2,3,4,5-tetrahydro-1,4-benzothiazepine, their stereoisomers or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition having anticonvulsant action

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with anticonvulsant activity. Disclosed 2,3,4,5-tetrahydro-1,4-benzothiazepine formula II, where n = 0 or 1, R1, R2, R6and R7- H, R3and R4- H or methyl, or together imino, methylimino, phenylimino, hydroxyimino or methoxyimino; R5- H or methyl, or when R3and R4- H or methyl, R5- H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulphonyl or ethylsulfonyl; R8- H, methyl, fluorine or chlorine; R9, R10and R11- H, provided that R1- R11not all H, and when n = 0 and R1- R4and R6- R11- H, R5is not a benzoyl or acetyl, and when n = 0 or 1, and R4is methyl, R1- R3and R5- R11- not all hydrogen, their stereoisomers or their pharmaceutically acceptable salts. Method for obtaining compounds of formula II recovery of the corresponding 3-oxo derivatives of 2,3,4,5-tetrahydro-1,4-benzothiazepine, as well as a pharmaceutical composition having anticonvulsant activity, containing as active principle compounds of formula II or a similar proizvodnym 2, 3, 4, 5-tetrahydro - 1,4-benzothiazepine, containing pharmaceutical compositions, and methods for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means to prevent such painful conditions as paralysis.

In particular, in accordance with the present invention provides compounds of formula I

< / BR>
where

n = 0,1 or 2;

R1, R2, R6and R7is independently H or alkyl with 1-4 carbon atoms (optionally substituted by one or more Halogens);

R3and R4is independently H or alkyl with 1-4 carbon atoms, or together a group of the formula = NR12where R12- H, hydroxy, alkyl with 1-4 carbon atoms, phenyl or alkoxy with 1-4 carbon atoms, and each alkyl, phenyl and alkoxy optionally substituted by one or more Halogens;

R5(a) H, (b) alkyl with 1-4 carbon atoms, (c) a group of the formula - COR13where R13- H, alkyl with 1-4 carbon atoms or phenyl when R3and R4Is H or alkyl (optionally substituted by one or more Halogens) or (d) a group of formula - S(O)pR14where p=1 or 2 and R14is alkyl with 1-4 halogen atom, each alkyl and phenyl optionally substituted by one or more Halogens;

R8-R11is independently H, halogen, cyano, nitro, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkanoyl with 1-4 carbon atoms, carboxy, alkanoyloxy with 1-4 carbon atoms, carbarnoyl (optionally substituted by alkyl with 1-4 carbon atoms) or sulfamoyl (optionally substituted by alkyl with 1-4 carbon atoms), each alkyl, alkoxy, alkanoyl, alkanoyloxy optionally substituted one of their pharmaceutically acceptable salts, provided: that

(I) when n=0, then at least one of the radicals R1-R11is other than H;

(II) when n=0, 1, or 2, R1, R2and R3is independently H or alkyl, R4and R6both H, R5Is H, alkyl or alkanoyl and one radical R8or R9and one of the radicals R9-R10- independently H, halogen, nitro, alkyl, alkoxy or trifluoromethyl, and the other of the radicals R8-R11-H, R7- other than alkyl, which are useful in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means for protection from conditions such as paralysis.

The compounds of formula I, where n and, known from Srabo et al, Chem Ber S. 2904-2913, 1986.

The compounds of formula I, where n=0 or 2, R1-R6, R10-R11- all H, R7is methyl and R9and R10both methoxy, known from J. org, Chem 30(8) C. 2812-2818, (1965), (England).

The compounds of formula I, where n=0, R1, R2, R5, R6and R7- all H, R3- nonbranched alkyl with 1-4 carbon atoms, R4-nonbranched alkyl with 2 to 4 carbon atoms and R8-R11is independently H, halogen, nitro, alkyl with 1-4 carbon atoms (optionally substituted by one or more Halogens), known as intermediates in obtaining the compounds claimed in the application WO 93/16055 (Wellcome) for the international patent (see formula XIV S. 18)

The compounds of formula I, where n=0, 1, or 2, R1, R2and R3is independently H or alkyl with 1-4 carbon atoms, R4and R6both H, R5-H, alkyl with 1-4 carbon atoms or alkanoyl with 1-5 carbon atoms, R7is alkyl with 1-4 carbon atoms and one of R8or R9and one of R10or R11is independently H, halogen, nitro, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or trifluoromethyl, and the other of the radicals R8-R11- H, known from the application 4916-M (Hoffmann la Roche) on putievsky activity as anti-convulsants, application pharmaceutical no data to support this statement.

The compounds of formula I, n= 0, R1-R4, R6-R8, R10and R11- all H, R5-H or bromacetyl and R9- H or alkoxy with 1-3 carbon atoms, known as intermediates in obtaining the compounds claimed in the application WO 92/12148 (Kaneko) international patent (see S. 4, 5 and 7) ( which corresponds to EP 0565721)

The compounds of formula I, where n=0 or 1, R1-R4, R6and R7independently H or alkyl with 1-4 carbon atoms, R5-H, alkyl with 1-4 carbon atoms or alkanoyl with 1-5 carbon atoms and one of R8or R9and one of R9or R10- independently H, halogen, cyano, nitro, alkyl with 1-4 carbon atoms, alkanoyl with 1-5 carbon atoms or alkanoyloxy with 1-4 carbon atoms, and the remaining one of R8and R9- H or chlorine and the remaining one of R9and R10- H, known as the catalysts of the Friedel-craft from the application 0368063 (Bayer) for the European patent priority application DE 3837574 and DE 3837575 and meet US 4990707)

The compounds of formula I, where n = 0, R1-R3and R6-R11- all H, R5- H benzoyl known from Boudet et al. C. R. Acad. Sci. Paris Series c.282, 249-251, (26. 01. 1976).

Couetil, where n = 1 or 2, R1-R3and R5-R11all H and R4-H or methyl, and salts of compounds of formula I, where n = 1 or 2, R1-R11all H and the salt is a hydrochloride, famous Indian J. Chem, 7(9), S. 862-5T (England)(with Chem Abs, 71 124391 p (1969) and Chem Abs.Sth. Coll Subst. Ind. p 4452)

Further, the present invention offers new compounds of formula II

< / BR>
where

n=0,1 or 2;

R1, R2, R6and R7is independently H or alkyl with 1-4 carbon atoms (optionally substituted by one or more Halogens);

R3and R4is independently H or alkyl with 1-4 carbon atoms, or together a group of the formula NR12where

R12- H, hydroxy, alkyl with 1-4 carbon atoms, phenyl or alkoxy with 1-4 carbon atoms, and each alkyl, phenyl and alkoxy optionally substituted by one or more Halogens;

R5(a) G, (b) alkyl with 1-4 carbon atoms, (c) a group of the formula - COR13where R13- H, alkyl with 1-4 carbon atoms or phenyl when R3and R4Is H or alkyl (optionally substituted by one or more Halogens) or (d) the group - S(O)pR14where p=1 or 2, and R14is alkyl with 1-4 carbon atoms or phenyl when R3and R4Is H or alkyl (optional, Sametime Halogens;

R8-R11- H, halogen, cyano, nitro, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkanoyl with 1-4 carbon atoms, carboxy, alkanoyloxy with 1-4 carbon atoms, carbarnoyl (optionally substituted by alkyl with 1-4 carbon atoms) or sulfamoyl (optionally substituted by alkyl with 1-4 carbon atoms), each alkyl, alkoxy, alkanoyl, alkanoyloxy optionally substituted by one or more halogenate, their stereoisomers and their pharmaceutically acceptable salts, provided that:

(A) when n=0, R1-R4, R6-R8and R11- G or acetyl, and R9- methoxy, R10is other than methoxy;

(B) when n=0 or 2, R1-R6, R8and R11- all H, R7is methyl and R9- methoxy, R10is other than methoxy;

(C) when n=0, R1, R2, R5, R6and R7- all H, R3- unbranched alkyl and R8-R11is independently H, halogen, nitro, alkyl (optionally substituted by one or more halogen or alkoxy (optionally substituted by one or more Halogens), R4- other than unbranched alkyl with 2 to 4 carbon atoms;

(D) when n=0,1 or 2, R1, R2and R3is independently H or alkyl>11is independently H, halogen, nitro, alkyl, alkoxy or trifluoromethyl, and the other of R8-H11- H, R7is other than alkyl;

(E) when n=0, R1-R4, R6-R8and R10-R11- all H, and R5- H or bromacetyl, R9is other than H or alkoxy with 1-3 carbon atoms;

(F) when n=0 or 1, R1-R4, R6and R7is independently H or alkyl, and one of R8or R9and one of R9or R10- independently H; halogen, cyano, nitro, alkyl, alkoxy, alkanoyl or alkanoyloxy, and the remaining one of R8or R9- H or chlorine and the remaining one of R9-R10- H, R5is other than H, alkyl or alkanoyl;

(G) when n= 0, and R1-R4and R6-R11- all H, then R5is other than H or benzoyl;

(H) when n=0, R1-R3and R6-R11all H, and R4- H or methyl, R5- other than dichloracetyl, when n=1 or 2, and R1-R3and R5-R11- all H, then R4is other than H or methyl, and when n=1 or 2, and R1-R11- all H, then the salt of the compounds of formula I other than the hydrochloride.

Preferred compounds of formula I or II are those in which (with the above-mentioned conditions (I) and (II):

n=0 or 1;

R1natural pose imino, methylimino, phenylimino, hydroxyimino or methoxyimino;

R5H or methyl, and when R3and R4- H or methyl, R5- formyl, acetyl, propionyl, benzoyl, methylsulfonyl, methyl-sulfonyl or ethylsulfonyl;

one of the radicals R8-R11- H, fluorine, chlorine, bromine, iodine, methyl (optionally substituted by one or more Halogens), methoxy (optionally substituted by one or more Halogens), nitro, cyano, carboxy, acetyl, dimethylcarbamoyl, or dimethylsulphamoyl, and the rest of the radicals R8-R11- H, their stereoisomers, their pharmaceutically acceptable salts.

More preferred compounds of formula I or II are those in which (with the above-mentioned conditions (I) and (II):

n=0 or 1;

R1, R2, R6and R7- H, R3and R4- H or together - methyl-imino, phenylimino, hydroxyimino or methoxyimino;

R5- H or methyl, and when R3and R4- H, R5formyl, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulphonyl, or ethylsulfonyl;

R8is methyl, fluorine or chlorine;

R9-R11all H; their stereoisomers and pharmaceutical acceptable salts.

Specific compounds of formula 1 is Yaseen,

6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

4-acetyl-2,3,4,5-tetrahydro-2,4-benzodiazepin,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,8-benzothiazepin,

4-acetyl-6-fluoro-2,3,4,,5-tetrahydro-1,4-benzothiazepin,

4-acetyl-6-methyl-2,3,4,5-tetrahydro-1.4-benzodiazepin,

4-propionyl 2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-4-propionyl 2,3,3,5-tetrahydro-1,4-benzothiazepin,

4-benzoyl-6-chloro-2,3,4,4-tetrahydro-1,4-benzothiazepin,

6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

3 hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin,

3 hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepin,

3 methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin,

6-chloro-3-methoxyimino-2,3,4,,4,5-tetrahydro-1,4-benzothiazepin

their stereoisomers, their pharmaceutically acceptable salts.

Specific compounds of formula 1 or 2, in which n=1, are:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-tetrahydro-1,4 - benzothiazepine-1-oxide,

their stereoisomers and

their pharmaceutically acceptable salts

It is clear that the group containing a chain of three or more carbon atoms, can be unbranched or branched. Used in the description of the term "halogen" means fluorine, chlorine, bromine and iodine.

Some compounds of formula I or II can form salts with organic and inorganic acids. The link below for the compounds of formula 1 or 2 includes all such salts of compounds of formula I or II, which are pharmaceutically acceptable. Particularly suitable salts of the compounds of formula I or II are, for example, salts of inorganic acids, such as hydroxychloride, hydrobromide, hydroiodide, nitrates, sulphates and phosphates, organic acid salts, for example, maleate, acetates, CII amino acids, such as glutamic acid. It is clear that such salts, if they are pharmaceutically acceptable, may be used for the treatment instead of the corresponding compounds of the formula I or II. Such salt is produced by interaction of the compounds of formula I or II with a suitable acid in a traditional way.

Some compounds of formula I or II or their salts may exist in more than one crystal form and the present invention covers each crystal form and mixtures thereof.

Some compounds of formula I or II or their salts may also exist in the form of a solvate (e.g. hydrate), and the mixture. The present invention covers each MES and their salts.

For specialists in this field it is clear that some of the compounds of formula I or II contain one or more chiral centers. For example, the compounds of formula I or II in which n=1, have a chiral center at the sulfur atom, the compounds of formula I or 2, in which R1and R2not the same, contain a chiral center at the carbon atom in position 2, the compounds of formula I or 2, in which R3and R4not the same, have a chiral center at the carbon atom in position 3 and the compounds of formula I or II in which Ris like one chiral center may exist in two enantiomeric forms. The present invention covers each enantiomer of compounds of formula I or II and a mixture of enantiomers.

Enantiomers can be obtained well-known to specialists in this field means. Such methods typically include:

separation through education diastereoisomeric salts or complexes which may be separated, for example by crystallization,

education diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid chromatography and liquid chromatography, followed by separation in a free form the desired enantiomer of the separated derivative,

selective formation of derivatives of one enantiomer by reaction with an enantiomer-specific reagent, for example enzymatic esterification, oxidation, or restoration, followed by separation of the modified and unmodified enantiomers, or

gas-liquid chromatography or liquid chromatography in a chiral environment, for example on a chiral medium such as silicon dioxide, with a bound chiral ligand or in the presence of a chiral solvent.

In accordance with another variations is active reagents, substrates, catalysts or solvents, or to convert one enantiomer to the other by asymmetric transformation.

When the compound of formula I or II contains more than one chiral center, it may be then reduced to diastereoisomeric forms. Diastereoisomer pairs can be separated by known experts in the field of technology of ways, for example by chromatography or crystallization, and individual enantiomers in each pair can be separated as described above. The present invention covers every diastereoisomer compounds of the formula I or II and a mixture of diastereoisomers.

It is clear that the transformation of the active part by performing the above-described methods of separation may be necessary to convert this product back into the active part.

Some compounds of formula I or II may exist in different tautomeric forms or as different geometric isomers, for example, when R3and R4together represent a group of formula = NP12. The present invention covers every tautomer and/or geometric isomers and mixtures thereof.

Some compounds of formula I or II may exist in zwitterionic is eenie also concerns pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I or II together with a pharmaceutically acceptable diluent or excipient. Such pharmaceutical compositions can be used as neuroprogenitors means for protection from conditions such as paralysis and/or for the treatment of seizures and/or neurological disorders such as epilepsy. Specific compounds which may be included in compositions in accordance with the present invention, are the compounds referred to in this description as examples.

Used hereinafter, the term "active compound" means one or more compounds of the formula I or II. Therapeutic application of the active compound may be introduced into the body orally, rectally, or parenterally, preferably orally. Therefore, therapeutic composition in accordance with the present invention can be performed in any known dosage form for such methods of administration. The composition can be made known to experts in the field of technology in the forms of providing modified release (for example, rapid or prolonged release) active soedineny in the field of pharmacy. The composition can contain from about 0.1% to about 99% by weight of active compound and is usually made in the form of single dose. A single dose of the active component is preferably from about 1 mg to about 1000 mg Used in the manufacture of these compositions fillers and excipients known in the field of pharmacy.

Compositions in accordance with the present invention are preferably administered orally in the known pharmaceutical forms for such administration. Dosage forms suitable for oral administration may include tablets, pills, capsules, pills, granules, powders, elixirs, syrups, solutions, aqueous or oil suspensions.

Solid dosage forms for oral administration such as tablets, can be manufactured by mixing the active compounds with one or more of the following components:

inert fillers, for example lactose, powder sugar, pharmaceutical grade starch, kaolin, mannitol, calcium phosphate or calcium sulfate.

loosening substances, such as corn starch, methylcellulose, agar, bentonite, pulp, wood products, alginic acid, diatomaceous earth which measures stearate, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, or polyethylene glycol,

binders, for example starch, gelatin, sugars (such as sucrose, molasses or lactose) or natural or synthetic resins such as the resin of acacia, sodium alginate, extract of Irish moss, carboxymethylcellulose, methylcellulose, ethylcellulose, polyethylene glycol, waxes, microcrystalline cellulose or polyvinylpyrrolidone)

colorants, such as conventional pharmaceutically acceptable dyes,

sweetening and flavouring agents, preservatives, and

other optional components known in the manufacture of oral dosage forms by known methods, such as tableting.

Solid oral dosage forms can be manufactured by well-known specialists in the field of technology way with providing a gradual release of the compounds in accordance with the present invention. For example, tablets or pills can be optionally equipped with an external coating applied by known methods, for example, by using acetylcellulose and/or hydroxypropylmethylcellulose the active compound with added excipients or without them, for example, fatty oil, can be produced by traditional methods and, if necessary, can be provided in a known manner topcoats. The content of soft gelatin capsules can be prepared by known methods by providing a gradual release of the active compounds. Depending on the nature of the active compound desired can be solid oral dosage forms with an external coating containing compositions in accordance with the present invention. For coverage or other modification of the physical form of oral dosage forms can be used in a variety of materials, such as shellac and/or sugar.

Liquid oral dosage forms containing the composition in accordance with the present invention, may be made in the form of elixirs, solutions, suspensions or syrups, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agents, such as sodium carboxymethylcellulose, or oily suspensions containing a compound in accordance with the present invention in a suitable vegetable oil, such as peanut or sunflower oil. LM the VA and/or preservatives.

The active compound can be prepared in the form of granules or powders with excipients and fillers or without them. The patient can take granules or powders inside directly, or before you can add them to a suitable liquid carrier (e.g. water). Granules or powders may contain leavening agents (e.g., pharmaceutically acceptable effervescent couple, formed from the acid and the carbonate or bicarbonate salt) to facilitate dissolution of the dosage form in a liquid medium.

Each of the above-described oral dosage forms may contain from about 1 mg to about 1000 mg of active compound.

Compositions in accordance with the present invention can be introduced into the body of the patient rectally in a known pharmaceutical forms for such administration, for example in the form of suppositories with solid fat basics of using semi-synthetic glycerides, cocoa butter or polyethylene glycol.

Compositions in accordance with the present invention may be introduced parenterally (for example, by intravenous injection) in the known pharmaceutical forms for such administration, for example in the form of STERI"ptx2">

The active compound can also be introduced by continuous infusion either from an external source (e.g., intravenous infusion), or from a source placed in the patient's body. Internal sources include implanted reservoirs containing input connection, which is continuously released, for example, by osmosis) or implant. Implants can be a liquid such as a suspension or solution in a pharmaceutically acceptable oil input connection (for example, in the form of a very sparingly water-soluble derivative such as a salt or an ester of dodecanoic). Implants can be solid in the form of an implanted device, such as a synthetic resin or waxy material) to pour the connection. The media can be a single body that contains all the connection, or a group of separate bodies, each of which contains part delivered into the body connection. The number of active connections in the internal source should be such that a therapeutically effective amount of the compounds were delivered over a long period of time.

In the manufacture of some dosage forms may be advantageous and is ASTIC very small size, such as is produced by grinding on a slender mill.

In the above compositions the active compound may be combined with other compatible pharmacologically active ingredients.

In accordance with the present invention also proposes the use of compounds of the formula I or II to obtain drugs for the treatment of seizures and/or neurological disorders such as epilepsy, and/or to protect the nervous system with the purpose of protection from conditions such as paralysis.

And in accordance with the present invention offers a method for the treatment of seizures and/or neurological disorders such as epilepsy, and/or a way to protect the nervous system with the purpose of protection from conditions such as paralysis, which contains the introduction into the body of a patient in need thereof a therapeutically effective amount of compounds of the formula I or II and/or pharmaceutical compositions containing a therapeutically effective amount of compounds of the formula I or II. Thus, the compounds of formula I or II are suitable for the prevention of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors the organisations, entered in the above-mentioned methods of treatment depends on many factors, such as severity of condition, age and previous medical history of the patient and is always based on the choice of the attending physician, a suitable daily dose of the compounds of formula I or 11 for introduction into the human body is usually from about 1 mg to about 5000 mg, and more appropriate from about 5 mg to about 1000 mg, and entered as single dose or divided doses, administered one or more times during the day. It is preferable to oral administration.

The compounds of formula I or II can be used in adjunctive therapy with one or more other compounds exhibiting activity in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means for protection from conditions such as paralysis. It is clear that the term "therapy" used in this description covers prophylactic use of compounds of the formula I or II and pharmaceutical compositions containing the compounds of formula I or II, for example, as neuroprogenitors funds for protection from conditions such as paralysis, or before the mules I or II, can be used to provide local and/or systemic therapeutic effect.

therapeutic activity of the compounds of formula I or II appear by testing standard laboratory animals. Such tests include, for example, the following test anticonvulsant activity in mice.

The following describes methods for obtaining compounds of formula I or II. These methods are also part of the present invention

The compounds of formula I or II, when R3and R4both H and R5Is H or alkyl, can be obtained by recovering the compounds of formula III

< / BR>
where

R5Is H or alkyl, regenerating agent, for example, sociallyengaged or complex with borane-dimethyl sulfide Compounds of the formula III are known and can be obtained as described in the application WO 92/21668 international patent.

The compounds of formula I or II, when R3and R4together represent a group of formula = NR12can be obtained by the interaction of the compounds of formula IV

< / BR>
with the compound of the formula R12NH2.

The compounds of formula I or II, when R3and R4together represent a group with ghoniem formula R12NH2.

The compounds of formula I or II, when R3and R4together represent alkoxyimino can be obtained by the interaction of the compounds of formula I or II where R3and R4together represent hydroxyimino, with an alkylating agent such as alkylsulfate.

The compounds of formula I or II, when R3and R4- H, or alkyl, and R5- alkyl, can be obtained by alkylation of compounds of formula I or II where R5for example, H, using an alkylating agent such as alkylhalogenide or reductive alkylation with an aldehyde or ketone and formic acid or regenerating agent, such as lambrogini sodium, or restoring the compounds of formula I or II where R5group of the formula - COR13.

The compounds of formula I or II, when R5group of the formula - COR13can be obtained by acylation of compounds of formula I or II where n = 0 or 2 and R5- H, for example, the acid chloride of formula R13COCl, the acid anhydride of formula (R13CO)2O or acid of the formula R13CO2H.

The compounds of formula I or II, when R5is a group of formula S(O)pR14can be obtained from the interaction of the/SUB>SO2Cl, or sulfonylureas agent such as sulphonylchloride formula R14SOCl. For example, the compounds of formula I or II, when R5represents a group-SO2Me, can be obtained by the coupling of compounds of formula I or II where R5-H, methanesulfonanilide.

The compounds of formula I or II when n=1, can be obtained by oxidation of compounds of formula I or II where n=0, for example, using periodate sodium or 3-chlormadinone acid.

The compounds of formula I or II, when n= 2, can be obtained by oxidation of compounds of formula I or II where n=0 or 1, for example, with peracetic or 3-chlormadinone acid.

The compounds of formula IV can be obtained by the interaction of the compounds of formula III with reagents such as pentasulfide phosphorus or reagent Loison [which is a known compound 2,4-bis (4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide].

The compounds of formula V can be obtained by the interaction of the compounds of formula III with gloriouse agent, such as pentachloride phosphorus or phosphorylchloride.

Anticonvulsant activity of the compounds of formula I or II has been demonstrated lyrics by the formula I or II to counteract convulsive seizures, caused by the introduction of (+)-bicuculline. Next, this test is referred to as "BICM

When BICM-test group mice-females weighing from 25 to 30 grams had free access to food and water for one hour prior to injection of the test compounds of formula I or II. The test compound is administered orally in single or multiple doses in a 1% aqueous solution of methylcellulose. An hour later, were injected intravenously into the tail vein of (+)-bicucullin with a dose of 0.55 mg/kg is Generally considered that such a dose of (+)-bicuculline should call in mice attack.

In the next two minutes was observed for the animals and recorded the percentage of animals whose seizures were suppressed. With higher anticonvulsant activity of the compounds, the higher was recorded interest in BICM-test. If more than one dose value for the dose that reduces seizures in 50% of animals (ED50), was calculated from the straight line graph of a regression of the percentage of animals whose seizures were suppressed, depending on the administered dose of the compounds of formula I or II.

The second test anticonvulsant activity included monitoring the ability of the compound to inhibit mice seizures caused maximum electroo 30 grams had free access to food and water for one hour prior to injection of the test compounds of formula I or II. The test compound is administered orally in single or multiple doses in a 1% aqueous solution of methylcellulose. An hour later mice were affected by a shock with a duration of 1.0 s through ear electrodes. Electric shock had power 99 mA, a frequency of 50 Hz and pulse duration of 0.4 MS. It is usually assumed that such a punch in mice attack.

In the next two minutes was observed for the animals and recorded the percentage of animals whose seizures were suppressed. The higher anticonvulsant activity of the compounds, the higher was registered interest in MESM-test. If more than one dose value for the dose that reduces seizures in 50% of animals (ED50), was calculated from the straight line graph of a regression of the percentage of animals whose seizures were suppressed, depending on the administered dose of the compounds of formula I or II.

It was found that the compounds of formula I or II described later in examples 1-31, exhibit anticonvulsant activity when at least one of the tests BICM and MESM.

Further, the present invention is illustrated in the following non-limiting examples. The final product of each example horoscope, spectroscopy nuclear magnetic resonance and/or liquid chromatography. Temperatures are given in degrees Celsius.

Example 1. To a stirred solution of sociallyengaged (5,01 g) in dry tetrahydrofuran (400 ml) was added 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-he (9,8 g, obtained as described in example 11 application WO 92/21668 international patent). After the addition the reaction mixture was heated under reflux for five minutes and cooled. Excess sociallyengaged was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered and the filter solvent was removed by evaporation. The residue was dissolved in diethyl ether, acidified with gaseous hydrogen chloride, and the precipitated hydrochloride of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine was collected by filtration and recrystallized from ethanol. Yield 6.5 g (so pl. 244 - 246oC.

Under the above BICM-test ED50for this connection was 8.2 mg/kg

Example 2. To a stirred solution of sociallyengaged (5,01 g) in dry tetrahydrofuran (400 ml) was added 6-chloro-4,5-dihydro-1,4-benzothiazepin-3-(2H)-he (9,8 g, obtained as described in example 11 application WO 92/21668 on international patli. Excess sociallyengaged was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered and from the filtrate the solvent evaporated, resulting in 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin in the form of butter.

To a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2,88 g, obtained as described in the preceding paragraph) in dichloromethane (75 ml) was added dropwise with cooling to a solution of periodate sodium (3,09 g) in water (25 ml). Stirring was continued at room temperature for 10 hours was Removed from the mixture of the solvent by evaporation under reduced pressure. Purification of the residue by flash chromatography using as eluent a mixture (95: 5) dichloromethane and ethanol gave 1-oxide, 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine that precrystallization of ethyl acetate. Yield 2.15 g (so pl. 125-126oC).

In the description above BICM-test ED50for this connection amounted to 2.7 mg/kg

Example 3. To a stirred solution of sociallyengaged (5 g) in dry tetrahydrofuran (500 ml) was added 6-fluoro-4,5-dihydro-1,4-benzothiazepin-3(2H)-he (9 g, obtained as described in example 5 application WO 92/21668 international patent) After adding reaclied was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered, and the filtrate solvent was removed by evaporation, resulting in an oil which was dissolved in diethyl ether and acidified with gaseous hydrogen chloride. The precipitated hydrochloride of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine was collected by filtration and recrystallized from ethanol. The output of the 7.43 g (so pl. 265-268oC).

Under the above BICM-test ED50for this connection amounted to 17.7 mg/kg

Example 4. To a stirred solution of sociallyengaged (3,38 g) in dry tetrahydrofuran (340 ml) was added 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-he(6 g, obtained as described in example 13 application WO 92/21668 international patent). After the addition the reaction mixture was heated under reflux for ten minutes and cooled. Excess sociallyengaged was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered, and the filtrate solvent was removed by evaporation. The residue was dissolved in diethyl ether, acidified with gaseous chlorine-hydrogen, and the precipitated hydrochloride of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine was collected by filtration and recrystallized from ethanol. Output 2,87 g (so pl. 249-250othe example 5. To a stirred suspension of sodium hydride (0.6 g) in dimethyl sulfoxide (20 ml) was slowly added at room temperature a solution of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-she (5,33 g, obtained as described in example 11 application WO 92/21668 international patent) in dry dimethylsulfoxide (60 ml). After complete addition, the mixture was stirred for 30 min before adding dropwise under the conditions (6 ml), the reaction mixture was stirred at room temperature for one hour, was added water (160 ml) and the resulting mass was extracted with diethyl ether. The organic layer was washed with water, and removed from him the solvent by evaporation. Purification of the residue by flash chromatography using a mixture of (9,8:0,2) dichloromethane and ethyl acetate as eluent gave 6-chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-he. Yield 3.8 g (so pl. 122-125oC)

6-Chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-he (3.8 g) was added to a stirred solution of sociallyengaged (1.92 g) in dry tetrahydrofuran (160 ml). After the addition the reaction mixture was heated under reflux for 15 min and cooled. Excess sociallyengaged was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered, W as eluent a mixture of 9.5: 0.5) with dichloromethane and ethanol gave an oil (2,62 g), which was dissolved in diethyl ether and acidified with gaseous hydrogen chloride. The precipitated hydrochloride of 6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine was filtered and recrystallized from a mixture of ethanol and diethyl ether. The output of 2.38 g (so pl. 209-211oC).

In the description above test BICM dose of 100 mg/kg of this compound suppressed to fit in 50% of tested mice.

Example 6. To a stirred solution of sociallyengaged (6.3 g) in dry tetrahydrofuran (400 ml) was added 4,5-dihydro-1,4-benzothiazepin-3(2H)-he (12 g, obtained as described in example 1 application WO 92/21668 international patent). The resulting reaction mixture was heated under reflux for ten minutes and cooled. Excess sociallyengaged was dissolved by addition of a saturated aqueous solution of sodium sulfate. The mixture was filtered, and the filtrate solvent was removed by evaporation, resulting in 2,3,4,5-tetrahydro-1,4-benzothiazepin in the form of oil, which was used without further purification. The output of 9.4 g

A mixture of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4,56 g) in formic acid (20 ml) and toluene (60 ml) was heated under reflux at 90oC for 4 h and then at 120oC-chromatography using dichloromethane as eluent gave 4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which is recrystallized from hexane. The output of 3.73 g (so pl. 84-87oC).

Under the above BICM-test ED50for this connection amounted to 17.9 mg/kg

Example 7. A solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (1.5 g obtained as described in the first paragraph of the above-described example 6) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried, and removed from him the solvent by evaporation resulting in 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepin the connection is known as a catalyst of the Friedel-craft from example 46 EP 0368063.

The product was recrystallized from hexane. Yield 1.55 g (so pl. 69-70oC).

Under the above BICM-test ED50for this connection amounted to 65.7 mg/kg

Example 8. To a stirred solution of 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1,03 g, obtained as described above in example 7) in dichloromethane (50 ml) was added dropwise while cooling from 0 to -2oC solution of 3-chlormadinone acid (1,03 g) in dichloromethane (100 ml). The reaction mixture was stirred 15 min, then washed with water, drained and cleaned out resuelta mixture (9:1) of dichloromethane and ethanol gave 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide, which is recrystallized their ethyl acetate. The yield of 0.67 g (so pl. 156-157oC).

Under the above BICM-test ED50for this connection was of 37.8 mg/kg

Example 9. A solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.6 g, analogously to its hydrochloride in the above example 1) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried, and removed from him the solvent by evaporation, resulting in 4-acetyl-6-chloro-2,3,4,5-tetrahydro 1,4-benzodiazepine, which was precrystallizer from hexane. Yield 1.68 g (so pl. 79-81oC).

Under the above BICM-test ED50for this connection was 4.6 mg/kg

Under the above MESM-test ED50for this connection amounted to 48.5 mg/kg

Example 10. To a stirred solution of 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1,34 g, obtained as in the above example 9) in dichloromethane (50 ml) was added dropwise while cooling from 0 to -2oC solution of 3-chloro-adventurou acid (1,14 g) in dichloromethane (100 ml). The reaction mixture was stirred for 15 minutes, washed with water, chromatographia using as eluent a mixture (95:5) dichloromethane and ethanol gave 4-acetyl--6-chloro-2,3,4,5-tetrahydro-1,4 benzothiazepine-1-oxide, which is recrystallized from ethyl acetate. The yield of 1.15 g (so pl. 119-121oC).

Under the above test BICM ED50for this connection was 22.6 mg/kg

Under the above MESM-test ED50for this connection was 52.8 mg/kg

Example 11. A solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2,04 g similar to the hydrochloride in the above example 3) in acetic anhydride (22 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried, and removed from him the solvent by evaporation. Purification of the residue by flash chromatography using as eluent a mixture (97:3) dichloromethane and ethanol gave 4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepin in the form of oil. The output of 1.7 g

Under the above BICM-test ED50for this connection amounted to 21.5 mg/kg

Example 12. A solution of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0,91 g, obtained as its hydrochloride in the above example 4) in acetic anhydride (10 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which is recrystallized from hexane. The output of 0.93 g (so pl. 71-73oC).

Under the above BICM-test ED50for this connection was 49.4 mg/kg

Under the above MESM-test dose of 100 mg/kg of this compound suppressed seizures in 50% of exposed test mice.

Example 13. To a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (8,58 g, obtained as described in the above example 6) in dichloromethane (100 m) was added dropwise at room temperature a solution of propionitrile (2,39) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 45 min, washed with water and dried, then removed from the solvent by evaporation. Purification of the residue by flash chromatography using as eluent a mixture (98:2) dichloromethane and ethanol gave 4-propionyl 2,3,4,5-tetrahydro-1,4-benzothiazepin in the form of oil. The output of 2.9 g

Under the above BICM-test ED50for this connection amounted to 48.1 mg/kg

Example 14. To a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1,99 was obtained analogously to its hydrochloride in the above example 1) and triethylamine (1.01 g) in dichloromethane ment the mixture was stirred at room temperature for 30 min, washed with water, drained, and cleaned out the solvent by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-chloro-4-propionyl 2,3,4,5-tetrahydro-1,4-benzothiazepin, which was precrystallizer from hexane. The output of 1.14 g (so pl. 55-57oC).

Under the above BICM-test ED50for this connection amounted to 44.7 mg/kg

Example 15. To a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, obtained as its hydrochloride in the above example 1) and triethylamine (2,82 g) in dichloromethane (100 ml) was added dropwise at room temperature a solution of benzoyl chloride (3,93 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 15 minutes, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4 benzodiazepin, which was precrystallization from a mixture of ethanol and water. Output to 5.93 g (so pl. 64-72oC).

Under the above BICM-test ED50for this connection amounted to 49.2 mg/kg

Example 16. To the mix is use example 1) and triethylamine (1.01 g) in dichloromethane (50 ml) was added dropwise at room temperature a solution of methanesulfonamide (0.98 g) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using as eluent a mixture (98:2) dichloromethane and ethanol gave 6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro,4-benzodiazepin, which was recrystallized from a mixture of ethyl acetate and hexane. Yield 2.1 g (so pl. 82-84oC).

Under the above BICM-test ED50for this connection amounted to 19.6 mg/kg

Example 17. To a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.8 g), obtained as described in the first paragraph of the above example 6) and triethylamine (2.9 g) in dichloromethane (100 ml) was added dropwise at room temperature a solution of methanesulfonamide (3.3 grams) in dichloromethane (15 ml) the Reaction mixture was stirred at room temperature for one hour, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was recrystallized from hexane. Yield 3 g (so pl. 98-100oC).

If opisannaya ED50for this connection amounted to 51.6 mg/kg

Example 18. To a stirred solution of 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1, obtained as described above in example 17) in dichloromethane (50 ml) was added dropwise while cooling from 0oC to -2oC solution of 3-chlormadinone acid (1.4 g) in dichloromethane (200 ml). The reaction mixture was stirred for 15 minutes, washed with water, drained and removed from the solvent by evaporation under reduced pressure. Purification of the residue by flash chromatography using as eluent a mixture (95:5) dichloromethane and ethanol gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide, which was recrystallized from standard. The output of 1.65 g (so pl. 195 - 197oC)

Under the above BICM-test ED50for this connection amounted to 27.4 mg/kg

Example 19. To a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5,2 g, obtained as its hydrochloride in the above example 1) and triethylamine (3.03 g of 0.03 ml) in dichloromethane (100 ml) was added dropwise at room temperature a solution of methanesulfonamide (3,43 g) in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for cartografia using dichloromethane as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which is recrystallized from hexane.

The output of the 6.06 g (so pl. 85 - 86oC).

Under the above BICM-test ED50for this connection amounted to 41.3 mg/kg

Under the above MESM-test ED50for this connection was 19.5 mg/kg

Example 20. To a stirred solution of 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin (3,05 g, obtained as described in the above example 19) in dichloromethane (100 ml) was added dropwise while cooling from 0oC to -20oC solution chloracetic acid and 2.26) in dichloromethane (150 ml). The reaction mixture was stirred for 15 minutes, washed with water and dried, after which the solvent was removed by evaporation under reduced pressure. Purification of the residue by flash chromatography using as eluent a mixture (95: 5) dichloromethane and ethanol gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide, which was recrystallized from ethyl acetate. Yield 2.86 g (so pl. 167 - 169oC).

Under the above BICM-test ED50for this connection amounted to 36.2 mg/kg

Under the above MESM-test ED50for this connection amounted to 31.9 mg/kg

Example 21. To paramashiva the m above example 3) and triethylamine (1.6 g) in dichloromethane (60 ml) was added dropwise at room temperature a solution of methanesulfonamide (1,83 g) in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for 20 min, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzazepin, which was recrystallized from hexane. The yield of 3.3 g (so pl. 115 - 117oC)

Under the above BUCM-test ED50for this connection amounted to 33.8 mg/kg

When above ME M-test ED50for this connection amounted to 30.5 mg/kg

Example 22. To a stirred solution of 6-methyl-2,3.4,5-tetrahydro-1,4-benzothiazepin (2 g, obtained as its hydrochloride in the above example 4) and triethylamine (1.51 g) in dichloromethane (30 ml) was added dropwise at room temperature a solution of methanesulfonamide (1,69 g) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent Dala-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was recrystallized from I this compound was 116,3 mg/kg).

Under the above MESM-test ED50for this connection amounted to 102.2 mg/kg

Example 23. To a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4,29 g obtained as described in the first paragraph above example 6) and dichloromethane (100 ml) was added dropwise at room temperature a solution of acanaloniidae (3.8 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, drained and removed from the solvent by evaporation. Purification of the residue by flash chromatography using trichloromethane as eluent gave 4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was recrystallized from hexane. The output of 4.25 g (so pl. 78 - 80oC)

Under the above MESM-test ED50for this connection was 22.3 mg/kg

Example 24. To a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1,99 g, obtained as its hydrochloride in the above example 1) and triethylamine (1.01 g) in dichloromethane (50 ml) was added dropwise at room temperature a solution of acanaloniidae (1.28 g) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature teces-chromatography using dichloromethane as eluent gave 4-ethylsulfonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was precrystallization from a mixture of ethyl acetate and hexane.

The output of 2.53 (so pl. 126 - 128oC)

Under the above BICM-test ED50for this connection was $ 90.4 mg/kg

Under the above MESM-test ED50for this connection amounted to 35.1 mg/kg

Example 25. Stir a mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-she (1,79 g, obtained as described in example 1 application WO 92/21668 international patent) and reagent Loison (2,22 g) in dry toluene (100 ml) was heated at 100oC for 3 hours the Mixture was allowed to cool to room temperature. The precipitated solid was filtered, washed with toluene and dried, resulting in a 4.5-dihydro-1,4-benzothiazepin-3(2H)-tion. Yield 1.78 g (so pl. 215 - 219oC)

A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (1.56 g) hydroxylaminopurine (0,83 g) and sodium acetate (0,98 g) in dry standard (100 ml) was heated under reflux for three hours. The mixture was cooled and the precipitated solid was filtered and washed with water. Purification of the precipitate by flash chromatography using as eluent a mixture (95: 5) dichloromethane and ethanol gave 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin, kotori
for this connection amounted to 31.5 mg/kg

Example 26. Stir a mixture of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-she (4,27 g, obtained as described in example 11 application WO 92/21668 international patent) and reagent Loison (4,90 g) in dry toluene (170 ml) was heated under reflux for one hour. The reaction mixture was cooled to room temperature and precipitated 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-tion was filtered, washed with toluene and dried. The output of 4.16 g (so pl. 210 - 212oC)

Stir a mixture of 6-chloro-4,5-dihydro-1.4-benzothiazepin-3(2H)-thione (3,90 g) hydroxylaminopurine (1.77 g) and sodium acetate (2,09 g) in dry ethanol (175 ml) was heated under reflux for one hour. The reaction mixture was cooled, and the precipitated 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzodioxepin was filtered, washed with water and recrystallized from ethanol. Yield 2.6 g (so pl. 180-183oC)

Under the above BICM-test ED50for this connection was 5.0 mg/kg

Example 27. Stir a mixture of 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-she (3,26 g, obtained as described in example 13 application WO 92/21668 international patent) and reagent Loison (3,93 g) in dry toluene (y and precipitated 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-tion was filtered, washed with toluene and dried. Output 3,30 g (so pl. 228-230oC)

Stir a mixture of 6-methyl-4,5-gedida-1,4-benzothiazepin-3(2H)-thione (3.13 g) hydroxylaminopurine (1.56 g) and sodium acetate (1.84 g) in dry ethanol (175 ml) was heated under reflux for one hour. The reaction mixture was cooled and the precipitated 3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepin was filtered, washed with water and recrystallized from ethanol. The output of 2.23 g (so pl. 188-190oC)

Under the above BICM-test ED50for this connection amounted to 20.1 mg/kg

Example 28. To intensively stirred suspension of 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2G, obtained as described in the above example 25) in a mixture of 10% aqueous sodium hydroxide solution (4 ml) and ethanol (150 ml) was added dropwise dimethylsulfate (1.26 g). The reaction mixture was kept at room temperature for 24 h, then was extracted with dichloromethane. The organic layer was dried, and removed from him the solvent by evaporation. Purification of the solid residue by flash chromatography using dichloromethane as eluent gave 3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin, which precrystallization is for this solid connection was 58.1 mg/kg

Example 29. To a suspension of 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzodioxepine (to 2.29 g obtained as described in the above example 26) in the standard (150 ml) was added 10% aqueous sodium hydroxide solution (4 ml). After 15 min, to the mixture was added dropwise dimethylsulfate (1,33 g) the Reaction mixture was stirred at room temperature for 22 h, after which it was removed the solvent by evaporation under reduced pressure. Purification by chromatography on silica gel using as serial alantolactone, and then the mixture (97:3) dichloromethane and ethanol gave 6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was recrystallized from n-hexane. The output of 1.21 g (so pl. 120-121oC)

Under the above BICM - test dose of 100 mg/kg of this compound suppressed seizures in 50% of exposed test mice.

Example 30. A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-it (lower than the 5.37 g) obtained as described in example 1 application WO 92/21668, international patent) and pentachloride phosphorus (6.3 g) in dry toluene was heated at 50oC for two hours. Wasp Albanian product was filtered, washed with toluene and dried, resulting in 3-chloro-2,5-dihydro-1,4-benzothiazepin. The output of 5.2 g (is>/P>3-Chloro-2,5-dihydro-1,4-benzothiazepin (5g) and 33% solution of methylamine in absolute ethanol (150 ml) was heated under reflux for one hour. The mixture was cooled and filtered. Purification of the residue by flash chromatography using as eluent a mixture (1:1) of ethyl acetate and ethanol gave 3 - methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepin, which was recrystallized from ethanol. The yield of 0.51 g (so pl. 278-280oC)

In the description above BICM-test ED50for this connection amounted to 20.8 mg/kg

Example 31. To a stirred suspension of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-she (6.0 g, obtained as described in example 1 application WO 92/21668 international patent) in dry toluene (450 ml) was added parts of pentachloride phosphorus (of 5.84 g). Then the reaction mixture was heated in an oil bath at 50-60oC for 5 1/2 hours After cooling was filtered crude residue 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine and washed his toluene. The output of 4.5 G. of This crude product was used in the next stage without further purification.

To a stirred solution of 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine (2.5 g) in dry ethanol (65 ml) was added dropwise at room temperature a solution of aniline (4,8 anatoy temperature, was filtered and from the filtrate solvent was removed by evaporation under reduced pressure. The oily residue was separated into fractions by chromatography on silica gel using as eluent a mixture (50:1) of chloroform and ethanol. Purification of these fractions containing the product by flash chromatography using as eluent a mixture (2:3) ethyl acetate and hexane gave 6-chloro-3-phenylimino-2.3,4,5-tetrahydro-1,4-benzothiazepin that precrystallization from a mixture of ethyl acetate and hexane. Yield 0.27 g (so pl. 150-152oC)

Under the above BICM-test ED50for this connection was 16,3,

1. 2,3,4,5-tetrahydro-1,4-benzothiazepine General formula II

< / BR>
their stereoisomers or their pharmaceutically acceptable salt,

where n = 0 or 1;

R1, R2, R6and R7- each H;

R3and R4is independently H or methyl or together imino, methylimino, phenylimino, hydroxyimino or methoxyimino;

R5Is H or methyl or, when R3and R4- H or methyl, R5- H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulphonyl or ethylsulfonyl;

R8- H, methyl, fluorine or chlorine;

R9, R10and R11each H SUB>5is not a benzoyl or acetyl, and, when n = 0 or 1 and R4is methyl, R1- R3and R5- R11- not all hydrogen.

2. 2,3,4,5-Tetrahydro-1,4-benzothiazepine General formula II under item 1, chosen from:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine,

3 hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

3 methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine or

6-chloro-3-phenylamino-2,3,4,5-tetrahydro-1,4-benzothiazepine,

their stereoisomers or pharmaceutically acceptable salts.

3. 2,3,4,5-Tetrahydro-1,4-benzothiazepin General formula II under item 1, chosen from:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,
Il-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine or

6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, their stereoisomers or pharmaceutically acceptable salts.

4. 2,3,4,5-Tetrahydro-1,4-benzothiazepin General formula II under item 1, chosen from:

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide,

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide or

6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,

their stereoisomers or pharmaceutically acceptable salts.

5. 2,3,4,5-Tetrahydro-1,4-benzothiazepin General formula II under item 1, a 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepin, its stereoisomers, or its pharmaceutically acceptable salt.

6. Pharmaceutical composition having convulsants, containing pharmaceutically acceptable diluent or carrier and an active ingredient, otlichalsa formula I

< / BR>
where n = 0, 1, or 2;

R1and R2is independently H or alkyl with 1 to 4 carbon atoms (optionally substituted by one or more Halogens);

R3and R4is independently H, alkyl with 1 to 4 carbon atoms, or together a group of the formula =NR12where R12- H, hydroxy, alkyl with 1 to 4 carbon atoms, phenyl or alkoxy with 1 to 4 carbon atoms, and each alkyl, phenyl and alkoxy optionally substituted by one or more Halogens;

R5- H, alkyl with 1 to 4 carbon atoms, a group of the formula-COR13where R13- H, alkyl with 1 to 4 carbon atoms or phenyl when R3and R4Is H or alkyl (optionally substituted by one or more Halogens), or a group of formula-S(O)pR14where p = 1 or 2, R14is alkyl with 1 to 4 carbon atoms or phenyl when R3and R4Is H or alkyl (optionally substituted by one or more Halogens), where each alkyl and phenyl optionally substituted by one or more Halogens;

R6and R7each hydrogen;

R8- R11is independently H, halogen, cyano, nitro, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkanoyl with 1 to 4 carbon atoms, carboxy, alkanoyloxy with 1 to 4 atoms of plastics technology: turning & the config by alkyl with 1 to 4 carbon atoms), each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted by one or more halogen,

its stereoisomers, or its pharmaceutically acceptable salts, provided that when n = 0, then at least one of R1- R11other than H.

7. The pharmaceutical composition according to p. 6, characterized in that it contains as active ingredient a therapeutically effective amount of the compounds of formula I, where n = 0 or 1; R1and R2is independently H or methyl; R3and R4is independently H or methyl or together imino, methylimino, phenylimino, hydroxyimino or methoxyimino; R5- H or methyl when R3and R4- H or methyl, R5is hydrogen, methyl, formid, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulphonyl or ethylsulfonyl; R6and R7- H; and one of R8- R11- H, fluorine, chlorine, bromine, iodine, methyl (optionally substituted by one or more Halogens), methoxy (optionally substituted by one or a couple of Halogens), nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl, and the remainder of R8- R11- H, its stereoisomers, or its pharmaceutically acceptable salt.

8. Farmaci ffektivnoe amount of the compounds of formula I, where n = 0 or 1; R1, R2, R6and R7- each H; R3and R4- H or together methylimino, phenylimino, hydroxyimino or methoxyimino; R5- H or methyl when R3and R4- H, R5- H, methyl, formyl, acetyl, propionyl, benzoyl, methylsulfinyl, methylsulphonyl or ethylsulfonyl; R8- H, methyl, fluorine or chlorine; R9- R11all H; its stereoisomers, or its pharmaceutically acceptable salt.

9. The pharmaceutical composition according to p. 6, characterized in that it contains as active ingredient a therapeutically effective amount of the compounds of formula I, selected from:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide;

6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide;

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide;

4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-6-met the Il-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-methylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide;

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide;

6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-ethylsulfonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3 hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3 hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3 methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3 methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

their stereoisomers or their pharmaceutically acceptable salts.

10. The compound of formula II according to any one of paragraphs.1 to 5 showing anticonvulsant activity.

B>7, R8, R9, R10, R11and n take the values defined in paragraph 1;

R3and R4both H;

R5- hydrogen, including the restoration of the compounds of formula III

< / BR>
where R1, R2and R6- R11take the values defined in paragraph 1;

R5is hydrogen, regenerating agent.

12. The method according to p. 11, characterized in that it further comprises the acylation of compounds of formula II, where R3and R4both hydrogen and R5is hydrogen, the acid chloride acid anhydride or acid to obtain the compounds of formula II, where R5group of the formula-COR13where R13is hydrogen, alkyl with 1 or 2 carbon atoms or phenyl.

 

Same patents:

The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

The invention relates to compounds of formula (1)

< / BR>
in which

R1is a hydrogen atom;

R2is a hydrogen atom, (C3-C12) alkenylboronic, (C3-C12)cycloalkylcarbonyl, (C3-C12)cycloalkylcarbonyl, (C3-C12)alkylcarboxylic, (C3-C12)cycloalkyl (C1-C12)alkylcarboxylic, pyridyloxy, morpholinoethoxy or tetrahydropyranyloxy, halogen(C1-C6)alkylsulfonate, (C1-C6)alkylsilane;

R3is a hydrogen atom or halogen;

R4is a hydrogen atom or a (C1-C6)alkyl, or geometric, optical or stereoisomers, or pharmaceutically acceptable additive salts, which are useful for the treatment of various memory disorders characterized by a decrease cholinergic function such as Alzheimer's disease

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

The invention relates to veterinary medicine, in particular, to methods of treatment of endometritis in cows using medicinal product prepared from peracetic acid-desoxin, in combination with the organic active substances

The invention relates to a derivative of galantamine, in particular a derivative of galantamine General formula (II)

< / BR>
in which R1represents hydrogen, (C1-C12)alkylsulphonyl, (C1-C12)alkoxycarbonyl, mono-(C1-C12)alkylaminocarbonyl or di-(C1-C12)alkylaminocarbonyl; R2represents a mono-(C1-C18)alkylaminocarbonyl or di-(C1-C8)alkylaminocarbonyl group; R3represents hydrogen or halogen; or pharmaceutically acceptable acid additive salts

The invention relates to medicine, in particular to Oncology, and for the treatment of metastatic tumors

The invention relates to Oncology, in particular, gynecology, and can be used in therapy of patients with endometrial cancer

The invention relates to medicine, namely to funds with anti-anxiety action

The invention relates to new derivatives of N-acyl-2,3-benzodiazepine General formula [I]

< / BR>
in which R is C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkylamino, di(C1-4alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s), or R is a benzoyl, cyclopropanecarbonyl, C1-5-carbarnoyl or phenylcarbamoyl group, or R is absent when the N(3) and C(4) atoms there is a double bond, R1represents a hydrogen atom, or R1no, when between N(3) and C(4) atoms there is a double bond, R2represents C1-3alkyl, or R1and R2together represent a methylene group, and between the N(3) and C(4) atoms, no double bond, R3means a hydrogen atom or a C1-4-aliphatic acyl group, R4represents a hydrogen atom, a C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkyl-amino-, di (C1-4alkyl) amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen (s), and benzoyl, Palmitoyl, cyclo who can present valence bonds, provided that, when both of the substituent R3and R4represent hydrogen atoms between the N(3) and C(4) atoms, no double bonds, as well as the stereoisomers of these compounds along with acidic salts accession (when possible) and pharmaceutical compositions containing these compounds

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

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

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

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

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