond, as well as new derivatives carboxamide of the formula I, where a represents pyrazinone ring, or their salts
Up!