Derivatives of 1-benzazolyl-1,3-dihydro-indol-2-it, the way they are received and containing pharmaceutical compositions

 

(57) Abstract:

Derivatives of 1-benzazolyl-1,3-dihydroindol-2-it General formula I, where R1halogen, trifluoromethyl, or C1-7-alkoxyl; R3, R4- -hydroxyalkyl, in which the hydroxyl possibly substituted by alkyl, tetrahydrofuranyl or tetrahydropyranyl, or R3, R4together form a group -(CH2)pX(CH2)q-, or R3, R4together with the carbon atom to which they are bound, form a hydrocarbon WITH3-12-cycle, possibly condensed, possibly substituted by alkyl, exography, 1-2 hydroxyl; R5- C1-7-alkoxyl; R6- guanidine radical (other designations, see p. 1 f-ly), as well as their possible salts have affinity for receptors vasopressin and/or ocytocin.

< / BR>
6 C. and 5 C.p. f-crystals, 7 PL.

The object of the present invention are derivatives of 1-benzazolyl-1,3-dihydro-indol-2-it, the way they are received and containing pharmaceutical compositions.

In the international patent application WIPO 91/01306 describes derivatives of 2-oxoindole suitable for the treatment of senile dementia. These compounds correspond to the formula (I)

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in which R1The SUB>3denotes alkyl, cycloalkenyl, benzodioxolyl or, if necessary, substituted benzyl;

R4denotes 1-propyl-butyl, pyridyl, or if necessary substituted phenyl.

In addition, the number of patent applications describe a group of compounds with ones structure, possessing activity against receptors of vasopressin and/or ocytocin. These include European patent application EP 382185, EP 444945, EP 514667, EP 469984 and EP 526348, the international application to WIPO 91/05549 and 93/15051, patent application Japan 04/321 669, in particular patent application Japan 03/127 732. In this latter application describes derivatives of indole-3-propanoic acid of formula (II)

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in which R"'1denotes hydrogen, alkyl, alkenyl, phenylalkyl, tetrahydrofuryl, alkoxycarbonyl, alkoxycarbonylmethyl, carboxyethyl or alkanoyl;

R"'2denotes hydrogen, hydroxyl, alkoxyl, alkyl, phenylalkyl, funeralcare or halogen;

R"'3denotes hydrogen, alkoxy, an amino group, a free or substituted, or amino acid residue;

R"'4denotes hydrogen, alkyl or phenylalkyl;

R"'5represents benzoyl, phenyl, alkyl, phenylacetylcarbinol, thienylboronic, phenylsulfonyl substituted.

These compounds are antagonists of vasopressin.

In U.S. patent 4 803217 claimed healingalien obtained by fermentation, which are antagonists of vasopressin.

These compounds correspond to the following formula (III)

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in which R denotes hydrogen or chlorine.

Currently, the applicant has developed new derivatives of 1-benzazolyl-1,3-dihydro-indol-2-it, which also have an affinity to receptors of vasopressin and ocytocin.

Vasopressin is a hormone known for its antidiuretic effect and its action in regulating blood pressure. It stimulates several types of receptors:

V1(V1aV1b)V2. These receptors are localized in the liver, the blood vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal glands, Central nervous system, the pituitary gland. Ocytocin peptide has a structure similar to that of vasopressin. Receptors ocytocine are also found in the smooth muscle of the uterus, they are also found in muscle and epithelial cells of the mammary gland, the Central nervous system and the kidney. Localization of different receptors described S. Jars and other Vasopressin and ocytocin're 1987, 16 (10), 481-495; J. Lab. Clin. Med. 1989, 114, (6), 617-632 and Pharmacol Rev. 1991, 43 (1), 73-108. Vasopressin also has cardiovascular, hepatic, antidiuretic, an aggregating action affects the Central and peripheral nervous system, as well as in the uterine area. Ocytocin participates in childbirth, lactation and sexually behavior.

Compounds according to the present invention allows a selective manner or to simulate the effect of a hormone (connection agonists) or suppress (connection antagonists). Antagonists of vasopressin receptors may participate in the regulation of the Central or peripheral circulatory disorders, especially coronary, renal and gastric blood circulation, as well as in water regulation and release adrenocorticotropic hormone (ACTH). Agonists of vasopressin may replace vasopressin or its analogs in the treatment of diabetes; they can also be used in the treatment of enuresis and in the regulation of hemostase : treatment of hemophilia, the syndrome of VopWillebrand's antidote aggregation of platelets; F. A. Laszlo, Pharmacol Rev. 1991, 43, 73-108. Drug Investigation 1990, 2, (Appendix 5), 1-47. The hormones vasopressin and ocytocin and their peptide or ones analogues and their terpene suitable for the treatment of diseases of the Central and peripheral nervous system, cardiovascular system, renal activity, gastric activity and disorders of sexual behavior in humans and animal.

The object of the present invention are compounds of the formula /I/

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in which R1and R2each, independently of one another represent hydrogen; hydroxyl halogenoalkanes with 1-7 C atoms, halogen, alkyl with 1 to 7 C-atoms; trifluoromethyl; alkoxy with 1-7 C atoms; POLYHALOGENATED with 1-7 C atoms; - hydroxyalkoxy with 2-7 C atoms; - methoxyethoxy, in which the alkyl contains 2 to 7 C-atoms; - aminoalcohol with 2-7 C atoms, free or substituted by one or two alkilani with 1-7 C atoms; cycloalkylation with 3-7 C-atoms; cycloalkylation, in which cycloalkyl contains 3-7 C atoms, phenoxy, benzyloxy, alkylthio with 1-7 C atoms; penalty, the nitro-group, an amino group, a free or substituted by one or two alkilani with 1-7 C atoms; cyano; (C1-C6-alkylsulphonyl; formyl; (C1-C6)-alkylcarboxylic; formyloxy; alkylsulfonamides with 1-7 C atoms; phenylsulfonyl; benzylmaleimide; alkylamide with 1-7 C atoms; alkoxycarbonylmethyl with 1-7 C atoms; raidgroup, unsubstituted or substituted phenyl, Bedlam or one or two alkilani with 1-7 C atoms;

R3and R4each, independently of one another, denote alkyl with 1 to 7 C-atoms; cycloalkyl with 3-7 C atoms; phenyl; benzyl; cycloalkenyl in which cycloalkyl represents itself with 3-7 C-atoms; - hydroxyalkyl with 2-7 C atoms, in which the hydroxyl is free or substituted by a group selected among alkyl with 1-4 C-atoms, (C1- C5)- CNS, in which the alkyl has 1-4 C-atoms, fenilalkilamina in which alkoxyl has 1-2 C-atoms and the alkyl contains 1-4 C-atoms, tetrahydropyranyloxy and tetrahydropyranyloxy groups; or

R3and R4together form a group - C(H2)pX(CH2)q-; or R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, unsubstituted or substituted by one or more alkyl groups with 1 to 7 C-atoms; oxo group; spirocyclohexane with 3-5 C atoms; one or two hydroxyl, free or substituted by a group selected among alkyl with 1-4 C-atoms, (C1-C5)-alkoxyalkyl, in which the alkyl contains 1-4 C-atoms, - hydroxyalkyl in which the alkyl contains 1-4 C-atoms, Trifan the C-atom and the alkyl contains 1-4 C-atoms, tetrahydrofuranyl, tetrahydropyranyl, formyl and (C1-C7)-alkylcarboxylic groups;

R5and R6each, independently of one another, denote hydrogen; halogen; alkyl with 1 to 7 C-atoms; trifluoromethyl; cyano; nitro-group; an amino group, a free or substituted by one or two alkilani with 1-7 C atoms; hydroxyamino; hydroxyl; carboxyl; guanidinium, unsubstituted or substituted one or twice by alkyl with 1 to 7 C-atoms, phenyl or benzyl; a group OR7; group SR7; (C1-C6-alkylsulphonyl; formyl; alkoxycarbonyl with 1-7 C atoms; phenoxycarbonyl; benzyloxycarbonyl; carbarnoyl, substituted groups R'6and R6; thiocarbamoyl, free or substituted by one or two alkilani with 1-7 C atoms; sulfamoyl; alkylsulfonyl or dialkylamino, in which the alkyl contains 1 to 7 C-atoms; a group of SO2R'7; alkyl fenamidone, in which the alkyl contains 1 to 7 C-atoms; vinylsulfonate; benzylmaleimide; a group COR'7; group NR8R9; group CO2NH-CR10R'10-COR12; and phenyl group, a component of the substituent R5and/or R6may be not substituted or is substituted by one or whamola, in which the alkyl contains 1 to 7 C-atoms, carboxyla, alkoxycarbonyl, in which the alkyl contains 1 to 7 C-atoms, (C1-C6-alkylcarboxylic, imidazolium;

R'6and R6each, independently of one another, denote hydrogen;

alkyl with 1-7 C atoms, unsubstituted or substituted by one or more halogen atoms or the radical R6; cycloalkyl with 3-7 C atoms, unsubstituted or substituted (C1-C4)- alkyl; phenyl; pyridyl; methylpyridyl; piperidine-4-yl; methylpiperidin-4-yl; pyrrolidin-1-yl; or

R'6and R6with the nitrogen atom to which they are bound, form pyrrolidino substituted by hydroxymethyl, carbamoyl, free or substituted by one or two alkilani with 1-7 C atoms;

R"'6denotes hydroxyl; alkoxyl with 1-7 C atoms, an amino group, a free or substituted by one or two alkilani with 1-7 C atoms; carbarnoyl, free or substituted by one or two alkilani with 1-7 C atoms, or in which two Deputy together with the nitrogen atom to which they are bound, form pyrrolidino-, piperidino or peligrosamente; cyano; carboxyl, free or esterified by alkyl with 1 to 7 C-atoms, or by benzyl, phenyl, cycloalkyl with 3-7 C-at triidothyronine, thienyl, methyldienolone, pyrrolidino-, piperidino-peligrosamente;

R7denotes alkyl with 1 to 7 C-atoms; phenyl, benzyl; cycloalkyl with 3-7 C-atoms; alkenyl with 2-7 C atoms; - halogenated with 2-7 C atoms; POLYHALOGENATED with 1-7 C atoms; - hydroxyalkyl with 2-7 C atoms; (C1-C6-alkylsulphonyl, formyl; - carboxyethyl with 1-7 C atoms, free or esterified by alkyl with 1 to 7 C-atoms or benzyl; - aminoalkyl with 2-7 C atoms, in which the free amino group substituted by one or two alkilani with 1-7 C atoms, or is in the form of ammonium ion; - carbamoylethyl with 1-7 C atoms, free or substituted by one or two alkilani with 1-7 C atoms;

R'7means piperazine-1-ilen group, unsubstituted or substituted in position 4 by a group R ' 7; piperidinium, unsubstituted or substituted in position 4 by a group R'7; azetidin-1-ilen group, unsubstituted or substituted in the 3 position by a group R'7; pyrrolidinone, unsubstituted or substituted by a group R""7;

R7denotes alkyl with 1 to 7 C-atoms; phenyl; benzyl; (C1-C6-alkylsulphonyl; formyl;

R"'7denotes the R7or an amino group, a free or containing a protective group; a
R8and R9each, independently of one another, denote hydrogen; alkyl with 1 to 7 C-atoms; benzyl; phenyl; and R9,

in addition, you may designate alkene with 3-8 C atoms; (C1-C6-alkylsulphonyl; formyl; (C1-C6- alkylthiomethyl; cycloalkylcarbonyl in which cycloalkyl contains 3-7 C-atoms; cycloalkylcarbonyl in which cycloalkyl contains 3-7 C-atoms; - amino (C2-C6-alkylsulphonyl, hydroxy - (C1-C6-alkylaryl; - benzyloxy - (C1-C6-alkylsulphonyl; phenoxycarbonyl; phenoxythiocarbonyl; teenageboys; pyridylcarbonyl; methylphenylcarbinol; alkoxycarbonyl with 1-7 C atoms; benzoyl; phenacetin; group CO-CR10R'10-NR11R'11; group CR10R'10COR12; group (CH2)t+ COR12; group CO(CH2)t'COR12; carbamoyl, unsubstituted or substituted with R14and R'14; thiocarbamoyl, unsubstituted or substituted with R14and R'14; heterocyclic radical chosen among pyrazolidine, imidazolidine, triazoline, tetrazolyl, peredelnoj, pyridazinyl, pyrimidinamine, peredelnoj, thiazolidine groups;

or R8and R9together with ATOL-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl or isoindoline-2-yl, in which the benzene nucleus may be substituted or substituted with halogen, alkyl with 1 to 7 C-atoms, trifluoromethyl or methoxy group;

R10and R'10each, independently of one another, denote hydrogen, alkyl with 1 to 7 C-atoms or benzyl, or R10and R'10together with the carbon atom to which they are bound, form cycloalkyl with 3-7 C-atoms;

R11and R'11each, independently of one another, denote hydrogen or alkyl with 1 to 7 C-atoms;

R12denotes hydroxyl, alkoxy with 1-7 C atoms, amino group, unsubstituted or substituted by one or two alkilani with 1-7 C atoms;

R13denotes hydrogen, alkyl with 1 to 7 C-atoms, phenyl, benzyl, (C1-C6-alkylsulphonyl, formyl, alkoxycarbonyl with 1-7 C atoms, carbarnoyl, unsubstituted or substituted by one or two alkilani with 1-7 C atoms;

R14and R'14each, independently of one another, denote alkyl with 1-7 C atoms, unsubstituted or substituted with R15; phenyl, unsubstituted or substituted with R'15cycloalkyl with 3-7 C-atoms; substituted;

or R14and R'14together with the nitrogen atom to which they are bound, form a heterocycle, cybercam the above heterocycle is not substituted or substituted by one or more methyl groups, by phenyl, amino group, a free or containing a protective group;

R15denotes phenyl, pyridine, hydroxyl, alkoxyl with 1-7 C atoms, an amino group, a free or substituted by one or two alkilani with 1-7 C atoms; carboxyl, free or esterified by alkyl with 1 to 7 C-atoms;

R'15denotes a hydroxyl, an amino group, a free or substituted by one or two alkilani with 1-7 C atoms;

"m" is 1, or, when R6represents halogen, alkyl with 1 to 7 C-atoms or alkoxy with 1-7 C atoms, "m" may also refer to 2, 3 or 4, or (R6)mcan mean "m" substituents are different, selected among halogen, alkyl with 1 to 7 C-atoms or alkoxyl with 1-7 C atoms;

"p" and "q" refers to each integer, and the sum may vary within 3-6;

"t" denotes an integer that varies from 2 to 5;

"t'" denotes an integer that can vary from 0 to 3;

X is oxygen, a group S(O)ngroup NR13group N(O) R13;

"n" represents 0, 1 or 2;

with the limitation that when

R1and R2such as defined above, except raidgroup, substituted benzyl group, or cheoreography, illegal the SUB> each, independently of one another, denote alkyl with 1-6 C-atoms, cycloalkyl with 3-7 C-atoms, phenyl, benzyl, cycloalkenyl in which cycloalkyl contains 3-7 C-atoms;

or

R3and R4together form a group - (CH2)ppX(CH2)qin which X denotes oxygen, sulphur or the group NR13;

or

R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3-10 C atoms, saturated or unsaturated, which may be condensed, unsubstituted or substituted by one or more alkyl groups with 1 to 7 C-atoms or spirocyclohexane with 3-5 C atoms;

R5and R6other than hydrogen, halogen; alkyl with 1 to 7 C-atoms; trifluoromethyl; cyano; nitro-group; amino group, a free or substituted by one or two alkilani with 1-7 C atoms; gidroksilaminopurina; hydroxyl; carboxyl, group OR7the group SR7; /C1-C6/-alkylsulphonyl; formyl; alkoxycarbonyl with 1-7 C atoms; phenoxycarbonyl; benzyloxycarbonyl, carbamoyl, substituted groups R'6and R6; thiocarbamoyl, free or substituted by one or two alkilani with 1-7 C atoms; sulfamoyl; alkylsulfonyl or dialkylamide who will win 1-7 C-atoms; the group COR'7the group NR8R9; group of CO2NH-CH/R10/-COR12and in a desirable way, phenyl group, a component of the substituent R5and/or R6may not be substituted or substituted one or more times by alkyl with 1 to 7 C-atoms, trifluoromethyl, methoxy group, halogen, sulfamoyl, alkylsulfonyl, in which the alkyl contains 1 to 7 C-atoms, carboxyla, alkoxycarbonyl, in which the alkyl contains 1 to 7 C-atoms, (C1-C6)- alkylcarboxylic, formyloxy, imidazolium;

moreover, in groups of R5and/or R6;

R'6and R6each, independently of one another, denote hydrogen; alkyl with 1 to 7 C-atoms, unsubstituted or substituted with R'6; phenyl; pyridyl; methylpyridyl; piperidine-4-yl; methylpiperidin-4-yl;

R"'6denotes hydroxyl; cyano; carboxyl, free or esterified by alkyl with 1 to 7 C-atoms, or by benzyl, phenyl; pyridyl; methylpyridyl; an amino group, a free or substituted by one or two alkilani with 1-7 C atoms;

R7denotes alkyl with 1 to 7 C-atoms; phenyl; benzyl; cycloalkyl with 3-7 C-atoms; alkenyl with 2 to 4 C-atoms; - halogenated with 2-7 C atoms; POLYHALOGENATED with 1-7 C atoms, /C1-C6/-alquiler is m; - aminoalkyl with 2-7 C atoms, in which the free amino group substituted by one or two alkilani with 1-4 C atoms, or is in the form of ammonium ion;

R'7means piperazine-1-ilen group, unsubstituted or substituted in position 4 by a group R ' 7; piperidinium, unsubstituted or substituted in position 4 by a group R'7; azetidin-1-ilen group, unsubstituted or substituted in the 3 position by a group R'7;

R7denotes alkyl with 1-4 C-atoms; phenyl; benzyl; /C1-C3/-alkylsulphonyl;

R"'7denotes the R7or an amino group, a free or containing a protective group;

R8and R9each, independently of one another, denote hydrogen; alkyl with 1 to 7 C-atoms; phenyl; benzyl; moreover, R9can refer to a /C1-C6/- alkylsulphonyl; formyl; cycloalkylcarbonyl in which cycloalkyl contains 3-7 C atoms, cycloalkylcarbonyl in which cycloalkyl contains 3-7 C-atoms; a-amino-/C2-C3/- alkylsulphonyl; hydroxy-/C1-C3/-alkylaryl; -benzyloxy /C1-C3/-alkylsulphonyl; phenoxycarbonyl; teenageboys; pyridylcarbonyl, methylphenylcarbinol; alkoxycarbonyl with 1-4 C-atoms, a benzoyl group CO-CH/R10/-NRtCOR12; carbarnoyl, unsubstituted or substituted by phenyl or one or two alkilani with 1-4 C-atoms;

t" denotes an integer that varies from 1 to 3;

R10denotes hydrogen, alkyl with 1-4 C atoms or benzyl;

R11and R'11each, independently of one another, denote hydrogen or alkyl with 1-4 C-atoms;

R12denotes hydroxyl, alkoxy with 1-4 C-atoms, amino group, unsubstituted or substituted by one or two alkilani with 1-4 C-atoms;

R13denotes hydrogen; alkyl with 1-4 C-atoms; phenyl; fensel;

/C1-C3/-alkylsulphonyl; formyl; alkoxycarbonyl with 1-4 C-atoms; carbarnoyl; unsubstituted or substituted one or two alkilani with 1-4 C-atoms; as well as their possible salts.

When the connection according to the invention contains an asymmetric carbon atom or asymmetric carbon atoms, the invention includes all optical isomers of this compound.

When the connection according to the invention has the conformational isomerism of axial-Equatorial type, the invention encompasses all conformational isomers of this compound.

Salts of compounds of the formula /1/ in accordance with the present invention includes the tion of the compounds of the formula /1/, such as picric acid, oxalic acid or an optically active acid, such as mandelic acid or campanulaceae, and those which form physiologically acceptable salts such as hydrochloride, bromine hydrate, sulfate, hydrosulfate, dihydrophosphate, maleate, fumarate, 2-naphthalenesulfonate.

Salts of compounds of the formula /1/ include salts with organic or inorganic bases, for example, salts of alkaline or alkaline earth metals, such as salts of sodium, potassium, calcium, preferably sodium and potassium salts, or amine, such as trometamol, or salts of arginine, lysine, or any physiologically acceptable amine.

Under the protective group of the amine understand such a group as C1-C4alkyl, in particular methyl or tert-butyl, benzhydryl, trityl; benzoyl, (C1-C4-alkylsulphonyl, for example, acetyl (C1-C4)alkoxycarbonyl, for example, methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl, benzyloxycarbonyl or benzyl, or substituted benzyl, for example, para-nitrobenzyl, a pair of chlorbenzyl or para-methoxybenzyl.

According to the present invention, under an alkyl with 1-4 C-atoms or with 1 to 3 C-atoms, 1-5 C-atoms is P> According to the present invention, under the life cycle of hydrocarbons with 3 to 12 C-atoms, if necessary condensed, saturated or unsaturated, understand various hydrocarbon cycles monocyclic, bicyclic or tricyclic structure, for example, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, indan, hexahedronal, adamantane, norbornane, norbornene, dehydrogenase, tricyclo[5.2.1.02.6]-Dean, tricyclo[5.2.1.02.6] Dec-8-ene, bicyclo-[2.2.1]-heptane, bicyclo[3.3.1]nonan.

According to the present invention, when R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by hydroxyl, preferred groups for substitution of the above hydroxyl are: methyl, ethyl, methoxymethyl, methoxyaniline, fenilmetilketil, tetrahydrofuranyl and tetrahydropyranyl group.

The compounds of formula I in which R1is in position 5 of the Indo-2-she and R2represent hydrogen, represent the preferred connection.

The compounds of formula I in which R1oboznachenii the preferred connection.

The compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C-atoms, are preferred compounds, especially preferred compounds in which R3and R4together with the carbon atom to which they are bound, form a Cycloheptane, adamantane, tricyclo-/5.2.1.02.6/-Dec-8-ene, tricyclo-/5.2.1.02.6/-decane, bicyclo/2.2.1/-heptane, bicyclo/3.3.1/nonan, or cyclohexane, unsubstituted or substituted by spirocyclohexane with 3-5 C atoms or one or two alkyl groups with 1 to 7 C-atoms.

Mostly prefer compounds in which R3and R4together with the carbon atom to which they are bound form a cyclohexane, substituted by a group selected among methoxy, ethoxy-, 2-methoxyethoxy.

The compounds of formula I in which the substituents R5and R6are in the 2,4-position of the phenyl nucleus, are the preferred compounds.

The compounds of formula I in which R5denotes the ortho-methoxy group and R6located in the para-position and denotes a group chosen among /piperidine-1-yl/-carboxamido-, /2-cyanoprop-2-yl/-carbonyl, pyrrolidin-1-is In the description and in the examples the following abbreviations are used:

DHM: dichloromethane

ether: diethyl ether

ISO-ether: diisopropyl ether

Boc: tert-butoxycarbonyl

Me, MeO: methyl, methoxy

Et, EtO ethyl, ethoxy

Pr, iPr, nPr: propyl, isopropyl, n-propyl

Bu, iBu, tBu: butyl, isobutyl, tert-butyl

Ph: phenyl

Bz: benzil

Ts: tosel

Ac: acetyl

AcOEt: ethyl acetate

AcOH: acetic acid

HCl: hydrochloric acid

MeOH: methanol

EtOH: ethanol

DMF: dimethylformamide

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

DIPEA: diisopropylethylamine

NaOH: sodium hydroxide

NaHCO3: sodium bicarbonate

The tea: triethylamine

TFK: triperoxonane acid

TMEDA: tetramethylethylenediamine

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

So pl.: melting point

saline water, saturated sodium chloride

TLC: thin layer chromatography

HPLC: high performance liquid chromatography

hydrochloric acid water: dilute hydrochloric acid with a concentration of about 1 N.

TC: room temperature

So Kip.: boiling point

NMR: nuclear magnetic resonance

C. = singlet; n = broadened singlet; D. = doublet;is also the method of obtaining the compounds according to the invention and their salts, characterized in that:

1/. 1,3-dihydro-indol-2-it, disubstituted in positions 3, formulas

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in which R'1, R'2, R'3and R'4denote, respectively, or R1, R2, R3and R4such as defined for formula (I) or group precursor R1, R2, R3and R4,

enter into interaction with benzosulphochloride formula /III/:

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in which Hal denotes a halogen atom, preferably chlorine, and R'5and RVIdenote, respectively, or R5and R6and RVIdenote, respectively, or R5and R6such as defined for formula (I) or group precursor R5and R6;

2/ or, when R'1= R1, R'2= R2, R'3= R3, R'5= R5and RVI= R6allocate the thus obtained compound of the formula /I/;

3/ or when any of the groups R'1, R'2, R'3, R'4, R'5and/or RVIdenotes, respectively, the group is the predecessor of R1, R2, R3, R4, R5and/or R6received connection, below called a compound of formula I, is subjected to further processing to obtain connected to the, the respectively, R1, R2, R3, R4, R5and/or R6and

4/ if desired, the compound obtained of the formula /I/ turn into one of its salts.

The reaction of stage 1 is carried out in an anhydrous solvent, such as DMF or THF, in the presence of a metal hydride, such as, for example, sodium hydride, or in the presence of alcoholate as tert-butyl potassium.

1,3-Dihydro-indol-2-ones (II) are known or can be produced according to various known methods.

Compounds of the formula II, in which R'1and/or R'2denote halogen, and R'3and R'4together with the carbon atom to which they are bound, form spirocyclopentane, spirocyclohexane or spirocyclopentane known, for example, from D. W. Robertson and others, J. Med, Chem. 1987, 30 /5/, 824-829. Moreover, 5-chloro-3-spirocyclopentane-2-it is described in U.S. patent 3947451.

To obtain the compounds of formula (II) when R'3and R'4together represent a hydrocarbon group, you can use the reaction of Brunnera described by R. F. Moore, and S. G. P. Plant in J. Chem. Soc. 1951, 3475-3478, which leads to the formation of compounds of formula (II), in which CR3R4indicates a cyclopentane or cyclohexane.

This reaction is carried out SUB> have the above for formula (II) is, for example, by heating in quinoline in the presence of calcium oxide.

Derived phenylhydrazide formula /IV/ receive, according to the same authors, by reacting hydrazine derivative of the formula /V/:

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in which R1and R2have the above for formula (II) values, with halogenerator acid formula /VI/:

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in which R'3and R'4have the above for formula /II/.

According to the method implementation variant, when R'3and R'4together with the carbon atom to which they are bound, form polycondensating hydrocarbon cycle, for example, norbornene or norbornene, operate according to the method described by J. Wolff and other Tetrahedron, 1986, 42 /15/, 4267- 4272 : first get the lithium salt of the compounds of formula /IV/ by exposure laisteridge reagent, such as n-utility, in an inert solvent, such as THF, at low temperature, then carry out the cyclization by heating in a solvent such as naphthalene or peniten[1,2,3,4-tetramethylbenzene].

The compounds of formula (II) in which R'1= R'2= H and CR'3R'4denotes the adamantane described I. Fleming and others, J. Chem. Soc. Perkin Trans.) - Rev. Ana form adamantane and R'1and R'2different from hydrogen, can be obtained as described above.

Hydrazine derivatives of the formula /V/ is known or obtained by known methods. The same applies to galodamadruga acid /VI/.

Disubstituted in positions 3 1,3-dihydro-indol-2-he formula (II) can also be obtained from 1,3-dihydroindol-2-it formula /VII/

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in which R'1and R'2have the above for the compounds of formula (II) values using different methods.

For example, according to the method described by A. S. Kende and J. C. Hodges, Synth. Commun. , 1982, 12 /1/, 1-10, implement adding an alkylating agent in an appropriate solvent. Thus, to obtain the compounds of formula (II) in which R'3= R'4the reaction is carried out in THF at -75oC, in the presence of TMEDA by adding alkylate, for example, utility, then introducing into interaction with the halide of formula R3Hal, when R'3and R'4different, the alkylation reaction can be performed in 2 stages, using two different alkylhalogenide formula R'3Hal and R'4Hal. To obtain the compounds (II) in which R'3and R'4together form a group of the formula /CH2oC, then adding the compound of the formula Z-a/CH2/nZ, such as the above.

Similarly receive the compounds of formula (II) in which R'3and R'4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 4-8 C atoms, substituted by one or more alkyl groups with 1 to 7 C-atoms or spirocyclohexane with 3-5 C atoms.

The compounds of formula (II) in which R'3and R'4each, independently of one another, denote alkyl or phenyl, are known. For example, in the patent Germany 3300522 describes the 5-alkoxy-3,3-dimethyl-indol-2-ones.

When R'3and R'4together form a group - /CH2/pX/CH2/q- in which "p", "q" and X have the above for the compounds of formula (I) values, disubstituted in positions 3 1,3-dihydro-indol-2-ones of the formula (II) can be obtained from unsubstituted in position 3 1,3-dihydro-indol - 2-it formula /VII/ by impact with the value and X, "p", "q" have the above for the formula /I/ values. The reaction is carried out in the presence of an alcoholate, for example, of potassium tert-butylate, in an anhydrous solvent, such as, for example, THF.

When X denotes a nitrogen atom, substituted /C1-C6/- alkylcarboxylic, formyl, alkoxycarbonyl with 1-7 C atoms or allylcarbamate with 1-7 C atoms, the substitution of X can be implemented either before derived 1,3-dihydro-indol-2-it /II/ or to the target connection /I/ based on compounds in which the nitrogen atom /X = NH/ not substituted.

Thus, when X denotes a nitrogen atom substituted by alkoxycarbonyl with 1-7 C atoms, first get connected /II/ or /I/, where X = NH, then enter into interaction with the corresponding chloroformate to obtain the desired compounds of formula (II) or /I/. In the same way, enter into interaction with the connection /II/ or /I/, where X = NH, alkilizotsyanat with 1-7 C atoms, to obtain a derivative of formula (II) or the compounds of formula I in which X is replaced by allylcarbamate the nitrogen atom. With the compound of the formula (II) or a compound of the formula /I/, where X = NH, you can enter in the interaction of the acid chloride of the acid or acid anhydride or, respectively, arabinosidases respectively, /C1-C6/-alkylcarboxylic or formyl.

When X represents a sulfur atom or a nitrogen atom substituted with R13also you can first obtain the compound of formula (II)':

< / BR>
in which R'1, R'2, Z, p, and q have the above meanings, and to carry out nucleophilic substitution using a salt of hydrogen sulfide or amine of the formula H2NR13in a solvent such as alcohol, ether, DMF, or a mixture thereof, at a temperature of from 5oC to the boiling temperature under reflux.

1,3-Dihydro-indol-2-ones of the formula (II' is obtained from the corresponding diols, optionally protected, for example, tetrahydropyran-2-ilen group. The reaction can be carried out according to J. Chem. Soc. Chem. Commun., 1989, 1619, by the impact of dibromothiophene.

The compounds of formula (II) in which R'3and R'4together with the carbon atom to which they are bound, form a pyrolidine or N-methyl pyrolidine, piperidinyl or N-alkyl-piperidinyl cycle, described by M. J. Korner in J. Med. Chem., 1976, 19 /7/, 892-899.

In particular, vorotilin formula:

< / BR>
is an alkaloid described A. Jossang, and others, in J. Org. Chem., 1991, 56, /23/, 6527-6530.

To obtain the compounds of formula the cyclo/5.2.1.02.6/Dean or tricyclo/5.2.1.02.6/Dec-8-ene, affect the connection formula /VII/, respectively, the connection formula /VII/' or a compound of the formula /VII/":

< / BR>
in which Z has the above meaning. To obtain compounds of the formula II, in which the above carbocycle replaced, use connections /VII/' and /VII/", substituted by one or more alkyl groups with 1 to 7 C-atoms.

The compound of formula (II) in which R'3and R'4together with the carbon atom to which they are bound, form tricyclo/5.2.1.02.6/Dean, can be obtained by catalytic hydrogenation, e.g. in the presence of palladium-on-coal or Raney Nithe compounds of formula (II) in which R'3and R'4together with the carbon atom to which they are bound, form tricyclo/5.2.1,02.6/-Dec-8-ene.

The compound of formula I in which R3and R4together with the carbon atom to which they are bound, form tricyclo/5.2.1.02.6/Dean, can also be obtained by catalytic hydrogenation, e.g. in the presence of palladium-on-coal or Raney Nickel, the compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form tricyclo/5.2.1 Ohm carbon, with which they are linked, form, respectively, indan or hexahedronal affect the connection formula /VII/, respectively, the connection formula /VIII/' or a compound of the formula /VIII/":

< / BR>
which is specified above for the compounds of formula /VII/ value.

To obtain compounds of the formula II, in which indan or hexahedronal replaced, use connections /VIII/' and /VIII/", substituted by one or more alkyl groups with 1 to 7 C-atoms.

You can use method A. S. Kende and J. C. Hodges, described above, or its variant, described above, to obtain compounds of the formula II, in which the substituents R'3and R'4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or more alkyl groups with 1 to 7 C-atoms or a group chosen among the following groups : oxoprop protected in the form of an acetal, spiratically with 3-5 C atoms, one or two hydroxyl, substituted by alkyl with 1-4 C-atoms, /C1-C5/- alkoxyalkyl, in which the alkyl contains 1-4 C-atoms; triphenyltetrazolium, in which the alkyl contains 1-4 C-atoms, generalkonsulat. To obtain compounds of the formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two hydroxyl, carry out the removal of protective groups from the corresponding compounds of the formula I, in which a hydroxyl group or a hydroxyl group substituted with a /C1-C5/-alkoxyalkyl, in which the alkyl contains 1-4 C-atoms, tetrahydrofuranyl or tetrahydropyranyl.

This removal of the protective groups is carried out in acidic medium, for example, in the presence of inorganic or organic acids, alcohol or simple ether as solvent, such as THF, at a temperature of from 15oC to the boiling temperature under reflux, for example, removing the protective groups can be carried out in the presence of hydrochloric acid or pyridinedicarboxylate in alcohol.

To obtain compounds of the formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted on the corresponding compounds of formula (I), in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two /C1-C5/- alkoxy-/C1-C4/-alkoxygroup. This removal of the protective groups is carried out in acidic medium, for example, in triperoxonane acid, in a solvent such as DHM.

The compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two /C1-C4/-alkoxylate or one or two /C1-C5/-alkoxy-/C1-C4/-alkoxygroup, can also be obtained by alkylation of compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two hydroxyl. For this tend to work with a strong alkylating reagents, such as alkylarylsulfonate, dissolve the n, according to the method described in Carbohydrate Research, 1975, 44, C5-C7. Alkylarylsulfonate can be obtained from alkylation by introducing them into interaction with the salt of triftoratsetata, such as silver salt / Chemical Reviews, 1977, 77/.

The compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two formylchromones or, respectively, one or two /C1-C7/-alkylcarboxylic, can be obtained by exposure dimethylsulfate in the presence of cesium carbonate, or respectively by the impact of galodamadruga acid or anhydride and the acid compound of formula I in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted by one or two hydroxyl.

The compounds of formula I in which R3and R4together with the carbon atom to which they are bound, form tricyclo/5.2.1.02.6/Dean-8,9-diol, also can be obtained from riciclo-/5.2.1.02.6/-Dec-8-ene, which is administered in cooperation with metachromatically acid at room temperature in a solvent such as DHM, to obtain the intermediate compounds of formula (I) in which R3and R4together with the carbon atom to which they are bound, form tricyclo/5.2.1.02.6/Dean-8,9-epoxypropyl; intermediate epoxy compound is then hydrolized by boiling under reflux in water in the presence of sulphuric acid, or in the environment of the main character.

The compounds of formula (II) in which R'3and R'4together with the carbon atom to which they are bound, form or hydrocarbon cycle with 3 to 12 C atoms, saturated or unsaturated, if necessary condensed, substituted oxopropoxy or group /CH2/p-X-/CH2/qwith X denoting the group SO, SO2or N/O/ R13produced by well-known reactions of oxidation of the corresponding compounds of formula II, in which R'3and R'4together with the carbon atom to which they are bound, form, respectively, or a hydrocarbon cycle 3-12 C atoms, saturated or unsaturated, if necessary condensed, substituted by hydroxyl, or a group - /CH2/

Oxidation of the compounds (II) containing a sulfur atom or nitrogen /X = S, NR13/, can be performed in the presence of hydrogen peroxide or nagkalat, such as peracetic acid or metaglidasen acid, in inert solvents, such as ketones or acetic acid, at temperatures of 0-50oC.

When R'3and R'4each represent phenyl, you can use the method described in Helv. Chim. Acta, 1946, 29, 415-432, for connection /II/.

Derivatives of 1,3-dihydro-indol-2-it /VII/ known or obtained by known methods. Can be called, for example, J. V. Rajan Babu b J.Org. Chem., 1986, 51, 1704-1712.

The compound of formula (II) containing one of the substituents R'1, R'2in its benzene part, are used as precursors for producing compounds of formula (II) containing other substituents R'1, R'2. For example, the compounds of formula (II) in which R'1and/or R'2denote hydrogen, can be nitrated using the classical reagents, they can also be etilirovany by who is lots Lewis, such as aluminum chloride, to obtain the compounds of formula (II) in which R'1and/or R'2= COR.

Of the compounds of formula (II) in which R'1denotes the nitro-group and R'2denotes hydrogen by catalytic hydrogenation to obtain the compound of formula (II) in which R'1denotes the amino group.

Benzosulphochloride formula /III/ get known methods. So, for example, 4-dimethylaminobenzophenone receive according to C. N. Sukenik, etc. J. Amer. Chem. Soc. 1977, 99, 851-858. Usually, benzosulphochloride formula /III/, in which the substituent R'5is dimethylaminopropyl known or obtained by known methods; p-benzyloxybenzophenone get under the European patent application EP 229566.

Alkoxysilylated get from alkoxybenzyl sodium, which itself is produced by the impact of alkylhalogenide on hydroxybenzenesulfonate sodium.

2,4-Dimethoxybenzenesulfonamide receive according to J. Am. Chem. Soc., 1952, 74, 2008.

Halogenlithiumcarbenoid can be obtained according to U.S. patent 2540057.

Benzosulphochloride formula /III/':

< / BR>
in Kotor the atoms, cycloalkyl with 3-7 C-atoms, alkenyl with 2-7 C atoms, - halogenated with 1-7 C atoms, POLYHALOGENATED with 1-7 C atoms, benzyl/C1-C6/-alkylsulphonyl, formyl, - carboxyethyl with 1-7 C atoms, esterified to complex ester with alkyl with 1-4 C atoms or benzyl; receive according to D/Hofmann and others in Liebigs Ann. Chem., 1982, 287-297.

Work by affecting trimethylsilyldiazomethane on benzene compounds with substituents VRvand to OAI in the 1,3 position, in a solvent such as DHM at room temperature. Then use the method of R. Passerini, etc. in Gazz. Chim. Hal., 1960, 90, 1277-1289 and then neutralized, for example, by using a carbonate of an alkali metal, then put halide, such as POCl3to obtain the target benzosulphochloride.

Benzosulphochloride formula /III/, in which the substituent R'5denotes alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, alkylthio, phenylthio, benzylthio or group SR7where R7is specified for the formula /I/ is, get under Col Czechoslov. Chem. Commun., 1984, 49, 1184, derived from aniline, substituted by the same group R'5and the above derived aniline itself is obtained from the corresponding nitro-poezii this acid to obtain the corresponding alkyl and phenyl esters.

Benzylisothiocyanate /III. , R'5= SO2Hal/ famous or get them by known methods. For example, 2,4-dimethoxybenzene - 1,5-disulfonic-dichloride described in R. J. W. Cremlyn in J. Chem. Soc. C., 1969, 1344.

Halogenlithiumcarbenoid /III, R'5= - halogenoalkane/ used for producing compounds according to the invention, in which the substituent R5indicates aminoethoxy, unsubstituted or substituted by one or two alkilani, according to the following scheme:

O-Alk' - Hal + NH AA' ---> O-Alk' - N AA',

in which Alk represents alkyl with 2-7 C atoms,

A and A', independently of one another, denote hydrogen or alkyl with 1 to 7 C-atoms.

For some values of the substituents R1, R2, R5or R6compounds according to the invention of formula I can be obtained from the predecessor of the formula /I/', substituted by a group R'1, R'2, R'5and/or RVIcalled group-the predecessor of R1, R2, R5or R6using well-known specialist methods.

In the following description shows how to obtain the compounds of formula (I) containing substituents R1and/or R5; the same methods are used to obtain compounds in which the Deputy is ly /I/, in which R1and/or R5denote hydroxyl, can be obtained by catalytic hydrogenation, e.g. in the presence of palladium-on-charcoal, the compounds of formula I in which R'1and/or R'5denotes benzyloxy. These compounds can also be obtained from the analogous compounds of formula I in which R'1and/or R'5denotes the amino group using the method described in J. Org. Chem., 1977, 42, 2053.

The compounds of formula I in which R1and/or R5denotes alkoxy with 1-7 C atoms, can be obtained directly by the method according to the invention from the compound of formula (II) and (III duly replaced.

Of the compounds of formula I' in which R'1and/or R'5means hydroxyl, you can also obtain the compounds of formula I in which R1and/or R5means alkoxyl with 1-7 C atoms by impact of alkylhalogenide with 1-7 C atoms in the presence of a base such as a metal hydride or carbonate of alkali or alkaline earth metal, for example, K2CO3or CS2CO3in a solvent such as THF or DMF. Similarly, the compounds of formula I in which R1and/or R5indicates aminoalkylsilane, the unity, in which R1and/or R5indicates hydroxyalkoxy produced by the impact of chloroalkyl-alcohol, in the special case of obtaining the compounds of formula I in which R1and/or R5= O/CH2/2OH, you can also ethylene carbonate resulting to enter into interaction with the compound of the formula I', wherein R'1and/or R'5= OH.

The compounds of formula I in which R1and/or R5indicates a /C1-C6/-alkylcarboxylic or formyloxy, respectively, received by the interaction of galodamadruga acid or acid anhydride with the compound of the formula I' in which R'1and/or R'5denotes hydroxyl or by treatment with formic acid in the presence of directorexception J. Huang and others, journal of Chem. Res. (S) 1991, 292-293).

The compounds of formula I in which R5refers to a group OR7and R7represents carbamoylethyl with 1-7 C atoms, free or substituted by one or two alkilani with 1-7 C atoms, can be obtained from the compounds of formula I' in which R5refers to a group ORvand Rvrepresents carboxyethyl with 1-7 C atoms, esterified to complex ester with alkyl with 1 to 7 C-atoms of the early amine.

To obtain compounds of the formula I in which R1and/or R5indicates a /C1-C7/-monoalkylamines, compound of formula I' in which R'1and/or R'5denotes an amino group, enter into interaction with the aldehyde or ketone in an acidic medium in the presence of a reducing agent, such as cyanoborohydride sodium; by identical reactions receive the compounds of formula I in which R1and/or R5denotes dialkylamino.

The compounds of formula I in which R5denotes the amino group, substituted benzyl, which in some cases replaced, or alkene with 3-8 C atoms, can be obtained by exposure benzylchloride or chloroalkane with 3-8 C atoms in the compound of formula I' in which R5represents amino or alkylamino.

The compounds of formula I in which R5denotes 3 - pyrrolin-1-ilen group, obtained by exposure in an inert atmosphere, CIS-1,4-dichlorobut-2-ene compounds of formula I' in which R'5denotes the amino group, in the presence of a base like triethylamine. By hydrogenation then obtain the compounds of formula I in which R'5denotes pyrrolidin-1-ilen group. The reaction of CIS-1,4-dichlorobutene in the presence of a base, as sodium carbonate, and in these conditions it leads to the formation of a mixture of compounds of formula I in which R5denotes 3-pyrrolin-1-yl, with the compound of the formula I in which R5means pyrrol-1-ilen group, which can be separated using chromatography.

The compounds of formula I in which R5means of isoindoline-2-ilen group, produced by impact - dibromo-axilla on the compounds of formula I' in which R'5denotes the amino group, in the presence of a base such as triethylamine and in a solvent such as dimethylformamide at the boiling temperature under reflux.

The compounds of formula I in which R5refers to 1-methyl-2,4-dioxoimidazolidin-3-ilen group, the group NR8R9means N-methylhydantoin get in two stages : sarcosin enter into interaction with the compound of the formula I' in which R'5denotes phenoxycarbonylamino, in the presence of a base such as triethylamine, to obtain the compounds of formula I' in which R'5denotes N'-carboxymethyl-N'-methyluridine, followed by heating at 100oC in vacuum videolocity product cyclist. Similarly, the compound of formula I, in kotoroy glycine with the compound of the formula I', above.

When R'1and/or R'5denotes the amino group can be carried out by the nitrosation of, for example, in the presence of nitrous acid or sodium nitrite to obtain the compounds of formula I' in which R'1and/or R'5means salt, page by well-known specialist of reactions then obtain the compounds of formula I according to the invention, in which R1and/or R5denotes cyano, halogen or dialkyl with 1-7 C atoms. Finally, by classical reactions of compounds of formula I' in which R'1and/or R'5= NH2you can obtain the compounds of formula I in which R1and/or R5denotes one of the groups of the formula R CONH-, R OCONH-, R NHCONH - or RSO2NH-, in which R denotes alkyl with 1-7 C atoms, phenyl or benzyl.

The compounds of formula I in which R5denotes alkoxycarbonyl with 1-7 C atoms, can be obtained directly by using the method according to the invention. Well-known expert in the ways of them can be obtained the compounds of formula I in which R5denotes a carboxyl group.

Of the compounds of formula I' in which R' denotes benzyloxycarbonyl, can be obtained by the catalytic hiderow is with the compounds of formula I', in which R'5denotes halogencarbonic. Of these compounds get the compounds of formula I in which R'5means carbarnoyl, substituted radicals R'6and R6by processing the connection HNR'6R6. You can also use the compounds of formula I', in which the substituent R'6is phenoxycarbonyl, to obtain compounds of the formula I in which R5indicates phenylcarbamoyl or allylcarbamate with 1-7 C atoms, by exposure to aniline or alkylamine with 1-7 C atoms. Substituted on the phenyl aniline or substituted by alkyl alkylamine allow one to obtain the compounds of formula I in which R5indicates phenylcarbamoyl, substituted by phenyl, or substituted on the alkyl allylcarbamate radical R6.

Similarly, the compounds of formula I in which R5refers to a group - CONHCR10R'10COR12produced from compounds of the formula I' in which R'5denotes a group COCl or phenoxycarbonyl group, by reacting with H2NCR10R'10COR12.

The compounds of formula I in which R5refers to a group COR7receive from S="ptx2">

Of the compounds of formula I in which R'5denotes a nitro-group, can be obtained by catalytic hydrogenation, e.g. in the presence of platinum oxide, Raney Nickelor palladium-on-charcoal, or by chemical recovery, for example, in the presence of tin or iron in an acidic medium, the compound of formula I in which R5denotes an amino group; then you can get other compounds in which the amino group substituted by the use of well-known specialist reactions.

For example, when you want to obtain the compound of formula I according to the invention, in which R5refers to the group NR8R9where R9represents benzoyl, if necessary substituted, benzoyl chloride in which the phenyl contains the appropriate Deputy, enter into interaction with the compound of the formula I' in which R'5denotes the amino group, in the presence of an amine, such as triethylamine. You can, for example, to enter into interaction 4-chlorosulfonylbenzoic to obtain the compounds of formula I in which R'5means 4-chlorosulfonylbenzoic, followed by exposure to ammonia, or, respectively, alkylamine with 1-4 C-atoms, receive connection .-sulfamoylbenzoic. Similarly, the acid chloride of the acid R11R'11NCR10R'10COCl enter into interaction with the compound of the formula I' in which R5denotes a group other8to obtain the compounds of formula I in which R5means a group NR8substituted with COCR10R'10NR11R'11.

When you want to obtain the compound of formula I in which R5refers to the group NR8, R9and R9is a /C1-C6/-alkylsulphonyl or formyl, enter into interaction compound of formula I in which R5denotes the amino group, with an appropriate anhydride or acid chloride of the acid, or acid chloride acid or, respectively, with formic acid in the presence of acetic anhydride.

According to another example of obtaining the compound of formula I in which R5denotes alkylsulfonamides produced by the impact of alkylsulfonate on the compound of the formula I' in which R'5denotes the amino group.

The compound of formula I' in which R'5denotes the amino group, are also suitable for producing compounds in which the amino group substituted by the group /CH2/t5
indicates the amino group, to obtain compounds of formula I in which R5= NHCO/CH2/tCO2H c "t'" = 2 or 3. In the desirable case, the thus obtained acid is converted into ester or amide.

To obtain the compounds of formula I in which R5means the group-NHCOCO2Floor or NHCOCH2CO2EB, you can also interact acrocallosal or, respectively, ethoxalyl with the compound of the formula I, where R'5means an amino group.

Similarly, the compounds of formula I in which R'5means an amino group substituted by the group CR10, R'10COR12produced by the effect of the compound of the formula Hal-CR10R'10COR12on the corresponding compounds of formula I', in which the substituent R'5is the amino group.

If estealam which R'5is amino group, obtain the connection formula (I) in which R'5denotes an amino group substituted by alkoxycarbonyl with 1-7 C atoms or phenoxycarbonyl.

Similarly, by the impact of phenoxythiocarbonyl on the compound of the formula I' in which R'5denotes an amino group, get the connection formula (I) in which R'5denotes phenoxythiocarbonyl.

By exposure to ammonia compound of the formula I' in which R'5denotes an amino group substituted by phenoxycarbonyl or phenoxythiocarbonyl receive compound of the formula I in which R5indicates ureido or cheoreography, by acting on the connection formulas /I/', correspondingly substituted aniline or appropriately substituted mono - or dialkylamino with 1-7 C atoms, obtain the connection formula (I) in which R5means appropriately substituted N'-phenylurazole, N'-allylurea - or N',N'-dialkylamides, in which the alkyl contains 1 to 7 C-atoms, and which are properly replaced.

The compound of formula I in which R5denotes raidgroup [-NHCONR14R'14] or, respectively, cheoreography [-NHCSNR14I/', in which R'5denotes phenoxycarbonylamino or, respectively, phenoxythiocarbonyl.

The compound of formula I in which R5denotes raidgroup [-NHCONR14R'14] or, respectively, cheoreography, can be obtained by exposure of carbamoylated [ClCONR14R'14] or, respectively, thiocarbanilide, compound of formula I' in which R'5denotes the amino group.

The compound of formula I in which R5denotes cheoreography, you can still be obtained by exposure of the reagent Lawesson on the compound of the formula I' in which R'5denotes the corresponding raidgroup.

The compounds of formula I in which R5denotes guanidinium, unsubstituted or substituted by one or twice by alkyl with 1 to 7 C-atoms, phenyl or benzyl, can be obtained from compounds of the formula I' in which R'5denotes proximitor by the impact of cyanamide or one of its derivatives appropriately substituted on the nitrogen.

By exposure of the corresponding amine in the presence of phosgene on the compound of the formula /I/', Deputy which R'5denotes the amino group is whether the two alkyl groups with 1 to 7 C-atoms.

The compound of formula I in which R5denotes an amino group substituted by allylcarbamate or phenylcarbamoyl, can also be obtained by exposure alkylsulfonate or phenylisocyanate connection formula /I/', Deputy which R'5denotes the amino group.

In addition, the compound of formula I in which R5means sulfamoyl group, unsubstituted or substituted by alkyl with 1 to 7 C-atoms, obtained by exposure to ammonia or alkylamine with 1-7 C atoms in the compound of formula I' in which R'5means halogencontaining group.

The affinity of the compounds according to the invention to the receptor vasopressin determined in vitro using the method described by C. J. Lynch and others in J. Biol. Chem., 1985, 260 /5/, 2844-2852. This method consists in studying the substitution /displacement/ vasopressin containing Tretiy, fixed on plots of Y1membranes of rat liver. The concentration inhibiting 50% /IR50/ commit containing tritium vasopressin, compounds according to the invention insignificant, reaching up to 10-7M.

The affinity of compounds of the formula I according to the invention to the receptor Y2measured on membrane preparation from pocky, 223, 50-54. Compounds according to the invention inhibit the fixation containing tritium arginine-vasopressin receptors on the membrane of the drug. IR50compounds according to the invention is negligible, amounting to 10-9M.

Antagonistic activity to the receptor Y2compounds according to the invention is detected by the test when performing quantitative analysis activity adenylate-cyclase activity, carried out according to the method, adapted M. Laburthe and other Molecular Pharmacol., 1986, 29, 23-27. The use of membrane preparation from the kidney of an ox, and every product is incubated for 10 minutes at 37oC, alone or in the presence of AVP [arginine-vasopressin] at a concentration of 310-8M. Received cyclic AMP [cyclic adenosine monophosphate] determined by radioimmunoassay for quantitative analysis. Determine the concentration, inhibitory 50% /IR50/ stimulation adenylate-cyclase activity caused 310-8M AVP. IR50that determine the order of 10-7M, reaching up to 10-8M.

Agonistic or antagonistic activity of the receptors of vasopressin compounds according to the invention, administered orally assess in rats [strain OFA, Sprague - Dawley] in the form of water per anywayt in rats, at normal water mode [OFA strain or strain Sprague - Dawley], according to the method described in Br. J. Pharmacol., 1992, 105, 787-791. Diuretic effect observed for some compounds at a dose of 10 mg/kg

Similarly, the affinity of the compounds of the formula I according to the invention to the receptor of ocytocin determine in vivo by substitution /displacement/ radioiodinated analog ocytocine, fixed on the receptor membrane preparation of the mammary glands of pregnant rats, according to the manner similar to that described by J. Eland and others, Eur. J. Pharmacol., 1987, 147, 197-207. IR50compounds according to the invention reaches 10-8M.

Compounds according to the invention are active after the introduction of various ways, especially oral.

In the case of these compounds in pharmacologically active doses, there is no sign of toxicity.

Thus, the compounds according to the invention can be used for the treatment or prevention of various vasopressin-dependent or dependent ocytocine diseases, cardiovascular diseases such as hypertension, pulmonary hypertension, heart failure, myocardial infarction, or coronary vasospasm, in features especially hemophilia, syndrome von Willebrand disease of the Central nervous system, migraine, cerebral vasospasm, cerebral haemorrhage, swelling of the brain, depression, anxiety-related psychosis state, for example, memory disorders, diseases of the renal system as edemas, renal vasospasm, Necros renal peel, hyponatremia, hypokalemia syndrome Schwartz Barter; diseases of the gastrointestinal system, as gastric vasospasm, hepatocirrhosis ulcer, pathological vomiting, for example, nausea, including nausea caused by chemotherapy, transport disease or syndrome of inappropriate secretion of antidiuretic hormone [SI ADH] , diabetes insipidus and enuresis. Compounds according to the invention can also be used in the treatment of disorders of sexual behavior, in the case of women the compounds according to the invention can be used to treat dysmenorrhea or premature birth. Compounds according to the invention can also be used to treat lung cancer small cell, gipokaliemichesky encephalopathy, disease Raynaud pulmonary syndrome, glaucoma, and postoperative treatments, especially after abdominal surgery.

The subject of the present invented what or pharmaceutically acceptable salts and suitable AIDS /excipients/.

The above-mentioned excipients selected depending on the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for administration by the oral, sublingual, subcutaneous, intramuscular, intravenous, tapicerki intratrahealno through the nose, transdermally, or rectally, effective the beginning of the above formula (I) or their possible salts can be introduced in unit forms of administration, mixed with classical pharmaceutical carriers, to animals or humans for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of introduction include oral forms such as tablets, gelatin capsules with the medicine, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, form insertion through the nose, subcutaneous, intramuscular or intravenous forms of administration and rectal forms of administration. For topical application, it is possible to use the compounds according to the invention in creams, lipsticks or lotions.

In order to achieve the desired prophylactic or therapeutic effect, the dose of the beginning of the current may vary in the range from 0.01 to 50 mg per kg of body weight of talantov in combination with a pharmaceutical carrier. This dose can be administered 1-5 times a day for the introduction of a daily dose of 0.5 to 5000 mg, preferably 1-2500 mg

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or similar substances. Tablets may be coated with sucrose, a derivative of cellulose or other appropriate materials or they can be treated so that they have a prolonged or delayed activity and that they continuously released a set number of applicable beginning.

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

A preparation in syrup or elixir or for administration in the form of drops can contain the active ingredient together with sweetening substance, preferably low-calorie, methyl paraben or propyl paraben as antiseptics, as well as with the agent, gives taste, and an appropriate dye.

Powders or dispersible in water, the granules may contain actinieria, similarly, with sweetening matter or improving the taste substances.

For rectal use of candles, which are prepared with binders, melting at rectal temperature, for example cocoa butter or polyethylene glycol.

For parenteral administration using aqueous suspensions, isotonic saline solutions or sterile and injectisome solutions, which contain dispersing agents and/or wetting, which are pharmaceutically acceptable, for example, propylene glycol or butyleneglycol.

The active principle can also be formulated as microcapsules, if necessary with one or more carriers or excipients.

Compositions of the present invention may contain, in addition to the aforementioned products of formula (I) or one of the pharmaceutically acceptable salts, other operating beginnings, which may be suitable for treatment of the above disorders or diseases.

Thus, the object of the present invention are also pharmaceutical compositions containing several active principles of the Association, one of which is the connection according to the invention.

Such compositions will be especially suitable for the treatment of hypertension or heart failure.

You can also associate the two compounds according to the invention: specific to the receptor Y1antagonist with a specific receptor Y2antagonist or specific to the receptor Y1antagonist specific to ocytocine antagonist.

These associations will enhance therapeutic activity of the compounds according to the invention.

Obtaining 1,3-dihydro-indol-2-it

Preparation 1: 1,3-Dihydro-4,6-dimethyl - 3-spirocyclohexane-indole-2-he

A mixture containing 15 ml of quinoline and 10 g of calcium oxide support at the boiling point under reflux in an inert atmosphere and added dropwise within 30 minutes, 5 g of 3,5-dimethylphenylsilane the ionic environment cool, then poured into a mixture of ice / hydrochloric acid. Extracted with ethyl acetate, washed with 1 N. hydrochloric acid, with water until neutral, then dried and concentrated in vacuo to obtain a solid substance brown. By rubbing in itapira get the target connection

So pl. = 223oC.

In doing this the same way, but replacing the original hydrazide, get derivatives of 1,3-dihydro-indol-2-it is described in the following table 1.

These compounds purified by chromatography on a column of silica, elwira using DHM, or by chromatography on a column of aluminum oxide, elwira using DHM or ISO-ether.

Preparation 2:

Described in table 1 1,3-dihydro-3-spirocyclohexane - 2-it can also be obtained by alkylation of indole-2-it is in the application of the method, according to A. S. Kende and J. C. Hodges, or the following options.

To a solution of 30 g of 1,3-dihydro-indol-2-it in 900 ml of THF, supported at -40oC in nitrogen atmosphere add 101 g of potassium tert-butylate.

Leave the temperature to rise to 0oC for 1 hour, then cooled to -60oC and added dropwise a solution of 52 g of 1,5-dibromoethane in 50 ml of THF. After 30 the tel is evaporated under reduced pressure. The residue is treated with 500 ml DHM and 200 ml of water, and then the insoluble part is filtered off and separate the organic phase, which is washed with 100 ml of water, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane and ether. Get the target compound, which is recrystallized from heptane. Output = 34,

So pl. = 123 - 124oC.

This way of working can be applied on the basis of other 1,3-dihydro-indol-2-ones and other alkylating agents.

As an example, the source compounds of the formula /VII/, you can use 5-chloro-1,3-dihydro-indol-2-he (described in J. Am. Chem. Soc., 1956, 78, 221 and Rajanbabu in J. Org. Chem., 1986, 51, 1704), 4-Chloro-1,3-dihydro-indol-2-he who rubs can be obtained from 2-chloro-6-nitro-toluene, according to the method described in J. Am. Chem. Soc., 1956, 78, 221).

1,3 - Dihydro-5-methoxyindol-2-it is obtained from 4-methoxyaniline according to the method described in J. Am. Chem. Soc., 1974, 96, 5512.

In the same way from the corresponding aniline derivative gain various 1,3-dihydro-indol-2-ones.

Preparation of 3: 5-Ethoxy-1,3-dihydro-indol-2-he

A. 3-Methylthio-5-ethoxy-1,3-dihydro-indol-2-he

To a cooled to -70oC to a solution of 12.5 GE the temperature, add a solution of 4-ethoxyaniline /48,3 g/ 120 ml DHM. Stirred for 1 hour about -70oC add to 39.3 ml of triethylamine and leave the temperature to rise to room. Add 200 ml water, the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The residue is treated with 500 ml of isopropanol and 20 ml of concentrated hydrochloric acid. Stirred for about 16 hours at room temperature, filtered and the precipitate is separated. The filtrate is concentrated under reduced pressure to obtain the target product.

B. 5-Ethoxy-1,3-dihydro-indol-2-he

Visaelectron solid in 1500 ml of isopropanol will decimetric in the presence of 100 g of Raney Nickel/80-100 m2on g/ at the boiling point under reflux for 3 hours in nitrogen atmosphere. Filtered through talc, washed with 1000 ml of isopropanol and the filtrate concentrated under reduced pressure. After recrystallization from toluene, allocate 16 g of the target product.

So pl. = 156oC.

In the same way from the corresponding anilines, get:

5-benzyloxy-1,3-dihydro-indol-2-he's so square = 152oC

5-n-propyl-1,3-dihydro-indol-2-O2-he's so square = 145oC

5-trifluoromethyl-1,3-dihydro-indol-2-he's so square = 193oC

5-fluoro-1,3-dihydro-indol-2-he's so square = 143oC

Acting in accordance with the method described in Preparation 2, but on the basis of the corresponding derived 1,3-dihydro-indol-2-it alkylating agent, get the following compounds of the formula (II) (see tab. 2)

Preparation 4: 1,3-Dihydro-3-spiroadamantane-2-he

This connection receive according to I. Fleming and others, Tetrahedron Letters., 1982, 2053-2056, 2-bromoaniline and adamantane-2-it.

Preparation 5: 5-Chloro-1,3-dihydro-3,3-difenidol-2-he

This connection receive according to the method described in He Iv. Chim. Acta. , 1946, 29, 415 - 431, by exposure to benzene at 5-chloroisatin in the presence of aluminium chloride. So pl. = 281oC.

Preparation 6: 1,3-Dihydro-5-nitro-3 - spirocyclohexane-2-he

This connection receive according to the method described in J. Am. Chem. Soc. , 1945, 67, 499, by nitration of 1,3-dihydro-3-spirocyclohexane-2-it. So pl. = 192oC.

In the same manner from 1,3-dihydro-3-spiroadamantane-2-it, get 1,3-dihydro-5-nitro-spiroadamantane-2-it. T. p. L. > 260oC.

Also receive 1,3-dihydro-5-nitro-3-Spiro (4,4-dimethylcyclohexyl)-indole-2-it. So pl. = 195are defined manner, described in J. Chem/ Soc., 1951, 3475, by restoring 1,3-dihydro-5-nitro-3-spirocyclohexane-2-she obtained above. So pl. = 176oC.

In the same way, get 5-amino-1,3-dihydro-3 - spiroadamantane Dol-2-it. So pl. = 245oC.

Preparation 8: 5-fluoro-1,3-dihydro-3 - spirocyclohexane-2-he

A. Tetrafluoroborate 5-diezani-1,3-dihydro-3 - spirocyclohexane-2-it

A solution containing 4 g of 5-amino-1,3-dihydro-3 - spirocyclohexane-2-it 9.2 ml 6 N. hydrochloric acid, cooled to 0oC and add to it, and 2.27 g of sodium nitrite in 2.6 ml of water, then of 2.54 g of tetrafluoroborate sodium in 9 ml of water. After stirring for 5 minutes, the precipitate is filtered off, washed with a 5% solution of tetrafluoroborate, then 3 ml of methanol, cooled to 0oC, after which 5 ml of ether.

The obtained salt is dried under vacuum at room temperature in the presence of phosphoric anhydride.

B. 5-fluoro-1,3-dihydro-3-spirocyclohexane-indole-2-he

1 g obtained in stage A connection make in 5 ml of xylene and heated at 115oC for 2 hours. Cooled to room temperature, the precipitate filtered off, washed with toluene and the filtrate add 0.1 g of active charcoal. After hoteltravel isout from pentane. So pl. = 114oC.

Preparation 9: 5-Cyano-1,3-dihydro-3-spirocyclohexane - 2-he

At room temperature, 4,78 g of potassium cyanide and 4.95 g of copper cyanide-/I/ is dissolved in 40 ml of DMSO. Cooled to 15oC and added 4.15 g diazonium salts obtained in the preceding Receipt in stage A.

After stirring for 30 minutes at room temperature, add 100 ml of water and 100 ml of ether, then the organic phase is separated, which is dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane and ether. Get the target compound, which is recrystallized from heptane. Weight = 1,4, So pl. = 216oC.

Preparation 10 : 5-Chloro-1,3-dihydro-3-spiroadamantane - 2-he

1 g p-Chlorophenylhydrazone adamantane-2-carboxylic acid is dissolved in THF and at -40oC add 2.5 ml n-utility in the form of a solution /1.6 M in hexane/. After stirring for 5 minutes, concentrated in vacuo, maintaining at a temperature below 30oC. Add 30 ml of 1,2,3,4-tetramethylbenzene and refluxed for 1 hour. Concentrate under reduced pressure, the residue is treated with 1 N. hydrochloric acid, extragear the home of silicon, elwira using DHM; obtain 0.3 g of the desired product in the form of wax, which crystallized from itapira. So pl. = 249oC.

Preparation 11: 5-Chloro-3-cyclohexyl-1,3-dihydro-3-methyl - indole-2-he

Use the method described in Synth. Commun., 1982, 12 /1/, 230, for intermediate 5-chloro-3-cyclohexyl-1,3 - dihydro-indol-2-it, then get the target compound by exposure methyliodide.

Preparation 12: 5-Acetyl-1,3-dihydro-3 - spirocyclohexane-2-he

To a cooled to 5oto a solution of 1,3-dihydro-3 - spirocyclohexane-2-it in 35 ml of 1,2-dichloroethane add 2,56 g acetylchloride, then of 8.25 g of anhydrous aluminium chloride. Refluxed for 2 hours, the solvent is evaporated under reduced pressure, the environment hydrolyzing with 50 g of ice and extracted with ethyl acetate.

The organic phase is washed with water, dried over magnesium sulfate, then evaporated under reduced pressure. The remainder chromatographic on a column of silica, elwira mixture of heptane with diethyl ether, and obtain 3.6 g of the target product. So pl. = 192oC.

Preparation 13: 5-Chloro-1,3-dihydro-3-Spiro/4 - tetrahydrothiopyran/-indol-2-he

A. 5-Chloro-1,3-dihydro-3,3-di/2 bromet the HMM, then add 4,58 g of 5-chloro-1,3-dihydro-3,3-di-2-/tetrahydropyran-2-yloxy/ethyl/- indol-2-it is described in Table 2. After 16 hours at room temperature, add 60 ml of water, separate the organic phase, which is washed with 60 ml of water, then dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on a column of silica, elwira using DHM. Obtain 3.12 g of the target product. So pl.= 215oC.

B. 5-Chloro-1,3-dihydro-3-Spiro-/4-tetrahydrothiopyran/-indol-2-he

In an inert atmosphere, 3 g of the product obtained in stage A, 3.2 ml of DMF is added 2 g of the monohydrate of sodium sulfide and heated 2 hours at 50oC. Cool to room temperature, add 6 ml of water and extracted with DHM. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The obtained oily residue is purified by chromatography on silica, elwira using DHM. Get 2,02 g of target compound.

NMR spectrum at 200 MHz in CDCl3M. D. 8,12 /s, 1H/; 7,2 /m, 2H/, 6,8 /e, 1H/; 3,25 /m, 2H/, 2,65 /m, 2H/; 2 /m, 4H/.

Preparation 14 : 5-Ethoxy-1,3-dihydro-3-Spiro[4- /methoxyethoxy/cyclohexane]-indol-2-he

A. - 3-/Methoxyethoxy/-UP>o
C and add a solution of 63 g of diethyl-3-/methoxyethoxy/-glutarate [obtained according to J. L. Cras, in Synthesis, 1985, 74] in 400 ml of THF. Leave under stirring and at room temperature for 16 hours, then cooled to 0oC and successively added 3 ml of water, 30 ml of 15% NaOH solution and 9 ml of water. The inorganic salt is filtered off and the filtrate is evaporated in vacuum. Obtain 24 g of the target product after distillation under reduced pressure. So Kip. = 125oC at a pressure of 1.2 PA.

B - 3-/Methoxyethoxy/-1,5-diethylaminopentane

A solution of 46 g of p-toluensulfonate and 38 ml of triethylamine in 80 ml of THF is cooled to 0oC, add a solution of 18 g of the compound obtained in the preceding stage in 100 ml of THF and left for 16 hours under stirring and at room temperature. Add 150 ml of water to the reaction mixture, the solvent is evaporated in vacuo, extracted with ethyl acetate and the latter is evaporated in vacuum. The oil obtained is treated with 250 ml of ether and 200 ml of 2n. NaOH solution and left for 16 hours under stirring and at room temperature. After decanting, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Obtain 45 g of the target product, after Christological]-indol-2-he

This connection receive according to the operation method described in the Getting 2 of 5-ethoxy-1,3-dihydro-indol-2-she and compounds obtained in the previous stage. Get the target product as a mixture of isomers. So pl. = 98oC.

Preparation 15: 5-Ethoxy-1,3-dihydro-3-Spiro/4 - tricyclo/5.2.1,02.6/Dean/-indol-2-he

A mixture of 3 g of 5-ethoxy-1,3-dihydro-3-Spiro[4-tricyclo- /5.2.1.02.6/-Dec-8-ene]-indol-2-it is described in Table 2, and 1.5 g of 10% palladium on coal in 160 ml of methanol hydronaut for 16 hours at 40oC and a pressure of 20 bar. The catalyst is filtered off on Celitewashed with methanol and the filtrate is evaporated in vacuum. Get 2,95 g of the target product. So pl.= 236oC.

Preparation 16 and 17: 5-Ethoxy-1,3-dihydro-3-Spiro-/4 - methoxycyclohexene/-indol-2-he; the least polar isomer and the most polar isomer

A. - 3-Methoxybutan-1,5-diol

To a solution of 30 g of diethyl-3-hydroxy-glutarate, 33 ml of 2,6-di-tert-butylpyridinium 500 ml DHM add 25 ml methyltrichlorosilane and refluxed for 6 hours. After cooling, add 500 ml of 0.5 n HCl solution decanted organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum.

B. - 3-Methoxy-1,5-diethylaminopentane

A solution of 31 g of p-toluensulfonate and 26 ml of triethylamine in 120 ml of THF is cooled to 0oC, add 10 g of the compound obtained in the previous stage, and leave for 24 hours under stirring and at room temperature. To the reaction mixture are added 120 ml of water, the solvent is evaporated in vacuo, extracted with ethyl acetate, dried over magnesium sulfate and the solvent is evaporated in vacuum. The oil obtained is treated with 200 ml of ether and 200 ml of 2n. NaOH solution and left for 16 hours under stirring and at room temperature. After decanting, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Obtain 26 g of the target product, after crystallization from cyclohex the e polar isomer and the most polar isomer

These connections get in the way of work described in the Getting 2 from 11,85 g 5-ethoxy-1,3-dihydroindol-2-it, 34 g of potassium tert-butylate and 26 g of compound obtained in the previous stage. Chromatographic on dioxide silicon, elwira with a mixture of cyclohexane with etiracetam /80:20 by volume/. Share two isomers:

the least polar : the Receive connector 16, so pl.= 173oC

the most polar : the Receive connector 17, so pl.= 186oC

In addition, using the method described in the General part, get benzosulfimide described in the following table 3.

Of the various described above, 1,3-dihydro-indol-2-ones and the corresponding benzosulfimide get a connection according to the invention, using appropriate methods of work indicated in the examples below.

Examples 1 and 2

5-Ethoxy-1,3-dihydro-1-{ 2-methoxy-4-/pyrrol-1-yl/benzazolyl} - 3-Spirito-hexanol-2-he and 5 ethoxy-1,3-dihydro-1- [2-methoxy-4-/ 3-pyrrolin-1-yl-benzene-sulfonyl]-3 - spirocyclohexane-indole-2-he

A. - 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4 - nitrobenzenesulfonyl/-3-spirocyclohexane-indole-2-he

A solution of 15 g of 5-ethoxy-1,3-dihydro-3-Spiro-cyclohexane-indole - 2-it in 150 ml TGFb oil, then portions during 30 minutes, enter 18 g of 2-methoxy-4-nitrobenzenesulfonyl-chloride. After stirring for 18 hours at room temperature the resulting suspension was poured into a chilled solution of sodium chloride, then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated to dryness, then the residue crystallized when heated from 200 ml of ISO-ether. Obtain 23 g of the target product. So pl. = 160oC.

This connection also receive according to the following method.

And'/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4-nitrobenzenesulfonyl/- 3-spirocyclohexane-indole-2-he

A solution of 15 g of 5-ethoxy-1,3-dihydro-3-spirocyclohexane - 2-it in 300 ml of THF is cooled to a temperature of about -50oC and added 7.2 g of potassium tert-butylate. Leave with stirring, allowing the temperature to rise to 0oC then cooled to -50oC and add a solution of 16.2 g of 2-methoxy-4 - nitrobenzenesulfonyl-chloride in THF. Leave for 1 hour. under stirring at room temperature, add 100 ml of water and the solvent is evaporated in vacuum. The aqueous phase is extracted with DHM, dried over magnesium sulfate and the solvent is evaporated in vacuum. Get target prodshow of suitable 1,3-dihydro-indol-2-ones, get the following nitro-derivatives (see table 4).

B/ 1-/4-Amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3 - dihydro-3-spirocyclohexane-indole-2-he

The suspension containing 20 g of the compound obtained in the previous phase, 20 g of iron powder, 70 ml of water and 70 ml of 96oalcohol, bring to the boiling point under reflux for 30 minutes, add a solution of 7 ml of concentrated hydrochloric acid in 35 ml of water. After boiling under reflux for 4 hours, add 15 ml of sodium lye, then extracted with DHM. The organic phase is filtered over Celite, then dried over sodium sulfate. The residue crystallized when heated from 100 ml of a mixture of itapira with ethyl acetate /80:20 by volume/. Get to 15.8 g of the target product. So pl. = 177oC.

This connection also receive according to the following method.

B'/. 1-/4-Amino-2-methoxybenzenesulfonyl/5-ethoxy-1,3-dihydro - 3-spirocyclohexane-indole-2-he

A solution of 0.5 g obtained in stage a compound in 10 ml of ethanol is cooled to 5oC and add 0.8 ml of concentrated HCl and 0.4 g of tin powder. Heated at 40oC for 45 minutes and the solvent is evaporated in vacuum. Celiteand the filtrate is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira mixture DHM / methanol / 99:1 by volume)/

Get the target product.

Also according to this last method will receive the following anilines (see table 5).

B"/. The compound obtained in stage B above can also be obtained from the corresponding nitro derivative by hydrogenation for 2 hours at 50oC and at a pressure of 1 bar, in the presence of 10% palladium-on-charcoal grill.

In/. 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-/pyrrol-1-yl/- benzazolyl] -3-spirocyclohexane-indole-2-he and 5 ethoxy-1,3 - dihydro-1-[2-methoxy-4-/3-pyrrolin-1-yl/benzazolyl]- 3-spirocyclohexane-2-he

A mixture containing 500 mg of the compound obtained in stage B, 10 ml of DMF 0.3 g of sodium carbonate and 300 mg of CIS-1,4-dichloro-but-2-ene, refluxed for 4 hours. The reaction mixture was poured into a mixture of ice water, then extracted with ethyl acetate and washed with water, the solvent is evaporated, then the residue that is obtained, chromatographic on the silicon dioxide. Elute with a mixture DHM/heptane /95:5 by volume/, then clean DHM. Receive 70 mg of the least polar product /compound of example 1/; so pl. = 174

The compounds described in tables phases a and B, can be used to obtain compounds according to the invention, similar to that obtained in stage Century.

Example 3

5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-/pyrrolidin-1-yl/- benzazolyl] -3-spirocyclohexane-indole-2-he

450 mg of the Compound obtained in Example 2, bring in 25 ml of 95oethanol and 25 ml of ethyl acetate, in the presence of 150 mg of 5% palladium-on-charcoal, and hydronaut 35oC at a pressure of 40 bar for 4 hours. The catalyst is filtered off, the filtrate is evaporated to dryness. The target product is crystallized from ISO ether. Weight = 110 mg, so pl. = 185oC.

Example 4

5-Ethoxy-1,3-dihydro-1-/4-/isoindoline-2-yl/-2 - methoxybenzenesulfonyl/-3-spirocyclohexane-indole-2-he

A mixture containing 500 mg obtained in Example 1, step B, compound, 10 ml of DMF, 0.5 ml of tea and 310 mg ,- dibromo-ortho-xylene for 2 hours, refluxed. The reaction mixture was poured into a mixture of ice water, extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness. The remainder chromatographic on the silicon dioxide, elwira using DHM, then the mixture DHM with ethyl acetate /95:5 by volume/. Get the target product, which crystallize the yen-2-yl]- carboxamido} -benzazolyl)-3-spirocyclohexane-indole-2-he

Within 3 hours at room temperature stirred mixture containing 500 mg obtained in example 1, step B, compound, 10 ml DHM, 2 ml of pyridine and 250 mg of the acid chloride of 3-methylthiophene-2-carboxylic acid. Wednesday, washed with 1 N. hydrochloric acid, then water. Dried over sodium sulfate, then evaporated to dryness. The remainder chromatographic on the silicon dioxide, elwira using DHM. The target product is recrystallized from ISO-ether. Weight = 0.21 g, so pl. = 174oC.

Example 6

1-[4-/N-Benzylcarbamoyl/-2-methoxybenzenesulfonyl] -5 - ethoxy-1,3-dihydro-3-spirocyclohexane-indole-2-he

A/. Benzyl ester of 3-methoxy-4-[/5-ethoxy-2,3-dihydro-2 - oxo-3-spirocyclohexane-indol-1-yl/-sulfonyl]-benzoic acid.

Small portions of 1.4 g of sodium hydride are added to a solution of 11.8 g of 5-ethoxy-1,3-dihydro-3-spirocyclohexane-2-it in 100 ml of THF. After stirring for 30 minutes at room temperature, add 17 g of benzyl ester 4-chlorosulfonyl-3-methoxybenzoic acid and continue stirring at room temperature for 1 hour.

Poured into 400 ml of a mixture of water with ice /50:50 by volume/. The formed precipitate is filtered off, dried, then crystallized from alcohol. Weight = 22,65, T is sauna acid

To a solution of 22,65 g complex ensilage ester obtained in the previous stage, in 600 ml of ethyl acetate added 2.5 g of 10% palladium-on-coal oil, then hydronaut at atmospheric pressure for 2 hours at 40oC. Filtered the insoluble part, then Wednesday concentrate. The target product is crystallized from pentane. Weight = 18,3, So pl. = 181oC.

In/. 3-Methoxy-4-[/5-ethoxy-2,6-dihydro-2-oxo-3 - spirocyclohexane-1-yl/-sulfonyl]-benzoyl chloride

Within 3 hours refluxed solution of 2.3 g of the previous acid in 20 ml of thionyl chloride. Reaction medium was concentrated to dryness, the product is used in the next stage, untreated, in the form of a solution in DHM.

G/. 1-[4-/P-Benzylcarbamoyl/-2-methoxybenzenesulfonyl]- 5-ethoxy-1,3-dihydro-3-spirocyclohexane-indole-2-he

For 30 minutes at room temperature stirred mixture containing 500 mg of the compound obtained in the previous stage, and 200 mg of benzylamine in 20 ml. DHM and 0.5 ml of tea. Washed with 1N HCl solution, dried over sodium sulfate and concentrated. The target product is crystallized from ISO ether. Weight. = 440 mg, so pl. = 196oC.

The compound of Example 6 is not included in the compounds of formula I according to the invention,

The method of operation described in Example 6, step G, is also used for producing the compound of Examples 44-54, using the appropriate amines.

Example 7

2-[4-/2-Carbamoylation-1-yl-carbonyl/-2 - methoxybenzenesulfonyl]-5-chloro-1,3-dihydro-3-spirocyclohexane-indole - 2-he

A/. Difficult phenyl ester 4-[/5-chloro-2,3-dihydro-2-oxo-3 - spirocyclohexane-indol-1-yl/-sulfonyl]-3-methoxybenzoic acid

A mixture containing 1 g of 5 - chloro-1,3-dihydro-3 - spirocyclohexane-2-it, 50 ml THF and 115 mg of sodium hydride, stirred for 30 minutes at room temperature in a nitrogen atmosphere. Contribute 1.5 g of 2-methoxy-4-phenoxycarbonylamino - chloride and incubated with stirring for 20 hours at room temperature.

The reaction medium was concentrated in vacuo, the residue is treated with 30 ml of water and extracted with ethyl acetate. The organic phase is washed, dried and concentrated in vacuo. The resulting product was then purified by chromatography on silica, elwira a mixture of ISO-ether with hexane /40:60 by volume/. Obtain 1.4 g of the target compound. So pl. = 165oC.

B/. 1-[4/2-Carbamoylation-1-yl-carbonyl/-2 - methoxybenzenesulfonyl-5-chloro-1,3-dihydro-3-spirocyclohexane and the rata, 1 ml of tea and 20 ml of peniten refluxed for 1 hour. After cooling, the reaction medium is treated with ethyl acetate, washed with 1N. HCl solution, water, then dried over sodium sulfate and concentrated. The remainder chromatographic on the silicon dioxide, elwira mixture DHM with methanol /98:2 by volume/. Obtain 0.09 g of the target product. So pl. = 142oC.

Example 8

5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-/2/ethoxycarbonylpyrimidine - 1-yl-carbonyl/-benzazolyl]-3-spirocyclohexane-indole-2-he

To 500 mg of 3-methoxy-4-[/5-ethoxy-2,3-dihydro-2-oxo-3 - spirocyclohexane-indol-1-yl/-sulfonyl] -benzoyl-chloride obtained in Example 6, stage, add 500 mg of methyl ester hydrochloride /L - Proline, 0.5 ml of tea and 20 ml DHM. After stirring for 1 hour at room temperature, washed with 1 N. HCl solution, dried and concentrated. The remainder chromatographic on the silicon dioxide, elwira mixture DHM /methanol / 98:2 by volume/. Receive 300 mg of the target product, characterized by its NMR spectrum:

NMR spectrum at 200 MHz in DMSO /2,5 D., m / m D. 1,25 /so, 3H/; 1,3 - 2,35 /m , 14H/, 3,1 - 3,7 /m, 8H/, 3,8 /K. m, 2H/; 4,35 /MT 1H/; 6,7 - 8 /m, 6H/.

Example 9

1-[4-N'-Cyclopentylamine/-2-methoxybenzenesulfonyl] -5 - this is - benzazolyl/-3-spirocyclohexane-indole-2-he

Cooled to a temperature below the 5oC mixture containing 2 g of 1-/4-amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3-dihydro-3 - spirocyclohexane-2-[obtained in Example 1, step B] , 3.6 ml of phenylcarbamate and 120 ml of ether. Add 960 mg of sodium hydroxide in 16 ml of water and leaves the temperature to rise for 24 hours under stirring. The precipitate is filtered off, washed with water, then ether. The remainder chromatographic on the silicon dioxide, elwira using DHM. Get the target product. So pl. = 181oC.

B/. 1-[4-/N'-Cyclopentylamine/-2-methoxybenzenesulfonyl] -5 - ethoxy-1,3-dihydro-3-Spirito-hexane-indole-2-he

2 g obtained in the previous stage of the compounds dissolved in 40 ml of ethanol, 100oand 30 ml DHM. Add 2 ml of cyclopentylamine and leave for 18 hours under stirring at room temperature. The alcohol is evaporated in vacuo, then the residue chromatographic on the silicon dioxide, elwira mixture DHM /ethyl acetate [95:5 by volume]. Obtain 1.8 g of the target product, which is crystallized from ISO ether. So pl. = 195oC.

Example 10

5-Chloro-1,3-dihydro-1-[4-N', N'-diethylurea/-2 - methoxybenzenesulfonyl/-3-Spiro(4-tetrahydrothiopyran-1-oxide - indole-2-it.

This compound floor is/-2 - methoxybenzenesulfonyl/-3-Spiro(tetrahydrothiopyran-4)-indole-2-it. So pl. = 214oC;

from 5-chloro-1,3-dihydro-1-/4-amino-2-methoxybenzenesulfonyl/- 3-Spiro-/tetrahydrothiopyran-4/-indol-2-it. So pl. = 229oC.

B/. 5-Chloro-1,3-dihydro-1-[4-/N', N'-diethylurea/-2 - methoxybenzenesulfonyl]-3-Spiro(4-tetrahydrothiopyran-1-oxide)- indole-2-it.

A mixture of 0.45 g obtained in stage a compound, 0.2 g of periodate of sodium in 3 ml of methanol and 2 ml of water, stirred for 24 hours at room temperature. The precipitate is filtered off and the methanol is evaporated from the filtrate under reduced pressure. Extracted using DHM, dried over magnesium sulfate and the solvent is evaporated. The remainder chromatographic on a column of silica, elwira mixture DHM /methanol / 98:2 by volume/ and allocate 0.4 g of the target product.

So pl. = 217oC.

Example 11

5-Chloro-1,3-dihydro-1-[4-/N', N'-diethylurea/-2 - methoxybenzenesulfonyl] -3-Spiro(4-tetrahydrothiopyran-1,1-dioxide - indole-2-he

Within 4 hours at room temperature stirred mixture of 0.45 g of the compound of example 10 and 0.5 g metacompetencies acid in 10 ml DHM. Then add 12 ml of aqueous saturated sodium bicarbonate solution, decanted and washed with water the organic phase, which is dried and evaporated under ponizhennogo product. So pl. = 211oC.

Example 12

1-[4-/N'-Cyclopentadienide/-2-methoxybenzenesulfonyl] -5 - ethoxy-1,3-dihydro-3-spirocyclohexane-indole-2-he

Obtained in Example 9 compound contribute in 50 ml of toluene in the presence of 1.5 g of reagent Lawesson. Within 24 hours refluxed. The toluene is removed, then the residue chromatographic on dioxide silicon, elwira using pure DHM, then using a mixture of DH /ethyl acetate [reaching the ratio of 90:10 by volume]. Get the target product, which is crystallized from ISO ether.

So pl. = 197oC.

Example 13

1-{ 4-[3-N-Boc-amino/-azetidin-1-yl-carboxamido] -5 - methoxybenzenesulfonyl}-2-ethoxy-1,3-dihydro-3 - spirocyclohexane-indole-2-it.

A/. 1-Benzhydryl-3-/N-Boc-amino/-azetidin

For 2 hours at room temperature stirred mixture containing 5 g of 3-amino-1-benzhydryl-azetidin and 5 g /Boc/2O in 130 ml of dioxane and 4 ml of tea. The dioxane is evaporated, the residue treated with ethyl acetate and washed with water. Dried over sodium sulfate, then evaporated to dryness. The target product is crystallized from ISO ether. Weight = 6,

B/. Hydrochloride 3-/N-Boc-amino/-azetidine

Prepare a mixture containing 6 g obtained in predict for 2 hours at 35-40oC at a pressure of 2 bars. The catalyst is filtered off and the filtrate is evaporated to dryness. The target product is crystallized from ISO ether. Weight = 3,4,

In/. 1-{ 4-[3-/N-Boc-amino/-azetidin-1-yl-carboxamido] -5 - methoxybenzenesulfonyl}-2-ethoxy-1,3-dihydro-3-spirocyclohexane - indole-2-he

Within 24 hours at room temperature stirred mixture containing 500 mg obtained in Example 9, step A, compound, 20 ml 100oalcohol, 15 ml DHM, 250 ml obtained in stage B/ connections and 0.5 ml of tea. The solvent is evaporated, then carry out a chromatography on a column of silica, elwira mixture DHM with ethyl acetate 95:5 by volume. The target product is crystallized from ISO ether. Weight = 200 mg. So pl. = 156oC.

Example 14:

1-[4-/N'-Carboxymethyl-N'-methylurea/-2 - methoxybenzenesulfonyl] -5-ethoxy-1,3-dihydro-3-spirocyclohexane - indole-2-he

Prepare a mixture containing 500 mg obtained in Example 9, step A, compound, 20 ml of ethanol, 100o15 ml DHM, 1.5 g of sarcosine and 2 ml of triethylamine. After stirring for 24 hours at room temperature, the solvent is evaporated, then the residue is treated with ethyl acetate when heated and filtered, the insoluble part. The filtrate is evaporated to dryness, the mu]. Get the target product, which is characterized by its NMR spectrum at 200 MHz in DMSO /2.5 M. D./:

M. D., 1,3 /so, 3H/; 1,4 - 2,1 /m, 10H/; 2,96 /s, 3H/; 3,5 /s, 3H/; 3,9 /s, 2H/; 4 /K., 2H/; 6,7 - 7,9 /m, 6H/; 9,45 /n 1H/.

Example 15

5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-/1-methyl-2,4 - dioxoimidazolidin-3-yl-benzene-sulfonyl]-3-Spiro-cyclohexane-indole - 2-he

By heating at 100oC for 24 hours in vacuum cyclist the product obtained in the previous example. Obtain 230 mg of the target product. So pl. = 200oC.

Example 16

1-[4-/N',N"-Diethylthiourea/2-methoxybenzenesulfonyl]-5 - ethoxy-1,3-dihydro-3-spirocyclohexane-2-he

A/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4 - phenoxythiocarbonyl-benzazolyl-/3-Spiro-cyclohexane - indole-2-he

Prepare a mixture containing 500 mg of the compound obtained in Example 9, step A, 900 mg phenoxythiocarbonyl, 30 ml of ether, 8 ml of water, 120 mg of sodium hydroxide and 20 ml DHM. After stirring for 24 hours at room temperature, the solvent is evaporated, then the residue chromatographic on the silicon dioxide, elwira using DHM. The target product is crystallized from ISO ether. Weight = 140 mg, So pl. = 157oC.

B/. 1-[4-/N', N'-Diethylthiourea/-2-methoxybenzenesulfonyl]- 5-ethoxy is, containing 140 mg) obtained in stage a compound, 20 ml of ethanol, 100owith 5 ml. DHM and 1 ml of diethylamine. The solvent is evaporated, then the residue chromatographic on a column of silica, elwira using pure DHM, then the mixture DHM /ethyl acetate [until the ratio of 90:10 by volume]. The target product is crystallized from ISO ether.

Weight = 105 mg. So pl. = 167oC.

Example 17

5-Ethoxy-1,3-dihydro-1-/2-methoxy-4-guanidinopentanoic/- 3-spirocyclohexane-indole-2-he

Within 1 hour, refluxed mixture containing 500 mg obtained in Example 1,step B, compound, 125 mg of cyanamide, 7 ml of ethyl acetate, 1 ml of ethanol and 0.2 ml of 20% aqueous solution of hydrogen chloride in ethanol. The solvent is evaporated, then the residue chromatographic on a column of silica, elwira using DHM, then with methanol. The isolated product utverjdayut in the air. Add 2n. the solution of NaHCO3then extracted formed the basis of the ethyl acetate, evaporated to dryness and the desired product is solidified in from the ether.

Weight = 0,055, So pl. = 235oC.

Example 18

5-Ethoxy-1,3-dihydro-1-{ 2-methoxy-4-[N-methyl-carbamoylmethyl] - benzazolyl}-3-Spiro-cyclohexane-indole-2-he

is enocsi/-acetic acid is mixed with 30 ml DHM and to the mixture for 20 minutes, add 7.5 ml of trimethylsilylmethylamine in 30 ml DHM. Leave under stirring to rise to room temperature and after 2 hours add 30 g of ice and again mix. After decanting, the aqueous phase washed with ether, and add a sufficient amount of potassium carbonate to achieve a pH of 7. The precipitate is white, which is formed, filtered off, then washed it with acetone and ether. Thereby obtaining 3.1 g of the target product, which is characterized by the NMR spectrum.

B/. 2-Methoxy-4-/ethoxycarbonylmethoxy/-phenylsulfonyl-chloride

Within 3 hours refluxed 3.1 g of the compound obtained in the previous phase, in 30 ml of phosphorus oxychloride. Wednesday was concentrated in vacuo, then the residue is treated with ice. Extracted with ethyl acetate, washed with water, then 1N. the sodium hydroxide solution, then with water again, dried over sodium sulfate and concentrated in vacuo. The target product is crystallized from ISO ether.

Weight = 2,5, So pl. = 80oC.

In/. Ethyl ester of 3-methoxy-4-[/5-ethoxy-2,3-dihydro-2 - oxo-3-spirocyclohexane-indol-1-yl/-sulfonyl]-phenoxyalkanoic acid

Prepare a mixture containing 0.5 g of 5-ethoxy-1,3-dihydro-3 - spirocyclohexane-indole-2-it, 5 ml of THF and 60 mg of sodium hydride. After paramesh the stirring for 15 minutes, the mixture is then concentrated in vacuo. Extracted with ether, washed with water, then the target product is crystallized from ISO ether. Weight = 0.85 grams, so pl. = 160oC.

G/. 5-Ethoxy-1,3-dihydro-1-{2-methoxy-4-[N-methyl - carbamoylmethyl]-benzazolyl}-3-spirocyclohexane-indole - 2-he

Within 4 days at room temperature stirred mixture containing 0.5 g obtained in the preceding stage connection, 15 ml of 33% solution of methylamine in methanol and 15 ml of ethanol. Concentrated in vacuo, then chromatographic balance silicon dioxide. The column is washed with DHM, then elute with ethyl acetate to obtain the desired product. Weight = 0,1, So pl. = 192 - 195oC.

Example 19

5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-{ N-methyl-N-/2 - methylallyl/-amino}-benzene-sulfonyl]-3-Spiro-cyclohexane - indole-2-he

A/. 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-/N-methyl/-amino - benzazolyl]-3-spirocyclohexane-indole-2-he

2 g Obtained in example 1, step B, compound, while cooling in an ice bath to 10oC, dissolved in 6 ml of 37% formaldehyde in the form of a solution in water and 40 ml of acetonitrile. Add 1.7 g of cyanoborohydride sodium 85% purity, then 0.5 ml of acetic acid, and left under stirring at on irout, the organic phase is dried, then spend 2 consecutive chromatography on silica, elwira mixture DHM /heptane / 85:15 by volume/, then clean DHM and, finally, the mixture DHM /ethyl acetate / 98:2 by volume/. Get the target connection. Weight = 0,36, So pl.=157oC.

B/. 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-{N-methyl-N-/2 - methylallyl/amino} -benzazolyl]-3-spirocyclohexane-indole-2-he

Within 10 hours refluxed mixture containing 500 mg obtained in the preceding stage connection, 10 ml of DMF, 0.5 ml of diethylamine and 0.5 ml of 3-chloro-2-methylpropene. The reaction mixture was poured into a mixture of ice water, then extracted with ethyl acetate, washed with water and chromatographic on the silicon dioxide, elwira using DHM. The target compound is crystallized from pentane. Weight = 190 mg. So pl. = 118oC.

Acting according to the procedures described in the previous Examples to obtain the compounds of formula I according to the invention described in the following table 6:

/a/ : this connection will receive according to the procedure described in Example 2, stage, carrying out the reaction in an inert atmosphere and using triethylamine as base;

/b/ : this connection will receive according to the procedures described in the crystals;

/c/ : this connection will receive according to the method described in Example 9, step B, using amino-derivatives or the corresponding nitrogen-containing heterocycles;

/d/ : this connection will receive according to the procedures described in Example 16, step A, then phase B;

/e/ is the connection receive in accordance with the method described in Example 6, step G, using the appropriate amines;

/f/ : this connection will receive according to the method described in Example 17, using N,N-decisionaid;

/g/ : this connection will receive according to the procedure described in Example 1, step A, using 2,4-dimethoxybenzenesulfonamide and the corresponding indole-2-he;

/h/ : this connection will receive according to the procedure described in Example 68, from the compound obtained in Example 57 /mixture of isomers/;

/i/ : a mixture of isomers.

Example 59

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro-/4-oxocyclohexa/-indol-2-he 0,25 H2O

For 16 hours at room temperature stirred mixture of 0.3 g obtained in Example 68 compound, 0.3 g of chlorproma pyridinium and 1.5 ml DHM. To the reaction mixture add 10 ml of water, DHM is evaporated in vacuum, the residue is extracted with ethyl acetate, dried extract the comfort on the silicon dioxide, elwira mixture DHM /methanol/ /98: 2 by volume/. Obtain 0.26 g of the target product. So pl. = 100oC.

Example 60

5-fluoro-1,3-dihydro-1-[2-methoxy-4-/ 3-pyrrolin-1-yl/- benzazolyl] -3-Spiro-/4,4-dimethylcyclohexane/-indol-2-he

This connection receive in accordance with the method described in Example 2, stage, carrying out the reaction in an inert atmosphere and using triethylamine as the base.

Example 61

5-Chloro-3,3-dihydroxyethyl-1,3-dihydro-1-/2,4 - dimethoxybenzonitrile/-indol-2-he

This connection receive according to the method described in J. Org. Chem., 1977, 42, 3772. To 0.92 g of compound of Example 56, described in the above Table 6, add 0,037 g pyridinedicarboxylate in 12 ml of ethanol for 3 hours, heated to approximately 55oC.

The solvent is evaporated under reduced pressure and the residue chromatographic on a column of silica, elwira using DHM.

Allocate the target product, which is crystallized by heating of a mixture of cyclohexane to ethyl acetate in the ratio of 50:50 /volume/.

So pl. = 166oC.

Examples 62 and 63

5-Ethoxy-1,3-dihydro-1-/2-methoxy-4-nitrobenzenesulfonyl/- 3-Spiro-[4-/methoxyethoxy/-cyclohexane]-indol-2-he;

described in Example 1, stage And, on the basis of 5-ethoxy-1,3-dihydro-3-Spiro-[4- /methoxyethoxy/-cyclohexane]-indol-2-it. Chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane to ethyl acetate /95:5 by volume/.

Share two isomers:

the least polar: compound of Example 62, so pl. = 127oC;

the most polar: compound of Example 63, so pl. = 118oC.

Examples 64 and 65

1-/4-Amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3-dihydro-3 - Spiro-[4-/methoxy-metiloksi/-cyclohexane]-indol-2-he;

the least polar isomer and the most polar isomer.

These connections receive according to the operation method described in Example 1, step B from a mixture of compounds obtained in Examples 62 and 63 before chromatography. Chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane to ethyl acetate /95:5 by volume/. Share two isomers:

the least polar: compound of Example 64; so pl. = 103oC

the most polar: compound of Example 65; T. pl. = 111oC.

Example 66

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro[4-/methoxyethoxy/-cyclohexane]-indol-2-it, the least polar isomer.

This connection receive according to the method of Example 9, the hundred and the minutes The target product is obtained after recrystallization from a mixture of cyclohexane with ethyl acetate.

So pl. = 160oC.

Example 67

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro[4-/methoxyethoxy/-cyclohexane]-indol-2-he, the most polar isomer

This connection receive in accordance with the method described in Example 9, step A, then phase B, based on the compound obtained in Example 65 and using the second stage diethylamin. The target product is obtained after recrystallization from a mixture of cyclohexane with ethyl acetate.

So pl. = 137oC.

Example 68

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro-/4-hydroxycyclohexane/-indol-2-it, monohydrate, the least polar isomer

Within 30 minutes, heated at 50oC a solution of 2.2 g obtained in Example 66 compound in 6 ml of methanol and 1.2 ml of concentrated HCl. To the reaction mixture add 10 ml of water, extracted with ethyl acetate, dried over magnesium sulfate and the solvent is evaporated in vacuum.

The remainder chromatographic on the silicon dioxide, elwira mixture DHM /methanol [90: 10 by volume]. Get 1,9 g of the target product, after precrystallization/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro/4-hydroxycyclohexane/indole-2-it, monohydrate, the most polar isomer.

This connection receive according to the procedure described in Example 68, proceeding from the compound obtained in Example 67. The target product is obtained after recrystallization from a mixture of cyclohexane with ethyl acetate.

So pl. = 144oC.

Example 70

5-Ethoxy-1,3-dihydro-1-/2/methoxy-4-nitrobenzenesulfonyl/- 3-Spiro-/4-methoxycyclohexene/indole-2-he, the most polar isomer

This connection receive according to the procedure described in Example 1, stage A', on the basis of 5-ethoxy-1,3-dihydro-3-Spiro/4 - methoxycyclohexene/indole-2-it, the most polar isomer [connect Get 17].

Get the target product. So pl. = 141oC.

Example 71

1-/4-Amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3-dihydro-3 - Spiro/4-methoxy-cyclohexane/-indol-2-he, the most polar isomer

This connection receive according to the procedure described in Example 1, stage B, on the basis of the compounds obtained in Example 70. So pl. = 199oC.

Example 72

5-Ethoxy-1-[4-(N', N'-diethylurea)-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro/4-methoxycyclohexene/indole-2-it, the least polar isomer.

A/s ' isomer

This connection receive according to the procedure described in Example 1, stage A', based on the compounds obtained in the Obtaining 16 /the least polar isomer/.

B/. 1-/4-Amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3-dihydro-3 - Spiro-[4-methoxy-cyclohexane/-indol-2-it, the least polar isomer

This connection receive according to the procedure described in Example 1, stage B, on the basis of the data obtained in the previous stage of the connection.

In/. 5-Ethoxy-1-[4-(N',N'-diethylurea)-2 - methoxybenzenesulfonyl]-1,3-dihydro-3-Spiro/4-methoxycyclohexene/- indol-2-it, the least polar isomer.

Get this connection according to the method described in Example 9, step A, then phase B, based on the compound obtained in the previous stage, and using diethylamine. So pl. = 118oC.

Example 73

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro/4-methoxycyclohexene/-indol-2-he, the most polar isomer.

This connection receive in accordance with the method described in Example 9, step A, then phase B, based on the compound obtained in Example 71, using the second stage diethylamin. The target product is obtained after recrystallization from a mixture of cyclohexane with solarpanel/-3 - Spiro-/4-haproxy-cyclohexane/-indol-2-it, the most polar isomer

For 1 hour at 50oC heated mixture of 2.2 g of the compound obtained in Example 63, 1.2 ml of concentrated HCl in 6 ml of methanol. To the reaction mixture add 10 ml of water, the precipitate is sucked off, washed with water and dried in vacuum at 50oC.

Obtain 1.3 g of the target product. So pl. = 135oC.

Example 75

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro/4-Toxicological/-indol-2-it.

A/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4-nitrobenzenesulfonyl/- 3-Spiro-/4-ethoxy-cyclohexane/indole-2-he

For 6 hours at 40oC stirred solution of 0.25 g of 5-ethoxy-1,3-dihydro-1-/2-methoxy-4-nitrobenzenesulfonyl/-3 - Spiro-/4-hydroxycyclohexane/-indol-2-[obtained according to the procedure described in Example 74, based on the mixture of isomers obtained from Examples 62 and 63 before chromatography], 0.6 ml of 2,6-di-tert-butylpyridinium, and 0.37 ml ethyltrichlorosilane in DHM. To the reaction mixture add 5 ml of 5N. HCl, extracted with ethyl acetate, the organic phase is washed 3 times with a 0.5 n HCl solution, then with saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated in vacuum.

Receive 0.5 g zel-methoxybenzenesulfonyl/-5-ethoxy-1,3 - dihydro-3-Spiro-/4-ethoxy-cyclohexane/-indol-2-he

This connection receive according to the procedure described in Example 1, stage B' by the chemical recovery of the compounds obtained in the previous phase. Chromatographic on the silicon dioxide, elwira mixture DHM with methanol /99:1 by volume/. Get the target product.

So pl. = 110oC.

In/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4 - phenoxycarbonylamino/-3-Spiro-/4-Toxicological/- indol-2-it.

This connection receive according to the operation method described in Example 9, step A, from compound obtained in the previous phase. Get the target product, which is used as is in the next stage.

G/. 5-Ethoxy-1-[4-N', N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro/4-Toxicological/-indol-2-he

This connection receive in accordance with the method described in Example 9, step B, based on the compound obtained in the previous stage, and diethylamine. Get the target product. So pl. = 121oC.

Example 76

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro-[4-/2-methoxyethoxy/-cyclohexane/-indol-2-he

A/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4-nitro-benzazolyl/- 3-Spiro-[4-/2-methoxy-ethyl) - Rev. 5-ethoxy-1,3-dihydro-1-/2-methoxy-4-nitrobenzenesulfonyl/- 3-Spiro-/4-hydroxycyclohexane/-indol-2-it, 2 g of 1-iodine-2-methoxyethane, 0.9 ml of 2,6-di-tert-butylpyridinium, 2.15 g triftoratsetata silver in 17 ml of CCl4and 8 ml DHM. To the reaction mixture was added 100 ml of 0.1 G. of HCl, the solvent is evaporated in vacuo, extracted with ethyl acetate, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira cyclohexane. Obtain 0.36 g of the target product, which is used as is in the next stage.

B/. 1-/4-Amino-2-methoxybenzenesulfonyl/-5-ethoxy-1,3 - dihydro-3-Spiro-[4-/2-methoxyethoxy/-cyclohexane]-indol-2-he

This connection receive according to the procedure described in Example 1, stage B, by restoring charged at the previous stage of the connection. Get the target product. So pl. = 118oC.

In/. 5-Ethoxy-1,3-dihydro-1-/2-methoxy-4 - phenoxycarbonylamino/-3-Spiro[4-/2-methoxyethoxy/- cyclohexane]-indol-2-it.

This connection receive in accordance with the method described in Example 9, stage And, based on the obtained at the previous stage of the connection. Get the target product, which is used as is in the next stage.

G/. 5-Ethoxy-1-[4-/N',N'-diethylurea/-2 - methoxybenzenesulfonyl]-1,3-dihydro-3-pulling in Example 9, stage B, based on the obtained at the previous stage of the connection and diethylamine. Get the target connection. So pl. = 98oC.

Example 77

5-Ethoxy-1-[4-N',N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro/4-n-prophylaxisflomax/-indol-2-he

This connection receive according to the methods of operation described in Example 76, step A, starting from 5-ethoxy-1,3-dihydro-1-/2-methoxy - 4-nitrobenzenesulfonyl/-3-Spiro-/4-hydroxycyclohexane/-indol-/2 - it 1-iodopropane in benzene, then come in stages B, C, and Get a business product. So pl. = 115oC.

Example 78

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl] - 1,3-dihydro-3-Spiro/4-isopropylcyclohexane/-indol-2-it, hemihydrate

This connection receive according to the methods of operation described in Example 76, step A, starting from 5-ethoxy-1,3-dihydro-1-/2-methoxy-4 - nitrobenzenesulfonyl/-3-Spiro-/4-hydroxycyclohexane/indole-2-it 2-iodine-propane, then come in stages B, C, , Get the target product.

So pl. = 130oC.

Example 79

5-Ethoxy-1-[4-/N', N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro[4-/2-tert-butylacetate/-cyclohexane]- indol-2-he

This connection get callpanel/-3-Spiro-/4-hydroxycyclohexane/-indol-2-it 1-iodine-2-tert-butylacetate, then proceed as in stages B, C, and Obtain the target product. So pl. = 103oC.

Example 80

5-Ethoxy-1-[4-/N',N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-5-Spiro[4-/2-hydroxyethyloxy/-cyclohexane]-indol-2-he

For 2 hours at room temperature stirred mixture of 0.35 g obtained in Example 79 connection, 4 ml trifter - acetic acid in 15 ml DHM. Add 40 ml of a saturated solution of NaHCO3after decanting, the organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira mixture DHM with methanol /90:10 by volume/. Get the target connection. So pl. = 109oC.

Example 81

5-Ethoxy-1-[4-/N',N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro-/4-formylcyclohex/-indol-2-he, the most polar isomer

Within 12 hours at 40oC heat the mixture of 0.25 g obtained in Example 69 compound, 0.18 g of cesium carbonate, 0.45 ml of dimethylsulfate and 12 ml of DMF. Add 10 ml of water, the reaction mixture was extracted with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic dioxide by chromatiaceae. So pl. = 155oC.

Example 82

5-Ethoxy-1-[4-/N',N'-diethylurea/-2-methoxybenzenesulfonyl]- 1,3-dihydro-3-Spiro/4-ecotoxicological/-indol-2-he, the most polar isomer.

For 5 hours at 40oC heat a mixture of 3 g obtained in Example 69 compound, 0.75 g of 4-dimethylaminopyridine, 3 ml of acetic anhydride and 5 ml DHM. To the reaction mixture, water is added, extracted with DHM, washed with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira mixture DHM with cyclohexane. Receive, after recrystallization from ISO-ether, the target product. So pl. = 140oC.

Example 83

5-Ethoxy-1,3-dihydro-1-/2,4-dimethoxybenzonitrile/3 - Spiro-[8,9-dihydrotetrazolo/5.2.1.02.6/Dean-4]-indol-2-it.

A/. 5-Ethoxy-1,3-dihydro-1-/2,4-dimethoxybenzonitrile/3 - Spiro-[8,9-epoxy-tricyclo/5.2.1.02.6/Dean-4/-indol-2-it.

Within 3 hours at room temperature stirred mixture of 0.3 g of 5-ethoxy-1,3-dihydro-1-/2,4-dimethoxybenzonitrile/-3 - Spiro[tricyclo/5.2.1.02.6/Dec-8-EN-4] -indol-2-it, 0.2 g of metacompetencies acid in 20 ml. DHM. Add 15 ml of a saturated solution of NaHCO3after decanting, referat on the silicon dioxide, elwira using DHM. Obtain 0.25 g of the target product, after recrystallization from a mixture of acetone with DHM.

So pl. = 263oC.

B/. 5-Ethoxy-1,3-dihydro-1-/2,4-dimethoxybenzonitrile/3 - Spiro-[8,9-dihydrotetrazolo/5.2.1.02.6/Dean-4-indol-2-he

Within 8 hours refluxed mixture of 0.2 g of the compound obtained in the previous stage, 20 ml of water, 2 ml of concentrated sulfuric acid and 20 ml of THF. The reaction mixture is neutralized by adding a saturated solution of NaHCO3, extracted with DHM, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira mixture DHM with methanol /99:1 by volume/. Obtain 0.17 g of the target product.

So pl. = 150oC.

Pharmaceutical research

The new compounds were investigated in relation to the affinity of the compounds for receptor V2vasopressin and receptors ocytocin in accordance with the adapted methodology P. Crause al., in Molecular and Cellular Endocrinology, 1982, 28, 529-541, and F. L. Stassen al., J. Pharmacol. Exp. Ther., 1982, 223, 50-54., to determine the affinity for vasopressin receptors, and in accordance with the method of J. Eland al., in Eur. J. Pharmacol, 1987, 147, 197-207, to determine cromok kidney bull and oxytocin receptors of cell membranes of the mammary glands of pregnant rats.

The measurement results are expressed in terms nanomole concentration of compounds, providing 50% inhibition (CI50nM).

The results are shown table 6 7.

Below is an example of a pharmaceutical composition (for example, gelatin capsules dosage of the active substance 25 mg):

Component - Quantity, mg

The compound of formula (I) 25,0

Modified maize starch - 131,45

Lactose crystal fine - 306,75

Anhydrous colloidal silicon dioxide - 2,4

Magnesium stearate - 4,8

Talc - 9,6

On one capsule with white opaque, size N On, filled up to 480 IHO

1. Derivatives of 1-benzazolyl-1,3-dihydroindol-2-it General formula I

< / BR>
in which R1- halogen, trifluoromethyl or alkoxygroup1- C7;

R3and R4- independently from each other mean-hydroxyalkyl2- C7in which the hydroxyl is free or substituted by a radical selected from the group: alkyl WITH1- C4tetrahydrofuranyl and tetrahydropyranyl, or R3and R4form a group - (CH2)pX (CH2)q- , or R3and R4together with the carbon atom to which the new, unsubstituted or substituted by one or more alkyl radicals WITH1- C7oxopropoxy; one or two hydroxyl, free or substituted by a group selected from the groups: alkyl WITH1- C4, (C1- C5- alkoxyalkyl, in which alkyl (C1- C4); - hydroxyalkyl, in which alkyl WITH1- C4; formyl and (C1- C7) alkylsulphonyl;

R5- alkoxyl1- C7;

R6- guanidine radical, unsubstituted or substituted one or twice by alkyl WITH1- C7, group or SIG7; carbamoyl radical, substituted by groups R'6and R"6; group R'7the group NR8R9; group CO-NH-CR10R'10-R12, R'6and R"6- independently of one another denote hydrogen; alkyl WITH1-C7substituted by one or more halogen or the radical R"'6cycloalkyl3-C7pyrrolidin-1-yl, or R'6and R"6together form with the nitrogen atom to which they relate, pyrolidine group, substituted carbamoyl; R"'6- alkoxyl1- C7carbarnoyl, free or SUB>-C7-carbamoylethyl1- C7free or substituted by one or two alkilani1- C7; R"7- pyrolidine group substituted by a group R""7; R""7- carboxypropyl, esterified by alkyl WITH1-C7; R8and R9independently of one another denote hydrogen; alkyl WITH1- C7; the radical R9may additionally mean of alkenyl3- C8; carbarnoyl, unsubstituted or substituted radicals R14and R'14; unsubstituted or substituted radicals R14and R'14thiocarbamoyl; or R8and R9together with the nitrogen atom to which they are bound, form as N-methylhydantoin or heterocycle, selected from the group pyrrol-1-yl, Delta-pyrrolin-1-yl, pyrrolidin-1-or or isoindoline-2-yl; R10and R'10mean hydrogen; R12is unsubstituted or substituted by one or two alkilani1-C7-an amino group; R14and R'14independently of one another denote alkyl WITH1-C7, unsubstituted or substituted by a radical R15cycloalkyl3-C7or R14and R'14together with the nitrogen atom to which they relate, whether peligrosas, the heterocycle may be unsubstituted or substituted by one or more methyl radicals, phenyl, and amino group-free or having a protective group; R15- pyridyl, hydroxyl, free or substituted by one or two alkyl radicals WITH1- C7amino group, a free or esterified by alkyl WITH1- C7carboxypropyl; p and q each indicates an integer, the sum of which is 3 to 6; X is an oxygen atom or a group S(O)n; n means 0, 1 or 2; provided that when R1is as defined above; R3and R4together form a group - (CH2)pX (CH2)q-, in which X can be oxygen or sulfur, or R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle3-C10saturated or unsaturated, possibly condensed, unsubstituted or substituted by one or more alkyl radicals WITH1-C7; R5is arcoxia1-C7then R6is guanidinopropionic, unsubstituted or substituted one or twice by alkyl WITH1- C7group or SIG7; carbamoyl group, substituted R'61-C7free or substituted by one or two alkyl radicals WITH1-C7; R'6and R"6each independently from each other mean WITH1- C7is an alkyl radical, substituted by one or more halogen or the radical R"'6WITH3-C7-cycloalkyl; pyrrolidin-1-yl, or R'6and R"6form together with the nitrogen atom to which they relate, pyrolidine group, substituted carbamoyl; R"'6is arcoxia1-C7, carbamoyl group, free or substituted by one or two alkyl radicals C1- C7or adamantium, or tetrahydrofuranyl; R'7is pyrrolidino group substituted by the radical R""7; R""7is carboxypropyl, esterified by alkyl WITH1- C7; R8is hydrogen or alkyl WITH1- C7; R9is alkenyl3-C8, carbamoyl group, substituted R14or R'14or thiocarbamoyl group, substituted R14and R'14or R8and R9together with the nitrogen atom to which they are linked, form as N-metil and isoindoline-2 - Il; R14and R'14represent independently of each1- C7is an alkyl radical substituted by a radical R15or form WITH3-C7- cycloalkyl; or R14and R'14together with the nitrogen atom to which they are bound, form a heterocycle selected from the group of: morpholine, thiomorpholine, piperazine, azetidine, pyrrolidine, piperidine or peligrosas, and the heterocycle is unsubstituted or substituted by one or more methyl radicals, phenyl or amino group, a free or having a protective group; R15means pyridyl, hydroxyl, amino group, free or substituted by one or two alkilani1- C7carboxypropyl, free or esterified by alkyl WITH1-C7,

as well as their possible salts.

2. The compound of formula I under item 1, in which R1means chlorine atom, fluorine or ethoxypropan in position 5 1,3-dihydro-indol-2-it.

3. The compounds of formula I under item 1 or 2, in which R3and R4together with the carbon atom to which they are bound, form a hydrocarbon cycle with 3 to 12 C-atoms.

4. The compounds of formula I on p. 3 in which R3and R4together with the carbon atom, ]Dean, bicyclo-[2.2.1]-heptane, bicyclo[3.3.1] nonan; or cyclohexane, unsubstituted or substituted by one or two alkyl groups with 1 to 7 C-atoms.

5. The compounds of formula I under item 1 or 2, in which R3and R4together with the carbon atom to which they are bound form a cyclohexane, substituted by a group selected among methoxy, ethoxy-, 2-methoxyethoxy.

6. The compounds of formula I according to any one of paragraphs.1-5, in which R5denotes the ortho-methoxy group and R6in paraprotein denotes a group chosen among a (piperidine-1-yl)-carboxamido, pyrrolidin-1-ilen, 3,3-diethylaniline-, N,N'-diethylthiourea.

7. The compound of the formula I, in which R1represents a 5-ethoxypropan, R3and R4together with the carbon atom to which they are bound, form spirocyclohexane, R5is a 2-methoxy group, R6represents a group NR8R9in which R8is hydrogen, and R9group 3-methyltin-2-yl carbonyl.

8. The compound of the formula I, in which R1represents a 5-ethoxypropan, R3and R4together with the carbon atom to which they are bound, form spirocyclohexane, R5is a 2-SUB>9
- karbamoilnuyu group, substituted stands and metaxylem.

9. The compound of the formula I, in which R1represents a 5-ethoxypropan, R3and R4together with the carbon atom to which they are bound, form spirocyclohexane, R5is a 2-methoxy group, R6represents a group NR8R9in which R8is hydrogen, and R9- karbamoilnuyu group, substituted stands and hydroxyl.

10. The method of obtaining derivatives of 1-benzazolyl - 1,3-dihydro-2-p. 1, characterized in that 1,3 - dihydroindol-2-he substituted in position 3, the General formula II

< / BR>
in which R1and R2have the meanings given in paragraph 1,

R'3and R'4matter;

R3and R4defined in paragraph 1, or are precursors of R3and R4selected from the group: each independently from each other, means tetrahydropyranyloxy2-C7; educated together a group - (CH2)pX -(CH2)q-, in which X is a sulfur atom; educated together a group tricyclo (5.2.1.02,6)Dec - 8-ene; educated together hydrocarbon cycle3-C12saturated or unsaturated, the SUB> - C5-alkoxy WITH1- C4-alkyloxyaryl,

subjected to interaction with the halide benzosulfimide General formula III

< / BR>
in which Hal is halogen, preferably chlorine;

R5radical described in paragraph 1;

RvIthe radical R6described in paragraph 1, or is a precursor of R6selected from the group of: amino, -carboxy(C1-C7)alkoxy, esterified by alkyl WITH1-C7; phenoxycarbonylamino-, carboxy-, benzyloxycarbonyl, phenoxycarbonyl, nitrogroup, phenoxythiocarbonyl-,

with the release of compound I or, if one of the groups R'3, R'4and RvIis a precursor, respectively, of the radicals R3, R4and R6then the obtained compound is subjected to subsequent processing, to obtain compound I, if necessary, the compound I is converted into one of its salts.

11. Pharmaceutical composition having affinity to receptors of vasopressin and/or ocytocine containing the active ingredient and pharmaceutically acceptable additives, characterized in that it contains as active principle compounds of formula I in an effective amount.

 

Same patents:

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The invention relates to the field of medicine and is suitable for the treatment of various inflammatory diseases of soft tissues, joints, musculoskeletal system: rheumatoid arthritis, arthritis, radiculitis, plexitis, eczema, psoriasis, etc
The invention relates to medicine, namely to experimental Oncology, and can be used to reduce toxicity and enhance the antitumor activity of cyclophosphamide

The invention relates to the field of medicine and for the new drug treatment of hypertension, representing a N-acetyl-5-methoxytryptamine (melatonin), and a method of treatment of hypertension using the specified funds or in combination with other antihypertensive agents

The invention relates to a derived indole of General formula (I)

< / BR>
or its physiologically acceptable salt, or metabolically labile ether complex, where R is chlorine in positions 4 and 6 of the indole ring, R2represents phenyl, possibly substituted by one or two groups selected from fluorine, trifloromethyl, lower alkyl, alkoxy, hydroxy and nitro group, X represents NH

The invention relates to medicine, in particular to rheumatology, and for the treatment of arthritis

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: agent comprises glucosamine salt as saccharide, dimethylsulfoxide, ointment base and ibuprofen or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen as a nonsteroid anti-inflammatory agent. Glucosamine hydrochloride, glucosamine sulfate sodium, potassium or calcium salt is used as glucosamine, and diclofenac potassium or sodium salt is used as diclofenac salt. New ointment shows high perfusion rate of active substances to the articulation zone and enhanced effectiveness. Invention expands assortment of agents used in treatment of articulations.

EFFECT: improved, enhanced and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: invention relates to agents of topical applying used in treatment of articulation diseases. Proposed agent comprises mixture of chondroitin sulfate and glucosamine salts as a saccharide, the compound taken among the group nonsteroid anti-inflammatory agents, in particular, ibuprofen or nimesulid, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen, dimethylsulfoxide and an ointment base taken in the definite ratio of components. Invention provides enhancing effectiveness due to the content a mixture of low-molecular and high-molecular saccharides in it that results to increasing diffusion rate of active component to the articulation zone and also the compound taken among the group of nonsteroid anti-inflammatory agents. The combined using these agents provides the curative synergetic effect.

EFFECT: improved and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

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