(pyrido/thieno)[f]oxazepine-5-one derivatives, pharmaceutical composition based on the same and method for treatment of neurological diseases or mental disorders

FIELD: organic chemistry.

SUBSTANCE: invention relates to derivatives of general formula I , wherein R1, R2 and R3 are independently H or C1-C4-alkyl; Ar is condensed thiophene or pyridine ring optionally substituted with one or more substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkyloxy(C1-C4)-alkyl, CF3, halogen, nitro, cyano, NR4R5 NR4COR6 and CONR4R5 (R4 and R5 are independently H or C1-C4-alkyl; or R4 and R5 together with adjacent nitrogen atom form 5- or 6-membered saturated heterocyclic ring; R6 is C1-C4-alkyl): A is residue of 4-7-membered saturated heterocyclic ring optionally containing nictogen atom and optiomally substituted with 1-3 substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, hydroxyl, halogen, and alkoxy; and pharmaceutical composition based on the same; with the proviso, that compound of formula I wherein A represents condensed [3,2-f]pyridine ring; each R1, R2 and R3 represents H, and A represents (CH2)3. Also described are application of abovementioned derivatives, pharmaceutical composition enhancing of synaptic response mediated with AMPA receptors in CNS based on the same, and method for treatment of neurological diseases or mental disorders.

EFFECT: new compounds with value biological properties.

7 cl, 1 tbl, 12 ex

 

This invention relates to a derivative (pyrido/thieno)[f]oxazepine-5-it, to contain their pharmaceutical compositions and to the use of these derivatives (pyrido/thieno)[f]oxazepine-5-it is in the treatment of neurological and psychiatric diseases.

In the Central nervous system of mammals (CNS), the transmission of nerve impulses is governed by the interaction between the neurotransmitter that is released from the end of the sending neuron to the surface receptors of the receiving neuron, which causes excitation of the receiving neuron. Most rich neurotransmitter in the Central nervous system is L-glutamate. He mediates the main exciting path in mammals and belongs to the excitatory amino acids (EAA). Excitatory amino acids have important physiological significance, playing a role in various physiological processes such as learning and memory, development of synaptic plasticity, regulation of movements, breathing, regulation of the cardiovascular system and touch sensations.

The receptors that respond to glutamate, called receptors of excitatory amino acids (EAA receptors). These receptors are classified in two main types:

(1) "ionotropic" receptors, which are directly aligned with the opening of cation channels in the cell membrane of neurons, and (2) associated with G-protein "is metabotropic" receptors, which are associated with complex secondary signaling system that lead to increased hydrolysis of phosphoinositol, activation of phospholipase D, an increase or decrease in formation with AMR and change the function of ion channels.

Ionotropic receptors can be subdivided into three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA).

Activation of synaptic AMPA receptors mediates independent voltage fast (˜1 MS to peak value) current postsynaptic excitation (fast EPSC), whereas activation of synaptic NMDA receptor generates dependent voltage slow (˜20 MS to peak value) of the excitation current. Regional distribution of AMPA receptors in the brain proves that the AMPA receptors mediate synaptic transmission in this region may be responsible for cognitive functions and memory.

Activation of AMPA receptors by agonists leads to a conformational change in the receptor, causing rapid opening and closing of ion channels. The degree and duration of activation of the channels can be easily reduced drug that acts as a negative allosteric modulator (in the example, GYKI 52466), or may be increased by the drug, which then acts as a positive allosteric modulator.

Structural class of positive modulators of AMPA receptor produced from aniracetam (for example, CX 516), called AmprakinesTM. Positive modulators of the AMPA receptor can thus be contacted with glutamate receptor and by subsequent binding of agonist to the receptor provides a flow of ions through the receptor extended duration.

Defects in glutamate neurotransmission may be associated with many neurological and psychiatric diseases. therapeutic potential of positive AMPA receptor modulators in the treatment of neurological and psychiatric diseases analyzed Yamada K.A (Exp. Opin. Invest, Drugs, 2000, 9, 765-777), G.J. Lees (Drugs, 2000, 59, 33-78) and Grove S.J.A. and other (Exp. Opin. Ther. Patents, 2000, 10, 1539-1548).

Various classes of compounds that enhance the function of AMPA receptor, have been recently discovered and analyzed Grove S.J.A. and others (above). N-Anisoyl-2-pyrrolidinone (aniracetam; Roche) refers to the prototype AmprakineTM(Ito. I. and others, J. Physiol. 1990, 424, 533-543), soon after this followed the discovery of some sulfonamides (for example, cyclothiazide; Eli Lilly & Co) as modulators of AMPA (Yamada, K.A. and S.M. Rothman, J. Physiol., 1992, 458, 385-407). Based on the structure of aniracetam were developed Lynch G.S. and ogers G.A., its derivatives with improved efficiency and stability, as described in International patent application WO 94/02475 (Regents of University of California). Additional ampakine in the form of benzoylpiperidine and pyrrolidine were subsequently disclosed in WO 96/38414 (Rogers G.A. and L. Nilsson; Cortex Rharmaceuticals), followed by compounds in which the amide function was conformationally restricted in benzoxazinone ring system, as disclosed in WO 97/36907 (Rogers G.A. and G. Lynch, Regents of University of California; Cortex Pharmaceuticals) or in arylbenzothiazoles ring system, as disclosed in WO 99/51240 (Rogers G.A. and Johstrom P., Regents of University of California). Structurally related derivatives benzoxazine and especially 1,2,4-benzothiadiazin-1,2-dioxides, structural derivatives CyclothiazideTMwere disclosed in WO 99/42456 (Neurosearch A/S) as positive modulators of the AMPA receptor.

Positive modulators of AMPA receptor potentially applicable to humans. For example, increasing the power of the excitation synapses, they could compensate for the loss of synapses or receptors associated with aging and diseases of the brain (for example, Alzheimer's disease). Increasing mediated by AMPA receptor activity, it was possible to cause a more rapid development of polysynaptic circuits in the higher parts of the brain and thus improve the motility of sensations and mental figure of the spine. Later it was proved that ampakine potentially applicable as a means of improving memory, to improve the ability of people with sensory-motor problems and people with impairments in cognitive abilities that depend on networks of the brain, using the AMPA receptors, in the treatment of depression, alcoholism and schizophrenia and to accelerate recovery of people suffering from injuries.

On the other hand, observed that while maintaining activation of the AMPA receptor in experimental animals (for example, when high doses of certain modulators of AMPA, especially those that are potential inhibitors of desensibilization receptor) can cause serious and also other potentially proconvulsive side effects (Yamada, K.A., Exp. Invest. Drugs, 2000, 9, 765-777). Mean (impact) potential excitotoxicity activation of the AMPA receptor (in particular, modulators class thiadiazine) remains a need to develop a positive modulators having sufficient therapeutic index.

This invention relates to a derivative (pyrido/thieno)[f]oxazepine-5-it General formula I

where

R1, R2and R3independently of one another denote H or (C1-4)alkyl;

Ar means a condensed thiophene or pyridine ring, possibly samewe the Noah one or more substituents, selected from (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy(C1-4)alkyl, CF3, halogen, nitro, ceanography, NR4R5, NR4COR6and CONR4R5;

R4and R5independently of one another denote H or (C1-4)alkyl; or R4and R5together with the nitrogen atom to which they are attached, form a 5 - or 6-membered saturated heterocyclic ring containing an additional heteroatom selected from O, S or NR6;

R6means (C1-4)alkyl;

A represents the residue of a 4-7-membered saturated heterocyclic ring may contain an oxygen atom; ring possibly substituted by 1-3 substituents selected from (C1-4)alkyl, (C1-4)alkyloxy, hydroxy-group, halogen and carbonyl group; or its pharmaceutically acceptable salt;

provided that the compound of formula I where Ar means [3,2-f]-condensed pyridine ring; each of R1-R3means H and a means (CH2)3, is excluded.

Derivatives of pyrido[3,2-f]oxazepine-5-it, which is not protected as such, disclosed A.G. Schultz and others (J.Org. Chem. 1986, 51, 838-841) and Sleevi M.C. and others (J. Med. Chem., 1991, 34, 1314-1328), which describes the specified derived pyrido[3,2-f]oxazepine-5-she as a synthetic intermediate product without any pharmacologists is a mini activity.

Found that (pyrido/thieno)[f]oxazepine-5-ones of formula I, including previously described by Schultz and other derivatives of pyrido[3,2-f]oxazepine-5-it, are positive modulators of the AMPA receptor, which can be used in the treatment of neurological and psychiatric disease requiring enhancement of synaptic responses mediated by AMPA receptors.

In the definition of formula I, Ar means the condensed pyridine or thiophene ring in position [f] oxazepine rings. The condensation of the pyridine ring can occur through four possible relationships, giving pyrido[3,2-f]-, pyrido[4,3-f]-, pyrido[3,4-f]pyrido[2,3-f]-condensed rings, respectively. The condensation of thiophene rings can occur in three possible relationships, giving thieno[2,3-f]-, thieno[3,4-f]thieno[3,4-f]-condensed rings, respectively.

The term (C1-4)alkyl as used in the definition of formula I means a branched or unbranched alkyl group containing 1-4 carbon atoms, such as butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.

In the term (C1-4)alkyloxy (C1-4)alkyl has the meaning given above.

The term (C1-4)alkyloxy(C1-4)alkyl means a (C1-4)alkyl group which is substituted by (C1-4)alkyloxy, about the importance, as specified above.

The term halogen means F, Cl, Br or I.

In the definition of formula I, R4and R5together with the nitrogen atom to which they are attached, may form a 5 - or 6-membered saturated heterocyclic ring may contain an additional heteroatom selected from O, S or NR6. Examples of such heterocyclic rings are piperidino, pyrrolidino, morpholino, N-methylpiperazine, N-ethylpiperazine and the like.

In the definition of formula I, a represents the residue of a 4-7-membered saturated heterocyclic ring may contain an oxygen atom, which means that a is a divalent radical containing 2 to 5 carbon atoms, such as ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentile, one carbon atom which may be substituted by oxygen. Examples 4-7-membered heterocyclic ring formed by residue And together with atoms of nitrogen and carbon, And is associated with which are azetidin, pyrrolidine, piperidine, oxazolidine, isoxazolidine, morpholine and azacycloheptan.

Preferred derivatives (pyrido/thieno)[f]oxazepine-5-it formula I, where R1, R2and R3mean N.

More preferred compounds of formula I where Ar means [3,2-f]-condensed pyridine or [2,3-f]-condensed thiophene ring.

Derivatives (pyrido/thieno)[f]oxazepa the-5-she of the invention can be obtained by the General methods, known in organic chemistry. More specifically, these compounds can be obtained using the method A.G.Schultz and others (J. Org. Chem. 1986, 51, 838-841) or modification of this method.

Derivatives (pyrido/thieno)[f]oxazepine-5-it formula I can be, for example, obtained by cyclization of the compounds of formula II where Ar, A, and R1-R3have the meanings as defined above, any functional group with an acidic hydrogen protected with suitable protecting group, and where Q denotes a hydroxy-group, halogen or (C1-4)alkyloxy, after which any protective group, if present, are removed. The cyclization reaction of the compounds where Q denotes a halogen or (C1-4)alkyloxy, can be carried out in the presence of a base such as sodium hydride or cesium carbonate, in a solvent such as dimethylformamide, and at a temperature of 0-200°C, preferably 25-150°C.

For compounds of formula II, where Q denotes a hydroxy-group, the cyclization can be carried out in conditions of Mitsunobu (O. Mitsunobu, Synthesis 1981, 1), using triarylphosphine, for example, triphenylphosphine, and dialkyldithiocarbamate, such as diisopropylethylamine, in a solvent such as tetrahydrofuran.

Suitable protective groups for functional groups, which temporarily protects while synthetic is a, known state of the art, for example from P.G.M. Wuts and Greene, T.W.: Protectine Groups in Organic Synthesis, third edition, Wiley, new York, 1999.

The compounds of formula II can be obtained by condensation of compounds of formula III where Ar and Q have the above meanings and M denotes carboxylic acid or its derivative, such as an ether carboxylic acid or gelegenheid carboxylic acid, preferably the acid chloride or bromohydrin, with the compound of the formula IV, where R1-R3and a have the above values.

If M stands for a carboxylic acid, a condensation reaction, for example, the acylation may be carried out using a reagent combinations, such as, for example, carbonyldiimidazole, dicyclohexylcarbodiimide and the like, in a solvent such as dimethylformamide or dichloromethane.

If M denotes gelegenheid carboxylic acid, the condensation with the amine derivative (IV can be carried out in the presence of a base, such as triethylamine, in a solvent such as methylene chloride.

If M denotes the ether carboxylic acid derivative, direct condensation with the amine derivative of formula IV can be carried out at elevated temperature, for example, from about 50 to 200°C. this condensation can also be carried out using a Lewis acid in the example, trichloride aluminum, as described D.R.Barn and others (Biorg. Med. Chem. Lett., 1999, 9, 1329-34).

The compounds of formula I can be obtained by the methods described above, by using ignoreaction two-stage process, keeping in mind that the compound of formula II, which is the result of the condensation reaction between the compound of formula III and a compound of formula IV is not isolated from the reaction mixture, and then treated with base to form compounds of formula I.

The compounds of formula II can also be obtained by reaction of compounds of formula V where Ar, R3and As defined above and T denotes hydrogen, C(1-4)alkyl or C(1-4)alkyloxy,

With(1-4)altimetrically reagent such as a Grignard reagent, in a solvent such as tetrahydrofuran.

The compound of formula II, where R1means hydrogen, and R2means

With(1-4)alkyl group, can be obtained from compounds of formula V, where T means(1-4)alkyl group, recovery, for example, sodium borohydride, in a solvent such as ethanol.

The compound of formula V, where T means alkyloxy can be obtained from compounds of formula III, where M means the acid chloride of carboxylic acid, and alkanolamines obtained from alkylphenolate as described D.E.Thurston and others (J. Chem. Soc., Chem. ommun., 1990, 874-876).

The compound of formula V can be obtained by the reaction of a combination of compounds of formula III where Ar, M and Q are as defined above, with a compound of formula VI, where R3And T are as defined above values using the methods described above for the combination of compounds of formulas III and IV.

Compounds of formulas III, IV and VI can be obtained from commercial sources, obtained as described in the literature methods or modifications described in the literature methods known to experts in this field.

Professionals can easily appreciate that the various compounds of formula I can be obtained from the corresponding reactions of transformation of functional groups corresponding to some of the substituents of the aromatic ring. For example, the reaction

(C1-4)Olkiluoto alcohol with a compound of formula I where Ar, A, and R1-R3as defined above, and where one or more substituents in ring Ar are leaving groups such as, but not limited to, fluorine or chlorine, in the presence of a base such as sodium hydride, gives the compounds of formula I where one or more of the substituents at the ring Ar is (C1-4)alkyloxyaryl.

The compounds of formula I where one or more of the substituents at the ring Ar is CONR4R5can be obtained by conversion of compounds is ormula I, where one or more of the substituents at the aromatic ring are halogen, the corresponding esters of carboxylic acid using palladium(II), for example, dichlorobis(triphenylphosphine)palladium catalytic carbonylation reaction, as described by A. Schoenber and others (J. Org. Chem. 1974, 39, 3318). Saponification of ester to a carboxylic acid, such as sodium hydroxide in a mixture of tetrahydrofuran/water, and a combination of a carboxylic acid with an amine of the formula with other4R5using, for example, carbonyldiimidazole as agent combination, gives the compounds of formula I where one or more of the substituents at the aromatic ring is CONR4R5. The precursor carboxylic acid compounds of formula I where one or more substituents of the aromatic ring is CONR4R5can be obtained by oxidation of compounds of formula I where one or more of the substituents at the aromatic ring is a methyl group, with the use of an oxidant, for example, chromium trioxide. The compounds of formula I where one or more of the substituents at the aromatic ring are CONR4R5can be obtained catalyzed by palladium(II), such as dichlorobis(triphenylphosphine)palladium, carbonyliron the compounds of formula I where one or more of the substituents at the aromatic ring are halogen, in the presence of amine form is s NR 4R5using the method described by A. Schoenberg and Heck (J. Org. Chem. 1974, 39, 3327).

The compound of formula I where one or more substituents in the ring Ar is CN can be obtained from the compounds of formula I where one or more of the substituents at the ring Ar is CONH2, de-hydration dehydrating agent such as phosphorus oxychloride. The compound of formula I where one or more of the substituents at the ring Ar is CN can be obtained from the compounds of formula I where one or more of the substituents at the ring Ar is bromine or iodine, using catalyzed by palladium(0) cyanation reaction, as described M.Alterman and A. Halberg castle (J. Org. Chem. 2000, 65, 7984).

The compound of formula I where one or more of the substituents at the ring Ar is NR4R5can be obtained from the compounds of formula I where one or more of the substituents at the ring Ar is fluorine or chlorine, by displacement of the halogen with the amine of the formula with other4R5. The compound of formula I where one or more of the substituents at the ring Ar is NR4R5can be obtained from the compounds of formula I where one or more of the substituents at the ring Ar is chlorine, bromine or iodine catalyzed by palladium amination reaction with the amine of the formula with other4R5as described J.P.Wolfe and others (J. Org. Chem. 2000, 65, 1158). The compound of formula I where one or more of the substituents at the ring Ar is NR4, R 5and one of R4or R5is hydrogen, can be obtained from the compounds of formula I where one or more of the substituents at the ring Ar is NR4R5and both R4and R5mean N-alkylation of the nitrogen atom alkylating agent of the formula C(1-4)the alkyl, where Y represents a leaving group, such as alkyl - or arylsulfonate, chlorine, bromine or iodine. The compound of formula I where one or more of the substituents at the ring Ar is NR4R5and both R4and R5mean N, can be obtained from the compounds of formula I where one or more of the substituents at ring Ar are nitro groups, recovery, for example, catalyzed by palladium recovery of hydrogen. The compound of formula I where one or more of the substituents at the ring Ar is NR4COR6can be obtained from the compounds of formula I where one or more substituents at the aromatic ring are other4by processing allermuir agent such as an acid chloride or anhydride With(1-5)acid, for example acetic anhydride, in a solvent, for example pyridine.

Treatment of compounds of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring, substituted by 1-3 hydroxy groups, a base such as sodium hydride, in a solvent such as tetrahydrofuran, an alkylating agent to form the s (1-4)the alkyl, where Y is as defined above, with the formation of the compounds of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring, possibly substituted by 1-3 alkyloxyaryl. In the compound of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring with 1 to 3 hydroxy groups, the hydroxy-group(s) may be substituted with halogen treatment halogenation agent such as TRIFLUORIDE (diethylamino)sulfur (DAST) or in combination with pierodellavalentina.com.

Similarly, the compound of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring, possibly substituted 2 halogen atoms on the same carbon atom, can be obtained from the corresponding oxopropanal processing halogenation agent such as DAST.

Oxidation of compounds of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring, possibly substituted by 1-3 hydroxy groups, such oxidant, as in the case of oxidation in Turn described R.E.Ireland and D.W.Norbeck (J. Org. Chem. 1985, 50, 2198-2200), gives the compounds of formula I, where a represents the residue of a 4-7-membered saturated heterocyclic ring, possibly substituted by 1-3 exography.

Derivatives (pyrido/thieno)[f]oxazepine-5-it formula I and their salts contain at least one centre of chirality and therefore is in there in the form of stereoisomers, including enantiomers and, where possible, the diastereomers. The invention includes the above stereoisomers and each individual R and S enantiomer of compounds of formula I and their salts, practically free, for example, associated with less than 5%, preferably less than 2% and in particular less than 1%, of other enantiomers as well as mixtures of these enantiomers in any ratio, including a racemic mixture, which contains essentially equal amounts of the two enantiomers. Methods of asymmetric synthesis, in which the pure stereoisomers are well known in the art, for example, synthesis of chiral induction or proceeding from chiral intermediates, enantioselective enzymatic conversion, separation of stereoisomers or enantiomers using chromatography or chiral environment. Such methods are, for example, described in Chirality in Industry (published A.N.Collins, G.N.Sheldrake and J.Crosby, 1992; John Wiley). Specific techniques that can be applied for stereoselective obtain derivatives of arelaxation of this invention are described A.G. Schultz and others (J. Org. Chem. 1986, 51, 838-841).

Pharmaceutically acceptable salts can be obtained by treating the free base of the compounds of formula I with a mineral acid, such as hydrochloric acid, Hydrobromic acid, phosphoric acid and the RNA acid, or organic acid, such as, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonate and the like.

Compounds of the invention can exist in resolutiony and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In General, the present invention solvated forms are considered equivalent nonsolvated forms.

This invention also relates to pharmaceutical compositions comprising a derivative (pyrido/thieno)[f]oxazepine-5-it General formula I or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable excipients and possibly other therapeutic agents. The term "acceptable" means compatible with other ingredients of the composition and emissions of recipients. Compositions include, for example, compositions suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, local or rectal administration and the like, all in a unit dosage forms for injection.

For oral administration the active ingredient may be made the flax in the form of discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions and the like. For parenteral administration of the pharmaceutical composition in accordance with the invention can be presented in containers in the form of doses for single or multiple applications, for example, liquid for injection in pre-defined quantities, for example, in sealed vials and vials, and may also be stored in a dry frost-free conditions (liofilizovannyh) States, before use, requiring only the addition of sterile liquid carrier, for example water.

Mixing with the specified pharmaceutically acceptable auxiliary substances, for example, as described in the standard reference, Gennaro A.R., and others, Remington: The Science and Practice of Pharmacy (20th edition, Lippincot Williams & Wilkins, 2000, see especially part 5: Pharmaceutical Manufacturing), the active agent may be compressed into solid dosage units such as pills, tablets, or processed into capsules or suppositories. With the help of pharmaceutically acceptable liquids the active ingredient can be used in the form of liquid compositions, for example, in the form of a preparation for injection, in the form of solution, suspension, emulsion or in the form of a spray, for example, a nasal spray.

For the manufacture of solid dosage units are considered conventional additives such as fillers, paints the Lee, polymeric binder and the like. In General, can be any pharmaceutically acceptable additives which do not interfere with the function of active connections. Suitable carriers, with which an active agent of the invention can be introduced in the form of solid compositions, are lactose, starch, cellulose derivatives and the like or mixtures thereof, used in the right quantities. For parenteral administration can be used aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butyleneglycol.

The invention further includes a pharmaceutical composition, as described above, in combination with packaging material suitable for the specified composition; specified packaging material contains instructions for using the composition in the aforementioned applications. Derivatives (pyrido/thieno)[f]oxazepine-5-she of the invention are positive modulators of the AMPA receptor, as may be determined by increasing the steady-state current induced by the introduction of glutamate usual method of clamping a hollow area of the cell where (pyrido/thieno)[f]oxazepine-5-Oh according to the invention (see example 10 and table I). Connections can be IP is alsomany in the treatment of neurological and psychiatric diseases, where required increase synaptic response mediated by AMPA receptors, such as neurodegenerative disorders, disorders of cognitive activity or memory, trauma, sudden attack, epilepsy, Alzheimer's disease, depression, schizophrenia, psychotic disorders, sexual dysfunction, autism, or diseases or disorders caused by neurotic agents or dependence on substances, and alcohol intoxication.

Compounds of the invention can be administered to the person with a dose of 0.001-50 mg / kg body weight, preferably in a dose of 0.1-20 mg per kg of body weight.

The invention is illustrated in the following examples:

Example 1

(S)-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[2,3-f][1,4]oxazepine-5-he

To a solution of 3-chlorothiophene-2-carboxylic acid (0.5 g; 6,325 mmole) in dimethylformamide (5 ml) was added 1,1'-carbonyldiimidazole (1.07 g; 6,64 mmole) and the solution was stirred at room temperature for 1 h followed by addition of (S)-(+)-2-pyrrolidineethanol (0,655 ml; 6,64 mmole). The reaction mixture was stirred at room temperature overnight, then carefully added 60%sodium hydride in mineral oil (0,507 g, 12.7 mmole) and the mixture was slowly heated to 150°With monitoring of the reaction by thin-layer chromatography. The reaction mixture was carefully diluted with the water, were extracted with ethyl acetate and the organic layer was washed with water, then dried (Na2SO4) and was evaporated, obtaining the crude product. Purification with flash chromatography, elwira 0-10% (vol./about.) methanol in dichloromethane, followed by crystallization from a mixture of ethyl acetate/petroleum ether (40-60) gave specified in the title compound (0.15 g). TPL 167-167,5°C; mass spectrometry with ionization by electron impact (EIMS): m/z=to 222.2 [M+H]+.

Example 2

The procedure described in example 1, and then used to obtain the following compounds:

2A: (R)-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[2,3-f][1,4]oxazepine-5-it was obtained from 3-chlorothiophene-2-carboxylic acid and (R)-(-)2-pyrrolidineethanol. TPL 168-168,5°C; EIMS: m/z=to 222.2 [M+H]+

2B: (S)-8-trifluoromethyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-it was obtained from 2-chloro-6-triftormetilfosfinov acid and (S)-(+)-2-pyrrolidineethanol. TPL: 152-153°C; EIMS: m/z=173,2 [M+H]+2C: (R)-8-trifluoromethyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-it was obtained from 2-chloro-6-triftormetilfosfinov acid and (R)-(-)-2-pyrrolidineethanol. TPL: 152-153°C; EIMS: m/z=273,2 [M+H]+

Example 3

Cleaners containing hydrochloride salt of (S)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-she

To a solution of 2-chloro-6-methylnicotinic acid (4.3 g; 25 mmol) in dimethylformamide (50 ml) and alali 1,1'-carbodiimide (5 g; 30 mmol) and the solution was stirred at room temperature for 1 h followed by addition of (S)-(+)-2-pyrrolidineethanol (3,3 ml). The reaction mixture was stirred at room temperature for 2 h, then was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and was evaporated, receiving the intermediate amide in the form of oil. Specified oil was placed in dimethylformamide (50 ml) was added cesium carbonate (7.8 g). The reaction mixture was heated for 2 h at 60°C, then cooled to room temperature, was distributed between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and was evaporated. The transformation in cleaners containing hydrochloride salt using HCl in a simple ether and crystallization from methanol-ether gave specified in the header of the product. TPL: 176-180°C; EIMS: m/z=219,2 [M+H]+

Example 4

The procedure described in example 3, and then used to obtain the following compounds:

4A: (S)-8-chloro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-it was obtained from 2,6-dichloronicotinic acid and (S)-(+)-2-pyrrolidineethanol. TPL 164-166°C; EIMS: m/z=239 [M+H]+

4B: (R)-8-chloro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-it was obtained from 2,6-dichloronicotinic acid and (R)-(-)-2-pyrrolidineethanol. TPL 162-164°C; EIMS: m/z=239,2 [M+H]+

4C: (S)-1,2,11,11a-tetrahydroazepine[2,1-c][1,4]PI is IDO[3,2-f][1,4]oxazepine-5-it was obtained from 2-chloronicotinic acid and (S)-(-)-2-hydroxymethylamino (.Pasquier and others, Organometallics 2000, 19, 5723-5732).

TPL 135-136°C; EIMS: m/z=191,4 [M+H]+

4D: (±)-6,6a,7,8,9,10-hexahydro-N-pyrido[2,1-c]pyrido[3,2-f][1,4]oxazepine-12-it was obtained from 2-chloronicotinic acid and 2-piperidinemethanol.

TPL: 86-87°C; EIMS: m/z=239 [M+H]+

4E: (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[4,3-f][1,4]oxazepine-5-it was obtained from 3-chloropyridin-4-carboxylic acid (A.R. Krapcho, etc., J. Het. Chem. 1997, 34,27-31) and (S)-(+)-2-pyrrolidineethanol.

TPL 153 to 155°C; EIMS: m/z=205,2 [M+H]+

4F: (R)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[4,3-f][1,4]oxazepine-5-it was obtained from 3-chloropyridin-4-carboxylic acid and (R)-(-)-2-pyrrolidineethanol. TPL 156-157°C; EIMS: 205 [M+H]+

Example 5

(S)-7-chloro-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[3,2-f][1,4]oxazepine-5-he

To methyl 2,5-dichlorothiophene-3-carboxylate (1.47 g; 7 mmol) was added (S)-(+)-2-pyrrolidineethanol (1,75 g, 8.3 mmole). The reaction mixture was stirred for 1 hour at 160°C, then cooled to room temperature and carefully added 60%sodium hydride in mineral oil (0.5 g, 12.5 mmole) and the mixture was heated 2 hours at 50°C. the Reaction was suppressed by the addition of isopropanol was evaporated and added ethyl acetate. The solution was washed with water and brine and evaporated. Crystallization from a mixture of ethyl acetate/petroleum ether gave 307 mg specified in the header of the product. T square 162,5-163,5°C; EIMS: m/z=244,2 [M+H] +

Example 6

The procedure described in example 5, then used to obtain the following compounds:

6A: (R)-7-chloro-2,3,10,10A-tetrahydro-1H,5H-pyrrolo[2.1-c]thieno[3,2-f][1,4]oxazepine-5-it was obtained from (R)-(-)-2-pyrrolidineethanol.

TPL 162,5-163,5°C; EIMS: m/z=244,2 [M+H]+

6B: (2R,10aS)-7-chloro-2-hydroxy-2,3,10,10A-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[3,2-f][1,4]oxazepine-5-it was obtained from methyl 2.5-dichlorothiophene-3-carboxylate and (3R,5S)-3-hydroxy-5-hydroxyethylpyrrolidine (M.W. Reed and others, J. Med. Chem., 1995, 98 4587-4596), using conditions cyclization with cesium carbonate described in example 3. TPL of 193.5-194°C; EIMS: m/z=260 [M+H]+

Example 7

(S)-8-methoxy-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he

To a solution of the substance obtained in example 4A (1.2 g)in methanol (20 ml) was added sodium methylate (0.27 g). The solution was boiled for 2 hours, then evaporated, transferred in dichloromethane, washed with water and dried over sodium sulfate. The organic layer was evaporated and the residue was recrystallized from a mixture of dichloromethane/simple ether/petroleum ether, getting listed in title product (200 mg).

TPL 136-138°C; EIMS: m/z=253,0 [M+H]+

Example 8.

(S)-8-piperidinyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[2,3-f][1,4]oxazepine-5-he

To a solution of the substance obtained in example 4A (600 mg)in dimethylformamide (20 ml) was added piperidine (0.26 per ml). Solution heating and 2 h, then cooled, washed with water and was extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4) and was evaporated, the obtained solid substance was recrystallized from a mixture of dichloromethane/petroleum ether, receiving specified in the header of the product (650 mg).

TPL 148-152°C; EIMS: m/z=288,0 [M+H]+

Example 9

(2R,11aS)-2-hydroxy-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he

To the HCl-salt of (3R,5S)-3-hydroxy-5-hydroxyethylpyrrolidine (874 mg; M.W.Reed and others, J.Med. Chem., 1995, 38, 4587-4596) in water (20 ml) was added sodium bicarbonate (960 mg, 5.7 mmole) and then the acid chloride of 2-chloronicotinic acid (1.0 g; 5.7 mmole). The mixture was stirred for 2 days, then was extracted with dichloromethane, evaporated and purified flash chromatography, elwira 10%methanol in dichloromethane, receiving the intermediate amide which was cyclically under the conditions described in example 3, receiving specified in the header of the product.

TPL: 174°C; EIMS: m/z 221,4 [M+H]+

Example 10: the electrophysiology patch-clamp a cell.

A: cell culture.

Neural cells in the hippocampus were obtained from embryonic or 1-3-day-old rats, Sprague-Dawley, who were decapitated and the heads were immediately placed in ice-cold solution of HBS (HEPES buffer solution: 130 mm NaCl, 5.4 mm KCl, 10 mm HEPES, 1.0 mm MgCl2group , 1.8 CaCl2, 25 mm glucose, brought to pH 7.4). The whole brain was cut was pomedli on pre-sterilized filter paper soaked HBS and the cerebellum was removed. The brain was crushed and added to the solution of enzyme (0.5 mg/ml protease X and 0.5 mg/ml protease in HBS), then left for 40 minutes at room temperature to break down before rubbing. Cells are again suspended and then counted, receiving a final concentration of 1,C6on Jr. was Selected aliquots of the cells on the cover glass, treated with poly-D-lysine and Matrigel®and incubated at 37°C for 1-2 hours. After the incubation was added 1 ml of culture medium in each well cover glass and the cells were returned to the incubator. After 3-5 days added mitotic inhibitor cytosine arabinoside (5 μm) and the cells were returned to the incubator for you to retrieve.

In: check-in the patch-clamp.

Used the patch-clamp technology configuration of the whole cells (Hamill and others, Pfluegers Arch. 1981, 39, 85-100) for interruptible measuring glutamate currents of postnatal hippocampal neurons sustained in culture 4-7 days. Top glass containing culture was transferred in registration chamber (Warner Instrument Corp., Hamden, CT)mounted on the table investicionnogo microscope (Nikon, Kingston, UK). Registration Luggage contained 1-2 ml extracellular solution (145 mm NaCl, 5.4 mm KCl, 10 mm HEPES, 0.8 mm MgCl2group , 1.8 CaCl2, 10 mm glucose and 30 mm sucrose, brought to pH 7.4 1M NaOH) and were subjected to perfusion with a speed of 1 the l/min. Registration was carried out at room temperature (20-22° (C)using additional lens Axopatch 200B (Axon Instruments Ltd., Foster City, CA). Definition data and analysis were processed using the software Signal (Cambridge Electronic Design Ltd., Cambridge, UK). Pipettes were made from glass GC120F-10 (Harvard Apparatus, Edenbridge UK) using an electrode puller model P-87 (Sutter Inatruments Co, Novarto, CA). Point electrodes usually had a resistance of 3-5 M Ωwhen they are filled with intracellular solution (140 mm potassium gluconate, 20 mm HEPES, 1.1 mm EGTA, 5 mm phosphocreatine, 3 mm ATP, 0.3 mm GTP, 0.1 mm CaCl2, 5 mm MgCl2brought to pH 7.4 1M KOH)Kletki subjected to constant voltage of -60 mvolt and applied glutamate (0.5 mm)using a 12-channel device insertion with reasonable speed (DAD-12. Digitimer Ltd., Welwyn Garden city, UK). Agonist glutamate was injected for 1 sec every 30 sec. The reaction was not "reduced" during the time when the used configuration of the whole cell. Between the introduction was added to the saline solution to clean the "broken" solution in the system. For each introduction of steady-state currents were determined from the differences in the source lines of the steady-state current and the average (these differences were above 300 MS.

Two solutions of the compounds in the extracellular solution was one with glutamate and one without it. Protocol: 10 seconds in which edenia connection 1 second introduction connections+glutamate and then 10 seconds washing with saline, followed by 10 seconds of exposure. If the connection was insoluble, as a co-solvent used 0.5%DMSO (dimethyl sulfoxide). The results are presented in table I as an increasing percentage of the steady-state current at a 10 μm concentration of the compound of the invention in the extracellular solution.

Table I
Connection% increase in the steady-state current at 10 µm
(S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[3,2-f][1,4]oxazepine-5-he*22
(S)-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[2,3-f][1,4]oxazepine-5-he (example 1)32
(R)-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[2,3-f][1,4]oxazepine-5-he (example 2A)20
(S)-8-trifluoromethyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he (example 2B)21
(R)-8-trifluoromethyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he (example 2C)19
cleaners containing hydrochloride salt of (S)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-it (example 3)12
(S)-8-chloro-2.3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[,2-f][1,4]oxazepine-5-he (example 4A) 16
(R)-8-chloro-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he (example 4B)29
(±)-6,6A,7,8,9,10-hexahydro-N-pyrido[2,1-c]pyrido[3,2-f][1,4]oxazepine-12-he (example 4D)13
(S)-7-chloro-2,3,10,10A-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[3,2-f][1,4]oxazepine-5-Oh (example 5)16
(R)-7-chloro-2,3,10,10A-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[3,2-f][1,4]oxazepine-5-he (example 6A)20
(S)-8-methoxy-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he (example 7)22
*received as described A.G. Schultz and others (J. Org. Chem. 1986, 51, 838-841)using alternative title: 1,2,3,10,11,11a(S)-hexahydro-5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he;

Sleevi M.C. and others (J. Med. Chem., 1991, 34, 1314-1328) used for the specified connection name 6A,7,8,9-tetrahydro-6N,11N-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepine-11-he.

Example 11

Differential reinforcement of low speed response, 72 seconds (DRL72)

Rats was previously prepared in a standard operating room procedures DRL72 according to Andrews and others (Andrews JS, Jansen JHM, Linders S, Princen A, Drinkenburg WHIM, Coenders CJH and Vossen JHM (1994). The effect of imipramine and mitrazapine on the response of rats. Drug Development Research, 32, 58-66). Session tests continued the ü within 60 minutes unlimited number of tests. Every trial started with a light stimulus to the above active funds. The answer to the tool occurred only if shipping in the pills was 72 seconds. If the answer to the tool previously 72 seconds passed restarting the timer and the reaction was not supported. The number of obtained granules and the number of clicks on the lever were recorded and used to calculate the efficiency values. Test compounds were administered intraperitoneally 30 minutes before sampling. Antidepressants increase the number of obtained granules and reduce the number of compressed funds. Antidepressant similar profile is (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he.

Example 12

Inhibition enhanced locomotor activity induced by amphetamine.

Mice were done by injection subcutaneously with medication or control media. After 30 minutes, the mice were injected subcutaneously with 1.5 mg/kg sulfate, d-amphetamine or saline and immediately placed in camera to determine locomotor activity using infrared rays, where the measured motor activity (long-duration beam was divided into two adjacent beam) and stereotypica behavior (repeating the separation of short duration beam) over a period of 60 minutes. The experiment was analyzed using a 3-volnovye ANOVA with experimental SES is AI, an infrared camera to determine the physical activity and health factors, and in the case of processing with the use of samples Tukey (HSD) observed a noticeable effect. (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c]pyrido[3,2-f][1,4]oxazepine-5-he (S)-2,3,10,10a-tetrahydro-1H,5H-pyrrolo[2,1-c]thieno[2,3-f][1,4]oxazepine-5-he (example 1) inhibit the enhanced locomotor activity induced by amphetamine.

1. Derivatives (pyrido/thieno)[f]oxazepine-5-it General formula I

where R1, R2and R3independently of one another denote H or (C1-4)alkyl;

Ar means a condensed thiophene or pyridine ring, possibly substituted by one or more substituents selected from (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy(C1-4)alkyl, CF3, halogen, nitro, ceanography, NR4R5, NR4COR6and CONR4R5;

R4and R5independently of one another denote H or (C1-4)alkyl, or

R4and R5together with the nitrogen atom to which they are attached, form a 5 - or 6-membered saturated heterocyclic ring;

R6means (C1-4)alkyl;

A represents the residue of a 4-7-membered saturated heterocyclic ring may contain an oxygen atom, the ring is available is substituted by 1-3 substituents, selected from (C1-4)alkyl, (C1-4)alkyloxy, hydroxy-group, halogen and actigraphy,

or their pharmaceutically acceptable salt,

provided that eliminates the compound of formula I where Ar means [3,2-f]condensed pyridine ring; each of R1-R3means H and a means (CH2)3.

2. Derivatives (pyrido/thieno)[f]oxazepine-5-she according to claim 1, where R1, R2and R3mean N.

3. Derivatives (pyrido/thieno)[f]oxazepine-5-she according to claim 1 or 2, where Ar means [3,2-f]condensed pyridine or [2,3-f]condensed thiophene ring.

4. The use of derivative (pyrido/thieno)[f]oxazepine-5-it General formula I

where R1, R2and R3independently of one another denote H or (C1-4)alkyl;

Ar means a condensed thiophene or pyridine ring, possibly substituted by one or more substituents selected from (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkyloxy(C1-4)alkyl, CF3, halogen, nitro, ceanography, NR4R5, NR4COR6and CONR4R5;

R4and R5independently of one another denote H or (C1-4)alkyl, or R4and R5together with the nitrogen atom to which they are attached, form a 5 - and 6-membered saturated heterocyclic ring;

R6means (C1-4)alkyl;

A represents the residue of a 4-7-membered saturated heterocyclic ring may contain an oxygen atom, and the ring may substituted by 1-3 substituents selected from (C1-4)alkyl, (C1-4)alkyloxy, hydroxy-group, halogen and carbonyl group,

or their pharmaceutically acceptable salts in the preparation of drugs for the treatment of neurological diseases and psychiatric disorders that are sensitive to increased synaptic susceptibility mediated by AMPA receptors in the Central nervous system.

5. The use according to claim 4, where the disease or disorder is selected from neurodegenerative disorders, cognitive dysfunction, memory and learning, which may be the result of aging, disorders of care, trauma, sudden attack, epilepsy, Alzheimer's disease, depression, schizophrenia, psychotic disorders, anxiety, sexual dysfunction, autism or disorders, or diseases caused by neurotic agents or dependence on substances and alcohol intoxication.

6. The method of treatment of neurological diseases or psychiatric disorders that are sensitive to increased synaptic susceptibility mediated by AMPA receptors, in General the Central nervous system, moreover, this method provides for the introduction of a therapeutically effective amount of a derivative (pyrido/thieno)[f]oxazepine-5-it is according to formula I of claim 1.

7. Pharmaceutical composition, enhancing synaptic responses mediated by AMPA receptors in the Central nervous system, including derivative (pyrido/thieno)[f]oxazepine-5-she, of General formula I according to claim 4 together with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

FIELD: medicine.

SUBSTANCE: method involves transplanting bone marrow stem cells. Autologic mononuclear cells taken from patient bone marrow are used. The cells are divided into two fraction after 24 h long incubation. The cell fraction sticking to plastic is introduced into empty intramedullary cyst cavity in the amount not exceeding cyst cavity size. The cell fraction with no adhesion to plastic is intravenously introduced.

EFFECT: reduced intensity neurologic deficiency manifestations in later vertebral column injury stage.

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to nicotine-containing pharmaceutical compositions comprising 0.5-10 mg of nicotine and 17-70 % cocoa powder as taste masking agent, filler/diluent and smoothing or corrective agent; to application of such composition in production of medicine preparation for nicotine replacement therapy (NRT), withdrawal from tobacco, application reducing and temporary cancellation of tobacco, in treatment of Alzheimer disease, Parkinson disease, ulcerative colitis and/or Tourette's syndrome, and/or in body weight loss therapy; as well as to methods for nicotine replacement therapy (NRT), withdrawal from tobacco, application reducing and temporary cancellation of tobacco, in treatment of tobacco dependence, treatment of Alzheimer disease, Parkinson disease, ulcerative colitis and/or Tourette's syndrome, and/or in body weight loss therapy by administration of such compositions.

EFFECT: new preparation for nicotine replacement therapy and for treatment of other diseases and conditions.

22 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

FIELD: medicine, in particular clinical pharmacology for treatment of bipolar disorder.

SUBSTANCE: claimed method includes administration of therapeutically effective amount of enantiomere of formula Ib ,namely from 0.01 to 100 mg/kg per day to subject.

EFFECT: agent for effective arresting bipolar disorder of type I and type II, cyclothymic disorder, bipolar depression, acute folie, stroke, associated with bipolar disorder, etc.

5 cl, 2 ex, 2 tbl

FIELD: medicine, in particular clinical pharmacology for treatment of bipolar disorder.

SUBSTANCE: claimed method includes administration of therapeutically effective amount of enantiomere of formula Ib ,namely from 0.01 to 100 mg/kg per day to subject.

EFFECT: agent for effective arresting bipolar disorder of type I and type II, cyclothymic disorder, bipolar depression, acute folie, stroke, associated with bipolar disorder, etc.

5 cl, 2 ex, 2 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in migraine treatment as a solid dosed medicinal formulation for the peroral administration that comprises 5-HT1-agonist sumatriptan or its pharmaceutically active salt or solvate as an active component (in the amount 20-150 mg of sumatriptan as a base) and a main component of a carbonated pair, a loosening agent and an insoluble excipient wherein the amount of the main component id from about 5 to about 50%% by mass, the amount of a loosing component is from about 0.5 to about 10% by mass, and the amount of insoluble excipient is from about 35 to about 80% by mass. Also, invention relates to using the proposed composition in migraine treatment. The composition can be used orally as a whole and provides the curative effect after rapid absorption typical for carbonated compositions.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

8 cl, 6 tbl, 3 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: composition comprises gel-forming matrix having one or more active ingredients with prolonged release time of one or more active substances under gastrointestinal tract fluids action. Hydroxypropylmethyl cellulose of high or moderate viscosity or hydroxyethyl cellulose of high or moderate viscosity are available in the composition in 1:0.85-1:1.2 proportion, respectively. The composition optionally comprises also hydroxypropylmethyl cellulose of low viscosity with hydroxypropylmethyl cellulose of low viscosity to one of high or moderate viscosity proportion being equal to 1:0.01-1.0.2, respectively. The composition essentially does not depend on ionic force of dissolving medium habitual for gastrointestinal tract fluids as norm even if the composition is not enclosed into coating shell.

EFFECT: enhanced effectiveness of treatment.

12 cl, 4 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoxazepine and describes derivative of benzoxazepine of the general formula (I): wherein X represents -CO or -SO2; R1, R2, R3 and R4 are chosen independently from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkyloxy-(C1-C4)-alkyl, -CF3, halogen atom, nitro-group, cyano-group, -NR8R9, -NR8COR10 and -CONR8R9; R5, R6 and R7 represent independently hydrogen atom (H) or (C1-C4)-alkyl; R8 and R9 represent independently hydrogen atom (H) or (C1-C4)-alkyl; or R8 and R9 in common with nitrogen atom to which they are bound form 5- or 6-membered saturated heterocyclic ring comprising optionally the additional heteroatom chosen from oxygen atom (O), sulfur atom (S) or the group -NR11; R10 represents (C1-C4)-alkyl; R11 represents (C1-C4)-alkyl; A represents residue of 4-7-membered saturated heterocyclic ring comprising optionally oxygen atom wherein ring is substituted optionally with 1-3 substitutes chosen from (C1-C4)-alkyl, (C1-C4)-alkoxy-, hydroxy-group, halogen atom and oxo-group, or to its pharmaceutically acceptable salt under condition that compounds of the formula (I) are excluded wherein X represents -CO, and each among R1-R7 represents hydrogen atom (H), and A represents -(CH2)3 or -(CH2)4; compounds of the formula (I) wherein X represents -CO; R1 represents hydrogen atom (H); R2 represents methyl (CH3); each among R3-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; R1 and R2 represent hydrogen atom (H); R3 represents methyl; each among R4-R7 represents hydrogen atom (H), and A represents -(CH2)3; compounds of the formula (I) wherein X represents -CO; each among R1-R3 represents hydrogen atom (H); R4 represents methyl; each among R5-R7 represents hydrogen atom (H), and A represents -(CH2)3, and compounds of the formula (I) wherein X represents -CO; each among R1-R4 represents hydrogen atom (H); R5 represents methyl; R6 and R7 represent hydrogen atom (H), and A represents -(CH2)3. Also, invention describes pharmaceutical compositions comprising indicated derivatives and using these benzoxazepine derivatives in treatment of neurological diseases and psychotic disorders sensitive to enhancing responses mediated by AMPA receptors in the central nervous system. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 31 ex

FIELD: medicine.

SUBSTANCE: invention proposes a method for inhibition of chorionic neovascularization. Method involves irradiation of undesirable novel vascular reticulum in combination with photosensitive agent (porphyrine) and an anti-angiogenic agent taken among antagonist of phospholipase A2, inhibitor of complex kappa B, inhibitor of the growth hormone, inhibitor of insulin-like growth factor-1, inhibitor of cyclooxygenase II, inhibitor of protein kinase C (stautosporin PKC 412) and inhibitor of angiotensin II. The claimed combined treatment provides potentiation of effect of adjunctive photodynamic therapy in combination with enhanced safety.

EFFECT: improved treatment method.

7 cl

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.

EFFECT: improved and valuable properties of composition.

13 cl, 3 dwg, 2 tbl, 5 ex

Derivative to-a // 2205184
The invention relates to new derivatives of K-a (a derivative of indolocarbazole), which are represented by the General formula 1, as well as to a method for improving the functioning and/or increase the survival of cholinergic neurons and the way to improve cell survival at risk of death because of the compounds of formula 1 inhibit production of interleukin-2 and have immunosuppressive activity

The invention relates to medicine and relates to methods of suppressing excessive secretion of tumor necrosis factor alpha and interleukin-1 beta, as well as the treatment of diseases associated with excessive synthesis of these cytokines, Alzheimer's and Parkinson's disease using the derived indolocarbazole K-252a
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