Derivatives phenylalkylamines acid and pharmaceutical compositions on their basis

 

(57) Abstract:

Describes the new derivatives phenylalkylamines acid of the formula (I), where R1represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, R2is alkylenes group with a straight or branched chain, having from 2 to 6 carbon atoms, R3represents a hydrogen atom, Z represents alkylenes group with a straight or branched chain, having from 1 to 6 carbon atoms, W represents (i) an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) amino group, (v) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) dialkylamino group with straight or branched chain, alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vii) N-alkyl-N-arylamino group having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part, with Ethical , specified below in the aryl part, (ix) aristeo group having from 6 to 10 carbon atoms, (x), arylamino group having from 6 to 10 carbon atoms, (xi) Uralkaliy group having from 7 to 12 carbon atoms or (xii) 1-pyrrolidinyl group, X represents an aryl group having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, and the Deputy is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (i) halogenated alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, (iii) halogen atom, (iv) aryl group having from 6 to 10 carbon atoms (the aryl part can be substituted alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, or a halogen atom) or (v) pyridyl, and Y represents an oxygen atom, pharmacologically acceptable salts or their pharmaceutically acceptable esters. The above new derivatives phenylalkylamines acid have excellent activity in lowering blood sugar levels in the blood, as well as their pharmacologically acceptable salts or pharmaceutically acceptable esters. Also described composition, including oksanaeroshina drug for the treatment or prevention of hyperglycemia.

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2 C. and 28 C.p. f-crystals, 70 PL.

The invention relates to new derivatives phenylalkylamines acid, having superior activity in lowering blood sugar levels in the blood, and their pharmacologically acceptable salts or pharmaceutically acceptable esters, compositions comprising the specified connection as the active ingredient for the treatment or prevention of hyperglycemia; their use as a medicinal product for treatment or prevention of hyperglycemia; or the treatment or prevention of hyperglycemia, in which a warm-blooded animal is administered a pharmacologically effective amount of the compounds.

Insulin and connections sulfonylureas, such as tributed and Glipizide (Glipizide), used as therapeutic agents for the treatment of diabetes and hyperglycemia, and recently reported on the use of derivatives phenylalkylamines acid for the treatment of insulin-independent diabetes. These compounds include, for example,

(1-1) 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl]-2-(acetylthio)propionic acid and its esters, 2-methoxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] propionic acid, 3-[[4-(4-benzyloxyphenyl) is ruwayda in published PCT application N WO 91/19702 (Japanese PCT application (Kokai) N Hei 5 - 507920).

(1-2) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2-((N-ethyl-N-phenyl)amino)propionic acid and its esters, etc. are disclosed in published PCT application N WO 94/29285.

(1-3) 3-[4-[2-[2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2-paraproteinemia acid and its esters, etc. are disclosed in published PCT application N WO 94/29302.

(1-4) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy] phenyl] -2-(propyl) propionic acid and its esters, 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2- (3-phenylpropyl) propionic acid and its esters, 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy]phenyl]-2- (3-methylbutyl) propionic acid and its esters, etc. are disclosed in published PCT application N WO 95/03288.

(1-5) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy] phenyl] -2-(2,2,2-triptoreline) propionic acid and its esters, etc. are disclosed in published PCT application N WO 96/04260.

In addition, recently it was reported about the use of a large number of derivatives of thiazolidine as therapeutic agents for the treatment of insulin-independent diabetes. These compounds include, for example,, (2-1) 5-[4-[(6- hydroxy-2,5,7,8-tetramethylchroman-2-yl) methoxy] benzyl] -2,4-thiazolidinedione (International Non (2-2) 5-[[4-[2-(5-ethylpyridine-2-yl)ethoxy]phenyl]methyl]-2, 4-thiazolidinedione (INN: Pioglitazone) is disclosed in EP 8203A, USP 4287200, USP 4340605, USP 4438141, USP 4444779, USP 4725610 and Japanese patent publications (Kakoki) N Hei 5-66956 and sho62 - 42903.

(2-3) 5-[[3,4-dihydro-2-(phenylmethyl)-2H-benzopyran-6 - yl] methyl]-2,4-thiazolidinedione (INN: Englitazone) disclosed in USP 4703052 and Japanese patent publication (Kokoku) N Hei 5-86953.

(2-4) 5-[[4-[2-[N-methyl-N-(pyridin-2-yl)amino] ethoxy] phenyl]methyl]-2,4-thiazolidinedione (Code Designation: BRL-49653) disclosed in EP 306228A, USP 5002953, USP 5194443, USP 5232925, USP 5260445 and Japanese patent application (Kokoku) N Hei 1-131169.

The relationship between these compounds and (treatment) of diseases described in the following references, in relation to, for example, derivatives of thiazolidine.

Steps derivatives of thiazolidine on hyperglycemia described in (1) Diabetes. , 32 (9), 804-810 (1983); (2) Diabetes., 37 (II), 1549-1558 (1988); (3) Prog. Clin. Biol. Res., 265, 177-192 (1988); (4) Metabolism., 37 (3), 276-280 (1988); (5) Arzneim.- Forsch., 40 (1), 37-42 (1990); (6) Arzneim.-Forsch. , 40(2, Pt. 1), 156-162 (1990); and (7) Arzneim.-Forsch., 40 (3), 263-267 (1990).

About actions derivatives of thiazolidine on hyperglycemia reported in (1) Diabetes. , 40 (12), 1669-1674 (1991); (2) Am. J. Physiol., 267(1, Pt. 1), E95-E101 (1994); and Diabetes., 4.3 (10), 1203-1210 (1994).

About actions derivatives of thiazolidine on degraded (weakened) glucose tolerance and insulin resistance reported tx2">

About actions derivatives of thiazolidine on hypertension reported in (1) Metabolism. , 42 (1), 75-80 (1993); (2) Am. J. Physiol 4., 265(4, Pt. 2), R726-R732 (1993); and (3) Diabetes., 43(2), 294-211 (1994).

About actions derivatives of thiazolidine on cachexia reported in (1) Endocrinology. , 135 (5), 2279-2282 (1994); and (2) Endocrinology., 136(4), 1474-1481 (1995).

About actions derivatives of thiazolidine on nephropathy reported in (1) Diabetes. , 38 (Special Edition) (1995) (38th Annual Technical Meeting of the Japan Diabetes Society, Program Proceedings, 38th Meeting of the Japan Diabetes Society, 1995).

About actions derivatives of thiazolidine disease coronary - artery reported in (1) Am. J. Physiol., 265(4, Pt. 21, R726-R732 (1993); and (2) Hypertension., 24 (2), 170-175 (1994).

About actions derivatives of thiazolidine on arteriosclerosis reported in (1) Am. J. Physiol., 265(4, Pt. 2), R726-R732 (1993).

In addition, recently (1) N. Engl. J. Med., 331 (18), 1226-1227 (1994) it was reported that normal individuals with insulin resistance, are not accompanied by impaired glucose tolerance, have a high risk of diabetes (referred to as "insulinorezistentne, not accompanied by impaired glucose tolerance ("insulin-resistant non-IGT: NGT")). Assume that drugs that can improve insulin resistance, could be useful as a prophylactic in addition to the LASS="ptx2">

However, these compounds differ from the compounds of the present invention in that they do not have oximes communication in their side chain, while the compounds of this invention have oximo communication in its side chain.

In addition, compounds that have oximo communication in its side chain and is insulin-independent medicines for diabetes, acting in the same way (connections), described above, were disclosed after the date of the application the priority of this application. These compounds include, for example, aromatic oximino derivatives, such as

(4-1) 5-[4-[2-[(4-hydroxyine-1-yl)aminoxy]ethoxy] benzyl]-2,4-thiazolidinedione, 5-[4-[2-[(2,3-dihydro-6 - phenylbenzophenone-3-yl)aminoxy] ethoxy] benzyl] -2,4-thiazolidinedione, 5-[4-[2-[(5-Clorinda-1-yl)aminoxy] ethoxy] benzyl] -2,4-thiazolidinedione, 5-[4-[2-[(5-methylinden-1-yl)aminoxy] ethoxy] benzyl]-2, 4-thiazolidinedione, 5-[4-[2-[(5,6-methylenedioxybenzene-1-yl)aminoxy] ethoxy] benzyl] -2,4-thiazolidinedione, 5-[4-[2-[(5-phenylindol-1 - yl)aminoxy] ethoxy] benzyl] -2,4-thiazolidinedione, and they are disclosed in published PCT application N WO 96/38427 (publication date: December 5, 1996) and Japanese patent application (Kokai) N Hei 9-48770 (publication date: February 18, 1997);

Aksinya p is 2-pyridyl)phenyl] ethylidene] amino] oxy]ethoxy]benzyl]thiazolidin-2,4-dione; 5-[4-[2-[[[1-(2- phenyl-5-pyridyl)ethylidene]amino]oxy]ethoxy]benzyl] thiazolidin-2,4-dione; 5-[4-[2-[[[1-(2-methoxy-5-pyridyl) ethylidene]amino]oxy]ethoxy]benzyl] thiazolidin-2,4-dione are disclosed in EP 708098 (publication date: April 24, 1996) and patent application of Japan (Kokai) N Hei 9-48779 (publication date: February 18, 1997).

The invention

The inventors of the present invention, a study was conducted derivatives phenylalkylamines acid having an extremely strong current activity and extremely high safety, and it was found that these derivatives improve (reduce) hyperglycemia, etc. and, in addition, have an inhibitory effect on alderetes.

Namely, this invention relates to new derivatives phenylalkylamines acid of the formula (I) having excellent activity in lowering blood sugar, and their pharmacologically acceptable salts or pharmaceutically acceptable esters, compositions comprising a compound of formula (I) as an active ingredient for the treatment or prevention of hyperglycemia; their use as pharmaceuticals for the treatment or prevention of hyperglycemia, or method of treatment or prevention of hyperglycemia, to

Derivatives phenylalkylamines acids of this invention have the formula (I):

< / BR>
where R1represents a hydrogen atom or alkyl group with straight or branched chain, having from 1 to 6 carbon atoms,

R2is alkylenes group with a straight or branched chain, having from 2 to 6 carbon atoms,

R3represents (i) hydrogen atom, (ii) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (iii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) halogen atom, (vi) nitro group, (vii) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (viii) aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, or (ix) Uralkaliy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part,

Z represents a single bond or alkilinity group with a straight or branched chain, having from 1 to 6 carbon atoms, (ii) hydroxyl group, (iii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) amino group, (vi) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (vii) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (viii) N-alkyl-N-arylamino group having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, (ix) aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, (x) aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xi) aristeo group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xii) arylamino group having from 6 to 10 carbon atoms, which may have the atoms, which may have from 1 to 3 substituents mentioned below in the aryl part, (xiv) aralkylated group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xv) Uralkali group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xvi) aralkylamines group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents , mentioned below in the aryl part, (xvii) 1 - pyrrolidinyl group, (xviii) 1-pyrrolidinyloxy group, (xix) 1 - imidazolidinyl group, (xx) piperidino group or (xxi) morpholino group

X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, or (5 to 10)-membered monocyclic or bicyclic heteroaromatic group which has from 1 to 3 substituents mentioned below, containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur,

The Deputy is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl group with straight or branched chain, having from 1 to 4 carbon from 1 to 4 carbon atoms, (v) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vii) aralkylated group having from 7 to 12 carbon atoms, (viii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (ix) alkylsulfonyl group, straight or branched chain, having from 1 to 4 carbon atoms, (x) halogen atom, (xi) nitro group, (xii) dialkylamino group with straight or branched chain, alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (xiii) Uralkaliy group having from 7 to 12 carbon atoms, (xiv) aryl group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen, alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xv) aryloxy group having from 6 to 10 carbon atoms (ar is halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen, alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvi) aristeo group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen, alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvii) arylsulfonyl group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen, alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xviii) arylsulfonyl group having from 6 to 10 carbon atoms (ar, galogenirovannami the alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen, alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, and the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), (xix) (5-10) membered monocyclic or bicyclic heteroaromatic group containing from 1 to 4 heteroatoms, selected from the group consisting of atoms of oxygen, nitrogen or sulfur, (xx) (5-10) membered monocyclic or bicyclic heteroaromatic hydroxy group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, (xxi) (5-10) membered monocyclic or bicyclic heteroaromatic tigroup containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, (xxii) (5-10) membered monocyclic or bicyclic heteroaromatic sulfonyl group containing from 1 to 4 heteroatoms, selected from the group consisting of atoms of oxygen, nitrogen and sulfur, or (xxiii) (5-10) membered monocyclic or a bicyclic heteroa is oxygen, nitrogen and sulfur (the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), and

Y represents an oxygen atom, a sulfur atom or a group of the formula: >N-R4(where R4represents a hydrogen atom, alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, or an aliphatic acyl group with a straight or branched chain or an aromatic acyl group having from 1 to 8 carbon atoms).

In the case where R1, R3, W, and R4represent an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, the alkyl group includes, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1-ethylpropyl, hexeline, 1 - methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl or 1,2,2-Tr carbon atoms, more preferably methyl, ethyl, sawn, ISO-propyl, boutelou or isobutylene group. R1, R3and R4even more preferably represent alkyl straight or branched chain, having from 1 to 3 carbon atoms, most preferably alkyl having one or two carbon atom. W even more preferably is sawn or boutelou group, most preferably boutelou group.

In the case where R2is alkylenes group with a straight or branched chain, having from 2 to 6 carbon atoms, Allenova group includes, for example, ethylene, methylethanol, ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, trimethylene, 1-methyltrienolone, 1-ethyltrimethylammonium, 2-methyltrienolone, 1,1-dimethyltrimethylene, tetramethylene, pentamethylene or hexamethylene group, preferably alkylenes group with a straight or branched chain, having from 2 to 5 carbon atoms, more preferably alkylenes group with a straight or branched chain, having from 2 to 4 carbon atoms, even more preferably ethylene, melatoninbuy or trimethylene group, most predpochiol chain having from 1 to 6 carbon atoms, Allenova group includes, for example, methylene, ethylene, methylethanol, ethylethylene, 1,1 - dimethylethylene, 1,2-dimethylethylene, trimethylene, 1 - methyltrienolone, 1-ethyltrimethylammonium 2-methyltrienolone, 1,1-dimethyldi-methylene, tetramethylene, pentamethylene or hexa-methylene group, preferably alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms (e.g. methylene, ethylene, metilidinovy, ethylethylene, trimethylene, 1-methyltrienolone or 2 - methyltrienolone group), more preferably alkylenes group having one or two carbon atoms, most preferably a methylene group.

In the case where R3and W represent alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy or isobutoxy group.3preferably represents an alkoxy group having one or two carbon atoms, most preferably methoxy group, and W preferably represents an alkoxy group having from 1 to 3 upcity group with a straight or branched chain, having from 1 to 4 carbon atoms, alkylthio group includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio or isobutyric group. R3preferably represents alkylthio group having one or two carbon atoms, most preferably a methylthio group, and W is preferably alkylthio group having from 1 to 3 carbon atoms, most preferably a methylthio group.

In the case where R3represents a halogen atom, the halogen atom includes fluorine atom, chlorine, bromine or iodine, preferably fluorine atom, chlorine or bromine, more preferably fluorine atom or chlorine.

In the case where W represents monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, monoalkylamines group includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino or isobutylamino group, preferably monoarylamino group with a straight or branched chain, having from 1 to 3 carbon atoms, most preferably acylamino group.

In the case where R3and W represent dialkylamino group with straight or branched zadnych atoms, dialkylamino group includes, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-methyl-N-ethylamino or N-ethyl-N-isopropylamino group, preferably dimethylamino or diethylamino group, most preferably diethylamino group.

In the case where R3and W represent an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below unsubstituted aryl group includes, for example, phenyl or naftalina group, preferably phenyl group. The substituted aryl group includes, for example, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-trifloromethyl, 4-hydroxyphenyl, 4-acetoxyphenyl, 4-metoksifenilny, 3,4-methylenedioxyphenyl, 4-benzyloxyphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-florfenicol, 4-chloraniline, 4-nitroaniline, 4-dimethylaminophenyl, 4-benzylphenol, 4-biphenylyl, 4-phenoxyphenyl, 4-finitively, 4-phenolsulfonephthalein, 4-vinylsulfonylacetamido, 4-(2-pyridyl)phenyl, 4-(2-pyridyloxy)phenyl, 4-(2-pyridylthio)phenyl or 4-(2-pyridylsulfonyl the ing, 4-methylthiophenyl or 4-chloraniline group.

In the case where R3and W are aracelio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below, unsubstituted kalkilya group represents a group in which an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, substituted by the above aryl group and includes, for example, benzyl, fenetylline, 3-phenylpropyl, 4 - phenylbutyl, 1-naphthylmethyl or 2-naphthylmethyl group. R3preferably represents benzyl or fenetylline group, most preferably a benzyl group, and W is preferably benzyl, fenetylline, 3 - phenylpropyl or 4-phenylbutyl group, most preferably fenetylline or 3-phenylpropyl group. Substituted kalkilya group includes, for example, 4-methylbenzyl, 4-triphtalocyaninine, 4-methoxybenzyl, 3,4-methylenedioxybenzene, 4-methylthiophenyl, 4-methylsulfonylbenzoyl, 4-forbindelse, 4-chloraniline, 2-(4-were)ethyl, 2-(4-methoxyphenyl)ethyl, 3-(4-were)through 3-(4-methoxyphenyl)through 4-(4-were)boutelou or 4-(4-meters case where W represents N-alkyl-N-arylamino group having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl portion and the alkyl portion of the unsubstituted N-alkyl-N-arylamino group includes, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou or tert-boutelou group, preferably methyl, ethyl, through ISO-propyl, boutelou or isobutylene group, most preferably a methyl or ethyl group. Aryl includes, for example, phenyl or naftalina group, preferably phenyl group. Example unsubstituted N - alkyl-N-arylamino group includes, for example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N-propyl-N-phenylamino, N-isopropyl-N - phenylamino, N-butyl-N-phenylamino, N-isobutyl-N-phenylamino or N - methyl-N-naphthylamine group, preferably N-methyl-N-phenylamino or N-ethyl-N-phenylamino group, most preferably N-ethyl-N-phenylamino group. Substituted N-alkyl-N-arylamino group includes, for example, N-methyl - N-(4-were)amino, N-ethyl-N-(4-were)amino, N-methyl-N-(4-methoxyphenyl)amino or N-ethyl-N-(4.

In the case where W represents aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, unsubstituted, aryloxy group includes, for example, phenoxy or naphthyloxy group, preferably phenoxy group. Replaced aryloxy group includes, for example, 4-methylphenoxy, 4-ethylenoxy, 4-propylenoxide, 4-isopropylphenoxy, 4-methoxyphenoxy, 4 - ethoxyphenoxy, 4-methylthiophenol, 4-ethylthiophene, 4-biphenyloxy or 4 methylsulfinylphenyl group, preferably a 4-methylphenoxy, 4-ethylenoxy or 4 isopropylphenoxy group.

In the case where W represents aaltio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, unsubstituted, aaltio group includes, for example, phenylthio or naphthylthio group, preferably phenylthio group. Replaced aaltio group includes, for example, 4 - methylphenylthio, 4-atinfinity, 4-propylphenyl, 4 - isopropylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4 - methylthiophenyl, 4-ethylthiophene, 4-biginelli or 4 methylsulfinylphenyl group, preferably a 4-methylphenylthio, 4-atinfinity or 4 isopropylphenyl group.

<3 substituents , mentioned below in the aryl part, unsubstituted, arylamino group includes, for example, phenylamino or naphthylamine group, preferably phenylamino group. Replaced arylamino group includes, for example, 4-methylpentylamino, 4-ethylvanillin, 4-propylaniline, 4-isopropylbenzylamine, 4 - methoxybenzylamine, 4-ethoxyphenylurea, 4-methyldiphenylamine, 4-ethyldiethanolamine, 4-biphenylamine or 4-methyl-sulfonylamino group, preferably a 4-methylpentylamino, 4-ethylvanillin or 4 isopropylbenzylamine group.

In the case where W represents aralkylated group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, unsubstituted, aralkylated group represents a group in which alkyloxy group with a straight or branched chain, having from 1 to 4 carbon atoms, substituted by the above aryl group and includes, for example, benzyloxy, penetrate, 3 phenylpropoxy, 4-phenylbutyrate, 1 naphthalenyloxy or 2-naphthalenyloxy group, preferably benzyloxy or penetrox group, most preferably a benzyloxy group. Replaced aralkylated group includes, for example, 4-methylbenzylamine, 4-methoxybenzyloxy, 2-(4 - meth is XI or 4-(4-methoxyphenyl)butoxy group, preferably 4-methylbenzylamine or 2-(4-were)ethoxy group.

In the case where W represents Uralkali group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, unsubstituted, Uralkali group represents a group in which alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, substituted by the above aryl group and includes, for example, benzylthio, penetito, 3 phenylpropyl, 4-phenylbutyl, 1 naphthylmethyl or 2-naphthylmethyl group, preferably benzylthio or venatici group, most preferably benzylthio group. Replaced Uralkali group includes, for example, 4-methylbenzyl, 4-methoxybenzylthio, 2-(4-were)ethylthio, 2-(4 - methoxyphenyl)ethylthio, 3-(4-were)propylthio, 3-(4 - methoxyphenyl)propylthio, 4-(4-were)butylthio or 4-(4 - methoxyphenyl)butylthio group, preferably a 4-methylbenzyl or 2-(4-were)ethylthio group.

In the case where W represents aralkylamines group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, unsubstituted, aralkylamines group represents a group in cocoanuts aryl group and includes, for example, benzylamino, phenethylamine, 3 phenylpropylamine, 4-phenylbutyramide, 1 naphthylethylene or 2-naphthylethylene group, preferably benzylamine or phenethylamine group, most preferably benzylamino group. Replaced aralkylamines group includes, for example, 4 - methylbenzylamino, 4-methoxybenzylamine, 2-(4-were)ethylamino, 2-(4-methoxyphenyl)ethylamino, 3-(4-were)propylamino, 3-(4-methoxyphenyl)propylamino, 4-(4-were)butylamino or 4-(4-methoxyphenyl)butylamino group, preferably a 4-methylbenzylamino or 2-(4-were)ethylamino group.

In the case where R4represents an aliphatic acyl group with a straight or branched chain, having from 1 to 8 carbon atoms, or an aromatic acyl group, the acyl group includes, for example, formyl, acetyl, propionyl, butyryloxy, pentanoyl, hexanoyl, heptanoyl or octanoyl group, or benzoyloxy or p-toluylene group, preferably alkanoyloxy group with a straight or branched chain, having from 1 to 8 carbon atoms, more preferably alkanoyloxy group with a straight or branched chain, having from 2 to 5 carbon atoms, most preferably acetosa may have from 1 to 3 substituents , mentioned below unsubstituted aryl group includes, for example, phenyl or naftalina group, preferably phenyl group. In the case where X represents an aryl group which is substituted by 1-3 substituents mentioned below, the number of substituents is preferably one or two, more preferably one.

In the case where X is (5 to 10)-membered monocyclic or bicyclic heteroaromatic group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, which may have 1 to 3 substituents mentioned below, unsubstituted heteroaromatic group includes monocyclic ring or bicyclic ring system. In the case where the group is a bicyclic ring system, one of them, at least, is a heterocyclic ring. In the case of a bicyclic ring system group is a condensed ring, and this is a case where the one ring is a heterocyclic ring, and the other is a carbocyclic ring, or the case when both rings are heterocyclic rings. Heterocyclic ring is 5 - or 6-membered ring and contains from 1 to 4 heterothermy group, having from 6 to 10 carbon atoms. Monocyclic ring system and the bicyclic ring system is monocyclic heteroaromatic group and condensed heteroaromatic ring group, respectively. In the case of a ring having four heteroatoms, preferably, all four were heteroatom nitrogen atoms in the absence of heteroatoms selected from the group consisting of oxygen atoms and sulfur. In the case of a ring having three heteroatoms, preferably one to three, two or one of them was a nitrogen atom, and one or two heteroatoms are selected from the group consisting of oxygen atoms and sulfur. In the case of a ring having two heteroatoms, preferably two, one or none of them was a nitrogen atom, and none of the heteroatoms, one or two heteroatoms were not selected from the group consisting of oxygen atoms and sulfur. In the case where X represents a heteroaromatic group, which is substituted by 1-3 substituents mentioned below, the number of substituents is preferably one or two, more preferably one.

Unsubstituted monocyclic heteroaromatic group includes, for example, pyrrolidinyl group, such as 2-pyrrolyl and 3-Piru group, such as 2-pyridyl, 3-pyridyl and 4-pyridyl; imidazolidinyl group, such as 2-imidazolyl and 4-imidazolyl; pyrazolidine group, such as 3-pyrazolyl and 4-pyrazolyl; oxazolidinyl group, such as 2-oxazolyl, 4-oxazolyl and 5-oxazolyl; isoxazolyl group, such as 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl; thiazolidine group, such as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; isothiazolinone group, such as 3-isothiazole, 4-isothiazolin and 5-isothiazolin; triazolyl group, such as 1,2,3-triazole-4-yl and 1,2,4-triazole-3-yl; thiadiazolyl group, such as 1,3,4-thiadiazole-2-yl; oxadiazolyl group, such as 1,3,4-oxadiazol-2-yl; tetrazolyl group, such as 5-tetrazolyl; pyridazinyl group, such as 3-pyridazinyl and 4-pyridazinyl; pyrimidinyl group, such as 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl; personilnya group; oxazinyl group, such as 1,4-oxazin - 2-yl and 1,4-oxazin-3-yl; casinillo group, such as 1,4-thiazin-2-yl and 1,4-thiazin-3-yl.

Unsubstituted condensed aromatic heterocyclic ring group includes, for example, indolenine group, such as indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl; indazolinone group, such as indiso furan-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl; benzothiophene group, such as benzothiophen-2-yl, benzothiophen-3-yl, benzo-thiophene-4-yl, benzothiophen-5-yl, benzothiophen-6-yl and benzothiophen-7-yl; benzimidazolyl group, such as benzimidazole-2-yl, benzimidazole-4-yl, benzimidazole-5-yl, the benzimidazole-6-yl and the benzimidazole-7-yl; benzoxazolyl group, such as benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl and benzoxazol-7-yl; benzothiazolyl group, such as benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl and benzothiazol-7-yl; pinolillo group, such as 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin and 8-chinolin; izohinolinove group such as 1-ethanolic, 3-ethanolic, 4-ethanolic and 8-ethanolic; benzoxazolyl group, such as 1,4-benzoxazin-2-yl and 1,4-benzoxazin-3-yl; benzothiazyl group, such as 1,4-benzothiazin-2-yl and 1,4 - benzothiazin-3-yl; pyrrolo[2,3-b]pyridyloxy group, such as pyrrolo[2,3-b] pyrid-2-yl and pyrrolo[2,3-b]pyrid-3-yl; furo[2,3-b]pyridyloxy group, such as furo[2,3-b] pyrid-2-yl, furo[2,3 - b]pyrid-3-yl; thieno[2,3-b] pyridyloxy group, such as thieno[2,3 - b]pyrid-2-yl and thieno [2,3-b] pyrid-3-yl; naphthyridinone group is PU, such as imidazo[4,5-b]pyrid-2-yl, imidazo[4,5-b]pyrid-5-yl; oxazolopyridine group, such as oxazolo[4,5-b]pyrid-2-yl and oxazolo[5,4-b]pyrid-2-yl; triazolopyrimidine group, such as thiazolo[4,5-b] pyrid-2-yl and thiazolo[4,5-c]pyrid-2-yl.

Monocyclic heteroaromatic group, preferably represents a 5 - or 6-membered ring group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, and includes pyrrolidino, follow, thienyl, pyridyloxy, imidazolidinyl, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, triazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl and personilnya group, illustrirovannye above. Condensed heteroaromatic group is preferably a condensed ring group of the benzene ring with a 5 - or 6-membered heteroaromatic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, mentioned above, and includes indolenine, benzofuranyl, benzothiophene, benzoimidazole, benzoxazolyl, benzothiazolyl, pinolillo and izohinolinove groups illustrated above. Will predpochtitelney or izohinolinove group, and perederina, indayla, kinolinna or izochinolina group are more preferred, even more preferred are perederina, kinolinna or izochinolina group and the most preferred group is Peregrina group.

In the case where the above-mentioned X represents an aryl group having from 6 to 10 carbon atoms, or (5 to 10)- membered monocyclic or bicyclic heteroaromatic group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, aryl group and the heteroaromatic group may have from 1 to 3 substituents mentioned above.

In the case where the substitution is alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen atom or dialkylamino group with straight or branched chain, alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, these groups include the same groups, as illustriou the group with a straight or branched chain, having from 1 to 4 carbon atoms, halogenated alkyl group includes, for example, chlormethine, bromatology, formeterol, otmetilo, deformational, triptorelin, pentatration, 2,2,2-triptoreline, 2,2,2-trichlorethylene or trichlorethylene group, preferably methyl group, having from 1 to 3 fluorine atoms, most preferably triptorelin group.

In the case where the Deputy is aliphatic, acyloxy group with a straight or branched chain, having from 1 to 4 carbon atoms, acyloxy group includes, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, graylox, methacryloyloxy or crotonville group, preferably alkanoyloxy group, more preferably alkanoyloxy group having one or two carbon atoms, most preferably acetoxy group.

In the case where the Deputy is alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, alkylenedioxy group includes, for example, methylenedioxy, Ethylenedioxy, trimethylenediamine, tetramethoxy or Propylenediamine group, preferably methylenedioxy or Ethylenedioxy group, the most preferred is th from 7 to 12 carbon atoms, aralkylated group represents aralkylated group, in which kalkilya part is the same aralkyl as defined for R3and includes, for example, benzyloxy, penetrate, 3 phenylpropoxy, 4 - phenylbutane, 1 aftermatket or 2-aftermarket group, preferably benzyloxy, penetrate, 1 aftermatket or 2 - aftermarket group, most preferably a benzyloxy group.

In the case where the Deputy is alkylsulfonyl group with a straight or branched chain, having from 1 to 4 carbon atoms, alkylsulfonyl group includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylacetanilide, butylsulfonyl, isobutyronitrile, second-butylsulfonyl or tert - butylsulfonyl group, preferably methylsulfonyl, ethylsulfonyl or isopropylacetanilide group, more preferably alkylsulfonyl group having one or two carbon atom.

In the case where the Deputy is aracelio group having from 7 to 12 carbon atoms, kalkilya group is a group having the same meaning as defined for R3and includes, for example, benzyl, fenetylline, fenetylline, 1-naphthylmethyl or 2 - naphthylmethyl group, most preferably a benzyl group.

In the case where the Deputy represents an aryl group having from 6 to 10 carbon atoms (the aryl group may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), and the alkyl, halogenated alkyl, alkoxy, halogen, alkylenedioxy substituents aryl group have the same meanings as defined above for the substituent R3and x

The aryl group includes, for example, phenyl, 1-naftalina, 2-naftalina, 4 - methylphenyl, 4-triftormetilfullerenov, 4-metoksifenilny, 3-ethoxyphenyl, 4 - florfenicol, 4-chloraniline, 3-bromperidol or 3,4 - methylenedioxyphenyl group, preferably phenyl, 4 - metoksifenilny or 3,4-methylenedioxyphenyl group.

In the case where the Deputy is aryloxy group having from 6 from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), alkyl, halogenated alkyl, alkoxy, halogen, alkylenedioxy have the same meanings as defined above.

Aryloxy group includes, for example, phenoxy, 1 naphthoxy, 2-naphthoxy, 4-methylphenoxy, 4-triptoreline, 4-methoxy-phenoxy, 3 ethoxyphenoxy, 4-chlorophenoxy, 3 bromophenoxy or 3,4-methylenedioxyphenoxy group, preferably phenoxy group.

In the case where the Deputy is aaltio group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), alkyl, halogenated alkyl, alkoxy, halogen, alkylenediamine, 4 cryptosecurity, 4-methoxyphenyl, 3 ethoxyphenyl, 4-chlorophenylthio, 3 pampanito, 3,4-methylenedioxyphenyl, 1 naphthylthio or 2-naphthylthio group, preferably phenylthio group.

In the case where the Deputy is arylsulfonyl group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), alkyl, halogenated alkyl, alkoxy, halogen, alkylenedioxy have the same meanings as defined above.

Arylsulfonyl group includes, for example, phenylsulfonyl, 4-methylphenylsulfonyl, 4-triftormetilfullerenov, 4-methoxyphenylacetyl, 3-ethoxybenzonitrile, 4-chlorophenylsulfonyl, 3-bromophenylacetonitrile, 3,4-methylenedioxyphenylacetone, 1-naphthylmethyl or 2-naphthylmethyl group, preferably phenylsulfonyl group.

Arylsulfonyl group includes, for example, phenylcarbonylamino, 4-methylenebismethacrylamide, 4-triftormetilfullerenov, 4-methoxyphenylethylamine, 3 ethoxypropylamine, 4-chlorophenylsulfonyl, 3 bromophenylacetonitrile, 3,4-methylenedioxyphenethylamine, N-methylphenylethylamine, 1 naphthylamine, 2-naphthylamine or N-methylnaphthalene group, preferably phenylcarbonylamino or N-methylphenylsulfonyl group.

In the case where the Deputy is (5 to 10)-membered monocyclic or bicyclic heteroaromatic group containing from 1 to 4 heteroatom is enilno, oxazolidines, isoxazolidine, thiazolidine, imidazolidine, chinoline, isohynolines, indolines or peredelnoj group, preferably imidazolines, chinoline or peredelnoj group, most preferably peredelnoj group.

In the case where the Deputy is (5 to 10)-membered monocyclic or bicyclic heteroaromatic hydroxy group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur heteroaromatic hydroxy group includes, for example, forelocks, titilate, oxazolidone, isoxazolidine, thiazolidine, imidazolidine, hinomisaki, athinaiki, intolerance or pyridyloxy group, preferably isoxazolyl or pyridyloxy group, most preferably pyridyloxy group.

In the case where the Deputy is (5 to 10)-membered monocyclic or bicyclic heteroaromatic thio group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur heteroaromatic thio group includes, for example, furylthio, tianity, oxazolyl, isoxazolyl, thiazolino, imidazolidine, finality, izochinolina, indelity or piredeu.

In the case where the Deputy is (5 to 10)-membered monocyclic or bicyclic heteroaromatic sulfonyloxy group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur heteroaromatic sulfonylurea group includes, for example, fenilalanina, thienylmethyl, oxazolidinyl, isoxazolecarboxylic, triazolylmethyl, imidazolylalkyl, henrylmoreno, ethynodiolthinyl, indolylmaleimide or pyridylsulfonyl group, preferably imidazolylalkyl, isoxazolecarboxylic or pyridylsulfonyl group, most preferably pyridylsulfonyl group.

In the case where the Deputy is (5 to 10)-membered monocyclic or bicyclic heteroaromatic sulfonylamino group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur (the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), heteroaromatic, sulfonylamino group includes, for example, fenilalanina, teilzunehmen, oxytrichloride, the Mino, chinaincorporated, ethynodiolthinyl, indolealkylamine, pyridinesulfonamide or N-methylphenylsulfonyl group, preferably imidazolidinylideneamino, N-methylmethanesulfonamide, pyridinesulfonamide or N-methylphenylsulfonyl group, more preferably pyridinesulfonamide or N-methylphenylsulfonyl group.

Therefore, in the case where X represents a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms, or substituted or unsubstituted (5 to 10)-membered monocyclic or bicyclic heteroaromatic group containing from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, the preferred examples include phenyl, 1-naftalina, 2-naftalina, m-trillou, p-trillou, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-tert-butylaniline, 4-tert-butylaniline, 4-chloromethylpyridine, 4-bromomethylphenyl, 4-formatieren, 4-idnetifying, 3 - deformational, 4-triftormetilfullerenov, 4-pentafluorophenyl, 4-trichlorocarbanilide, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy - 3,5-dimethylaniline, 3-acetoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3,4-methylenedioxyaniline, benzyloxyaniline, penetratively, 1-naphthylmethyl), 3-methylthiophenyl, 4-methylthiophenyl, 3-ethylthiophene, 4-ethylthiophene, 3 - isopropylacetanilide, 4-isopropylaniline, 3-methylsulfinylphenyl, 4-methylsulfinylphenyl, 3-ethylsulfonyl, 4-ethylsulfonyl, 3-isopropylacetanilide, 4-isopropylacetanilide, 3-chloraniline, 4-chloraniline, 3-bromperidol, 4-bromperidol, 4-nitroaniline, 4-aminoaniline, 3-methylaminophenol, 4 - ethylaminoethanol, 3-propylaminoethyl, 4-butylaminoethyl, 3-dimethylaminophenyl, 4-diethylaminophenyl, 3-dipropylenetriamine, 4-dibutylaminoethanol, 3-benzylaniline, 4-benzylaniline, 3-fenetylline, 4-(1-naphthylmethyl)phenyl, 3-biphenylyl, 4-biphenylyl, 3-(4 - were)phenyl, 4-(4-were)phenyl, 3-(4-ethylphenyl)phenyl, 3-(4-triptoreline)phenyl, 4-(4 - triptoreline)phenyl, 3-(4-methoxyphenyl)phenyl, 4-(4 - methoxyphenyl)phenyl, 3-(2,4-acid)phenyl, 4-(2, 4-acid) phenyl, 3-(2,5-acid)phenyl, 4-(2,5-dimethoxyphenyl is, -(3,4-methylenedioxyphenyl)phenyl, 4- (3,4-methylenedioxyphenyl)phenyl, 3-benzylaniline, 4 - benzylaniline, 3-phenoxyphenyl, 4-phenoxyphenyl, 3 - finitively, 4-finitively, 3-phenylsulfonyl-phenyl, 4-phenolsulfonephthalein, 3-(phenylcarbonylamino) phenyl, 4-(phenylcarbonylamino) phenyl, 3-(N - methylphenylsulfonyl)phenyl, 4-(N-methylphenylsulfonyl-amino) phenyl, 3-(imidazol-1-yl)phenyl, 4-(imidazol-1-yl) phenyl, 3-(1-Mei-4-yl)phenyl, 4-(1-methyl - imidazol-4-yl)phenyl, 3-(2-furyl)phenyl, 4-(2-furyl) phenyl, 3-(2-thienyl)phenyl, 4-(2-thienyl)phenyl, 3-(3 - thienyl) phenyl, 4-(3-thienyl)phenyl, 3-(2-pyridyl) phenyl, 4-(2-pyridyl)phenyl, 3-(3-pyridyl) phenyl, 4-(3 - pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(4-pyridyl) phenyl, 4-(imidazol-1-ylthio)phenyl, 4-(2-furylthio) phenyl, 4-(2-tianity)phenyl, 4-(2-pyridylthio) phenyl, 4-(4-pyridylthio)phenyl, 3-(2-pyridylsulfonyl) phenyl, 4-(2-pyridyl-sulfonyl)phenyl, 3-(3 - pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3-(2-pyridylsulfonyl) phenyl, 3-(N-methyl-2 - pyridylsulfonyl)phenyl, 4-(2 - pyridylsulfonyl)phenyl, 4-(N-methyl-2 - pyridylsulfonyl)phenyl, 3-(3-pyridyl) - Rev.-(N-methyl-3 - pyridinesulfonamide)phenyl, 3-(oxazol-2-yl)phenyl, 4-(oxazol-2-yl)phenyl, 3-(oxazol-4-yl)phenyl, 4-(oxazol-4-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-(oxazol-5 - yl)phenyl, 3-(thiazol-2-yl)phenyl, 4-(thiazol-2-yl)phenyl, 3-(thiazol-4-yl)phenyl, 4-(thiazol-4-yl)phenyl, 3-(thiazol-5 - yl)phenyl, 4-(thiazol-5-yl)phenyl, 1-methyl-2 - pyrrolidinyl, 1-phenyl-2-pyrrolidino, 1-benzyl-2-pyrrolidinyl, 5-methyl-2-follow, 5-phenyl-2-follow, 5-methyl-2-thienyl, 5 - phenyl-2-thienyl, 5-methyl-3-thienyl, 5-phenyl-3-thienyl, 1-methyl-3-pyrazolidine, 1-phenyl-3-pyrazolidine, 1-methyl-2-imidazolidinyl, 1-phenyl-2-imidazolidinone, 1-methyl-4-imidazolidinyl, 1-phenyl-4-imide-asailing, 1-methyl-2-phenyl-4-imidazolidinyl, 1,5-dimethyl-2-phenyl-4-imidazolidinyl, 1,4-dimethyl - 2-phenyl-5-imidazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2 - methyl-4-oxazolidinyl, 2-phenyl-4-oxazolidinyl, 2-methyl-5-oxazolidinyl, 2-phenyl-5-oxazolidinyl, 4-methyl-2-phenyl-5-oxazolidinyl, 5-methyl-2-phenyl-4-oxazolidinyl, 4-thiazolidine, 5-thiazolidine, 2-methyl-4-thiazolidine, 2-phenyl-4-thiazolidine, 2-methyl-5-thiazolidine, 2-phenyl-5-thiazolidine, 4-methyl-2-phenyl-5 - thiazolidine, 5-methyl-2-phenyl-4-thiazolidine, 1-methyl-3 - pyrazolidine, 1-phenyl-3-pyrazolidine, 3-methyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 2-pyridyldithio, 2 - ethyl-5-pyridyloxy, 2-phenyl-5-pyridyloxy, 2-hydroxy-5-pyridyloxy, 2-methoxy-5-pyridyloxy, 2-ethoxy-5-pyridyloxy, 2-isopropoxy-5-pyridyloxy, 2-benzyloxy-5-pyridyloxy, 2-methylthio-5-pyridyloxy, 2-ethylthio-5-pyridyloxy, 2-isopropylthio-5 - pyridyloxy, 2-methylsulphonyl-5-pyridyloxy, 2-ethylsulfonyl - 5-pyridyloxy, 2-isopropylphenyl-5-pyridyloxy, 2 - benzyl-5-pyridyloxy, 2-phenoxy-5-pyridyloxy, 2-phenylthio-5-pyridyloxy, 2-phenylsulfonyl-5-pyridyloxy, 2 - phenylcarbonylamino-5-pyridyloxy, 2-(N-methylphenylsulfonyl)-5-pyridyloxy, 3-methyl-6-pyridinol, 3-phenyl-6-pyridinol, 2 - methyl-6-pyridinol, 2-phenyl-6-pyridinol, 2-methyl-4 - pyrimidinyl, 2-phenyl-4-pyrimidinyl, 2-methoxy-4 - pyrimidinyl, 2-ethoxy-4-pyrimidinyl, 2-isopropoxy-4-pyrimidinyl, 2-methylthio-4-pyrimidinyl, 2-ethylthio-4-pyrimidinyl, 2-isopropylthio-4-pyrimidinyl, 2-phenylthio-4 - pyrimidinyl, 2-methylsulphonyl-4-pyrimidinyl, 2-ethylsulfonyl-4-pyrimidinyl, 2-isopropylphenyl-4 - pyrimidinyl, 2-phenylsulfonyl-4-pyrimidinyl, 2-methyl - 5-pyrimidinyl, 2-phenyl-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-methylthio-5-pyrimidinyl, 2-ethylthio-5-pyrimi the-ethylsulfonyl-5-pyrimidinyl, 2-isopropylphenyl - 5-pyrimidinyl, 2-phenylsulfonyl-5-pyrimidinyl, 2-indolenine, 3-indolenine, 1-methyl-2-indolenine, 1-methyl-3-indolenine, 2-benzimidazolyl, 1-methyl-2-benzimidazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-pinolillo, 3-pinolillo, 4-pinolillo, 1-izohinolinove, 3-izohinolinove, 4-izohinolinove and 8-izohinolinove group, more preferably phenyl, 1-naftalina, 2-naftalina, m-trillou, p-trillou, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4 - isopropylphenyl, 4-triftormetilfullerenov, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylaniline, 3 - acetoxyphenyl, 4-acetoxyphenyl, 5-acetoxy-2-hydroxy - 3,4,6-trimethylphenyl, 3-metoksifenilny, 4-metoksifenilny, 3-ethoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl, 4 - isopropoxyphenyl, 3,4-methylenedioxyaniline, benzyloxyaniline, 3-methylthiophenyl, 4-methylthiophenyl, 3-ethylthiophene, 4-ethylthiophene, 3-methylsulfinylphenyl, 4 - methylsulfinylphenyl, 3-ethylsulfonyl, 4-ethylsulfonyl, 3-chloraniline, 4-chloraniline, 3 - benzylaniline, 4-benzylaniline, 3-biphenylyl, 4 - biphenylyl, 3-(4-were)phenyl, 4-(4-m is th, 3-(4 - methoxyphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 3-(2,4 - acid)phenyl, 4-(2,4-acid) phenyl, 3- (2,5-acid)phenyl, 4-(2,5-acid) phenyl, 4-(3-chlorophenyl)phenyl, 4-(4-chlorophenyl) phenyl, 3-(3,4-methylenedioxyphenyl)phenyl, 4-(3,4-methylenedioxyphenyl) phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 3 - finitively, 4-finitively, 3-phenylsulfonyl, 4-phenolsulfonephthalein, 3-(phenylcarbonylamino) phenyl, 4-(phenylcarbonylamino)phenyl, 3-(N - methylphenylsulfonyl)phenyl, 4-(N-methylphenylsulfonyl) phenyl, 3-(2-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 3-(4 - pyridyl) phenyl 4-(4-pyridyl)phenyl, 4-(2-pyridyloxy) phenyl, 4-(4-pyridyloxy)phenyl, 4-(2-pyridylthio) phenyl, 4-(4-pyridylthio)phenyl, 3-(2-pyridylsulfonyl) phenyl, 4-(2-pyridylsulfonyl)phenyl, 3-(3 - pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3- (2-pyridylsulfonyl) phenyl, 3-(N-methyl-2-pyridylsulfonyl)phenyl, 4-(2-pyridylsulfonyl) phenyl, 4-(N-methyl-2-pyridylsulfonyl)phenyl, 3-(3 - pyridylsulfonyl)phenyl, 3-(N-methyl-3 - pyridylsulfonyl)phenyl, 4-(3-PIR is dilou, 3-methyl-5 - pyridyloxy, 3-ethyl-5-pyridyloxy, 3-phenyl-5-pyridyloxy, 2-methyl-5-pyridyloxy, 2-ethyl-5-pyridyloxy, 2-phenyl-5-pyridyloxy, 2-hydroxy-5-pyridyloxy, 2-methoxy-5-pyridyloxy, 2-ethoxy-5 - pyridyloxy, 2-isopropoxy-5-pyridyloxy, 2-benzyloxy-5 - pyridyloxy, 2-methylthio-5-pyridyloxy, 2 ethylthio-5 - pyridyloxy, 2-isopropylthio - 5-pyridyloxy, 2-methylsulphonyl-5-pyridyloxy, 2-ethylsulfonyl-5-pyridyloxy, 2-isopropylphenyl-5-pyridyloxy, 2-benzyl-5-pyridyloxy, 2-phenoxy-5-pyridyloxy, 2-phenylthio-5-pyridyloxy, 2-phenylsulfonyl-5-pyridyloxy, 2-phenyl-sulfonylamino-5-pyridyloxy, 2- (N-methylphenylsulfonyl)-5-pyridyloxy, 3-methyl-6 - pyridinol, 3-phenyl-6-pyridinol, 2-methyl-6-pyridinol, 2-phenyl-6 - pyridinol, 2-pinolillo, 3-pinolillo, 4-pinolillo, 1-izohinolinove, 3-izohinolinove, 4-izohinolinove and 8-izohinolinove group,

most preferably phenyl, m-trillou, p-trillou, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylaniline, 3-acetoxyphenyl, 4-acetoxyphenyl, 5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl, 3-chloraniline, 4-chloraniline, 3-benzylaniline, 4 - benzylaniline, 3-biphenylyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 3-finitively, 4- (phenylcarbonylamino)phenyl, 3-(N-methylphenylsulfonyl - amino)phenyl, 4-(N-methylphenylsulfonyl)phenyl, 3-(2 - pyridyl)phenyl, 4-(2-pyridyl)phenyl, 3-(3 - pyridyl)phenyl, 4-(3-pyridyl)phenyl, 3-(4-pyridyl) phenyl, 4-(4-pyridyl)phenyl, 4-(2-pyridyloxy)phenyl, 4-(4-pyridyloxy)phenyl, 4-(2-pyridylthio)phenyl, 4-(4 - pyridylthio)phenyl, 3-(2-pyridyl-sulfonyl)phenyl, 4- (2 - pyridylsulfonyl)phenyl, 3-(3-pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3-(2-pyridylsulfonyl) phenyl, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, 2-methoxy - 5-pyridyloxy, 2-ethoxy-5-pyridyloxy, 2 isopropoxy-5 - pyridyloxy, 2-benzyloxy-5-pyridyloxy, 2-methylthio-5-pyridyloxy, 2-ethylthio-5-pyridyloxy, 2-methylsulphonyl-5-pyridyloxy, 2 - ethylsulfonyl-5-pyridyloxy, 2-benzyl-5-pyridyloxy, 2-phenyl-5 - pyridyloxy, 3-phenyl-5-pyridyloxy, 2-phenyl-6-pyridinol, 3 - phenyl-6 - pyridinol, 2-phenoxy-5-pyridyloxy, 2 phenylthio-5-pyridyloxy, 2-phenylsulfonyl-5-pyridyloxy, 2-phenylcarbonylamino - 5-pyridinol and 2-(N-methylphenylsulfonyl)-5 - pyridyloxy group.

In the case where Y represents a group of formula >N-R4(where R4represents a hydrogen atom, alkyl group with straight or razvetvlenno) or an aliphatic acyl group with a straight or branched chain, having from 1 to 8 carbon atoms (which includes alcoholnye group having from 1 to 8 carbon atoms, and alkenone group having from 3 to 8 carbon atoms) or an aromatic acyl group), a group of the formula >N-R4includes, for example, imino, methylimino, ethylimino, propylimino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert - butylamino, pentylamine, 1 methylbutylamine, 2-methylbutylamine, 3 methylbutylamine, 1,1-dimethylpropylene, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1 ethylpropylamine, hexylamino, 1 methylpentylamino, 2-methylpentylamino, 3 methylpentylamino, 4 - methylpentylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3 - dimethylbutylamino, 3,3-dimethylbutylamino, 1 ethylbutylamine, 1,1,2 - trimethylpropyl, 1,2,2-trimethylpropyl, acetylimino, propionamido, Butylimino, pentanediamine, hexanamine, leptanillinae, actinolite, benzoylamino or p-toluylene group, preferably imino, alkylamino group with a straight or branched chain, having from 1 to 4 carbon atoms, or acetylamino group, more preferably imino, methylimino, ethylimino or acetylamino group.

Proizvoditel ways, when they have the main group. Such a salt includes, for example, salts of halogen acids such as hydrofluoric acid, hydrochloric acid, Hydrobromic acid and itestosterone acid; salts of inorganic acids, such as nitrate, perchlorate, sulfate and phosphate; salts of lower alkanesulphonic acid, such as methanesulfonate acid, triftormetilfullerenov acid and econsultancy acid; salts arylsulfonic acid, such as benzolsulfonat acid and p-toluensulfonate acid; salts of amino acids such as glutamic acid and aspartic acid; and salts of carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid, preferably salts of halogen acids.

In addition, the compounds of formula (I) can be converted into a salt of the metal according to standard methods, when they have a carboxyl group. Such a salt includes, for example, salts of alkaline metal such as lithium, sodium and potassium; alkaline earth salt is ptx2">

Derivatives phenylalkylamines acid of the formula (I) can be converted into a pharmacologically acceptable ester according to standard methods. Pharmacologically acceptable esters derived phenylalkylamines acid of the formula (I) are used as medicines along with phenylalkylamines acid of the formula (I) and they are not limited, as it is pharmacologically acceptable.

Ester phenylalkylamines acid of the formula (I) of the present invention includes, for example, alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, aracelio group having from 7 to 19 carbon atoms, alkyl group with straight or branched chain, having from 1 to 5 carbon atoms which is substituted, alkanoyloxy group with a straight or branched chain, having from 1 to 6 carbon atoms, alkyl group with straight or branched chain, having from 1 to 5 carbon atoms, which replaced allyloxycarbonyl group with a straight or branched chain, having from 1 to 6 carbon atoms, alkyl group with straight or branched chain, having from 1 to 5 carbon atoms which is substituted, cycloalkylcarbonyl group having from 5 to 7 ug is I replaced cycloalkylcarbonyl group, having from 5 to 7 carbon atoms, alkyl group with straight or branched chain, having from 1 to 5 carbon atoms which is substituted, arylcarboxylic group having from 6 to 10 carbon atoms, alkyl group with straight or branched chain, having from 1 to 5 carbon atoms which is substituted, aryloxypropanolamine group having from 6 to 10 carbon atoms, and 2-oxo-1,3 - dioxolan-4-yl group having an alkyl straight or branched chain, having from 1 to 6 carbon atoms, as the substituent in the 5-position.

Here, an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, and an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms include, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1 - dimethylpropyl, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1-ethylpropyl, hexeline, 1-methylpentyl, 2 - methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1 - dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2 - dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, more preferably methyl, ethyl, sawn, ISO-propyl, boutelou and isobutylene, most preferably methyl and ethyl.

Kalkilya group having from 7 to 19 carbon atoms, includes, for example, benzyl, fenetylline, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl or diphenylmethylene group, preferably benzyl group.

Cycloalkyl group having from 5 to 7 carbon atoms, includes, for example, cyclopentyl, cyclohexyl and cycloheptyl, preferably cyclohexyl.

Aryl group having from 6 to 10 carbon atoms, includes, for example, phenyl or naphthyl, preferably phenyl.

Examples of preferred ester residual groups include, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, tert-boutelou, benzyl, acetoxymethyl, 1-(acetoxy) ethyl, propionylthiocholine, 1-(propionyloxy)ethyl, butyrylcholine, 1-(butyryloxy) ethyl, isobutyrylacetate, 1-(isobutyryloxy)ethyl, valeriucciobello, 1-(valeriote) ethyl, isovalerylglycine, 1-(isovalerianic)ethyl, the ing, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, propoxycarbonyl, 1-(propoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl) ethyl, butoxycarbonyloxyimino, 1-(butoxycarbonylamino) ethyl, msobuttoniconandcaption, 1- (isobutoxyethene)ethyl, tert-butoxycarbonyloxyimino, 1-(tert-butoxycarbonylamino)ethyl, cyclopentanecarboxaldehyde, 1-(cyclopentanecarbonyl) ethyl, cyclohexanecarbonitrile, 1- (cyclohexanecarbonyl)ethyl, cyclopentanecarboxaldehyde, 1-(cyclopentanecarbonyl)ethyl, cyclohexyloxycarbonyloxy, 1-(cyclohexyloxycarbonyloxy)ethyl, benzoyloxymethyl, 1-(benzoyloxy)ethyl, phenoxycarbonylamino, 1-(phenoxycarbonylamino)and ethyl 5-methyl-2-oxo-1,3-dioxolan-4-yl group.

Incidentally, the compound of formula (I) has a different isomers. For example, there are optical isomers, obtained as a consequence of the asymmetry of the carbon - apologizee carboxyl group. In the formula (I), the stereoisomers based on the asymmetric carbon atom, and equivalent and non-equivalent weight of a mixture of these Stere is their isomers.

In addition, derivatives phenylalkylamines acid of the formula (I) CIS-isomers and TRANS-isomers, geometric isomerism, can exist in oximes part. In the formula (I) both isomers, geometric isomerism, and equivalent and non-equivalent weight mixture of these isomers, all represented by a single formula. Therefore, this invention includes all of these isomers and a mixture of these isomers.

In addition, in the case where phenylalkylamine acid of the formula (I) or its salt forms a solvate (e.g. hydrate), this invention includes all these connections.

In addition, this invention includes all compounds that are metabolized in vivo into derivative phenylalkylamines acid of the formula (I) or its salts, for example, amide derivatives, i.e., prodrugs.

Derivatives phenylalkylamines acid of the formula (I) preferably include

(1) the compound in which R1represents a hydrogen atom or alkyl group with straight or branched chain, having from 1 to 4 carbon atoms,

(2) the compound in which R1represents a hydrogen atom or alkyl group with straight or branched chain, having from 1 to 3 the nternet or branched chain, having one or two carbon atom,

(4) the compound in which R1represents an alkyl group having one or two carbon atom,

(5) the compound in which R2is alkylenes group with a straight or branched chain, having from 2 to 5 carbon atoms,

(6) the compound in which R2is alkylenes group with a straight or branched chain, having from 2 to 4 carbon atoms,

(7) a compound in which R2is ethylene, trimethylene or melatoninbuy group

(8) the compound in which R2represents ethylene group,

(9) a compound in which R3represents a hydrogen atom, alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group having one or two carbon atoms, alkylthio group having one or two carbon atoms, or a halogen atom.

(10) the compound in which R3represents a hydrogen atom,

(11) a compound in which X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, or (5 to 10)-membered heteroaromatic group (including monocyclic or bizi which may have from 1 to 3 substituents , mentioned below

Deputy chosen from the group consisting of (i) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) hydroxy, (iv) alkanoyloxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vii) aralkylated group having from 7 to 12 carbon atoms, (viii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (ix) alkylsulfonyl straight or branched chain, having from 1 to 4 carbon atoms, (x) of a fluorine atom, (xi) chlorine atom, (xii) bromine atom, (xiii) aralkyl having from 7 to 12 carbon atoms, (xiv) phenyl (the phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy Hrbaty substituted alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvi) phenylthio (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvii) phenylsulfonyl (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xviii) phenylcarbonylamino (phenyl part of lots of the alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, and the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), (xix) of furil, (xx) tanila, (xxi) oxazolyl, (xxii) isoxazolyl, (xxiii) thiazolyl, (xxiv) pyridyl, (xxv) pyridyloxy, (xxvi) pyridylthio, (xxvii) pyridylsulfonyl, (xxviii) of imidazolyl (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms) and (xxix) pyridinesulfonamide (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms),

(12) a compound in which X represents phenyl, naftalina, imidazolidinyl, oxazolidinyl, pyridyloxy, indolenine, pinolillo or izohinolinove group, and these groups may have 1 to 3 substituents mentioned below

Deputy chosen from the group consisting of (i) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 Perednik atoms, (v) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) methylenedioxy, (vii) aralkylated group having from 7 to 12 carbon atoms, (viii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (ix) alkylsulfonyl straight or branched chain, having from 1 to 4 carbon atoms, (x) of a fluorine atom, (xi) chlorine atom, (xii) bromine atom, (xiii) aralkyl, having from 7 to 12 carbon atoms, (xiv) phenyl (the phenyl portion may be substituted with stands, trifluoromethyl, methoxy, fluorine or methylenedioxy), (xv) phenoxy (phenyl portion may be substituted with stands, trifluoromethyl, methoxy, fluorine or methylenedioxy), (xvi) phenylthio (phenyl portion may be substituted with stands, trifluoromethyl, methoxy, fluorine or methylenedioxy), (xvii) phenylsulfonyl (phenyl portion may be substituted with stands, trifluoromethyl, methoxy, fluorine or methylenedioxy), (xviii) phenylcarbonylamino (phenyl portion may be substituted with stands, trifluoromethyl, methoxy, fluorine or methylendioxy, and the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), (xix) of furil, (xx) tanila, (xxi) oxazolyl, (xxii) isoxazolyl, (xxiii) thiazolyl, (xxi can be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms) and (xxix) pyridinesulfonamide (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms),

(13) the compound in which X represents phenyl, naftalina, imidazolidinyl, oxazolidinyl, pyridyloxy, indolenine, pinolillo or izohinolinove group, and these groups may have 1 to 3 substituents mentioned below

Deputy chosen from the group consisting of (i) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) hydroxy, (iv) alkanoyloxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) methylenedioxy, (vii) benzyloxy, (viii) penetrate, (ix) aftermatket, (x), alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (xi) alkylsulfonyl straight or branched chain, having from 1 to 4 carbon atoms, (xii) of a fluorine atom, (xiii), a chlorine atom, (xiv), bromine atom, (xv) benzyl, (xvi) phenyl (the phenyl portion may be substituted with stands, triforma tilam, methoxy, fluorine or methylenedioxy), (xviii) phenylthio, (xix) phenylsulfonyl, (xx) phenylcarbonylamino, (xxi) N-methylphenylethylamine, (xxii) of furil, (xxiii) tanila, (xxiv) oxazolyl, (xxv) isoxazolyl, (xxvi) thiazolyl, (xxvii) pyridyl, (xxviii) pyridyloxy, (xxix) pyridylthio, (xxx) pyridylsulfonyl, (xxxi) pyridinesulfonamide, (xxxii) N-methylenebismethacrylamide and (xxxiii) imidazolyl (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms),

(14) the compound in which X represents phenyl, naftalina, pyridyloxy, indolenine, pinolillo or izohinolinove group, and these groups may have one or two substituent mentioned below

Deputy chosen from the group consisting of alkyl straight or branched chain, having from 1 to 3 carbon atoms, methyl, having from 1 to 3 fluorine atoms, hydroxy, alkanoyloxy group having one or two carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 3 carbon atoms, methylenedioxy, benzyloxy, alkylthio group having one or two carbon atoms, alkylsulfonyl having one or two carbon atom, fluorine atom, chlorine atom, bromine atom, benzyl, phenyl, 4-methylphenyl, 4 tritylmorpholine, N - methylphenylethylamine, furil, teinila, oxazolyl, thiazolyl, imidazolyl, N-methylimidazole, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridinesulfonamide and N - methylphenylsulfonyl groups

(15) the compound in which X represents phenyl, naftalina, pyridyloxy, pinolillo or izohinolinove group, and these groups may have one Deputy mentioned below

Deputy chosen from methyl, ethyl, isopropyl, trifloromethyl, hydroxy, acetoxy, methoxy, ethoxy, isopropoxy, methylenedioxy, benzyloxy, alkylthio group having one or two carbon atoms, alkylsulfonyl having one or two carbon atom, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylcarbonylamino, N-methylphenylethylamine, pyridyl, pyridyloxy, pyridylthio, pyridylsulfonyl, pyridinesulfonamide and N-methylphenylsulfonyl groups

(16) the compound in which X represents a phenyl group which may have one Deputy mentioned below

Deputy chosen from the group consisting of methyl, hydroxy and acetoxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylcarbonylamino, N-methylphenylsulfonyl the ing group, which may have one Deputy mentioned below

here, Deputy chosen from the group consisting of methoxy, ethoxy, isopropoxy and benzyloxy groups, alkylthio group having one or two carbon atoms, alkylsulfonyl having one or two carbon atoms, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylcarbonylamino and N-methylphenylsulfonyl groups

(17) the compound in which X represents a phenyl group which may have one Deputy mentioned below

Deputy chosen from the group consisting of hydroxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, pyridyl, pyridyloxy, pyridylthio groups

(18) the compound in which Y represents an oxygen atom or sulfur, or a group of the formula >N-R4(where R4represents a hydrogen atom, alkyl group with straight or branched chain, having from 1 to 3 carbon atoms, or alkanoyloxy group with a straight or branched chain, having from 2 to 5 carbon atoms),

derivatives phenylalkylamines acid, their pharmacologically acceptable salts or their pharmaceutically acceptable esters.

(19) the compound in which Y represents an oxygen atom,

(20) connecting the t 1 to 4 carbon atoms,

(21) the compound in which Z represents alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms,

(22) the compound in which Z represents alkylenes group with a straight or branched chain having one or two carbon atom,

(23) the compound in which Z represents a methylene group,

(24) the compound in which W represents (i) an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl - N-arylamino group in which the alkyl part has an alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (vii) aryloxy group, the ima(viii) aristeo group, having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (ix) arylamino group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (x) Uralkaliy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xi) 1-pyrrolidinyl group, (xii) 1-pyrrolidinyloxy group, (xiii) 1-imidazolidinyl group, (xiv) piperidino group, or (xv) morpholino group

here, Deputy chosen from the group consisting of (1) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) hydroxy, (iv) alkanoyloxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vi) alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vii) aralkylated group having from 7 to 12 carbon atoms, (viii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (ix) alkylsulfonyl with Roma (xiii) aralkyl having from 7 to 12 carbon atoms, (xiv) phenyl (the phenyl may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xv) phenoxy (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvi) phenylthio (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy grog may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xviii) phenylcarbonylamino (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, and the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms), (xix) of furil, (xx) tanila, (xxi) oxazolyl, (xxii) isoxazolyl, (xxiii) thiazolyl, (xxiv) pyridyl, (xxv) pyridyloxy, (xxvi) pyridylthio, (xxvii) pyridylsulfonyl, (xxviii) of imidazolyl (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms) and (xxix) pyridinesulfonamide (the nitrogen atom of the amino part of the can b, the where W is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N - arylamino group in which the alkyl part has an alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (vii) aryloxy group having from 6 to 10 carbon atoms, which may have from 1 to 3 substituents mentioned below in the aryl part, (viii) aristeo group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (ix) arylamino group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, the Fort worth , mentioned below in the aryl part, or (xi) 1-pyrrolidinyl group

Deputy chosen from hydroxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, pyridyl, pyridyloxy, pyridylthio groups

(26) the compound in which W represents (i) an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, (ii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N - alkyl-N-arylamino group in which the alkyl part has an alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (vii) phenoxy group, (viii) phenylthio group, (ix) phenylamino group, (x) Uralkaliy group having 7 to 10 carbon atoms, (xi) 1-pyrrolidinyl group, (xii) 1-pyrrolidinyloxy group, or (XIII) 1-imidazolidinyl group

(27) the compound in which W pre to 3 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 3 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylamino group, (vi) N-phenyl-N-ethylamino group, (vii) phenoxy group, (viii) phenylthio group, (ix) phenylamino group, (x) 3-phenylpropionyl group, (xi) 4-phenylbutyl group, or (xii) 1-pyrrolidinyl group,< / BR>
(28) the compound in which W represents boutelou, ethoxy, methylthio, ethylamino, diethylamino, N-phenyl-N-ethylamino, phenoxy, phenylthio, phenylamino, 3-phenylpropyl or 1-pyrrolidinyl group

(29) the compound in which W represents boutelou, ethoxy, methylthio, ethylamino, phenoxy, phenylthio, phenylamino or 3 - phenylpropyl group.

In addition, R1choose from (1) to(4), R2choose from (5)-(8), R2choose from (9) and (10), X is chosen from (11)-(17), Y is chosen from (18) and (19), Z is chosen from (20)-(23) and W is chosen from (24)-(29), and compounds obtained by their combination, are also preferred.

Derivatives phenylalkylamines acid of the formula (I) include, for example,

(30) the compound in which R1represents a hydrogen atom or alkyl group with straight or branched chain, having from 1 to 4 carbon the s atoms;

R3represents a hydrogen atom, alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group having one or two carbon atoms, alkylthio group having one or two carbon atoms, or a halogen atom;

Z represents a single bond or alkilinity group with a straight or branched chain, having from 1 to 4 carbon atoms;

W is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino group with a straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-arylamino group in which the alkyl part has an alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl casth below, in the aryl part, (viii) aristeo group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (ix) arylamino group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (x) Uralkaliy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xi) 1-pyrrolidinyl group, (xii) 1 - pyrrolidinyloxy group, (xiii) 1-imidazolidinyl group, (xiv) piperidino group, or (xv) morpholino group;

X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below, or (5 to 10)-membered heteroaromatic group (including monocyclic or bicyclic) having from 1 to 4 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, which may have 1 to 3 substituents mentioned below;

here the Deputy mentioned below, which are selected from the group consisting of (i) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) hydroxy, (iv) alkanoyl branched chain, having from 1 to 4 carbon atoms, (vi) alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, (vii) aralkylated group having from 7 to 12 carbon atoms, (vili) alkylthio group with a straight or branched chain, having from 1 to 4 carbon atoms, (ix) alkylsulfonyl straight or branched chain, having from 1 to 4 carbon atoms, (x) of a fluorine atom, (xi) chlorine atom, (xii) bromine atom, (xiii) aralkyl having from 7 to 12 carbon atoms, (xiv) phenyl (the phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xv) phenoxy (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkalinity may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xvii) phenylsulfonyl (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms), (xviii) phenylcarbonylamino (phenyl portion may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms, halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, halogen or alkylenedioxy group with a straight or branched chain, having from 1 to 4 carbon atoms, and the nitrogen atom of the amino part of the can b is a, (xxi) oxazolyl, (xxii) isoxazolyl, (xxiii) thiazolyl, (xxiv) pyridyl, (xxv) pyridyloxy, (xxvi) pyridylthio, (xxvii) pyridylsulfonyl, (xxviii) of imidazolyl (the nitrogen atom of the ring may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms) and (xxix) pyridinesulfonamide (the nitrogen atom of the amino part may be substituted by alkyl straight or branched chain, having from 1 to 6 carbon atoms); and

Y represents oxygen atom or sulfur or a group of the formula >N-R4(where R4represents a hydrogen atom, alkyl group with straight or branched chain, having from 1 to 3 carbon atoms, or alkanoyloxy group with a straight or branched chain, having from 2 to 5 carbon atoms);

(31) the compound in which R1represents an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms;

R2is alkylenes group with a straight or branched chain, having from 2 to 5 carbon atoms;

R3represents a hydrogen atom;

Z represents alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms;

W is (i) alkyl group with straight or branched chain, having from 1 to 6 guilty group with a straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino group with straight or branched chain, alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-arylamino group in which the alkyl part has an alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (vii) aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (viii) aristeo group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (ix) arylamino group, having from 6 to 10 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (x) Uralkaliy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents mentioned below in the aryl part, (xi) 1-pyrrolidinyl group;

X represents a phenyl group which may have one zamestitel, phenyl, phenoxy, phenylthio, peredelnoj, pyridyloxy, pyridylthio groups; and

Y represents an oxygen atom;

(32) the compound in which R1represents an alkyl group having one or two carbon atom;

R2represents ethylene group;

R3represents a hydrogen atom;

Z represents a methylene group;

W represents (i), sawn or boutelou group, (ii) alkoxy group with a straight or branched chain, having from 1 to 3 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 3 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylamino group, (vi) N-phenyl-N - ethylamino group, (vii) phenoxy group, (viii) phenylthio group, (ix) phenylamino group, (x) 3-phenylpropionyl group, (xi) 4 - phenylbutyl group, or (xii) 1-pyrrolidinyl group;

X represents a phenyl group which may have one Deputy , mentioned below;

here the Deputy is chosen from the group consisting of methyl, hydroxy, acetoxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylcarbonylamino, N - methylphenylethylamine, pyridyl, pyridyloxy, Piri is the Titel , mentioned below;

here the Deputy is chosen from the group consisting of methoxy, ethoxy, isopropoxy, benzyloxy, alkylthio group having one or two carbon atoms, alkylsulfonyl having one or two carbon atoms, benzyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, phenylcarbonylamino and N - methylphenylsulfonyl groups; and

Y represents an oxygen atom;

(33) the compound in which R1represents an alkyl group having one or two carbon atom;

R2represents ethylene group;

R3represents a hydrogen atom;

Z represents a methylene group;

W represents (i), sawn or boutelou group, (ii) alkoxy group with a straight or branched chain, having from 1 to 3 carbon atoms, (iii) alkylthio group with a straight or branched chain, having from 1 to 3 carbon atoms, (iv) monoalkylamines group with a straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylamino group, (vi) N-phenyl-N-ethylamino group, (vii) phenoxy group, (viii) phenylthio group, (ix) phenylamino group, (x) 3-phenylpropionyl group, (xi) 4-phenylbutyl group, or (xii) 1-pyrrolidinyl group;

X represents a phenyl group which may have the Laura, of benzyl, phenyl, phenoxy, phenylthio, pyridyl, pyridyloxy, pyridylthio groups; and

Y represents an oxygen atom;

(34) the compound in which R1represents an alkyl group having one or two carbon atom,

R2represents ethylene group;

R3represents a hydrogen atom;

Z represents a methylene group;

W represents boutelou, ethoxy, methylthio, ethylamino, diethylamino, N-phenyl-N-ethylamino, phenoxy, phenylthio, phenylamino, 3-phenylpropyl or 1-pyrrolidinyl group;

X represents a phenyl group which may have one Deputy , mentioned below;

Deputy chosen from the group consisting of hydroxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, pyridyl, pyridyloxy, pyridylthio groups; and

Y represents an oxygen atom; and

(35) the compound in which R1represents an alkyl group having one or two carbon atom;

R2represents ethylene group;

R3represents a hydrogen atom;

Z represents a methylene group;

W represents boutelou, ethoxy, methylthio, ethylamino, phenoxy, phenylthio, phenylamino or 3-phenylpropyl group;

X represents phenyl PPI, consisting of hydroxy, chlorine atom, benzyl, phenyl, phenoxy, phenylthio, pyridyl, pyridyloxy, pyridylthio groups; and

Y represents an oxygen atom.

Examples of derivatives phenylalkylamines acid of formula I, their pharmacologically acceptable salts or their pharmaceutically acceptable complex ester include compounds illustrated below.

In Tables 1-68 used the following abbreviations.

Ac: acetyl, Bu: butyl, tBu: tert-butyl, Bimid: benzimidazolyl, Boxa: benzoxazolyl, Bthiz: benzothiazolyl, Bz: benzyl, Et: ethyl. Fur: furyl. Hex: hexyl, Imid: imidazolyl, Ind: indolyl, Isox: isoxazolyl, Mdo: methylendioxy. Me: methyl. Mor: morpholino, Np: naphthyl, Oxa: oxazolyl. Pen: pencil, Ph: phenyl, Pip: piperidyl, Pr: propyl, iPr: isopropyl. Pym is not: pyrimidinyl, Pyr: pyridyl, Pyrd: pyrrolidinyl, Pyrr: pyrrolyl, Pyza: pyrazolyl, Quin: hinely, iQuin: ethanolic, Thi: thienyl, Thiz: thiazolyl.

The compounds in Tables 1-55 and tables 66-68 have the following formula (Ia) and compounds in tables 56-65 have the following formula (Ib).

< / BR>
< / BR>
Derived phenylalkylamines acid of formula (1) of the present invention, its pharmacologically acceptable salt or a pharmacologically acceptable ester easily get under the crystals, (IV), and the connection is produced by the interaction of the compounds of formula (II) with the compound of the formula (III).

In the case where U is hydroxyl group, the reaction is carried out under standard Mitsunobu reaction [O. Mitsunobu, Synthesis, 1 (1981)].

The reaction is usually carried out by contacting the source of compounds with azo compounds and phosphines in the solvent. Azo compounds used in the reaction, are C1-C4the alkyl azodicarboxylate, such as diethylazodicarboxylate, and azodicarboxamide, such as 1,1'-(azodicarbon)dipiperidino. As phosphines use triarylphosphine, such as triphenylphosphine, and three(C1-C4alkyl)phosphine, such as tributylphosphine.

The reaction is usually carried out preferably in a solvent. The solvent is not particularly limited because it does not have a deleterious effect on the reaction. Examples of suitable solvents include hydrocarbons, such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, such as dimethylformamide, dimethylacetamide and creamrose esters. The reaction temperature is in the range from 10 to 100oC, preferably from 20 to 80oC.

Although the reaction time varies depending on the reaction reagent, reaction temperature and solvent, it usually is in the range from one hour to 3 days, preferably from 5 hours to 2 days.

In the case where U represents a halogen atom or a group of the formula: -O-SO2-R5(where R5has the same meaning as defined above), the reaction is carried out in the presence of a base in an inert solvent.

Used the base includes, for example, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride; alkali metal alkoxides such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and lithium methoxide; nitially, such as utility and motility; lithium amides such as diethylamide lithium, diisopropylamide lithium - bis(trimethylsilyl)amide lithium; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; tertiary organic amines, such as 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo[5.4.0] undec-7-ene and N,N - diisopropylamino

The inert solvent used in the reaction, is not particularly limited because it does not have a deleterious effect on the reaction. Examples of suitable solvents include hydrocarbons, such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol and tert-butanol; amides, such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; ketones, such as acetone and 2-butanone; NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide, and a mixture thereof, preferably ethers, amides, ketones and sulfoxidov.

In the case where the reaction is carried out in the presence of a phase transfer catalyst, such as benzyltriethylammonium iodide and tetrabutylammonium iodide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, are used as the base. The reaction is carried out in a solvent, representing a two-layer system: ox and halogenated hydrocarbons such as methylene chloride and chloroform.

The reaction temperature is in the range from -10 to 120oC, preferably from 10 to 100oC.

Although the reaction time varies depending on the reagent, the temperature of REE W1represents a primary or secondary amino group, which protects using a conventional protective group such as tert-butoxycarbonyl, after the reaction, removing the protection can be carried out according to a known method, for example, by reacting the compounds of formula (IV) with an acid, such as hydrochloric acid, at room temperature for from 30 minutes to 2 hours.

Stage A2

Stage A2 is to obtain a derived phenylalkylamines acid of the formula (I), and the connection is obtained by removal of the ester residue of the compounds of formula (IV).

This stage is carried out by hydrolysis of compounds of formula (IV) with a base in a solvent.

In this reaction the solvent is not particularly limited because it does not have a deleterious effect on the reaction, and preferably includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; water; and their mixtures.

The base used in the reaction includes, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as lithium carbonate, carbon and varies depending on the solvent and the base, it ranges from 0 to 100oC, preferably from 10 to 80oC.

Although the reaction time varies depending on the solvent used for the base and the reaction temperature, it is usually from 10 minutes to 24 hours, preferably from 30 minutes to 16 hours.

Further, in the case where the ester residue is tert-boutelou, diphenylmethylene or p-methoxybenzyloxy group, this stage is also carried out by reaction of compounds of formula (IV) with organic acids such as formic acid, acetic acid, triperoxonane acid, methanesulfonate, benzosulfimide, p-toluensulfonate, triftoratsetata, and mineral acids such as hydrochloric acid and sulfuric acid, in the presence or in the absence of solvent. This stage is conducted preferably by interacting with triperoxonane acid or hydrochloric acid.

In this reaction, in the case where the use of a solvent, the solvent used is not particularly limited because it does not have a deleterious effect on the reaction. Examples of suitable solvents include hydrocarbons, such as benzene, toluene, cciperiod; ethers, such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; amides such as dimethylformamide, dimethylacetamide and triamide hexamethylphosphoric acid; esters such as methyl acetate and ethyl acetate; water; and a mixture thereof, preferably ethers.

Although the reaction temperature varies depending on the acid used, it is in the range from -10 to 120oC, preferably from 0 to 100oC.

Although the reaction time varies depending on the acid and the reaction temperature, it is usually from 10 minutes to 24 hours, preferably from 30 minutes to 16 hours.

Further, in the case where the ester residue is aracelio group, such as benzyl and diphenylmethylene group, this stage is also carried out by catalytic hydrogenation of compounds of formula (IV). Used catalyst includes, for example, palladium on carbon, palladium black, platinum oxide and platinum black, preferably palladium on carbon.

The reaction is usually carried out preferably in the presence of a solvent. Solvent used is not particularly limited because it does not have harmful vosgean and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol and isopropanol; amides, such as dimethylformamide, dimethylacetamide and triamide hexamethylphosphoric acid; carboxylic acids such as formic acid and acetic acid; and a mixture thereof, preferably alcohols.

The reaction temperature is in the range from 10 to 140oC, preferably from 20 to 120oC.

Although the reaction time varies depending on the reaction reagent, reaction temperature and solvent, it is usually from 30 minutes to 3 days, preferably from one hour to one day.

The compound of formula (IV) used in method A, can also be obtained according to method B (see end of description)

Stage B1 in method B is to obtain the compounds of formula (IV). Connection get through interaction of the compounds of formula (V) with the compound of the formula (VI).

The reaction is carried out analogously to the method described in stage A1 of method A, which was already described in detail.

Derived phenylalkylamines acid of the formula (I) and soy is the SCP is a protective group, known in organic synthetic chemistry. Examples of such protective groups include C7-C14aracelio group, such as benzyl, diphenylmethyl, trityl, C1-C4aliphatic acyl group which may be substituted by fluorine, such as formyl and TRIFLUOROACETYL; (C1-C4alkoxy) carbonyl group, such as tert-butoxycarbonyl; and benzyloxycarbonyloxy group which may be substituted by methoxy or nitro, such as benzyloxycarbonyl, p-methoxybenzenesulfonyl and p-nitrobenzenesulfonyl. In the case where R6and R7taken together, represent aminosidine group, protective groups include, for example, palorinya group. The preferred benzyl, triticina, tert-butoxycarbonyl, benzyloxycarbonyl and calolina group.

Stage C1

Stage C1 is to obtain the compounds of formula (VIII) and it is conducted through the interaction of the compounds of formula (VII) with the compound of the formula (III).

This stage is conducted in a similar way as described in stage A1 of method A.

Stage C2

Stage C2 is to obtain the compounds of formula (IX) and it is conducted by removing the protective group R7soedinitelnotkannymi recovery such as kalkilya and aracelikarsaalyna group, or a group that can be removed using an acid, such as triticina and tert-butoxycarbonyl group, the reaction unprotect 4 conduct a similar method described in stage A2 of method A.

In the case where the protective group R7represents an aliphatic acyl group such as formyl and TRIFLUOROACETYL, it is removed in basic terms.

The base used herein include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate, preferably the alkali metal hydroxides.

This reaction is preferably carried out in an inert solvent, for example alcohols, such as methanol and ethanol; water; ethers such as tetrahydrofuran and dioxane; or mixtures thereof, more preferably in alcohols.

The reaction temperature is in the range from 0 to 100oC, preferably from 10 to 80oC.

Although the reaction time varies depending on the reagent, the reaction temperature and solvent, it is usually from 30 minutes to 24 hours, preferably from 1 to 16 the group includes palolo group, and it can be removed by treatment with hydrazine or primary amines.

The hydrazines used here include, for example, hydrazine, methylhydrazine and phenyl, preferably hydrazine. In addition, primary amines, which can be used include methylamine, ethylamine, Propylamine, butylamine, isobutylamine, pentylamine and hexylamine, preferably Propylamine and butylamine.

This reaction is carried out in an inert solvent, for example alcohols, such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; or mixture thereof, the preferred alcohols.

The reaction temperature is in the range from 0 to 100oC, preferably from 10 to 80oC.

Although the reaction time varies depending on the reaction reagent, reaction temperature and solvent, it is usually from 30 minutes to 24 hours, preferably from one hour to 16 hours.

Stage C3

Stage C3 is to obtain the compounds of formula (IV), and it is carried out by reaction of dehydration-condensation of amino compounds of the formula (IX) with a carbonyl compound of the formula (X)

This stolko it has no adverse effect on the reaction. Examples of suitable solvents include hydrocarbons such as hexane, benzene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; esters such as ethyl acetate and butyl acetate; and amides, such as dimethylformamide and dimethylacetamide, preferably hydrocarbons, halogenated hydrocarbons, ethers, and alcohols.

The reaction temperature is in the range from 0 to 120oC, preferably from 10 to 100oC.

Although the reaction time varies depending on the reaction reagent, reaction temperature and solvent, it is usually from 30 minutes to 24 hours, preferably from 1 hour to 16 hours.

Stage C4

Stage C4 is to obtain the compounds of formula (I). In the case where W1represents an amino group which protects using a conventional protective group such as tert - butoxycarbonyl, if necessary, after removal aminosidine group, the compound of formula (IV) into a compound of formula (I), removing the ester residual group. In reaction to the destruction of aminosidine group perform a similar Spandau in stage A2 of method A.

The compound of formula (II), which is the starting material in method A, can be obtained, for example, according to method D (see the end of the description).

The compound of formula (IIa) obtained according to this method, is the compound of formula (II) in which U is a hydroxyl group. The compound of formula (IIb) is a compound of formula (II) in which U is a halogen atom or a group of the formula: - O-SO2-R5(where R5has the same meaning as defined above).

Stage D1

Stage D1 is to obtain the compounds of formula (XII), and the connection is produced by the interaction of the compounds of formula (V) with the compound of the formula (XI).

This reaction is carried out a method similar to that already described in stage A1 of method A, where U is a halogen atom or a group of the formula: -O-SO2-R5(where R5has the same meaning as defined above).

Stage D2

Stage D2 is to obtain the compounds of formula (IIa), and this compound is obtained by removing tetrahydropyranyloxy group of compounds of formula (XII).

This reaction is performed in a manner analogous to that described for removing the protection with the acid in stage A2 of the way the t by conversion of the hydroxyl group in the compound of formula (IIA) in the halogen atom - or a group of the formula: -O-SO2-R5(where R5has the same meaning as defined above).

In the case where U1in the compound of formula (IIb) represents a halogen atom, the compound of formula (II) is produced by interaction of the compounds of formula (IIA) with a halogenation agent in a solvent.

Used halogenation means includes thionylchloride, such as thionyl chloride and thienylboronic; pentavalent phosphorus, such as pentachloride phosphorus and pentabromide phosphorus; oxychlorine phosphorus, such as phosphorus oxychloride and oxybromide phosphorus; oxalicacid etc., preferably thionylchloride and oxalicacid.

Used here, the inert solvent is not particularly limited because it does not have a deleterious effect on the reaction. Examples of suitable solvents include hydrocarbons such as hexane, benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate and butyl acetate, preferably halogenated hydrocarbons and ethers.

The reaction temperature is in the range from -10 to 100o

Alternatively, the compound of formula (IIb) is also produced by the interaction of the compounds of formula (IIa) with a halogenation agent, such as tetragonopterinae carbon, such as carbon tetrachloride and tetrabromide carbon, and N-halogenating, for example, N-bromosuccinimide and N-chlorosuccinimide, in the presence of tri-C6-C10aryl or three-C1-C4alkylphosphines, such as triphenylphosphine and tributylphosphine. The reaction conditions for this reaction are similar to the conditions of the Mitsunobu reaction described in stage A1 of method A.

In the case where U1in the compound of formula (IIa) represents a group of formula: -O-SO2-R5(where R5has the same meaning as defined above), a compound of formula (IIb) are obtained by reacting the compounds of formula (IIa) with the compound of the formula: -R-SO2-Cl (where R5has the same meaning as defined above) or a compound of the formula: (R5-SO2)2O (where R5has the same meaning as defined above) in an inert solvent in the presence of a base.

Used the base preferably includes tertiary amines such as Tr is not limited to, because it does not have a deleterious effect on the reaction. Examples of suitable solvents include hydrocarbons such as hexane, benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate and butyl acetate, preferably halogenated hydrocarbons and ethers.

The reaction temperature is in the range from -10 to 100oC, preferably from 0 to 60oC.

Although the reaction time varies depending on the reagent, temperature and solvent, it is usually from 30 minutes to 24 hours, preferably from 1 to 16 hours.

In addition, the compounds of formula (V), which are used as starting compounds are known compounds or they can easily get according to a known method. The connection is easily obtained by reaction of dehydration-condensation of the corresponding carbonyl compounds with hydroxylamine (for example, Shin-jikken called koza, 14 (III), p. 1325, complied by The Chemical Society of Japan, published by Maruzen K. K., "Comprehensive Organic Functional Group Transformation", 3, P. 425, authors: A. R. Katritzby et al., published by Pergamon (United Kingdom), 1995, etc.).

The desired compounds are obtained in which, what rekristallizatsiei, presidenial, etc. after each reaction. The purified product can be obtained, for example, by appropriate neutralization of the reaction mixture, adding a solvent in the reaction mixture to be extracted it, evaporating the solvent from the extract and purification of the residue by column chromatography using silica gel.

Derivatives phenylalkylamines acid of the formula (I) of this invention, their pharmaceutically acceptable salts or their pharmaceutically acceptable esters are used as therapeutic or prophylactic agents, particularly as therapeutic agents for the treatment of many diseases. Examples of such diseases are diseases caused by insulin resistance, such as hyperlipemia, hyperglycemia, obesity, a condition of impaired glucose tolerance (the state of impaired glucose tolerance (IGT)), the state of insulin resistance with undisturbed glucose tolerance (the state of insulin resistant non-IGT (NGT)), hypertension, osteoporosis, pancreatitis, cachexia, fatty infiltration, diabetic complications (e.g. retinopathy, nephropathy, cataract, coronary artery disease and etc.), arteriosclerosis, cataract, goes the s diseases (for example, epiphyseal osteomyelitis, pain, hyperthermia, inflammatory enteritis and so on), acne, solar erythema (sunburn), psoriasis, eczema, allergic diseases, asthma, ulcer, gastrointestinal tract, cardiovascular diseases (e.g. coronary heart disease (ishemic heart diseases), etc.), cellular damage caused by atherosclerosis and ischemic diseases (e.g. brain damage caused by apoplexy), autoimmune diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, Sjogren''s syndrome, diffuse scleroderma (diffuse scleroderma)diffuse disease of connective tissue (mixed connective-tissue disease), dermatomyositis (dermatomyositis), Hashimoto''s disease, primary myxedema (primary myxedema), hyperthyroidism (thyrotoxicosis), perniciosa anemia (permicious anemia), ulcerative colitis, autoimmune atrophic gastritis (autoimmune athrophic gastritis), idiopathic Addison disease, male sterility, Goodpasture''s syndrome, acute progressive glomerular nephritis, myasthenia gravis (myasthenia gravis, polymyositis, common bladderwort, bullous pemphigoid (bullous pemphigoid), sympathetic ophthalmia, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (idiop, Behcet's disease (Bechet's), CREST syndrome, etc), preferably, therapeutic or prophylactic agent (particularly a therapeutic agent for hyperglycemia, osteogenesis, pancreatitis or rheumatism, particularly hyperglycemia, pancreatitis or rheumatism.

Derivatives phenylalkylamines acid of formula I, their pharmacologically acceptable salts or their esters are used in various forms. Form of application is not particularly limited and is determined depending on various types of preparative forms, age, sex and other conditions of the patient, etc., for Example, the connection is used orally in the form of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In addition, in the case of injection, intravenously can be used as such or in a mixture with a standard adjuvant, such as glucose and amino acid, and in addition, if necessary, separately injected intramuscularly, intradermally, subcutaneously or administered intraperitoneally. In the case of suppositories, it is injected (intra)rectal. Preferably oral administration.

Different types of these drugs can be obtained by mixing a known adjuvant commonly used in the field of technology is the Torah, the corrigentov (gives taste and smell) and the means for covering, with a component of the formula (I) according to the standard method.

When this connection is made in the form of tablets, can be widely used substance, commonly known in this area as carriers. Examples of such substances include fillers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, purified syrup (single syrop), glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; disintegrators such as starch, sodium alginate, agar powder,

the powder laminaran, sodium bicarbonate, calcium carbonate, ester of polyoxyethylenesorbitan and fatty acids, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose; inhibiting the disintegration tools, such as sucrose, stearic acid, cocoa butter and gidrirovannoe oil; accelerating the absorption means, such as Quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbing media the initial talc, stearate, boric acid powder and polyethylene glycol. In addition, if necessary, you can get the tablets covered with a film coating, for example, a tablet with a sugar coating the pill with a gelatin coating the tablet with interoperation, tablet film coated tablet with dual layer or multilayer tablet.

When this connection is made in the form of pills, can be widely used (connection), well known in this area as carriers, and these include, for example, excipients such as glucose, lactose, starch, cacao butter, gidrirovannoe vegetable oil, kaolin and talc; binders such as powdered Arabian gum, powder tragakant, gelatin and ethanol; and dezintegriruetsja tools, such as laminaran and agar. When the proposed connection is made in the form of suppositories, can be widely used substances are well known in this area, and they include, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohol, gelatin and semi-synthetic glycerides.

In the case where the connection receive in the form of injection, it is preferable that the solution and suspension were sterilized and were isotonic by ethnostate all substances usually used in this field as diluents, and they include, for example, water, ethanol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol and an ester of polyoxyethylenesorbitan and fatty acids. In this connection, in this case, the pharmaceutical preparation may contain a sufficient amount of NaCl, glucose, or glycerin to produce isotonic.

In addition, there can be also added substances that improve solubility, buffers, and sedatives. In addition, they (the drugs), if necessary, may contain coloring tools, preservatives, odorants, corrigentov, sweetening agents and other pharmaceutical medicines.

The number of active ingredients contained in the above-mentioned pharmaceutical compositions, particularly not limited, and (), respectively, is selected within a wide range, and appropriate to the content (the active ingredients) in all compositions ranged from 1 to 70% by weight, preferably from 1 to 30% by weight.

The dose may vary depending on the condition of the patient, age, body weight, method p is respectfully 0.01 mg, more preferably 0.1 mg) as a lower limit and 2000 mg, preferably 200 mg, more preferably 20 mg) as an upper limit for a single admission to several times a day.

(The preferred embodiment of the invention)

Below the invention is described in more detail using examples, comparative examples, sample test and examples of formulations, but the invention is not restricted by them.

Example 1. Ethyl 2-ethoxy-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate(ethyl ester of compound N 2-35)

49 mg of sodium hydride (55% oil suspension) are added to a mixture of 242 mg of ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate in 4 ml of N,N-dimethylformamide and 2 ml of toluene and the mixture is stirred at room temperature for 30 minutes.

A solution of 340 mg of 4'-(2-pyridyl)acetophenone O-2- (methanesulfonate) ethyl ester obtained in reference example 2 in 3 ml of N,N-dimethylformamide is added dropwise to the reaction mixture and the resulting reaction mixture was stirred at 80oC for 3 hours. After the reaction, the reaction mixture are added ethyl acetate and water, the ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated PR is the best 373 mg of the desired compound in the form of syrup, which soon crystallizes.

1) so pl. 59-61oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMC (TMS) (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.16 (3H, t, J=7 Hz), of 1.23 (3H, t, J=7 Hz), 2,28 (3H, s), 2,95 (2H, d, J= 6.5 Hz), 3,29 is 3.40 (1H, m), 3,54-the 3.65 (1H, m), of 3.97 (1H, t, J=6.5 Hz), 4,17 (2H, q, J=7 Hz), 4,28 (2H, t, J=5 Hz), 4,55 (2H, t, J=5 Hz), to 6.88 (2H, d, J= 8.5 Hz), 7,16 (2H, d, J=8 Hz), 7,22-7,27 (1H, m), 7,75-7,80 (2H, m), 7,76 (2H, d, J=8.5 Hz), 8,01 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=5 Hz).

Example 2. 2 ethoxy-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy] ethoxy]phenyl] propionic acid (Illustrative compound N 2-35)

1,30 ml of 1N. an aqueous solution of sodium hydroxide are added to a solution of 310 mg of ethyl 2-ethoxy-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethoxy] phenyl]propionate obtained in example 1 in 5 ml of ethanol and the mixture is stirred at room temperature for 1.5 hours. After the reaction, the ethanol is evaporated under reduced pressure and the pH of the mixture was adjusted to 3 with 1N. hydrochloric acid. Thus obtained reaction mixture was extracted with ethyl acetate and the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Received such OBO connection.

1) so pl. 133-135oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following: of 1.18 (3H, t, J=7 Hz), 2,28 (3H, s), 2,95 (1H, d, d, J=7,5, 14 Hz), is 3.08 (1H, d,d, J=4,5, 14 Hz), 3,39-3,50 (1H, m), 3,55-3,66 (1H, m), Android 4.04 (1H, d,d, J=4,5, 7.5 Hz), the 4.29 (2H, t, J=5 Hz), 4,56 (2H, t, J= 5 Hz), 6.89 in (2H, d, J=8.5 Hz), 7,17 (2H, d, J=8.5 Hz), 7,25-7,30 (1H, m), 7,74 (2H, d, J=8.5 Hz), 7,76-7,80 (2H, m), of 7.96 (2H, d, J=8.5 Hz), 8,72 (1H, d, J=4.5 Hz).

Example 3. Methyl 2-phenylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene] aminoxy] ethoxy] phenyl] propionate (methyl ester illustrative compounds N 31-35)

of 3.3 ml of a solution of 222 mg of diethylazodicarboxylate in toluene is added dropwise to a solution of 256 mg 2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethanol obtained in Reference example 1, 288 mg of methyl 3-(4-hydroxyphenyl)-2-(phenylthio)propionate obtained in Reference example 7, and 289 mg of triphenylphosphine in 5 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours and the reaction mixture is concentrated. The residue is subjected to double-column chromatography on silica gel (ethyl acetate: hexane = 1: 2 ethyl acetate: benzene = 1:4) to give 366 mg of the desired compound in the form of syrup.

1)1
of 2.27 (3H, s) of 3.00 (1H, d,d, J=6, 14 Hz), 3,14 (1H, d,d, J=9, 14 Hz), to 3.58 (3H, s), 3,86 (1H, d,d, J=6, 9 Hz), 4,27 (2H, t, J=5 Hz), 4,55 (2H, t, J= 5 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8.5 Hz), 7,22-7,34 (4H, m), 7,41 was 7.45 (2H, m), 7,72-7,80 (2H, m), 7,76 (2H, d, J=8.5 Hz), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=4.5 Hz).

Example 4. 2 phenylthio-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy] ethoxy]phenyl] propionic acid (Illustrative compound N 31-35)

2,00 ml of 1N. an aqueous solution of sodium hydroxide is added to a mixture of 350 ml of methyl 2-phenylthio-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethoxy] phenyl] propionate obtained in Example 3, 3 ml of methanol and 2 ml of dioxane and the mixture is stirred at 50oC for 4 hours. After the reaction, the reaction mixture was concentrated and diluted with water. Then the pH of the reaction mixture is adjusted to 3 with 1N. hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated, obtaining 324 mg of the desired compound as a foam solid.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.24 (3H, s), 3,01 (1H, d,d, J=6, 14 Hz) and 3.15 (1H, d,d, J=8.5 Hz), 7,68-7,80 (2H, m), a 7.85 (2H, d, J=8.5 Hz), 8,66 (1H, d, J=5,5 Hz).

Example 5. Ethyl 2-phenylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene] aminoxy] ethoxy]phenyl]propionate (ethyl ester of illustrative compounds N 32-35)

The reaction and post-processing is carried out according to Example 3, using 256 mg 2-[[1-[4- (2-pyridyl) phenyl] ethylidene] aminoxy] ethanol obtained in Reference example 1, 285 mg of ethyl 3-(4-hydroxyphenyl)-2-(phenylamino)propionate obtained in Reference example 5, 289 mg of triphenylphosphine and 222 mg of diethylazodicarboxylate, receiving 375 mg of the desired compound in the form of crystals.

1) so pl. 140oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following: to 1.19 (3H, t, J=7 Hz), 2,28 (3H, s), 3.00 and - 3,14 (2H, m), of 4.13 (2H, q, J=7 Hz), 4,15 (1H, brs), 4.26 deaths-4,34 (3H, m), 4,55 (2H, t, J=5 Hz), 6,60 (2H, d, J=8.5 Hz), was 6.73 (1H, t, J=7.5 Hz), to 6.88 (2H, d, J= 8.5 Hz), to 7.09 (2H, d, J=8.5 Hz), 7,13 - 7,27 (3H, m), 7,75 for 7.78 (2H, m), 7,76 (2H, d, J=8.5 Hz), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=4.5 Hz).

Example 6. 2 phenylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy]ethoxy]phenyl] propionic acid (Illustrative compound N 32-35)

The reaction is carried out according to Example 4, using 260 mg of ethyl 2-Fenn. an aqueous solution of sodium hydroxide. After the reaction, the reaction mixture was concentrated and diluted with water. the pH of the reaction mixture is adjusted to 4 with 1N. hydrochloric acid and the precipitate obtained by filtration. The precipitate is washed with water and isopropyl ether, getting 224 mg of the desired compound.

1) so pl. 149-152oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.27 (3H, s), 3.04 from (1H, d,d, J=6,5, 14 Hz), 3,17 (1H, d,d, J=5,5, 14 Hz), 4,25-4,30 (3H, m), of 4.54 (2H, t, J=5 Hz), 6,60 (2H, d, J=8 Hz), 6,69 (1H, d, J=7.5 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,12-7,17 (4H, m), 7,25-7,30 (1H, m), 7,76 (2H, d, J=8.5 Hz), to 7.77-7,83 (2H, m), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=4.5 Hz).

Example 7. Ethyl 2-(N,N-diethylamino)-3-[4-[2-[[1-[4-(2- pyridyl)phenyl]ethylidene] aminoxy] ethoxy]phenyl] propionate (ethyl ester of illustrative compounds N 47-35)

The reaction and post-processing is carried out according to Example 1, using 337 mg of 4'-(2-pyridyl)acetophenone O-2-(methanesulfonate)ethyl ester obtained in Reference example 2, 243 mg of ethyl 2-(N,N-diethylamino)-3-(4-hydroxyphenyl) propionate obtained in Reference example 9, and 44 mg of sodium hydride (55% oil suspension (270 MHz), defined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.02 (6H, t, J=7 Hz), of 1.16 (3H, t, J=7 Hz), 2,28 (3H, s), 2,52 (2H, sextet, J=7 Hz), 2,78 (2H, sextet, J=7 Hz), 2,80 (1H, d,d, J=6 and 13.5 Hz), 3,01 (1H, d,d, J=9 and 13.5 Hz), of 3.56 (1H, d,d, J=6, 9 Hz), 4,00-to 4.14 (2H, m), 4,27 (2H, t, J=5 Hz), 4,55 (2H, t, J=5 Hz), 6,86 (2H, d, J=8.5 Hz), 7,12 (2H, d, J= 8.5 Hz), 7,22-7,27 (1H, m), 7,75 for 7.78 (4H, m), 8,01 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=4.5 Hz).

Example 8. 2-(N,N-Diethylamino)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene] aminoxy] ethoxy] phenyl] propionic acid (Illustrative compound N 47-35)

2,75 ml of 1N. an aqueous solution of sodium hydroxide is added to a mixture of 474 mg of ethyl 2-(N,N-diethylamino)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy] ethoxy]phenyl] propionate obtained in Example 7, 5 ml of methanol and 3 ml of dioxane. The resulting mixture was stirred at 50oC for 18 hours. After the reaction, methanol and dioxane is evaporated under reduced pressure and then the residue is diluted with water. the pH of the mixture was adjusted to 4 by the addition of 2.75 ml of 1N. hydrochloric acid and the precipitate collected by filtration. The precipitate is washed with water and isopropyl ether, receiving 440 mg of the desired compound.

1) so pl. 157-159oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), ODA is the sulfoxide, is the following: to 0.96 (6H, t, J=7 Hz), of 2.23 (3H, s), 2,54 - 2,78 (5H, m), 2,96 (1H, d,d, J=7,5, 14 Hz), 3,48 (1H, t, J=7 Hz), 4,25 (2H, t, J=5 Hz), to 4.46 (2H, t, J=5 Hz), to 6.88 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8.5 Hz), 7,35-7,40 (1H, m), 7,80 (2H, d, J=8.5 Hz), of 7.90 (1H, d, t, J=l,5, 7.5 Hz), 8,01 (1H, d, J=8 Hz), 8,13 (2H, d, J=8.5 Hz), 8,68 (1H, d, J=4 Hz).

Example 9. Ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy] ethoxy]phenyl] -2-(phenylamino) propionate (ethyl ester of illustrative compounds N 32-4) Reaction and post-processing is carried out according to Example 3, using 179 mg of 2-[[1-(4 - biphenylyl)ethylidene] aminoxy]ethanol obtained in Reference example 3, 200 mg of ethyl 3-(4-hydroxyphenyl)-2-(phenylamino) propionate obtained in Reference example 5, 183 mg of triphenylphosphine and 122 mg of diethylazodicarboxylate getting 282 mg of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.19 (3H, t, J=7 Hz), and 2.27 (3H, s), 3.00 and-3,14 (2H, m), of 4.12 (2H, d, q, J=l, 7 Hz), 4,25-to 4.33 (3H, m), of 4.54 (2H, t, J=5 Hz), 6,60 (2H, d, J=8.5 Hz), was 6.73 (1H, t, J=7.5 Hz), to 6.88 (2H, d, J=8,5 Hz)that was 7.08 (2H, d, J=8.5 Hz), 7,16 (2H, t, J=7.5 Hz), 7,33 - of 7.48 (3H, m), 7,58-to 7.61 (4H, m), 7,70-7,74 (2H, m).

Example 10. 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy] ethoxy]phenyl]-2-(phenylamino) PR added to a solution of 282 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene] aminoxy]ethoxy]phenyl] -2-(phenylamino) propionate, obtained in Example 9, in 3 ml of dioxane. The mixture was stirred at 60oC for one hour. After the reaction, the reaction mixture was concentrated and diluted with water. Then 1,71 ml of 1N. hydrochloric acid is added to the mixture and the resulting product is extracted with a large amount of hot ethyl acetate. The extract was concentrated to approximately 5 ml and 229 mg of the desired compound is obtained by filtering.

1) so pl. 184-187oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated dimethyl sulfoxide, is the following:

of 2.20 (3H, s), 2,90 (1H, d,d, J=8, 14 Hz) of 3.00 (1H, d,d, J=6, 14 Hz), of 4.05 (2H, d, d, J= 6, 8 Hz), 4,25 (2H, t, J=5 Hz), to 4.46 (2H, t, J=5 Hz), 6,51 return of 6.58 (3H, m), 6.89 in (2H, d, J=8.5 Hz), 7,05 (2H, t, J=8 Hz), 7,21 (2H, t, J=8.5 Hz), of 7.36-7,51 (3H, m), 7.68 per-to 7.77 (6H, m).

Example 11. Ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy] ethoxy]phenyl] -2-[N-phenyl-N-ethylamino] propionate (ethyl ester of illustrative compounds N 49-4)

The reaction and post-processing is carried out according to Example 3, using 230 mg of 2-[[1-(4-biphenylyl)ethylidene] aminoxy] ethanol obtained in Reference example 3, 300 mg of ethyl 3-(4-hydroxyphenyl) -2-(N-phenyl-N-ethylamino)prmg the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

a 1.08 (3H, t, J=7 Hz) and 1.15 (3H, t, J=7 Hz), and 2.27 (3H, s), 3,05 (1H, d,d, J= 7,5, 14 Hz), 3,24-of 3.46 (3H, m), 4.09 to (2H, q, J=7 Hz), 4.26 deaths (2H, t, J=5 Hz), 4,39 (1H, t, J=7.5 Hz), a 4.53 (2H, t, J=5 Hz), 6,66-6,76 (3H, m), 6,86 (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8.5 Hz), 7.18 in-to 7.25 (2H, m), 7,33-7,38 (1H, m), 7,45 (2H, d, J=7.5 Hz), 7,58-to 7.61 (4H, m), 7,72 (2H, d, J=8,5 Hz).

Example 12. Hydrochloride 3-[4-[2-[[1-(4-biphenylyl)ethylidene] aminoxy]ethoxy]phenyl]-2-[N-phenyl-N-ethylamino]propionic acid (hydrochloride illustrative compounds N 49-4)

The reaction and post-processing is carried out according to Example 4, using 353 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy] ethoxy]phenyl]-2-(N-phenyl-N-ethylamino) propionate obtained in Example 11 and 2 ml of 1N. an aqueous solution of sodium hydroxide. Thus obtained product is then treated with a solution: 4h. hydrogen chloride-dioxane, getting 280 mg of the hydrochloride of the desired compound as amorphous powder.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated dimethyl sulfoxide, presented the Hz), a 4.53 (1H, d,d, J=6, 9 Hz), 6,61-6,72 (3H, m), 6,86 (2H, d, J=8.5 Hz), 7,12-7,17 (4H, m), of 7.36-7,51 (3H, m), 7,69 for 7.78 (6H, m).

Example 13. Ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene] aminoxy]ethoxy]phenyl]-2-pyrrolidione (ethyl ester illustrative compounds N 50-4)

The reaction and post-processing is carried out according to Example 1, using 333 mg of 2-[[1-(4-biphenylyl)ethylidene] aminoxy] ethyl of methanesulfonate obtained in Reference example 4, 260 mg of ethyl 3-(4-hydroxyphenyl)-2-pyrrolidione obtained in Reference example 8, and 50 mg of sodium hydride (55% oil suspension) to give 440 mg of the desired compound in the form of resin.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.20 (3H, t, J=7 Hz), and 2.27 (3H, s), 3,19 (1H, d,d, J=8,5, 14 Hz), 3,34 (1H, d, d, J= 6,5, 14 Hz), 4,17 (2H, q, J=7 Hz), 4,25 (2H, t, J=5 Hz) to 4.52 (1H, t, J=5 Hz), and 4.68 (1H, d, d, J=6,5, 8.5 Hz), 6,13-x 6.15 (2H, m), of 6.71-6.73 x (2H, m), PC 6.82 (2H, d, J=8.5 Hz), 6,93 (2H, d, J=8.5 Hz), 7,33-of 7.48 (3H, m), 7,58-to 7.61 (4H, m), 7,72 (2H, d, J=8,5 Hz).

Example 14. 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy] ethoxy]phenyl]-2-paralipophobia acid (Illustrative compound N 50-4)

The reaction and post-processing is carried out according to Example 10, using 167 mg of ethyl the hydrate of lithium hydroxide, getting 135 mg of the desired compound in the form of crystals.

1) so pl. 163-165oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard in deuterated chloroform and a small amount of deuterated dimethyl sulfoxide, is the following:

of 2.26 (3H, s), 3,17 (1H, d,d, J=9,5, 14 Hz), 3,38 (1H, d,d, J=5,5, 14 Hz), 4,24 (2H, t, J=5 Hz), 4,51 (2H, t, J=5 Hz), of 4.67 (1H, d,d, J=5,5, 9.5 Hz), 6,09-6,11 (2H, m), 6,70-6,72 (2H, m), to 6.80 (2H, d, J-8.5 Hz), 6,92 (2H, d, J=8.5 Hz), 7,33-of 7.48 (3H, m), 7,56 to 7.62 (4H, m), 7,72 (2H, d, J=8,5 Hz).

Example 15. Hydrochloride ethyl 2-ethylamino-3-[4-[2-[[I-[4- (2 - pyridyl)phenyl] ethylidene]aminoxy]ethoxy]phenyl] propionate (hydrochloride of ethyl ether complex illustrative compounds N 43-35)

(a) Ethyl 2-(N-tert-butoxycarbonyl)ethylamino-3-[4-[2- [[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl] propionate

The reaction and post-processing is carried out according to Example 3, using 256 mg 2 -[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy] ethanol obtained in Reference example 1, 337 mg of ethyl 2-N- (tert-butoxycarbonyl)ethylamino-3-(4-hydroxyphenyl)propionate obtained in Reference example 10, 289 mg of triphenylphosphine and 556 mg of diisopropylcarbodiimide, receiving 320 mg of the desired compound is of TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 0.92 (3H, t, J= 7 Hz), 1.18 to 1.32 to (3H, m), of 1.45 (9H, s) to 2.29 (3H, s), 2,55-to 2.85 (1H, m), 3.00 and is 3.40 (3H, m), 3,85-of 4.25 (3H, m), 4,28 (2H, t, J=5 Hz), 4,55 (2H, t, J=5 Hz), to 6.88 (2H, d, J=8.5 Hz), 7,05-7,14 (2H, brd, J=8.5 Hz), 7,22-7,26 (1H, m), 7,75-of 7.82 (4H, m), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=5 Hz).

(b) Hydrochloride of the ethyl 2-ethylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy]ethoxy]phenyl] propionate

312 mg of ethyl 2-N-(tert-butoxycarbonyl)ethylamino-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene] aminoxy]ethoxy]phenyl]propionate obtained in Example 15 (a), dissolved in 5 ml of a solution: 4N hydrogen chloride-dioxane and the mixture is stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated. The residue is converted into a powder in ethyl acetate, and the powder is collected by filtration, getting 273 mg hygroscopic hydrochloride of the desired compound.

1) 1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated dimethyl sulfoxide, is the following:

of 1.10 (3H, t, J=7 Hz), 1,24 (3H, t, J=7 Hz), of 2.25 (3H, s), 2.95 and-a 3.06 (2H, m), 3,39 (1H, q, J=7 Hz), 4,08 (2H, q, J=7 Hz), 4,18-4,22 (1H, m), the 4.29 (2H, t, J=5 Hz), 4,50 (2H, t, J=5 Hz), to 6.95 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8.5 Hz), to 7.59-to 7.64 (1H, m), a 7.85 (2H, d, J=8.5 Hz), 8,15 (2H, d, J=8.5 Hz), 8.17-a 8,21 (2H, m), 8,77 (1H, d, J=5 Hz).< the (Illustrative compound N 43-35)

The reaction is carried out according to Example 2, using 273 mg of ethyl 2-ethylamino-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy] ethoxy]phenyl] propionate obtained in Example 15, and 2.4 ml of 1N. an aqueous solution of sodium hydroxide. When the pH of the thus obtained reaction mixture was adjusted to 4 with 1N. hydrochloric acid, to obtain the desired compound in the form of sludge. The precipitate is collected by filtration and washed with water, getting 186 mg of the desired compound.

so pl. 220-222oC (decomp.)

Example 17. Ethyl 2-methylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene] aminoxy]ethoxy]phenyl] propionate (ethyl ester of illustrative compounds N 26-35)

The reaction and post-processing is carried out according to Example 1, using 1.26 g of 4'-(2-pyridyl) acetophenone O-2-(methanesulfonate) ethyl ester obtained in Reference example 2, or 0.83 g of ethyl 3-(4-hydroxyphenyl)-2-(methylthio) propionate obtained in Reference example 11 (b), and 0.17 g of sodium hydride (55 about oil suspension) to give 1.50 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, t d,q, J=3, 7 Hz), 4,28 (2H, t, J=5 Hz), 4,55 (2H, t, J=5 Hz), 6.89 in (2H, d, J= 8.5 Hz), 7,13 (2H, d, J=8.5 Hz), 7,22-7,27 (1H, m), 7,75 for 7.78 (4H, m), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=4.5 Hz).

Example 18. 2-Methylthio-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethoxy]phenyl] propionic acid (Illustrative compound N 26-35)

of 5.05 ml of 1N. an aqueous solution of sodium hydroxide are added to a solution of 1.20 g of ethyl 2-methylthio-3- [4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy] phenyl] propionate obtained in Example 17, in 20 ml of ethanol and the mixture is stirred at 50oC for 30 minutes. After the reaction, the ethanol is evaporated under reduced pressure and of 5.05 ml of 1N. hydrochloric acid is added to the thus obtained residue, followed by extraction of the precipitated product by ethyl acetate. Thus obtained extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Thus obtained residual powder was washed with isopropyl ether, receiving 0.95 g of the desired compound.

1) so pl. 114-118oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

2,22 (3H, s in), 2.25 (3H, s), 2.91 in (1H, d,d1H, m), 7,63 (2H, d, J=8.5 Hz), 7,71-to 7.84 (2H, m), 7,87 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=4.5 Hz).

Example 19. Ethyl 2-(3-phenylpropyl)-3-[4-[2-[[1-[4-(2- pyridyl)phenyl] ethylidene] aminoxy] ethoxy] phenyl]propionate (ethyl ester of illustrative compounds N 66-8)

The reaction and post-processing is carried out according to Example 1, using 1,09 g of 4'-(2-pyridyl)acetophenone O-2-(methanesulfonate) ethyl ester obtained in Reference example 2, and 1.00 g of ethyl 2-(4 - hydroxybenzyl)-5-phenylvaleric obtained in Reference example 12 (C), and 160 mg of sodium hydride (55% oil suspension) to give 1.54 g of the desired compound in the form of crystals.

1) so pl. 53-55oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.14 (3H, t, J=7 Hz), 1,49 is 1.75 (4H, m), of 2.28 (3H, s), 2,56-a 2.71 (4H, m), 2,84 (1H, d,d, J=7,5, 12,5 Hz), of 4.05 (2H, q, J=7 Hz), 4,27 (2H, t, J=5 Hz), 4,55 (2H, t, J=5 Hz), 6,86 (2H, d, J=8,5 Hz), 7,05 (2H, d, J=8.5 Hz), 7,12-7,29 (6H, m), 7,75 for 7.78 (4H, m), 8,01 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=5 Hz).

Example 20. 2-(3-Phenylpropyl)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl]ethylidene] aminoxy] ethoxy] phenyl] propionic acid (Illustrative compound N 66-8)

of 0.67 g of potassium hydroxide are added to a solution of 1.20 g of the ore 19, in 20 ml of ethanol and the mixture is stirred at 80oC for 2 hours. After the reaction, the reaction mixture was concentrated. To the residue add water, ice and ethyl acetate and the pH of the reaction mixture is brought to a value of 4 through 3h. hydrochloric acid, and then the ethyl acetate layer is separated. Thus obtained extract is dried over anhydrous magnesium sulfate and then evaporated under reduced pressure, obtaining 1.10 g of the desired compound in the form of resin.

415 mg of the thus obtained desired compound was dissolved in 10 ml of ethanol there is added to 0.80 ml of 1N. aqueous sodium hydroxide solution, followed by concentration of the mixture. The thus obtained solid substance was washed with ethyl ether, receiving at 0.42 g of sodium salt of the desired compound as an amorphous solid.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated dimethyl sulfoxide, is the following:

1,40-to 1.67 (5H, m), 2,24 (3H, s), 2,36 is 2.51 (4H, m), and 2.83 (2H, d,d, J=7, 13.5 Hz), to 4.23 (2H, t, J=4 Hz), 4,48 (2H, t, J=4 Hz), for 6.81 (2H, d, J=8.5 Hz), 7,06 for 7.12 (5H, m), 7,17-of 7.23 (2H, m), 7,35 (1H, d,d, J=5, 6 Hz), 7,79 (2H, d, J=8.5 Hz), 7,87 (1H, d,t, J=l,5, 8 Hz), of 7.97 (1H, d, J=8 Hz), to 8.12 (2H, d is enyl] propionate (ethyl ester of illustrative compounds N 68-2)

The reaction and post-processing is carried out according to Example 1, using 1.18 g of 4'-(2-pyridyl)acetophenone O-2-(methanesulfonate)ethyl ester obtained in Reference example 2, 1.28 g of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate obtained in Reference example 13 (C), and 154 mg of sodium hydride (55% oil suspension) to give 1.28 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.19 (3H, t, J=7 Hz), and 2.26 (3H, s), 3,17-3,20 (2H, m) to 4.17 (2H, q, J=7 Hz), 4,27 (2H, t, J=5 Hz), of 4.54 (2H, t, J=5 Hz), 4,74 (1H, d,d, J=5,5, 6,5 Hz), 6,82-of 6.96 (5H, m), 7,21-7,26 (5H, m), 7,74 - to 7.77 (4H, m), 8,01 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=5 Hz).

Example 22. 2 Phenoxy-3- [4-[2-[[1-[4- (2-pyridyl) phenyl] ethylidene]aminoxy] ethoxy] phenyl] propionic acid (Illustrative compound N 68-2)

The reaction and post-processing is carried out according to Example 18, using 1.28 g of ethyl 2-phenoxy-3-[4-[2-[[1-[4-(2-pyridyl) 4 phenyl]ethylidene]aminoxy]ethoxy] phenyl] propionate obtained in Example 20 and 7,00 ml of 1N. an aqueous solution of sodium hydroxide, getting 1.13 g of the desired compound in the form of crystalline powder.

1) so pl. 145-148oC

2B as an internal standard in deuterated chloroform, is the following:

of 2.25 (3H, s), up 3.22 (2H, d, J 6 Hz), the 4.29 (2H, t, J=4.5 Hz), of 4.54 (2H, t, J= 4.5 Hz), to 4.81 (1H, t, J=6 Hz), 6,86-6,97 (5H, m), 7,21-7,31 (5H, m), to 7.67-7,89 (6H, m), 8,72 (1H, d, J=5 Hz).

Example 23. Ethyl 2-butyl-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethoxy]phenyl] propionate (ethyl ester of illustrative compounds N 67-8)

The reaction and post-processing is carried out according to Example 1, using 1.35 g of 4'-(2-pyridyl)acetophenone O-2-(methanesulfonate) ethyl ester obtained in Reference example 2, and 1.00 g of ethyl 3-(4 - hydroxybenzyl)kaproata obtained in Reference example 14 (C), and 200 mg of sodium hydride (55% oil suspension), receiving 0,94 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 0.87 (3H, t, J=7 Hz), of 1.16 (3H, t, J=7 Hz), 1,20-1,40 (4H, m), 1,40-1,70 (2H, m), of 2.28 (3H, s), of 2.51-of 2.72 (2H, m), 2,86 (1H, d,d, J=8,5, and 13.5 Hz), 4,06 (2H, q, J=7 Hz), 4,27 (2H, t, J=5 Hz), of 4.54 (2H, t, J=5 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,07 (2H, d, J=8.5 Hz), 7,21-7,27 (1H, m), 7,71-7,80 (4H, m), 8,01 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=5 Hz).

Example 24. 2-Butyl-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy] ethoxy]phenyl] propionic acid (Illustrative compound N 67-8)

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 0.88 (3H, t, J=8.5 Hz), of 1.23 to 1.37 (4H, m), USD 1.43-of 1.73 (2H, m), 2,60-to 2.74 (2H, m), 2,90 (1H, d,d, J=8,5, and 13.5 Hz), 4,30 (2H, t, J=5 Hz), 4,55 (2H, t, J= 5 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8.5 Hz), 7.24 to 7,28 (1H, m), 7.68 per-7,81 (4H, m), 7,95 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=5 Hz).

Example 25. Sodium salt of 2-butyl-3-[4-[2-[[1-[4-(2- pyridyl)phenyl]ethylidene] aminoxy] ethoxy]phenyl] propionic acid (sodium salt illustrative compounds N 67-8)

0,69 g of 2-Butyl-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid obtained in Example 24, the process of 1.50 ml of 1N. sodium hydroxide according to Example 20, receiving 0.65 g of the desired compound in the form of a powder.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated dimethyl sulfoxide, is the following:

of 0.79 (3H, t, J=6.5 Hz), 1.04 million-of 1.30 (5H, m), 1.30 and for 1.49 (1H, m), 2,09 was 2.25 (1H, m), of 2.23 (3H, s), 2,39 (1H, d,d, J=7,5, 13,5 GC (1H, d,t, J=2, 8.5 Hz), 8,00 (1H, d, J=8 Hz), 8,13 (2H, d, J=8.5 Hz), 8,69 (1H, d, J=4.5 Hz).

Reference example 1. 2-[[1-[4-(2-pyridyl)phenyl]ethylidene] aminoxy]ethanol

a) 4'-(2-Pyridyl)acetophenone

After adding dropwise 21 ml solution: 3M methylmagnesium-diethyl ether to a solution of 3.10 g of 4-(2-pyridyl) benzonitrile in 120 ml of dichloromethane under ice cooling in a nitrogen atmosphere, the mixture is stirred at room temperature for 20 hours. After the reaction, to the reaction mixture an aqueous solution of ammonium chloride and ethyl acetate, followed by stirring the resulting mixture. An ethyl acetate layer is separated from the reaction mixture, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel (ethyl acetate: hexane = 1: 2) to give the crude desired compound in the form of crystals. Next, the crude compound was washed with a mixture of diisopropyl ether-hexane, receiving, 1.56 g of the desired compound.

1) so pl. 116-118oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.66 (3H, s), 7,30 (1H, d,d, J=4,5, is doxylamine added to a solution: sodium methoxide-methanol, obtained from 14.1 g of sodium and 300 ml of methanol, and the mixture was stirred at 50oC for 30 minutes. 23,0 g of 4'-(2-pyridyl)acetophenone obtained in Reference example 1 (a) is added to the resulting suspension and the mixture was stirred at 50oC for 3 hours. After the reaction, the reaction mixture was concentrated. 0.3 l of ethyl acetate and 0.3 l of water added to the residue and the mixture is stirred, then collect 10,98 g besieged the desired connection filtering. The ethyl acetate layer in the filtrate was separated and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. Thus obtained crystalline residue was washed with diisopropyl ether, receiving 12,56 g of the desired compound.

1) so pl. 177-178oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.20 (3H, s), 7,35 (1H, d,d, J=4, 7.5 Hz), 7,78 (2H, d, J=8.5 Hz), 7,89 (1H, d, d, J=7,5, 8 Hz), 8,00 (1H, d, J=8 Hz), to 8.12 (2H, d, J=8.5 Hz), 8,68 (1H, d, J=4 Hz).

(c) 4'-(2-Pyridyl)acetophenone O-2- [(tetrahydropyran-2-yl)oxy] ethyl ester

6,00 g of potassium carbonate are added to a solution 3,20 g 2-(2-bromoethoxy)tetrahedral stirred at 80oC for 16 hours. After the reaction, the reaction mixture was dissolved in ethyl acetate and water. An ethyl acetate layer is separated and the extract is dried over anhydrous magnesium sulfate. The ethyl acetate is evaporated under reduced pressure and the residue purified by column chromatography on silica gel (hexane: ethyl acetate = 3:1), receiving a 2.01 g of the desired compound in the form of syrup.

(d) 2-[[1-[4-(2-Pyridyl)phenyl]ethylidene]aminoxy] ethanol

of 1.30 g of the monohydrate of p-toluenesulfonic acid are added to a solution 2,01 g of 4'-(2-pyridyl)acetophenone O-2- [(tetrahydropyran-2-yl)oxy] ethyl ester obtained in Reference example 1 (C), in 30 ml of methanol and the mixture is stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue is dissolved in ethyl acetate and aqueous sodium bicarbonate and neutralized with powdered sodium bicarbonate. An ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, obtaining the crude desired compound in the form of crystals. This crude compound was washed with a mixture of diisopropyl ether-hexane, obtaining 1.35 g of the desired compound.

1) so pl. 74-76oC

2)1H NMR spectrum: ppm;

1< in deuterated chloroform, is the following:

2,31 (3H, s), to 2.57 (1H, t, J=6 Hz), 3.95 to 3,99 (2H, m), 4,34 is 4.36 (2H, m), 7.24 to 7,27 (1H, m), 7,74-to 7.77 (4H, m), 8,02 (2H, d, J=8.5 Hz), 8,71 (1H, d,d, J=l,5, 5 Hz).

Reference example 2. 4'-2-(2-Pyridyl)acetophenone O-2- (methanesulfonate) ethyl ester

of 0.82 ml of triethylamine are added dropwise to a solution of 10 ml of dichloromethane containing 1,00 g 2-[[1-[4-(2-pyridyl) phenyl] ethylidene]aminoxy]ethanol obtained in Reference example 1 and 493 mg methanesulfonanilide and the mixture is stirred at room temperature for 5 hours. After the reaction, the reaction mixture was concentrated and the residue is dissolved in ethyl acetate and water. Then an ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. An ethyl acetate layer is concentrated and receiving crystalline residue. The residue is washed with isopropyl ether and hexane, obtaining 1.26 g of the desired compound.

1) so pl. 99-101oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.30 (3H, s), 3.04 from (3H, s), 4,46-of 4.49 (2H, m), 4,55-4,58 (2H, m), 7.23 percent-7,28 (1H, m), 7,74 for 7.78 (4H, m), 8,02 (2H, d, J=8.5 Hz), 8,71 (1H, d, J=5 Hz).

Reference example 3. 2-[[1-(4-Biphenylyl)]ethylidene]AMI is the processing carried out according to Reference example 1(C), using to 15.8 g of 2-(2-bromoethoxy)tetrahydropyran, 6,40 g of 4-acetylbiphenyl and 20.9 g of potassium carbonate, getting 10.2 g of the desired compound in the form of syrup.

(b) 2- [1-(4-Biphenylyl)ethylidenemalonate]ethanol

The reaction and post-processing carried out according to Reference example 1(d), using 10.2 g of 4-acetylbiphenyl O-2-[(tetrahydropyran-2 - yl)oxy]ethyl ester obtained in Reference example 3(a), receiving 6,53 g of the desired compound.

1) so pl. 128-130oC

2) 1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 2.30 (3H, s), 2,58 (1H, br.s), 3.95 to 3,99 (2H, m), 4,32 is 4.36 (2H, m), of 7.36-of 7.48 (3H, m), to 7.59 to 7.62 (4H, m), 7,71 (2H, d, J=8,5 Hz).

Reference example 4. 2-[[1-(4-Biphenylyl)ethylidene]aminoxy] ethyl methanesulfonate

The reaction and post-processing carried out according to Reference example 2 using 3,20 g 2-[1-(4-biphenylyl)ethylidenemalonate] ethanol obtained in Reference example 3, 1,49 g methanesulfonanilide and of 1.80 g of triethylamine, getting 3.80 g of the desired compound.

1) so pl. 103-104oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), defined ispolzovaniem:

of 2.30 (3H, s), 3.04 from (3H, s), 4,45-4,48 (2H, m), 4,54-4,58 (2H, m), 7,34-of 7.48 (3H, m), to 7.61 (4H, d, J=8.5 Hz), 7,73 (2H, d, J=8,5 Hz).

Reference example 5. Ethyl 3-(4-hydroxyphenyl)-2-(phenylamino) propionate

(a) Ethyl 3-(4-benzyloxyphenyl)-2-(phenylamino)propionate

A mixture of 4.00 g of ethyl 3-(4-benzyloxyphenyl)-2 - methanesulfonylaminoethyl and 5 ml of aniline was stirred at 110oC for 24 hours. The reaction mixture was purified by column chromatography on silica gel (ethyl acetate: hexane = 1:4) to give 3.94 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.17 (3H, t, J=7 Hz), 3.00 and-3,14 (2H, m), of 4.12 (2H, d,q, J=1,5, 7 Hz), 4,30 (1H, t, J=6 Hz), 5,04 (2H, s), 6,60 (2H, d, J=8.5 Hz), was 6.73 (1H, t, J= 7.5 Hz), 6.89 in (2H, d, J=8.5 Hz), to 7.09 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8.5 Hz), 7,31-7,44 (5H, m).

(b) Ethyl 3-(4-hydroxyphenyl)-2-(phenylamino)propionate

to 0.80 g of 5% palladium-carbon is added to a mixture of 3.94 g of ethyl 3-(4 - benzyloxyphenyl)-2-(phenylamino)propionate obtained in Reference example 5 (a), 40 ml of ethanol and 20 ml of tetrahydrofuran and the mixture was stirred at 50oC in hydrogen atmosphere at normal pressure for 6 hours. From reaney chromatography on silica gel (ethyl acetate: hexane = 1:2), getting 2,95 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.19 (3H, t, J=7 Hz), 3.00 and-3,13 (2H, m), 4,13 (2H, d,q, J=1.7 Hz), 4,30 (1H, brt, J=6 Hz), 4,88 (1H, brs), 6,60 (2H, d, J=8 Hz), of 6.71-6,76 (3H, m), 7,03 (2H, d, J=8 Hz), 7,14-7,20 (2H, m).

Reference example 6. Ethyl 3-(4-hydroxyphenyl)-2-(N-phenyl-N-ethylamino)propionate

(a) Ethyl 3-(4-benzyloxyphenyl)-2-(N-phenyl-N-ethylamino) propionate

The reaction and post-processing carried out according to Reference example 5 (a), using 4,50 g of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonylaminoethyl and 5.6 ml of N-ethylaniline getting 6,30 g of a mixture of the desired compounds and N-ethylaniline in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.07 (3H, t, 3H, J=7 Hz), to 1.14 (3H, t, J=7 Hz), 3,01 is - 3.45 (4H, m), 4.09 to (2H, q, J= 7 Hz), 4,39 (1H, t, J=7.5 Hz), 5,02 (2H, s), 6,66 to 6.75 (3H, m), 6.87 in (2H, d, J=8 Hz), 7,10 (2H, d, J=8.5 Hz), 7,15-of 7.25 (2H, m), 7,31-7,44 (5H, m).

(b) Ethyl 3-(4-hydroxyphenyl)-2-(N-phenyl-N-ethylamino) propionate

The reaction constant is ylamino)propionate and N-ethylaniline, obtained in Reference example 6 (a) to give 2.37 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.07 (3H, t, J=7 Hz) and 1.15 (3H, t, J=7 Hz), 3,05 (1H, d,d, J=8,14 Hz), 3,26 (1H, d,d, J=7,5, 14 Hz), 3,30-of 3.46 (2H, m), 4,10 (2H, q, J=7 Hz), to 4.38 (1H, t, J=8 Hz), and 4.75 (1H, br.s), 6,67-6,79 (5H, m), 7,05 (2H, d, J=8.5 Hz), 7.18 in-7,26 (2H, m).

Reference example 7. Methyl 3-(4-hydroxyphenyl)-2-(phenylthio) propionate

(a) Methyl 3-(4-methoxyethoxymethyl)-2-(phenylthio)propionate

A solution of 15 ml of N,N-dimethylformamide containing 745 mg of methyl 3-(4-methoxyethoxymethyl)-2-methanesulfonylaminoethyl, 310 mg of thiophenol and 390 mg of potassium carbonate, stirred at 50oC for 0.5 hours and the reaction mixture are added ethyl acetate and water. Then an ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. An ethyl acetate layer is concentrated under reduced pressure and the residue is subjected to column chromatography on silica gel (ethyl acetate:hexane = 1:4), receiving 698 mg of the desired compound in the form of syrup.

1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), defined ispolzovanie:

of 3.00 (1H, d,d, J=6,5, 14 Hz) and 3.15 (1H, d,d, J=9, 14 Hz), 3,47 (3H, s) and 3.59 (3H, s), 3,86 (1H, d,d, J=6,5, 9 Hz), further 5.15 (2H, s), 6,94 (2H, d, J=8.5 Hz), 7,10 (2H, d, J=8.5 Hz), 7,29-7,33 (3H, m), 7,40 was 7.45 (2H, m).

(b) Methyl 3-(4-hydroxyphenyl)-2-(phenylthio)propionate

The solution 689 mg of methyl 3-(4-methoxyethoxymethyl)-2- (phenylthio)propionate obtained in Reference example 7 (a), 3 ml of a mixture of: 4h. hydrogen chloride-dioxane was stirred at room temperature for 0.5 hour and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and water, and then an ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting 595 mg of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 2.99 (1H, d,d, J=6,5, 14 Hz), 3,12 (1H, d,d, J=9, 14 Hz), to 3.58 (3H, s), 3,86 (1H, d,d, J=6,5, 9 Hz), equal to 4.97 (1H, br s), 6,72 (2H, d, J=8.5 Hz), 7,05 (2H, d, J=8.5 Hz), 7.23 percent-7,34 (3H, m), 7,40 was 7.45 (2H, m).

Reference example 8. Ethyl 3-(4-hydroxyphenyl)-2 - pyrrolidione

(a) Ethyl 3-(4-benzyloxyphenyl)-2-pyrrolidione 3,30 g of 1,4-dichloro-1,4-diethoxybutane added to a solution 3,30 g of ethyl 3-(4-benzyloxyphenyl)-2-aminopropionic in 80 ml of d is room temperature for 18 hours. After the reaction, the reaction mixture was filtered. The filtrate is concentrated and the residue purified by column chromatography on silica gel (ethyl acetate:hexane = 1:5), receiving of 1.00 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.19 (3H, t, J=7 Hz), 3,19 (1H, d,d, J=8,5, 14 Hz), 3,34 (1H, d,d, J=7, 14 Hz), 4,14 (2H, q, J=7 Hz), and 4.68 (1H, d,d, J=8.5 Hz), free 5.01 (2H, s), x 6.15 (2H, t, J=2 Hz), 6.73 x (2H, t, J=2 Hz), at 6.84 (2H, d, J=8.5 Hz), 6,94 (2H, d, J=8.5 Hz), 7,28-the 7.43 (5H, m).

(b) Ethyl 3-(4-hydroxyphenyl)-2-[N-(phenyl) ethylamino]propionate

The reaction and post-processing carried out according to Reference example 5 (b), using a 1.00 g of ethyl 3-(4 - benzyloxyphenyl)-2-pyrrolidione obtained in Reference example 8 (a), and 0.12 g of 5% palladium-carbon, receiving 0.71 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.20 (3H, t, J=7 Hz), 3,18 (1H, d,d, J=8,5, 14 Hz), to 3.33 (1H, d,d, J=7, 14 Hz), is 4.15 (2H, q, J=7 Hz), of 4.67 (1H, d,d, J=7, 8.5 Hz), 4,80 (1H, s), 6,14 (2H, t, J= 2 iphenyl) propionate

0.3 ml of acetic acid and 0.5 ml of acetaldehyde added to a solution of 491 mg hydrochloride DL-tyrosine ethyl ether complex in 5 ml of methanol. There under cooling with ice add Lamborghini sodium (126 mg), followed by stirring the mixture at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated. The residue is dissolved in ethyl acetate and water, and then an ethyl acetate layer is separated. The extract was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (methanol: dichloromethane = 1:20) to give 420 mg of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.02 (6H, t, J=7 Hz), of 1.16 (3H, t, J=7 Hz), 2,53 (2H, sextet, J=7 Hz), and 2.79 (2H, sextet, J=7 Hz), of 2.81 (1H, d,d, J=6 and 13.5 Hz), 2,99 (1H, d,d, J=9 and 13.5 Hz), 3,55 (1H, d,d, J=6, 9 Hz), as 4.02-4,11 (2H, m), 6,72 (2H, d, J-8.5 Hz), 7,02 (2H, d, J=8,5 Hz).

Reference example 10. Ethyl 2-N-(tert-butoxycarbonyl) ethylamino-3-(4-hydroxyphenyl) propionate

(a) Ethyl 2-ethylamino-3-(4-hydroxyphenyl)proposin ethyl ether complex, of 0.26 ml of acetaldehyde and 100 mg laborgerate sodium, getting 515 mg of the desired compound in the form of a syrup, which soon crystallizes.

1) so pl. 87-89oC

2)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

a 1.08 (3H, t, J=7 Hz), of 1.18 (3H, t, J=7 Hz), 2,48-of 2.72 (2H, m), 2,82-2,96 (2H, m), 3,50 (1H, t, J=7 Hz), 4,11 (2H, q, J=7 Hz), of 6.68 (2H, d, J=8.5 Hz), 7,01 (2H, d, J=8,5 Hz).

(b) Ethyl 2-N-(tert-butoxycarbonyl)ethylamino-3-(4 - hydroxyphenyl)propionate

1 ml of triethylamine is added dropwise under ice cooling to a solution of 569 mg of ethyl 2-ethylamino-3-(4-hydroxyphenyl)propionate obtained in Reference example 10 (a), 785 mg of di-tert-BUTYLCARBAMATE in 10 ml of dichloromethane and the mixture is stirred at room temperature for 4 hours. After the reaction, the reaction mixture was concentrated. The residue is dissolved in ethyl acetate and water, and then an ethyl acetate layer is separated. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel (ethyl acetate: hexane = 1:2) to give 663 mg of the desired compound in the form of syrup.

1)
of 0.90 (3H, br t, J=7 Hz), to 1.21 to 1.31 (3H, m), of 1.45 (9H, s), 3,15-3,37 (1H, m), is 3.08 (1H, d,d, J=10, 14 Hz), 3,15-3,37 (1H, m), 3,24 (1H, d,d, J=5, 14 Hz), 3,85-4,30 (3H, m), 6,76 (2H, br d, J=8,5 Hz), 7,00-7,11 (2H, m).

Reference example 11. Ethyl 3-(4-hydroxyphenyl)-2-(methylthio) propionate

(a) Ethyl 3-(4-methoxyethoxymethyl)-2-methylthiopropionate

A solution of 17.2 g of ethyl 3-(4-methoxyethoxymethyl)-2-methane - sulphonilecarbomide, 4,20 g timelocked of sodium in 300 ml of N,N-dimethylformamide was stirred at 50oC for 1.5 hours. After the reaction, to the reaction mixture are added ethyl acetate and water. Then an ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. Thus obtained extract was concentrated and the residue is subjected to column chromatography on silica gel (ethyl acetate: hexane = 1:4), receiving 11,37 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.22 (3H, t, J=7 Hz), 2,17 (3H, s), 2.91 in (1H, d,d, J=6,5, 14 Hz) and 3.15 (1H, d,d, J=9, 14 Hz), to 3.41 (1H, d,d, J=6,5, 9 Hz), 3,47 (2H, s), 4.09 to to 4.23 (2H, m), 5,15 (3H, s), of 6.96 (2H, d, J=8.5 Hz), 7,13 (2H, d, J=8,5 Hz).

(b) Ethyl 3-(4-hydroxyphenyl)-2-(methylthio)propionate

Re- (methylthio)propionate, obtained in Reference example 11 (a), and 11 ml of a mixture of: 4h. hydrogen chloride-dioxane, receiving 1.70 g of the desired compound.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.22 (3H, t, J=7.5 Hz), 2,17 (3H, s), 2,89 (1H, d,d, J=6,5, 14 Hz), 3,13 (1H, d,d, J=9, 14 Hz), to 3.41 (1H, d,d, J=6,5, 14 Hz), 4.09 to-4,20 (2H, m), of 5.05 (1H, s), 6,74 (2H, d, J=8.5 Hz), 7,07 (2H, d, J=8,5 Hz).

Referential example 12. Ethyl 2-(4-hydroxybenzyl)-5 - phenylvaleric

(a) Diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate

of 0.48 g of sodium hydride (55% oil suspension) is added to the mixture 2,78 g of diethyl 2-(3-phenylpropyl)malonate, 20 ml of toluene and 10 ml of N,N-dimethylacetamide and the mixture was stirred at room temperature for 30 minutes. Then to the reaction mixture of 2.45 g of 4 - benzyloxybenzaldehyde and the mixture is stirred at room temperature for 30 minutes and then at 60oC for 30 minutes. After the reaction, to the reaction mixture are added ethyl acetate and water and then an ethyl acetate layer is separated. Thus obtained extract is dried over anhydrous magnesium sulfate and concentrated. Thus obtained residue is I in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.21 (6H, s), 1,57-of 1.66 (2H, m), 1,76-of 1.85 (2H, m), 2,61 (2H, t, J=6.5 Hz), 3,14 (2H, s), is 4.15 (4H, d,q, J=1,5, 7 Hz), free 5.01 (2H, s), 6,79 (2H, d, J=8.5 Hz), 6.89 in (2H, d, J=8.5 Hz), 7,15-7,44 (10H, m).

(b) Ethyl 2-(4-benzyloxybenzyl)-5-phenylvaleric

a 2.00 g of potassium hydroxide is added to the mixture 3,91 g of diethyl 2- (4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate obtained in Reference example 12 (a), 30 ml of 2-methoxyethanol and 3 ml of water and the resulting mixture is stirred at an oil bath at 130oC for 1.5 hours. After the reaction, the reaction mixture was concentrated, to the concentrated mixture are added water and ethyl acetate and, to make it sour, there is added 6N. hydrochloric acid. Then an ethyl acetate layer is separated, washed with aqueous NaCl and dried over anhydrous magnesium sulfate, and then concentrated. The residual syrup was dissolved in 20 ml of xylene and the mixture is stirred for one hour and concentrated. Thus obtained serapeptase 2-(4-benzyloxybenzyl)-5-phenylalaninol acid dissolved in 40 ml of ethanol there is added 1 ml conc. sulfuric contenitore for 16 hours. The reaction mixture was concentrated and the residue is dissolved in ethyl acetate and water, after which separate an ethyl acetate layer. Thus obtained extract is dried over anhydrous magnesium sulfate and concentrated, obtaining of 3.32 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.13 (3H, t, J=7 Hz), 1,50-1,80 (4H, m), 2,53-a 2.71 (4H, m), 2,82-2,90 (1H, m), Android 4.04 (2H, q, J=7 Hz), 5,04 (2H, s), 6.87 in (2H, d, J=8.5 Hz), 7,05 (2H, d, J=8.5 Hz), 7,10-7,44 10H, m).

(C) Ethyl 2-(4-hydroxybenzyl)-5-phenylvaleric

The reaction and post-processing carried out according to Reference example 5(b), using of 3.32 g of ethyl 2-(4-benzyloxybenzyl)-5-phenylvaleric obtained in Reference example 12(b), and 0.4 g of 5% palladium - carbon, receiving of 2.56 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.14 (3H, t, J=7 Hz), 1,50-1,75 (4H, m), 2,53-a 2.71 (4H, m), 2,78 - 2,87 (1H, m), of 4.05 (2H, q, J=7 Hz), 6,70 (2H, d, J=8.5 Hz), 6,98 (2H, d, J=8.5 Hz), 7,12-7,29 (5H, m).

Senat

The reaction and post-processing carried out according to Reference example 12 (a), using 2,81 g diethylpyrocarbonate, 2,59 g of 4-benzyloxybenzaldehyde and 530 mg of sodium hydride (55% oil suspension), receiving of 3.10 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.12 (6H, t, J=7 Hz), of 3.57 (2H, s), is 4.15 (4H, q, J=7 Hz), 5,02 (2H, s), 6,84-7,14 (6H, m), 7,22-7,41 (8H, m).

(b) Ethyl 3-(4-benzyloxyphenyl)-2-phenoxypropionate

The reaction and post-processing carried out according to Reference example 12 (b), using 3,10 g of diethyl 2-(4-benzyloxybenzyl)-2 - proximamente obtained in reference example 13 (a) and 2.10 g of potassium hydroxide, receiving of 2.10 g of the desired compound in the form of syrup through serapeptase 3-(4-benzyloxyphenyl)-2-phenoxypropionic acid.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 1.18 (3H, t, J=7 Hz), 3,11-3,20 (2H, m), of 4.16 (2H, q, J=7 Hz), 4,74 (1H, d, d, J=5,5, 6,5 Hz), 5,04 (2H, s), at 6.84 (2H, d, J=8 Hz), 6,91 (2H, d, J=8.5 Hz), 6,9 is the Ktsia and postprocessing is carried out according to Reference example 5(b), using 2,10 g of ethyl 3-(4-benzyloxyphenyl)-2 - phenoxypropionate obtained in Reference example 13(b), and 0.32 g of 5% palladium-carbon, receiving 1.01 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

to 1.19 (3H, t, J=7 Hz), 3,10-3,24 (2H, m) to 4.17 (2H, q, J=7 Hz), 4,74 (1H, d,d, J=6, 7 Hz), 5,00 (1H, s), 6,74 (2H, d, J=8.5 Hz), at 6.84 (2H, d, J=8 Hz), to 6.95 (1H, t, J=7.5 Hz), 7,16 (2H, d, J=8.5 Hz), 7,21-7,26 (2H, m).

Reference example 14. Ethyl 2-(4-hydroxybenzyl)caproate

(a) Diethyl 2-(4-benzyloxybenzyl)-2-butylmalonate

The reaction and post-processing carried out according to Reference example 12 (a), using 2.16 g of diethylmalonate, 2,44 g of 4-benzyloxybenzaldehyde and 480 mg of sodium hydride (55% oil suspension), getting to 3.67 g of the desired compound in the form of crystals.

1) so pl. 73oC

2) 1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 0.91 (3H, t, J=7 Hz), 1,24 (6H, t, J=7 Hz), 1,20-to 1.38 (4H, m), 1,74 and 1.80 (2H, m), 3,18 (2H, s), 4,11-to 4.23 (4H, m), 5,02 (2H, s), 6,86 (2H, d, J=8.5 Hz), 6, is t according to Reference example 12 (b), using of 3.60 g of diethyl 2-(4 - benzyloxybenzyl)-2-butylmalonate obtained in Reference example 14 (a), and 2.00 g of potassium hydroxide, receiving a 2.71 g of the desired compound in the form of syrup through the crystalline 2-(4 - benzyloxybenzyl) Caproic acid.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 0.87 (3H, t, J=7 Hz), to 1.14 (3H, t, J=7 Hz), 1,20-1,70 (6H, m), of 2.51-of 2.72 (2H, m), 2,85 (1H, d,d, J=8,5, and 13.5 Hz), of 4.05 (2H, q, J=7 Hz), to 5.03 (2H, s), to 6.88 (2H, d, J=8.5 Hz), 7,07 (2H, d, J=8,5 Hz), 7,31 was 7.45 (5H, m).

(C) Ethyl 2-(4-hydroxybenzyl)caproate

The reaction and post-processing carried out according to Reference example 5 (b), using a 2.71 g of ethyl 2-(4-benzyloxybenzyl)kaproata obtained in Reference example 14 (b), and 0.40 g of 5% palladium-carbon, receiving 1,90 g of the desired compound in the form of syrup.

1)1H NMR spectrum: ppm;

1H NMR spectrum (270 MHz), determined using TMS (tetramethylsilane was) as an internal standard, deuterated chloroform, is the following:

of 0.87 (3H, t, J=7 Hz), of 1.16 (3H, t, J=7 Hz), 1,20-of 1.35 (4H, m), 1,40-1,70 (2H, m), 2,53-of 2.72 (2H, m), 2,84 (1H, d,d, J=8,5, and 13.5 Hz), 4,06 (2H, q, J=7 Hz), is 4.93 (1H, s), 6,72 (2H, d,J=8.5 Hz), 7,02 (2H, d, J=8,5 Hz)deposits are mixed in a solvent, consisting of polyethylene glycol 400 and 0.5% wt./about. the carboxymethyl cellulose in the ratio of 1:1 in physiological saturated salt solution, and injected oral hyperglycemic male-KK mice with a body weight of 40 g or higher. Animals kept under good feeding for 18 hours. Then take samples of blood from the tail vein in the absence of anesthesia with subsequent measurement of glucose in blood using glucose analyzer (GL-101: Mitsubishi Chemical Corp.).

The degree of reduction of glucose level in blood is calculated by the following equation:

The degree of reduction of glucose (%) =

[(glucose group of animals, which were injected solvent - glucose group of animals, which were injected compound of formula (I) /glucose group of animals, which were injected solvent] × 100

The results obtained are presented in Table 69.

Table 69 can be seen that the compounds of this invention have excellent lowering the level of glucose action.

The effect of lowering the level of glucose in the blood (Method 2)

Each of the test compounds is mixed with powdered food F-2 (Funabashi Farms) at a ratio of 0.01% to about 10 mg/kg/day). The mixture is administered orally guy is our only give powdered food and this group is used as the control group. Then draw samples of blood from the tail vein in the absence of anesthesia and measure the level of glucose in blood plasma obtained by separation by centrifugation, using Glucorotor F (A & T Corp.).

The degree of reduction (level) blood glucose (%) =

[(the level of glucose in the control group, the level of glucose group that was administered the test compound)/glucose level of the control group] × 100

The results obtained are presented in Table 70

Table 70 can be seen that the compounds of this invention possess excellent lowering the level of glucose in the blood by the action.

[Example of preparation of a medicinal drug]

(1) Capsule

The compound of example 2 of 10 mg

Lactose - 110 mg

Corn starch - 58 mg

Magnesium stearate 2 mg 180 mg

The powder of each component specified above, mix well and pass through a sieve of 60 mesh (standard mesh-based Tyler). To obtain a capsule, 180 mg of the thus obtained powder is weighed and filled gelatin capsule (N 3).

(2) Tablet

The compound of example 2 of 10 mg

Lactose - 85 mg

Corn starch - 34 mg

Finely crystalline cellulose 20 mg

mouth pressing into tablets weighing 150 mg If necessary, these tablets can be coated with sugar or film.

(3) Pellet

The compound of example 2 of 10 mg

Lactose - 839 mg

Corn starch 150 mg

Hydroxypropylcellulose - 1 mg - 1000 mg

The powder of each component above, mix well and moisten with clean water, then granularit by drum-type granulator and dried, obtaining a pellet.

[Industrial applicability]

Derivatives phenylalkylamines acid, their pharmacologically acceptable salts or their pharmaceutically acceptable esters are used as therapeutic or prophylactic agents for many diseases. Examples of such diseases include hyperlipemia, hyperglycemia, a condition of impaired glucose tolerance (the state of impaired glucose tolerance), the state of insulin resistance with undisturbed glucose tolerance (the state of insulin resistant non-IGT), hypertension, osteoporosis, pancreatitis, diabetic complications, arteriosclerosis, cataracts, caused by pregnancy diabetes, polycystic ovary syndrome, inflammatory diseases, psoriasis, asthma, atherosclerosis, autoimmune diseases, etc.

Additional examples the x in the weak field on tetramethylsilane (TMS), used as an internal standard, constants megatonnage spin-spin interaction are given in Hertz (Hz).

Additional example 1

Ethyl 2- (4-chlorophenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene]aminoxy]ethoxy]phenyl]propionate

To a solution of ethyl 2-(4-chlorophenoxy)-3-(4 - hydroxyphenyl)propionate (504 mg), representing an additional product of reference example 5(d), in a mixture of dimethyl sulfoxide (2 ml) and toluene (2 ml) was added sodium hydride (55%, 85 mg) and the mixture was stirred at 40oC for one hour. To the mixture was added dropwise a solution of O-2-(metamathematics) ethyl simple ether of the oxime of 4'-(2-pyridyl)acetophenone (649 mg), which represents the product of reference example 2, in dimethyl sulfoxide (2 ml). The reaction mixture was stirred at 60oC for 4 hours and was added ethyl acetate and water. The organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate =9/1 as eluent, obtaining mentioned in the title compound (504 mg) as a colourless oil.

Additional example 2

2-(4-Chlorophenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene] aminoxy] ethoxy]phenyl]propionic acid

To a solution of ethyl 2-(4-chlorophenoxy)-3-[4-[2-[[1-[4- (2-pyridyl)phenyl] ethylidene] aminoxy] ethoxy]phenyl] propionate (500 mg), which is an additional product of example 1 in ethanol (8 ml) was added an aqueous solution of sodium hydroxide (1N. , 1,79 ml) and the mixture was heated at the boil under reflux for 3 hours. The reaction mixture was evaporated under reduced pressure. To neutralize the residue was added hydrochloric acid (1N.) to the neutralized residue was added ethyl acetate. An ethyl acetate layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel using a mixture of methylene chloride/methanol = 9/1 as eluent, obtaining mentioned in the title compound (169 mg) as a colorless foam mass.

1H NMR (270 MHz, CDCl3): M. D.

2,17 (3H, s) to 2.99 (2H, user.C) of 4.13 (2H, ush

Ethyl 3-[4-[2-[[1-(4'-fluoro-4-biphenylyl) ethylidene]aminoxy]ethoxy]phenyl] -2-(4-fervency)propionate

The reaction was carried out by a method similar to that described in additional example 1, using ethyl 2-(4-pertenece)-3-(4-hydroxyphenyl)propionate (1.8 g), which is an additional product of reference example 6(b), sodium hydride (55%, 271 mg) and 2-[[1-(4'-fluoro-4-biphenylyl) ethylidene] aminoxy] ethylmethanesulfonate (2.14 g), representing an additional product of reference example 7(b), and treated reaction mixture, getting listed in the title compound (1.45 g) as a white powder.

so pl. 103 - 105oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.20 (3H, t, J=7,0 Hz), and 2.26 (3H, s), and 3.16 (2H, d, J=6.5 Hz), 4,17 (2H, q, J=7.0 Hz), 4,27 (2H, t, J=4.5 Hz), of 4.54 (2H, t, J=4.5 Hz), of 4.66 (1H, t, J= 6.5 Hz), 6,74-6,79 (2H, m), 6,88-6,94 (4H, m), 7,13 (2H, t, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,52-to 7.59 (4H, m), 7,71 (2H, d, J=8,5 Hz).

Additional example 4

3-[4-[2-[[1-(4'-Fluoro-4-biphenylyl)ethylidene] aminoxy] ethoxy] phenyl]-2-(4-pertenece)propionic acid

The reaction was carried out by a method similar to that described in additional example 2, using ethyl 3-[4-[2-[[1- (4'-fluoro-4-biphenylyl)ethylidene] aminoxy]ethoxy]phenyl]-2- (4-pertenece)propionate (1.44 g), probatively the reaction mixture, getting listed in the title compound (1.13 g) as colorless crystals.

so pl. 109-110oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.25 (3H, s), 3,18-is 3.21 (2H, m), 4,27 (2H, t, J=5.0 Hz), of 4.54 (2H, t, J= 5.0 Hz), 4.72 in (1H, t, J=5.5 Hz), 6.75 in-to 6.80 (2H, m), to 6.88 - 6.89 in (4H, m), 7,13 (2H, t, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,52 - 7,58 (4H, m), of 7.70 (2H, d, J=8,5 Hz).

Additional example 5

2-Trimethylsilylmethyl (S)-3-[4-[2-[[1-(4-biphenylyl)ethylidene] aminoxy] ethoxy]phenyl]-2-(4-methylphenoxy)propionate

To a solution of 2-[1-(4-biphenylyl)ethylidenemalonate]ethanol (288 mg), representing the product of reference example 3(b), 2 - trimethylsilylmethyl (S)-3-(4-hydroxyphenyl)-2-(4 - methylphenoxy)propionate (280 mg), representing an additional product of reference example 1(e), and triphenylphosphine (296 mg) in toluene (10 ml) was added dropwise at 0oC solution of diisopropylcarbodiimide (40% in toluene (0,61 ml)). Then the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 9/1 as eluent, obtaining mentioned in the title compound (270 mg) as a colourless oil.

H, t, J=5.0 Hz), of 4.54 (2H, t, J= 5.0 Hz), of 4.66 (1H, t, J=6.5 Hz), 6.73 x (2H, d, J=8.5 Hz), 6.89 in (2H, d, J= 8.5 Hz), 7,02 (2H, d, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,33-of 7.48 (3H, m), 7,58 to 7.62 (4H, m), 7,71 (2H, d, J=8,5 Hz).

Additional example 6

(S)-3-[4-[2-[[1-(4-Biphenylyl)ethylidene] aminoxy]ethoxy] phenyl]-2-(4-methylphenoxy) propionic acid

To a solution of 2-trimethylsilylmethyl (S)-3-[4-[2-[[1- (4-biphenylyl)ethylidene] aminoxy] ethoxy] phenyl] -2- (4-methylphenoxy)-propionate, which is a product of an additional example 5 in tetrahydrofuran (5 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.1 ml) and the mixture was stirred at ambient temperature for 1.5 hours. Then the reaction mixture was evaporated under reduced pressure, to neutralize the residue was added an aqueous solution of hydrogen chloride (1N.) to the neutralized residue was added ethyl acetate. An ethyl acetate layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crystals were collected by filtration using hexane, getting mentioned in the title compound (210 mg) as colorless crystals.

so pl. 128 - 130oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.26 (6H, SN, d, J=8.5 Hz), 7,31-of 7.48 (3H, m), 7,58 to 7.62 (4H, m), 7,71 (2H, d, J=8,5 Hz).

Additional example 7

2-Trimethylsilylmethyl (S)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl) ethylidene]aminoxy]ethoxy]phenyl]-2-(4-methylphenoxy)propionate

The reaction was carried out by a method similar to that described in additional example 5, using 2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy] ethanol (1.65 g), representing the product of reference example 1 (d), 2-trimethylsilylmethyl S-3- (4-hydroxyphenyl)-2-(4-methylphenoxy)-propionate (1.60 g), representing an additional product of reference example 1(e), triphenylphosphine (1,69 g) and a solution of diisopropylcarbodiimide (40% in toluene (3,47 ml) and was treated with the reaction mixture, getting mentioned in the title compound (2.20 g) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

0,00 (9H, s) of 0.91 (2H, t, J= 8.5 Hz), 2,24 (3H, s), and 2.26 (3H, s), 3,14-3,17 (2H, m), 4.09 to to 4.23 (2H, m), 4.26 deaths (2H, t, J=5.0 Hz), of 4.54 (2H, t, J= 5.0 Hz), with 4.64-and 4.68 (1H, m), of 6.71 (2H, d, J=8.5 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,01 (2H, d, J=8.5 Hz), 7,19 - 7,28 (3H, m), 7,73-7,79 (4H, m), of 8.00 (2H, d, J=8.5 Hz), to 8.70 (1H, d, J=5,5 Hz).

Additional example 8

(S)-3-[4-[2-[1-[4-(2-Pyridyl)phenyl)ethylidene] aminoxy] ethoxy]phenyl]-2-(4-methylphenoxy)propionic acid

The reaction was carried out in a manner analogous to describe what Inoxi] ethoxy] phenyl]-2- (4-methylphenoxy) propionate (2.20 g), representing the additional product of example 7, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 9,00 ml) and the reaction mixture was treated, getting mentioned in the title compound (1.48 g) as colorless crystals.

so pl. 54 - 56oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.25 (6H, s), 3,21 (2H, d, J=6.0 Hz), the 4.29 (2H, t, J=4.5 Hz), 4,55 (2H, t, J= 4.5 Hz), 4,78 (1H, t, J=6.0 Hz), 6,77 (2H, d, J=8.5 Hz), to 6.88 (2H, d, J= 8.5 Hz), 7,03 (2H, d, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,26-7,30 (1H, m), 7,69-7,83 (4H, m), 7,89 (2H, d, J=8.5 Hz), 8,72 (1H, d, J=5.0 Hz).

Additional example 9

2-Trimethylsilylmethyl (S)-3-[4-[2-[[1-(4-biphenylyl)ethylidene] aminoxy] ethoxy]phenyl]-2-(4-tert-butylphenoxy) propionate

The reaction was carried out by a method similar to that described in additional example 5, using 2-[1-(4-biphenylyl)ethylidene]aminoxy]ethanol (288 mg), representing the product of reference example 3(b), 2 - trimethylsilylmethyl S-2-(4-tert-butylphenoxy)-3-(4-hydroxyphenyl) propionate (311 mg), representing an additional product of reference example 2(e), triphenylphosphine (296 mg) and a solution of diisopropylcarbodiimide (40% in toluene (0,61 ml))and was treated with the reaction mixture, getting mentioned in the title compound (300 mg) as pale-yellow mass is m), 4,21-to 4.28 (4H, m), a 4.53 (2H, t, J=4.5 Hz), of 4.67 (1H, DD, J= 6,0, 7.5 Hz), to 6.75 (2H, d, J=9.0 Hz), to 6.88 (2H, d, J=8.5 Hz), 7,19-7,24 (4H, m), 7,32-of 7.48 (3H, m), EUR 7.57 to 7.62 (4H, m), 7,71 (2H, d, J=8,5 Hz).

Additional example 10

(S)-3-[4-[2-[[1-(4-Biphenylyl) ethylidene] aminoxy] ethoxy]phenyl]-2-(4-tert-butylphenoxy) propionic acid

The reaction was carried out by a method similar to that described in additional example 6, using 2-trimethylsilylmethyl (S)-3-[4-[2-[1-(4-biphenylyl)ethylidene] aminoxy] ethoxy] phenyl] -2- (4-tert-butylphenoxy) propionate (300 mg), which is an additional product of example 9, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1H, 1,20 ml), and treated reaction mixture. Then the residue was subjected to column chromatography on silica gel using mixtures of methylene chloride/methanol=24/1 and 19/1 as eluents. Specified in the title compound (170 mg) was collected by filtration in the form of colorless crystals, using a mixture of isopropyl ether and hexane.

so pl. 141 - 143oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.27 (9H, s), and 2.26 (3H, s), 3,21 (2H, d, J=6.5 Hz), 4,27 (2H, t, J=5.0 Hz), of 4.54 (2H, t, J=5.0 Hz), to 4.81 (1H, t, J=6.5 Hz), 6,79 (2H, d, J=9.0 Hz), 6.89 in (2H, d, J= 8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,27 (2H, d, J=9.0 Hz), 7,33-of 7.48 (3H, m), 7,58 to 7.62 (4H, m), 7,72 (2H, d, J=8,5 Hz).


The reaction was carried out by a method similar to that described in additional example 5, using 2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy] ethanol (290 mg), representing the product of reference example 1 (d), 2-trimethylsilylmethyl S-2- (4-tert-butylphenoxy)-3-(4-hydroxyphenyl)propionate (311 mg), representing an additional product of reference example 2(e), triphenylphosphine (296 mg) and a solution of diisopropylcarbodiimide (40% in toluene (0,61 ml) and was treated with the reaction mixture, getting mentioned in the title compound (310 mg) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

0,00 (9H, s) to 0.92 (2H, t, J= 8.5 Hz), 1,25 (9H, s), and 2.26 (3H, s), 3,13-3,17 (2H, m), 4,15-to 4.28 (4H, m), of 4.54 (2H, t, J=4.5 Hz), with 4.64-4,69 (1H, m), of 6.75 (2H, d, J= 9.0 Hz), to 6.88 (2H, d, J=8.5 Hz), 7,19-7,26 (5H, m), 7,72-7,76 (4H, m), of 8.00 (2H, d, J=8.5 Hz), 8,69-8,71 (1H, m).

Additional example 12

(S)-2-(4-tert-Butylphenoxy)-3-[4-[2-[[1-(4-(2-pyridyl)phenyl] ethylidene] aminoxy]ethoxy]phenyl]propionic acid

The reaction was carried out by a method similar to that described in additional example 6, using 2-trimethylsilylmethyl (3)-2-(4-tert-butylphenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl] ethylidene] aminoxy]ethoxy]phenyl]propionate (310 mg), representing an additional product is ü. Then the residue was subjected to column chromatography on silica gel using mixtures of methylene chloride/methanol=24/1 and 19/1 as eluents. Specified in the title compound (180 mg) was collected by filtration in the form of colorless crystals, using a mixture of isopropyl ether and hexane.

so pl. 148 - 150oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.30 (9H, s), 2,31 (3H, s), 3,26 (2H, d, J=6.0 Hz), 4,34 (2H, t, J=5.0 Hz), 4,59 (2H, t, J=5.0 Hz), 4,84 (1H, t, J=6.0 Hz), 6,86 (2H, d, J=9.0 Hz), 6,93 (2H, d, J=8.5 Hz), 7,25 - to 7.35 (5H, m), 7,74-7,88 (4H, m), 7,95 (2H, d, J=8.5 Hz), 8,76 (1H, d, J=4.5 Hz).

Additional example 13

2-Trimethylsilylmethyl (S)-3-[4-[2-[[1-(4-biphenylyl) ethylidene] aminoxy] ethoxy]phenyl]-2-(4-pertenece) propionate

The reaction was carried out by a method similar to that described in additional example 5, using 2-[1-(4-biphenylyl)ethylidene]aminoxy]ethanol (83 mg), representing the product of reference example 3 (b), 2-trimethylsilylmethyl S-2-(4-pertenece)-3-(4-hydroxyphenyl)propionate (100 mg), representing an additional product of reference example 3(e), triphenylphosphine (86 mg) and a solution of diisopropylcarbodiimide (40% in toluene (0,14 ml)), and was treated with the reaction mixture, getting mentioned in the title compound (88 mg) in W (3H, C), and 3.16 (2H, d, J= 6.5 Hz), 4,16-4,24 (2H, m), 4,28 (2H, t, J=5.0 Hz), of 4.54 (2H, t, J=5.0 Hz), 4,63 (1H, t, J=6.5 Hz), 6,76 (2H, DD, J=4,0, 9.0 Hz), make 6.90 (2H, d, J= 8.5 Hz), 6,91(2H, DD, J=8,5, 9.0 Hz), 7,21 (2H, d, J=8.5 Hz), was 7.36 (1H, t, J=7.0 Hz), was 7.45 (2H, DD, J=7,0, 8.5 Hz), 7,60 (2H, d, J=8.5 Hz),7,61 (2H, d, J=8.5 Hz), 7,73 (2H, d, J=8,5 Hz).

Additional example 14

(S)-3-[4-[2-[[1-(4- Biphenylyl)ethylidene] aminoxy] ethoxy] phenyl]-2-(4 - pertenece)propionic acid

The reaction was carried out by a method similar to that described in additional example 6, using 2-trimethylsilylmethyl (S) -3-[4-[2-[[1-(4-biphenylyl)ethylidene] -aminooxy] ethoxy] phenyl]-2-(4 - pertenece)propionate (938 mg), representing an additional product of example 13, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, and 3.8 ml), and treated reaction mixture, getting mentioned in the title compound (568 mg) as colorless crystals.

1H NMR (270 MHz, CDCl3): M. D.

of 2.26 (3H, s), 3,20 (1H, d, J=5.0 Hz), 3,21 (1H, d, J=7.5 Hz), 4,28 (2H, t, J= 5.0 Hz), of 4.54 (2H, t, J=5.0 Hz), to 4.73 (1H, DD, J=5.0 and 7.5 Hz), 6,79 (2H, DD, J= 4,0, 9.0 Hz), make 6.90 (2H, d, J=8.5 Hz), 6,92 (2H, DD, J=8,0, 9.0 Hz), 7,22 (2H, d, J=8.5 Hz), was 7.36 (1H, t, J=7.0 Hz), was 7.45 (2H, DD, J=7,0, 8.5 Hz), 7,60 (2H, d, J=8.5 Hz), to 7.61 (2H, d, J=8.5 Hz), 7,72 (2H, d, J=8,5 Hz).

Additional example 15

2-Trimethylsilylmethyl (S)-2-(4-pertenece)-3-[4-[2-[[1- (4'-methoxy-4-Biff is in an additional example 5 using 2-[1-(4'-methoxy-4-biphenylyl]ethylidene]aminoxy] ethanol (325 mg), representing the product of reference example 4 (b), 2-trimethylsilylmethyl S-2-(4-pertenece)-3-(4 - hydroxyphenyl)propionate (286 mg), representing an additional product of reference example 3(e), triphenylphosphine (299 mg) and a solution of diisopropylcarbodiimide (40% in toluene (0,61 ml), and treated reaction mixture, getting listed in the title compound (438 mg) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

of 0.01 (9H, s) of 0.91 (2H, DD, J=7,5, 10,0 Hz in), 2.25 (3H, s) and 3.15 (2H, d, J= 6.5 Hz), 3,85 (3H, s), 4,14-to 4.23 (2H, m), 4.26 deaths (2H, t, J=5.0 Hz), a 4.53 (2H, t, J= 5.0 Hz), to 4.62 (1H, t, J=6.5 Hz), 6.75 in (2H, DD, J=4,5, and 9.0 Hz), 6.89 in (2H, d, J= 8.5 Hz), make 6.90 (2H, DD, J=8,5, 9.0 Hz), 6,97 (2H, d, J=8.5 Hz), 7,20 (2H, d, J=8.5 Hz), 7,53 (2H, d, J=8.5 Hz), 7,54 (2H, d, J=8.5 Hz), to 7.68 (2H, d, J=8,5 Hz).

Additional example 16

(S)-2-(4-Pertenece)-3-[4-[2-[[1-(4'-methoxy-4-biphenylyl) ethylidene] aminoxy]ethoxy]phenyl]propionic acid

The reaction was carried out by a method similar to that described in additional example 6, using 2-trimethylsilylmethyl (S)-2- (4-pertenece)-3-[4-[2-[[1-(4'-methoxy-4-biphenylyl)ethylidene] aminoxy]ethoxy]phenyl]propionate (438 mg), representing an additional product of example 15, and restroe the title compound (243 mg) as colorless crystals.

so pl. 118-120oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.25 (3H, s), 3,20 (1H, d, J=7,0 Hz), 3,21 (1H, d, J=4.0 Hz), 3,86 (3H, s), 4,27 (2H, t, J=5.0 Hz), a 4.53 (2H, t, J=5.0 Hz), to 4.73 (1H, DD, J=4,0, 7,0 Hz), 6,78 (2H, DD, J=4,0, 9.0 Hz), make 6.90 (2H, d, J=8.5 Hz), 6,92 (2H, DD, J= 8,0, 9.0 Hz), 6,98 (2H, d, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,54 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), to 7.68 (2H, d, J=8,5 Hz).

Additional example 17

2-Trimethylsilylmethyl (S)-2-(4-pertenece) -3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy] phenyl]propionate

The reaction was carried out by a method similar to that described in additional example 5, using 2-[[1-[4-(2-pyridyl) phenyl]ethylidene]aminoxy] ethanol (520 mg), representing the product of reference example 1 (d), 2-trimethylsilylmethyl S-2- (4-pertenece)-3-(4-hydroxyphenyl)-propionate (380 mg), representing an additional product of reference example 3(e), triphenylphosphine (537 mg) and a solution of diisopropylcarbodiimide (40% in toluene (0,94 ml), and treated reaction mixture, getting mentioned in the title compound (531 mg) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

of 0.01 (9H, s) to 0.92 (2H, DD, J=7,5, 10,0 Hz), and 2.26 (3H, s) and 3.15 (2H, d, J= 6.5 Hz), 4,15-to 4.23 (2H, m), 4,28 (2H, t, J=5.0 Hz), of 4.54 (2H, t, J=5.0 Hz), 4,63 (1H, t, J=6.5 Hz), 6,76 (2H, DD, J=4,0, 9.0 Hz), make 6.90 (2H, d, J= 8.5 Hz), 6,91 (2H, emer 18

(S)-3-[4-[2-[[1-(4-Biphenylyl)ethylidene] aminoxy] ethoxy] phenyl]-2-(4-tert-butylphenoxy) propionic acid

The reaction was carried out by a method similar to that described in additional example 6, using 2 - trimethylsilylmethyl (S)-2-(4-pertenece)-3-[4-[2-[[1-[4-(2- pyridyl)phenyl]ethylidene]aminoxy] ethoxy] phenyl] propionate (1.84 g), representing an additional product of example 17, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 7.5 ml), and treated reaction mixture, receiving specified in the header connection (1,16 g) in the form of colorless crystals.

so pl. 88 - 90oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.25 (3H, s), 3,20 (1H, d, J=7,0 Hz), 3,21 (1H, d, J=5.5 Hz), 4,30 (2H, t, J= 5.0 Hz), 4,55 (2H, t, J=5.0 Hz), 4.72 in (1H, DD, J=5,5, 7,0 Hz), for 6.81 (2H, DD, J= 4,5, and 9.0 Hz), 6.89 in (2H, d, J=8.5 Hz), 6,91 (2H, DD, J=8,5, 9.0 Hz), 7,22 (2H, d, J=8.5 Hz), 7,27-to 7.32 (1H, m), of 7.69 (2H, d, J=8.5 Hz), 7,72 (1H, d, J= 7.5 Hz), 7,80 (1H, DD, J=2.0 a, 7.5 Hz), 7,86 (2H, d, J=8.5 Hz), 8,72 (1H, d, J=5.0 Hz).

Additional reference example 1

2-Trimethylsilylmethyl (S)-3-(4-hydroxyphenyl)-2- (4-methylphenoxy)propionate

(a) (S)-4-Benzyl-3-[4-methylphenoxy)acetyl]oxazolidin-2-he

To a solution of 4-methylphenoxyacetic acid (of 6.73 g) in dichloromethane (70 ml) at ambient temperature was added oxalicacid (8,83 who was interaval under reduced pressure and the residual acid gas azeotrope was evaporated using toluene, getting 4-methylphenoxyacetic. The residue was dried under reduced pressure.

To a solution of (S)-4-benzyl-2-oxazolidinone (7,08 g) in tetrahydrofuran (70 ml) at -78oC was added dropwise a solution of n - utility in hexane (1,61 N., 25,2 ml) and the mixture was stirred at the same temperature for 30 minutes. To this solution was added at -78oC solution of 4-methylphenoxyacetic, which was obtained above in tetrahydrofuran (70 ml). The mixture was stirred at 0oC for 1 hour. The reaction mixture was distributed between ethyl acetate and water. An ethyl acetate layer was washed with hydrochloric acid (1N.), saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. An ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 3/1 and 1/1 as eluents, obtaining the target compound (9.00 g) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

of 2.30 (3H, s) 2,84 (1H, DD, J=a 9.5 and 13.5 Hz), to 3.36 (1H, DD, J=3,0 and 13.5 Hz), 4,25-4,37 (2H, m), 4,68 was 4.76 (1H, m), with 5.22 (2H, s), to 6.88 (2H, d, J=8.5 Hz), 7,11 (2H, d, J=8.5 Hz), 7,20 - 7,38 (5H, m).

(b) (S)-4-Benzyl-3-[(2S, 3R)-3-(4-benzyloxy] oxazolidin-2-it (9.00 g), representing a product additional reference example 1(a), in dichloromethane (90 ml) at 0oC was added a solution of triflate dilutive in dichloromethane (1M, 33,2 ml) and triethylamine (5,12 ml). The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise at -78oTo a solution of 4-benzyloxybenzaldehyde (6,46 g) in dichloromethane (6 ml). The reaction mixture was additionally stirred at 0oC for 2 hours. At the end of this time the reaction mixture was added a mixture of saturated aqueous sodium chloride solution/methanol = 1/1 (20 ml) and an aqueous solution of hydrogen peroxide (31%)/methanol = 2/1 (100 ml) and was stirred for 1 hour. The methanol was removed by evaporation in a vacuum. The residue was distributed between ethyl acetate and water and the layers separated. An ethyl acetate layer was washed with hydrochloric acid (1N. ) saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 3/1 and 1/1 as eluents, obtaining the target compound (9.80 g) in the form of a foamed mass.

1H NMR (270 MHz, CDCl3): M. D.

2,2(2H, d, J=8.5 Hz), to 6.95 (2H, d, J=8.5 Hz),? 7.04 baby mortality-7,10 (4H, m), 7,25-7,44 (10H, m).

(C) (3)-4-Benzyl-3-[(2S, 3R)-3-hydroxy-3-(4 - hydroxyphenyl)-2-(4-methylphenoxy)propionyl]oxazolidin-2-he

To a solution of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-3-hydroxy-2- (4-methylphenoxy)propionyl] oxazolidin-2-it (9.80 g), representing an additional product of reference example 1(b), in ethanol (150 ml) was added palladium on coal (5%, and 1.00 g). The mixture was stirred in hydrogen atmosphere at 50oC for 4 hours, at the end of this time the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water and the layers separated. An ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, obtaining the target product (9,10 g) as a foam.

1H NMR (270 MHz, CDCl3): M. D.

of 2.28 (3H, s), is 2.74 (1H, DD, J=9,0, 13.5 Hz), 3.04 from-3,10 (2H, m), 3,74 (1H, t, J= 8.5 Hz), Android 4.04 (1H, DD, J=1.5 and 8.5 Hz), 4,28-4,34 (1H, m), 5.08 to, (1H, t, J=5.5 Hz), 5,15 (1H, s), 6,17 (1H, d, J=5.5 Hz), 6,79 (2H, d, J=8.5 Hz), to 6.88 (2H, d, J=8.5 Hz),? 7.04 baby mortality-7,10 (4H, m), 7,25-7,38 (5H, m).

(d) (S)-4-Benzyl-3-[(S)-3-(4-hydroxyphenyl)-2-(4-methylphenoxy) propionyl]oxazolidin-2-he

To a solution of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-3-(4 - hydroxyphenyl)-2-(4-methylphenoxy)phloroglucinol acid (90 ml) at ambient temperature was added triethylsilane (24,0 ml). The mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water and the layers were separated. An ethyl acetate layer was washed with a saturated aqueous solution of sodium bicarbonate, hydrochloric acid (1N.) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals were collected by filtration using a mixture of isopropyl ether and hexane, obtaining the target compound (6,70 g) as colorless crystals.

so pl. 135 - 136oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.26 (3H, s), 2,77 (1H, DD, J=a 9.5 and 13.5 Hz), is 3.08 is 3.23 (3H, m); 4,01 (1H, t, J=8.5 Hz), 4,15 (1H, DD, J=2,0, 8.5 Hz), 4,46-4,55 (1H, m), 4.80 to 4,88 (1H, m) 6,09 (1H, DD, J=6,0, 8.0 Hz), 6.75 in (2H, d, J=8.5 Hz), to 6.80 (2H, d, J= 8.5 Hz), 7,05 (2H, d, J=8.5 Hz), 7,10 - to 7.15 (2H, m), 7,21-7,33 (5H, m).

(e) 2-Trimethylsilylmethyl (S)-3-(4 - hydroxyphenyl)-2-(4-methylphenoxy) propionate

To a suspension of (S)-4-benzyl-3-[(S)-3-(4-hydroxyphenyl)-2-(4 - methylphenoxy)propionyl] oxazolidin-2-it (6.50 g), representing an additional product of reference example 1 (d), in methanol (80 ml) was added dropwise a mixture of an aqueous solution of lithium hydroxide (1N., 37,7 ml) and an aqueous solution of hydrogen peroxide (31%, 4,14 ml is actor of dithionite sodium (6,56 g) in water (20 ml) and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue for alkalizing was added an aqueous solution of sodium hydroxide (1N.). The aqueous solution was washed with dichloromethane and then acidified by adding hydrochloric acid. Added ethyl acetate and the mixture was stirred, an ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was led from a mixture of isopropyl ether and hexane, obtaining (S)-3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionic acid (3,38 g) as a white powder. To a suspension of this carboxylic acid (3.25 g) in dichloromethane (40 ml) at ambient temperature was added oxalicacid (to 5.21 ml) and N,N - dimethylformamide (5 drops). The mixture was stirred for 1 hour. At the end of this time the reaction mixture was concentrated under reduced pressure. Residual acid gas was removed by azeotropic distillation using toluene to remove excess reagent. To a solution of the residue in dichloromethane (40 ml) was added trimethylsilylethynyl (8,55 ml). This mixture was stirred at ambient temperature for 15 hours. To the mixture was added triethylamine (4,16 ml) and 4-N,N - dimethylaminopyridine (146 mg). This mixture was stirred at campanii. The residue was distributed between ethyl acetate and water and the layers separated. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 6/1 and 4/1 as eluents, obtaining the target compound as colorless crystals.

so pl. 94 - 95oC

1H NMR (270 MHz, CDCl3): M. D.

of 0.02 (9H, s) to 0.92 (2H, t, J=8,5 Hz in), 2.25 (3H, s), 3,13-3,19 (2H, m), 4,10-to 4.28 (2H, m), of 4.66 (1H, DD, J=6,0, 7,0 Hz), of 4.77 (1H, s), 6.73 x (2H, d, J= 8.5 Hz), 6.75 in (2H, d, J=8.5 Hz), 7,02 (2H, d, J=8,5 Hz), 7,16 (2H, d, J= 8,5 Hz).

Additional reference example 2

2-Trimethylsilylmethyl (S)-2-(4-tert-butylphenoxy)-3-(4 - hydroxyphenyl)propionate

(a) (S)-4-Benzyl-3-[(4-tert-butylphenoxy) acetyl] oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(a), using 4-tert-butylphenoxyacetyl acid (17.0 g), oxalicacid (17,8 ml), (S)-4-benzyl-2-oxazolidinone (14.2 g) and a solution of n-utility in hexane (1,61 N., and 50.4 ml), and treated reaction mixture, receiving specified in the header connection (28,3 g) as colorless crystals.

(b) (S)-4-Benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-2-(4 - tert-butylphenoxy)-3-hydroxypropionic]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(b), using (S)-4-benzyl-3-[(4-tert-butylphenoxy)acetyl] oxazolidin-2-it (28,2 g), representing an additional product of reference example 2 (a), a solution of triflate dilutive in dichloromethane (1H, to 92.1 ml), triethylamine (13,9 ml) and 4-benzyloxybenzaldehyde (17.9 g) and the reaction mixture was treated, getting mentioned in the title compound (30.0 g) in the form of a colorless oil.

1H NMR (270 MHz, CDCl3): M. D.

of 1.28 (9H, s), 2,73 (1H, DD, J=9,0, 13.5 Hz), 3,03-of 3.12 (2H, m) to 3.58 (1H, t, J= 8.5 Hz), of 3.97 (1H, DD, J=1.5 and 8.5 Hz), 4,23-the 4.29 (1H, m), of 5.05 (2H, s) 5,08 (1H, t, J=5.5 Hz), to 6.19 (1H, d, J=5.5 Hz), 6,92 (2H, d, J=8.5 Hz), to 6.95 (2H, d, J=8.5 Hz), 7,06-was 7.08 (2H, m), 7,25-7,40 (12H, m).

(s) (S)-4-Benzyl-3-[(2S, 3R)-2-(4-tert-butylphenoxy) -3-hydroxy-3-(4-hydroxyphenyl)-propionyl]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(c), using (S)- 4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-2-(4-tert - butylphenoxy)-3-hydroxypropionic]oxazolidin-2-it (30 the mixture was processed, getting listed in the title compound (27,0 g) in the form of a foamed mass.

1H NMR (270 MHz, CDCl3): M. D.

is 2.05 (9H, s), was 2.76 (1H, DD, J=9,0, 13.5 Hz), 3,07-3,13 (2H, m in), 3.75 (1H, t, J= 8.5 Hz), of 4.05 (1H, DD, J=2,0, 8.5 Hz), 4,29-4,34 (1H, m), 5.08 to, (1H, t, J=5.5 Hz), 5,32 (1H, s), 6,18 (1H, d, J=5.5 Hz), to 6.80 (2H, d, J=8.5 Hz), 6,92 (2H, d, J=8.5 Hz), 7,06-to 7.09 (2H, m), 7,25 was 7.36 (7H, m).

(d) (S)-4-Benzyl-3-[(S)-2-(4-tert-butylphenoxy) -3-(4-hydroxyphenyl)propionyl]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1 (d), using (S)-4-benzyl-3-[(2S,3R)-2-(4-tert-butylphenoxy)-3-hydroxy-3- (4-benzyloxyphenyl)propionyl]oxazolidin-2-it (30.0 g), representing an additional product of reference example 2 (C), and triethylsilane (66 ml) and was treated with the reaction mixture, getting mentioned in the title compound (18.2 g) in the form of colorless crystals.

so pl. 160 - 161oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.26 (9H, s), and 2.79 (1H, DD, J=a 9.5 and 13.5 Hz), is 3.08 is 3.23 (3H, m), a 4.03 (1H, t, J= 8.5 Hz), 4,17 (1H, DD, J=2.5 and 8.5 Hz), 4,48-4,56 (1H, m), of 4.77 (1H, user. C) between 6.08 (1H, DD, J=5,5, 8.0 Hz), 6.75 in (2H, d, J=8.5 Hz), 6,83 (2H, d, J=8.5 Hz), 7,11 - 7,14 (2H, m), 7,22-to 7.32 (7H, m).

(e) 2-Trimethylsilylmethyl (S)-2-(4-tert-butylphenoxy)- 3-(4-hydroxyphenyl) propionate

The reaction was carried out by way of Enoki)-3-(4-hydroxyphenyl) propionyl] oxazolidin-2-it (24.3 g), representing a product additional reference example 2(d), an aqueous solution of lithium hydroxide (1N., 128 ml) and an aqueous solution of hydrogen peroxide (31%, 14.1 ml), and treated reaction mixture, obtaining (S)-2-(4-tert-butylphenoxy)-3-(4-hydroxyphenyl)propionic acid (13,4 g) as a white powder.

By the way, is similar to that described in additional reference example 1(e), carried out the reaction using this carboxylic acid (13.3 g) oxalicacid (of 18.45 ml) and 2-trimethylsilylethynyl (30,3 ml) and was treated with the reaction mixture, getting mentioned in the title compound (16.0 g) as colorless crystals.

so pl. 71 - 72oC

1H NMR (270 MHz, CDCl3): M. D.

0,06 (9H, s) of 0.93 (2H, t, J=8.5 Hz), is 1.31 (9H, s), 3,18-is 3.21 (2H, m), 4,18-to 4.33 (2H, m), 4,69-to 4.73 (2H, m), 6,79 (2H, d, J=8.5 Hz), to 6.80 (2H, d, J=8.5 Hz), 7,21 (2H, d, J=8.5 Hz), 7,28 (2H, d, J=8,5 Hz).

Additional reference example 3

2-Trimethylsilylmethyl (S)-2-(4-pertenece)-3-(4 - hydroxyphenyl) propionate

(a) (S)-4-Benzyl-3-[(4-pertenece)acetyl]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(a), using 4-ftordesoxyglucose acid (1.70 g), oxalicacid (2,18 ml), (3)-4-benzyl-2-oxazol the e in the title compound (2.76 g) as colorless crystals.

so pl. 113-115oC

1H NMR (270 MHz, CDCl3): M. D.

to 2.85 (1H, DD, J=a 9.5 and 13.5 Hz), to 3.36 (1H, DD, J=3,0 and 13.5 Hz), 4.26 deaths-of 4.38 (2H, m), 4,68-of 4.77 (1H, m), a total of 5.21 (2H, s), 6.90 to? 7.04 baby mortality (4H, m), 7,20-7,38 (5H, m).

(b) (S)-4-Benzyl-3-[(2S, 3R)-3-(4-benzyloxyphenyl)-2- (4-pertenece)-3-hydroxypropionic]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(b), using (S)-4-benzyl-3-[(4-pertenece)acetyl]oxazolidin-2-it (1,96 g), representing an additional product of reference example 3(a), a solution of triflate dilutive in dichloromethane (1M, 7,14 ml), triethylamine (1.08 ml) and 4-benzyloxybenzaldehyde (1.39 g) and the reaction mixture was treated, receiving specified in the header connection (2,68 g) in the form of a foamed mass.

1H NMR (270 MHz, CDCl3): M. D.

of 2.72 (1H, DD, J=9,0, 13.5 Hz), 2,97-3,11 (1H, m), 3,05 (1H, DD, J=3,0 and 13.5 Hz), 3,57 (1H, t, J=8.5 Hz), of 3.97 (1H, DD, J=2,0, 8.5 Hz), 4,21-4,27 (1H, m), 5,03-5,13 (1H, m), of 5.05 (2H, s), 6,16 (1H, d, J=5.5 Hz), 6,85-7,06 (6H, m), 7,07 for 7.12 (2H, m), 7,25-the 7.43 (10H, m).

(s) (S)-4-Benzyl-3-[(2S, 3R)-2-(4-pertenece) -3-hydroxy-3-(4-hydroxyphenyl)-propionyl]oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(C), using (S)-4-benzyl-3- [(2S,3R)-3-(4-benzilate reference example 3(b) and palladium on coal (5%, 490 mg) and the reaction mixture was treated, receiving specified in the header connection (1,94 g) in the form of a foamed mass.

1H NMR (270 MHz, CDCl3): M. D.

of 2.75 (1H, DD, J=9,0, 13.5 Hz), 3,03-3,10 (1H, m), of 3.07 (1H, DD, J=3,0 and 13.5 Hz in), 3.75 (1H, t, J=8.5 Hz), 4,06 (1H, DD, J=2,0, 8.5 Hz), 4.26 deaths-4,34 (1H, m), 5.08 to, (1H, DD, J=4,5, 5,5 Hz), 6,16 (1H, d, J=5.5 Hz), for 6.81 (2H, d, J= 8.5 Hz), 6.89 in-7,01 (4H, m), 7,02-7,10 (2H, m), 7.24 to 7,30 (5H, m), 7,34 (2H, d, J=8,5 Hz).

(d) (S)-4-Benzyl-3-[(S)-2-(4-pertenece)-3-(4-hydroxyphenyl) propionyl] oxazolidin-2-he

The reaction was carried out by a method similar to that described in additional reference example 1(d), using (S)- 4-benzyl-3-[(2S,3R)-3-hydroxy-2-(4-pertenece)-3-(4 - hydroxyphenyl)propionyl] oxazolidin-2-it (1.89 g), representing an additional product of reference example 3(C), and triethylsilane (5,4 ml) and was treated with the reaction mixture, receiving specified in the header connection (1,21 g) in the form of colorless crystals.

so pl. 137 - 138oC

1H NMR (270 MHz, CDCl3): M. D.

2,77 (1H, DD, J= 9,0, 13.5 Hz), is 3.08-3,20 (3H, m), was 4.02 (1H, t, J=8.5 Hz), 4,17 (1H, DD, J=2.5 and 8.5 Hz), 4,46-of 4.54 (1H, m), 4,82 to 4.92 (1H, m), the 6.06 (1H, DD, J=6,0, 7.5 Hz), 6,76 (2H, d, J=8.5 Hz), 6,86 (2H, DD, J=4,5, and 9.0 Hz), 6,94 (2H, DD, J=8,0, 9.0 Hz), 7,09 for 7.12 (2H, m), 7,22 (2H, d, J=8.5 Hz), 7,26-7,30 (5H, m).

(e) 2-Trimethylsilylmethyl (S)-2-(4-pertenece)-3-(4-person example 1(e), using (S)-4-benzyl-3-[(S)-2-(4-pertenece)-3-(4-hydroxyphenyl) -propionyl]oxazolidin-2-it (4,20 g), representing an additional product of reference example 3 (d), an aqueous solution of lithium hydroxide (1N., 24,1 ml) and an aqueous solution of hydrogen peroxide (31%, of 2.64 ml), and treated reaction mixture, obtaining (S)-2-(4-pertenece)-3-(4-hydroxyphenyl)-propionic acid (2,31 g) as a white powder.

In accordance with the method similar to that described in additional reference example 1(e), carried out the reaction using this carboxylic acid (2.30 g), oxalicacid (1.80 ml) and 2-trimethylsilylethynyl (15,96 ml), and treated reaction mixture, receiving specified in the header connection (1,81 g) as colorless crystals.

so pl. 99 - 100oC

1H NMR (270 MHz, CDCl3): M. D.

of 0.02 (9H, s) of 0.93 (2H, DD, J=7,5, 10,0 Hz) and 3.15 (2H, d, J=6.5 Hz), 4,16-4,24 (2H, m), to 4.62 (1H, t, J=6.5 Hz), 4,82 (1H, user.C) 6,74-6,79 (4H, m) 6,91 (2H, DD, J=8,5, 9.0 Hz), 7,16 (2H, d, J=8,5 Hz).

Additional reference example 4

2-[1-(4'-Methoxy-4-biphenylyl)ethylidene]aminoxy]ethanol

(a) the Reaction of 4'-(4-methoxyphenyl)acetophenone

To a solution of potassium hydroxide (2.9 g) in a mixture of methanol (40 ml) and water (8 ml) was added hydroxylamine hydrochloride is). The reaction mixture was stirred at 50oC for 7 hours, and then was added potassium hydroxide (2.9 g) and hydroxylamine hydrochloride (of 3.07 g). The reaction mixture was additionally stirred at 50oC for 65 hours and then concentrated under reduced pressure. To the residue was added ethyl acetate and water, and precipitated from the solution, the crystals were collected by filtration and washed with water and ethyl acetate. The crystals were additionally washed with isopropyl ether, receiving specified in the header of the connection (of 4.05 g) as colorless crystals.

so pl. 82 - 84oC

1H NMR (270 MHz, DMSO-d6: M. D.

to 2.18 (3H, s), of 3.80 (3H, s), 7,03 (2H, d, J=8.5 Hz), to 7.64 (4H, d, J=8.0 Hz,), 7,71 (2H, d, J=8,5 Hz).

(b) 2-[1-(4'-Methoxy-4-biphenylyl)ethylidene]aminoxy]ethanol

To a solution of 2-(2-bromoethoxy)tetrahydropyran (494 mg) and the reaction of 4'-(4-methoxyphenyl)acetophenone (380 mg), representing an additional product of reference example 4 (a), in 10 ml of N,N-dimethylacetamide was added potassium carbonate (660 mg) and the resulting mixture was stirred at 80oC for 16 hours. At the end of the interaction, the reaction mixture was dissolved in a mixture of ethyl acetate and water. An ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, after which via on silica gel using a mixture of 5/1 by volume of hexane and ethyl acetate, getting simple 0-2-[(tetrahydropyran-2 - yl)oxy] ethyl ester oxime 4'-(4-methoxyphenyl)acetophenone (590 mg) as a white solid. To a solution of simple O-2- [(tetrahydropyran-2-yl)oxy] ethyl ester oxime 4'-(4 - methoxyphenyl)acetophenone (561 mg) in 30 ml of methanol was added monohydrate p-toluensulfonate acid (290 mg) and the resulting mixture was stirred at room temperature for 2 hours and then was concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure. The crystals were collected by filtration with the use of isopropyl ether, getting mentioned in the title compound (390 mg) as colorless crystals.

so pl. 164 - 166oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.30 (3H, s), of 3.80 (3H, s), 3,94-3,98 (2H, m), 4,32 is 4.35 (2H, m), of 6.99 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), to 7.68 (2H, d, J=8,5 Hz).

Additional reference example 5

Ethyl 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)propionate

(a) Ethyl 3-(4-benzyloxyphenyl)lactate

Methyl benzyl (21,9 g) and potassium carbonate (35,3 g) doC for 2 hours. The reaction mixture was distributed between ethyl acetate and water. An ethyl acetate layer was separated, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 7/3 as eluent, obtaining the target compound (31.0 g) as a pale yellow oil.

(b) Ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonylaminoethyl

To a solution of ethyl 3-(4-benzyloxyphenyl)lactate (3,32 g), representing an additional product of reference example 5 (a), in anhydrous dichloromethane (30 ml) was added methanesulfonamide (0,94 ml). To this mixture was added dropwise in an ice bath triethylamine (2,47 ml). The mixture was stirred at ambient temperature for 3 hours the Reaction mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water. An ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was led from hexane, obtaining the target product (of 3.60 g) as colorless crystals.

so pl. 81 - 83oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.27 (3H, t, J=7.0 Hz), 2,80 Il 3-(4-benzyloxyphenyl)-2-(4-chlorophenoxy)propionate

To a solution of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonylaminoethyl (8,82 g), representing an additional product of reference example 5(b), and 4-chlorophenol (3.00 g) (2.85 g) in N,N-dimethylformamide (110 ml) was added potassium carbonate (6,44 g). This mixture was stirred at 70oC for 16 hours. The reaction mixture was distributed between ethyl acetate and water and the layers were separated. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 9/1 as eluent, obtaining the target

connection of 5.99 g) as colorless crystals.

so pl. 63 - 64oC

1H NMR (270 MHz, CDCl3): M. D.

of 1.18 (3H, t, J=7.0 Hz), 3,17 (2H, d, J=6,5 Hz) to 4.16 (2H, q, J=7.0 Hz), 4,69 (1H, t, J=6.5 Hz), 5,04 (2H, s), of 6.75 (2H, d, J=9.0 Hz), 6,91 (2H, d, J=8.5 Hz), 7,13-of 7.23 (4H, m), 7,25-of 7.55 (5H, m).

(d) Ethyl 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)propionate

A solution of ethyl 3-(4-benzyloxyphenyl)-2-(4-chlorphenoxy)-propionate (of 5.99 g), representing an additional product of reference example 5 (C), in a solution of hydrogen bromide in acetic acid (25%, 60 ml) was stirred at ambient temperature for 3 hours. Reactione (4.68 g). This mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water and the layers were separated. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel using mixtures of hexane/ethyl acetate = 9/1 - 4/1 as eluent, obtaining the target compound (3,85 g) as colorless crystals.

so pl. 90 - 93oC

1H NMR (270 MHz, CDCl3): M. D.

to 1.19 (3H, t, J=7,0 Hz), and 3.16 (2H, d, J=6.5 Hz), 4,17 (2H, q, J=7.0 Hz), 4,69 (1H, t, J=6.5 Hz), of 4.95 (1H, user.C) 6,76 (4H, d, J=8.5 Hz), to 7.15 (2H, d, J=8.5 Hz), 7,18 (2H, d, J=8,5 Hz).

Additional reference example 6

Ethyl 2-(4-pertenece)-3-(4-hydroxyphenyl)propionate

(a) Ethyl 3-(4-benzyloxyphenyl)-2-(4-pertenece)propionate

The solution diethylazodicarboxylate (40% solution in toluene, 6,40 ml) in toluene (3.0 ml) was added dropwise to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (10.0 g), representing an additional product of reference example 5 (a), 4-terfenol (4.15 g) and triphenylphosphine (10.6 g) in toluene (10 ml) at ambient temperature. After stirring the mixture C. the STATCOM was purified column chromatography on silica gel using mixtures of dichloromethane/ethyl acetate = 3/2 as eluent, obtaining specified in the header connection (7,00 g) as a colourless oil.

1H NMR (270 MHz, CDCl3): M. D.

of 1.18 (3H, t, J=7,0 Hz), and 3.16 (2H, d, J=6,5 Hz) to 4.16 (2H, q, J=7.0 Hz), of 4.66 (1H, t, J=6.5 Hz), 5,04 (2H, s), 6,72-to 6.80 (2H, m), 6.89 in-6,97 (4H, m), 7,21 (2H, d, J=8.5 Hz), 7,31-of 7.48 (5H, m).

(b) Ethyl 2-(4-pertenece)-3-(4-hydroxyphenyl)propionate

A solution of ethyl 3-(4-benzyloxyphenyl)-2-(4 - pertenece)propionate (7,00 g), representing an additional product of reference example 6 (a), in a solution of hydrogen bromide in acetic acid (25%, 70 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in ethanol (70 ml) was added potassium carbonate (6.90 to g). This mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate and water and the layers were separated. An ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with Espoo powder.

so pl. 80 - 81oC

1H NMR (270 MHz, CDCl3): M. D.

to 1.19 (3H, t, J=7,0 Hz) and 3.15 (2H, d, J=6.5 Hz), 4,17 (2H, q, J=7.0 Hz), 4,65. (1H, t, J=6.5 Hz), was 4.76 (1H, s) of 6.71-to 6.80 (4H, m), 6.87 in-6,95 (2H, m), 7,16 (2H, d, J=8,5 Hz).

Additional reference example 7

2-[[1'-(4-Fluoro-4-biphenylyl)ethylidene]aminoxy]ethylmethanesulfonate

(and) 2-[[1'-(4-Fluoro-4-biphenylyl)ethylidene]aminoxy]ethanol

In accordance with methods similar to those described in reference examples 1(C) and (d), but using 6,84 g 2-(2-bromoethoxy)tetrahydropyran, 5,00 g of the oxime 4'(4 - forfinal)of acetophenone, of 6.02 g of potassium carbonate and catalytic amounts of monohydrate p-toluensulfonate acid was obtained of 3.84 g specified in the title compound as white crystals.

so pl. 131 - 133oC

1H NMR (270 MHz, CDCl3): M. D.

of 2.30 (3H, s), of 3.96 (2H, t, J=4.5 Hz), 4,34 (2H, t, J=4.5 Hz), 7,14 (2H, t, J=8.5 Hz), 7,53-to 7.59 (4H, m), of 7.69 (2H, d, J=8,5 Hz).

(b) 2-[[1'-(4-Fluoro-4-biphenylyl)ethylidene]aminoxy] -ethylmethanesulfonate

To a solution of methanesulfonamide (1,15 ml) and 2-[[1'-(4-fluoro-4-biphenylyl)ethylidene] aminoxy] ethanol (3,70 g), representing an additional product of reference example 7 (a), in dichloromethane (40 ml) was added dropwise at 0oC triethylamine and 2.83 ml). After peremeci is whether under reduced pressure. The residue was distributed between ethyl acetate and water and the layers were separated. An ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystals were collected by filtration using hexane and isopropyl ether, receiving specified in the header connection (4,70 g) as colorless crystals.

so pl. 103 - 106oC

1H NMR (270 MHz, CDCl3): M. D.

to 2.29 (3H, s), 3.04 from (3H, s), to 4.46 (2H, t, J=4.5 Hz), 4,56 (2H, t, J=4.5 Hz), 7,14 (2H, t, J=8.5 Hz), 7,54-to 7.59 (4H, m), 7,72 (2H, d, J=8,5 Hz). T T7

1. Derivatives phenylalkylamines acid of the formula I

< / BR>
where R1represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms;

R2is alkylenes group with a straight or branched chain, having from 2 to 6 carbon atoms;

R3represents a hydrogen atom;

Z represents alkylenes group with a straight or branched chain, having from 1 to 6 carbon atoms,

W is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon at the v) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (vi) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vii) N-alkyl-N-killingray having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (viii) alloctype having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, in the aryl part, (ix) killigrew having from 6 to 10 carbon atoms, (x) killingray having from 6 to 10 carbon atoms, (xi) Uralkaliy group having from 7 to 12 carbon atoms or (xii) 1-pyrrolidinyl group

X represents an aryl group having from 6 to 10 carbon atoms which may have 1 Deputy , specified below,

the Deputy is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, (iii) halogen atom, (iv) aryl group having from 6 to 10 carbon atoms (the aryl part can be substituted by alkoxygroup with direct or razwell is ikorodu,

their pharmacologically acceptable salts or their pharmaceutically acceptable esters.

2. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms.

3. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group with straight or branched chain, having from 1 to 3 carbon atoms.

4. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group having one or two carbon atom.

5. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R2is alkylenes group with a straight or branched chain, having from 2 to 5 carbon atoms.

6. Derived phenylalkylamines acid, its pharmacologically group with a straight or branched chain, having from 2 to 4 carbon atoms.

7. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R2is ethylene, trimethylene or melatoninbuy group.

8. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R2represents ethylene group.

9. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where X represents an aryl group having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, and the Deputy is chosen from the group consisting of phenyl (the phenyl portion may be substituted alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, or halogen) and pyridyl.

10. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where X represents a phenyl group which may have 1 Deputy , specified below, and for what PR) and pyridyl.

11. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where X represents a phenyl group which may have 1 Deputy , specified below, and the Deputy is chosen from the group consisting of phenyl, 4-methoxyphenyl, 4-ftoheia and pyridyl.

12. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where X represents a phenyl group which may have 1 Deputy , specified below, and the Deputy is chosen from the group consisting of phenyl and pyridyl.

13. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where Z is alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms.

14. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where Z is alkylenes group with a straight or branched chain having one or two carbon atom.

15. Derived ventilatory under item 1, where Z represents a methylene group.

16. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where W is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-killingray having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (vii) alloctype having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, in the aryl part, (viii) killigrew, having from 6 to 10 carbon atoms, (ix) killingray having from 6 to 10 carbon atoms, (x) Uralkaliy group having from 7 to 12 carbon atoms Il the military chain having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) fluorine atom, (iv) chlorine atom, and (v) bromine atom.

17. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where W is (i) alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-killingray having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (vii) alloctype having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, in the aryl part, (viii) killigrew, with the total from 7 to 12 carbon atoms or (xi) 1-pyrrolidinyl group, the Deputy represents a methyl group, tert.-boutelou group, a chlorine atom or a fluorine atom.

18. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where W is (i) alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-killingray having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (vii) fenoxaprop, which may have 1 Deputy , specified below, (viii) phenylthiourea, (ix) phenylaminopropyl, (x) Uralkaliy group, having 7 to 10 carbon atoms or (xi) 1-pyrrolidinyl group, and the Deputy is m the new acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where W is (i), sawn or boutelou group, (ii) alkoxygroup straight or branched chain, having from 1 to 3 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 3 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylaminopropyl (vi) N-phenyl-N-ethylamino, (vii) fenoxaprop, which may have 1 Deputy , specified below, (viii) phenylthiourea, (ix) phenylaminopropyl, (x) 3-phenylpropionyl group, (xi) 4-phenylbutyl group and (xii) 1-pyrrolidinyl group, with the Deputy represents a methyl group, tert.-boutelou group, a chlorine atom or a fluorine atom.

20. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where W represents boutelou, ethoxy, methylthio, ethylamino, diethylamino, N-phenyl-N-ethylamino, phenoxy, 4-chlorophenoxy, 4-fervency, 4-methylphenoxy, 4-tert. -butylphenoxy, phenylthio, phenylamino, 3-phenylpropyl or 1-pyrrolidinyl group.

21. Derived phenylalkylamines gislative boutelou, ethoxy, methylthio, ethylamino, phenoxy, 4-chlorophenoxy, 4-fervency, 4-methylphenoxy, 4-tert. -butylphenoxy, phenylthio, phenylamino or 3-phenylpropyl group.

22. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, R2is alkylenes group with a straight or branched chain, having from 2 to 5 carbon atoms, R3represents a hydrogen atom, Z represents alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms, W represents (i) an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 upperbody atoms, and aryl part has from 6 to 10 carbon atoms, (vii) alloctype having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, in the aryl part, (viii) killigrew having from 6 to 10 carbon atoms, (ix) killingray having from 6 to 10 carbon atoms, (x) Uralkaliy group having from 7 to 12 carbon atoms, or (xi) 1-pyrrolidinyl group, X represents an aryl group having from 6 to 10 carbon atoms, which may have 1 Deputy , specified below, and the Deputy is chosen from the group consisting of (i) alkyl straight or branched chain, having from 1 to 6 carbon atoms, (ii) halogenated alkyl straight or branched chain, having from 1 to 4 carbon atoms, (iii) fluorine atom, (iv) chlorine atom, (v) bromine atom, (vi) phenyl (the phenyl portion may be substituted alkoxy group with a straight or branched chain, having from 1 to 4 carbon atoms, or halogen) or (vii) pyridyl; and Y represents an oxygen atom.

23. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group with straight or branched chain, imoudu the th from 2 to 5 carbon atoms, R3represents a hydrogen atom, Z represents alkylenes group with a straight or branched chain, having from 1 to 4 carbon atoms, W represents (i) an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, (ii) alkoxygroup straight or branched chain, having from 1 to 4 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 4 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 4 carbon atoms, (v) dialkylamino straight or branched chain, in which the alkyl groups are the same or different from each other and each has from 1 to 4 carbon atoms, (vi) N-alkyl-N-killingray having alkyl straight or branched chain, having from 1 to 4 carbon atoms, and aryl part has from 6 to 10 carbon atoms, (vii) alloctype having from 6 to 10 carbon atoms which may have 1 Deputy , specified below, in the aryl part, (viii) killigrew, having from 6 to 10 carbon atoms, (ix) killingray having from 6 to 10 carbon atoms, (x) Uralkaliy group having from 7 to 12 carbon atoms, or (xi) 1-pyrrolidinyl group; X represents phenyl GRU is tilen group, tert.-butilkoi group, fluorine atom, chlorine atom, phenyl group (which may be substituted methoxy group or fluorine) and pyridyl; and Y represents an oxygen atom.

24. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group having one or two carbon atoms; R2represents ethylene group; R3represents a hydrogen atom; Z represents a methylene group; W represents (i), sawn or boutelou group, (ii) alkoxygroup straight or branched chain, having from 1 to 3 carbon atoms, (iii) allylthiourea straight or branched chain, having 1 to 3 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylaminopropyl, (vi) N-phenyl-N-ethylamino, (vii) fenoxaprop, which may have 1 Deputy , specified below, (viii) phenylthiourea, (ix) phenylaminopropyl, (x) 3-phenylpropionyl group, (xi) 4-phenylbutyl group, or (xii) 1-pyrrolidinyl group; X represents a phenyl group which may have 1 Deputy , specified below, and the Deputy is chosen from the group of Niley group, 4-forfamilies group and peredelnoj group; and Y represents an oxygen atom.

25. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group having one or two carbon atoms; R2represents ethylene group; R3represents a hydrogen atom; Z represents a methylene group; W represents (i), sawn or boutelou group, (ii) alkoxygroup straight or branched chain, having from 1 to 3 carbon atoms, (iii) allylthiourea straight or branched chain, having from 1 to 3 carbon atoms, (iv) monoalkylamines straight or branched chain, having from 1 to 3 carbon atoms, (v) diethylaminopropyl, (vi) N-phenyl-N-ethylamino, (vii) fenoxaprop, which may have 1 Deputy, selected from the group consisting of methyl group, tert. -butilkoi group, fluorine atom and chlorine atom, (viii) phenylthiourea, (ix) phenylaminopropyl, (x) 3-phenylpropionyl group, (xi) 4-phenylbutyl group, or (xii) 1-pyrrolidinyl group; X represents a phenyl group which may have 1 Deputy , specified below, and the Deputy is chosen from the group with whom to place the oxygen atom.

26. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group having one or two carbon atoms; R2represents ethylene group; R3represents a hydrogen atom; Z represents a methylene group; W represents boutelou, ethoxy, methylthio, ethylamino, diethylamino, N-phenyl-N-ethylamino, phenoxy, 4-chlorophenoxy, 4-fervency, 4-methylphenoxy, 4-tert.-butylphenoxy, phenylthio, phenylamino, 3-phenylpropyl or 1-pyrrolidinyl group; X represents a phenyl group which may have 1 Deputy , specified below, and the Deputy is chosen from the group consisting of phenyl group, 4-metoksifenilny group, 4-forfamilies group and peredelnoj group; and Y represents an oxygen atom.

27. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1, where R1represents an alkyl group having one or two carbon atoms; R2represents ethylene group; R3represents a hydrogen atom; Z represents a methylene group; W represents boutelou, uh, is enylamine or 3-phenylpropyl group; X represents a phenyl group which may have 1 Deputy , specified below; and the Deputy is chosen from the group consisting of phenyl groups and peredelnoj group; and Y represents an oxygen atom.

28. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1 selected from the group:

2 ethoxy-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-methylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2 phenylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

3-[4-[2-[[1-(4-biphenylyl) ethylidene] aminoxy] ethoxy] phenyl] -2-(phenylamino) propionic acid,

2 phenylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2 ethylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-(N, N-diethylamino)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

3-[4-[2-[[1-(4-biphenylyl) ethylidene] aminoxy] ethoxy] phenyl]-2-[N-phenyl-N-ethylamino] propionic acid is ropyl)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-butyl-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid and

2 phenoxy-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid.

29. Derived phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable esters under item 1 selected from the group:

2 ethoxy-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-methylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2 phenylthio-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

3-[4-[2-[[1-(4-biphenylyl) ethylidene] aminoxy] ethoxy] phenyl] -2-(phenylamino) propionic acid,

2 ethylamino-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-(3-phenylpropyl)-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid,

2-butyl-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid and

2 phenoxy-3-[4-[2-[[1-[4-(2-pyridyl) phenyl] ethylidene] aminoxy] ethoxy] phenyl] propionic acid.

30. Composition exhibiting hyperglycemic actively svodnoe phenylalkylamines acid, its pharmacologically acceptable salt or a pharmacologically acceptable ester according to any one of paragraphs.1 - 29.

 

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The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

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< / BR>
where R2, R3, R4and R5independently from each other mean a hydrogen atom or an alkyl with a number of carbon atoms one to four;

Z denotes alkyl with the number of carbon atoms from 1 to 8, cycloalkyl with the number of carbon atoms from 3 to 6, alkenyl with the number of carbon atoms from 3 to 8, naphthyl; pyridyl, not substituted or substituted by substituents from the series: halogen, the nitro-group, cyano, triptorelin group, alkyl with the number of carbon atoms from 1 to 4, alkoxygroup with the number of carbon atoms from 1 to 4 or a group

< / BR>
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< / BR>
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< / BR>
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