Derivatives spirobiindane, remedy, method of prevention or treatment

 

(57) Abstract:

The invention relates to new derivatives of spirobiindane General formula (I), where R1represents a phenyl group which may be optionally substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, halogenized alkyl groups, lower alkoxygroup, lower alkoxycarbonyl groups, hydroxyl groups, lower aliphatic acylamino, cyano groups, or a 5 - or 6-membered heterocyclic group containing 1-3 oxygen atom, sulfur and/or nitrogen, which may be optionally condensed with a phenyl group; R2represents a phenyl group which is substituted by 1-3 fluorine atoms or chlorine; a represents a carbonyl group; represents a simple bond; D represents an oxygen atom or sulfur; E represents C1-4Allenova group; a represents a group of formula (II), where G represents C5-8alonovoa ring, which is substituted by hydroxyl group; Ar represents a phenyl ring; n represents the integer 1 or 2, or their pharmacologically acceptable salts. Drug, possess antagonizes action against NK1NK2and NK3the receptor is l and excipient. The proposed connection can be used for treatment or prevention of diseases which can be treated or prevented by means of, which has antagonistic activity against NK1NK2and NK3receptors, by introducing a warm-blooded animal an effective amount of the compounds of formula 1 or its pharmacologically acceptable salt. The technical result - the new derivatives spirobiindane. 3 S. and 9 C. p. F.-ly, 3 PL.

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[Technical field]

The invention relates to new derivatives of spirobiindane which exhibit antagonistic activity against receptors tachykinin (NK1NK2and PC3).

[The prior art]

As is known, NK1receptors, NK2receptors and PC3the receptors act as receptors tachykinin. The number of known compounds exhibiting antagonistic action against one of these receptors. Recently, compounds that inhibit the same subtypes as possible among the three subtypes, have attracted attention for use in methods for the prevention or treatment of diseases caused by tachykinins. Investigated compounds exhibiting Anta is s And, shown below is disclosed in EP-776893 as compounds with antagonistic activity towards both NK1and NK2the receptors. However, it is reported that this compound exhibits antagonistic activity against NK3the receptor.

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[The invention]

The present invention relates to:

(1) the compound represented by formula (I) or its pharmacologically acceptable salt, complex ether or other derivative

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{ where R1and R2are the same or different and each represents an aryl group, heteroaryl group, aryl group, substituted from 1 to 3 groups selected from foster Group, or heteroaryl group, substituted by 1 to 3 groups selected from foster Group,

A represents a methylene group, carbonyl group or sulfonyloxy group

In represents a single bond, C1-4alkylenes group or2-4alkenylamine group

D represents an oxygen atom or a sulfur atom,

E represents C1-4alkylenes group or2-4alkenylamine group

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where G represents C5-8cycloalkenyl cycle, With
AG represents aryl cycle, heteroaryl cycle, aryl cycle, substituted from 1 to 3 groups selected from foster Group, or heteroaryl cycle, substituted from 1 to 3 groups selected from foster Group,

R3represents a lower alkyl group, and

n represents an integer from 1 to 3;

provided that G does not include group, substituted only oxopropoxy};

[Proxy Group]

the halogen atoms, lower alkyl groups, halogenide alkyl groups, lower alkoxygroup, lower alkoxycarbonyl group, carboxyl group, hydroxyl group, a lower aliphatic acyl group, a lower aliphatic alluminare, amino and cyanopropyl;

[Placeholder Group]

the carbonyl group, hydroxyl group, carboxyl group or tirinya group; and, as substituents of the nitrogen atom, lower alkyl, aryl, kalkilya, lower aliphatic acyl and lower alkanesulfonyl groups, each of which may be substituted by a group selected from foster Group A.

Among them, preferred compounds are:

(2) connection, HDMI, selected from foster Group,

(3) compounds, where R1represents an aryl group or aryl group substituted by from 1 to 3 groups selected from foster Group AND1defined below,

(4) compounds, where R2represents an aryl group or aryl group substituted by from 1 to 3 groups selected from foster Group,

(5) compounds, where R2represents an aryl group substituted by at least one group selected from foster Group,

(6) compounds, where a represents a carbonyl group,

(7) compounds, where In represents a simple bond,

(8) compounds, where D represents an oxygen atom,

(9) compounds, where E represents C1-4alkylenes group

(10) compounds, where E represents C2-3alkylenes group

(11) compounds, where

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(12) compounds, where G is cyclopentane or cyclopentenone cycle, substituted by one or two groups selected from foster Group,

(13) compounds, where G is cyclopentane or cyclopentenone cycle, substituted hydroxy-group,

(14) compounds where n is 1 or 2, and

(15) compounds where n is 2;

and a]

lower alkyl group, halogenide alkyl groups and lower alkoxygroup.

Of the above compounds, compounds that include a combination of factors selected from the eight groups consisting of (2) and (3); (4) and(5); (6); (7); (8); (9) and (10); (11) to (13) and (14) and (15) are also preferred.

(16) is More preferred compounds are:

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(2-hydroxy)indan-1,4'-piperidine],

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine],

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(1H-inden-1,4'-piperidine],

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl]ethyl} Spiro[(2-hydroxy)indan-1,4'-piperidine],

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl]ethyl} Spiro[(3-hydroxy)indan-1,4'-piperidine], and

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(1H-inden-1,4'-piperidine],

and their pharmacologically acceptable salts, esters and other derivatives.

(17) the Most preferred are the compounds:

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine],

and their pharmacologically acceptable salts, esters and other derivatives.

A new drug of the present invention comprises as an effective ingredient a compound selected from any one of the compounds described above in (1) to(17), or its pharmacologically acceptable salt, ester or other derivative and can be used especially as a preventive or cure for asthma and/or bronchitis, rhinitis, allergies and incontinence.

In the formula (I), examples of the "aryl group" in the definitions of R1and R2, aryl group n aryl group, a substituted from 1 to 3 groups selected from foster Group" in the definitions of1and R2and "aryl group" of the "aryl group which may be substituted by a group selected from foster Group" in the definition of "Substituted groups include5-8aromatic hydrocarbon groups such as phenyl, indenyl, naphthyl, phenanthrene and anthracene, of which phenyl groups are preferred.

In this case, the above "aryl group" may form a condensed nucleus with3-10cycloalkyl group, and examples of such groups include 5-indan the "heteroaryl group, substituted from 1 to 3 groups selected from foster Group" in the definitions of R1and R2means a 5-7 membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms. Examples include groups of furil, teinila, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Among such 5-7-membered aromatic heterocyclic groups are most preferred are groups, each of which contains at least one nitrogen atom and also it can additionally contain an oxygen atom or a sulfur atom. Examples include groups pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, of which more preferred groups are groups of pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl.

In addition, the above "heteroaryl group" may form a condensed nucleus with another cyclic group. Examples of such groups.

Examples of "lower alkyl group" in the definition of R3, Replacement Group a] and [Replacement group a'] and "lower alkyl group" of the "lower alkyl group which may be substituted by a group selected from foster Group" in the definition of [Substitute Group] include C1-6alkyl group with a linear or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, among them1-4alkyl group with a linear or branched chain are preferred.

Examples "1-4alkalinous group" in the definitions of b and E include C1-4alkylene group with a linear or branched chain such as methylene, METROTILE, ethylene, propylene, trimethylene, tetramethylene, 1-metallisation, 2-metallisation and 3-metallisation.

Relatively preferred are C1-3alkylene group with a linear or branched chain.

Regarding E predpochtitelnye are ethylene and trimethylene group, and the ethylene group is most preferred.

Examples "2-4alkenylamine group" in the definitions of b and E include2-4alkenylamine group with a linear or branched chain, such as ethenylene, 2-propanole, 1-methyl-2-propanole, 2-methyl-2-propanole, 2-ethyl-2-propanole and 2-butylen, of which Actilingua, 2-propylea and 3-battilana group are preferred, and groups of ethenylene and 2-propylene preferred.

Examples "5-8cycloalkanones cycle" and "C5-8cycloalkanones cycle", "C5-8cycloalkanones cycle, substituted 1 or 2 groups selected from foster Group" in the definition of G include cyclopentenone, cyclohexenone, cycloheptenyl and cyclooctanone cycles, of which "C5-6cycloalkenyl cycle is preferred, and cyclopentenone cycles are preferred.

Examples "5-8cycloalkanones cycle" "C5-8cycloalkanones cycle, substituted 1 or 2 groups selected from foster Group" representing G include cyclopentane, cyclohexane, Cycloheptane and cyclooctane cycles, of which "C5-6cycloalkanones cycle is predpochtitelno cycle" "aryl cycle, substituted from 1 to 3 groups selected from foster Group" in the definition of Hypertension include6-14aromatic hydrocarbon cycles, such as benzene, indene, naphthalene, financedby and anthracene cycles, of which benzene cycles are preferred.

"Heteroaryl cycle" and "heteroaryl cycle" heteroaryl cycle, substituted from 1 to 3 groups selected from foster group, each in the determination of AG, indicate 5-7-membered aromatic heterocycle containing 1 to 3 sulfur atoms, oxygen atoms or/and nitrogen atoms. Examples include such courses as furan, thiophene, pyrrole, azepin, pyrazole, imidazole, oxazole, isoxazol, thiazole, isothiazol, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, Piran, pyridine, pyridazine, pyrimidine and pyrazin. Among these 5-7-membered aromatic heterocycles are preferred cycles that contain at least one nitrogen atom and which may contain an oxygen atom or a sulfur atom, and examples include such courses as pyrrole, azepin, pyrazole, imidazole, oxazole, isoxazol, thiazole, isothiazol, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine and piratin, of which more than predpochtitelney, represented by the following formula:

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include 2-hydroxyine-1,1-diyl (in particular, 2S-hydroxyine-1,1-diyl), 3-hydroxyine-1,1-diyl, 2,3-dihydroxyethane-1,1-diyl and inden-1,1-diyl.

"Halogen atoms" in the definition of Replacement " Group] include fluorine atoms, chlorine, bromine and iodine, of which fluorine atoms and chlorine are preferred.

"Halogenide alkyl group" in the definition of [Substitute group a] and [proxy Group'] denotes a group in which the above "halogen atom" attached to the "lower alkyl group". Examples include trifluoromethyl, trichloromethyl, deformity, dichloromethyl, dibromomethyl, vermeil, 2,2,2-trichloroethyl, 2,2,2-triptorelin, 2-bromacil, 2-chloroethyl, 2-foradil and 2,2-dibromoethyl, of which trifluoromethyl, 2-bromacil, 2-chloroethyl and 2-foradil are preferred.

"The lower alkoxygroup" in the definitions of [Substitute group a] and [Replacement group a'] and "low alkoxygroup" lower alkoxycarbonyl group" in the definition of [Substitute group a] means a group in which the above-described "lower alkyl group" is attached to the oxygen atom. Examples include C1-6alkoxygroup with a linear or branched chain, such as labels 2 methylbutoxy, neopentane, n-hexology, 4-methylphenoxy, 3 methylpentane, 2-methylpentane, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane and 2,3-Dimethylbutane, WITH1-4alkoxygroup with a linear or branched chain are preferred.

Each of the "lower aliphatic acyl group", "lower aliphatic acyl group", "lower aliphatic acylamino" in the definition of [Substitute group a] denotes2-7aliphatic acyl group. Examples include formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, pentanoyl, pivaloyl, valerino and isovaleryl group, of which acetyl and propylaniline group are preferred.

R1is, preferably, aryl group, heteroaryl group, or aryl group substituted by 1-3 groups selected from foster Group; more preferably is an aryl group or aryl group substituted by 1-3 groups selected from foster Group; even more preferably is an aryl group substituted by 1-3 groups selected from foster Group'; and most preferred is abileneyou, substituted from 1 to 3 groups selected from foster Group; more preferably is an aryl group substituted by 1-3 groups selected from foster Group; even more preferably is an aryl group substituted by 1-3 halogen atoms; and most preferred is a phenyl group substituted by 1-3 halogen atoms.

The following formula is preferably a group in which the carbon atom adjacent to the carbon atom forming spirostane between the group G and piperidinium ring, and the adjacent carbon atom form part of a cyclic group AG, as well as part of a cyclic group G

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As the compound (I) of the present invention may form a salt, their pharmacologically acceptable salts" are of such a salt.

Preferred examples of the salts include compounds (I) of the invention and the acid include inorganic salts, such as salts of halogen acids (for example, hydroptere, hydrochloride, hydrobromide, hydroiodide, and so on), nitrates, perchlorates, sulfates, phosphates and the like; organic acid salts such as lower alkanesulphonic (for example, methanesulfonate, triftorbyenzola, aconsultant and the slots, fumarate, succinate, citrate, tartrate, oxalate, maleate and the like; and salts of amino acids such as glycine salt, lysine salt, arginine salt, ornitine salt, glutamate, aspartate and the like; of which more preferred salts of halogen acids and salts of organic acids, even more preferred salts of halogen acids, and the hydrochloride is preferable.

On the other hand, preferred examples of the salt formed by the compound (I) of the invention and the base include metal salts, for example alkali metal salts, such as salts of potassium, sodium and lithium salts, salts of alkaline earth metals such as calcium salts and magnesium salts, aluminum salts and iron salts; amine salts such as inorganic salts such as ammonium salts, and organic salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, a complex salt phenylglycylamino ester, salt, Ethylenediamine salt, N-methylglucamine, salt of guanidine, salts diethylamine, salt, triethylamine salt dicyclohexylamine, salts of N,N-dibenziletilendiaminom, salt chloroprocaine, salts of procaine, salt, diethanolamine, salts of N-benzylpenicillin, salt, piperazine salt of retreat is Nitin, glutamic acid and a salt of aspartic acid.

As the compound (I) of this invention can be transformed into the corresponding Quaternary salt by modifying the nitrogen atom piperidino group in the molecule with a group R3, salt between such catinaadrian connection and anion (there are no particular restrictions on the anion, provided that it is used as an anion, and examples include halogen anions, such as chloride anion and iodide anion) are also covered by the present invention.

In addition, compound (I) of the present invention absorb water and contain this absorbed water is added to them, or become a hydrate when they leave to stand on the air. Such salts are also covered by the present invention.

"Ester, or another derivative" means a compound in which a functional group (for example, the hydroxy-group, carboxypropyl or amino group) modified protective or other similar group, and which can be transformed into compound (I) of the present invention after its introduction into a living organism. Whether the connection is so derived, can be established by introducing an experimental animal, tachometer compound or its pharmaceutically acceptable salt.

As the compound (I) of this invention can be transformed into the corresponding esters, the "esters" means such esters. Examples of esters include esters of hydroxyl groups, and esters of carboxylic groups. This means an ester in which the ester residue is a "conventional protecting group" or "protective group which can be removed in vivo by a biological method such as hydrolysis".

"Traditional protective group" means a protective group which can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

Preferred examples of "traditional protective group" for "complex ester of the hydroxyl group" include the above-described "lower aliphatic acyl group"; the above "aromatic acyl group"; "tetrahydropyranyloxy or tetrahydropyranyloxy groups, such as tetrahydropyranyl-2-yl, 3-bromo-tetrahydropyranyl-2-yl, 4-methoxycarbonylpropionyl-4-yl, tetrahydrothiopyran-2-yl and 4-methoxycarbonylaminophenyl-4-yl; "tetrahydrofuranyl or tetrahydropyranyl group" such as tetrahydrofuran-2-yl and tetrahydrofuran-2-yl; "silyl group", for example, three(dimethylaminopropylamine, methyl-di-tert-Boticelli and triisopropylsilyl and three(lower alkyl) silyl group, substituted by 1 or 2 aryl groups, such as diphenylmethylene, diphenylbutyric, diphenylethylene and phenyldimethylsilane; "alkoxymethyl groups, for example lower alkoxymethyl groups, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tert-butoxymethyl, lower alkoxymethyl groups, substituted lower alkoxycarbonyl, such as 2-methoxyethoxymethyl group and halogen lower alkoxy)methyl group, such as 2,2,2-trichloroacetyl and bis(2-chloroethoxy)methyl; "substituted ethyl group such as ethyl group, a substituted lower alkoxygroup, such as 1-ethoxyethyl and 1-(isopropoxy)ethyl and halogenated ethyl group such as 2,2,2-trichlorethylene group; "kalkilya groups, for example lower alkyl groups, substituted 1-3 aryl groups such as benzyl, -naphthylmethyl-naphthylmethyl, diphenylmethyl, triphenylmethyl-naphthylmethyl and 9-intellilink group, and lower alkyl groups, each of which is substituted by from 1 to 3 aryl groups having aryl, substituted lower alkyl, halogen(low alkylbenzene, 3,5-di(trifluoromethyl)benzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; and the above-described "lower alkoxycarbonyl group".

Preferred examples of "traditional protective group" for complex ester carboxyl group include the above-described "lower alkyl groups; lower alkeneamine groups such as ethynyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; lower alkyline groups, such as ethinyl, 2-PROPYNYL, 1-methyl-2-PROPYNYL, 2-butynyl, 1-methyl-2-butenyl, 1-ethyl-2-butinyl, 3-butinyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butinyl, 2-pentenyl, 1-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hikity, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl; "lower aliphatic acyl" - "lower alkyl groups" such as acetylecholine group; the above "kalkilya group" and the above "silyl group".

"Protective groups which can be cleaved in vivo by a biological method such as hydrolysis" means a protective group which is removed in vivo by a biological method such as hydrolysis and forms a free acid or its salt. Is an ester of such a derivative can be installed with intravenous this ether experimental animal, such as rat or mouse, the study of body fluids such animal after injection and detection of the parent compound or its pharmacologically acceptable salt.

Preferred examples of protective groups which can be removed in vivo by a biological method such as hydrolysis" to "complex ester of the hydroxyl group include 1-(acyloxy) "lower alkyl group", for example 1-("lower aliphatic acyl"oxy), "lower alkyl groups" such as formyloxyethyl, acetoxymethyl, dimethylaminoacetonitrile, propionylacetate, butyraldoxime, pivaloyloxymethyl, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-valeriansee, 1-isovalerianic, 1-hexaniacinate, 1-formylacetate, 1-acetoxymethyl, 1-propionyloxy, 1-butyryloxy, 1-pivaloyloxymethyl, 1-alariaceae, 1-isovalerylglycine, 1-hexanolactone, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl and 1-pivaloyloxymethyl, 1-(cycloalkyl"carbonyloxy) "lower alkyl groups" such as cyclopentanecarboxylate, cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate and 1-cyclohexylcarbodiimide, and 1-("aromatic acyl"oxy) "lower alkyl groups" such as benzoyloxymethyl group; (lower alkoxycarbonyl)alkyl groups, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, ventilatsioonisusteemi, hexyloxybenzoyl, cyclohexyloxycarbonyloxy, C is oxycarbonate)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonylamino)ethyl, 1-(isobutoxyethene)ethyl, 1-tert-butoxycarbonylamino)ethyl, 1-ventilatsioonile)ethyl, 1-(hexyloxyethoxy)ethyl, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclopentanecarbonyl)propyl, 1-cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentanecarbonyl)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyl)propyl, 2-(methoxycarbonylamino)ethyl, 2-ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl, 2-(isopropoxycarbonyl)ethyl, 2-(butoxycarbonylamino)ethyl, 2-(isobutoxyethene)ethyl, 2- (ventilatsioonile)ethyl, 2-(hexyloxyethoxy)ethyl, 1-methoxycarbonylamino)propyl, 1-(ethoxycarbonyl)propyl, 1-(propoxycarbonyl)propyl, 1-(isopropoxycarbonyl)propyl, 1-(butoxycarbonylamino)propyl, 1-(isobutoxyethene)propyl, 1-(ventilatsioonile)propyl, 1-(hexyloxyethoxy)propyl, 1 methoxycarbonyl)butyl, 1-(ethoxycarbonyl)butyl, 1-(propoxycarbonyl)butyl, 1-(isopropoxycarbonyl)butyl, 1-(butoxycarbonylamino)butyl, 1-(isobutoxyethene)butyl, 1-(methoxycarbonylamino)pentyl, 1-(ethoxycarbonyl)pentyl, 1-(methoxycarbonyl)hexyl and 1-(etoxycarbonyl the-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-forfinal)-2-oxo-1,3-dioxolan-4-yl] methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolan-4-yl] methyl, (2-oxo-1,3-dioxolan-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl and (5-butyl-2-oxo-1,3-dioxolan-4-yl)methyl; "phthalidyl group", such as phthalidyl, dimethylphthalate and dimethoxytrityl; the above "lower aliphatic acyl group", the above "aromatic acyl group"; "salt polufinale residue of succinic acid"; "the remains of the phosphate salt"; "ester - forming residues such as amino acids"; carbamoyl group; carbamoyl group, substituted by 1 or 2 lower alkyl groups; and 1-(acyloxy)alkylcarboxylic groups, such as pivaloyloxymethyl, of which "carbonylcyanide groups are preferred.

Preferred examples of the protective group that can be removed in vivo by a biological method such as hydrolysis" to "complex ester carboxypropyl" includes "alkoxylate alkyl group", for example (lower alkoxy)(lower alkyl) group, such as methoxyethyl, 1-atomic, n-propoxymethyl, isopropoxide, n-butoxymethyl and tert-butoxymethyl, (lower alkoxy)lower alkyl groups, substituted lower alkoxy, such as 2-methoxyethoxymethyl, "aryl"oxy"lower alkyl group" such as phenoxymethyl group and halogenated lower alkoxy) (lower alkyl groups such as 2,2,2-trichloroacetyl and bis(2-chloroethoxy)methyl group; "lower alkoxy"carbonyl <

The compound (I) of the present invention contain asymmetric carbon atom in its molecule, and stereoisomers, whose asymmetric atom has the R - or S - configuration, are present. Stereoisomers and their mixtures in any ratio are also included in the present invention.

[Embodiments of the invention]

Derivatives spirobiindane of the present invention can be obtained below way.

[Method]

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In the above reaction scheme,

R1, R2A , b, D, E, M and n take the same above-described values.

Y' can be any group capable of removal as nucleophilic residue, and is not particularly limited. Preferred examples of such groups include halogen atoms such as chlorine, bromine and iodine; trihalomethanes, such as trichloromethane; low alkanesulfonyl, such as methanesulfonate and econsultancy; (halogeno lower alkyl)sulfonyloxy, so benzosulfimide-, p-toluensulfonate - and p-nitrophenylglyoxylate, of which the atoms of halogen and lower alkanesulphonic are even more preferred.

Stage A1 is the stage of obtaining the compound (I) of the present invention by the interaction of the compound (II) with compound (III) in a solvent in the presence of a base.

On the nature of the used solvent has no particular restrictions, provided that it does not adversely affect the reaction and can, at least to some extent, to dissolve raw materials.

Preferred examples include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and nitril; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoramide; and sulfoxidov, such as dimethyl sulfoxide and sulfolane, of which preferred are amides, ethers, and NITRILES, and amides are the most preferred.

On the nature of the used grounds there are no particular restrictions, provided that the base is used in conventional reactions. Preferred examples include a combination of a metal iodide (e.g., potassium iodide), and inorganic bases such as carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate or lithium carbonate, bicarbonate of an alkali metal (e.g. sodium bicarbonate, potassium bicarbonate or lithium bicarbonate), alkali metal hydride (e.g. lithium hydride, sodium hydride or potassium hydride), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) or a fluoride of an alkali metal (e.g. sodium fluoride or potassium fluoride); or organic base, such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-Pirro is,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), of which more preferred is a combination of a metal iodide and inorganic bases, and most preferred is a combination of a metal iodide and hydrogen carbonate of an alkali metal.

Limits the reaction temperature is 0 to 150oFrom 20 to 120oC.

Although the reaction time depends mainly on the temperature and nature of raw materials, reaction reagents and solvent used, it usually ranges from 30 minutes to 48 hours, from 1 to 12 hours.

The compound of formula (I), where the carbon atom, which is a ring atom of the group G and which is not adjacent to piperidinium cycle and has a hydroxyl group, can be obtained by reduction of the corresponding derivative of the ketone obtained in accordance with the above method A.

On the nature of the used solvent has no particular restrictions, provided that it does not adversely affect the reaction and can, at least to some extent, to dissolve raw materials. Preferred examples include alcohols, such as meth is Herod, dichloroethane, chlorobenzene and dichlorobenzene; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, of which preferred are the alcohols, ethanol is the most preferred.

On the nature of the used recovery agent has no particular restrictions, provided that it is usually used as a reducing agent. Preferred examples include hydride reagents, such as borhydride alkali metal (e.g. sodium borohydride or lithium borohydride), compounds of aluminum hydride (for example, alumoweld lithium or triaxiality lithium), telluride sodium, and organic alumohydride recovery agents [e.g., diisobutylaluminum or di(methoxyethoxy)alumothermic sodium] , of which the most preferred are borhydride alkali metal and organic alumohydride recovery agents, the most preferred are borhydride alkali metal.

Limits the reaction temperature is from -78 to 50oC, -20 to 20oC.

The reaction time depends mainly on temperature and the nature of the cheese is s, from 10 minutes to 2 hours.

After completion of the corresponding reactions of compounds derived the corresponding reactions can be isolated from the reaction mixture in the usual way.

For example, the reaction mixture respectively neutralize and, after removal by filtration of the insoluble matter, if any, add water-immiscible organic solvent (e.g. ethyl acetate). After washing with water, and like her, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate, and the like. The solvent is then distilled off to obtain the target compounds.

The obtained target compound, if desired, is isolated and purified by conventional means such as crystallization and pereosazhdeniya, or methods that are typically used for isolation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina - or miniserial, Florisil; a method using a synthetic adsorbent, for example separating column chromatography using Sephadex LH-20 (produced by Pharmacia Co. ), Amberlite XAD-11 (produced by Rohm & ostroy chromatography with normal/reversed phase high performance liquid chromatography, use silica gel or alkilirovanny silica gel; or in combination with suitable solvent.

In this case, the raw material is commercially available or can be easily obtained by known methods. For example, the compound of formula (II) can be obtained by the method disclosed in EP-776893, and the like, while the compound of the formula (III) can be obtained by a method well known from the prior art (see, for example, patent US 5578593) and the like.

New derivatives of spiroperidol of the present invention have excellent antagonism against tachykinin, excellent antagonistic activity against NK1NK2and PC3receptors, excellent oral absorption and less toxicity, which makes them useful as a drug. Examples of conditions for which this drug is useful as a preventive or therapeutic agent include diseases of the Central nervous system as anxiety, depression, psychosis and schizophrenia; the syndrome of sleep apnea; neurodegenerative diseases such as dementia caused by AIDS, senile dementia,

Alzheimer's disease, down's syndrome, dem is rnie disease, such as chronic obstructive lung disease, bronchitis, pneumonia, bronchostenosis, asthma and cough; inflammatory diseases such as inflammation of digestive tract diseases (IBD), psoriasis, fibrosis, Epiphany osteomyelitis, osteoarthritis and rheumatoid arthritis; allergic diseases such as rhinitis and eczema; disease hypersensitivity, such as increased sensitivity to grapes; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, spring catarrh of the upper respiratory tract, destruction gematologicheskogo barrier in the case of various inflammatory eye disease, increased intraocular pressure, and cramps; skin diseases, such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addiction, such as alcohol dependence; somatic diseases caused by stress; sympathetic dystrophy reflex, such as the wrist and shoulder syndrome; dysthymia; unwanted immune response, including graft rejection, a disease associated with the immune potential, including lupus erythematosus and immune suppression; digestive diseases, including diseases caused Nar is vomiting, caused by the harmful effects of x-ray radiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorder apparatus, postoperative pain, gastro-intestinal occlusion, low moving along the gastro-intestinal tract, visceral pain, migraine, increased intra-arterial pressure, intracranial pressure or the introduction of different medications; functional diseases of the bladder such as cystitis or urinary incontinence; Sosnoviy caused by collagen diseases, scleroderma, or infection with Fasciola hepatica (liver Fluke); diseases caused by abnormal blood flow, caused by expansion or contraction of blood vessels, such as angina, migraine and Raynaud's disease; and disease pain nocireceptors, such as migraine, cephalalgia and odontalgia.

The compound (I) of the present invention can be administered orally, for example in the form of tablets, capsules, granules, powders or syrups or injected parenterally, for example, in the form of injectable preparations or suppositories. Such drugs you can get, essentially, in a known manner, using additives such as excipients (for example, sugar derivatives, racially starch, -starch, dextrin or carboxymethoxy starch; cellulose derivatives such as crystalline cellulose, maltamedia hydroxypropylcellulose, hypromellose, carboxymethylcellulose, calcixerollic or internally cross-linked sodium carboxymethyl cellulose; aravena gum; dextrin; organic excipients such as pullulan; silicon derivatives such as light anhydrous silicic acid, synthetic aluminum silicate or marialuisa metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; inorganic excipients, such as sulfates (such as calcium sulfate)]; lubrication [for example, metal stearates, such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid;, sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as anhydrous silicic acid and silicate hydrate; and the above-mentioned starch derivatives] ; binder ); disintegrator, for example, the same compounds as the above-mentioned excipients and chemically modified brahmacarya, such as croscarmellose sodium, natrocarbonatite starch and cross-linked polyvinylpyrrolidone] ; stabilizers [for example, a pair of oxybenzoates, such as methyl para-aminobenzoic acid (methyl paraben and propyl-para-aminobenzoic acid (propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzylaniline; phenols such as phenol and cresol; timetotal; dehydroacetic acid; and sorbic acid]; modifiers drugs [for example, commonly used sweeteners, sour agents or flavourings]; and the diluent according to known methods.

The dose varies depending on severity of disease, age, route of administration and the like. For example, in the case of oral administration, favorable, if the connection of the present invention is introduced from one to several times a day in a dose of from 0.01 mg/kg body weight (0.1 mg/kg body weight, the preferred lower limit) to 100 mg/kg body weight (50 mg/kg body weight, the preferred upper limit) depending on the severity of the disease. In the case of intravenous introduction is,01 mg/kg body weight (0.05 mg/kg body weight, the preferred lower limit) to 100 mg/kg body weight (50 mg/kg body weight, the preferred upper limit) depending on the severity of the disease.

[Best options for carrying out the invention]

Hereinafter the present invention will be described with more detail and give examples, examples, compositions and examples of tests. But don't take them to limit the scope of the present invention.

[Example]

[Example 1]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(2-hydroxy)indan-1,4'-piperidine] (the Following compound No. 138)

In 4 ml of anhydrous dimethylformamide are suspended 200 mg (from 0.37 mmol) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethanol methanesulfonate, 96 mg (0.40 mmol) of Spiro[(2-hydroxy)indan-1,4'-piperidine]hydrochloride obtained in Reference example 3, 92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) of potassium iodide, followed by heating at 80oC for 8 h under nitrogen atmosphere. In the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled under vacuum. The residue is purified thin layer chroma connection in the form of white crystals.

[]D+11,8(=of 0.56, chloroform).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: 7,16-to 7.67(7H, m), of 6.52 (2H, s), and 4.40 (1H, s), 3,85 (N, C), 3,37-4,04 (6N, m), with 3.27(1H, DD, J= 16,7, a 5.3 Hz), 2,82 (1H, d, J=16,7 Hz), 2,62-is 2.88 (2H, m), 1,49-to 2.40 (10H, m).

IR absorption spectrummaxcm-1(KBr):

3432, 2934, 1634, 1584

Mass spectrometric analysis (FAB) m/e: 655 (M+H)+.

Elemental analysis (% based on C35H40N2O6CL20.5 H2O)

Calculated: 63,25, N 6,22, N 4,21, Cl 10,67.

Found: 63,24, N 6,37, N 4,14, Cl 10,41.

[Example 2]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine] (the Following compound 106)

[Example 2A]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine]

In 4 ml of anhydrous dimethylformamide suspension 200 mg (from 0.37 mmol) of 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethanolgasoline, 95 mg (0.40 mmol) of Spiro[(3-hydroxy)indan-1,4'-piperidine] hydrochloride obtained in Reference example 5, 92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) of potassium iodide, followed by heating at 80oC for 8 h in ATI layer is dried over anhydrous magnesium sulfate. The solvent is distilled under vacuum. The residue is purified by thin-layer chromatography on silica gel (solvent; methylene chloride: methanol = 10:1), to obtain 167 mg (70%) specified in the title compound as white crystals.

[]D+11,8(s=0,53, chloroform).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: 7,29 for 7.78 (7H, m), of 6.49 (2H, s), 3,85 (N, C), 3,30-3,92 (6N, m), 2,74-2,96 (2H, m), 2,52 (2H, s), 1.93 and-of 2.30 (8H, m), 1,47 of 1.50 (2H, m).

IR absorption spectrummaxcm-1(KBr):

3416, 2933, 1714, 1637, 1603.

Mass spectrometric analysis (FAB) m/e: 653 (M+N)+.

Elemental analysis (% based on C35H38N2O6Cl2O,5H2O)

Calculated: 63,44, N 5,93, N 4,22, Cl 10,70.

Found: 63,63, N 6,20, N 4,11, Cl 10,26.

[Example 2]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl-yl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine]

In 1 ml of ethanol dissolving 24 mg (of 0.62 mmol) sodium borohydride. To the resulting solution was added a solution of 1-{2[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl]ethyl}Spiro[(3-indanone)-1,4'-piperidine] (100 mg (0.16 mmol)) obtained in Example 2A, in ethanol (1 ml) under ice cooling, followed by stirring the m The organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled under vacuum. The residue is purified by thin-layer chromatography on silica gel (solvent; methylene chloride: methanol= 10: 1) to give 80 mg (78%) specified in the title compound as white crystals.

[]D+8,3(s=0,52, chloroform).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: 7,19-7,69 (7H, m), 6,50 (2H, s), 5,23 (1H, t, J=5,9 Hz), 3,85 (N, C), 3,41-was 4.02 (6N, m), 2,78-2,89 (2H, m), 1,37-2,45 (N, m).

IR absorption spectrummaxcm-1(KBr):

3424, 2928, 1634, 1584.

Mass spectrometric analysis (EI) m/e: 654 (M)+.

Elemental analysis (% based on C35H40N2O6Cl20.5 H2O)

Calculated: 63,25, N 6,22, N 4,21, Cl 10,67.

Found: 63,24, N 6.35mm, N 4,05, Cl 10,22.

[Example 3]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[((2S)-hydroxy)indan-1,4'-piperidine]

(The following compound No. 138)

In 6 ml of dimethylacetamide suspended 300 mg (0,547 mmol) 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethanolgasoline, 144 mg (0,602 mmol) of Spiro[((2S)-hydroxy)indan-1,4'-piperidine] hydrochloride, obtained in Siloc the 80oC for 8 h In the reaction mixture, water is added and the resulting mixture extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. The solvent is distilled under vacuum. The residue is purified column chromatography on silica gel (silica gel; 15 g, eluent; hexane:ethyl acetate = 1:1 --> 1:3 methylene chloride: methanol = 50:1 --> 20:1), with 297 mg(83%) 1-{2[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro[((2S)-hydroxy)indan-1,4'-piperidine] in the form of white crystals.

Melting point: 121oC.

(C=0,96, chloroform).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: to 7.67-7,16 (7H, m), of 6.52 (2H, Shir. C), and 4.40 (1H, Shir. C), 3,85 (N, s), 4.04 the-3,37 (6N, m), with 3.27 (1H, DD, J=16,7 Hz, 5.3 Hz), 2,82(1H, d, J=16,7 Hz), 2,88-2,62 (2H, m), 2.40 a-1,49 (10H, m).

IR absorption spectrummaxcm-1(KBr):

3427, 2933, 1634, 1584, 1465, 1428, 1415, 1330, 1237, 1128.

Mass spectrometric analysis (FAB) m/e: 655 (M+N)+.

Elemental analysis (% based on C35H40C12N2O6H2O)

Calculated: 62,41, N 6,29, N 4,16, Cl 10,53.

Found: 62,33, N 6,27, N 3,90, Cl 10,49.

[Example 4]

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(3,4,drochloride).

In 3.0 ml of ethanol is dissolved 297 mg (0,453 mmol) 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro[((2S)-hydroxy)indan-1,4'-piperidine, obtained in Example 3. To the obtained solution under cooling with ice add 0,57 ml of 4 N solution of hydrogen chloride in 1,4-dioxane, followed by stirring for 30 minutes the solvent is Then evaporated under reduced pressure, the residue was washed with ether to obtain 304 mg (yield:97%) 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro[((2S)-hydroxy)indan-1,4'-piperidine] hydrochloride as white crystals.

Melting point: 169oC.

(C=1.0, methanol).

Spectrum of nuclear magnetic resonance (400 MHz, DMCO-d6) , MD: 10,78 (1H, m), 7,88-to 7.32 (3H, m), 7,27-7,06 (4H, m), 6,76-of 6.61 (2H, m), 4,93 to 4.92 (1H, m), 4,39-to 4.38 (1H, m), 3,81 (6N, (C), 3,70 (3H, s), 4,22-2,58 (15 NM, m), 2,41-of 1.18 (4H, m), 1,69 is 1.48 (1H, m).

IR absorption spectrummaxcm-1(KBr):

3360, 2937, 2561, 1635, 1584, 1464, 1427, 1330, 1237, 1127.

Mass spectrometric analysis (FAB) m/e: 655 ([M+H]+) free form).

Elemental analysis (% based on C35H40Cl2N2O61/2H2O)

Calculated: 59,96, N Of 5.89, N 4,00, Cl 15,17.

Found: 59,94, N Of 5.81, N 3,94, the n in the above examples.

< / BR>
In this case, in the following table, "AC" means acetyl group, "Me" denotes a methyl group, "Ph" means phenyl, "iPr" means isopropyl, and each Deputy (in the table marked as "Zam") refers to a group, are presented in table.A.

In table. 1-3 connection, designated as Compound 1-192 and Connections 321-384, are preferred, of which connection, designated as Compounds 97-192 are preferable, and the compounds indicated as Connections 101-106, 133-138 and 165-179, are even more preferred.

Most preferred are the compounds:

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(2-hydroxy)indan-1,4'-piperidine],

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine],

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[1H-inden-1,4'-piperidine],

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl]ethyl} Spiro[(2-hydroxy)1H-indan-1,4'-piperidine],

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl]ethyl} Spiro[(3-hydroxy)1H-indan-1,4'-piperidine] and

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzo the
1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(2-hydroxy)indan-1,4'-piperidine] and

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl}Spiro[(3-hydroxy)indan-1,4'-piperidine].

[Referential example]

The present invention will be described hereinafter with reference to Reference examples.

[Reference example 1]

N-tert-Butoxycarbonyl-Spiro(1H-inden-1,4'-piperidine)

In 60 ml of anhydrous tetrahydrofuran was dissolved 11.6 g (0.10 mol) of indene, followed by precapitalism 200 ml (0.20 mol) of bis-tri-methylsilicone lithium (1.0 M solution of tetrahydrofuran (THF) for one hour under ice cooling. After 30 minutes of stirring to the reaction mixture was added dropwise 50 ml of tertrahydrofuran ring solution of 24.2 g (0.10 mol) of N-tert-butoxycarbonyl-bis(2-chloroethyl)amine within 20 minutes the resulting mixture is then stirred for 2 hours under ice cooling. The reaction mixture is evaporated under vacuum. The residue is purified column chromatography on silica gel (eluent; n-hexane: ethyl acetate = 97:3) to obtain 21,3 g (89%) of the titled compound as white crystals.

Spectrum of nuclear magnetic resonance (400 MHz, CDCl3) , MD:

7,21-7,41 (4H, m), 6,85 (1H, d, J=5.7 Hz), 6,79 (1H, d, J=5.7 Hz), 4,11 the m-1(KBr):

2965, 1680, 1425, 1365, 1245, 1165.

Mass spectrometric analysis (EI) m/e: 285(M)+.

[Referential example 2]

N-tert-Butoxycarbonyl-Spiro[(2-hydroxy)indan-1,4'-piperidine] and

N-tert-butoxycarbonyl-Spiro[(3-hydroxy)indan-1,4'-piperidine]

In 100 ml of anhydrous tetrahydrofuran was dissolved 10.0 g (35,0 mmol) N-tert-butoxycarbonyl-Spiro(1H-inden-1,4'-piperidine), obtained as described in Referential example 1, followed by precapitalism of 52.5 ml (52,5 mmol) tetrahydropyrazino complex (1.0 M tertrahydrofuran ring solution) for 1.5 h under ice cooling. The resulting mixture was stirred for 30 minutes under ice cooling and then 4 h at room temperature. Under ice cooling to the reaction mixture was added ethanol. Then stirred for 5 min and the reaction mixture was added dropwise 13 ml of 6 N aqueous sodium hydroxide solution for 20 minutes Then added dropwise at 13.0 ml of 30% aqueous hydrogen peroxide solution for 25 min, followed by stirring for 20 minutes under ice cooling and 3 h at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried over anhydrous sodium sulfate. Then the solvent oacett = 7:30 to 60:40), get of 5.83 g (55%) of N-tert-butoxycarbonyl-Spiro[(2-hydroxy)indan-1,4'-piperidine] as a non-polar substances and 4,20 g (40%) of N-tert-butoxycarbonyl-Spiro[(3-hydroxy)indan-1,4'-piperidine] as polar substances, each in the form of white crystals.

N-tert-Butoxycarbonyl-Spiro[(2-hydroxy)indan-1,4'-piperidine]

Spectrum of nuclear magnetic resonance (400 MHz, CDCl3) , MD:

7,20-7,29 (4H, m), 4,48-to 4.52 (1H, m), of 3.96 (2H, Shir. C) of 3.32 (1H, DD, J=16,7, a 5.3 Hz), 3,24 (2H, m), of 2.86 (1H, DD, J=16,7, 1.0 Hz), 2,02-to 2.06 (1H, m) of 1.84 (1H, m), 1,52-of 1.65 (3H, m), 1,49 (N, C).

IR absorption spectrummaxcm-1(KBr):

3620, 2980, 2935, 1680, 1430, 1365.

Mass spectrometric analysis (EI) m/e: 303 (M)+.

N-tert-Butoxycarbonyl-Spiro[(3-hydroxy)indan-1,4'-piperidine]

Spectrum of nuclear magnetic resonance (400 MHz, CDCl3) , MD:

7,42 (1H, d, J=7,0 Hz), 7,26 and 7.36 (2H, m), 7.23 percent (1H, d, J=7,0 Hz), from 5.29 (1H, d, J= 7,2 Hz), of 4.12 (2H, m), 2,95 (1H, m), 2,53 (1H, q, J=6.9 Hz), 1,9-to 1.98 (2H, m), 1,72 and 1.80 (2H, m), 1,61-to 1.67 (1H, m), 1,49 (N, C), 1,38-of 1.42 (1H, m).

IR absorption spectrum maxcm-1(KBr):

3605, 2980, 2935, 1680, 1430, 1365.

Mass spectrometric analysis (EI) m/e: 303 (M)+.

[Referential example 3]

Spiro[(2-hydroxy)indan-1,4'-piperidine]hydrochloride

In 10 ml of ethanol RA is in Reference example 2, then add 10.0 ml (40.0 mmol) of 4 N hydrochloric acid in dioxane for 5 minutes under ice cooling. After that the reaction mixture is stirred for 30 minutes under ice cooling and 4 h at room temperature. The solvent is distilled in vacuo from the reaction mixture. The residue is recrystallized from methanol/diethyl ether, to obtain 1.64 g (83%) specified in the title compound as white crystals.

Melting point: 250-251oC.

Spectrum of nuclear magnetic resonance (400 MHz, DMCO-d6) , MD:

8,99 (2H, m), 7,13-7,22 (4H, m), 5,19 (1H, s), to 4.38 (1H, s), 3,13-3,26 (5H, m), 2,77 (1H, DD, J=16.5, and a 3.2 Hz), 2,07 (1H, d, J=14,0 Hz), 1,82 of 1.99 (2H, m), 1,60 (d, J=14,0 Hz).

IR absorption spectrum maxcm-1(KBr):

3390, 2973, 2826, 1598.

Mass spectrometric analysis (EI) m/e: 203(M)+(free form).

[Reference example 4]

N-tert-Butoxycarbonyl-Spiro[(3-indanone)-1,4'-piperidine]

In 40 ml of methylene chloride was dissolved 2.00 g (6,59 mmol) N-tert-butoxycarbonyl-Spiro[(3-hydroxy)indan-1,4'-piperidine] , obtained as described in Reference example 2. To the resulting solution was added 12.0 g of powdered molecular sieves 4 Angstrom and 2,84 g (13,2 mmol) Harrogate pyridinium when Ure. Then add 80 ml of diethyl ether to the reaction mixture, the resulting mixture was filtered through a Zeolite. The filtrate was concentrated in vacuo. The residue is purified column chromatography (eluent; n-hexane: ethyl acetate = 75:25), receive 1.98 g (99%) specified in the title compound as white crystals.

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD:

of 7.75 (1H, d, J=8.0 Hz), the 7.65 (1H, DD, J=8,0, 8.0 Hz), 7,49 (1H, d, J=8.0 Hz), 7,42 (1H, DD, J=8,0, 8.0 Hz), to 4.23 (2H, Shir. C) of 2.86 (2H, m) of 2.64 (2H, s) to 1.99 (2H, dt, J=13,2, 4,4 Hz), 1,50-1,53 (11N, m).

IR absorption spectrummaxcm-1(CHCl3):

2980, 2940, 1710, 1685, 1430.

Mass spectrometric analysis (EI) m/e: 301(M)+.

[Reference example 5]

Spiro [(3-indanone)-1,4'-piperidine]hydrochloride

In 20 ml of ethanol is dissolved 1,94 g (6,50 mmol) N-tert-butoxycarbonyl-Spiro[(3-indanone)-1,4'-piperidine] , obtained as described in Reference example 4, and then added dropwise 17,0 ml (65,0 mmol) of 4 N solution of hydrogen chloride in dioxane for 5 minutes under ice cooling. After that the reaction mixture is stirred for 30 minutes under ice cooling and for 2 hours at room temperature. The solvent is distilled in vacuo from the reaction mixture and the residue is recrystallized from a mixture of methane is Alenia: 227-228oC.

Spectrum of nuclear magnetic resonance (400 MHz, DMCO-d6) , MD:

9,07 (2H, Shir. C), 7,78 (1H, DD, J=7,8, and 7.8 Hz), the 7.65 (1H, J=7.8 Hz), to 7.59 (1H, d, J= 7.8 Hz), to 7.50 (1H, DD, J=7,8, and 7.8 Hz), 3,34-3,37 (2H, m), 2,99-3,37 (2H, m), was 2.76 (2H, m), and 2.27 (2H, dt, J=13,8, 4,1 Hz), 1,64 by 1.68 (2H, m).

IR absorption spectrummaxcm-1(KBr):

3030, 2703, 2500, 1690, 1610, 1470.

Mass spectrometric analysis (EI) m/e: 201(M)+(free form).

[Reference example 6]

N-tert-Butoxycarbonyl-Spiro[((2S)-hydroxy)indan-1,4'-piperidine]

To 0,42 ml (0.42 mmol) of 1.0 M toluene solution of (R)-2-methyl-S-oxazaborolidine at a speed of 1.0 ml/min type (8,3 ml) tertrahydrofuran ring solution of 2.5 g (8,30 mmol) N-tert-butoxycarbonyl-Spiro[(2-indanone)-1,4'-piperidine] and 4.2 ml of 1 M tertrahydrofuran ring solution of borane-tertrahydrofuran ring complex. The resulting mixture was stirred for 1 hour at room temperature, then water is added while cooling with ice. After extraction of the reaction mixture with ethyl acetate, the organic layer was washed with saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent is then evaporated under vacuum. The residue is purified column chromatography on silica gel (eluent; hexane:ethyl acetate = 1:1), gain of 2.51 g (yield: 100%, od CLASS="ptx2">

The resulting crystals are dissolved in 5.0 ml of ethyl acetate under heating on a water bath. Add 150 ml of hexane and the resulting mixture is allowed to stand, get to 1.9 g of white crystals. Again repeat the same procedure and obtain 1.52 g (yield: 61%, optical purity: 199%) N-tert-butoxycarbonyl-Spiro[((2S)-hydroxy)indan-1,4'-piperidine] in the form of white crystals.

In this case, the optical purity of the compound indicated in the title, determined by high-performance liquid chromatography (HPLC) nitrobenzoyl derived titled compound, which was obtained as described in Reference example 8.

Melting point: 106oC.

(C=1.0, methanol).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD:

7,28-to 7.18 (4H, m), 4,50 (1H, DD, J=4,9,1,9 Hz), 4,07-a 3.83 (2H, m), 3,32 (1H, DD, J=16,7 Hz and 4.9 Hz), 3,30-of 3.12 (2H, m), of 2.86 (1H, DD, J=16,7 Hz and 1.9 Hz), 2,08 of 1.99 (1H, m), 1,89-of 1.78 (1H, m), 1,49 (N, C), 1,64-of 1.42 (2H, m).

IR absorption spectrummaxcm-1(KBr):

3349, 2934, 1698, 1425, 1367, 1168, 1162.

Mass spectrometric analysis (FAB) m/e: 304 (M+N)+.

Elemental analysis (% based on C18H25NO3)

Calculated: 71,26, N 8,31, N 4,62.

Found: 70,99,l of ethanol was dissolved 1.5 g (of 4.95 mmol) N-tert-butoxycarbonyl-Spiro[((2S)-hydroxy)indan-1,4'-piperidine] , obtained as described in Reference example 6. To the resulting solution was added 6.2 ml of 4 N solution of hydrogen chloride in 1,4-dioxane under ice cooling, and subsequent 5-hour stirring at room temperature. The solvent is distilled in vacuo from the reaction mixture. The residue is washed with ether, to obtain 1.1 g (yield: 93%) of Spiro[((2S)-hydroxy) indan-1,4'-piperidine] hydrochloride as white crystals.

Melting point: 247oC.

(C=0,50, methanol).

Spectrum of nuclear magnetic resonance (400 MHz/ DMSO-d6) , MD:

8,98(2H, m), 7,22-7,17 (4H, m), 5,20 (1H, d, J=5.0 Hz), 4,40-4,37 (1H, m), 3,26-3,13 (5H, m), 2,77 (1H, DD, J=16.5, and a 3.2 Hz), 2,07 (1H, d, J=14,0 Hz), 1,99-to 1.82 (2H, m), 1,60 (1H, d, J=14,0 Hz).

IR absorption spectrummaxcm-1(KBr):

3413, 3269, 2937, 1607, 1431, 1074, 765.

Mass spectrometric analysis (EI) m/e: 203 (M)+(free form).

Elemental analysis (% based on C13H17NOHCl)

Calculated: 65,13, N. EUR 7.57, N Of 5.84, Cl 14,79.

Found: 64,89, N Of 7.48, N Of 5.82, Cl 15,01.

[Referential example 8]

N-tert-Butoxycarbonyl-Spiro[(2S)-(4-nitrobenzyloxy)indan-1,4'-piperidine]

N-tert-Butoxycarbonyl-Spiro[((2S)-hydroxy)indan-1,4'-piperidine, to 30.3 mg (0.1 mmol), obtained as the 0.3 mmol) of triethylamine, 1.2 mg (0.01 mmol) of 4-dimethylaminopyridine and 28 mg (0.15 mmol) 4-nitrobenzoyl chloride, stirred at room temperature for 3 hours. The solvent is evaporated from the reaction mixture under vacuum. The residue is purified column chromatography on silica gel (eluent; n-hexane:ethyl acetate = 2:1) obtain 42 mg (yield: 93%, optical purity: 100% EE) N-tert-butoxycarbonyl-Spiro[((2S)-(4-nitrobenzyloxy)indan-1,4'-piperidine] in the form of white crystals. The optical purity of the compounds determined HPLC.

Melting point: 75,6oC.

(C=1,18, chloroform).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: of 8.25 (2H, d, J= 8,9 Hz), 8,11 (2H, d, J=8, 9 Hz), 7,34-7,17 (4H, m), of 5.83 (1H, d, J=5.3 Hz), 4,11-a-3.84(2H, m), 3,52 (1H, DD, J=17,4 Hz, 5.3 Hz), 3,32-3,13 (1H, m), 3.04 from (1H, d, J= 17,4 Hz), 3,02 of 2.92 (1H, m), 2,16-of 1.97 (2H, m), 1,73 is 1.58 (2H, m), 1,47 (N, C).

IR absorption spectrummaxcm-1(KBr):

2975, 1723, 1695, 1530, 1279, 1167.

Mass spectrometric analysis (FAB) m/e): 452 [(M+N)+].

Elemental analysis (% based on C25H28N2O6)

Calculated: Collected 66.36, N 6,24, N Is 6.19, 21,21.

Found: 66,33, N 6,37, N 5,95.

HPLC analysis

Column: Chiral Cel AD (production Daicel Chemical Industris, Ltd., the internal diameter of 4.6 m is ur: 40oC.

Detection: 254 nm.

Retention time: 17,1 minutes

[Referential example 9]

N-tert-Butoxycarbonyl-Spiro[((2R)-hydroxy)indan-1,4'-piperidine

Using a procedure similar to that described in Reference example 6, 0.5 g (of 1.66 mmol) N-tert-butoxycarbonyl-Spiro[(2-indanone)-1,4'-piperidine using 0,083 ml (0,083 mmol) of 1.0 M toluene solution of (S)-2-methyl-CDS-oxazaborolidine obtain 215 mg (yield: 43%, optical purity: 100% EE) N-tert-butoxycarbonyl-Spiro[((2R)-hydroxy)indan-1,4'-piperidine in the form of white crystals.

(Optical purity of the above connections that determine high performance liquid chromatography (HPLC) nitro-sensornogo derived titled compound, which was obtained as described in Referential example 10).

The melting point range of nuclear magnetic resonance, infrared absorption spectrum, the spectrometric analysis of the target compounds coincide with (S)-form of the same compound obtained in Reference example 6.

(C=1.0, methanol).

Elemental analysis (% based on C18H25NO3)

Calculated: 71,26, N 8,31, N 4,62.

Found: 71,09, N 8,25, N 4,68.

[Referential example 10 is ulichney described in Reference example 9, from the 30.3 mg (0.1 mmol) N-tert-butoxycarbonyl-Spiro[(2R)-hydroxy)indan-1,4'-piperidine] obtain 43 mg (yield: 95%, optical purity: 100% EE) N-tert-butoxycarbonyl-Spiro[(2R)-(4-nitrobenzyloxy)indan-1,4'-piperidine] in the form of white crystals. The optical purity of the compounds determined HPLC. The melting point range of nuclear magnetic resonance, infrared absorption spectrum, mass spectrometric analysis of the target compounds coincide with (S)-form of the same compound obtained in Reference example 8.

(s=0,76, chloroform).

Elemental analysis (% based on C25H28N2ABOUT61/4H2O)

Calculated: 65,70, N 6,29, N 6,13.

Found: 65,97, N 6,38, N 6,01.

HPLC analysis

Column: Chiral Cel AD (production Daicel Chemical Industris, Ltd., inner diameter 4.6 mm, length 250 mm)

Eluent: hexane:2-propanol = 50:50.

The flow rate: 0.5 ml/min

Temperature: 40oC.

Detection: 254 nm.

Retention time: 10,1 minutes

[Reference example 11]

N-tert-Butoxycarbonyl-Spiro[((2R, 3S)-epoxy)indan-1,4'-piperidine]

In 2.0 ml of methylene chloride was dissolved N-tert-Butoxycarbonyl-Spiro[1H-indan-1,4'-piperidine] , 100 mg (0.35 mmol). To poluchennom) chloride, and then 19 mg (0.11 mmol) 4-phenylpyridine-N-oxide. The resulting mixture was stirred for 10 minutes Then added to the mixture of 1.1 ml (0.7 mmol) of 1.0 M aqueous sodium hypochlorite solution and the resulting mixture is stirred for 2 hours. To the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl, and then dried with anhydrous sodium sulfate. The solvent extract was evaporated in vacuum. The residue is subjected to preparative thin-layer chromatography (solvent, hexane: ethyl acetate = 2:1), receive only 53.6 mg (yield: 51%, optical purity: 91%) of N-tert-butoxycarbonyl-Spiro[((2R, 3S)-epoxy)indan-1,4'-piperidin] in the form of white crystals.

The optical purity of the compounds determined HPLC.

Melting point: 149oC.

(C=1, methanol, 99% EE).

Spectrum of nuclear magnetic resonance (400 MHz, D13) , MD: 7,49 (1H, d, J= 7,3 Hz), 7,32-to 7.15 (3H, m), 4,28 (1H, d, J=2,9 Hz), 4,11 (1H, d, J=2,9 Hz), 4,30-a 4.03(2H, m) and 3.15 (2H, Shir. t, J=12.0 Hz), 1,95-of 1.74 (3H, m) and 1.51 (N, C), 1,58 of 1.50 (1H, m).

IR absorption spectrummaxcm-1(KBr):

2949, 1679, 1424, 1365, 1244, 1168, 765.

Mass spectrometric analysis (EI) m/e: 301 (M+free form).

Elemental analysis (%, dry basis is>/P>HPLC analysis

Column: Chiral Cel AD (production Daicel Chemical Industris, Ltd., inner diameter 4.6 mm, length 250 mm).

Eluent: hexane:2-propanol = 80:20.

The flow rate: 0.5 ml/min

Temperature: 40oC.

Detection: 210 nm.

Retention time: 13,2 minutes

[Reference example 12]

N-tert-Butoxycarbonyl-Spiro[((2R,3S)-hydroxy)indan-1,4'-piperidine]

In 5.0 ml of 1,4-dioxane dissolved 125 mg (0,415 mmol) N-tert-butoxycarbonyl-Spiro[((2R, 3S)-epoxy)indan-1,4'-piperidine] . To the resulting solution was added 151 mg (2.49 mmol) of ammonium formate and 10 mg of 5% palladium-on-coal and stirred at 80oWith 1 hour. To the reaction mixture add additional 120 mg of ammonium formate and 10 mg of 5% palladium-on-coal and stirred for 1 hour. Then the reaction mixture is left at room temperature and filtered. The solvent of the filtrate is evaporated under vacuum. The residue is purified column chromatography on silica gel (eluent; hexane:ethyl acetate = 3:1) obtain 118 mg (yield: 94%) of N-tert-butoxycarbonylamino[(2S) -hydroxy)indan-1,4'-piperidine] in the form of white crystals.

All physical data titled compound coincide with those for the compound of Reference example 6.

The optical purity of the compounds determined HPLC. The melting point range of nuclear magnetic resonance, infrared absorption spectrum, mass spectrometric analysis of the target compounds coincide with (2R, 3S)-form the same compound obtained in Reference example 11.

(C=0,50, methanol, 99% EE).

Elemental analysis (% based on C18H23NO31/3H2O)

Calculated: 70,33, N 7,76, N 4,56.

Found: 72,22, N 7,79, N 4,53.

HPLC analysis

Column: Chiral Cel AD (production Daicel Chemical Industris, Ltd., inner diameter 4.6 mm, length 250 mm).

Eluent; hexane:2-propanol = 80:20

The flow rate: 0.5 ml/min

Temperature: 40oC.

Detection: 210 nm.

Retention time: 10,9 minutes

[Example of composition]

Pharmaceutical composition containing compound (I) of the present invention or an ester or else its derivative as the active ingredient, was prepared as follows:

[Example compositions 1] Powder

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[Example composition 2] Granules

Obtaining granules: to the mixture of compound of Example 2 (5 g), lactose (865 g) and malonamate hydroxypropylcellulose (100 g) added 300 g of a 10% aqueous solution of hydroxypropylcellulose, mix in the total weight of the mixture, granularit plasticized mass in the extrusion granulator, followed by drying the granulated product.

[Example of composition 3] Capsules

Capsules is obtained by mixing the compound of Example 3 (5 g), lactose (115 g), corn starch (58 g) and magnesium stearate (2 g) in a V-shaped mixer, followed by filling the mixture in portions at 180 mg capsules 3.

[Example of composition 4] Pill

Tablets obtained by mixing the compound of Example 4 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) in the mixer and subsequent pelletizing the mixture in teletrauma machine.

[Example test]

[Example test 1] Analysis of binding NK1receptor

(a) Preparing samples of untreated pulmonary membranes

Samples of untreated pulmonary membranes prepared from the lung of male Guinea pigs Harty. Namely killed by exsanguination from abdomina the rakta.

After perfusion dissected lung buffer (1) (50 mm Tris-HCl, pH 7.4), easy cut into thin slices and then homogenized in buffer (2) (buffer (1) containing 120 mm sodium chloride and 5 mm potassium chloride) using Polytron'a.

Tissue mass removed from the homogenate, passing through a nylon mesh (50 nm), and separated by centrifugation (HD, 30 min, 4oC). Sediment resuspended while cooling with ice in a buffer (3) (buffer (1), containing 10 mm EDTA and 300 mm KCl) and leave quietly to stand for 60 min at 4oWith, the resulting suspension is centrifuged and washed twice (HD, 15 min, 4oC).

The crude membrane samples stored at -80oWith until use.

(b) Analysis of receptor binding

250 μl of the sample solution of the crude membranes added to 250 μl of a mixed solution of the test drug and [3N]-substance P (final concentration: 1 nm) (50 mm Tris-HCl, pH 7.4, 6 mm manganese chloride, 800 μg/ml BSA, 8 μg/ml of hemostasia, 8 µg/ml leupeptin, 80 μg/ml bacitracin, 20 μg/ml of phosphoramidon) and incubated for 30 min at room temperature.

After the reaction component membranes secrete on GF/B glass filter (Whatman) using an automatic filtrat the first solution polyethyleneamine to minimize nonspecific binding.

The filtrate containing the component membranes, transferred into minifestival tube containing 4 ml Picoflow and measure

the radioactivity of the liquid acquired scintillation counter (Beckman, LCS3500).

[Example tests 2] Analysis of binding NK2receptor

(a) sample Preparation of crude membranes ileum

Untreated samples of membranes prepared from the ileum of male Hartly Guinea pigs. Namely killed by exsanguination from the abdominal aorta under chloroform anesthesia followed by immediate excision of ileum.

Isecheno ileum is separated from the components, secrets and epithelium by means of scraping the slide. Then cut into thin phase in the buffer (1) (950 mm Tris-HCl, pH 7.4) and homogenized in buffer (2) (buffer (1) containing 120 mm sodium chloride and 5 mm potassium chloride) using Polytron.

Tissue mass removed from the homogenate, passing through a nylon mesh (50 μm) and separating by centrifugation (HD, 30 min, 4oC). Sediment resuspended while cooling with ice in a buffer (3) (buffer (1), containing 10 mm EDTA and 300 mm KCl) and leave quietly to stand for 60 min at 4oWith, the resulting suspension is centrifuged and enta use.

(b) Analysis of receptor binding

250 μl of a solution of the crude sample membranes added to 250 μl of a mixed solution of the test drug and [3H]-SR-48968 (Amercham, final concentration: 1 nm) (50 mm Tris-HCl, pH 7.4, 6 mm manganese chloride, 800 μg/ml BSA, 8 μg/ml of hemostasia, 8 µg/ml leupeptin, 80 μg/ml bacitracin, 20 μg/ml of phosphoramidon) and incubated for 30 minutes at room temperature.

After the reaction component membranes secrete on GF/B glass filter (Whatman) using an automatic filtration system.

In this case, the glass filter pre-treated for about 4 hours with 0.1% solution of polyethylenimine to minimize nonspecific binding.

The filtrate containing the component membranes, transferred into minifestival tube containing 4 ml Picoflow, and measure radioactivity in a liquid scintillation counter (Beckman, LSC3500).

[Experiment 3] Inhibitory effect on increased vascular permeability.

Inhibitory effect on the increased vascular permeability induced by antagonist NK1receptor - substance P (SP), is assessed based on the measurement of the amount of leaked pigment obtained is of Asadov was caused by the sequential introduction of the pigment (Evans blue: 20 mg/kg) Guinea pigs, shot by pentobarbital (25 mg/kg, intraperitoneally), with subsequent immediate intravenous administration of SP (1 µg/kg). After 15 minutes of Guinea pigs death during anaesthesia with chloroform, and measure the amount of pigment that may have leaked into the main areas of the respiratory tract, the method of Harada (J. Pharm. Pharmacol, 23, 218, (1971)). The test compound suspended in 0.5% suspension of tragakant and the resulting suspension is administered orally 1 hour prior to the introduction of SP. The inhibitory effect is set by the number of leaked pigment in Guinea pigs, which was introduced to test the connection.

[Example tests 4] Inhibitory effect on the reduction of the respiratory tract.

The inhibitory effect of the test drug to the reduction of the respiratory tract caused by neirokinina A (NKA), which is an agonist NK2the receptor is assessed based on the internal pressure of the respiratory tract of normal Guinea pigs (male Hartley Guinea pigs weighing about 500 g) in accordance with the modified method Konzet-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 71 (1940)).

Namely, after the implantation of the cannula respiratory tract of Guinea pigs, shot by pentobarbital (30 mg/kg, the sustained fashion pressure of 8 ml/kg and 60 cycles/minute (Ugo-Basile, 7025). The internal pressure of the respiratory tract during breathing intensified by the pressure transducer (Nippon Danco, 200T), introduced into the cannula side bronchus respiratory tract obtained (Nippon Denco, AP-601G), and was detected by the device (Nippon Denco WT-685G). To reduce the contraction of the respiratory tract in 5 minutes after pre-treatment with atropine (1 mg/kg, intravenously) and propanolol (1 mg/kg, intravenously) administered 4 mg/kg NKA, intravenously. Then within 10 minutes measure the internal pressure of the respiratory tract. The test compound is prepared in a manner analogous to the one described in Example test 3, and administered orally one hour before the induction of NKA.

Inhibitory activity is determined by comparing the area of the internal pressure of the respiratory tract of animals, which were administered the test compound or a control group.

[Test example 5] Analysis of binding NK3the receptor.

(a) sample Preparation of crude membranes of the brain.

Samples of the crude membranes prepared from brain to brain in male Hartley Guinea pigs. Specifically, animals killed by exsanguination from the abdominal aorta under anesthesia with chloroform. After perforat buffer (2) (buffer (1), containing 120 mm sodium chloride and 5 mm potassium chloride) using Polytron'and. Tissue mass removed from the homogenate, passing through nylon mesh (50 μm), and separated by centrifugation (HD, 30 min, 4oC). The sediment component of membranes) resuspending while cooling with ice in a buffer (3) (buffer (1), containing 10 mm EDTA and 300 mm KCl) and leave quietly to stand for 60 min at 4oWith, the resulting suspension is centrifuged and washed twice (HD, 15 min, 4oC). For preparation of crude sample component membranes membranes are suspended in the buffer (1). It stored at -80oWith until use in the analysis of receptor binding.

(b) Analysis of receptor binding.

The tube used in the reaction, pre-treated with buffer (1) containing 5 mg/kg bovine serum albumin (BSA). To 100 μl of buffer (1), containing... [3H]-Sentido, 6 mm manganese chloride, 800 μg/ml BSA, 8 μg/ml of hemostasia, 8 µg/ml leupeptin, 80 μg/ml bacitracin, 20 μg/ml of phosphoramidon add 150 mcg buffer (1) containing 400 μg/ml BSA, and test the connection. In order to start the reaction, the obtained mixture is added to 250 μg/ml of the crude sample of the membrane (concentration of protein argument is="ptx2">

After incubation at room temperature for 60 min component membranes secrete on GF/B glass filter (Whatman) using an automatic filtration system (Brandel), which is pre-treated with a 0.1% solution of polyethylenimine for more than 4 hours, with subsequent washing three times with 5 ml ice buffer (4) (5 mm Tris-hydrochloric acid containing 400 μg/ml BSA and 0.01% sodium dodecyl sulfate, pH 7.4).

The filtrate containing the component membranes, transferred into minifestival tube containing 4 ml Picoflow and measure the radioactivity of the liquid acquired scintillation counter (Aloka, LCS 3500).

In order to determine the radioactivity due to nonspecific binding of [3N] -Sentido (linking to sites other than the receptor, for example, a filter), the experiment is carried out with excess Sentido (final concentration: 10 μm) and measure radioactivity.

The ratio of inhibition sectid-receptor binding, due to the test compound is calculated using the following equation:

The ratio of inhibition (%)=[1-(s-a)/(B-A)]100

A: radioactivity due to nonspecific svyazyvayuschaya with the addition of the test compounds

Compounds of the present invention, showing antagonism against all NK1NK2and NK3receptors on the antagonistic activity surpass the Connection A.

Industrial applicability.

As derivatives of spirobiindane according to this invention exhibit excellent antagonistic activity against NK1NK2and PC3receptors have a lower toxicity and excellent pharmacokinetics, they can be used as a medicine, especially for the prevention or treatment of asthma and/or bronchitis, rhinitis, allergies or incontinence.

1. Derivatives spirobiindane represented by the formula (I)

< / BR>
where R1represents a phenyl group which may be optionally substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups defined below, halogen - lower alkyl groups defined below, lower alkoxygroup defined below, lower alkoxycarbonyl groups comprising carbonyl groups, substituted lower alkoxygroup defined below, hydroxyl groups, lower aliphatic acylamino, including amino, substituted yeupou, containing from 1 to 3 atoms of oxygen, sulfur and/or nitrogen, which may be optionally condensed with a phenyl group;

R2represents a phenyl group which is substituted by 1-3 fluorine atoms or chlorine;

A represents a carbonyl group;

In represents a simple bond;

D represents an oxygen atom or sulfur;

E represents C1-4alkylenes group;

< / BR>
where G represents C5-8cycloalkane ring, which is substituted by hydroxyl group;

AG represents a phenyl ring; and

n represents the integer 1 or 2;

or their pharmacologically acceptable salts; lower alkyl groups mentioned above, represent a straight or branched (C1-6) alkyl groups; halogenide alkyl groups mentioned above, represent lower alkyl groups defined above which is substituted by 1 or more halogen atoms; lower alkoxygroup above, represent lower alkyl groups, as defined above, attached to an oxygen atom; a lower aliphatic acyl of a lower aliphatic acylamino mentioned above, is WITH2-7aliphatic acyl group.

2. Connection on p. 1, where R groups, halogen - lower alkyl groups and lower alkoxygroup, as defined in paragraph 1, or its pharmacologically acceptable salt.

3. Connection under item 1 or 2, where D represents an oxygen atom, or its pharmacologically acceptable salt.

4. The compound according to any one of paragraphs. 1-3, where E represents C2-3alkylenes group, or its pharmacologically acceptable salt.

5. The compound according to any one of paragraphs. 1-4, where G represents a cyclopentane ring, a substituted hydroxyl group, or its pharmacologically acceptable salt.

6. The compound according to any one of paragraphs. 1-5, where n = 2 or its pharmacologically acceptable salt.

7. Connection on p. 1, where R1represents a phenyl group, optionally substituted by 1-3 groups selected from lower alkyl groups, halogen - lower alkyl groups and lower alkoxygroup, as defined in paragraph (1; R2, A and b have the meanings given in paragraph 1; D represents an oxygen atom; E represents C2-3alkylenes group;

< / BR>
where G represents a cyclopentane ring, a substituted hydroxyl group; and n = 2; or its pharmacologically acceptable salt.

8. Connection on p. 1, selected from the group comprising the following piperidin] ,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl) morpholine-2-yl] ethyl} Spiro [(3-hydroxy)indan-1,4'-piperidine] ,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro [(2-hydroxy)indan-1,4'-piperidine] ,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,5-dimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro [(3-hydroxy)indan-1,4'-piperidine] ,

or their pharmacologically acceptable salts.

9. Connection on p. 1, selected from the group comprising the following compounds:

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl) morpholine-2-yl] ethyl} Spiro [(2-hydroxy)indan-1,4'-piperidine] ,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl) morpholine-2-yl] ethyl} Spiro [(3-hydroxy)indan-1,4'-piperidine] ,

or their pharmacologically acceptable salts.

10. The compound according to any one of paragraphs. 1-9 or its pharmacologically acceptable salt as an active ingredient of a medicinal product for the prevention or treatment of diseases which can be treated or prevented by means of, which has antagonistic activity against NK1NK2and NK3the receptors.

11. The drug, which has antagonistic activity against NK1NK2and NK3receptors, soda is ski effective ingredient contains a compound according to any one of paragraphs. 1-9 or its pharmacologically acceptable salt.

12. The method of prevention or treatment of diseases which can be treated or prevented by means of, which has antagonistic activity against NK1NK2and NK3receptors, including the introduction of a warm-blooded animal an effective amount of a prophylactic or therapeutic agent, where the specified tool is a compound according to any one of paragraphs. 1-9 or its pharmacologically acceptable salt.

 

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The invention relates to new derivatives 7-[3-[4-(6-toranzo[d] isoxazol-3-yl)piperidine-1-yl] propoxy] -chromen-4-it formula I, where R is hydrogen, Cho, CH2OR2or COOH; R1means alkyl containing from 1 to 4 carbon atoms, provided that one of substituents R and R1is hydrogen, and their pharmaceutically acceptable salts, intended for use in the treatment of psychosis and schizophrenia, as well as to a method for producing these compounds, pharmaceutical compositions and method of inhibiting D2-, 5-HT2aand H1receptors in the treatment of psychosis and schizophrenia

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to new derivatives naphthiridine formula I, where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl; R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, elcamino, Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing ether and/or ester bond, or its N-oxide in free form or in the form of a pharmaceutically acceptable salt

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to new derivatives of piperidineacetate-2-it General formula I, where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3; R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms; And indicates WITH1-C6alkyl; Hal denotes F, CL, Br or J

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to an improved process for the preparation of substituted indole derivatives useful in the treatment and prevention of migraine

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent
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