Indolinone derivatives, method of their production, intermediate compounds, pharmaceutical composition

 

(57) Abstract:

The invention relates to new indolinone derived formula, method of production thereof and to pharmaceutical compositions based on them. These compounds can be used in the treatment of disorders of the Central nervous system, cardiovascular system and gastrointestinal system in humans and animals. 4 C. and 10 C.p. f-crystals, 7 tab., 6 Il.

The invention relates to N-sulfadimidinum derivatives, method for their production and pharmaceutical compositions based on them.

Some derivatives of N-sulfanilyl[1], corresponding to the formula

< / BR>
in which

is hydrogen, alkyl, or substituted or unsubstituted phenyl;

is halogen, alkyl, -alkoxy, nitro or trifluoromethyl;

is alkyl, phenyl or alkylphenyl;

is alkyl, substituted or unsubstituted phenyl, alkoxy or phenoxy;

n' = 0, 1, or 2.

These compounds (1) are the intermediate compounds to obtain indole derivatives, which are active with respect to the Central nervous system, having the formula

< / BR>
in which

R" is alkyl, substituted or nezu, have affinity towards vasopressive and ocytocine receptors.

Vasopressin is known antidiuretic hormone action, is also known for its role in regulating blood pressure. It stimulates the activity of several types of receptors

V1V2V1AV1band thus have cardiovascular, hepatic, antidiuretic, gag and aggregation effect, and demonstrate a proliferative and mitotic effects, especially in the cardiovascular and hepatic tissues. Receptor antagonists of vasopressin can affect the regulation of the Central or peripheral circulatory disorders, especially coronary, renal and gastrointestinal blood circulation, and water metabolism and secretion of adrenocorticotropic hormone (ACTH). Vasopressin receptor like receptor ocytocine also found in the smooth muscle of the uterus. Ocytocin peptide has a structure similar to that of vasopressin. Its receptors are also found in myoepithelial cells of the mammary gland and the Central nervous system (Presse Medicale 1987, 16 (10) 481-485, J. Lab. Chin. Med. .1989, 114 (6), 617-632 and Pharmacol^Rev. 1991, 43 (1), 73-108).

Thus, soedinenii system, the cardiovascular system and in the gastric region of humans and animals.

The invention relates to indolinone derived formulas

< / BR>
in which

R1is a halogen atom, a C1-C4-alkyl, C1-C4- alkoxy;

R2C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, unsubstituted or substituted by one or more groups C1-C4-alkyl, or halogen;

R3is a hydrogen atom;

R4- carnemolla group of the formula CONR6R7;

R5-C1-C4; phenyl, unsubstituted or substituted by one or more substituents selected from halogen, C1-C4-alkyl, C1-C4-alkoxy;

R6- C1-C6-alkyl, or R6same as R7;

R7the group piperidine-4-yl, unsubstituted or substituted on the nitrogen C1-C4-alkyl, C1-C4-alkoxycarbonyl; group (CH2)r, which is itself substituted by a group of 2-, 3 - or 4-pyridyl or an amino group, a free or substituted by one or two C1-C4-alkilani, a carboxyl group, a C1-C4-alkoxycarbonyl, carbamoyl group, free or substituted by one or two C a heterocycle, choose from the research, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, piperazine unsubstituted or substituted in position 4 by a group R ' 8unsaturated 5-membered cycle containing a single nitrogen atom, substituted by the radical R8or saturated 3,4,5, or 6-membered cycle, containing a single nitrogen atom and substituted by the radicals R8and R9;

R8means R18or group (CH2)r, which is itself substituted by a hydroxyl or amino group, a free or substituted by one or two C1-C4-alkilani;

R18mean group (CH2)g, which is itself substituted by a carboxyl group, a C1-C4--alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, a free or substituted hydroxyl or one or two C1-C4-alkilani or aminocarbonyl group, free or substituted by one or two C1-C4-alkilani;

R8means R18or group (CH2)2NH2free or substituted by one or two C1-C4- -alkilani;

R9represents hydrogen, a group (CH2)rNR10R11, grouprt or C1-C4-alkyl;

n is 0,1 or 2;

m is 0,1 or 2;

q - 0,1,2 or 3;

r - is 0,1,2 or 3, provided that r is not equal to zero when R8or R9located in the alpha position relative to the intra-cyclic amide nitrogen, as well as to their possible salts.

Salts of compounds of formula (1) include salts with inorganic or organic acids which allow for the selection or crystallization of the compounds of formula (1), such as picric acid, oxalic acid, or with optically active acids, such as mandelic acid or camphorsulfonate, and with such acids which form pharmaceutically acceptable salts such as hydrochloride, gidrogensulfat, dihydrogen phosphate, methanesulfonate, maleinate, fumarate or 2-naphthalenesulfonate.

Salts of compounds of formula (1) include salts with organic or inorganic bases, for example salts of alkaline or alkaline-earth metals, such as salts of sodium, potassium or calcium, preferred are sodium and potassium salts, or amine, such as trometamol, or salts of arginine, or lysine, or any pharmaceutically acceptable amine.

Compounds (1) are CIS-trenia (1), in which R2and R4located on one side of the ring, called cisisomers.

Compounds (1), in which R2and R4located on different sides of the ring are called TRANS fats.

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In addition, the compounds corresponding to the invention, have 2 asymmetric carbon atoms or more, when R4contains 1 or 2 asymmetric carbon. Optical isomers of the compounds (1) form part of the invention.

In the present description, the halogen should be understood fluorine atom, chlorine, bromine or iodine, under the alkyl group denoted linear or branched hydrocarbon group.

Preferred compounds (1), relevant to the invention are those which satisfy the following conditions:

R1is a chlorine atom or bromine or methoxy group, and n = 1;

R2represents chlorophenyl, methoxyphenyl, or cyclohexyl;

R4is a group CONR6R7in which R6and R7or NR6R7have one of the following values:

NR6R7is pyrrolidino group which is substituted in position 2 by a group (CH2)qthat /SUB> is piperidino group, which is in position 4 is substituted amino group, a C1-C4-alkylamino or C1-C4-dialkylamino;

NR6R7is thiazolidine group, which is substituted by a group (CH2)qwhich in turn is substituted by carboxyl or carbamoyl group with a value of q= 0,1, 2, or 3.

NR6R7is pyrrolidino group which is substituted in position 2 by a group (CH2)q, which itself is substituted by carboxyl or carbamoyl group when q= 0, 1, 2 or 3 and in which position 4 is substituted amino group, a C1-C4-alkylamino or C1-C4dialkylamino,

R6represents a C1-C41-alkyl, and R7is a group (CH2)r, which is itself substituted by a carboxyl group or carboloy group when the value r = 1, 2, or 3.

R5is phenyl, substituted in position 3 and 4 or in position 2 and 4 methoxy group, or R5represents phenyl substituted in position 4 by methyl group, m = 0.

Most preferred are compounds (1) in the form of cisisomer.

In the description and examples use the following as canal

EtcOH: ethanol

Ether: ethyl ether

DMF: dimethylformamide

THF: tetrahydrofuran

The tea: triethylamine

DMSO: dimethyl sulfoxide

DIPEA: diisopropylethylamine

DCC: N,N' -dicyclohexylcarbodiimide

DBU: 1,8-diazabicyclo [5.4.0]undec-7-ene

LDP: 1,5,7-diazabicyclo [4.4.0]Dec-5-ene

DBN: 1,5-diazabicyclo [4.3.0]non-5-ene

DMAP: 4-dimethylaminopyridine

SLE: 3-dimethyl-2-oxohexanoate

TMEDA: tetramethylethylenediamine

LDA: lithium diisopropylamide

GMFA: hexamethylphosphoramide

HOBT: 1-hydroxybenzotriazole hydrate

BOF: benzothiazolylsulfenamide hexaphosphate

TFU: triperoxonane acid

The reagent Lawesson: 2,4-bis(4-methoxyphenyl)-1,3-dithia,4-diphosphate-2,4-disulfide

So pl.: melting point

Saline solution, water, saturated sodium chloride

Dry ice is solid carbon dioxide

TLC: thin layer chromatography

HPLC: high performance liquid chromatography

NMR: nuclear magnetic resonance

s: singlet

m: multiplet

condition: broadened singlet

d: doublet

Cleaners containing hydrochloride water: dilute hydrochloric acid concentration of about 1H

80%-l: isopentyl

iBu: isobutyl

tBu: tert-butyl, Bu: butyl

Bz: benzil

Ph: phenyl

Further, the invention relates to a method of preparing compounds (1)

The method of obtaining compounds of formula (1) is that is subjected to the interaction of 2 - aminophenazone derived formulas

< / BR>
in which

R1, R2and n have the meanings defined above, with sulfanilyl derived formulas

Hal-SO2-(CH2)m-R5(III)

in which Hal represents halogen, preferably chlorine or bromine,

m and R5have the meanings defined above, the resulting compound of formula IV:

< / BR>
treat halogenated derivatives of the formula

Hal'-CH2COA (V)

in which Hal' represents a halogen, preferably bromine, and A is a or a group NR6R7or group OR in which R is a tertiary bootrom or benzyl with obtaining the compounds of formula VI'

< / BR>
which is subjected to cyclization in the main environment, if A = NR6R7with obtaining the target product, or in the case when A = OR, is subjected to the operation of removing the protective group to obtain the corresponding acid of formula VI

< / BR>
or its acid chloride of formula VI"'

<>/BR>< / BR>
which is subjected to the above-mentioned cyclization to obtain the desired product of formula 1, divide if necessary, the resulting product of CIS-and TRANS-isomers and distinguish enantiomers.

2-aminophenazone derivatives of the formula (II) are known or are obtained by the known methods similar to those described by A. K. Singh and other Synth Conunun 1986,16 (4), 485 and G. N. Walker, J. Org.Chem. 1962, 21 1929

2-amino-2'-triftoratsetofenona and other triptoreline derivatives obtained in accordance with the method described in U.S. patent 3341592.

2,4-dimethoxybenzenesulfonamide obtained in accordance with the description in J. Am.Chem.Soc. 1952, 74, 2008.

Sulfonylurea derivatives of the formula (III) are known and are obtained by the known methods. So, for example, 4-dimethylaminobenzophenone obtained in accordance with the work of C. N. Sukenic, etc. J. Am.Chem. Soc. 1977, 19,851-858, obtaining p-benzyloxybenzaldehyde described in European patent application EP 229,566.

Alkoxysilylated obtained from sodium alkoxybenzyl, which in turn is obtained by the interaction of the halide main part with hydroxybenzenesulfonate sodium.

Halogenated proizvodnue.doc Chemistry: Longman 3rd.,1956, p.383 or G. Kirchner and others, J. Am.Chem.Soc. 1985, 107, 14, 7072.

The interaction of the compounds of formula II with the compound of the formula III is carried out in pyridine by heating at a temperature between room temperature and the boiling point of the solvent for from several hours to several days. If necessary, the reaction can be carried out in the presence of dimethylaminopyridine, which is used in catalytic or stoichiometric amounts.

Processing stage sulfonamida formula (IV) compound of the formula (V) is carried out with an excess of halogenated derivative of the formula (I) in a solvent such as dimethylformamide or dimethylsulfoxide, in an inert atmosphere at a temperature of from 0oC to room temperature over a period of time from several hours up to 24 h in the presence of sodium hydride.

In the case when the group-NR6R7contains a secondary amino group, i.e., when R6and/or R7are substituted amino group, prefer to use a halogenated derivative (V) of the formula Hal'-CH2-CO2R, in which R represents tert-butyl or benzyl, in order to obtain the intermediate compounds of formula (VI') and then (VI). In this case, the stage of education is Dios coal if R is a benzyl, either in an acidic environment, if R is tert-bootrom, for example, in the presence of TFU-acid or in the presence of Hydrobromic acid in acetic acid, or even in the presence of ZnBr2in dichloromethane.

Treatment of compounds of formula (VI) or (VI') with the amine is carried out under standard conditions amide combinations, for example in the presence of BOP or HOBT and DCC.

Connection HNR6R7are known or are obtained by the known methods. As an example, stereospecific synthesis of (R) and (S) 2-pyrrolidinyloxy acids is carried out in accordance with the work of N. Rueger and other Heterocycles, 1982, 19, (9), 1677 from prolinnova derived the appropriate configuration. Obtain methyl N-BOC-3,4-degidro-alpha-prolinate have been obtained shall be in accordance with the work of J. R. Dormoy Synthesis 1982, 753. Obtaining optical pure derivatives of pipecolinic acid is described, for example in Tetrahedron 1992, 48, (3), 431-442 and Tetrahedron, 1991, 47, (24),4039-4062.

Deriving aziridination acid is carried out in accordance with the work of K. Nakajima and others in Bull. Chem.Soc. Jap. 1978, 51 (5), 1577.

Phase cyclization proceeds by reacting aldossari: methylene group in alpha-position to the amide diproton the cyclization with the appearance of two asymmetric carbons (C*).

The reaction can be illustrated by the following scheme:

< / BR>
Principles of aldol reactions proceed considered C. H. Heathcock in Asymetric Synthesis, vol. 3 : Stereodifferentiating additions reactions, part b, 111-112, Academic Press, 1984, edition of J. D. Morrison.

It is known that andolina reaction of achiral amide anions leads to the formation of two racemic diastereoisomers beta hydroxylamino ratio, which largely depends on the experimental conditions. Among these conditions may be mentioned the following: the nature of the used inorganic or organic bases, the nature of the cations or the counterions, the possible presence of additives in the reaction medium, solvent, reaction temperature and the structure of the compounds involved in the reaction.

In the case when R6and R7do not contain groups gidrolizuacy in alkaline medium, it is possible to use sodium hydroxide in water in the presence of co-solvent, with or without added catalyst phase transition, you can also use a Quaternary ammonium hydroxide, such as hydroxide designed in methanol.

For carrying out this reaction dolgoletiya[4.4.0]-Dec-5-ene,

amidino, such as 1,8-diazabicyclo[5.4.0]undec-5-ene

or 1,5-diazabicyclo[4.3.0]non-5-ene

in a solvent or mixture of solvents selected from, for example, benzene, THF, dichloromethane, methanol and dimethylformamide, the reaction is carried out in an inert atmosphere in the range -10oC to 110oC, the number of used grounds at least is stoichiometric, the reaction can also be carried out without solvent at a temperature baths.

Preferably the phase cyclization carried out in the presence of 1,8 - diazabicyclo[5.4.0] undec-5-ene, (DBU) in a solvent such as dichloromethane or methanol, at a temperature in the range -10oC to the reflux temperature of the solvent.

You can also use the alcoholate primary, secondary and tertiary alcohol with lithium, sodium, potassium, calcium and magnesium.

The alcoholate is used in catalytic or stoichiometric amounts in anhydrous solvent, for example, in alcohol (if necessary in the presence of co-solvent, such as THF), or in stoichiometric quantities in THF, DMF or DMSO if necessary in the presence of crown-ethers, for example, DICYCLOHEXYL-18-crown-6, the reaction is carried out in the interval tempera as deproteinised agent, is a method of education Rostov amides, which are intermediate compounds in the reaction of aldossari, this method was considered R. E. Ireland and other J - Org.Chem., 1991, 56, 650. The reaction solvent may be benzene, hexane or THF used in anhydrous form in an inert atmosphere. Can be added adjuvant, such as LiF, LiCl, LiBr, LiI, LiBu

TMEDA, SLE, HMPA, or a crown ether. (M. Murakate and other J. Chem. Commen, 1990, 1657). As example can be mentioned the use of diisopropylamide lithium in the temperature range of -78oC and -80oC in anhydrous THF in an inert atmosphere or THF in the presence of additives, such as, for example, tetramerization, SLE or HMPA. Examples of other known amides, which can be used are cyclohexylamin lithium, and 2,2,6,6-tetramethylcyclopentadiene lithium. You can also receive other amides interaction required number of utility in hexane with a linear or cyclic secondary amines, and the reaction proceeds in one of the above solvents.

Another group of bases that can be used are silylamine lithium, sodium or potassium, among which may be mentioned (Me3Si)2NLi, (Me2PhSi)2

When the compound of formula (1), which must be obtained, has 2 asymmetric hydrocarbon atom, the use of chiral amides or alcoholate in phase cyclization makes it possible enantiomeric enrichment of each of the CIS - or transderivational. Then determined the proportion of each of the enantiomers by HPLC on a chiral column.

When the compound of formula (1), which must be obtained has a 3 or 4 asymmetric carbon atom, the phase cyclization of the compound of formula (VI') may be accompanied diastereoisomerism enrichment and the use of appropriate chiral base makes it possible to change diastereoisomeric enrichment.

At the last stage of CIS-and tracheomalacia isomers of the compound (1) extracted by standard methods and are separated by chromatographic methods or by fractional crystallization.

If necessary, the optical isomers of each of the CIS-and TRANS-isomers are separated, for example, preparative which the optically active salt in the presence of the respectively selected chiral acid or base.

Thus, if the connection corresponding to the invention, has 2 asymmetric carbon atom, the enantiomers can be separated by chiral HPLC.

When the connection corresponding to the invention has a 3 or 4 asymmetric carbon atom, diastereoisomer can be separated using chromatographic methods and fractional crystallization.

To identify cisisomer and TRANS-isomers of compounds of formula (1) can be used multiple methods. In the case when R3is hydrogen, is used for comparative analysis with the use of high field NMR (250 MHz) in combination, for example, in studying the effects of Noe (N. O. E), for example, between the proton indoline (R3=N) and the hydroxyl proton.

The IR spectra of CIS-and TRANS-isomers in solution DHM different. Cisisomer in most cases is intense, clear and symmetrical band absorbances in the field 3550-3520 cm-1related to the fluctuation of hydroxyl, while transisomer has no resolution vibrational lines in this area.

Based on the summary data set that cisisomer is basically more fluid in TLC on aminoaniline when chromatographicaliy on a column of alumina (aluminium oxide 90, the particle size 0,063-0,200 mm), cisisomer in the majority elyuirovaniya first, while the eluent was DHM containing various amounts AcOEt or MeOH.

Thus, CIS-and transitory connection (1) in most cases, can be identified by analytical method. It is also possible to use an analogy between similar compounds or between compounds obtained one from the other.

The absolute configuration of some compounds of the invention was determined by x-ray analysis. Proceeding from it, taking into account the value of the rotation of the polarization plane, you can also set the absolute configuration of other compounds obtained in the same way.

Of the compounds (1), in which the substituents R6and/or R7or the group NR6R7contain C1-C4-alkoxycarbonyl group, can be obtained by hydrolysis of the ester compounds (1), in which R6and/or R7or the group NR6R7contain a carboxyl group and the other substituents of the compounds (1) remain unchanged. In addition, the compounds in which R6and/or R7or NR6R7contain a carboxyl group can be obtained R7contain carbamoyl group which is free or substituted by one or two C1-C4-alkilani, and the other substituents are identical.

Finally, from compounds (1), in which R6and/or R7or the group NR61R7contains carbamoyl group can be obtained by the reaction of the Hoffmann rearrangement of compound (1) in which R6and/or R7or the group NR61R7contain the amino group, the other substituents are identical (J. Org. Chem. 1979, 41 (10) 1746).

Thus, in accordance with the invention, a method of obtaining compound (1) in which R6and/or R7or the group NR6R7contain an amino group which is free or substituted by one or two C1-C4-alkilani, may have two options

1) At the stage of interaction of the compounds of formula (IV) with compound (V) to carry out processing of the compound (IV) halogenated derivatives of the formula (V) Hal'-CH2CONR6R7in which R6and/or R7or the group NR61R7contain a group of the precursor amino groups, for example carboxyethyl, carboxy or carbarnoyl, then step cyclization and then group - predshestvennikami group, which then turns into karbamoilnuyu group and then into the amino group by Hoffmann rearrangement;

2) carry out the processing of the compound (IV) halogenated derivative (V) of the formula Hal'-CH2COOR, in which R is a benzyl or tert-bootrom; remove the protection from the ether compound (VI'), thus obtained, subjecting the corresponding processing, and then carry out the combination with the compound HNR6R7in which the amino radicals R6and/or R7can be protected, then the thus obtained compound (VI) is subjected to cyclization and, if necessary, obtain the compound (I), in which the amino group is free, by removing the protective groups from the amine.

The compounds of formula (VI) used as intermediates for producing compounds (I) are new and form part of the invention.

Accordingly, the invention also relates to intermediate compounds of General formula

< / BR>
where A' represents a group selected from HNR6R7;

-R1is a halogen atom, a C1-C4-alkyl, C1-C4-alkoxy;

R5- C1-C4-alkyl, phenyl, BR>
R6- C1-C4-alkyl, or R6same as R7;

R7the group piperidine-4-yl, unsubstituted or substituted on the nitrogen C1-C4-alkyl, C1-C4-alkoxycarbonyl; group (CH2)rwhich is itself substituted by a group of 2-, 3 - or 4-pyridyl or an amino group, a free or substituted by one or two C1-C4-alkilani, a carboxyl group, a C1-C4-alkoxycarbonyl, carbamoyl group, free or substituted by one or two C1-C4-alkilani;

or R6and R7form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, piperazine unsubstituted or substituted in position 4 by a group R ' 8unsaturated 5-membered cycle containing a single nitrogen atom, substituted by the radical R8or unsaturated 3-; 4-; 5 - or 6-membered cycle, containing a single nitrogen atom and substituted by the radicals R8and R9;

R8means R18or group (CH2)r, which is itself substituted by a hydroxyl or amino group, a free or substituted by one or two C1-C4-alkilani;
C4-alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, a free or substituted hydroxyl or one or two C1-C4-alkilani;

R8means R18or group (CH2)2NH2free or substituted by one or two C1-C4-alkilani;

R9represents hydrogen, a group (CH2)rNR10R11the group azido or the group NH-benzyloxycarbonyl;

R10and R11represent independently from each other hydrogen or C1-C4-alkyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

r is 0,1,2 or 3, provided that r is not equal to zero when R8or R9located in the alpha position relative to the intra-cyclic amide nitrogen, or to their possible salts.

The affinity of the compounds of the invention, the receptors of vasopressin was established in vitro using the method described in J. Biol.Chem., 1985, 260 (5), 2844-2851. This method consists in studying the displacement of tritium-labeled vasopressin, is associated with portions of the V1- receptor in the membranes of rat liver, 50% of inhibition concentration (IC50for compounds of the invention, in the>/P>In addition, for example, human plasma rich in platelets was observed inhibition of aggregation of platelets induced by vasopressin, when using the method described in Thrombosis Res. 1987, 45, 7-16. Compounds corresponding to the invention inhibit aggregation induced by concentrations of vasopressin from 50 to 100 nm at a low value ID50(inhibitory dose), suitable up to 10-9M. These results show antagonistic activity of the compounds of the invention, receptor V1.

The affinity of the compounds (1) to the receptor V2was measured by the method proposed by P. Crause and other Molecular and Cellular Endocrinology 1982, 28, 529-541.

Compounds corresponding to the invention and having isconfiguration in relation to communication 2.3 indoline, characterized by a noticeable selectivity in receptor V1.

The affinity of the compounds (1), corresponding to the invention, to ocytocine receptors was determined in virto offset of tritium-labeled ocytocine associated with the receptor in the membrane preparation glands of pregnant rats. The values of the IC50compounds of the invention are low and are between 10-5M and 10- the oral introduction.

These compounds did not show any symptoms of toxicity when receiving a pharmacologically active doses.

Therefore, the compounds of the invention can be used in the treatment or prevention of various related identity disorders, especially cardiovascular disorders such as hypertension, cardiac insufficiency, thrombosis, or coronary vasospasm, in particular in smokers, Central nervous system disorders, for example, when cerebral edema, psychotic conditions, disturbances of appetite or memory disorders, disorders of the renal system, such as renal vasospasm or necrosis of the cortical substance of the kidney, disorders of the gastrointestinal system, such as ulcers, or syndrome of inappropriate secretion of antidiuretic hormone.

Compounds corresponding to the invention can be used also as antibotic funds, especially when sickness motion sickness, and as antiproliferative agents, for example, in cancer or atherosclerosis.

Women are compounds corresponding to the invention can be used also for the treatment of dysmenorrhea or premature birth.

The invention relates also to F. farmacevtichesky acceptable salts and pharmaceutically acceptable additives. Called additive selected according to the pharmaceutical form and the required method.

In pharmaceutical compositions intended for oral, sublingual, subcutaneous, intramuscular, intravenous, local, intratracheal, nasal, cutaneous or rectal techniques, the content of the active substances of the formula (1) or its salts corresponds to a single dose and is mixed with standard pharmaceutical carriers.

The appropriate unit doses are available for oral administration in the form of tablets, gelatin capsules, powders, granules and solutions or suspensions, or in appropriate forms for sublingual, cheek, intratracheal or nasal reception, for subcutaneous, intramuscular or intravenous intake and rectal administration. For local application connections can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose of active content can vary in the range of 0.01 to 50 mg per 1 kg of body weight per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably 1 to 500 mg of active ingredient in combination with Osinovka 0.5 - 5000 mg, preferably 1 to 2 5000 mg.

To obtain a solid composition in the form of tablets the active ingredient is mixed with a pharmaceutical excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or the like.

Tablets can be coated with sucrose, a cellulose derivative or other relevant substances or they can be processed to provide prolonged action in order to continuously allocate a predetermined amount of the active component.

The drug is in the form of gelatin capsules are prepared by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The drug is in the form of a syrup or elixir or for reception in the form of drops can contain the active ingredient in combination with a non-nutritive sweetening substance, preferably with methyl paraben and propyl paraben as antiseptics, as well as the agent for flavor and the corresponding dye.

Water-dispersible granules and powders should contain the active ingredient mixed with dispersing agents or wetting agents, or suspendresume.

For rectal technique is used candles, which are prepared on the basis of bending, melting at rectal temperature, for example cocoa butter or polyethylene glycol.

For parenteral reception using aqueous suspensions, isotonic saline solutions or sterile solutions for injection, which contain pharmacologically compatible dispersing agents and/or moisturizing agents, for example propylene glycol or butyleneglycol.

The active compound can be used as microcapsule, if necessary with one or more carriers or additives.

In addition to the compounds of formula 1 and their pharmaceutically acceptable salts, compositions may contain other active-active components, which can be used in the treatment of the aforementioned disorders and diseases.

The compounds are characterized by their melting point (So pl.oC) (or their boiling point So Kip.) and/or NMR spectrum, recorded at 200 MHz in DMSO and/or rate of rotation of the polarization plane (D), measured at 25oC (unless otherwise specified).

The measured value of the rotation of the polarization plane depends on the amount of residual solvent, presutti" or "transisomer" means, that the isolated compound is a mixture of enantiomers or isconfigurable, or transconfiguration.

Optical purity of the compounds investigated using high performance liquid chromatography (HPLC)

Example 1. N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2-forfinal) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer.

A) Methyl - N-bromotetradecane

This compound is obtained according to T. D. Harris, and others in J. Heterocyclic, Chem., 1981, 18 423.

C) 5-bromo-2-(3,4-dimethoxybenzenesulfonamide) -2'-terbinafine.

20g 2-amino-5-bromo-2'-fermentation heated at 85oC for 48 h in 120 ml of dry pyridine in the presence of 20 g of 3,4-dimethoxybenzenesulfonamide. The mixture is cooled, poured into ice water, the solid is filtered off, extracted with AcOEt, the organic phase is washed with water, hydrochloric acid (1N), water and then salt water. After drying over magnesium sulfate and evaporation of the solvent in vacuo get solid, which is recrystallized from a mixture of (DHM) isopropyl ether.

m 28 grams

So pl. 125-128oC

C) 5-Bromo-2-1[N-(3,4-dimethoxyphenylacetone what about on the stage, dissolved in anhydrous DMF at 0oC in argon atmosphere and add 80% sodium hydride in 15 min add 4,85 g of compound obtained in stage A, and the mixture is allowed to mix at room temperature for 12 hours, the Reaction mixture was poured into water, the solid is filtered, then dissolved in AcOEt, the organic phase is washed with water, then with salt water, and the solvent is evaporated in vacuum. The oil obtained is filtered on silica with elution with a mixture DHM/AcOEt (85/15 by volume)

m 3.2 grams

So pl. 136-137oC

D) 14-methyl - N-methoxycarbonylmethyl-5-bromo-3- (2-forfinal) 1- (3,4-dimethoxyphenylacetone)-3-hydroxy-2-indolinecarboxylic, cisisomer.

3.2 g of the product obtained in the preceding stage, dissolved in DHM (3 ml), add 750 mg of DBU, and the mixture is left under stirring for 24 h at room temperature. The reaction mixture is poured into silicagel column, with elution with a mixture DHM/AcOEt (90/10 by volume), the resulting product is a mixture of isomers (CIS and TRANS) of target compound. This product is ground to powder in a mixture of hexane/isopropyl ether and the resulting solid filtered. The filtered fluid chromatographic on oxide-aluminievye eluted with a mixture DHM/AcOEt (60/40 by volume) and then precrystallization from a mixture DHM/hexane/isopropyl ether.

So pl. 95oC with evolution of gas

Examples 2 and 3. [(4-Benzyloxycarbonyl)-1-piperazinil] 2-carbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone)- 3-hydroxyindole, cisisomer and transisomer

A) 1-Bromoacetyl-4-(benzyloxycarbonyl) piperazine

A mixture of 22 g of 4-benzyloxycarbonylamino and 10.1 g of triethylamine in 200 ml of ether cooled to 0oC. for 30 min add 20,2 g bromoacetamide in 100 ml of ether, and the mixture is brought to room temperature. After 4 h the reaction mixture was washed with water, dried, concentrated and then chromatografic on silicon dioxide. The target connection alwarpet mixture DHM/AcOEt (95/5 by volume) and recrystallized from DHM/isopropyl ether.

m 9g

So pl. 100-101oC

A) 2',5-Dichloro-2-(3,4-dimethoxybenzenesulfonamide) benzophenone

5.6 g of 2 - amino-2',5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylethylamine heat during the night in pyridine at 100oC.

The pyridine is evaporated until dry, add water and the extraction is carried out with ethyl acetate containing a small amount DHM. After repeated washing with water and drying over sodium sulfate, the extract is evaporated in vacuum, and 7.7 g of the target product of paracrystals jocstarbunny-1-piperazinylmethyl)]-aminobenzophenone

2.3 g of benzophenone obtained on the stage, placed in 10 ml DMF and treated with 200 mg of 80% sodium hydride in oil. After 30 minutes add to 5.3 g of compound obtained in stage A, and the mixture is stirred for 60 h at room temperature. The mixture was poured into water, the precipitate is filtered, dissolved in DHM, dried and then concentrated and chromatographic on silicon dioxide. Target product elute with a mixture DHM/AcOEt. (90/10 by volume) and crystallized from a mixture of DGM/isopropyl ether.

m 2 g

So pl. 173-175oC

D) [(4-Benzyloxycarbonyl)-1-piperazinil] 2-carbonyl-5 - chloro 3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone)-3 - hydroxyindole, cisisomer and transisomer.

1 g of the compound obtained in the previous step is suspended in 20 ml of methanol and 20 ml of THF and subjected to the action of 75 mg of sodium methylate. After 2 h the mixture was neutralized by adding small amounts of dry ice, concentrated until dry and then absorb the water, then the mixture is extracted with DHM, the extract was dried and concentrated. The crude product is subjected to chromatography on a column of alumina with elution with a mixture DHM/AcOEt (80/20 by volume) consistently get two isomers.

Least p"ptx2">

m 262 mg

So pl. 169-179oC

The most polar isomer is recrystallized from a mixture of DGM/isopropyl ether

m 200 mg

So pl. 209-211oC

Example 4. 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-(1-piperazinylcarbonyl)indolin, cisisomer

200 mg cisisomer obtained in the previous example is dissolved in 10 ml ethanol and 5 ml of THF and hydronaut at room temperature in the presence of 10% palladium on coal. After 30 min the mixture was filtered through celite, the filtered liquid is concentrated and then subjected to chromatographicaliy on silicon dioxide. The target product is subjected to elution with a mixture of MeOH/DHM (10/90 by volume) and recrystallized from a mixture of DGM/isopropyl ether.

m 110 mg

So pl. 230-233oC

Examples 5 and 6. 5-Chloro-3-(2-chlorophenyl)-1- (3,4-dimethoxyphenylacetone)-3-hydroxy-2-morpholinosydnonimine, cisisomer and transisomer

A) 2',5-Dichloro[N-(3,4-dimethoxyphenethyl) -N-(morpholinomethyl)] 2-aminobenzophenone

5 g of 2',5-dichloro-2-(3,4-dimethoxybenzenesulfonamide) benzophenone expose 350 mg of 80% sodium hydride in 30 ml of DMF at room temperature for 20 minutes Add 4.5 g of morpholinopropan and the mixture is then re is DHM, the solution is dried and concentrated. Educated product is recrystallized from a mixture of DGM/isopropyl ether. Obtain 3.4 g of product.

So pl. 173-176oC

C) 5-Chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) - 3-hydroxy-2-morpholinosydnonimine, cisisomer

1 g of the product obtained in the previous step, dissolved in a mixture of methanol (10 ml) and THF (20 ml) and the resulting product are 92 mg of sodium methylate at room temperature for 1 h the Mixture was neutralized with dry ice, the solvent is partially evaporated, the mixture is dissolved in water, extracted with DHM, and the extract is dried, concentrated and chromatographic on aluminium oxide. Elution with a mixture DHM/AcOEt (70/30 by volume) gives the least polar isomer, which is recrystallized from a mixture of DGM/isopropyl ether.

m 215 mg cisisomer

So pl. 260-264oC

C) 5-Chloro-3- (2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone)- 3-hydroxy-2-morpholinosydnonimine, transisomer

Chromatographytandem product of the previous step and elution with a mixture of AcOEt/MeOH (90/10 by volume) have the most polar product. After recrystallization from a mixture of DGM/isopropyl ether get

m 513 mg transisomer

So pl. 240-241ocarboxamid, cisisomer

200 mg of the compound obtained in example 1 was dissolved in 3 ml of MeOH and 1 mg of water containing 13 mg of sodium hydroxide. After stirring for 24 h at room temperature, add one drop of concentrated sodium hydroxide solution to complete the reaction, and then after 15 min the mixture is acidified to pH 3 by addition of a solution of potassium hydrosulfate. Water is added, the mixture is extracted with AcOEt and the extract is washed with water and dried over magnesium sulfate, and the solvent is evaporated in vacuum. The resulting product is recrystallized from a mixture of DGM/isopropyl ether.

So pl. 206-208oC

Examples 8 and 9. 5-Chloro-3- (2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone)-3-hydroxy-2- (4-ethylcarboxylate) indolin, cisisomer, transisomer.

A) Ethyl-N-bromoacetyl-4-piperidinecarboxylate

This product is obtained from ethyl-4-piperidinecarboxylate, which is commercially available.

B) 2',5-Dichloro-[N-(3,4-dimethoxyphenylacetone)-N (4-ethylcarboxylate)] 2-aminobenzophenone

8 g of 2',5-dichloro-2-(3,4-dimethoxybenzenesulfonamide) benzophenone dissolved in 100 ml of DMF and then add 541 mg of sodium hydride. After stirring for 30 min add 9,tryout in vacuum, dissolved in water, extracted with ethyl acetate and the extract was dried and concentrated. The oil obtained chromatographic on silica using as eluent a mixture of ethyl acetate DHM/hexane (40/10/50 by volume). Extracted the product is crystallized from ether.

m 3.5 grams

So pl. 128oC

C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-(4-ethylcarboxylate)indolin, cisisomer, transisomer

A mixture containing 3.4 g of the compound obtained in the previous step, and 869 mg of DBU in 10 ml of chloroform for 18 h heated to 60oC. Then the reaction mixture was filtered through a column of alumina using as eluent a mixture of DGM/ethyl acetate (90/10 by volume) to obtain cisisomer.

m 700 mg

So pl. 110oC

Pure ethyl acetate aluinum transisomer.

m 610 mg

So pl. 187oC

Examples 10 and 11. N-methyl-N- (2-pyridylethyl) -5-chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer, transisomer

A) N-[2-(2-khlorfenilalanin)-5-chlorophenyl] - N-(3,4-dimethoxyphenylacetone) aminouksusnoy acid

a) 2',5-dichloro-2- (3,4-dimethoxybenzenesulfonamide) benzophenone.

172 g of the product obtained in the preceding stage, are dissolved in 800 ml DHM and cooled to 0oC. Gradually under nitrogen atmosphere add to 11.7 g of 80% sodium hydride, and then, after 30 minutes, add 256 g benzylbromide and the mixture is allowed to mix at room temperature for 24 h DMF is evaporated, the residue is dissolved in water, extracted in DHM, and the extract was dried and concentrated. The target product is crystallized from isopropyl ether and then recrystallized from a mixture of DGM/isopropyl ether.

m to 136.5 g

So pl. 102-104oC

C) N-[2-(2-Khlorfenilalanin)-5-chlorophenyl] -N- (3,4-dimethoxyphenylacetone) aminouksusnoy acid

50 g of the benzyl ester obtained in the previous step, dissolved in 500 ml ethyl acetate and in nitrogen atmosphere add 2.5 g of 5% palladium on coal. The solution rapidly stirred and through it pass for 5 h in a stream of hydrogen. At the end of gidrogenizirovanii the product is crystallized. The mixture is filtered through celite, the residue is rinsed with hot DHM and then the organic phase is concentrated. The target product is crystallized, and then recrystallized from a mixture of DGM/isopropyl ether.

m 33,7 g

So pl. 177-178oC

A) 2',5-Dichloro-[N-(3,4-is obtained in stage A, enter in 30 ml DHM and added 1.13 g of 2- (2-methylaminomethyl)-pyridine, then 844 mg of triethylamine and, finally, 1.92 g of BOP, and then the mixture is left to stand for 18 h at room temperature with stirring. The mixture is dissolved in water, the organic phase is separated, washed with sodium carbonate solution, dried and concentrated. After chromatography was carried out on silica target product is obtained by elution with a mixture DHM/MeOH (95/5 by volume)

m 2 g

So pl. 150oC

C) N-methyl-N-(pyrid-yl-ethyl)-5-chloro-3-(2-chlorophenyl)-1- (3,4-dimethoxyphenylacetone)-3-hydroxy-2-indolinecarboxylic.

A mixture of 1.7 g of the product obtained in the preceding stage, and 422 mg of DBU in DHM heated for 18 h at 55oC. the Reaction mixture chromatographic on aluminium oxide. Elution with a mixture of ethyl acetate/DHM (40/60 by volume) gives cisisomer

m 410 mg

So pl. 191oC

Pure ethyl acetate aluinum transisomer

m 790 mg

So pl. 154oC

Example 12.

2-(4-Carboxybenzeneboronic) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-indolin, cisisomer

500 mg of the isomer obtained in example 9, are placed in 5 ml of methanol in the presence of 48 mg of sodium hydroxide in 1 ml of water. Moslem extracted in DHM and the extract was dried and concentrated. The obtained solid is purified by chromatography on silica, elute with a mixture DHM/MeOH (95/5 by volume) and the resulting product is then crystallized from a mixture of DGM/isopropyl ether.

m 250 mg

So pl. 150oC

Examples 13 and 14.

N-Methyl-N - (1-methyl-piperidine-4-yl)-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone)-3-hydroxy-2-indolin-carboxamid, cisisomer and transisomer

A) 2',5-Dichloro-[N-(3,4-dimethoxyphenethyl)-N- (N'-methyl-N'-methyl-piperidine-4-yl)carbamoylmethyl] 2-aminobenzophenone

2 g of the acid prepared in example 10-11, step A, in 50 ml DHM mixed with 650 mg of 4-methylamino-1 methylpiperidine in the presence 1,90 g of BOP. After stirring at room temperature for 2 h, the organic phase is washed with carbonate with water, dried and concentrated. Then the rest chromatographic on silica with elution with a mixture DHM/MeOH (90/10 by volume). Obtain 1.2 g of the target product.

So pl. 165-boC

C) N-methyl-N-(methyl-piperidine-4-yl)-5-chloro-(2-chlorophenyl)-1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer

650 mg of the product obtained in the previous step process over night 100 mg of sodium methylate in 5 ml of methanol. Doba is their, then chromatografic on silicon dioxide. A mixture of methanol/DHM (5/95 by volume) aluinum consistently 2 isomer. Then, each isomer is recrystallized from a mixture of DGM/isopropyl ether.

Transisomer is in these conditions, the least polar

m 205 mg

So pl. 181oC

Cisisomer

m 150 mg

So pl. 97oC, contains 0.25 M isopropyl ether.

Examples 15 and 16.

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) - 3-hydroxy-2[(4-methyl)-piperazine-1-ylcarbonyl]-indolin, cisisomer and transisomer

A) 2'5-Dichloro-[N-(3,4-dimethoxyphenethyl) -N-((4-methyl-piperazine-1-yl)carbamoylmethyl)-, 2-aminobenzophenone

This compound is obtained by the action of N-methyl-piperazine acid obtained in examples 10 and 11, step A.

So pl. 165-167oC

C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) - 3-hydroxy-2-[(4-methyl)piperazine-1-ylcarbonyl]-indolin, cisisomer and transisomer.

The compound of the preceding stage cyclist according to the method of examples 12-13. Two educated isomers separated by chromatography on aluminium oxide. The mixture DHM/ ethyl acetate (75/25 by volume) aluinum the least polar product: cisisomer, which is recrystallized from mirouet the most polar compound, transisomer, which is then recrystallized from methanol.

So pl. 189oC

Examples 17 and 18. N-Isopropyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer.

A) N-Isopropyl - N -(methoxycarbonylethyl) bromoacetamide.

90 g of Isopropylamine added dropwise to 130 g of a solution of methyl acrylate in 300 ml of methanol, cooled to -10oC. After 72 h of exposure at room temperature the mixture is evaporated and then the residue is distilled. Formed oil is a methyl-(N-isopropyl) - 3-aminopropionic.

So Kip. 73-78oC at 15 mm RT. Art.

29 g of the obtained compound in 100 ml DHM mixed with 20.2 bromoacetamide 100 ml DHM withoC. After keeping the mixture at room temperature for 12 h the solvent is evaporated, the residue is dissolved in water, extracted with ethyl acetate and the extract is dried and concentrated. The oil obtained is used as such in the next step.

A) 2',5-Dichloro-N-(3,4-dimethoxyphenethyl)-N-(N'- isopropyl-N'-methoxycarbonylethyl)carbamoylmethyl] -2-aminobenzophenone

This compound is obtained by following the usual Metronom in the presence of sodium hydride.

So pl. 135-137oC (recrystallization: DHM/ isopropyl ether).

C) N-Isopropyl-N-Methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer.

This product is obtained by cyclization of the compound obtained in stage, in the presence of DBU. Cisisomer allocated chromatographytandem on alumina with elution with a mixture DHM/ethyl acetate (90/10 by volume). Then the product is recrystallized from a mixture of ethyl acetate/hexane.

So pl. 153 to 155oC

Transisomer obtained by elution of the column of aluminum oxide with ethyl acetate. The product is then recrystallized from methanol/isopropyl ether.

So pl. 182-185oC

Examples 19 and 20. N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone)-3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer.

2 isomer of this compound receive in accordance with the procedure described in example 1. They are separated by chromatography on aluminium oxide. The mixture DHM/ethyl acetate (80/20 by volume) aluinum cisisomer. It crystallized from a mixture of DGM/isopropyl ether as a white powder, containing 0.25 mol of isopropyl EPE is) is given in Fig.1.

Transisomer eluted pure ethyl acetate. It is recrystallized from a mixture of DGM/isopropyl ether.

So pl. 176-178oC

The NMR spectrum of transisomer (example 20) is given in Fig.2.

Examples 21 and 22.

N-Methyl-N-carboxymethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer

Each of these compounds derived from the compounds described in examples 19 and 20 in accordance with the methodology described in example 8.

Cisisomer: So pl. 220-222oC after recrystallization from a mixture of DGM/isopropyl ether/methyl alcohol

Transisomer: So pl. 222-225oC after recrystallization from a mixture of DGM/isopropyl ether.

Examples 23 and 24. N-Methyl-N-carbamoylmethyl-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer

Each isomer is obtained from the corresponding isomer of the acid prepared in examples 21 and 22.

605 mg transisomer acid obtained in the preceding example, dissolved in 10 ml DHM and add 435 mg of BOP and 260 mg DIPEA. After incubation for 5 min at room temperature with intensive peremeshivaniya, the mixture is then extracted in DHM. The organic phase is successively washed with water, a solution of sodium hydrosulphate, again with water and then dried over magnesium sulfate. After evaporation the residue chromatographic on silica gel and elute with a mixture of ethyl acetate/methanol (95/5 by volume).

The resulting product is crystallized twice from a mixture of DGM/ methanol at 0oC.

So pl. 236oC

The NMR spectrum of transisomer (example 23) is given in Fig.3.

Using the same methodology turns out cisisomer.

The target product is crystallized from a mixture of DGM/isopropyl ether. Ground connection, dried in vacuum at 70oC for 8 h, contains 0.25 mol of isopropyl ether.

An NMR spectrum of cisisomer (example 24) is given in Fig.4.

Examples 25 and 26.

5-Chloro-N-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone)-3 - hydroxy(4-hydroxy-piperidine-1-yl)-1-carbonimidoyl, transisomer

This compound is obtained from N-[2-(2-khlorfenilalanin) -5-chlorophenyl]-N-(3,4-dimethoxyphenylacetone) aminouksusnoy acid obtained in examples 10 and 11, step A. Then, the process continues in accordance with the methods of examples 11 and 12, step B, but using 4-hydroxypiperidine in the Pris the AI DBU. Two isomers share chromatography on aluminium oxide. The mixture DHM/methanol (99/1 by volume) aluinum cisisomer.

The product is crystallized from a mixture of DGM/hexane/methanol and then the resulting solid is ground to powder in a mixture DHM/hexane, forming the amorphous powder.

Cisisomer characterized by its NMR spectrum at K.

1-1.8 M. D.: m: 4H: CH2in positions 3 and 5 of the piperidine 2.8 - 3.65 M. D.: m: 5H : CH2in positions 2 and 6 of the piperidine, and CH in position 4.

3.75 M. D. : 2s:6H:20CH3< / BR>
4.15 M. D. : d:1H:HE piperidine

5.45 M. D. : s:1H:CH (indocin)

6.1 M. D.:s:1H:HE indolin

6.8-7.6 m days: m: 10H:aromatic H

DMSO: 2.4 M. D.

DON: 2.75 M. D.

The mixture DHM/methanol (97/3 by volume) aluinum transisomer that precrystallization from a mixture DHM/isopropyl ether.

So pl. 232-234o< / BR>
Synthesis of (L)-prolinnova series: examples 27 to 30.

Examples 27 and 27A. 5-Chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinecarbonyl] indoline, (cisisomer: 2 connections)

A) Methyl (L)-N-(bromoacetyl)prolinate have been obtained

20 g of triethylamine and 20 g of bromoacetamide in 30 ml DHM simultaneously added to a solution containing 16.7 g of m is t for 24 h at room temperature. Water is added, and the mixture is washed with a solution of KHSO4, water, sodium bicarbonate solution, again with water, then dried over magnesium sulfate. After evaporation receive the oil which is dried in vacuum. This oil, purified by TLC, actually used in the next step.

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl)-N-((2S)- (2-methoxycarbonyl) pyrrolidinecarbonyl)] 2-aminobenzophenone.

of 4.66 g of 2',5-dichloro-2-(3,4-dimethoxybenzenesulfonamide)benzophenone are dissolved in 40 ml of anhydrous DMF in an argon atmosphere at 0oC add 340 mg of 80% sodium hydride and then, after 30 minutes, 6.5 g of the compound obtained in step A. After incubation for 4 days at room temperature the mixture was poured into water, extracted with ethyl acetate, the extract washed with water, salt water and then dried over magnesium sulfate and evaporated in vacuum. Solid substance containing a small amount of the source of the brominated derivative, elute with a mixture DHM/ethyl acetate (85/15 by volume) chromatographytandem on silica gel. A sample recrystallized from a mixture of DGM/isopropyl ether.

m = 1.2 g

So pl. 141-142oC

2D5= -43,7oC (C = 1, methanol/ Ter the>C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) - 3-hydroxy-2- [(2S)-(2-methoxycarbonyl)pyrrolidinecarbonyl] indolin (cisisomer)

1.1 compound obtained in the previous step, is heated in 4 ml of methylene chloride for 24 h with an equivalent amount of DBU. Analysis of the aliquot share performed using HPLC, reveals the presence of 4 target isomers. After 24 h the reaction mixture was poured into a column of alumina, pre-equilibrated with a mixture DHM/ethyl acetate (90/10 by volume), and elute with a mixture DHM/ ethyl acetate (90/10 by volume to 70/30 by volume), obtain 510 mg of a mixture of 2 the least polar compounds with a ratio of 4/1 (measured by HPLC).

1oTwo successive crystallization from a mixture of DGM/ isopropyl ether in the cold state of the network connection, located in the largest quantity.

m 180 mg

2D5= -247oC (=0,4, chloroform)

So pl. 187-190oC

2o) Crystallization mother solution of the obtained compound is subjected to chromatographicaliy using alumina with elution with a mixture DHM/ethyl acetate (85/15 by volume). Thus the above compound is separated from the second, and the second connection of the

2D6= +136oC (=0,24, chloroform)

Example 28. 2-((2S)-2-Carboxypropanoyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer

430 mg of the compound obtained in example 27, dissolved in 6 ml of methanol, add 41 mg of sodium hydroxide in 1 ml of water, and the mixture is stirred at room temperature for 24 hours the Mixture is acidified to pH 3 with a few drops of solution of potassium hydrosulfate and extracted with ethyl acetate. The extract is washed with water, then dried over magnesium sulfate. Is the chromatography was carried out on a column of silica treated with a mixture DHM/pentane (80/20 by volume). Unreacted ether to elute the mixture DHM/AcOEt (about 70/30). A mixture of AcOEt/MeOH (80/20 by volume) aluinum target acid, which is recrystallized from a mixture of DGM/isopropyl ether.

So pl. 232-234oC

2D6= -254oC (C = 0.3, and chloroform)

Examples 29 and 29A. 2-((2S)-2-Carbamoyltransferase) -5-chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone)-3-hydroxyindole, (cisisomer: two connections)

230 mg of the compound obtained in example 28, dissolve in 5 ml DHM add 50 mg DIPEA and then 165 mg of BOP, and the mixture is left at room the s 1 min, after 15 min for 1 min, water is Added, and then a large amount of ethyl acetate to obtain two phases. The organic solution is washed with sodium carbonate solution, water, a solution of potassium hydrosulfate, water and then salt water. After drying, the residue is subjected to chromatographicaliy on silica with elution with a mixture DHM/methanol (93/7 by volume). The resulting product is ground to powder in a mixture DHM/isopropyl ether/hexane. It contains 1/3 mol of isopropyl ether.

2D6= -189o(C = 0,23, chloroform)

The compound of example 29 can be obtained using other methods.

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl) -N-((2S)- 2-carbamoyltransferase)] 2-aminobenzophenone

33,9 g of the acid obtained in example 10-11, step A, was dissolved in 300 ml of chloroform. Add 15 g of thionyl chloride, and the mixture for 1.5 h and maintained at the reflux. The mixture is evaporated until dry, and then the residue is dissolved in DHM, brought to 0oC and to it was added to 10.5 g of hydrochloride (L) - prolinamide, and then 18 g DIPEA in 20 ml DHM last added slowly so that the temperature of the reaction mixture did not exceed 3oC. After keeping overnight at FL (twice), the reaction mixture is dried and concentrated. The crude product is dissolved in a minimal amount DHM and added dropwise to isopropyl ether (1.2 l) under stirring. After stirring for 2 h the precipitate was filtered and then dried in vacuum at 60oC for 6 hours Obtain 42 g of the product.

2D5= -40,8o(C = 1,007, chloroform)

A) 2-((2S)2-carbamoyltransferase)-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole), (cisisomer: 2 connections)

5 g of the product prepared in the preceding stage, dissolved in 50 ml of methanol. The solution is cooled to -10oC add 1.35 g DBU and the mixture was incubated for 60 h at -10oC. the Compound crystallizes, it is filtered (tissuegene 1). Crystallization uterine solutions are neutralized KHSO4and the mixture is evaporated until dry. It is dissolved in water, extracted twice DHM, and the extract is dried and concentrated. The crude product chromatographic on silica using as eluent a mixture of ethyl acetate/DHM (28/72 by volume). The resulting mixture is hot dissolved in minimum quantity of methanol, Neretva is crystallized.

m = 25 g

2D5= -196o(C = 0,351, chloroform)

Analysis of the NMR spectrum reveals the presence of one mole of methanol per mole of product. Recrystallization of the product from ethanol gives the opportunity to remove the solvent from the crystals.

So pl. 154-162oC

2D5= -204o(C = 0.3, and chloroform)

2D5= -131o(C = 0,27, chloroform/methanol 8/2 by volume)

This connection is identical, excluding the solvent, the compound obtained according to the first method of this example.

The compound, which crystallizes on stage) above named tissuegene 1, is recrystallized from methanol.

So pl. 190oC

D= +115o(C = 0.3, and chloroform)

Example 30.

5-Chloro-3- (2-chlorophenyl)-1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2 -[(2S)(2-hydroxymethyl)pyrrolidinecarbonyl] indolin, cisisomer.

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl) -N - ((2-hydroxymethyl)pyrrolidinecarbonyl)] -2-aminobenzophenone.

This compound is produced by interaction of (L)-prolinol acid obtained in examples 10 and 11, step A, according to the following standard method.

C) 5-Chloro-3- (2-chloro who

1.5 g of the compound of the previous step cyclist in the presence of 380 mg of DBU in 2 ml DHM. After keeping at room temperature for 3 days add 1 ml DHM, and then the mixture is heated overnight at 40oC. When using TLC on silica (eluant ethyl acetate) revealed the formation of three compounds present in the greatest quantity.

The least polar fraction eluted with chromatographicaliy on silica using a mixture DHM/ ethyl acetate from 60/40 to 80/20 by volume. Then carry out the chromatography was carried out on alumina with elution DHM/methanol (99/1 by volume). The resulting fraction is homogeneous according to TLC. The product is recrystallized three times from a mixture of DGM/isopropyl ether. The target product is obtained using HPLC purity of more than 99%.

m 155 mg

So pl. 194-197oC

2D5= -195o(C = 0,2, chloroform)

Synthesis of C (D) - Prolinamide factions.

Example 31.

5-Chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2(2R)(2-methoxycarbonyl)pyrrolidinecarbonyl]indolin, cisisomer.

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl) -N - ((2R)(2-methoxycarbonyl)pyrrolidine and 11, step A (3 g), which is added 1.2 g of methyl (D)-prolinate have been obtained and 2.8 g of BOP in 10 ml DHM in the presence of 1.15 g of triethylamine. The mixture is left for 1 h at room temperature and then diluted DHM, the organic phase is washed with sodium carbonate and potassium hydrosulfate, dried and concentrated. The crude product chromatographic on silica with elution with a mixture DHM/ethyl acetate (95/5 by volume). The resulting product is then recrystallized from a mixture of DGM/isopropyl ether.

So pl. 140-141oC

2D5= +28,5 (C = 0.27 chloroform)

C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2- [(2R)(2-methoxycarbonyl)pyrrolidinecarbonyl]indolin, cisisomer.

1.5 g obtained in the previous phase connection boil over night under reflux in 5 ml DHM in the presence of 360 mg of DBU. The mixture chromatographic on aluminium oxide. The mixture DHM/ethyl acetate (95/5 by volume) aluinum the least polar fraction (m = 300 mg), which is twice recrystallized from a mixture of DGM/isopropyl ether.

So pl. 186-188oC

2D5= +245o(C = 0,4, chloroform)

This compound is an enantiomer obtained from (D)-Proline as described in primisulfuron)-3-hydroxy-2-indolin-carboxamid, transisomer and cisisomer.

A) 2', 5-Dichloro-[N-(4-ethoxybenzylidene) -N-(N'-methyl-N'-methoxycarbonylmethyl)carbamoylmethyl] -2-aminobenzophenone.

5.7 g of 2',5-dichloro-4-ethoxy-2-phenolsulfonephthalein dissolve in the atmosphere of argon in 40 ml of DMF and added 400 mg of 80% sodium hydride at 0oC, 15 min added 4.3 g of methyl-N-(bromoacetyl)sarcosinate. After 48 h extracted in the usual way and then purified by chromatographytandem on silica with elution with a mixture DHM/ethyl acetate (90/10 by volume) and recrystallization from a mixture of DGM/isopropyl ether.

So pl. 158-160oC

C) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)- 1- (4-ethoxybenzylidene) -3-hydroxy-2-indolinecarboxylic, transisomer

1 g of the compound obtained in the preceding stage, dissolved in 4 ml DHM and treated for 90 min at room temperature with 312 mg of biodiesel fuel. Add a solution of potassium hydrosulfate, DHM evaporated in vacuum, the mixture is extracted with ethyl acetate, and the extract is washed and dried over magnesium sulfate. The target product is obtained by chromatography on silica gel with elution DHM/ethyl acetate (90/10 by volume).

m 590 mg

So pl. 168-171oC after recrystallization the Roxy-2-indolinecarboxylic, cisisomer.

2,96 g of compound obtained in stage A, suspended in 20 ml of methanol and 10 ml of THF, is added 100 mg of sodium methylate, after which the mixture is left for 7 hours in the refrigerator. Water is added, the mixture is neutralized with a solution of potassium hydrosulfate, and part of the methanol is evaporated in vacuum. After extraction with ethyl acetate the residue chromatographic on aluminium oxide and then elute with a mixture DHM/ethyl acetate (80/20 by volume). Obtain 850 mg of the target product, which is recrystallized from a mixture of DGM/isopropyl ether.

The NMR spectrum is given in Fig.6.

When using methods similar to those described above were obtained intermediate compound (VI) for the synthesis of compounds (I), corresponding to the invention.

The compounds (VI) are described in the table.1.

The compounds (I) are described in the table. 2.

/3/ the Connection (see tab.1) is characterized by the magnitude of the rotation of the polarization plane:

2D5= -36,8o= 0,44; chloroform/.

For each connection formula /1/ having values of the substituents R'1, R'5, R'2and NR6R7( see PL.2), is specified isomer of CIS-and isometries.

Example 34.

Who WITH : 2.5 M. D.)

Example 34 explains Fig.5.

Example 38.

0,7-1,1 m days : m: 6H: 2CH3(Et)

2-4 M. D. : m: 17H:2CH2(Et), 2CH2-N, N-CH3, 2OCH3< / BR>
5,2-5,7 M. D. : 3C: 1H:H (indocin)

6,2-8,2 m days : m: 11N:HE+ aromatics

Example 39.

0,3-1,2 M. D. : m: 3H: CH3(Et)

1,5-4,3 m days : m: 15 NM: CH2-CO, CH2(Et), CH2-N, 2OCH3, CO2CH3< / BR>
5,2-5,6 M. D.: 3C: 1H:H (indocin)

6,2-8,2 m days :m: 11N: HE + aromatics

Example 40.

0,8-1,1 m days : m: 3H: CH3(Et)

2,2-3,9 M. D. : m: 15 NM: CH2CO, CH2(Et), CH2N CO2CH3, 2OCH3,

5,3-5,7 M. D. : 2c: 1H:H (indocin)

6,6-8,2 m days : m: 11N: HE: + aromatics

Example 63.

0,4-1 M. D. : Rassel, t: 3H:CH2-CH2-CH3< / BR>
5 M. D. : m: 2H: CH2-CH2-CH3< / BR>
2,5-4,4 M. D. : m: 13H: CH2-CH2-CH3, NCH2, COOCH3, 2OCH3< / BR>
5,2-5,8 M. D. : ush.with: 1H:H (indocin)

of 6.5 to 8.3 m days :m: 11N: HE + aromatics

Example 66.

from 0 to 1.5 M. D. :m: 3H:CH2-CH3,

2,3-5,8 M. D. : m: 14N: CH2-CH3, NCH2COOCH3, 2OCH3H(indocin)

of 6.1 to 8.3 m days :m: 11N: CH + aromatics.

Example 75.

1,95 m D.: ush.s: 2H: NH2< / BR>
from 2.7 to 5.3 m days: m: N: ON3, 2NCH2H(indocin), CH 11N2< / BR>
roform)

Example 76b.

alpha25D=-158o(C = 0,2, chloroform)

Some compounds corresponding to the invention described in the table.2, are used to obtain other compounds relating to the invention. For example, compound 41 was obtained from compound 39 processing of the primary environment in methanol a mixture of MeOH/H2Acting Compound 49 was obtained from compound 41 processing aqueous ammonia in the presence of DERAA and paph.

Example 77.

N-Ethyl-N-(2-amino-ethyl) -5-chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, (cisisomer)

500 mg of compound 49 was dissolved in 10 ml of acetonitrile and 10 ml of water and add 252 mg of pyridine and 380 mg of bis(Triptoreline) yogashala.

After stirring for 2 h the mixture absorb the hydrochloric acid solution, extracted with ether, alkalinized with dilute sodium hydroxide solution, extracted with DHM, and the extract is dried and concentrated. Produced oil, and the target product is then crystallized from ether.

m 150 mg

So pl. 164oC

Example 78.

N-Ethyl-N-[(lS) (1-etoxycarbonyl) ethyl] -5-chloro-3-(2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indoline the aminouksusnoy acid.

A mixture containing 11 g of the acid obtained in examples 10 and 11, step A, and 5 g of thionyl chloride in 10 ml of chloroform, and heated for 1 h at 60oC. the Mixture is left to the adoption room temperature, concentrated in vacuo, and the residue is dissolved in DHM (twice). Obtained yellow oil, which is used as such in the next step.

IR: 1800 cm-1(C=O)

A) 2' ,5-Dichloro-N-(3,4-dimethoxyphenethyl)-N-[N-ethyl-N'-((1S)(1-etoxycarbonyl)ethyl)ethoxycarbonyl-methyl]2-aminobenzophenone.

Obtaining this compound was carried out in accordance with the work J.Org. Chem. 1985, 50, 945-950.

of 5.15 g (L)-Boc (N-Et)AlaOEt: triturated with 10 ml triperoxonane acid at 0oC to delete a group Vos. The mixture was concentrated in vacuo, dissolved in 20 ml DHM, cooled to -78oC and add 2 equivalents of tea and the acid chloride of the acid obtained in the previous step, dissolved in DHM. After 18 h of exposure at room temperature the mixture is extracted with DHM, the extract washed with water and then chromatographic on silica using for the elution mixture DHM/ethyl acetate (90/10 by volume). The target product is crystallized from isopropyl ether.

So pl. 112oC

m 8 g

C) N-Ethyl-d (cisisomer)

The compound obtained in the preceding stage, stirred for 18 h at room temperature in 10 ml of THF and 20 ml ethanol in the presence of 1.46 g of DBU. The mixture was concentrated in vacuo, the residue is absorbed in DHM, washed with water, concentrated, and the product chromatografic on alumina with elution with a mixture of ethyl acetate /DHM/10/90 by volume)

NMR

About to 0.9 M. D. : Rassel, D.: 3H:-CH-CH3< / BR>
0,9-1,7 m days :m: 6N: 2CH3(ethyl)

from 2.6 to 5.8 m days :m: N: 2OCH3, NCH2, OCH2, NCH, COCH

of 6.1 to 8.3 m days :m: LN: HE-ON aromatics.

Examples 79 and 80.

N, N-di(2-methoxycarbonyl-ethyl)-5-chloro-3- ( 2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone)-3-hydroxy-2-indolinecarboxylic, cisisomer and transisomer.

A) N,N-di(2-methoxycarbonylethyl)benzylamine

The receipt shall be in accordance with the work of J. Am.Chem.Soc. 1950, 72, 3298.

107 g of benzylamine in 200 ml of ethanol cooled in an ice bath and slowly add 172,2 of methyl acrylate in 250 ml of ethanol. After keeping at room temperature for 13 days, the solvent is evaporated in vacuum, and then part of the oily residue is distilled.

So Kip. = 135-140oC at 0.6 mm RT.article.

m 30 g

IR: 1730 cm-1< / BR>
In) N,N-(2-m who're asked with 3 g of 5% palladium on coal and processed within 1 h under pressure in a hydrogen atmosphere. The mixture is filtered through Celite, washed with methanol, and the solvent is evaporated in vacuo, the residual oil is used directly in the next step.

C) N,N-di(2-methoxycarbonylethyl)bromoacetamide

A mixture containing 14.3 g amine obtained in the preceding stage, 100 ml DHM and 10.6 ml of tea, cooled in an ice bath, is added dropwise and 15.3 g of bromoacetamide, and the mixture is left for 48 h at room temperature with stirring. The mixture is extracted with DHM, the extract washed with water, followed by chromatography on silica with elution with a mixture DHM/methanol (97/3 by volume)

m 15.9 g

IR: 1650 cm-1and 1730 cm-1< / BR>
E) 2',5-Dichloro-[N-(3,4-dimethoxyphenethyl)-N-[(N,N-di (2-methoxycarbonylethyl))carbamoylmethyl]]2-amino-benzophenone

14.3 g of 2',5-dichloro-2-(3,4-dimethoxybenzenesulfonamide) -benzophenone are placed in 180 ml of DMF and added portions of 1.1 g of sodium hydride. After stirring for 1 h at room temperature the mixture is cooled in an ice bath and to it was added 14.3 g of the product obtained at the previous stage, after which the mixture is left to mix for 72 h at room temperature. The mixture is extracted with DHM, the extract washed/BR> m 28.4 g

So pl. 130oC

E) N,N-Di[(2-methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-indolinecarboxylic, cisisomer.

12 g of the compound obtained in the preceding stage, mixed with 0.930 g of sodium methylate in 150 ml of methanol at 0oC, and the mixture is then left overnight at room temperature under stirring. The reaction mixture is neutralized by adding 5% KHSO4, after which the solvent is evaporated in vacuum. The remainder chromatographic on alumina with elution with a mixture DHM/ethyl acetate (8/2 by volume). Extract 2.4 g of the target product, which crystallized from methanol.

So pl. 175oC

F) N,N-Di(2-methoxycarbonyl)ethyl] -5-chloro-3-(2-chloro-phenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, transisomer.

Continue the chromatography of the preceding stage and elution carried out with a mixture DHM/methanol (9,5/a 0.5 by volume). Get 1,82 g transisomer, which is crystallized from isopropyl ether.

So pl. 85oC

Examples 81, 82 and 83.

2-((2R)2-Carbamoyliminourea) -5-chloro-3- (2-chloro-phenyl) -1- (3,4-dimethoxyphenylacetone) -3-hydroxyindole, (cisisomer: two connections, trance the em. 1981, 24, 692.

A) 2', 5-Dichloro[N-(3,4-dimethoxyphenethyl)-N-(((2R) 2-carbarnoyl)thiazolidinediones)] 2-aminobenzophenone.

This connection receive conventional methods of acid obtained in examples 10-11, step A).

So pl. 125oC after crystallization from ether.

C) 2-((2R)2-Carbamoilaziridin)-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole.

4.3 g of the product obtained at stage B), in 90 ml of methanol cyclist at room temperature in the presence of 1 g of DBU. The mixture is concentrated and the residue absorb water and DHM, decanted, washed with KHSO4and then dried and concentrated. The remainder chromatographies on alumina with elution with a mixture DHM/methanol (97/3 by volume). Connection receive conforme (mix 2 diastereoisomers): 1.5 g and then transform (mix 2 diastereoisomers):

m 1 g

a) Caraccio crystallized from methanol/DHM order to obtain CIS connection 1.

So pl. 176oC after crystallization from isopropyl ether,

D= +57o(C = 0.1, chloroform)

C) Crystallization solutions from the product of the previous stage chromatographic on silica with elution with a mixture of these
C

D= -185o(C = 0.3, and chloroform)

(C) Transfektsii (mixture of two diastereoisomers) is obtained by recrystallization from isopropyl ether.

So pl. 170o< / BR>
Examples 84, 85, 86 and 86a

5-Chloro-3-(2-chlorophenyl) -1- (3,4-dimethoxyphenylacetone) -3 - hydroxy-2-[(2S) 2-N,N-dimethylthiocarbamyl-pyrrolidinecarbonyl]indolin, cisisomer (2 connections), (transisomer, 2 connections)

A) (L) N,N-dimethyl(N'-BOC)-prolintane

This compound is obtained according to J. Mod. Chem. 1989, 2178.

of 2.36 g of N,N-dimethyl (N-BOC) prolinamide heated in anhydrous toluene in an argon atmosphere at 80oC for 4 h in the presence of 2.3 g of reagent Lawesson. After 24 h the solvent is evaporated and add isopropanol. The resulting precipitate is decanted, the isopropanol is evaporated and the residue chromatographic on silica with elution with a mixture of hexane/ethyl acetate/ (30/70 by volume). The resulting product is recrystallized in the cold of a mixture DHM/ isopropyl ether (30/70 by volume)

So pl. 62oC

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl)-N- ((2S) (2 - N',N'-diethylthiocarbamoyl)pyrrolidinecarbonyl)] 2-aminobenzophenone

3 g of the product obtained in the preceding stage, dissolved in 10 ml DHM and clicks the tion, then add 20 ml DHM and 6.1 g of acid charged in examples 10 and 11, step A) is at 0oC and the mixture is neutralized by the action of 3 g DIPEA. of 5.15 g of BOP are dissolved in 30 ml DHM, and this solution is added within 30 min at 0oC to the previously obtained solution, pH neutral support the addition of DIPEA, and the mixture is left under stirring at 0oC for 3 h After keeping overnight at room temperature the mixture is extracted in the usual way, then chromatographic on silica with elution with a mixture DHM/ethyl acetate. G85/15, by volume). The resulting product is recrystallized from isopropyl ether.

So pl. 182-185oC

D= -72o(C = 0,32, chloroform)

C) 5-Chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxy-2-((2S)2-N, N dimethylthiocarbamyl-pyrrolidinecarbonyl)indolin (cisisomer: 2 transisomer: 2 connections)

3.8 g of the compound obtained in the previous step, dissolved in 15 ml DHM, and the mixture is heated under reflux for 36 h in the presence of 850 mg of DBU. Generated various isomers share the consecutive chromatographic runs on silicon dioxide.

a) using the mixture of DGM/ethyl acetate (85/15 by volume of the Omer twice crystallized from a mixture of DGM/isopropyl ether/methanol and then recrystallized from a minimum amount of DMF at 60 C, followed by addition of 2 volumes of ethanol.

So pl. 270oC

D= -278oC (C = 1, chloroform)

C) Absorb the crystallization of the liquid mixture from the previous stages of the second tisdaledreamer crystallized from a mixture of DGM/isopropyl ether.

So pl. 249-251oC

D+42 (C = 0,22, chloroform)

(C) Chromatographic fractions, erwerbende last, and crystallization mother liquor of stages a) and b) are combined and chromatographic again on silica with elution with a mixture of hexane/ethyl acetate (20/80 by volume). Highlight the first fraction, which is recrystallized three times from a mixture of DGM/isopropyl ether, and nerastvorimaya substance remains on the paper after each recrystallization. So get transisomer 1.

So pl. 191-193oC

D= +74,5o(C = 0,2, chloroform)

d) the Second fraction contains transisomer 2, which is subjected to recrystallization from a mixture of DGM/isopropyl ether and crystallized with 1/3 mole of isopropyl ether.

So pl. 170oC

D= -266o(C = 0,14, chloroform)

Examples 87, 88 and 89.

2-((2S) -2-Carbamoyltransferase) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylacetone) -3-hydroxy-indolin, (cisisomer: 2 Soeder of 35.6 g of 2-amino-5-chlorocyclohexanone and 39.5 g of 3,4-dimethoxyphenylethylamine in 340 ml of pyridine is stirred at room temperature for 24 hours The solvent is evaporated in vacuum and the residue is then washed with water and acid solution (0.5 NHCl). The target product is crystallized from ethanol.

So pl. 135oC

m 56,1 g

A) 2-[N-Benzyloxycarbonyl-N(3,4-dimethoxyphenylacetone) amino] -5-chlorocyclohexanone

3.2 g of sodium hydride are added in several portions to of 52.6 g of compound obtained in the previous step, in 520 ml of DMF and the mixture is stirred at room temperature for 1 h, After cooling in an ice bath are added dropwise 21 ml benzyloxycarbonylamino, and the mixture is stirred at room temperature for 24 hours the Solvent is evaporated in vacuo, and the residue is dissolved in water. It is extracted using DHM, and the extract washed with water, the product obtained is used directly in the next step.

C) N-(4-Chloro-2-cyclohexylcarbonyl)phenyl-N-(3,4-di-methoxybenzenesulfonyl) aminouksusnoy acid

The compound obtained in the preceding stage, are administered together with 3.9 g of 5% palladium on coal in 700 ml of acetic acid in a stream of hydrogen (1 atmosphere). At the end of the reaction, palladium is filtered on Celite and washed with hot acetic acid, the solvent is evaporated in vacuo, and the residue is dissolved in water. Its extras is omatography on silica with elution with a mixture DHM/methanol (97/3 by volume). The target product is crystallized from ethanol.

So pl. 160oC

m 22,4 g

D) 5-chloro-[N-(3,4-dimethoxyphenethyl)-N-((2S) -2-carbamoyltransferase)] 2-aminocyclohexanol

A mixture containing 9,92 g of the acid obtained in the previous step, 3 g (L)-polyamideacid and 3.5 ml DIPEA in 75 ml DHM cooled to 0oC. add 8,84 g of BOP in solution DHM and the pH of the support 7 by the addition of DIPEA. The mixture is left to mix for 24 h at room temperature. The mixture is extracted with DHM, and the extract was washed with a saturated solution of NaHCO3, saline solution, a 5% solution of KHSO4and again salt solution. Product chromatographic on silica with elution with a mixture DHM/ methanol (96/4 by volume). The target product is solidified in isopropyl ether.

So pl. 110oC

m to 7.3 grams

D= -53,9o(C = 1, chloroform)

E) 2-((2S) -2-Carbamoyltransferase) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer (2 connections), transisomer.

5.9 g of the compound obtained in the preceding stage, and 1.67 g of DBU are placed in 60 ml of methanol and stirred for 48 h at 0oC. the Solvent is evaporated in vacuo, water is added, the mixture amine with elution with a mixture DHM/methanol (98/2 by volume).

a) the Least polar fraction contains 2 cisisomer. This fraction is subjected to recrystallization from methanol. First thus obtained compound (CIS 1) purified using HPLC.

So pl. 185oC

The recrystallization mother solutions of methanol receive a second connection (CIS-2). The HPLC purity: 75% (it contains 25% of the CIS 1)

So pl. 132oC

in Most polar fraction contains transisomer, as, apparently, the only connections that are recrystallization from methanol.

So pl. 240oC

D= -55,1o(C = 1, chloroform)

Example 89a.

2-((2S) -2-Carbamoyltransferase) -5-chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer (2 connections), transisomer.

When using a technique similar to that described for examples 87, 88 and 89, the result is a connection using a connection (D) - prolinnova series.

The compound is obtained after crystallization from a mixture of DGM/methanol, is transconfiguration.

So pl. 238oC

D= +164o(C = 0,245, chloroform/methanol, 8,2 by volume).

The NMR spectrum of this compound and the compounds described on the stage of the 4-dimethoxyphenylacetone) -2-[(2S) -2-(N-methylaminomethyl) pyrrolidinecarbonyl] -3-hydroxyindole, cisisomer.

920 mg of the compound obtained in example 28, is injected under stirring in 20 ml DHM containing 371 mg of BOP, for 15 min, then let the current monomethylamine for 10 minutes, after which stirring is continued for further 30 minutes the Mixture is dissolved in water, decanted, washed with hydrosulphate of potassium and sodium carbonate, dried and concentrated. The remainder chromatographic on silica with elution with a mixture DHM/methanol (97,5/a 2.5 by volume). The obtained target product is crystallized from isopropyl ether/DHM.

m 750 mg

So pl. = 158oC

D= -216o(C = 0.3, and chloroform)

Acting in accordance with the techniques described in the previous examples (examples 27 to 31 and 90) using the derivatives of (L) - Proline (except in the opposite direction), there have been additional intermediate compound (VI) for the synthesis of compounds (1), corresponding to the invention.

The compounds (VI) are described in the table. 3.

The obtained compounds (1) are described in the table. 4.

The compound of example 107 is an enantiomer of the compound of example 106.

The compound of example 108A was obtained from the compound of example 28 by reaction of the hydrochloride hydroxyl is obreteniyu, described in table. 4, are used to obtain other compounds. Thus, the compound of example 99 allows you to obtain the compound of example 101, then of example 103 and, finally, the compounds of example 104.

Example 109.

2-((2S, 4S) 4-Azido-2-(methoxycarbonyl)pyrrolidinecarbonyl) -5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer.

A) 2', 5-Dichloro-2)-N-(3,4-dimethoxyphenethyl)-N- ((2S, 4R) 4-hydroxy-2-(methoxycarbonyl)pyrrolidinecarbonyl)] 2-aminobenzophenone

15 g of the acid obtained in examples 10 and 11, step A) and 6.25 g of methyl(2S,4R) 4-hydroxyproline hydrochloride cooled to 0oC in 150 ml DHM in the presence of 7.4 DIPEA. Dropwise within 30 min add 12.7 g of BOP in 30 ml DHM and add the number of DIPEA needed to neutralize the solution. After keeping overnight at room temperature the mixture is extracted in the usual way and chromatographic on silica with elution with a mixture DHM/ ethyl acetate (60/40 by volume). The target product is crystallized from a mixture of DGM/ether/isopropyl ether.

So pl. 128-131oC

D= +8,5o(C = 0.38 (chloroform)

A) 2', 5-Dichloro-[N-(3,4-dimethoxyphenethyl)-N-((2S, 4R) 4-mesilate-2- (methoxycarbonyl) piraat at 0oC in 10 ml DHM. Add 550 mg of triethylamine and then 550 mg methanesulfonanilide, and the mixture is left for 20 hours at 0o. Add water and washed with 0.5 N hydrochloric water and then with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The oil obtained is used directly in the next step.

C) [N-((2S, 4S)4-azido-2-(methoxycarbonyl) pyrrolidinecarbonyl) -N-(3,4/dimethoxyphenylacetone] 2-amino-2',5-dichlorobenzophenone

11 g of the product obtained in the previous step, is heated in 60 ml of DMSO at 80-90oC in the presence of 2.7 g of sodium azide for 18 hours the Mixture was poured into water, extracted with ethyl acetate, washed with water, dried and subjected to chromatographicaliy on silica with elution with a mixture of pentane/ethyl acetate (5o/50 by volume). Turns out the oil (10 g)

D= -25,5o(from 0.39, chloroform, 26oC)

D) 2-((2S,4S)4-Azido-2(methoxycarbonyl)pyrrolidinecarbonyl) -5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer.

to 3.38 g of the product obtained in the previous step, cyclist under normal conditions in the presence of DBU. Get the target product, which is subjected to recrystallization from a mixture of DGM/isopropyl ether.

2-[(2S,4S)(N-Benzyloxycarbonyl-N-methyl) 4-amino-2-(methoxycarbonyl)pyrrolidinecarbonyl]-5-chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone)-3-hydroxyindole, cisisomer.

A) Methyl ester of (N-BOC)-4-hydroxyproline.

The original substance is hydrochloride methyl ester (2S,4R) 4-hydroxyproline.

19 g of this compound are suspended in 100 ml of THF, add 22.9 grams (Vos)2O, after which the mixture is cooled to 0oC. added dropwise to 21.2 g of triethylamine in 25 ml of THF, and the mixture is then stirred for 12 h at 0oC and 4 h at 60oC., water is Added, the mixture extracted with ethyl acetate, washed with water, a solution of potassium hydrosulfate (4 times), water and then salt water. The solvent is evaporated and oil (21,6 g), which contains a small amount (Vos)2O.

C) Methyl ester of (2S,4R) - (N-BOC)-4-mesilate-Proline

The solution containing 22.9 grams of the product obtained in the previous step 250 ml DHM, cooled to 0oC. added dropwise to 22.9 g methylchloride in 10 ml DHM, then added dropwise 9.4 g of triethylamine in 100 ml DHM, and the mixture is left overnight to bring it to room temperature. The mixture is evaporated until dry, add water, mix extrage the produced oil, used directly in the next step.

C) Methyl ester of (2S,4S) - (N-BOC)-4-azidopyridine

This compound is obtained from the compound obtained in stage Century.

15.2 g of methyl ester (N-BOC)-4-methyloxirane dissolved in 70 ml of DMSO, and the solution is heated at 90oC for 5 h in the presence of 3.05 g of sodium azide. The mixture is cooled, water is added, the mixture extracted with ethyl acetate, washed with water, then with salt water and dried over MgSO4. The oil obtained is purified by chromatographytandem on silica with elution with a mixture of ethyl acetate/hexane (40/60 by volume)

D= -37,8o(3, chloroform)

D= -36,6o(from 2.8, chloroform) according to D. J. Abraham and others J. Med.Chem. 1983, 549, 26.

D) Methyl ester of (2S,4S) - (N-BOC)-4-aminopropane

8,45 g of compound obtained in stage C, is dissolved in 100 ml of methanol, is added 500 mg of 10% Pd/C,and the mixture is subjected to hydrogenation at 40oC for 18 hours the Catalyst is filtered off, half of the methanol is evaporated, add 100 ml of 0.5 N model HC1, then evaporated the remaining part of the methanol and unreacted starting material is extracted with ethyl acetate. The aqueous phase is treated with sodium carbonate, and the fraction containing the target diprolene.

The crude product obtained in the previous step, dissolved in 15 ml of ether and 15 ml DHM at 0o. Add 2.3 g of DIPEA and then 3.03 g of benzylchloride in 5 ml DHM for 70 min at 0oC. After 3 h the solvent is evaporated in vacuum at room temperature, add water and ethyl acetate, and the organic phase is washed successively with a solution of potassium hydrosulfate (3 times), water (3 times), sodium carbonate solution (3 times), water (3 times) and brine. The product is subjected to chromatographicaliy on silica by elution with a mixture of hexane/ethyl acetate (40/60 by volume) to obtain the target product.

D= -16,4o0.3, chloroform)

F) Methyl ester of (2S,4S) - (N-BOC)-(N'-benzyloxycarbonyl-N'-methyl) 4-aminopropane

2 g of the compound obtained in the preceding stage, dissolved in 20 ml of DMF at 0oC in argon atmosphere in the presence of 2.25 g of methyl iodide. In portions added 170 mg of 80% sodium hydride, and then the mixture is stirred for 90 min at 0oC. the Mixture is extracted with water and ethyl acetate, the organic phase is washed with water, then with salt water. The product is subjected to chromatographicaliy on silica by elution with a mixture of hexane/ethyl acetate (50/50 by volume-(3,4-dimethoxyphenylacetone) -N(N'-benzyloxycarbonyl-N'-methyl) 4-amino-2-methoxycarbonyl) pyrrolidinecarbonyl]2-aminobenzophenone.

This product is produced using conventional methods

D= -22,4o(C = 0,37, chloroform)

H) 2-[((2S,4S)N-Benzyloxycarbonyl-N-methyl)4-amino-2- (methoxycarbonyl) pyrrolidinecarbonyl] -5-chloro-3- (2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer

This product is obtained by cyclization in the presence of DBU in accordance with conventional methods. Educated crystalline substance is crystallized from a mixture of DGM/isopropyl ether.

So pl. 129oC

D= -129o(C = 0,321, chloroform)

Isomeric purity according to HPLC method is 99%

The compounds obtained in examples 109 and 110, are used to obtain compounds of the invention are described in the table.5.

The compound of example 112 allows you to obtain the compounds of examples 115 and 116, as described in table. 6 below, and the compound of example 114 provides an opportunity to obtain the compound of example 116A.

Connection example 116A may be obtained either by the conversion of example 114, or from (2S,4S)-(N-BOC)-4-(dimethylamino)prolinamide, the receipt of which is as follows.

1) Methyl (2S,4S)-(N-BOC)-4-aminopropanal prepared from methyl (2S,4S)-4-azidopyridine in sootvetsvenno, obtained in stage 1), dissolved in 50 ml of acetonitrile, add to 12.8 ml of 30% aqueous formalin and then, after 5 min, 3 g of cyanoborohydride sodium. After interaction of reagents for 2 h is added acetic acid to bring the pH of the solution to 6. After 3 h, the acetonitrile is evaporated, water is added, the potassium carbonate and solid sodium chloride, and the mixture is extracted with 4 volumes of ethyl acetate. The organic phase is evaporated, the residue is dissolved in 1 N hydrochloric acid and perform the extraction with ethyl acetate. To the aqueous phase add solid sodium carbonate, and then solid sodium chloride and the extraction is carried out with ethyl acetate. After evaporation the residue is subjected to chromatographicaliy on silica gel by elution with a mixture DHM/methanol (95/5 by volume), and hardened oil allocate.

m 2.1 g

IR (DHM): 1755-1see , 1695-1cm

3) 534 mg of the ester obtained in stage 2), dissolved in 4 ml of methanol and treated with sodium hydroxide (116 mg) in 1 ml of water for 48 h at room temperature. The mixture is acidified to pH 3.5 with 0.5 H hydrochloric acid and evaporated to the dry state. Conduct azeotropic drying of the residue in the presence of benzene (5 times) and then the residue is dried in vacuum for 8 hours then add IPAA. After 15 min passed through the current of gaseous ammonia twice within 30 minutes After incubation for 2 h at room temperature DHM evaporated, add carbonate water and sodium chloride, and the mixture is extracted with 4 volumes of ethyl acetate. After evaporation the residue is subjected to chromatographicaliy on silicon dioxide. A mixture of (DHM/methanol/NH4HE; 84,5/15/of 0.5 by volume) elute solid (m 185 mg), which is recrystallized from a mixture of DGM/isopropyl ether.

So pl. 183-186oC

D= -63,1o(from 0.24, chloroform)

Example 117.

Decarboxylation of N-(2-carboxyethyl)-N-ethyl-3-(2 - chlorophenyl) -5-chloro-1- (3,4-dimethoxyphenylacetone) -3-hydroxy-2-indolinecarboxylic, cisisomer.

630 mg of the compound obtained in example 41, was dissolved in 20 ml of THF in an argon atmosphere and then added 101 mg N-methylmorpholine at -15oC and 118 mg of isobutylacetate. After stirring for 5 min add 127 mg of N-hydroxy-2-pyridinethione and 101 mg TFU, the mixture was kept at -15oC under stirring for 15 minutes, and then add 900 mg tributylamine, and the mixture is left to bring it to room temperature. Then the reaction mixture is irradiated for 1 h 30 wolframium. The residue is subjected to chromatography on silica with elution DHM/ethyl acetate (95/5 by volume). Get the target product.

m 300 mg

So pl. 215oC

This compound similar to the compound of example 125, described in European Patent Application EP 469984. It has isconfiguration in relation to communication 2.3 indoline and used as the original product.

Example 118.

Decarboxylation of 2-((2R) 2-carboxymethyl pyrrolidinecarbonyl) -5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer.

Work on the technique of the previous example, but using the compound of example 102.

The resulting product is recrystallized from a mixture of DGM/isopropyl ether.

So pl. 215-220oC

D= -214,5o(C = 0,2, chloroform)

This connection is a 2((2$)2-methylpyrrolidinyl) -5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone)-3-hydroxyindole, cisisomer.

Example 119.

Decarboxylation of 2-(2-carboxypropanoyl) -5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer

Work on the technique of the previous example using the connection, the floor is pillowy ether-DHM.

So pl. 263oC

D= -201,5o(0.2, chloroform)

This compound is a 2-pyrrolidinecarbonyl-5-chloro-3-(2-chlorophenyl) -1-(3,4-dimethoxyphenylacetone) -3-hydroxyindole, cisisomer.

Examples of pharmaceutical compositions can include the following herbal form:

Gelatin capsule with a capacity of 480 mg

1) Active start - 5.0 mg

Corn starch - 137,45 mg

Crystalline lactose - 320,75 kg

Talc - 9.6 mg

Colloidal anhydrous silica - 2.4 mg

Magnesium stearate - 4,8 mg

2) Active start - 100.0 mg

Corn starch - 108,96 kg

Crystalline lactose - 257,24 mg

Talc - 9.6 mg

Anhydrous colloidal silicon dioxide - 2.4 mg

Magnesium stearate - 4,8 mg

Vials with a volume of 10 ml

1. Active start - 1 mg

The polyethylene glycol 400 - 1.5 grams

2. The active principle 10 mg/ml

The polyethylene glycol 400 4 grams

The results of biological testing of the compounds obtained are given in table.7.

1. Indolinone derivatives of General formula

< / BR>
in which R1halogen, C1WITH4-alkyl, C1- C4-alkoxy;

R2WITH1WITH6-alkyl, C3WITH7- cycloalkyl, phenyl, nezameddin;

R4carnemolla group of the formula CONR6R7;

R5WITH1WITH4-alkyl, phenyl, unsubstituted or substituted by one or more substituents selected from halogen, C1WITH4-alkyl, C1WITH4-alkoxy;

R6WITH1WITH6-alkyl, or R6same as R7;

R7the group piperidine-4-yl, unsubstituted or substituted on the nitrogen WITH1WITH4-alkyl, C1WITH4-alkoxycarbonyl, the group (CH2)r, which is itself substituted by a group of 2-, 3 - or 4-pyridyl or an amino group, a free or substituted by one or two1WITH4-alkilani, a carboxyl group, a group WITH1- C4-alkoxycarbonyl, carbamoyl group, free or substituted by one or two1WITH4-alkilani, or R6and R7form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, piperazine, unsubstituted or substituted in position 4 by a group of R8"unsaturated 5-membered cycle containing a single nitrogen atom, substituted by the radical R8or a saturated 3-, 4-, 5 - or 6-membered cycle, which contains the unity of the
, which is itself substituted by a hydroxyl or amino group, a free or substituted by one or two1WITH4-alkilani;

R'8group (CH2)q, which is itself substituted by a carboxyl group, a C1WITH4-alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, a free or substituted hydroxyl or one or two C1WITH4-alkilani, or aminocarbonyl group, free or substituted by one or two1WITH4-alkilani;

R8R'8or group (CH2)2NH2free or substituted by one or two1WITH4-alkilani;

R9hydrogen group (CH2)rNR10R11the band azido or the group NH-benzyloxycarbonyl;

R10and R11independently from each other hydrogen or C1WITH4-alkyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

r is 0, 1, 2 or 3, provided that r is 0 when R8and R9located in the alpha-position to the intra-cyclic amide nitrogen,

or their possible salts.

2. Derivatives under item 1, in which R1chlorine, or bromine, or metaxylene group, and n is 1.

3. Derivatives PP.1 and 2,R5phenyl, substituted in position 4 by the stands, or phenyl, substituted by a methoxy group in positions 3 and 4.

5. Derivatives PP.1 to 4, in which m is 0.

6. Derivatives PP.1 5, in which R4CONR6R7and NR6R7is pyrrolidinones, substituted in position 2 by a group (CH2)q, which is itself substituted by a carboxyl group or karbonilnoj group with a value of q 0, 1, 2, or 3.

7. Derivatives PP.1 5, in which R4CONR6R7and NR6R7is piperidino, substituted in position 4 the amino group, WITH1WITH4-alkylamino or1< / BR>
WITH4-dialkylamino.

8. Derivatives PP.1 5, in which R4CON6R7and NR6R7is thiazolidinones substituted by a group (CH2)qwhich is substituted by a carboxyl group or carbamoyl group with the value of q is 0, 1, 2, or 3.

9. Derivatives PP.1 5, in which R4CONR6R7and NR6R7is pyrrolidinones, substituted in position 2 by a group (CH2)q, which is itself substituted by a carboxyl group or carbamoyl group, and in position 4 aminogroup which R4CONR6R7while R6is1WITH4-alkyl, and R7group (CH2)r, which is itself substituted by a carboxyl group or carbamoyl group with a value of r 1, 2 or 3.

11. Derivatives PP.1 10 in the form of the CIS isomer, where R2and R4located on one side indolinone rings.

12. The method of obtaining compounds of formula I on p. 1, characterized in that they are subjected to the interaction of 2-aminophenazone derivative of the formula II

< / BR>
in which R1, R2and n have the meanings given in paragraph 1,

with sulfonyl derivative of the formula III

Hal-SO2-(CH2)m-R5,

in which Hal is halogen, preferably chlorine or bromine;

m and R5have the meanings given in paragraph 1,

the compound obtained of the formula IV

< / BR>
treat halogenated derivative of formula V

Hal' CH2SOA,

in which Hal' is halogen, preferably bromine;

A or the group NR6R7or the group OR in which R is tertiary butyl or benzyl,

obtaining the compounds of formula VI'

< / BR>
which is subjected to cyclization in the main environment, if A - NR6R7with obtaining the target product, or VI"

< / BR>
or its acid chloride of formula VI"'

< / BR>
which is subjected to the treatment with the amine HNR6P7to obtain an amide derivative of the formula VI

< / BR>
which is subjected to the specified cyclization to obtain the desired product of formula I, share if necessary, the resulting product of CIS - and TRANS-isomers and distinguish enantiomers.

13. Intermediate compounds of General formula

< / BR>
where A' is a group selected from NR6R7;

R1halogen, C1WITH4-alkyl, C1- C4-alkoxy;

R5WITH1WITH4-alkyl, phenyl, unsubstituted or substituted by one or more substituents selected from halogen, C1WITH4-alkyl;

R6WITH1WITH4-alkyl, or R6same as R7;

R7the group piperidine-4-yl, unsubstituted or substituted on the nitrogen WITH1WITH4-alkyl, C1WITH4-alkoxycarbonyl, the group (CH2)r, which is itself substituted by a group of 2-, 3 - or 4-pyridyl or an amino group, a free or substituted by one or two1WITH4-alkilani, a carboxyl group, a group WITH1- C4-alkoxycarbonyl, carbamoyl group, free or substituted animezone, a heterocycle selected from the research, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, piperazine, unsubstituted or substituted in position 4 by a group R ' 8unsaturated 5-membered cycle containing a single nitrogen atom, substituted by the radical R8or a saturated 3-, 4-, 5 - or 6-membered cycle, containing a single nitrogen atom and substituted by the radicals R8and R9;

R8R'8or group (CH2)r, which is itself substituted by a hydroxyl or amino group, a free or substituted by one or two1WITH4-alkilani;

R'8group (CH2)q, which is itself substituted by a carboxyl group, a C1WITH4-alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, a free or substituted hydroxyl or one or two C1WITH4-alkilani;

R8R'8or group (CH2)2NH2free or substituted by one or two1WITH4-alkilani;

R9hydrogen group (CH2)rNR10R11the band azido or the group NH-benzyloxycarbonyl;

R10and R11independently from each other hydrogen or C1or R9located in the alpha-position to the intra-cyclic amide nitrogen,

or their possible salts.

14. The pharmaceutical composition exhibiting inhibitory activity to the receptor ocytocin and/or vasopressin, comprising the active principle and a pharmaceutically acceptable additive, characterized in that the active agent it contains indolinone derivative of General formula I on p. 1 in an effective amount.

 

Same patents:

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to 5,6-disubstituted-3 - pyridylmethylamine compounds of the formula I

< / BR>
where Z is hydrogen, halogen;

Z1represents hydrogen, halogen, cyano and nitro;

X represents Cl, Br, J, or R3SO3;

R3represents C1-C4-alkyl or phenyl, are not necessarily substituted with one to three C1-C4-alkoxygroup, C1-C4- alkyl groups, nitro groups: cyano groups or halogen atoms;

Y and Y1each independently represents OR4, NR4R5or, if they are taken together, YY1represent-O-, -S - or;

R4and R5are each independently hydrogen, C1-C4-alkyl, does not necessarily substituted C1-C4- alkoxygroup, or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup or halogen atoms; or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup atoms or halogen;

R6represents hydrogen or C1- C4- alkyl;

Q is

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

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents

The invention relates to a method for producing N-(2,4-differenl)-3-(2-furoyl)-oxindole-1-carboxamide - new biologically active compounds that may find application in medicine

The invention relates to agriculture, namely, to the drugs designed to combat ectoparasites of farm and domestic animals and can be used in collective farms, state farms, joint stock and cooperative agricultural associations and farms

The invention relates to new derivatives of pyrrolidine and their pharmaceutically acceptable salts

The invention relates to acryloyl-substituted derivatives of pyrrole of the formula (I)

,

in which n is an integer from 1 to 5; each of R1and R2which may be identical or different, is hydrogen, halogen, -CN, -NO2C1-C4the alkyl, or a group:, R3is hydrogen, halogen, -CN or-NO2

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The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents
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