Acylated heteroalicyclic derivative, a drug with selective antagonistic activity against nk2receptor, the method of prevention or treatment of disease

 

(57) Abstract:

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. Also disclosed are a drug on the basis of these compounds with selective antagonistic activity against NK2receptors, and the method of prevention or treatment of diseases. The invention can be used in medicine for the treatment of, for example, diseases of the Central nervous system. 3 S. and 17 C.p. f-crystals, 3 PL.

The invention relates to izvestno, that NK1receptors, NK2receptors and NK3receptors act as tachykinin receptors. As for antagonists of tachykinins, in recent years the detected compounds exhibiting selective antagonistic activity against one of the NK1receptors, NK2receptors and NK3receptors and compounds exhibiting antagonistic activity against multiple subtypes of receptors (e.g., as against NK1receptors and NK2receptors). If you wish to completely inhibit the action of tachykinins it is important to use the connection, showing antagonistic activity against several types of receptors.

However, as generally predicted that the frequency other than the desired pharmacological effect, increases the inhibitory effect against several types of receptors, are also important compounds exhibiting selective and strong antagonistic effect against a specific receptor.

Compounds considered as similar in structure to the compounds of the present invention, is described in EP-776893, but these connections demonstrate antagonistic activity against NK1is tives such as from the compounds of the present invention, demonstrating selective antagonistic action against NK2-receptors.

With regard to selective antagonistic action against NK2receptors, has begun clinical trials with the compound SR48968 (compound having the structural formula As shown below). In addition, it is reported that SR144190 (compound having the structural formula shown below) has a selective antagonistic activity against NK2receptors, which is stronger than SR48968 (X. Emonds - Alt et al., Tachykinins in Health and Disease,. September 7-11, 1997 in Cairns, Australia, Abstract p.5).

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In the result of extensive research and development of antagonists of tachykinins, the authors of the present invention have found that new acylated heteroalicyclic derivatives have excellent antagonistic activity selectively against NK2, which created the present invention.

In addition, another objective of the present invention is a new therapeutic agent containing the above compound as an active ingredient. Examples of diseases in which case you can apply this remedy, are diseases of prices is such as dementia, AIDS senile dementia is Alzheimer's disease, Alzheimer's disease, down's syndrome, demyelinizing disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma and cough; inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, fibrosis, revisit, degenerative arthritis and rheumatoid arthritis; eczema; allergic diseases such as rhinitis; allergies such as increased sensitivity to curly plants; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, spring catarrh, destruction gematologicheskogo barrier, caused by various inflammatory diseases of the eye, increased eye pressure, and cramps; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis; addiction, such as alcohol dependence; physical illness caused by stress; reflex sympathetic dystrophy such as shoulder syndrome; dysthymia; unwanted immune responses such as transplant rejection, diseases, tie the th system, such as diseases caused by disorders of the nervous regulation of bodies, colitis, ulcerative colitis and Crohn's disease; emesis, such as emesis induced harmful effects of x-ray radiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative disorders, gastro-intestinal occlusion, impaired gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, reduced intracranial pressure or adverse reactions caused by the introduction of different therapeutic agents; functional diseases of the bladder such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleroderma or infection Fasciola hepatica; diseases caused by disorders of blood flow due to vasodilation or vasoconstriction, such as angina, migraine and Raynaud's disease; and pain when pain nociceptive reception, such as migraine, headache, dental pain; and sleep apnea. New therapeutic agent of the present invention can be applied, in particular, as a prophylactic or therapeutic agent in the case of asthma and/or bronchitis, rhinitis, allergic diseases and incontinence m R1is (C3-C7)-cycloalkyl group, a 3-7-membered saturated heterocyclic group, (C3-C7)-cycloalkyl group substituted by 1-3 substituents selected among the deputies of the group and of the substituents of group b, or a 3-7-membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among the substituents of group a and Vice group,

R2represents aryl group, heteroaryl group, aryl group, substituted by 1 to 3 substituents, selected from among the deputies of the group, or heteroaryl group, substituted by 1 to 3 substituents, selected from among the substituents of group a,

A represents a methylene group, carbonyl group or sulfonyloxy group

In represents a simple bond, (C1-C4)-alkylenes group, or (C2-C4)-alkynylamino group

D represents an oxygen atom or a sulfur atom,

G represents a (C1-C4)-alkylenes group, or (C2-C4)-alkynylamino group

L represents a group of formula-N(R3)- or-C(R4) (R5)-

[where R3represents aryl group, heteroaryl group, aryl group, substituted by 1-3 substituents, wide of the substituents of group a,

R4represents a hydrogen atom, aryl group, heteroaryl group, aryl group, substituted by 1 to 3 substituents, selected from among the substituents of group a, a heteroaryl group, substituted by 1 to 3 substituents, selected from among the substituents of group a, (C3-C7-cycloalkyl group, a 3-7-membered saturated heterocyclic group, (C3-C7)-cycloalkyl group substituted by 1-3 substituents selected among the deputies of the group and of the substituents of group b, or a 3-7 - membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among the substituents of group a and Vice group,

R5represents a lower alkyl group, amino group, allmenalp, acylamino (lower alkyl) group, allmenalp, where the nitrogen atom is substituted by a lower alkyl group, a hydroxy-group, hydroxy (lower alkyl) group, where the oxygen atom optionally substituted aranceles group, a lower alkoxygroup or a group of the formula-CO-R6(where R6represents a lower alkyl group, lower alkoxygroup, the remainder of the amine, aryl group, substituted by 1 to 3 substituents, selected from among the substituents of group a, or a heteroaryl group, a substituted is of Lerida, to which they are attached, form a (C5-C8)-cycloalkane ring, (C5-C8)-cycloalkene ring or 5-8-membered saturated heterocyclic ring (any of these rings may be optionally substituted by 1 or 2 substituents, selected from among the substituents of group a and the substituents of group b, and optionally may be condensed with an aryl ring, heteroaryl ring, an aryl ring, substituted by 1-3 substituents selected among the substituents of group a, or heteroaryl ring, substituted by 1-3 substituents, substituents selected from among group (A)],

R7represents a lower alkyl group,

Z represents two hydrogen atoms or an oxygen atom,

n = 0, 1, or 2}

and its pharmaceutically acceptable salt, complex ether or other derivative;

[the substituents of group a] represent

the atoms of Halogens, lower alkyl groups, halogenated lower alkyl groups, lower alkoxygroup, lower alkoxycarbonyl group, carboxyl group, hydroxy-group, a lower aliphatic acyl group, a lower aliphatic alluminare, amino and ceanography,

[Deputy group] represent

Among the compounds of formula (I) are preferred

(2) compounds where R1is a (C3-C6)-cycloalkyl group, 5 - or 6-membered saturated heterocyclic group, (C3-C6)-cycloalkyl group substituted by 1-3 substituents selected among the substituents of group a and Vice group, or a 5 - or 6-membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among the substituents of group a and Vice group,

(3) compounds, where R1is a (C3-C6)-cycloalkyl group, 5 - or 6-membered saturated heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among the substituents of group a and Vice group,

(4) compounds, where R2represents an aryl group, or aryl group substituted by 1-3 substituents selected among the substituents of group a,

(5) compounds, where R2represents an aryl group, a substituted 1-3 BR> (7) compounds, where a represents a carbonyl group, and Z represents two hydrogen atoms, or where a represents a methylene group, and Z represents an oxygen atom,

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

(9) compounds, where a represents a simple bond,

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

(11) compounds, where G is a (C1-C4)-alkylenes group

(12) compounds, where G is a (C2-C3)-alkylenes group

(13) compounds, where R3is a heteroaryl group or aryl group substituted by 1-3 substituents selected among the substituents of group a,

(14) compounds, where L represents a group of formula-C(R4) (R5)-,

(15) compounds, where R4and R5together with the carbon atom to which they are attached, form a (C5-C8)-cycloalkane ring, (C5-C8) -cycloalkene ring or 5-8-membered saturated heterocyclic ring (any of these rings may be optionally substituted by 1 or 2 substituents, selected from among the substituents of group a and the substituents of group b, and, optionally, meteliai, selected among the substituents of group a, or heteroaryl ring, substituted by 1-3 substituents selected among the substituents of group a),

(16) compounds, where R4and R5together with the carbon atom to which they are attached, form a (C5-C6)-cycloalkane ring, (C5-C6)-cycloalkene ring or 5 - or 6-membered saturated heterocyclic ring (any of these rings may be optionally substituted by 1 or 2 substituents, selected from among the substituents of group a and the substituents of group b, and optionally may be condensed with an aryl ring, heteroaryl ring, an aryl ring, substituted by 1-3 substituents selected among the substituents of group a, or heteroaryl ring, substituted by 1-3 substituents selected among the substituents of group a),

(17) compounds, where R4and R5together with the carbon atom to which they are attached, form a cyclopentane ring, a cyclopentenone ring, tetrahydrothiophene ring, tetrahydronaphtalene ring, tetrahydronaphtalene ring or piperidine ring (any of these rings may be optionally substituted by 1 or 2 substituents, selected from among the Deputy who ilen ring, aryl ring is substituted by 1-3 substituents selected among the substituents of group a, or heteroaryl ring, substituted by 1-3 substituents selected among the substituents of group a),

(18) compounds where Z represents two hydrogen atoms,

(19) compounds, where n = 0 or 1,

(20) compounds, where n = 1,

and their pharmaceutically acceptable salts, esters or other derivatives.

In addition, also preferred are compounds comprising a combination of factors, randomly selected from each of the ten groups, which are (2) and (3); (4) and(5); (6)-(8); (9); (10); (11) and(12); (13); (14)-(17); (18); and (19) and (20).

Particularly preferred compounds are

(21) compounds selected among the following compounds, or their pharmaceutically acceptable salts, esters or other derivatives:

1-{ 2-[(2R)-(3, 4-dichlorophenyl)-4-(cyclopropanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclobutanecarbonyl)morpholine-2-yl]ethyl} Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclopentanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclopropanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)oxide,

1-{ 2-[(2R)-(3,4-differenl)-4-(cyclobutanecarbonyl)morpholine-2-yl] ethyl} Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{ 2-[(2R)-(3,4-differenl)-4-(cyclopentanecarbonyl)-morpholine-2 - yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)- oxide,

1-{ 2-[(2R)-(3,4-differenl)-4-(cyclohexanecarbonyl) -morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'- piperidine]-(2S)-oxide,

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

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

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

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

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

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

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

1-{ 2-[(2R)-(3,4-differenl)-4-(cyclohexanecarbonyl) -morpholine-2-yl] ethyl}Spiro[((2S)-hydroxy-4-carboxamide and

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclopentanecarbonyl) -morpholine-2-yl] ethyl}-4-(2-pyridyl)piperidine-4-carboxamide.

In addition, a new therapeutic agent of the present invention contains as an active ingredient the compound or its pharmaceutically acceptable salt, ester or other derivative described in any group, selected from among the above groups (1) to(21). It can be used, in particular, as a preventive or therapeutic agent for thekingofsubbing diseases (e.g. asthma and/or bronchitis, rhinitis, allergic diseases, and urinary incontinence).

The following is a more specific definition of the groups in formula (1).

It is implied that used in the definition of R1and R4"(C3-C7)-cycloalkyl group, and (C3-C7)-cycloalkyl group in the term "(C3-C7)-cycloalkyl group substituted by 1-3 substituents selected among the deputies of the group and of the Deputy group" include cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo and cycloheptyl group.

The above "(C3-C7)-cycloalkyl group" may be, not necessarily the, selected among the deputies of the group" or "heteroaryl ring, substituted by 1-3 substituents selected among the substituents of group a".

(It is understood that "aryl ring" and the aryl ring in the term "aryl ring which may be optionally substituted by 1 to 3 substituents, selected from among the substituents of group a include (C6-C14) -aromatic hydrocarbon rings such as benzene ring, indene ring, naphthalene ring, phenanthrene ring and anthracene ring, preferably a benzene ring. It is understood that "heteroaryl ring and heteroaryl ring in the definition of "heteroaryl ring which may be optionally substituted by 1 to 3 substituents, selected from among the substituents of group a include 5-7-membered heteroaryl ring containing 1-3 atoms of sulfur, oxygen and/or nitrogen, such as furan ring, thiophene ring, pyrrole ring, azepino ring, pyrazol ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazol ring, 1,2,3-oxadiazole ring, triazole ring, tetrazole ring, thiadiazole ring, pernovae ring, pyridine ring, Piri is heteroaryl ring, which contain at least one nitrogen atom and also may contain, optionally, a sulfur atom or an oxygen atom, for example, pyrrole ring, azepino ring, pyrazol ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazol ring, 1,2,3 - oxadiazole ring, triazole ring, tetrazole ring, thiadiazole ring, pernovae ring, pyridine ring, pyridazine ring, pyrimidine ring and pyrazinone ring; more preferred heteroaryl groups are pyridine ring, imidazole ring, oxazole ring, pyrazinone ring and a thiazole ring.) As examples, (C3-C7)-cycloalkyl group fused with one of these cyclic systems can be called benzocyclobutene, indenolol, 4,5,6,7-tetrahydroindazole, tetrahydronaphthalene, 5,6,7,8-tetrahydroquinoline and 5,6,7,8 - tetrahydroisoquinoline group.

In the definition of R1and R4the term "3-7-membered saturated heterocyclic group" or a 3-7-membered saturated heterocyclic group in the term "3-7-membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among h is u, containing 1-3 atoms of sulfur, oxygen and/or nitrogen, preferably 5-6-membered non-aromatic heterocyclic group containing 1-3 atoms of sulfur, oxygen and/or nitrogen, preferably 5-6-membered non-aromatic group containing 1 or 2 sulfur atom, oxygen and/or nitrogen. Examples of such groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, oxazolidinyl, diazolidinylurea, piperidinyl, morpholinyl, thiomorpholine, piperazinilnom and aspenlea group.

These groups optionally may be condensed with a cyclic system, the same as in the case of "aryl ring", "heteroaryl ring", "aryl ring, substituted 1-3-substituents, selected from among the substituents of group a", and "heteroaryl ring, substituted by 1 to 3 substituents, selected from among the substituents of group a described above. Examples of such groups are 1,2,3,4 - tetrahydroisoquinoline group and similar groups.

In addition, examples 5-7-membered saturated heterocyclic group, substituted by 1 or 2 substituents, selected from among the substituents of group a and Deputy group" include 2-oxo-oxazolidinyl group, 2-oxothiazolidine grupul the term "aryl group, substituted by 1-3 substituents selected among the substituents of group A, in the definition of R2, R3, R4and R6and "aryl group" in the definition of "as the substituents at the nitrogen atom,... aryl group, which optionally can be substituted by the Deputy, selected among the substituents of group A, in determining [the Deputy group] mean (C5-C14)-aromatic hydrocarbon group such as phenyl, angenlina, naftalina, phenanthroline and antarctilyne group, preferably phenyl group.

In addition, the above-mentioned "aryl group" may be optionally condensed with a (C3-C10)-cycloalkyl group, and examples of such groups are 5-indayla group and similar groups.

"Heteroaryl group" in the definition of R2, R3and R4and "heteroaryl group" in the term "heteroaryl group substituted by 1-3 substituents selected among the deputies of the group" in the definition of R2, R3, R4and R6denote 5-7-membered heteroaryl group containing 1-3 atoms of sulfur, oxygen and/or nitrogen, such as furilla, thienyl, parallella, aspenlea, pyrazolidine, imidazolidine, lilina, thiadiazolidine, Pernilla, perederina, pyridinoline, pyrimidinamine and piratininga group, preferably a 5-7 membered heteroaryl group containing at least one nitrogen atom and optionally containing a sulfur atom or an oxygen atom, for example, parallel, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and preferably pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl.

In addition, the above-mentioned "heteroaryl group" may be optionally condensed with other cyclic system, and examples of such groups are indayla, benzoperylene, benzothiazoline, benzoxazolinone, benzimidazolyl, izochinolina, kinolinna and khinoksalinona group and similar groups.

In the definition of b and G, the term "(C1-C4)-Allenova group" denotes a linear or branched (C1-C4)-alkylenes group such as methylene, METROTILE, ethylene, propylene, trimethylene, tetramethylene, 1-metallisation, 2-metallisation and 3-metallisation.

As for V, it is preferred AssetLine is a linear or branched (C1-C3)Allenova group, and more preferred ethylene and trimethylene, and the most preferred ethylene.

In the definition of b and G, the term "(C2-C4)alkenylamine group" denotes a linear or branched (C2-C4)alkynylamino group, such as ethenylene, 2 - propanole, 1-methyl-2-propanole, 2-methyl-2-propanole, 2-ethyl-2 - propanole and 2-butylen, preferably ethenylene, 2-propanole or 3-butylen, and more preferably - ethenylene or 2 - propanole.

"Lower alkyl group" in the definition of R5, R6and R7and in determining [the substituents of group a]; a "lower alkyl group" in the term "alluminare, where the nitrogen atom substituted lower alkyl group" in the definition of R5; a "lower alkyl group" in the term "hydroxy (lower alkyl) group, where the oxygen atom optionally substituted aranceles group" in the definition of R5; a "lower alkyl group" in the term "acylamino (lower alkyl) group" in the definition of R5; a "lower alkyl group" in the term "as the substituents at the nitrogen atom,... lower alkyl,... which may be substituted by substituents, selected from among the deputies of the group" in the definition [Deputy isopropyl group, 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. More preferred is a linear or branched (C1-C4)-alkyl group.

"Acyl" in the "alluminare", "acyl" in "acylamino (lower alkyl) group" and "acyl" in the term "alluminare, where the nitrogen atom substituted lower alkyl group" in the definition of R; and "acyl" in the term "as substitutes at the nitrogen atom, ... acyl group" in the definition of [substitute group] indicate, for example, "aliphatic acyl group", including alkylcarboxylic group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, noninterbank, deceleron, 3-methylnonanoic, 8-methylnonanoic, 3-atheroclerosis, 3,7-dimethylethylamine, undecylenic, dodecacarbonyl, tridecylamine, tetradecylammonium, pentadecylcatechol, hexadecacarbonyl, 1 - methylpentadiene, 14-methylpentadiene, 13,13 - dimethylacetanilide is carbonyl, yozilganini and generationone; halogenated alkylcarboxylic group such as chloroacetyl, dichloroacetyl, trichloroacetyl and TRIFLUOROACETYL; lower alkoxycarbonyl group, such as methoxyacetyl; and unsaturated alkylcarboxylic group, such as arylcarbamoyl, propionylcarnitine, methacryloyl, crocodilopolis, isotretinoin.carbons, (E)-2-methyl-2-butanol; "aromatic acyl group", including arylcarbamoyl group such as benzoyl, -naphtol and naphtol; halogenated arylcarboxylic group, such as 2-bromobenzoyl and 4-chlorobenzoyl; lower alkilirovanny arylcarbamoyl group, such as 2,4,6-trimethylbenzoyl and 4-toluoyl; lower alkoxycarbonyl arylcarbamoyl group, such as 4-anisoyl; nitrosoureas arylcarbamoyl group, such as 4-nitrobenzoyl and 2 - nitrobenzoyl; lower alkoxycarbonylmethyl arylcarbamoyl group, such as 2-(methoxycarbonyl)benzoyl; and anilinophenol arylcarbamoyl group, such as 4-phenylbenzyl; "alkoxycarbonyl group, including lower alkoxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, second-butoxycarbonyl, tert-butoxycarbonyl and isobutoxide, such as 2,2,2-trichlorocyanuric and 2-trimethylsilylethynyl; "alkenylboronic group, such as vinylcarbazole and arylcarbamoyl; "aralkylamines group in which the aryl ring may be optionally substituted by 1 or 2 lower alkoxy or nitro groups, such as benzylcarbamoyl, phenacyl, 4 - methoxybenzylamine, 3,4-dimethoxybenzophenone, 2 - nitrobenzylamine and 4-nitrobenzylamine; "lower alkanesulfonyl group, such as methanesulfonyl, econsultancy and 1-propanesulfonyl; fluorine-containing "lower alkanesulfonyl group, such as trifloromethyl and pentafluoroethanesulfonyl; and arylsulfonyl group, such as benzazolyl and p-toluensulfonyl. Among these groups, preferred are aliphatic acyl group", "aromatic acyl group" and "lower alkanesulfonyl group".

"The lowest alkoxygroup" in the definition of R5, R6and [the substituents of group a] and lower alkoxygroup" in the term "lower alkoxycarbonyl group" in the definition of [the substituents of group a] denote the group, where the above "lower alkyl group" is attached to the oxygen atom, for example, linear or branched (C1-C6)-alxi, n-pentox, isopentane, 2-methylbutoxy, neopentane, n-hexyloxy, 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. Preferably, this group represents a linear or branched (C1-C4)-alkoxygroup.

"Kalkilya group" in the term "hydroxy (lower alkyl) group, where the oxygen atom optionally substituted aranceles group" in the definition of R5and kalkilya group" in the term "as the substituents at the nitrogen atom, lower alkyl, aryl and kalkilya group, which optionally can be substituted by substituents, selected from among the deputies of the group" in the definition [Deputy group] denote the group, where the above "aryl group" is attached to the above "alkyl group", for example benzyl, - naphthylmethyl-naphthylmethyl, intermetal, phenantrolinate, anthranilates, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1 - naphtalate, 2-naphtalate, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naftilamin, 2-naftilamin, 3-naftilamin, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-nativeint, 2-naphthylmethyl, 3-naphthylmethyl, 4-naphthylmethyl, 5-naphthylmethyl, 1-phenylhexa, 2-phenylhexa, 3-phenylhexa, 4-phenylhexa, 3-phenylhexa, 6-phenylhexa, 1-nattinger, 2-nattinger, 3-nattinger, 4-nattinger, 5-nattinger and 6-nattinger. Preferably, this is a group where a component of the "aryl group" represents a phenyl group, and a component of the "alkyl group" represents a (C1-C4)-alkyl group. More preferred are benzyl group or penicilina group.

"(C5-C8)-Cycloalkane ring", which R4and R5form together with the carbon atom to which they are attached, means, for example, cyclopropane ring, CYCLOBUTANE ring, cyclopentane ring, cyclohexane ring, Cycloheptane ring and cyclooctanone ring. Preferably, it is (C5-C6)-cycloalkane ring, and more preferably such a cycle is cyclopentane cycle.

"(C5-C8)-Cycloalkane ring", which R4and R5form together with the carbon atom to which they are attached, means, for example, cyclopropene ring, CYCLOBUTANE ring, cyclopentenone ring, cyclohexadienone ring. More preferably, such a cycle is cyclopentenone cycle.

"5-8-Membered saturated heterocyclic ring" "5-8-membered saturated heterocyclic ring which R4and R5form together with the carbon atom to which they are attached, means a 5-8-membered saturated heterocyclic ring containing 1-3 atoms of sulfur, oxygen and/or nitrogen (where the sulfur atom may be in the sulfoxide or sulfone, if the ring contains a sulfur atom). Preferably, it is a 5-6-membered saturated heterocyclic ring containing 1-3 atoms of sulfur, oxygen and/or nitrogen. More preferably, this ring represents a 5-membered saturated heterocyclic ring containing 1-2 sulfur atom, oxygen and/or nitrogen, such as imidazolidinone ring, oxazolidine ring, pyrolidine ring, tertrahydrofuran ring ring, tetrahydrothiophene ring, tetrahydronaphtalene ring, tetrahydronaphtalene ring and piperidine ring.

In addition, (C5-C8)-cycloalkane ring", "C5-C8)-cycloalkane ring" and "5-8-membered saturated heterocyclic ring may be optionally substituted by 1 or 2 substituents, which the above "aryl ring", "heteroaryl ring", "aryl ring is substituted by 1-3 substituents selected among the deputies of the group and of the Deputy group" or "heteroaryl ring, substituted by 1-3 substituents selected among the deputies of the group and of the Deputy group". Examples of such groups are 4-oxo-1-phenylimidazoline ring, 2-oxo-3 - phenyloxazolidine ring, 3-benzyl-2-oxoacridine ring, 1 - methylsulphonyl-2,3-dihydroindole ring, 1,3 - dihydroisobenzofuran ring, 1-oxo-2,3 - dihydrobenzo[b] thiophene ring, a 1,3-dihydrobenzo-[C] -thiophene ring, 2-oxo-1,3-dihydrobenzo[C] thiophene ring, 2,2-dioxo-1,3-dihydrobenzo[C] thiophene ring, 1,4-dihydro-3-isoquinoline ring, an indan ring, 1-hydroxyindole ring, 2 - hydroxyindole ring, 1-oxindole ring, 2-oxoindole ring, 1,2-dioxopentanoate ring, indene ring, and similar groups.

"The rest of Amin" in the definition of R6means the remainder of the amine that is attached via its nitrogen atom, including amino group, amino group, substituted by 1 or 2 "lower alkyl groups" such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino and debute is but cyclohexylamino, Dicyclopentadiene, dicyclohexylamine; the residue of a saturated cyclic amine containing at least one nitrogen atom in the ring, such as pyrrolidine, piperidine, piperazine derivatives, N-methylpiperazine, morpholine, thiomorpholine; arylamino or aralkylamines, optionally substituted at the nitrogen atom of the "lower alkyl group" such as aniline, benzylamine, N-methylaniline and N-methylbenzylamine; geteroarilsulfoksidu, optionally substituted at the nitrogen atom of the "lower alkyl group" such as pyridylamino, N-methylpyridine and N-Ethylenediamine; and similar groups. Preferably, this residue is an amino group; an amino group substituted 1 or 2 "lower alkyl groups", a residue of a saturated cyclic amine containing at least one nitrogen atom in the ring, such as pyrrolidine, piperidine, piperazine derivatives, N-methylpiperazine, morpholine, thiomorpholine; or arylamino or aralkylamines, optionally substituted at the nitrogen atom of the "lower alkyl group" such as aniline, benzylamine, N-methylaniline and N-methylbenzylamine.

It is understood that "the atoms of halogen in the definition of [the substituents of group a] represent fluorine atoms, atagawa lower alkyl group" in the definition of [the substituents of group a] mean group where the above "lower alkyl group" substituted by the above "halogen atoms, such as trifluoromethyl, trichloromethyl, deformity, dichloromethyl, dibromomethyl, vermeil, 2,2,2-trichloroethyl, 2,2,2-triptorelin, 2 - bromacil, 2-chloroethyl, 2-foradil or 2,2-dibromoethyl. Among these groups, preferred are trifluoromethyl, 2-bromacil, 2 - chloroethyl and 2-feratel.

"Lower aliphatic acyl group" in the definition of [the substituents of group a] and "lower aliphatic acyl group" in the "lower aliphatic aceraminophen" in determining [the substituents of group a] mean (C2-C7)-aliphatic acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovaleryl. Among them, preferred are acetyl and propionyl.

As for the "aryl group substituted by 1-3 substituents selected among the deputies of the group" in the definition of R2, it is preferable aryl group is substituted by 1 to 3 halogen atoms, and preferably a phenyl group substituted by 1 to 3 halogen atoms".

As the compound (I) of the present invention can be converted into the salt form, the term "pharmaceutically acceptable shashego of the invention and the acid, are salt halogenation acids, such as salts of hydrofluoric acid, salt chloroethanol acid, salts of Hydrobromic acid and salts modulational acids, salts of inorganic acids, such as salts of nitric acid, salt perchloro acids, salts of sulfuric acid, and salts of phosphoric acid; salts of lower alkylsulfonic acids, such as salts methansulfonate acids, salts triftormetilfullerenov acid and salts econsultancy acids, salts arylsulfonic acids, such as salts of benzosulfimide acid and salts of p-toluensulfonate acid; organic acid salts such as salts of acetic acid, salts of malic acid, salts of fumaric acid, salt of succinic acid, salts of citric acid, salts of tartaric acid, salts of oxalic acid, and salts of maleic acid; and salts of amino acids such as salts of glycine, lysine salt, arginine salt, ornithine salts, salts of glutamic acid and a salt of aspartic acid.

On the other hand, preferred examples of the salts composed of compounds (I) of the present invention and the bases are metal salts, such as salts formed by alkali metals, e.g. sodium salt, potassium salt and lithium salt, salt, obra; salts formed with amines, such as inorganic salts, for example, ammonium salts, organic salts, for example, salts of tert-octylamine, salt dibenzylamine, salt of the research, glucosamine salt, salt alkylation phenylglycine, 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 Tetramethylammonium and salt of Tris-(hydroxymethyl)aminomethane; and salts of amino acids, such as salts of glycine, lysine salt, arginine salt, ornithine salts, salts of glutamic acid and a salt of aspartic acid.

In addition, compound (I) of the present invention can be obtained Quaternary amine through modifications in the molecule, the nitrogen atom of piperidine group, R3, nationalease connection and anion (no restrictions, provided that the anion and ion halogen, and as examples of such anion can be called a chloride ion and iodide ion) may form a salt, and this salt is also in the scope of the present invention.

The compound (I) of the present invention is sometimes privatecustomer, this hydrate is also in the scope of the present invention.

"Ester" means an ester which can be converted to compound (I) of the present invention, and includes an ester of the hydroxy-group" and "live on the carboxyl group", and this term indicates the ether, when afrobrazilian group is "conventional protecting group" or "protecting group which can be split by a biological method such as hydrolysis in vivo".

The term "conventional protective group" denotes a protective group which can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis and photolysis.

Preferred examples of "conventional protective group" for "complex ester according hydroxyl group" is the aforementioned "lower aliphatic acyl group"; the above "aromatic acyl group", "tetrahydropyranyl or tetrahydropyrimidine groups, such as tetrahydropyran-2-yl, 3-bromotetradecane-2-yl, 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl and 4 - methoxytryptamine-4-yl; "silyl groups", such as tri (lower alkyl)silyl group such as trimethylsilyl, triethylsilyl, isopropylimidazole, tert-butyldimethylsilyl, m is amennye 1 or 2 aryl groups, for example, diphenylmethylsilane, diphenylbutyric, diphenylethylene and phenyldimethylsilane; "alkoxymethyl groups, such as lower alkoxymethyl group, for example, methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl and tert-butoxymethyl, lower alkoxycarbonyl lower alkoxymethyl group, for example, 2-methoxyethoxymethyl, and halogenated lower alkoxymethyl group, for example, 2,2,2-trichloroacetyl and bis (2-chloroethoxy) methyl; "substituted ethyl groups, such as lower alkoxyethyl group, for example, 1-ethoxyethyl and 1-(isopropoxy) ethyl, and halogenation group, for example, 2,2,2-trichloroethyl; "kalkilya groups such as lower alkyl groups, substituted 1-3 aryl groups, for example, benzyl, -naphthylmethyl-naphthylmethyl, diphenylmethyl, triphenylmethyl-naphthylmethyl or 9-antimetal, and a lower alkyl group substituted by 1-3 aryl groups which are substituted lower alkyl, halogenated lower alkyl, lower alkoxy - or nitro-group, a halogen atom or cyano, for example, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 3,5-di-(trifluoromethyl) benzyl, 4 - methoxybenzyl, 4-methoxyp what I alkoxycarbonyl group"; the above "altneratively group"; the above "aracelikarsaalyna group".

Preferred examples of "conventional protective group" for "complex ester at the carboxyl group" is the aforementioned "lower alkyl group, 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-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butinyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butinyl, 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, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; the above "dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4 - hydroxybutyl; ("lower aliphatic acyl") ("lower alkyl) group, such as acetylenyl; the above "kalkilya group" and the above "silyl group".

The term "protective group which can be split by a biological method such as hydrolysis in vivo" refers to a group that is cleaved by a biological method such as hydrolysis in the human body, and gives the free acid or its salt. Whether the connection derived or not can be determined as follows: the compound is injected in the experimental animal, such as rat or mouse, and then examine body fluids of the animal. If the original compound or its pharmacologically acceptable salt can be detected in body fluids, connection, studied thus considered derived.

Preferred examples of the protective group which can be split by a biological method such as hydrolysis in vivo" for the hydroxy-group are "carbonylcyanide group, such as 1-(acyloxy) ("lower alkyl) group", which includes (1-("lower aliphatic acyl")hydroxy) ("lower alkyl) group", for example, formyloxyethyl, acetoxymethyl, dimerocker, hexaniacinate, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 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) group", for example, cyclopentanecarboxylate, cyclohexylcarbodiimide, 1 - cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1 - cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1 - cyclopentanecarboxylate and 1-cyclohexyloxycarbonyloxy; 1- (("aromatic acyl")hydroxy) ("lower alkyl) group", for example, benzoyloxymethyl; (lower alkoxycarbonyl) alkyl groups, for example, methoxycarbonylmethyl,

ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyloxymethyl, butoxycarbonylmethyl, msobuttoniconandcaption, pentylcyclohexyl) methyl, 1-(methoxycarbonylamino) ethyl, 1-(ethoxycarbonyl)ethyl, 1-(propoxycarbonyl) 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)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- (isobut the forces and 1-(ethoxycarbonyl)hexyl; exodeoxyribonuclease group, for example, (5-phenyl-2-oxo-1,3-dioxolan-4-yl) methyl, [5-(4-were)-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; and similar groups; "phthalidyl group", for example, phthalidyl, dimethylphthalate and dimethoxytrityl; the above "lower aliphatic acyl group"; the above "aromatic acyl group", "the remains of salts profirov succinic acid"; "the remains of salts of esters of phosphoric acid"; "afrobrazilian amino acid residues or similar groups; carbamoyl group; carbamoyl group, substituted by 1 or 2 lower alkyl groups; and 1-(acyloxy)allyloxycarbonyl group, for example, pivaloyloxymethyl. Among these groups, preferred is "carbonylcyanide group".

Preferred examples of the protective group which can be split by the biological method, the Chille alkoxy) (lower alkyl) group, for example, methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxide, n-butoxymethyl or tert-butoxymethyl; ((lower alkoxy) (lower alkoxy)) alkyl groups such as 2-methoxyethoxymethyl; (lower alkoxycarbonyl lower alkoxy) (lower alkyl) group, for example, 2-methoxyethoxymethyl; ("aryl oxy) ("lower alkyl) group", for example, phenoxymethyl; and halogenated (lower alkoxy) (lower alkyl) group, for example, 2,2,2 - trichloroacetyl and bis(2-chloroethoxy)methyl; ("lower alkoxy) carbonyl ("lower alkyl) group", for example, methoxycarbonylmethyl; "cyano" ("lower alkyl) group", for example, cyanomethyl or 2-cyanoethyl; "("lower alkyl") thiomethyl group, for example, methylthiomethyl or ethylthiomethyl; "aryl" "thiomethyl group", for example, phenylthiomethyl or Aftertime; "(("lower alkyl")sulfonyl ("lower alkyl) group, optionally substituted by halogen atoms"), for example, 2-methansulfonate or 2-triftormetilfullerenov; "(("aryl"sulfonyl) ("lower alkyl) group"), for example, 2 - benzosulfimide or 2-toluensulfonate; the above "(("1-(acyloxy)") ("sosnitsa alkyl group; "carboxialkilnuyu group", for example, carboxymethyl group; and "ameloblastoma amino acid residues, for example, phenylalanine.

As the compound (I) of the present invention can be converted into another derivative than the "pharmaceutically acceptable salt" and above "ester", when the amino group and/or carboxypropyl, the term "more derived" refers to a derivative. Examples of such derivatives are amides.

The compound (I) of the present invention has several asymmetric centers, and thus R and S configurations for each asymmetric center can exist as stereoisomers. The present invention includes all the individual isomers and mixtures of these isomers in any ratio.

The method of carrying out the invention

Acylated heteroalicyclic derivatives of the present invention can be obtained as described below.

[Method]

Method a is a method of obtaining the compound (I) where Z represents two hydrogen atoms.

< / BR>
< / BR>
< / BR>
In the above scheme, R1, R2, A, B, D, G, L and n have the above values.

Y and Y' represent, preferred is a multidisciplinary group, the halogen atoms such as chlorine atoms, bromine and iodine; trigalogenmetany, such as trichloromethane; low alkanesulfonyl, such as methanesulfonate, econsultancy; galogensoderjasimi low alkanesulfonyl, such as tripterocalyx, pentafluoroethanesulfonyl; and arylsulfonate, such as benzosulfimide, p - toluensulfonate and p-nitrobenzenesulfonate. Among these groups, preferred are halogen atoms and lower alkanesulphonic.

R8represents a hydrogen atom or a group protecting the hydroxyl group. The group protecting the hydroxyl group means a group that protects the reaction, which can be removed by a chemical method such as hydrogenolysis, hydrolysis, electrolysis and photolysis, and examples of such groups are the same groups as "conventional protective group for complex live on the hydroxyl group."

Stage A1 is a method in which the compound (II) enter into interaction with the compound (III) in a solvent in the presence of a base to form compound (IV) in aminogroup of compound (II) is modified by a group of the formula-A-B-R1anichini provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and 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 cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; NITRILES such as acetonitrile and isobutyronitrile. Among these solvents, preferred are halogenated hydrocarbons and ethers, and the most preferred methylene chloride and tetrahydrofuran.

Used the base has no particular restrictions, provided that consists of the base that is used as a base in conventional reactions. Predpochtitelen, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N, N-dimethylamino) pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,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). Among these reasons is more preferred are triethylamine and diisopropylethylamine.

The interaction can be performed at a temperature of from -20oC to 100oC, preferably from 0oC to 20oC.

The reaction time varies depending on the reaction temperature, the starting compounds, reagents and solvent, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

In addition, when the compound (II) enter into interaction with the compound (III), where a represents a carbonyl group, the method can be carried out by conducting a reaction using compound of formula R1-B-AND-IT (where a, b and R1have the above values) and a condensing agent in a solvent, in the presence or in the absence of a base.

Examples used "condensing agent" are

(1) societyarrived (for example, 1,3 - dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl)-carbodiimide); a combination of one of the above carbodiimide and the base described below; or a combination of one of the above carbodiimide and N - hydroxycodone (for example, N-hydroxysuccinimide, 1 - hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3 - dicarboximide);

(3) a combination of a disulfide (e.g., 2,2'- piperidinomethyl or 2,2'-dibenzothiazepine and so on) and phosphine (e.g. triphenylphosphine or tributylphosphine);

(4) carbonate [e.g. N,N'-disuccinimidyl, di-2 - pyridylcarbonyl or 3,3'-bis(1-phenyl-1H-tetraol-5-yl) dithiocarbonate];

(5) phosphinic acid chloride acid [e.g. acid chloride, N,N'-bis (2-oxo-3-oxazolidinyl) phosphinic acid];

(6) oxalate [for example, N,N'-disuccinimidyl, N,N'-debtelimination, N,N'-bis (5-norbornene-2,3-dicarboximide)oxalate, 1,1'-bis(benzotriazolyl) oxalate, 1,1'-bis(6-chlorobenzotriazole)oxalate or 1,1'-bis (6-triftormetilfosfinov)oxalate];

(7) a combination of the above phosphine and azodicarboxylate or azodicarboxamide [for example, diethylazodicarboxylate, 1,1'- (azodicarbon)dipiperidino];

or a combination of vysheukazannoe N-ethyl-5-phenylisoxazole);

(9) deteroriated (for example, di-2-pyridylmethylene);

(10) arylsulfonate (for example, p-nitrobenzenesulfonate);

(11) a halide of 2-halogen-1-(lower alkyl)pyridinium (for example, 2-chloro-1-methylpyridinium);

(12) imidazole (for example, 1,1'-oxalylamino or N,N'-carbonyldiimidazole);

(13) perborate 3-(lower alkyl)-2-halogenbenzonitriles (for example, perborate 3-ethyl-2-chlorobenzothiazole);

(14) 3-(lower alkyl)-benzothiazol-2-laureate (for example, 3-methylbenzothiazol-2-laureate);

(15) phosphate (for example, phenyldichlorophosphine or polyphosphate);

(16) halogensulphonylphenyl (for example, chlorosulfonylisocyanate);

(17) haagensen (for example, trimethylsilyloxy or triethylsilane);

(18) the combination of lower alkanesulfonyl (for example, methanesulfonamido) and the base described below; and

(19) N,N,N',N'-Tetra(lower alkyl)galogyenpirimidinov (for example, N, N,N',N'-tetramethylpropylenediamine).

Of these agents, the preferred agent specified above in (1).

Used solvent has no particular restrictions, provided that it has no adverse effect on the interaction and can dissolve the original substance to necn; 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; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid.

Used the base has no particular restrictions, provided that consists of the base that is used as a base in conventional reactions. Preferred examples include organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N, N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N, N-dimethylaniline and N,N-diethylaniline.

In addition, you can use a catalytic amount of 4-(N,N-dimethylamino) pyrid is but you can add a dehydrating agent, such as molecular sieves, salts of Quaternary ammonium bases, such as chloride of benzyltriethylammonium and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, and sinks acids such as 3,4 - dihydro-2H-pyrido[1,2-a] pyrimidine-2-it.

The interaction can be performed at a temperature of from -20oC to 80oC, preferably from 0oC to room temperature.

The reaction time varies depending mainly on the reaction temperature, the starting compounds, reagents and solvent, and is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

Stage A2 is a method of obtaining the compound (V) by removing groups of R8of the compounds (IV) and subsequent conversion of the hydroxy-group, in the presence or in the absence of base, in the deleted group Y'.

The reaction of removal of R8varies depending on the nature of the group and is implemented as shown below, by methods known to experts in this field of technology.

In the case when R8represents a silyl group, it can be removed by processing soedinenie potassium; or by treatment with an organic acid, such as acetic acid, methanesulfonate acid, p-toluensulfonate acid, triperoxonane acid, triftormetilfullerenov acid or B-bromocatechol or inorganic acid, such as chloromethane acid.

In addition, in the case of removal by using fluoride-anion reaction can sometimes promote by adding organic acids such as formic acid, acetic acid or propionic acid.

Used solvent has no particular restrictions, provided that it has no adverse effect on the interaction and can dissolve the original substances to some extent, and preferred examples are ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, di-methoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid, and mixtures thereof.

The interaction can be performed at a temperature of from 0oC to 150oC (preferably from 10oC to 100oC) for the time from 1 hour to 48 hours (preferably from 2 hours to 12 hours).

Solvent used in the removal by catalytic hydrogenation has no particular restrictions, provided that it has no adverse effect on the interaction, and preferred examples include alcohols such as methanol, ethanol and isopropanol, ethers, such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters, such as ethyl acetate and propyl, amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl - 2-pyrrolidone and triamide hexamethylphosphoric acid, aliphatic acids such as formic acid and acetic acid, water, or mixtures thereof. Of these solvents, preferred are alcohols, aliphatic acids, mixtures of alcohols and ethers, mixtures of alcohols and water, or a mixture of aliphatic acids and water.

There is not a special ograniczenie catalytic hydrogenation, and preferred examples are palladium-on-charcoal, palladium black, Raney Nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate.

Pressure has no particular limitation, and is usually from 1 to 10 atmospheres.

The reaction time and temperature vary depending on starting compounds, solvent and catalyst, but generally the reaction is carried out at a temperature from 0oC to 100oC, preferably from 20oC to 70oC) for a time from 5 minutes to 48 hours (preferably from 1 hour to 24 hours).

The solvent used for removing, through oxidation, has no particular restrictions, provided that it has no adverse effect on the interaction, and preferably using an aqueous organic solvent.

Preferred examples of such organic solvent are ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, NITRILES, such as acetonitrile, ethers such as diethyl ether, tetrahydrofuran and dioxane, amides, such as dimethyl-formamide, dimethylacetal special restrictions in terms of oxidant provided what is the oxidizing agent commonly used in reactions of oxidation, and preferred examples are potassium persulfate, sodium persulfate, suryamaninagar (CAN) and 2,3-dichloro - 5,6-dicyano-p-benzoquinone (DDQ).

The reaction time and temperature vary depending on starting compounds, solvent and catalyst, but generally the reaction is carried out at a temperature from 0oC to 150oC for a time from 10 minutes to 24 hours.

This group can also be removed by using an alkali metal such as lithium metal or sodium metal in liquid ammonia or alcohol, such as methanol or ethanol, at temperatures from -78oC to -20oC.

In addition, this group can also be removed with the use of aluminium chloride and sodium iodide or alkylsalicylate, such as trimethylsilylmethyl, in a solvent.

Used solvent has no particular restrictions, provided that no adverse influence on the reaction, and preferably used are NITRILES, such as acetonitrile, halogenated hydrocarbons such as methylene chloride or chloroform, or mixtures thereof.

The reaction time and temperature vary depending on the starting compounds and the t to 3 days.

When the substrate in the reaction contains a sulfur atom, it is preferable to use aluminum chloride and iodide of sodium.

In the case when R8represents an aliphatic acyl group, aromatic acyl group or a lower alkoxycarbonyl group, it can be removed by treatment with base in a solvent.

Used the base has no particular restrictions, provided that it has no effect on any other part of the connection, and the preferred examples are the alkoxides of metals such as sodium methoxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate and lithium carbonate; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide; and ammonia, such as aqueous ammonia and concentrated solution of ammonia in methanol.

There is no specific limitation concerning the used solvent, provided that it is a solvent commonly used in reactions of hydrolysis, and preferred examples include water; organic solvents, such as alcohols (e.g. methanol, ethanol and n-propanol) and ethers (e.g. tetrahydrofuran and dioxane; or a mixture in which on the starting compounds, the solvent and the base, but, as a rule, the reaction is carried out at a temperature from 0oC to 150oC for a time from 1 hour to 10 hours in order to inhibit side reactions.

In the case when R8represents the lowest alkoxymethyl group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, tetrahydrofuranyl group, tetrahydropyranyl group or a substituted ethyl group, it usually can be removed by treatment with acid in a solvent.

Used acid has no particular restrictions, provided that it is commonly used as the acid Bronsted or Lewis acid, and preferred examples are acid Bronsted, such as hydrogen chloride; inorganic acids (for example, chloromethane acid, sulfuric acid or nitric acid; and organic acids (e.g. acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid); and a Lewis acid such as boron TRIFLUORIDE. Can also be used in strongly acidic cation-exchange resin such as Dowex 50W.

Used solvent has no particular restrictions, provided that he titlename examples are 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; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water, and mixtures thereof. Of these solvents, preferred are halogenated hydrocarbons, esters and ethers.

The reaction temperature and time vary depending on starting compounds, solvent, and the nature and concentration of acid used, but generally the reaction is carried out at a temperature from -10oC to 100oC (preferably from -5oC to 50oC) for a time from 5 minutes to 48 hours (suppose is inuu group, it can be removed by processing base in the reaction conditions similar to those described for the case when R8represents an aliphatic acyl group, aromatic acyl group or a lower alkoxycarbonyl group mentioned above.

In addition, in the case allyloxycarbonyl group is a convenient way using palladium and triphenylphosphine or hexaphosphate bis(methylphenylphosphinic) (1, 5cyclooctadiene) iridium (I), and the reaction may be carried out with negligible adverse reactions.

At the last stage, stage A2 solvent used has no particular limitation, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; ethers, such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; NITRILES, such as acetonitrile; and amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid. Of these, more than predpoletnoy a base, used as a base in conventional reactions. Preferred examples include organic bases such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N,N-dimethylamino) pyridine, 2,6-di(tert-butyl) -4-methylpyridine, quinoline, N, N - dimethylaniline, N,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). Among such preferred bases are triethylamine, pyridine and 4-(N, N - dimethylamino) pyridine, and most preferably, the reaction is carried out using pyridine as solvent and with the addition of catalytic amounts of 4-(N,N-dimethylamino) pyridine.

The interaction can be performed at temperatures from - 20oC to 50oC, preferably from -10oC to 20oC.

The reaction time varies depending on the reaction temperature, the starting compounds, reagents and solvent, and is usually from 15 minutes to 24 hours, preferably from 30 minutes to 6 hours.

As a reagent for the formation of the deleted group Y' using the appropriate halogenoalkane.

Stage A3 is a method of obtaining the compound (I) according to the present invention by reaction of compound (V) with compound (VI) in a solvent in the presence of a base.

Used solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and 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 cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; NITRILES such as acetonitrile and isobutyronitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2 - pyrrole sulfolan. Of them, preferred are amides, ethers, and NITRILES, and the most preferred amides.

Used the base has no particular restrictions, provided that it is the basis used in conventional reactions. Preferred examples are 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-pyrrolidinedione, picoline, 4-(N,N-dimethylamino) pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N - diethylaniline, 1,5-diazabicyclo[4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1.8-d is one reason, and most preferably a combination of a metal iodide and hydrogen carbonate of an alkali metal.

The interaction can be performed at a temperature of from 0oC to 150oC, preferably from 20oC to 120oC.

The reaction time varies depending on the reaction temperature, starting materials, reagents and solvents, and is usually from 30 minutes to 48 hours, preferably from 1 hour to 12 hours.

[Method]

The compound (I), where n is 0 and Z is an oxygen atom, can be obtained by way Century.

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In the above scheme, R1, R2, A, B, D, G, L, and Y' have the above values.

R2represents a group protecting the hydroxyl group, which is defined in the definition of R8as the "protective group in the reaction".

R10represents a group protecting aminogroup, and examples are the aforementioned "aliphatic acyl group"; the above "aromatic acyl group"; the above "lower alkoxycarbonyl group"; the above "altneratively group"; the above "aracelikarsaalyna group" and the above "silyl group". Of them Barbarella group.

Stage B1 is a method of obtaining amino compounds (X) by converting the primary hydroxy-group diol (VIII) in the deleted group and subsequent replacement of this group by the amino group of an amine (IX).

The reaction of conversion of primary hydroxy-group diol (VIII) in the group that you want carried out in a manner similar to the method described for the reaction of the last stage stage A2.

The last substitution reaction is carried out, as a rule, in a solvent using a metal salt.

Used solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; 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 cyclohexanone; NITRILES, such as acetonitrile, Propiedad, N-methylpyrrolidinone and triamide hexamethylphosphoric acid. Of them are preferred NITRILES, and the most preferred acetonitrile.

Examples used metal salt are the perchlorates such as lithium perchlorate, magnesium perchlorate and sodium perchlorate; metal chlorides such as calcium chloride, zinc chloride and cobalt chloride; tetrafluoroborate metals, such as tetrafluoroborate lithium and tetrafluoroborate potassium; and triftorbyenzola zinc. Of them, preferred are the perchlorates of the metals, and the most preferred lithium perchlorate.

The interaction can be performed at a temperature of from -20oC to 150oC, preferably from room temperature to 100oC.

The reaction time varies depending on the reaction temperature, starting materials, reagents and solvents, and is usually from 30 minutes to 2 days, preferably from 2 hours to 1 day.

Stage B2 is a method of obtaining compound (XI) by protection of the secondary amino group of the obtained amine (X) with the subsequent implementation of the cyclization.

Protection of the secondary amino group, R10you can implement the methods described Yes the mi (preferably 2-3 equivalents) of the compound of formula R10-X or the compounds of formula R10-O-R10(in the case when R10represents an acyl group) in a solvent, in the presence or in the absence of base;

[where

R10has the above values, and

X represents a group to delete, and remove the specified group has no particular restrictions, provided that it can be split, usually in the form of a nucleophilic group. Preferred examples are halogen atoms such as chlorine, bromine and iodine; lower alkoxycarbonylmethyl, such as methoxycarbonylamino, ethoxycarbonyl; the halogenated alkylcarboxylic, such as chloroacetoxy, dichloroacetylene, trichloroacetoxy, tripterocalyx;

low alkanesulfonyl, such as methanesulfonate, econsultancy; halogenated lower alkanesulfonyl, such as tripterocalyx, pentafluoroethanesulfonyl; and arylsulfonate, such as benzosulfimide, p-toluensulfonate and p-nitrobenzenesulfonate. Of them, preferred are halogen atoms, halogenated lower alkanesulfonyl and arylsulfonamides R10-OH (when R10represents an acyl group) in a solvent, in the presence or in the absence of the above-mentioned condensing agent and a catalytic amount of base.

[Method 3]

Way when, in particular, R10represents a tert-butoxycarbonyl group or benzyloxycarbonyl group, and protection of the secondary amino group, R10may be accomplished through the interaction of the compounds with the reagent tert-butoxycarbonylamino or reagent benzyloxycarbonylamino in a solvent in the presence of a base.

The solvent used in [method 1], has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; 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, takelonger; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid.

The basis used in [method 1], has no particular restrictions, provided that consists of the base that is used as a base in conventional reactions. Preferred examples include organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N,N - dimethylamino) pyridine, 2,6-di(tert-butyl)-4-methyl-pyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.

In addition, you can use a catalytic amount of 4-(N,N-dimethylamino) pyridine or 4-pyrrolidinedione in combination with another base. Moreover, in order to communicate effectively, you can add salt, Quaternary ammonium bases, such as chloride of benzyltriethylammonium or tetrabutylammonium chloride, or a crown ether, such as dibenzo-18-crown-6.

The interaction can be performed at a temperature of from -20oC to the boiling point ispolzuemoe depending on the reaction temperature, starting substances of the base and solvent, and is usually from 10 minutes to 3 days, preferably from 1 hour to 1 day.

Examples of compounds of formula R10-X are acylhomoserine, such as halides of aliphatic acids (for example, acetylchloride, propionitrile, butylbromide, valerianic and hexanoate); lower alkoxycarbonylmethyl (for example, methoxycarbonylamino, methoxycarbonylamino, ethoxycarbonylphenyl, propoxycarbonyl, butoxycarbonyl and hexyloxybenzoic); arylcarbamoyl (for example, benzoyl chloride, benzylbromide and aftercare); silicalite, such as tert-butyldimethylsilyloxy, trimethylsilane, triethylsilane, triethylsilane, triisopropylsilane, dimethylethoxysilane, diethylazodicarboxylate, tert - butyldiphenylsilyl, diphenylmethylsilane and triphenylmethylchloride; appropriate selectiveimmunisation; aralkylamines, such as benzylchloride and benzylbromide; and carbonyloxy (lower alkyl)halides, such as pivaloyloxymethyl and ethoxycarbonylmethylene.

Examples of compounds of formula R10-O-R10are anhydride or Caproic anhydride; and mixed anhydrides, such as a mixed anhydride of formic and acetic acids.

The solvent used in [method 2], has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include 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; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2 - pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid.

The basis described in method 1 can be used as the base method 2.

The interaction can be performed at a temperature of from -20oC to 80oC, preferably from 0oC to room temperature.

The solvent used in [3], has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; 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; NITRILES, such as acetonitrile and isobutyronitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2 - pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid; water; and a mixture of water and one of the above organic solvents.

The basis described in method 1, can be used as the basis of method 3.

Predpochtiteljno)-2-phenylacetonitrile, tert-butyl S-(4,6-dimethylpyridin-2-yl)thiolcarbamate, 1,2,2,2-tetrachloroethyl and tert-BUTYLCARBAMATE. Of those, more preferred is di-tert-BUTYLCARBAMATE.

Preferred examples of the reagent for benzyloxycarbonylamino are benzyloxycarbonylamino, benzyloxycarbonylamino and dibenzyldithiocarbamate.

The interaction can be performed at a temperature of from -20oC to 80oC, preferably from 0oC to room temperature.

The reaction time varies depending on the reaction temperature, the starting substances of the base and solvent, and is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

The cyclization reaction in the last step carried out usually in a solvent in the presence of a base.

Used solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, , tracecut, propyl, butyl acetate and diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid.

Used the base has no particular restrictions, provided that it is the basis used in conventional reactions. Preferred examples are inorganic bases, such as carbonates of alkali metals (e.g. sodium carbonate, potassium carbonate and lithium carbonate; bicarbonates of alkali metals (e.g. sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; hydrides of alkali metals (e.g. lithium hydride, sodium hydride and potassium hydride); hydroxides of alkali metals (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal fluorides (for example, sodium fluoride and potassium fluoride); and alkoxides of alkali metals such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium and Metor CLASS="ptx2">

The interaction can be performed at a temperature of from -20oC to 80oC, preferably from 0oC to room temperature.

The reaction time varies depending on the reaction temperature, the starting substances of the base and solvent, and is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

Stage B3 is a method of obtaining compound (XII) by removing the protection of the hydroxy-group of the compounds (XI) and subsequent conversion of the obtained hydroxy-group in the group that you want, which can be done as described for the last stage, stage A2.

Stage B4 is a method of obtaining compound (l-b) of the present invention through the condensation reaction between the compound (XII) and compound (VII), which can be done as described for stage A3.

[Method]

Connection (1), where n is 1 or 2, and Z represents an oxygen atom, can be obtained by method C.

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In the above formulas, R1, R2, R3, A, B, D, G, L, and Y' have the above meanings;

X and X' represent the deleted group that has the same values as above (XIV) by reaction of the secondary amino amine (X) with compound (XIII) in a solvent in the presence of a base and subsequent alkylation in the DH group.

The solvent used in the first stage, has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples include aliphatic hydrocarbons such as hexane and heptane; 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; NITRILES, such as acetonitrile and isobutyronitrile; and amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid.

Used the base has no particular restrictions, provided that consists of the base that is used as a base in conventional reactions. Preferred examples include organic bases such as N-methylmorpholine, triethylamine, tributylamine,laminitis) pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N, N-dimethylaniline and N,N-diethylaniline.

In addition, you can use a catalytic amount of 4-(N,N-dimethylamino) pyridine or 4-pyrrolidinedione in combination with another base, and in order to communicate effectively, you can add a dehydrating agent, such as molecular sieves, salts of Quaternary ammonium bases, such as chloride of benzyltriethylammonium and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, and sinks acids such as 3,4-dihydro-2H-pyrido [1,2-a] pyrimidine-2-it.

The interaction can be performed at a temperature of from -20oC to 80oC, preferably from 0oC to room temperature.

The reaction time varies depending on the reaction temperature, the starting substances of the reagent and solvent, and is usually from 10 minutes to 3 days, preferably from 30 minutes to 1 day.

The solvent used for the reaction of alkylation at the last stage, has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the original substances to some extent, and preferred examples avla methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile, propionitrile and isobutyronitrile; amides, such as formamide, N, N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2 - pyrrolidone, N-methylpyrrolidinone and triamide hexamethylphosphoric acid; and sulfoxidov, such as dimethyl sulfoxide and sulfolane. Of those, more preferred are ethers, and amides, and the most preferred tetrahydrofuran and N,N-dimethylformamide.

Used the base has no particular restrictions, provided that consists of the base that is used as a base in conventional reactions. Preferred examples are inorganic bases, such as carbonates of alkali metals (e.g. sodium carbonate, potassium carbonate and lithium carbonate; bicarbonates of alkali metals (e.g. sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; hydrides of alkali metals (e.g. lithium hydride, sodium hydride and potassium hydride); hydroxides of alkali metals (e.g. sodium hydroxide, the hydroxide and alkoxides of alkali metals, such as sodium methoxide, ethoxide sodium, potassium methoxide, ethoxide potassium tert-piperonyl potassium and lithium methoxide. Of those, more preferred are the hydrides of alkali metals and alkoxides of alkali metals.

The interaction can be performed at a temperature of from -20oC to 100oC, preferably from 0oC to 50oC.

The reaction time varies depending on the reaction temperature, the starting substances of the base and solvent, and is usually from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.

Stage C2 is a method of obtaining compound (XV) of the present invention by removing the protection of the hydroxy-group of the compounds (XIV), and subsequent conversion of the obtained hydroxy-group in the group that you want, and can be carried out as described for the last stage, stage A2.

Stage C3 is a method of obtaining compound (l-b) of the present invention through the condensation reaction between the compound (XV) and compound (VII), and can be carried out as described for stage A3.

Upon completion of each of the above reactions from the reaction mixture normal str the mixture, as necessary, removing insoluble substances by filtration, if required, addition of organic solvents that do not mix with each other, such as water and ethyl acetate, washing with water or similar solvent, separating the organic layer containing the desired compound, drying it over anhydrous magnesium sulfate or similar desiccant, and the subsequent removal of the solvent.

If necessary, the thus obtained desired compound can be extracted and purified by using conventional method such as recrystallization or pereosazhdeniya, and chromatography, if necessary combination method, usually used for separation and purification of organic compounds, and elution using an appropriate eluent. Examples of chromatography are adsorption column chromatography using a carrier such as silica gel, aluminum oxide or magnesium on silica gel type Florisil, chromatography using a synthetic adsorbent, for example, the distribution column chromatography using a carrier such as Sephadex LH-20 (product of Pharmacia), Amberlite XAD-11 (product of Rohm & Haas) or Diaion HP-20 (product of Mitsubishi Chemical), incommensurately), using silica gel or alkylated silica gel.

In addition, the starting materials are either commercially available, or can easily get known methods (for example, as described in EP-776893 and U.S. patent 5641777, and similar methods from commercially available starting materials.

New acylated heteroalicyclic derivatives of the present invention have high NK2-selective antagonistic activity and have low toxicity, and thus, they are useful as medicines. For example, they are useful as preventive and therapeutic agents in the case of diseases of the Central nervous system, such as fear, depression, psychosis and schizophrenia; sleep apnea; neurodegenerative diseases such as dementia, AIDS, senile dementia of Alzheimer's, Alzheimer's, down syndrome, demyelinizing disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma and cough; inflammatory diseases such as inflammatory disease to the problems such as rhinitis; Allergy, such as increased sensitivity to curly plants; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, spring catarrh, destruction gematologicheskogo barrier caused by various inflammatory eye diseases, increased intraocular pressure, and cramps; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis; addiction, such as alcohol dependence; somatic diseases caused by stress; reflex sympathetic dystrophy such as shoulder syndrome; dysthymia; unwanted immune responses such as transplant rejection, diseases associated with immunostimulating, such as systemic lupus erythematosus or immunosuppression; diseases of the digestive system, such as diseases caused by disorders of the nervous regulation of bodies, colitis, ulcerative colitis and Crohn's disease; vomiting, such as vomiting, caused by the harmful effects of x-ray radiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative disorders, gastro-intestinal occlusion, weakened gastrointestinal on what effect or adverse reactions, caused by the introduction of different therapeutic agents; functional diseases of the bladder such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleroderma or infection Fasciola hepatica; diseases caused by disorders of blood flow due to vasodilation or vasoconstriction, such as angina, migraine and Raynaud's disease; and pain when pain nociceptive reception, such as migraine, headache and toothache.

The method of introducing the compound (I) of the present invention include oral administration in the form of tablets, capsules, granules, powders or syrups, or parenteral administration in the form of injections or suppositories. Such compositions can be obtained by known methods using additives such as excipients (for example, organic excipients including sugar, such as lactose, sucrose, glucose, mannitol or sorbitol; starches such as corn starch, potato starch, a-starch, dextrin or carboximetilkrahmal; cellulose derivatives such as crystalline cellulose, hydroxypropylcellulose with a low degree of substitution, hypromellose, carboxymethylcellulose, calcixerollic or carbox the inorganic excipients, such as shaboobalawanda silicic acid, synthetic aluminum silicate or aluminate-metasilicate magnesium; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (e.g. stearic acid and metal salts of stearic acid such as 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 aliphatic acids; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as anhydrous silicic acid and silicate-hydrate; and the above starches), binders (for example polyvinylpyrrolidone, macrogel and the same compounds, which are described above as excipients, disintegrators (for example, the same compounds, which are described above as the excipients, and chemically modified brahmacarya, such as croscarmelose, carboximetilkrahmala and cross-linked polyvinylpyrrolidone), stabilizers (for example, peroxybenzoate, such as methylparaben is such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), corrigentov (for example, a common podslushivala, acidifying substances and perfumes) and thinners.

The dosage of compound (I) will vary depending on the nature and severity of the disease, age of the patient and the route of administration. Suitable single standard dose of compound (I) in the case of oral administration is from 0.01 mg per kg of body weight (preferably 0.1 mg per kg of body weight), as the lower limit, up to 100 mg per kg of body weight (preferably up to 50 mg per kg of body weight) as the upper limit. In the case of intravenous dose of from 0.01 mg per kg of body weight (preferably 0.05 mg per kg of body weight), as the lower limit, up to 100 mg per kg of body weight (preferably up to 50 mg per kg of body weight) as the upper limit. It is advisable to enter the above dose one or more times per day, depending on the nature and severity of the disease.

The best way of carrying out the invention

The following examples, reference examples, examples, compositions, and examples of the tests are intended to further explain the present invention and not intended to be any limitation of scope on the Spiro[benzo[C]thiophene-1 (3H),4'-piperidine]-(2S)-oxide

Example 1(a)

2-[(2R)-(3,4-Dichlorophenyl)-4-(cyclobutanecarbonyl) morpholine-2 - yl]ethanol

Water-soluble carbodiimide hydrochloride (WSC.HCl, 166 mg, 0.87 mmol), 1-hydroxybenzotriazole (117 mg, 0.87 mmol) and triethylamine (0.15 ml, of 1.09 mmol) at 0oC in nitrogen atmosphere in turn added to a solution cyclobutanecarbonyl acid (80 mg, 0.80 mmol) in methylene chloride (5 ml), and to the mixture is added 2-[(2R)-(3,4-dichlorophenyl)morpholine-2-yl]ethanol (200 mg, to 0.72 mmol) obtained in reference example 1. The mixture is stirred at room temperature for 6 hours. The reaction mixture was washed in turn with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is then distilled off under reduced pressure. The residue is purified by thin-layer chromatography on silica gel using as developing solvent a mixture of n-hexane and ethyl acetate (1:4), and obtain the desired compound (254 mg, 98%) as a white amorphous solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 7.59 (1H, Ushs), 7,44 (1H, d, J=8,4 Hz), 7,29 (1H, usl, J=8,4 Hz), 4,55 (1H, d, J=a 13.9 Hz), 3,71-of 3.80 (1H, m), 3,32-3,62 (6H, m), 3,09-up 3.22 (1H, m), 2,28-to 2.42 (1H, m), 1,79 astrometrically analysis (FAB), m/z: 358 (M+N)+).

Example 1 (b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclobutanecarbonyl)-morpholine-2-yl] ethanol and methanesulfonic acid

Methanesulfonanilide (0,071 ml of 0.92 mmol) and 4-dimethylaminopyridine (catalytic amount) under ice cooling and a nitrogen atmosphere are added to a solution of 2-[(2R)-(3,4 - dichlorophenyl) -4- (cyclobutanecarbonyl)morpholine-2 - yl]ethanol (219 mg, 0.61 mmol) obtained in example 1(a), in pyridine (2 ml). The mixture is stirred at the same temperature for 30 minutes. The reaction mixture is acidified with ice hydrochloric acid (10%) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off under reduced pressure. The residue is purified by thin-layer chromatography on silica gel using as developing solvent a mixture of n-hexane and ethyl acetate (1:4), and obtain the desired compound (255 mg, 96%) as a white amorphous solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

EUR 7.57 (1H, Ushs), 7,46 (1H, d, J=8.5 Hz), 7,20-7,30 (1H, m), 3,14-or 4.31 (9H, m), with 2.93 (3H, s), 2.26 and-to 2.42 (2H, m), 1,82-2,22 (6H, m).

Infrared spectrummaxcm-1(CBR>
1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclobutanecarbonyl)morpholine-2-yl]ethyl} Spiro[benzo[C]thiophene-1 (3H),4'-piperidine]-(2S)-oxide

Ester 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclobutanecarbonyl) morpholine-2-yl]ethanol and methanesulfonic acid (114 mg, 0.26 mmol) obtained in example 1(b), the hydrochloride Spiro[benzo [C] thiophene-1(3H),4'-piperidine]-(2S)-oxide (74 mg, 0.29 mmol), sodium hydrogen carbonate (66 mg, 0.78 mmol) and potassium iodide (65 mg, 0,39 mmol) suspended in anhydrous dimethylformamide (2 ml) and the mixture stirred at 80oC in nitrogen atmosphere for 8 hours. To the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by thin-layer chromatography on silica gel using as developing solvent a mixture of methylene chloride and methanol (10:1), and get named in the title compound (111 mg, 76%) as a white crystalline substance.

So pl. 99-101oC.

[]24D+65,4o(=of 0.54, chloroform).

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

7,22-to 7.59 (7H, m) to 4.52 (1H, d, J=13,8 Hz), the hydrated range,maxcm-1(KBr):

3432, 2949, 1643, 1436.

Mass spectrometric analysis (FAB), m/z: 561 (M+N)+).

Elemental analysis (%):

for C29H34N2O3SCl20.5 H2O

calculated: C - 61,04; H - 6,18; N-4,90; S - 5,61; Cl -12,43;

found: 61,75; H - 6,40; N - 4,86; S - 5,52; C l - 11,72.

Example 2

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclopropanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene - 1(3H),4'-piperidine]-(2S)-oxide

Example 2 (a)

2-[(2R)-(3,4-Dichlorophenyl)-4-(cyclopropanecarbonyl)morpholine-2-yl]ethanol

The desired compound (230 mg, 92%) was obtained as a white amorphous solid according to the procedure described in example 1(a), using cyclopropanecarbonyl acid (69 mg, 0.80 mmol) and 2-[(2R)-(3,4-dichlorophenyl)morpholine-2-yl]-ethanol (200 mg, to 0.72 mmol).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,58 (1H, Ushs), the 7.43 (1H, d, J=8.7 Hz), 7,28 (1H, OSD, J=8.7 Hz), of 4.54 (1H, d, J= a 13.9 Hz), of 3.5-3.9 (8H, m), 1,9-2,2 (2H, m), of 1.5-1.7 (1H, Ushs), of 0.7-1.0 (4H, m).

Infrared spectrummaxcm-1(CHCl3): 3623, 2968, 1732, 1637, 1471.

Mass spectrometric analysis (FAB), m/z: 344 (M+H)+).

Example 2(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclopropanecarbonyl)-morpholine-2-yl] EA substances in accordance with the procedure described in example 1(b), using 2-[(2R)-(3,4 - dichlorophenyl)-4-(cyclopropanecarbonyl)morpholine-2-yl] ethanol (220 mg, 0.64 mmol).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

EUR 7.57 (1H, Ushs), was 7.45 (1H, d, J=7.9 Hz), 7,25-to 7.32 (1H, m), 3,48-4,30 (8H, m), of 2.92 (3H, s), 2,09-2,49 (2H, m), 0,65-1,12 (4H, m).

Infrared spectrummaxcm-1(CHCl3): 2973, 1731, 1678, 1471.

Mass spectrometric analysis (FAB), m/z: 422 (M+N)+).

Example 2 (s)

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclopropanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide

The desired compound (63 mg, 45%) are obtained in the form of a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclopropanecarbonyl)morpholine-2-yl]ethanol and methanesulfonic acid (109 mg, 0.26 mmol) and hydrochloride Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide (71 mg, 0.28 mmol).

So pl. 96-99oC.

[]24D+56,7o(C = 0,30, chloroform).

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

7.23 percent-to 7.59 (7H, m), or 4.31 (1H, d, J=16,8 Hz), 3,99 (1H, d, J=16,8 Hz), 3,44-to 4.52 (5H, m), 2,73-2,96 (2H, m), 1,52-to 2.40 (12H, m), of 0.75 to 1.15 (4H, m).

Infrared spectrumm is">

Elemental analysis (%):

for C28H32N2SO3Cl20.5 H2O

calculated: C - 60,42; H is 5.98; N - 5,03; S - 5,76; Cl - 12,74;

found: C - 60,92; H - 6,32; N - 4,84; S - 5,71; Cl - 12,35.

Example 3

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclopentanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide

Example 3(a)

2-[(2R)-(3,4-Dichlorophenyl)-4-(cyclopentanecarbonyl)morpholine-2-yl]ethanol

The desired compound (389 mg, 96%) are obtained in the form of a white amorphous solid according to the procedure described in example 1 (a), using cyclopentanecarbonyl acid (186 mg, and 1.63 mmol) and 2-[(2R)-(3,4-dichlorophenyl)morpholine-2-yl]ethanol (300 mg, of 1.09 mmol).

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

to 7.59 (1H, d, J=20 Hz), the 7.43 (1H, d, J=8,4 Hz), 7,28 (1H, DD, J=8.4 and 2.0 Hz), to 4.62 (1H, d, J=a 13.9 Hz), 3,3-3,9 (7H, m), 3,37 (1H, d, J=a 13.9 Hz), 2,78 (1H, m), 1,4-2,1 (9H, m).

Infrared spectrummaxcm-1(CHCl3): 3622, 2960, 1732,. 1637, 1440.

Mass spectrometric analysis (FAB), m/z: 372 (M+H)+).

Example 3(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclopentanecarbonyl)-morpholine-2-yl] ethanol and methanesulfonic acid

The desired compound (435 mg, 95%) was obtained as a white amorphous solid vangaboys)morpholine-2-yl] ethanol (380 mg, of 1.02 mmol).

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

EUR 7.57 (1H, d, J=2.0 Hz), was 7.45 (1H, d, J=8,4 Hz), 7,27 (1H, DD, J=8.4 and 2.0 Hz), to 4.38 (1H, d, J= 3,9 Hz), 4,19-of 4.25 (1H, m), 3,94-4,00 (1H, m), 3,74-with 3.79 (1H, m), 3,45-3,62 (4H, m), 2,89-to 2.94 (4H, m), and 2.79 (IH, m), 2,27-2,34 (IH, m), 2,13-of 2.21 (1H, m), 1,53 is 1.91 (7H, m).

Infrared spectrummaxcm-1(CHCl3): 2964, 1640, 1440, 1362, 1175.

Mass spectrometric analysis (FAB), m/z: 450 (M+N)+).

Example 3(s)

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclopentanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide

The desired compound (132 mg, 49%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(c), using ether 2-[(2R)-(3,4 - dichlorophenyl)-4-(cyclopentanecarbonyl)morpholine-2-yl] ethanol and methanesulfonic acid (210 mg, 0.47 mmol) and hydrochloride Spiro[benzo [C] thiophene-(3H),4'-piperidine]-(2S)-oxide (144 mg, 0,56 mmol).

So pl. 99-100oC.

[]24D+55,0 (C = 0,50, chloroform).

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

7,55-to 7.59 (1H, m), 7,41-of 7.48 (1H, m), 7,20 and 7.36 (5H, m), 4,59 (1H, d, J= 13,8 Hz), or 4.31 (1H, d, J=16,8 Hz), 3,98 (1H, d, J=16,8 Hz), 3,43-3,82 (4H, m) to 3.36 (1H, d, J=13,8 Hz), 2,89-to 2.94 (1H, m), 2,73-2,84 (2H, m), 2,17 is 2.43 (6H, m), 2,04-to 2.15 (1H, m), 1,48-1,99 (11, ical analysis (FAB), m/z: 575 (M+H)+).

Elemental analysis (%):

for C30H36N2O3SCl20.5 H2O

calculated: 61,63; H - 6,38; N - 4,79; S - 5,49; Cl - 12,13;

found: C - 61,46; H - 6,28; N - 4,69; S Of 5.40; Cl - 11,57.

Example 4

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(cyclohexanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-(2S)-oxide

Example 4(a)

2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclohexanecarbonyl)morpholine-2-yl]ethanol

The desired compound (405 mg, 96%) are obtained in the form of a white amorphous solid according to the procedure described in example 1(a), using cyclohexanecarbonyl acid (147 mg, 1.15 mmol) and 2-[(2R)-(3,4-dichlorophenyl)morpholine-2-yl]ethanol (300 mg, of 1.09 mmol).

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

7,58 (1H, d, J=20 Hz), 7,42 (1H, d, J=8.0 Hz), 7,28 (1H, m), 4,63 (1H, d, J= 14,0 Hz), 3,40-3,93 (6H, m) to 3.34 (1H, d, J=14,0 Hz), 1,15-2,55 (13H, m).

The infrared spectrum, cm-1(CHCl3): 3623, 3536, 2936, 2858, 1711, 1634.

Mass spectrometric analysis (FAB), m/z: 386 (M+N)+).

Example 4(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclohexanecarbonyl)-morpholine-2-yl] ethanol and methanesulfonic acid

The desired compound (450 mg, 94%) was obtained as white amorphous Tverdov hexacarbonyl)morpholine-2-yl] ethanol (400 mg, 1.04 mmol).

Spectrum of nuclear magnetic resonance (400 MHz, CDCl3) memorial plaques;

7,56 (1H, d, J=2.0 Hz), 7,44 (1H, d, J=8.0 Hz), 7,26 (1H, DD, J=8.0 and 2.0 Hz), 4,39 (1H, d, J=14,0 Hz), 4,22 (1H, m), of 3.97 (1H, dt, J=10,0 and 7.0 Hz), of 3.77 (1H, dt, J=12,0 and 4.0 Hz), 3,60 (IH, m), of 3.48 (1H, m), of 3.43 (1H, d, J=14,0 Hz) to 2.94 (3H, s), 2,12-2,60 (3H, m), 1,15-of 1.85 (10H, m).

Infrared spectrummaxcm-1(CHCl3): 2936, 2858, 1634.

Mass spectrometric analysis (FAB), m/z: 464 (M+H)+).

Example 4(s)

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclohexanecarbonyl)-morpholine-2-yl] ethyl}Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide

The desired compound (168 mg, 70%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(c), using ether 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclohexanecarbonyl)morpholine-2-yl] ethanol and methanesulfonic acid (190 mg, 0.41 mmol) and hydrochloride Spiro[benzo[C] thiophene-1(3H),4'-piperidine]-(2S)-oxide (127 mg, 0.49 mmol).

So pl. 119-123oC.

[]24D+50,1o(C = 0,44, chloroform).

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

7,25-of 7.60 (7H, m), 4,60 (1H, d, J=14,0 Hz), 4,30 (1H, d, J= 17,0 Hz), 3,99 (1H, d, J=17,0 Hz), 3,40-are 3.90 (4H, m), 3,32 (1H, d, J=14,0 Hz) to 2.94 (1H, m), is 2.74 (1H, m), 1,15-2,60 (21H, m).

Infrared spectra CLASS="ptx2">

Elemental analysis (%):

for C32H38N2O3SCl20,2 H2O

calculated: C - 62,96; H - 6,51; N - 4,74; S - 5,42; Cl - 11,99;

found: C - 62,80; H - 6,69; N - 4,65; S - 5,39; C l - 12,07.

Example 5

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4- (cyclopropanecarbonyl)-morpholine-2-yl] ethyl}-4-phenylpiperidine-4 - carboxamide

The desired compound (93 mg, 69%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4-dichlorophenyl) -4-(cyclopropanecarbonyl) morpholine-2-yl] ethanol and methanesulfonic acid (107 mg, 0.25 mmol) and hydrochloride 4 - phenylpiperidines (627 mg, 0.30 mmol).

So pl. 94-96oC.

[]23D+39,6 (=of 0.54, methanol).

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

7,22-of 7.55 (8H, m) to 5.17 (2H, s), 1.85 to 4,43 (19H, m), 0,65-of 1.15 (4H, m).

Infrared spectrummaxcm-1(KBr): 3350, 2927, 1676, 1633, 1470.

Mass spectrometric analysis (FAB), m/z: 530 (M+H)+).

Elemental analysis (%):

for C28H33N3O3Cl20.5 H2O

calculated: C - 62,34; H - 6,35; N - 7,79; Cl - 13,14;

found: 62,40; H - 6,54; N - 7,47; Cl - 13,81.

Example 6

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4 - (what are square in form of white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4 - dichlorophenyl)-4-(cyclopentanecarbonyl) morpholine-2-yl] ethanol and methanesulfonic acid (150 mg, 0.33 mmol) dihydrochloride and 4- (2-pyridyl)piperidine-4-carboxamide (102 mg, and 0.37 mmol).

So pl. 189-190oC.

[]23D+43,3o(=of 0.53, methanol).

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

to 8.57 (1H, d, J=4,7 Hz), 7,15-to 7.68 (6H, m), 6,40 (1H, Ushs), 5,14 (1H, Ushs), of 4.57 (1H, d, J=13.5 Hz), 3,20-of 3.95 (5H, m), 1,45-2,98 (21H, m).

Infrared spectrummaxcm-1(KBr): 3412, 2953, 1679, 1639, 1468, 1433.

Mass spectrometric analysis (FAB), m/z: 559 (M+H)+).

Elemental analysis (%):

for C29H36N4O3Cl2< / BR>
calculated: C - 62,25; H - of 6.49; N - 10,01; Cl - 12,67;

found: C - 62,06; H - to 6.43; N - 9,89; Cl - 12,67.

Example 7

N, N-Dimethyl-1-{2-[(2R)-(3,4-dichlorophenyl)-4-(cyclopentanecarbonyl) morpholine-2-yl]ethyl}-4-(cyclohexyl)piperidine-4-carboxamide

The desired compound (152 mg, 77%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4-dichlorophenyl)-4- (cyclopentanecarbonyl)morpholine-2-yl] ethanol and methanesulfonic acid (150 mg, 0.33 mmol) and Ki
[]23D+40,9o(s = 0,52, methanol).

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

7,21-7,53 (3H, m), a 4.53 (1H, d, J=13,8 Hz), 2,60-of 3.95 (8H, m), to 3.02 (6H, s), 1,40-2,35 (22H, m), and 1.00 and 1.35 (7H, m).

Infrared spectrummaxcm-1(KBr): 3441, 2932, 2855, 1630, 1450.

Mass spectrometric analysis (FAB), m/z: 591 (M+H)+).

Elemental analysis (%):

for C32H47N3O3Cl20.5 H2O

calculated: C - 63,88; H - 8,04; N - 6,98; Cl - to 11.79;

found: C - 64,06; H - 7,97; N - 6,84; Cl - 11,72.

Example 8

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

The desired connection (817 mg, 78%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4-dichlorophenyl)- 4-(cyclopentanecarbonyl) morpholine-2-yl] ethanol and methanesulfonic acid (850 mg, 1,89 mmol) and hydrochloride [((2S)-hydroxy)-indan-1,4'-piperidine] (497 mg, of 2.08 mmol).

So pl. 192-193oC.

[]23D+ 63,1o(s = 0,52, methanol).

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

7,16-7,58 (7H, m), 4,60 (1H, d, J=13,6 Hz), and 4.40 (1H, d, J= 3.3 Hz), 3,24-3,98 (7H, m), 2,64-a 3.01 (4H, hromaticheski analysis (FAB), m/z: 557 (M+N)+).

Elemental analysis (%):

for C32H38N2O3Cl2< / BR>
calculated: C - up 66,78; H - 6,87; N - 5,02; Cl - 12,72;

found: C - 66,77; H - 6,79; N Is 5.07; Cl - 12,41.

Example 9

The dihydrochloride of 1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(L-prolyl)-morpholine-2-yl] ethyl}Spiro[((2S)-hydroxy)indan-1,4'-piperidine]

Example 9 (a)

2-[(2R)-(3,4-Dichlorophenyl)-4-(L-prolyl)morpholine-2-yl]ethanol

The desired compound (314 mg, 92%) was obtained as a white amorphous solid according to the procedure described in example 1(a), using 2-[(2R)-(3,4 - dichlorophenyl)-morpholine-2-yl] ethanol (200 mg, to 0.72 mmol) and N - tert-butoxycarbonyl-L-Proline (171 mg, 0.80 mmol).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,20 to 7.62 (3H, m), 3,98-4,94 (2H, m), 3,10-3,91 (9H, m), 1,55 was 2.25 (7H, m) of 1.46 (3H, s) to 1.38 (3H, s) to 1.14 (3H, s).

Infrared spectrummaxcm-1(KBr): 3442, 2975, 2876, 1695, 1401.

Mass spectrometric analysis (FAB), m/z: 473 (M+H)+).

Example 9(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4-(L-prolyl)morpholine-2-yl]-ethanol and methanesulfonic acid

The desired compound (313 mg, 94%) was obtained as a white amorphous solid according to the procedure described in example 1(b), use the spas resonance (270 MHz, CDCl3) memorial plaques:.

7,20-of 7.60 (3H, m), 4,10-of 4.77 (2H, m), 3,30-4,00 (9H, m), with 2.93 (3H, s), a 1.75-to 2.40 (6H, m) of 1.46 (3H, s) of 1.40 (3H, s) of 1.16 (3H, s).

Infrared spectrummaxcm-1(KBr): 2976, 1695, 1659, 1401, 1359, 1175.

Mass spectrometric analysis (FAB), m/z: 551 (M+H)+).

Example 9(s)

1-{2-[(2R)-(3,4-Dichlorophenyl)-4-(N-tert - butoxycarbonyl-L-prolyl) morpholine-2-yl] ethyl}Spiro [((2S)- hydroxy)indan-1,4'-piperidine]

The desired compound (175 mg, 73%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(c), using ether 2-[(2R)-(3,4-dichlorophenyl)-4-(L-prolyl)morpholine-2-yl]ethanol and methanesulfonic acid (200 mg, 0.36 mmol) and hydrochloride [((2S)-hydroxy)indan-1,4'-piperidine] (95 mg, 0.40 mmol).

So pl. 108-110oC.

[]24D+21,5o(s = 0,52, methanol).

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

7,20 to 7.62 (7H, m), 4,30-4,84 (3H, m), 3,20-3,98 (10H, m), 1,58-2,90 (16H, m) of 1.46 (3H, s) of 1.40 (3H, s) of 1.17 (3H, s).

Infrared spectrum maxcm-1(KBr): 3442, 2928, 1696, 1661, 1400.

Mass spectrometric analysis (FAB), m/z 658 (M+H)+).

Elemental analysis (%):

for C35H45N3O5Cl20.5 H2O

calculated:(2R)-(3,4-dichlorophenyl)- 4-(L-prolyl)-morpholine-2-yl] ethyl}Spiro[((2S)-hydroxy)indan - 1,4' -piperidine]

The dihydrochloride of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(L-prolyl)- morpholine-2-yl] ethyl[Spiro[((2S)-hydroxy)-indan-1,4'- piperidine]

A solution of hydrogen chloride in dioxane (4 N, 1.5 ml) under ice cooling are added to a solution in ethanol (2 ml), 1-{2-[(2R) -(3,4-dichlorophenyl)-4-(N-tert-butoxycarbonyl-L-prolyl)morpholine-2-yl] -ethyl} Spiro[((2S)-hydroxy)indan-1,4'- piperidine], obtained in example 9(d) (131 mg, 0.20 mmol). The solution was stirred at room temperature for 3 hours. The solvent is distilled off under reduced pressure. To the residue is added diethyl ether. After distillation to dryness obtain the desired compound (127 mg, 100%) as white crystals.

So pl. 290-294oC.

[]23D+24,7o(s = 0,52, methanol).

Spectrum of nuclear magnetic resonance (400 MHz, DMSO-d6) memorial plaques:

9,83-11,20 (2H, m), 8,45-8,63 (1H, m), 7,43-7,98 (3H, m), 7,05-of 7.25 (4H, m), 3,60-of 5.05 (8H, m), 2,85-to 3.58 (8H, m), 1,48-2,80 (13H, m).

Infrared spectrummaxcm-1(KBr): 3350, 2925, 2677, 2574, 1653, 1476.

Mass spectrometric analysis (FAB), m/z: 558 (M+N)+) free form).

Elemental analysis (%):

for C30H37N3O3Cl22HCI 0.5 H2O

calculated: 56.26 vertical; H - 6,29; N - 6,56; Cl - 22,14;

found: 56,02; H of 6.31; N - 6,55; Cl - 21,94.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

EUR 7.57 (1H, d, J=1.9 Hz), the 7.43 (1H, d, J=8.5 Hz), 7,26 (1H, DD, J=8,5, 1.9 Hz), 4,69 (1H, d, J=14,2 Hz), 3,99-4,22 (2H, m), of 3.73-of 3.85 (1H, m), 3,40-of 3.64 (5H, m), 3,32 (1H, d, J=14,2 Hz), 2,60-2,82 (2H, m), 2,45-of 2.58 (1H, m), 1,88-2,12 (2H, m), 1,50-of 1.85 (3H, m) of 1.45 (9H, s), 1,30-1,50 (2H, m).

Infrared spectrummaxcm-1(KBr): 3447, 2930, 1690, 1640, 1427.

Mass spectrometric analysis (FAB), m/z: 487 (M+H)+).

Example 10(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4-(N-tert-butoxycarbonyl-4 - piperidinylcarbonyl)morpholine-2-yl]ethanol and methanesulfonic acid

The desired compound (216 mg, 93%) was obtained as a white amorphous solid according to the procedure described in example 1(b), using 2-[(2R)-(3,4 - dichlorophenyl)-4-(N-tert-butoxycarbonyl-4 - piperidinylcarbonyl)morpholine-2-yl]ethanol (200 mg, 0.41 mmol).

SPE is), 4,43 (1H, d, J=a 13.9 Hz), 3,43 (1H, d, J=a 13.9 Hz), 3,40-4,30 (8H, m) to 2.94 (3H, s), 2,60-2,82 (2H, m), 2,45-2,60 (1H, m), of 2.10 to 2.35 (2H, m), 1,50-1,80 (2H, m) of 1.46 (9H, s), 1,35 of 1.50 (2H, m).

Infrared spectrummaxcm-1(KBr): 2974, 2932, 1689, 1642, 1175.

Mass spectrometric analysis (FAB), m/z: 565 (M+H)+).

Example 10(s)

1-{ 2-[(2R)-(3,4-Dichlorophenyl)-4-(N-tert - butoxycarbonyl-4-piperidinylcarbonyl)morpholine-2-yl]ethyl}Spiro [((2S)-hydroxy)-indan-1,4'-piperidine]

The desired compound (193 mg, 83%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[(2R)-(3,4-dichlorophenyl)-4- (N-tert-butoxycarbonyl-4-piperidinylcarbonyl)morpholine-2-yl] ethanol and methanesulfonic acid (195 mg, 0.35 mmol) and hydrochloride [((2S)-hydroxy)indan-1,4'-piperidine] (91 mg, 0.38 mmol).

So pl. 105-107oC.

[]23D+59o(=of 0.53, methanol).

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

7,56 (1H, d, J= 1.7 Hz), 7,42 (1H, d, J=8.5 Hz), 7,20-7,30 (5H, m), 3,20-4,75 (8H, m), 2,45-2,90 (6H, m) of 1.46 (9H, s), 1,35-2,40 (15H, m).

Infrared spectrum maxcm-1(KBr): 3448, 2926, 1693, 1644, 1426, 1169.

Mass spectrometric analysis (FAB), m/z 672 (M+N)+).

Elemental analysis (%):

for SS - Expenses 63.81; H? 7.04 Baby Mortality; N - 6,05; Cl - 10,56.

Example 10(d)

The dihydrochloride of 1-{ 2-[(2R)-(3,4-dichlorophenyl) -4-(4-piperidinylcarbonyl)morpholine-2-yl]ethyl}Spiro[((2S) - hydroxy)indan-1,4'-piperidine]

The desired compound (141 mg, 100%) are obtained in the form of a white crystalline substance in accordance with the procedure described in example 9 (d), using 1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(N-tert-butoxycarbonyl-4-piperidinylcarbonyl) morpholine-2-yl] ethyl}-Spiro[((2S)-hydroxy)indan-1,4' -piperidine] (147 mg, 0.22 mmol).

So pl. 216-220oC.

[]23D+45,6o(=of 0.53, methanol).

Spectrum of nuclear magnetic resonance (400 MHz, DMSO-d6) memorial plaques:

the 10.40-11,93 (1H, m), 8,60-9,27 (1H, m), 7,40-of 7.90 (3H, m), 7,05-of 7.25 (4H, m), 4,99 (1H, Ushs), 2,40-4,43 (22H, m), 2,12-to 2.40 (2H, m), 1,75-2,12 (4H, m), 1,48 is 1.75 (3H, m).

Infrared spectrum maxcm-1(KBr): 3381, 2933, 2712, 1636, 1457.

Mass spectrometric analysis (FAB), m/z: 572 (M+H)+) free form).

Elemental analysis (%):

for C31H39N3O3Cl22HCl 1,5 H2O

calculated: 55,36; H - 6,59; N - 6,25; Cl - 21,09;

found: 55,65; H - 6,89; N Is 6.19; Cl - 20,70.

Example 11

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(2-oxo-(4R) -thiazolidinedione)morpholine-2-yl]ethyl}Spiro [((2S)-hydroxy) indan-1,4'-piperno compound (92 mg, 31%) was obtained as a white solid according to the procedure described in example 1(a), using 2-oxo-(4R)-thiazolidinedione acid (107 mg, 0,724 mmol) and 2-[(2R)-(3,4-dichlorophenyl)morpholine-2-yl]-ethanol (200 mg, 0,724 mmol).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,53 (1H, d, J=2.0 Hz), 7,46 (1H, d, J=8,3 Hz), 7,28 (1H, d, J=8,3, 2.0 Hz), to 5.85 (1H, Ushs), 4,53-to 4.81 (2H, m), 3,28-3,91 (9H, m), 1.93 and is 2.10 (2H, m).

Infrared spectrum maxcm-1(KBr): 3251, 1680, 1470, 1375, 1239, 1092.

Mass spectrometric analysis (FAB), m/z: 405 (M+N)+).

Example 11(b)

Ester 2-[(2R)-(3,4-dichlorophenyl)-4-(2-oxo- (4R)-thiazolidinedione)morpholine-2-yl]ethanol and methanesulfonic acid

The desired compound (62 mg, 61%) was obtained as a white solid according to the procedure described in example 1(b), using 2-[(2R)-(3,4-dichlorophenyl)-4-(2-oxo-(4R)- thiazolidinedione)morpholine-2-yl] ethanol (85 mg, 0.21 mmol).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,56 (1H, d, J=1.9 Hz), of 7.48 (1H, d, J=8,3 Hz), 7,27 (1H, DD, J=8,3, 1.9 Hz), 5,78 (1H, Ushs), 4,18-of 4.66 (3H, m), 3,37-of 3.96 (8H, m), 2,96 (3H, s), 2.13 and of-2.32 (2H, m).

Infrared spectrum maxcm-1(KBr): 2934, 1687, 1468, 1352, 1241, 1174, 1095.

Mass spectromet carbonyl)morpholine-2-yl]ethyl}Spiro [((2S) - hydroxy)indan-1,4'-piperidine]

The desired compound (32 mg, 44%) was obtained as a white solid according to the procedure described in example 1(c), using ether 2-[(2R)-(3,4-dichlorophenyl)-4- (2-oxo-(4R)-thiazolidinedione) morpholine-2-yl]ethanol and methanesulfonic acid (60 mg, 0,124 mmol) and hydrochloride [((2S)-hydroxy)Jn-Dan-1,4'-piperidine] (31 mg, 0,130 mmol).

So pl. 155-156oC.

[]24D+41,6o(s = 0,38, methanol).

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

EUR 7.57 (1H, d, J=2.1 Hz), 7,44 (1H, d, J=8,3 Hz), 7,14-7,29 (5H, m), of 5.68 (1H, Ushs), 4,32 was 4.76 (3H, m), 3,22-of 3.85 (8H, m), 2.57 m-and 2.83 (3H, m), 1.41 to 2,43 (11H, m).

Infrared spectrummaxcm-1(KBr): 3400, 2924, 1683, 1472, 1238, 1090, 759.

Mass spectrometric analysis (FAB), m/z: 590 (M+N)+).

Elemental analysis (%):

for C29H33N3O4SCl2H2O

calculated: 57,23; H - 5,80; N - 6,90; Cl - 11,65; S - 5,27;

found: 56,54; H - 5,73; N - 6,53; Cl - 11,48; S - 5,61.

Example 12

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

Example 12(a)

(2R)-(3,4-Dichlorophenyl)-4-(triphenylmethane)butane-1,2-diol (DHQD)2PHAL (85 mg, 0.11 mmol), ferritin mixture added osmium tetroxide (55 μl (0.02 mmol) 0,393 M solution in toluene), and then add triphenylmethyl ester 3- (3,4-dichlorophenyl)-3-butene-1-ol (5,00 g, 10.9 mmol). This mixture was stirred at room temperature for 3 days. After adding to the reaction mixture of sodium sulfite (15 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is then distilled off under reduced pressure. The residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate(50: 1 - 2:1), and you get named in the header of the connection (of 3.56 g, 66%) as white crystals.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

the 7.43 (1H, d, J= 2.0 Hz), 7,19-7,39 (16H, m), 7,03 (1H, DD, J=8,5, 2.0 Hz), 4,69 (1H, s), 3,48-3,66 (2H, m), 3,34 is-3.45 (1H, m) to 2.94 (1H, m), 2.49 USD (1H, m), 2,32 (1H, m), with 1.92 (1H, m).

Infrared spectrummaxcm-1(KBr): 3446, 3059, 2932, 1449, 1062.

Mass spectrometric analysis (FAB), m/z: 513 (M+Na)+).

Example 12(b)

4-(Triphenylmethane)-(2R)-(3,4-dichlorophenyl)-1-[N-(chloroacetyl)-N- (cyclohexylmethyl)amino]-2-butanol

To a solution of (2R)-(3,4-dichlorophenyl)-4-(triphenylmethane) butane-1,2-diol (3.51 g, 7,11 mmol), obtained matney temperature during the night. To the reaction mixture are added water and extracted with a mixture of ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure. The residue is dissolved in acetonitrile (50 ml) and to the solution was added the lithium perchlorate trihydrate (3.42 g, is 21.3 mmol) and cyclohexylethylamine (2,78 ml of 21.3 mmol). The mixture was stirred at 100oC during the night. To the reaction mixture are added ethyl acetate and washed her saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure. Half of the remainder, by weight, is dissolved in methylene chloride (30 ml). To this solution while cooling with ice add triethylamine (2,48 ml, 17.8 mmol) and chlorocatechol (1,42 ml, 17.8 mmol). The mixture was stirred at 0oC for 1 hour. To the reaction mixture methylene chloride, the organic layer washed with water and then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distillation under reduced pressure, the obtained residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate(20:1 - 10:1), and get ) memorial plaques:

6,98-7,62 (18H, m), 4,84 4.99 (total 1H, each Ushs), 3,97-to 4.38 (3H, m), 2,81-and 3.72 (5H, m), 1.93 and-is 2.37 (2H, m), of 1.40 and 1.80 (6H, m), 1,10-1,30 (3H, m), 0,75-1,00 (2H, m).

Infrared spectrummaxcm-1(KBr): 3455, 2926, 2853, 1649, 1469, 1449, 1073, 1029.

Mass spectrometric analysis (FAB), m/z: 664 (M+H)+).

Example 12(s)

Triphenylmethyl ester 2-[4-(cyclohexylmethyl)-(2R)-(3,4-dichlorophenyl)-3-exmortis-2-yl] ethanol

Sodium hydride (127 mg (3,18 mmol) of a 60% suspension in oil) under ice cooling are added to a solution of 4-(triphenylmethane)-(2R) -(3,4-dichlorophenyl)-1-[N-(chloroacetyl)-N-(cyclohexylmethyl)- amino] -2-bugnolo (1,41 g, 2,12 mmol) obtained in example 12(b), in dimethylformamide (15 ml). The mixture is stirred at room temperature overnight. The reaction mixture was poured into ice water and then extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure. The residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate (10:1 to 5:1) and get named in the title compound (1.08 g, 81%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,19-7,35 (17H, m), 6.89 in (1H, DD, J=a 8.4 and 2.2 Hz), 7 (1H, m), 2,13-of 2.24 (2H, m), 1,10-of 1.80 (9H, m), 0,85-1,08 (2H, m).

Infrared spectrummaxcm-1(KBr): 2924, 2852, 1664, 1490, 1449.

Mass spectrometric analysis (FAB), m/z 628 (M+N)+).

Example 12(d)

Ester 2-[4-cyclohexylmethyl)-(2R)-(3,4 - dichlorophenyl)-3-oxo-morpholine-2-yl]ethanol and methanesulfonic acid

A solution of hydrogen chloride in dioxane (4N, 4,1 ml) under ice cooling are added to a solution triphenylmethanol ester 2- [(4-cyclohexylmethyl)-(2R)-(3,4-dichlorophenyl)-3-exmortis - 2-yl] ethanol (1.04 g, of 1.65 mmol) obtained in example 12(C), in ethanol (10 ml). The mixture is stirred at room temperature for 1 hour. To the reaction mixture, water is added and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate (10:1 to 0:1) and obtain an alcohol derivative (440 mg, 69%). The alcohol derivative (418 mg, of 1.08 mmol) dissolved in methylene chloride (10 ml) and to the solution add triethylamine (0,23 ml of 1.62 mmol) and methanesulfonamide ( methylene chloride, the mixture is washed with water and then saturated aqueous sodium chloride and the organic layer is dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate(1:1 - 1:3), and you get named in the title compound (500 mg, 99%).

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

7,49 (1H, d, J=8,4 Hz), 7,46 (1H, d, J=2.1 Hz), 7,20 (1H, DD, J=8,4, and 2.1 Hz), 4,27 (1H, d, J=17,0 Hz) to 4.23 (1H, m), 4,15 (1H, d, J=17,0 Hz), 4,00 (1H, DDD, J=10,5, to 7.3, and 7.3 Hz), of 3.69 (1H, d, J=13,2 Hz), 3,61 (1H, d, J=13,2 Hz), or 3.28 (1H, DD, J=13,6, 7,0 Hz), up 3.22 (1H, DD, J=13,6, 7,7 Hz), of 2.92 (3H, s), is 2.40 (1H, DDD, J=14,6, to 6.4, 6.4 Hz), and 2.26 (1H, DDD, J=14,6, to 7.3, and 7.3 Hz), 1,46-of 1.78 (6H, m), 1,12-of 1.29 (3H, m), 0,88 of-1.04 (2H, m).

Infrared spectrummaxcm-1(net): 2926, 2853, 1657, 1474, 1450, 1356, 1176.

Mass spectrometric analysis (El), m/z: 463 (M+).

Example 12(e)

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

The desired compound (94 mg, 76%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[4- (cyclohexylmethyl)-(2R)Roxie)indan-1,4'-piperidine] (57 mg, 0.24 mmol).

So pl. 84-86oC.

[]23D+35,8o(s = 0,52, methanol).

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

7,47 (1H, d, J=2,l Hz), 7,47 (1H, d, J=8.5 Hz), 7,17 - of 7.24 (5H, m) to 4.41 (1H, DD, J=5,2, 1.8 Hz), 4,24 (1H, d, J=17,0 Hz), 4,12 (1H, d, J=17,0 Hz), of 3.78 (1H, d, J=12.9 Hz), to 3.58 (1H, d, J=12.9 Hz), 3,23-of 3.31 (3H, m), 2,55-2,87 (3H, m), 1,45-2,40 (17H, m), 1,15-of 1.32 (3H, m), 0,91-1,08 (2H, m).

Infrared spectrummaxcm-1(KBr): 3417, 2924, 2851, 1654, 1474, 1450, 1381.

Mass spectrometric analysis (FAB), m/z: 571 (M+N)+).

Elemental analysis (%):

for C32H40N2O3Cl20,3 H2O

calculated: 66,61; H - to 7.09; N - 4,86; Cl - 12,29;

found: C - 66,89; H - 6,85; N Of 4.83; Cl - 11,83.

Example 13

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

Example 13(a)

Triphenylmethyl ester 2-[3-(cyclohexylmethyl)-(5R)-(3,4 - dichlorophenyl)-2-oxoacridine-5-yl]ethanol

To a solution of (2R)-(3,4-dichlorophenyl)-4- (triphenylmethane)butane-1,2-diol (3.51 g, 7,11 mmol) obtained in example 12(a), in pyridine (17 ml) is added p-toluensulfonate (2,03 g of 10.7 mmol). The mixture is stirred at room temperature overnight. To the reaction mixture in the Ute solvent under reduced pressure. The residue is dissolved in acetonitrile (50 ml) and to the solution was added the lithium perchlorate trihydrate (3.42 g, is 21.3 mmol) and cyclohexylethylamine (2,78 ml of 21.3 mmol). The mixture was stirred at 100oC during the night. To the reaction mixture are added ethyl acetate and washed her saturated aqueous sodium chloride, and the solvent is distilled off under reduced pressure. Half of the remainder, by weight, is dissolved in methylene chloride (30 ml) and to the solution under cooling with ice add triethylamine (2,48 ml, 17.8 mmol) and di-tert-BUTYLCARBAMATE (3,88 mg, 17.8 mmol). The mixture is stirred at room temperature overnight. To the reaction mixture methylene chloride, the mixture is washed with water and the organic layer is dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue is dissolved in dimethylformamide (30 ml). To the solution while cooling with ice, add sodium hydride (213 mg (of 5.34 mmol) of a 60% suspension in oil). The mixture is stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is purified of posledstviya (20:1 - 5:1) and get named in the title compound (1,76 g, 81%).

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

7,21-7,37 (17H, m),? 7.04 baby mortality (1H, DD, J=8,3, 2.3 Hz), 3,90 (1H, d, J=8,8 Hz), 3,53 (1H, d, J=8,8 Hz) and 3.31 (1H, DDD, J=10,9, to 5.4, 5.4 Hz), of 3.07 (1H, DD, J=13,9, 7,3 Hz), 2.93 which is 3.00 (2H, m) to 2.29 (1H, DDD, J=14,0, 7,0, 7,0 Hz) to 2.15 (1H, DDD, J=14,0, to 5.4, 5.4 Hz), 1,44 to 1.76 (6H, m), 1,07-1,22 (3H, m), 0,84 is 0.99 (2H, m).

Infrared spectrummaxcm-1(KBr): 3059, 2924, 2852, 1759, 1449, 1265, 1064.

Mass spectrometric analysis (FAB), m/z: 612 (M-H)+).

Example 13(b)

Ester 2-[3-(cyclohexylmethyl)-(5R)-(3,4 - dichlorophenyl)-2-oxoacridine-5-yl]ethanol and methanesulfonic acid

Get alcohol derivative (930 mg, 91%) according to the procedure described in example 12(d), using triphenylmethanol ester 2-[3-cyclohexylmethyl)- (5R)-(3,4-dichlorophenyl)-2-oxoacridine-5-yl]ethanol (1,69 g, a 2.75 mmol) and a solution of hydrogen chloride in dioxane (4N, 6.9 ml). The alcohol derivative (880 mg, 2.36 mmol) was dissolved in methylene chloride (18 ml) and to the solution add triethylamine (0,50 ml, 3,55 mmol) and methanesulfonamide (0,22 ml, 2,84 mmol). The mixture is stirred at room temperature overnight. To the reaction mixture are added methylene chloride and the mixture is washed with water and then saturated water is ri reduced pressure. The residue is purified by flash chromatography on a column of silica gel using as eluent a mixture of n-hexane and ethyl acetate(4: 1 - 1:1), and you get named in the title compound (1,03 g, 97%).

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

7,52 (1H, d, J=8,4 Hz), 7,51 (1H, d, J=2.3 Hz), 7,22 (1H, DD, J=8,4, and 2.3 Hz), 4,33 (1H, DDD, J=10,7, to 7.6 and 7.6 Hz), 4,10 (1H, DDD, J=10,7, to 6.9, 6.9 Hz), with 3.79 (1H, d, J=8,9 Hz) and 3.59 (1H, d, J=8,9 Hz), of 3.13 (1H, DD, J=13,9, 7,3 Hz), 3,05 (1H, DD, J= 13,9, 7,1 Hz) to 2.94 (3H, s), 2,48-of 2.54 (2H, m), 1,48-of 1.78 (6H, m), 1,12-of 1.28 (3H, m), 0,86-1,02 (2H, m).

Infrared spectrummaxcm-1(CHCl3): 2927, 2856, 1757, 1365, 1264, 1176.

Mass spectrometric analysis (FAB), m/z: 450 (M+N)+).

Example 13(C)

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

The desired compound (85 mg, 69%) was obtained as a white crystalline substance in accordance with the procedure described in example 1(C), using ether 2-[3- (cyclohexylmethyl)-(5R)-(3,4-dichlorophenyl)-3-oxoacridine-5 - yl] ethanol and methanesulfonic acid (100 mg, 0.22 mmol) and hydrochloride [((2S)-hydroxy)indan-1,4'-piperidine] (58 mg, 0.24 mmol).

So pl. 67-69oC.

[]24D-2,2o(C = 0,50, the J=8,4 Hz), 7,16-of 7.23 (5H, m), 4,43 (1H, DD, J= 5,4, 2.0 Hz), 3,80 (1H, d, J=8,8 Hz), of 3.56 (1H, d, J=8,8 Hz), or 3.28 (1H, DD, J=16,6, a 5.4 Hz), 3,14 (1H, DD, J=13,9, 7,4 Hz), to 3.02 (1H, DD, J=13,9 that 6.8 Hz), 2,82 (1H, DD, J=16,6, 2.0 Hz), 2,15-2,90 (8H, m), 1,47 is 2.10 (11H, m), 1,10-1,30 (3H, m), 0,85-1,02 (2H, m).

Infrared spectrummaxcm-1(KBr): 3437, 2924, 2852, 1752, 1475, 1449, 1268.

Mass spectrometric analysis (FAB), m/z: 557 (M+H)+).

Elemental analysis (%):

for C31H38N2O3Cl20.5 H2O

calculated: C - 65,72; H - 6,94; N - 4,94; Cl - 12,51;

found: C - 65,75; H - 6,70; N - 5,20; Cl - 12,72.

The compounds listed below in table. 1, can be obtained by methods similar to those described in the examples above.

< / BR>
In table. 1, each substituent (listed in table as "Zam") represents one of the following groups (see table. A).

Among the above compounds, preferred are compounds given as examples of the compounds under NN 1-180, 631-1230, 1681-2100, 3151-3330 and 3781-4200. More preferred are compounds given as examples of the compounds under NN 1051-1230, 1681-2100 and 3871-3874. Most preferred are compounds given as examples of the compounds under NN 1051-1054, 1081-1084, 1111-1114, 1141-1144, 1171-1174, 1201-1204, 1771-1774, 1921-1924, 1951�full example

Reference example 1

2-[(2R)-(3,4-Dichlorophenyl) morpholine-2-yl]ethanol

A solution of hydrogen chloride in dioxane (4 N, 500 ml) containing tert-butyldimethylsilyloxy ester 2-[4-tert-butoxycarbonyl-(2R)-(3,4-dichlorophenyl)morpholine-2-yl] ethanol (38,6 g, to 78.7 mmol), stirred at 60oC for 3 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in 1 N hydrochloric acid and the solution washed with diethyl ether. The aqueous layer was alkalinized 2 N aqueous solution of sodium hydroxide and then extracted with methylene chloride. After washing the organic layer with saturated aqueous sodium chloride solution, it is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixture of n-hexane (210 ml) and ethyl acetate (175 ml) and receive named the title compound (18.0 g, 83%) as a white crystalline substance.

So pl. 90-91oC.

[]24D+19,2 (or = 0.51, methanol).

Spectrum of nuclear magnetic resonance

Infrared spectrummaxcm-1(KBr): 3261, 3098, 2940, 1471, 1085, 1047.

Mass spectrometric analysis (El), m/z: 275 (M+).

Examples of compositions

[Example compositions 1] Powders

For g in mixer.

[Example composition 2] Granules

Granules can be obtained by mixing the compound of example 2 (5 g), lactose (865 g) and hydroxypropylcellulose with a low degree of substitution (100 g), added to a mixture of 300 g of a 10% aqueous solution of hydroxypropylcellulose, mixing, granulating the mixed mass using an extrusion granulator, and drying the granulated product.

[Example of composition 3] Capsules

Capsules can be 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 and subsequent filling mixture capsules N 3 portions at 180 mg.

[Example of composition 4] Pill

Tablets can be 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 tabletting the resulting mixture using a tablet press machines.

Examples test

[Example test 1] Test linking NK1receptor

(a) Receiving untreated pulmonary membrane fractions

Get the crude membrane proformas anesthesia and immediately remove the tissue of the pulmonary Airways.

The extracted light perfusion buffer (1) (50 mm Tris-HCl, pH 7,4), finely chopped in this buffer and then homogenized in buffer (2) [buffer (1) containing 120 mm sodium chloride and 5 mm potassium chloride] using a homogenizer transmitter station.

Tissue mass removed from the homogenate by filtration through a nylon sieve (50 μm) and the supernatant centrifuged (30000 x g, 30 minutes, 4oC).

The precipitate resuspended in ice buffer (3) [buffer (1), containing 10 mm etc and 300 mm potassium chloride], leave to stand at 4oC for 60 minutes and then washed twice by centrifugation (30000 x g, 15 min, 4oC).

The crude membrane fraction stored until use at -80oC.

(b) Testing the binding of receptors

To a mixed solution (250 µl) of the test compounds and3H]-substance P (final concentration 1 nm) (50 mm Tris-HCI, pH of 7.4, 6 mm manganese chloride, 800 μg/ml BSA, 8 μg/ml of hemostatis, 8 µg/ml leupeptin, 80 μg/ml bacitracin, 20 μg/ml of phosphoramidon) add a solution of the crude pulmonary membrane fractions (250 μl), and then carry out incubation at room temperature for 30 minutes.

After completion of the reaction membrane is Oh filtration (Brandel Co.).

The glass filter is used after pre-treatment with 0.1% solution of polyethylenimine for about 4 hours, in order to inhibit non-specific binding as possible.

Retrieved on the filter membrane ingredient is transferred into a plastic miniplate containing pico flow (4 ml), and measure the radioactivity using a liquid scintillation counter (Beckman Co., LSC3500) to determine the concentration of the medicinal product for 50% binding (IC50).

The value of the IC50compounds of the present invention is 1000 ng/ml or higher.

[Example tests 2] Test linking NK2receptor

(a) obtaining a crude membrane fraction of ileum

Get the crude membrane fraction from the ileum of male Hartley Guinea pigs. Namely, Guinea pigs shed blood from the abdominal cavity under chloroform anesthesia and immediately remove the terminal ileum.

After scraping content, secrets and epithelium using slides, extracted ileum finely pulverized in the buffer (1) (50 mm Tris-HCI, pH of 7.4) and then homogenized in buffer (2) [buffer (1), the soda is piss removed from the homogenate by filtration through a nylon sieve (50 μm) and the supernatant centrifuged (30000 x g, 30 minutes, 4oC).

The precipitate resuspended in ice buffer (3) [buffer (1), containing 10 mm etc and 300 mm potassium chloride], leave to stand at 4oC for 60 minutes and then washed twice by centrifugation (30000 x g, 15 min, 4oC).

The crude membrane fraction stored until use at - 80oC.

(b) Testing the binding of receptors

To a mixed solution (250 µl) of the test compounds and3H]-SR-48968 (Amasham Co. , final concentration 1 nm) (50 mm Tris-HCI, pH of 7.4, 6 mm manganese chloride, 800 μg/ml BSA, 8 μg/ml of hemostatis, 8 µg/ml leupeptin, 80 μg/ml bacitracin, 20 μg/ml of phosphoramidon) add a solution of the crude membrane fraction of the ileum (250 μl) and then carry out incubation at room temperature for 30 minutes.

After completion of the reaction membrane ingredient extract on glass fiber filter GF/B (Whatman Co.) using automatic filtration (Brandel Co.).

The glass filter is used after pre-treatment with a 10% solution of polyethylenimine for about 4 hours, in order to inhibit non-specific binding as possible.

Eraut radioactivity using a liquid scintillation counter (Beckman Co., LSC3500) to determine the concentration of the medicinal product for 50% binding (IC50).

As can be seen from the table. 2, the compounds of the present invention exhibit strong binding activity against NK2-receptors.

Industrial applicability

Compounds of the present invention have excellent NK2-selective antagonistic action and low toxicity, and thus, they are useful as medicines. For example, such compounds are useful as preventive and therapeutic agents in the case of diseases of the Central nervous system, such as fear, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, AIDS, senile dementia of Alzheimer's, Alzheimer's, down syndrome, demyelinizing disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma and cough; inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, fibrosis, revisit, degenerative arthritis and rheumatoid arteriosis plants; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, spring catarrh, destruction gematologicheskogo barrier, caused by various inflammatory diseases of the eye, increased eye pressure, and cramps; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis; addiction, such as alcohol dependence; somatic diseases caused by stress; reflex sympathetic dystrophy such as shoulder syndrome; dysthymia; unwanted immune responses such as transplant rejection, diseases associated with immunostimulating, such as systemic lupus erythematosus or immunosuppression; diseases of the digestive system, such as diseases caused by disorders of the nervous regulation of bodies, colitis, ulcerative colitis and Crohn's disease; vomiting, such as vomiting, caused by the harmful effects of x-ray radiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative disorders, gastro-intestinal occlusion, impaired gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased the level of disease of the bladder, such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleroderma or infection Fasciola hepatica; diseases caused by disorders of blood flow due to vasodilation or vasoconstriction, such as angina, migraine and Raynaud's disease; and pain when pain nociceptive reception, such as migraine, headache, dental pain; and sleep apnea. T Those

1. Acylated heteroalicyclic derivative of the formula (I)

< / BR>
where R1is a (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen atoms, oxygen and sulfur, which may be optionally substituted by oxopropoxy;

R2- aryl group as defined hereinafter, which optionally may be substituted by 1-3 halogen atoms;

A - methylene group or carbonyl group;

In simple communication;

D is an oxygen atom or a sulfur atom;

G - (C1-C4)alkylenes group

L is a group of the formula-C(R4)(R5)- where

R4a hydrogen atom, aryl group, as defined hereinafter, 5-8-membered heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen atoms, CI represent an amino group, which optionally may be substituted by 1 or 2 alkyl groups containing 1 to 6 carbon atoms), or R4and R5together with the carbon atom to which they are attached, form a (C5-C8)cycloalkane ring or 5-8-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen atoms, oxygen or sulfur, each of these cycloalkanes or heterocyclic rings optionally may be replaced by oxopropoxy or hydroxy-group, and these rings may be optionally fused with aryl ring defined below);

Z is two hydrogen atoms or an oxygen atom;

n=0 or 1;

or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate; aryl groups mentioned in the definition of the substituents R2, R4and R5represents an aromatic hydrocarbon group.

2. Connection on p. 1, where R1is a (C4-C6)cycloalkyl group, 5 - or 6-membered saturated heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, substituted exography, or its pharmaceutically acceptable salt, ester, fourth is)cycloalkyl group, 5 - or 6-membered saturated heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, substituted exography, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

4. The compound according to any one of paragraphs.1-3, where R2represents an aryl group substituted by 1-3 halogen atoms, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

5. The compound according to any one of paragraphs.1-4, where a represents a carbonyl group and Z is two hydrogen atoms, or a represents a methylene group, and Z is an oxygen atom, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

6. The compound according to any one of paragraphs.1-5, where a represents a carbonyl group, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

7. The compound according to any one of paragraphs.1-6, where D is an oxygen atom, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

8. The compound according to any one of paragraphs.1-7, where G is a (C2-C3)alkylenes group, or its pharmaceutically acceptable salt, complex epipo formula-C(R4)(R5), or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

10. The compound according to any one of paragraphs.1-9, where R4and R5together with the carbon atom to which they are attached, form a (C5-C6)cycloalkane ring or 5 - or 6-membered saturated heterocyclic ring (each of these cycloalkanes and saturated heterocyclic rings may be optionally substituted by hydroxy or exography, and these rings may be optionally fused with aryl ring), or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

11. The compound according to any one of paragraphs.1-9, where R4and R5together with the carbon atom to which they are attached, form a cyclopentane ring, tetrahydrothiophene ring, tetrahydronaphtalene ring, tetrahydronaphtalene ring or piperidine ring (each of these rings may be optionally substituted by hydroxy or exography, and these rings may be optionally fused with aryl ring), or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

13. The compound according to any one of paragraphs.1-12, where n=1, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

14. Connection on p. 1, where R1is a (C3-C6)cycloalkyl group, 5 - or 6-membered saturated heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, substituted oxopropoxy; R2- aryl group, or aryl group substituted by 1 to 3 halogen atoms; And a is a carbonyl group; a simple bond; D is an oxygen atom; G is - (C1-C4)alkylenes group, L is a group of the formula-C(R4)(R5)-, where R4and R5together with the carbon atom to which they are attached, form a (C5-C8)cycloalkane ring or 5-8-membered saturated heterocyclic ring (each of these cycloalkanes or saturated heterocyclic rings may also be optionally substituted by hydroxy or exography and these rings may be optionally fused with aryl ring); Z represents two hydrogen atom and n=0 or 1, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

15. Sennou heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, replaced by oxopropoxy; R2- aryl group, substituted by 1 to 3 halogen atoms; And a is a carbonyl group; a simple bond; D is an oxygen atom; G is - (C2-C3)alkylenes group, L group of formula-C(R4)(R5)-, where R4and R5together with the carbon atom to which they are attached, form a (C5-C6)cycloalkane ring or 5 - or 6-membered saturated heterocyclic ring (each of these cycloalkanes or heterocyclic rings may be optionally substituted by hydroxy or exography and these rings may also be optionally fused with aryl ring); Z is two hydrogen atoms and n=0 or 1, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

16. Connection on p. 1, where R1is a (C3-C6)cycloalkyl group, 5 - or 6-membered saturated heterocyclic group or a 5 - or 6-membered saturated heterocyclic group, substituted oxopropoxy; R2- aryl group, substituted by 1 to 3 halogen atoms; And a is a carbonyl group; a simple bond; D is an oxygen atom; G is - (C2-C3)alkylenes group, L is a group of formula C(R4)(R5)-, where R4and Rthe new ring, tetrahydronaphtalene ring, tetrahydronaphtalene ring or piperidine ring (each of these rings may be optionally substituted by hydroxy or exography and these rings may be optionally fused with aryl ring), Z represents two hydrogen atom and n=0 or 1, or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

17. Connection on p. 1, where the compound is selected from the group comprising the following compounds and their pharmaceutically acceptable salts, esters, Quaternary amines, amides or hydrates:

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(cyclopropanecarbonyl)-morpholine-2-yl]ethyl} Spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclobutanecarbonyl)-morpholine-2-yl]ethyl} Spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(cyclopentanecarbonyl)-morpholine-2-yl]ethyl} Spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

1-{2-[(2R)-(3,4-dichlorophenyl)-4-(cyclohexanecarbonyl)-morpholine-2-yl]ethyl} Spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide,

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

1-{2-[(2R)-(3,4-Dail)-4-(cyclopentanecarbonyl)-morpholine-2-yl]ethyl} -4-(2-pyridyl)piperidine-4-carboxamide.

18. The compound according to any one of paragraphs.1-17 or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate as an active ingredient of drugs with selective antagonistic activity against NK2-receptors.

19. Drug with selective antagonistic activity against NK2receptors containing as active ingredient a compound according to any one of paragraphs.1-17 or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate.

20. The method of prevention or treatment of a disease that is prevented or treated when introducing means having a selective antagonistic activity against NK2receptors, where the specified agent is a compound or its pharmaceutically acceptable salt, ester, Quaternary amine, amide or hydrate according to any one of paragraphs.1-17.

 

Same patents:

The invention relates to new derivatives pyridonecarboxylic acid, antitumor means containing them as effective ingredients, and to methods of producing new derivatives pyridonecarboxylic acid and t

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

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 nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity

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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
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