1,5-benzothiazepines and employment thereof as antihyperlipidemic drugs

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

 

Description

This invention relates to a derivative benzodiazepine or their pharmaceutically acceptable salts, solvate, solvate of such salts and prodrugs. Data benzodiazepine possess inhibitory activity against transport of bile acids in the ileum (ileal bile acid transport - IBAT), and therefore are of interest for the treatment of diseases associated with States of hyperlipemia, and useful in the methods of treatment of a warm-blooded animal such as man. The invention also relates to methods of producing these derivatives benzodiazepine, pharmaceutical compositions containing these compounds and to their use in the production of pharmaceuticals for inhibition of IBAT in the body of warm-blooded animal such as man.

It is well known that the state of hyperlipemia associated with elevated concentrations of total cholesterol and cholesterol low-density lipoprotein, are the major risk factors for cardiovascular atherosclerosis (see, e.g., "Coronary Heart Disease: Reducing the Risk; a Worldwide View" Assman G., Garmena R., Cullen P. et al.; Circulation 1999, 100, 1930-1938, "Diabetes and Cardiovascular Desease: A Statement for Healthcare Professionals from the American Heart Association" Grundy S., Benjamin I., Burke G., et al.; Circulation, 1999, 100, 1134-46). It is established that the violation of circulation of bile acids in the intestinal canal lowers cholesterol. Bit is botania earlier therapeutic methods of reducing the concentration of cholesterol include, for example, treatment with inhibitors of HMG-CoA reductase inhibitor, preferably a statin, such as simvastatin (simvastatin) and fluvastatin (fluvastatin), or treatment with substances that bind bile acids, such as resin. Widely used substances that bind bile acids are, for example, colestyramine (cholestyramine) and holestipol (cholestipol). One of the previously proposed methods of therapeutic treatment ("Bile Acids and Lopoprotein Metabolism: a Renaissance for Bile Acids in the Post-Statin Era" Angelin B., Eriksson m, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) includes the treatment of substances with inhibitory activity against IBAT.

Re-absorption of bile acids from the gastrointestinal tract is a normal physiological process that occurs mainly in the ileum by the mechanism of IBAT. IBAT inhibitors can be used in the treatment of hypercholesterolemia (see, for example, the publication "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties", Biochemica et Biophysica Acta, 1210 (1994) 255-287). Thus, suitable compounds with inhibitory activity against IBAT, useful in the treatment of painful conditions related hyperlipemia. Compounds with inhibitory activity against IBAT, have been described in the literature (see, for example, compounds described in WO 93/16055, WO 94/18183, WO 94/181884, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/3513, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906 and EP 0864582.

An additional aspect of this invention relates to the use of compounds of this invention in the treatment of dyslipidemias conditions and disorders, such as hyperlipemia, hypertriglyceridemia, hyperbetalipoproteinemia (high levels of LDL), hyperbetalipoproteinemia (high levels of VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low content of HDL). In addition, it is expected that these compounds will be useful for the prevention and treatment of various clinical conditions such as atherosclerosis, the narrowing of the arteries, arrhythmia, hyperchromatism status, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction, angina, peripheral vascular diseases, inflammation, cardiovascular tissues, such as heart valve, a vascular network of arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, macrophage, and/or macrobiotically infiltration, seal inner shell vessels (intimital thickening), medial thinning the vessel is in (medial thinning), infectious and surgical trauma, and vascular thrombosis, stroke and transient cerebral attacks.

This invention is based on the discovery of the fact that some derivatives benzodiazepine unexpectedly inhibit IBAT. It is expected that these properties are of interest for the treatment of diseases associated with hyperlipidemia.

Accordingly, this invention provides a compound of formula (I):

where

RVand RWindependently selected from hydrogen or C1-6of alkyl;

R1and R2independently selected from C1-6of alkyl;

Rxand Ryindependently selected from hydrogen or C1-6the alkyl, or one of Rxand Ryrepresents hydrogen or C1-6alkyl and the other represents hydroxyl or1-6alkoxy;

Rzselected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-6of alkyl, C2-6alkenyl,2-6the quinil,1-6alkoxy, C1-6alkanoyl,1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl,1-6S(O)awhere and takes the value from 0 to 2, C1-6alkoxycarbonyl,1-6alkoxycarbonyl, is reido, N'-(C1-6alkyl)ureido, N-(C1-6alkyl)ureido, N',N'-(C1-6alkyl)2ureido, N'-(C1-6alkyl)-N-(C1-6alkyl)ureido, N',N'-(C1-6alkyl)2-N-(C1-6alkyl)ureido, N-(C1-6alkyl)sulfamoyl and N,N-(C1-6alkyl)2sulfamoyl;

V takes a value from 0 to 5;

one of R4and R5represents a group of formula (IA):

R3and R6and second of R4and R5independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R3and R6and second of R4and R5may be optionally substituted on carbon by one or more R16;

D represents-O-, -N(Ra)-, -S(O)b- or-CH(Ra)-; where Rarepresents hydrogen or C1-6alkyl, and b takes the value from 0 to 2;

the ring And made the focus of an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17;

R7represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R7is optionally substituted by one or more substituents selected from R18;

R8represents hydrogen or C1-4alkyl;

R9represents hydrogen or C1-4alkyl;

R10represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R10is optionally substituted by one or more substituents selected from R19;

R11represents carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rdor

-P(O)(ORc)(Rd), where Rcand Rdindependently selected from C1-6of alkyl; or R11represents a group of formula (IB):

where:

X represents-N(Rq)-, -N(Rq)C(O)-, -O - and-S(O)a; where a takes the value from 0 to 2, and Rqrepresents hydrogen or C1-4alkyl;

R12represents hydrogen or C1-4alkyl;

R13and R14independently selected from hydrogen, C1-4of alkyl, carbocycle, heterocyclyl or R23; where these sub> 1-4alkyl, carbocyclic or heterocyclyl may be independently optionally substituted by one or more substituents selected from R20;

R15represents a carboxy group, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe),

-P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-6of alkyl; or R15represents a group of formula (IC):

where

R24selected from hydrogen or C1-4of alkyl;

R25selected from hydrogen, C1-4of alkyl, carbocycle, heterocyclyl or R27; where specified1-4alkyl, carbocyclic or heterocyclyl may be independently optionally substituted by one or more substituents selected from R28;

R26selected from carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rgor

-P(O)(ORg(Rh), where Rgand Rhindependently selected from C1-6of alkyl;

p value is from 1 to 3; where R13may be the same or different;

q takes a value from 0 to 1;

r takes a value from 0 to 3; where R14may be the same or different;

m takes a value from 0 to 2; where R10can be about incopyme or different;

n takes values from 1 to 3; where R7may be the same or different;

z takes a value from 0 to 3; where R25may be the same or different;

R16, R17and R18independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxy, C1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R16, R17and R18may be independently optionally substituted on carbon by one or more R21;

R19, R20, R23, R27and R28independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2CT is amaila, With1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl, N,N-(C1-4alkyl)2sulfamoyl, carbocycle, heterocyclyl, sulpho, sulfine, amidino, phosphono, P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra) or-P(O)(ORa)(Rb), where Raand Rbindependently selected from C1-6of alkyl; and R19, R20, R23, R27and R28may be independently optionally substituted on carbon by one or more R22;

R21and R22independently selected from halogen, hydroxyl, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifloromethyl, cryptomelane, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethinyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesila, N-methylcarbamoyl and N,N-dimethylsulphamoyl;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In accordance with another aspect of the present invention, the proposed compound of formula (I'):

where

R1and R2independently selected from C1-6of alkyl;

one of R4and R5is sobo is a group of formula (IA'):

R3and R6and second of R4and R5independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R3and R6and second of R4and R5may be optionally substituted on carbon by one or more R16;

Ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R13;

R7represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R7is optionally substituted by one or more substituents selected from R18;

R8represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R8is optionally substituted by one or more substituents selected from R 15;

R9represents represents carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc),

-P(O)(OH)(Rd) or-P(O)(ORc)(Rd), where Rcand Rdindependently selected from C1-6of alkyl; or R9represents a group of formula (IB');

where

R10represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R10is optionally substituted by one or more substituents selected from R16;

R11represents carboxy, sulfo, sulfine, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-6of alkyl;

p value is from 1 to 3; where R10may be the same or different;

m takes a value from 0 to 2; where R8may be the same or different;

n takes values from 1 to 3; where R7may be the same or different;

R12, R13and R14independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C 1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R12, R13and R14may be independently optionally substituted on carbon by one or more R17;

R15and R16independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl, N,N-(C1-4alkyl)2sulfamoyl, sulfo, sulfine, amidino, phosphono,

-P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra) or-P(O)(ORa)(Rb), where Raand Rbindependently selected from C1-6of alkyl; and R15and R16may be independently optionally substituted on carbon by one or more R18;

R17The R 18independently selected from halogen, hydroxyl, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifloromethyl, cryptomelane, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethinyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesila, N-methylcarbamoyl and N,N-dimethylsulphamoyl;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In accordance with another aspect of the present invention, the proposed compound of formula (I):

where

R1and R2independently selected from C1-6of alkyl;

one of R4and R5represents a group of formula (IA"):

R3and R6and second of R4and R5independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)a, g is e, and takes a value from 0 to 2, With1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R3and R6and second of R4and R5may be optionally substituted on carbon by one or more R16;

Ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17;

R7represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R7is optionally substituted by one or more substituents selected from R18;

R8represents hydrogen or C1-4alkyl;

R9represents hydrogen or C1-4alkyl;

R10represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic; where R10is optionally substituted by one or more substituents selected from R19;

R11represents carboxy, sulfo, sulfine, phosphono, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd) or-P(O)(ORc)(Rd), where Rcand Rdindependently selected from C1-6of alkyl; or R11represents a group of formula (IB");

where

X represents-N(Rq)-, -N(Rq)C(O)-, -O - and-S(O)a; where a takes the value from 0 to 2, and Rqrepresents hydrogen or C1-4alkyl;

R12represents hydrogen or C1-4alkyl;

R13and R14independently selected from hydrogen, C1-4of alkyl, carbocyclic or heterocyclyl; where R13and R14may be independently optionally substituted by one or more substituents selected from R20;

R15represents carboxy, sulfo, sulfine, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-6of alkyl;

p value is from 1 to 3; where R13may be the same or different;

q takes a value from 0 to 1;

r takes a value from 1 to 3; where R14may be the same or different;

m takes a value from 0 to 2; where R10may be the same or different;

n takes values from 1 to 3; where R7may be the same or different;

R16, R17and R18independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-41-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R16, R17and R18may be independently optionally substituted on carbon by one or more R21;

R19and R20independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxygroup,1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)awhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl, N,N-(C1-4alkyl)2sulfamoyl, carbocycle, heterocyclyl, sulpho, sulfine, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra) or-P(O)(ORa)(Rb), where Raand Rbindependently selected from C1-6of alkyl; and R19and R20may be independently optionally substituted on carbon by one or more R22;

R21and R22independently selected from halogen, hydrox the La, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifloromethyl, cryptomelane, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethinyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesila, N-methylcarbamoyl and N,N-dimethylsulphamoyl;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

It should be understood that if later in the description and in the claims, reference is made to the compound of formula (I), this applies also to compounds of formula (I') and compounds of formula (I").

In addition, a qualified specialist should be clear that the numbering system in the compounds of formula (I) and compounds of formula (I') is different. The numbering system used hereinafter, refers to compounds of the formula (I), but it should be understood that these formulations are also applicable to the corresponding values of the formula (I').

In this description, the term "alkyl" includes both straight and branched alkyl groups but references to individual alkyl groups such as "propyl" are specific only for the group with a straight chain. For example, the term "C1-6alkyl includes With1-4alkyl, C1-3alkyl, propyl, isopropyl and tert-bout the L. However references to individual alkyl groups such as "propyl"are specific only for the group with a straight chain, and references to individual alkyl groups branched chain, such as "isopropyl", are specific only for the group with a branched chain. This applies to other radicals, for example, the term "panels1-6alkyl, would include panels1-4alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term "halogen" refers to fluorine, chlorine, bromine and iodine.

In the case where the optional substituents are selected from one or more" groups, it should be understood that this definition includes all substituents that are selected from one of these groups or substituents which are selected from two or more of these groups.

"Heteroaryl" is a fully unsaturated mono - or bicyclic ring containing 3-12 atoms of which at least one atom selected from nitrogen atoms, sulfur or oxygen, and unless other terms, this ring may be joined through a carbon atom or nitrogen. Preferably, the term "heteroaryl" refers to a fully unsaturated monocyclic ring containing 5 or 6 carbon atoms, or a bicyclic ring containing 9 or 10 atoms of which at least one atom selected from nitrogen atoms, sulfur sludge is oxygen, and if not specified other conditions specified ring may be joined through a carbon atom or nitrogen. In another aspect of the present invention, the term "heteroaryl" refers to a fully unsaturated monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 8, 9 or 10 atoms of which at least one atom selected from nitrogen, sulfur or oxygen, and unless other conditions are specified ring may be joined through a carbon atom or nitrogen. Examples and suitable values of the term "heteroaryl are thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolin, triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and finalyl. Preferably, the term "heteroaryl" refers to tieniu or indolyl.

"Aryl" is a fully unsaturated mono - or bicyclic carbon ring that contains 3-12 atoms. Preferred "aryl" represents a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for the term "aryl" include phenyl or naphthyl. In particular, the "aryl" represents phenyl.

"Heterocyclyl" is a saturated, partially saturated or unsaturated mono - or bicyclic ring containing 3-12 atoms, from to the which, at least one atom chosen from nitrogen, sulphur or oxygen, the ring, if not specified other conditions, may be joined through a carbon atom or nitrogen, and in the specified ring group,- CH2- can optionally be replaced by a group-C(O)- or a ring sulfur atom may optionally be subjected to oxidation with the formation of the S-oxides. Preferably, "heterocyclyl" is a saturated, partially saturated or unsaturated mono - or bicyclic ring containing 5 or 6 atoms, of which at least one atom chosen from nitrogen, sulphur or oxygen, the ring, if not specified other conditions, may be joined through the carbon atom and nitrogen, and in the specified ring group,- CH2- can optionally be replaced by a group-C(O)- or a ring sulfur atom may optionally be subjected to oxidation with the formation of the S-oxide(s). Examples and suitable values of the term "heterocyclyl are diazolidinyl, pyrrolidinyl, pyrrolyl, 2-pyrrolidone, 2.5-dioxopyrimidine, 2-benzoxazolinone, 1,1-dioxotetrahydrofuran, 2,4-dioxoimidazolidin, 2-oxo-1,3,4-(4-triazolyl), 2-oxazolidinone, 5,6-dihydrouracil, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidone, morpholino, 2-oxitetraciclina, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothiazyl, tetr hydroporini, piperidyl, 1-oxo-1,3-dihydroisoquinolyl, piperazinil, thiomorpholine, 1,1-dioxothiazolidine, tetrahydropyranyl, 1,3-DIOXOLANYL, homopiperazine, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazole, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridinyl, chinosol and 1 sahinler.

"Carbocyclic" is a saturated, partially saturated or unsaturated mono - or bicyclic carbon ring that contains 3-12 atoms; and in ukazannom ring group,- CH2may be optionally substituted by a group-S(O). Preferably, "carbocyclic" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values of the term "carbocyclic include cyclopropyl, cyclobutyl, 1-oxocyclopent, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindole. In particular, "carbocyclic" is cyclopropyl, cyclobutyl, 1-oxocyclopent, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or 1-oxoindole.

Example groups "1-6alkanoyloxy" and "C1-4alkanoyloxy is acetoxygroup. Examples of groups With1-6alkoxycarbonyl" and "C1-4alkoxycarbonyl include IU oxycarbonyl, etoxycarbonyl, n - and tert-butoxycarbonyl. Examples of groups With1-6alkoxy" and "C1-4alkoxy" include methoxy, ethoxy and propoxy. Examples of groups With1-6alkanolamine" and "C1-4alkanolamine" include formamido, acetamido, propionamido. Examples of groups With1-6S(O)awhere and takes the value from 0 to 2 and C1-4S(O)awhere and takes the value from 0 to 2" include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methil and ethylsulfonyl. Examples of groups With1-6alkanoyl" and "C1-4alkanoyl include1-3alkanoyl, propionyl and acetyl. Examples of groups of "N-(C1-6alkyl)amino and N-(C1-4alkyl)amino" include methylamino, ethylamino. Examples of groups N,N-(C1-6alkyl)2amino and N,N-(C1-4alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of groups With2-6alkenyl" and "C2-4alkenyl" are vinyl, allyl and 1-propenyl. Examples of groups With2-6quinil" and "C2-4quinil are ethinyl, 1-PROPYNYL and 2-PROPYNYL. Examples of groups of "N-(C1-6alkyl)sulfamoyl" and "N-(C1-4alkyl)sulfamoyl" are N-(C1-3alkyl)sulfamoyl, N-(methyl)sulfamoyl and N-(ethyl)sulfamoyl. Examples of groups of "N-(C1-6alkyl)2sulfamoyl" and "N-(C1-4alkyl)2sulfamoyl" are N,N-(dimethyl)sulfamoyl and N-(methyl) - N-(ethyl)sulfamoyl. Examples of groups of "N-(C1-6alkyl)carbarnoyl" and "N-(C1-4alkyl)carbarnoyl are methylaminoethanol and ethylaminoethanol. Examples of groups N,N-(C1-6alkyl)2carbarnoyl" and "N,N-(C1-4alkyl)2carbarnoyl are dimethylaminoethyl and methylaminoethanol. Examples of the group "C1-6alkoxycarbonyl" are ethoxycarbonyl and tert-butoxycarbonylamino. Examples of groups of N'-(C1-6alkyl)ureido are N'-methylurea and N'-ethylurea. Examples of the group "N-(C1-6alkyl)ureido are N-methylurea and N-ethylurea. Examples of the group "N-(C1-6alkyl)2ureido are N',N'-dimethylurea and N'-methyl-N'-ethylurea. Examples of the group "N'-(C1-6alkyl)-N-(C1-6alkyl)ureido are N'-methyl-N-methylurea and N'-propyl-N-methylurea. Examples of the group "N',N'-(C1-6alkyl)2-N-(C1-6alkyl)ureido are N',N'-dimethyl-N-methylurea and N'-methyl-N'-ethyl-N-propylurea.

Suitable pharmaceutically acceptable salt of the compound of the present invention is, for example, an acid additive salt of the compound of the present invention, which has sufficient basicity, for example, an acid additive salt of inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, lemon or Malinovo the acid. In addition, a suitable pharmaceutically acceptable salt of the compound of the present invention, which has sufficient acidity, salt is an alkali metal, e.g. sodium or potassium, salts of alkaline-earth metal, e.g. calcium or magnesium salt, ammonium salt or a salt with an organic base, which forms a physiologically acceptable cation, for example, a salt with methylamine, dimethylamine, triethylamine, piperidine, morpholine or Tris(2-hydroxyethyl)amine.

The compounds of formula (I) may be introduced in the form of a prodrug which is broken down in the human or animal with obtaining the compounds of formula (I). Examples of prodrugs include esters of compounds of formula (I), can be subjected to hydrolysisin vivoand amides of the compounds of formula (I), can be subjected to hydrolysisin vivo.

Able to undergo hydrolysis of the ester compounds of formula (I)containing a carboxyl or hydroxyl group is, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal with the receipt of the original acid or alcohol. Suitable pharmaceutically acceptable esters of compounds containing a carboxyl group include complex1-6alkoxymethyl esters, for example, a complex IU oximately ether, complex1-6alkanolamine esters, for example, a complex pivaloyloxymethyl, Caligraphy esters, complex3-8cycloalkylcarbonyl1-6alkyl esters, for example, a complex 1-cyclohexylcarbodiimide ester; compound 1,3-dioxolan-2-animately esters, for example 5-methyl-1,3-dioxolan-2-animationy ether; and complex With1-6alkoxycarbonylmethyl esters, for example, 1-methoxycarbonylmethylene ether, and they can be obtained at any carboxy group of the compounds of this invention.

Can either hydrolyzed in vivo ester compounds of formula (I)containing a hydroxyl group complex includes inorganic esters such as phosphate complex esters and simple α-aryloxyalkyl ethers and related compounds which as a final product of hydrolysis in vivo, associated with the cleavage of ester, give the original hydroxyl group. Examples of simple α-aryloxyalkyl esters include acetoxymethyl and 2,2-dimethylpropionic-methoxyamine. The choice of groups capable of forming either hydrolyzed in vivo ester with a hydroxyl group, includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (getting complicated alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-kilcarbery (obtaining carbamates), dialkylaminoalkyl and carboxyethyl. Examples of the substituents on the benzoyl include morpholine, piperazine derivatives, attached through a ring nitrogen atom and the methylene group in position 3 or 4 of the benzene ring.

A suitable example can be subjected to hydrolysis in vivo amide compounds (I)containing a carboxy group is, for example, N-C1-6alkyl - or N,N-di-C1-6alkylamide, such as N-methyl, N-ethyl-, N-propyl, N,N-dimethyl-, N-ethyl-N-methyl - or N,N-diethylamide.

Some compounds of formula (I) may contain chiral centers and/or geometric isomerism (E - or Z-isomers), and it should be understood that the invention includes all possible diastereoisomeric and geometric isomers that possess inhibitory activity against IBAT.

The invention relates to any and all tautomeric forms of the compounds of formula (I), which have inhibitory activity against IBAT.

It should also be understood that certain compounds of formula (I) can exist in solvated, and resolutional forms, such as, for example, hydrated forms. And it should be understood that the invention includes all solvated forms which possess inhibitory activity against IBAT.

Below the preferred values of R1, R2, R3, R4, R5 and R6. These values can be used in suitable cases, in any of the definitions, claims or embodiments.

Preferably RVand RWboth represent hydrogen.

Preferably, R1and R2independently selected from C1-4the alkyl.

More preferably, R1and R2independently selected from ethyl or butyl.

More preferably, R1and R2independently selected from ethyl, propyl or butyl.

In particular, in one aspect of this invention, R1and R2both are butyl.

In another aspect of this invention, R1and R2both are drunk.

In another aspect of the present invention one of R1and R2in particular represents ethyl, and the second represents butyl.

Preferably, Rxand Ryindependently selected from hydrogen or C1-6the alkyl.

More preferably, Rxand Ryboth represent hydrogen.

Preferably, Rzselected from halogen, amino, C1-6of alkyl, C1-6alkoxycarbonyl or N'-(C1-6alkyl)ureido.

More preferably, Rzselected from chlorine, amino, tert-butyl, tert-butoxycarbonylamino or N-(tert-butyl)ureido.

Preferably, v is 0 or 1.

One is the aspect of the present invention, more preferably v is 0.

In one aspect of the present invention, more preferably, v is set to 1.

In one aspect of this invention R4preferably represents a group of formula (IA) (which is shown above).

In another aspect of this invention R5preferably represents a group of formula (IA) (which is shown above.)

Preferably, R3and R6represent hydrogen.

Preferably, the second from R4and R5that is not a group of formula (IA)selected from halogen, C1-4alkoxy or1-4S(O), where a takes the value from 0 to 2; and this R4or R5may be optionally substituted on carbon by one or more R16; where R16independently selected from hydroxyl and N,N-(C1-4alkyl)2amino.

More preferably, the second from R4and R5that is not a group of formula (IA)selected from bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesila; where the specified R4or R5may be optionally substituted on carbon atom by one or more R16; and where R16independently selected from hydroxyl, or N,N-dimethylamino.

In particular, the second from R4and R5that is not a group of formula (IA), the selected isbrae, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or mesila.

More precisely, the second of R4and R5that is not a group (IA)represents a methylthio.

Preferably, the second from R4and R5that is not a group of formula (IA)selected from hydrogen, halogen, C1-4alkoxy or1-4S(O)awhere and takes the value from 0 to 2; where the specified R4or R5may be optionally substituted on carbon by one or more R16; and where R16independently selected from hydroxyl, carboxy, and N,N-(C1-4alkyl)2amino.

More preferably, the second from R4or R5that is not a group of formula (IA)selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, ethylthio, isopropylthio or mesila; where the specified R4or R5may be optionally substituted on carbon by one or more R16; and where R16independently selected from hydroxyl, carboxy, and N,N-dimethylamino.

In particular, the second from R4and R5that is not a group (IA)selected from hydrogen, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio or mesila.

In another aspect of the present invention, more preferably, the second is th of R 4and R5that is not a group of formula (IA)selected from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, ethylthio or isopropylthio; where the specified R4or R5may be optionally substituted on carbon by one or more R16;and whereR16independently selected from hydroxyl, carboxy, and N,N-dimethylamino.

In another aspect of the present invention, the second from R4and R5that is not a group of formula (IA), selected in particular from hydrogen, chlorine, bromine, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio or 2-(N,N-dimethylamino)ethylthio.

In another aspect of the present invention, the second from R4and R5that is not a group of formula (IA), more accurately represents bromine or chlorine.

In another aspect of the present invention, the second from R4or R5that is not a group of formula (IA), more accurately represents methoxy.

In one aspect of the present invention, preferably, the ring a represents an aryl.

In another aspect of the present invention, preferably, the ring a represents heteroaryl.

When ring a represents an aryl, preferably, ring a is a phenyl.

When ring a represents heteroaryl, preferably, the ring is is thienyl or indolyl.

Preferably, the ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17; where

R17selected from halogen, hydroxyl or With the1-4of alkyl; R17may be optionally substituted on carbon by one or more R21; where

R21selected from halogen.

Preferably, D represents-O - or-S-.

In one aspect of the present invention, more preferably, D represents-O-.

In another aspect of the present invention, more preferably, D represents-S-.

More preferably, ring a is a phenyl, thienyl or indolyl; where ring a is optionally substituted by one or more zamestitelyami selected from halogen, hydroxyl or trifloromethyl.

In particular, ring a is selected from phenyl, 4-hydroxyphenyl, Tien-2-yl, 4-trifloromethyl, 3-hydroxyphenyl, 2-ftoheia, 2,3-dihydroxyphenyl or indol-3-yl.

More specifically, the ring a represents a phenyl.

In another aspect of the present invention, preferably, the ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17; where

R17selected from halogen, hydroc the sludge, With1-4the alkyl or C1-4alkoxy; where R17may be optionally substituted on carbon by one or more R21; where

R21selected from halogen.

In another aspect of the present invention, preferably, the ring a represents a phenyl, thienyl or indolyl; where ring a is optionally substituted by one or more substituents selected from halogen, hydroxyl, methoxy or trifloromethyl.

In another aspect of the present invention the ring And, in particular selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, Tien-2-yl, 4-trifloromethyl, 3-hydroxyphenyl, 2-ftoheia, 2,3-dihydroxyphenyl or indol-3-yl.

In another aspect of the present invention the ring And, in particular selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, Tien-2-yl, 4-trifloromethyl, 3-hydroxyphenyl, 2-ftoheia, 4-ftoheia, 2,3-dihydroxyphenyl or indol-3-yl.

Preferably, R7represents hydrogen, C1-4alkyl or carbocyclic.

More preferably, R7represents hydrogen, methyl or phenyl.

In particular, R7represents hydrogen.

In one aspect of the present invention, preferably, R8represents hydrogen.

In another aspect of the present invention, preferably, R8represents a C1-4Ala is l

In another aspect of the present invention, more preferably, R8represents hydrogen or methyl.

In one aspect of the present invention, preferably, R9represents hydrogen.

In another aspect of the present invention, preferably, R9represents a C1-4alkyl.

In another aspect of the present invention, more preferably, R9represents hydrogen or methyl.

Preferably, R10represents hydrogen.

In one aspect of the present invention, preferably, R11represents carboxy, sulfo, sulfine, phosphono,

-P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd) or-P(O)(ORc)(Rd), where Rcand Rdindependently selected from C1-6the alkyl.

In another aspect of the present invention, preferably, R11represents a group of formula (IB) (which is shown above).

Preferably, R11represents carboxy,

-P(O)(OH)(ORcor a group of the formula (IB) (which is shown above).

More preferably, R11represents carboxy,

-P(O)(OH)(OEt) or a group of the formula (IB) (which is shown above).

In another aspect of the present invention, preferably, R11represents carboxy, sulfo, -P(O)(OH)(ORc), where Rcselected and the 1-4the alkyl, or a group of the formula (IB) (which is shown above).

Preferably, X represents-NH - or-NHC(O)-.

More preferably, X represents-NHC(O)-.

In one aspect of the present invention, preferably, R12represents hydrogen.

In another aspect of the present invention, preferably, R12represents a C1-4alkyl.

In another aspect of the present invention, more preferably, R12represents hydrogen or methyl.

Preferably, R13represents hydrogen, C1-4alkyl or carbocyclic; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl.

More preferably, R13represents hydrogen, methyl or phenyl; where R13is optionally substituted by one or more substituents selected from R20; and where the

R20represents hydroxyl.

In particular, R13represents hydrogen, hydroxymethyl or phenyl.

More preferably, R13represents hydrogen or hydroxymethyl.

In another aspect of the present invention, preferably, R13represents hydrogen, C1-4alkyl or carbocyclic; where R13is long is Ino substituted by one or more substituents, selected from R20; and where the

R20represents hydroxyl, carboxy, carbocyclic or amino; where R20may be optionally substituted on carbon by one or more R22;

R22represents hydroxyl.

In another aspect of the present invention, more preferably, R13represents hydrogen, methyl, ethyl, butyl or phenyl; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl, carboxy, phenyl or amino; where R20may be optionally substituted on carbon by one or more R22; where

R22represents hydroxyl.

In another aspect of the present invention, in particular, R13represents hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In another aspect of the present invention, preferably, R13represents hydrogen, C1-4alkyl or carbocyclic; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl, carboxy, carbocyclic, heterocyclic or amino; where R20may be optionally substituted on carbon by one or more R22;

R represents hydroxyl.

In another aspect of the present invention, more preferably, R13represents hydrogen, methyl, ethyl, butyl or phenyl; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl, carboxy, phenyl, imidazolyl or amino; where R20may be optionally substituted on carbon by one or more R22;

R22represents hydroxyl.

In another aspect of the present invention, in particular, R13represents hydrogen, hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In another aspect of the present invention, preferably, R13represents hydrogen, C1-4alkyl, carbocyclic or R23; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl,1-4S(O)awhere and takes the value 0, C1-4alkoxy, amino, carbocyclic, heterocyclyl or mercapto; where R20may be independently optionally substituted on carbon by one or more R22;

R22selected from hydroxyl; and

R23represents carboxy.

Another AC is the object of the present invention, more preferably, R13represents hydrogen, methyl, ethyl, butyl, phenyl, or R23; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents hydroxyl, methylthio, methoxy, amino, imidazolyl or mercapto; where R20may be independently optionally substituted on carbon by one or more R22;

R22selected from hydroxyl; and

R23represents carboxy.

In another aspect of this invention R13in particular represents hydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl, imidazol-5-ylmethyl or phenyl.

In another aspect of this invention R13more precisely, is methylthiomethyl, methylsulfonylmethyl or methylsulfonylmethyl.

Preferably, R14represents hydrogen.

In another aspect of the present invention, preferably, R14selected from hydrogen, C1-4the alkyl or carbocyclic; where specified With1-4alkyl or carbocycle may be optionally substituted by one or more substituents selected from R20; and

R20predstavljaet a hydroxyl.

In another aspect of the present invention, more PR is doctitle, R14selected from hydrogen, methyl or phenyl; where the specified methyl or phenyl may be optionally substituted by one or more substituents selected from R20; and

R20represents hydroxyl.

In another aspect of this invention R14in particular represents hydrogen, phenyl or hydroxymethyl.

R15in particular represents carboxy or sulfo.

In one aspect of this invention R15more precisely, represents carboxy.

In another aspect of this invention R15more precisely, is sulfo.

Preferably, R15represents carboxy, sulfo,

-P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-4the alkyl.

More preferably, R15represents carboxy, sulfo, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Reor

-P(O)(ORe)(Rf), where Reand Rfindependently selected from methyl or ethyl.

Preferably, R15represents carboxy, sulfo,

-P(O)(OEt)(OEt), -P(O)(OH)(OEt), -P(O)(OH)(Me), or

-P(O)(OEt)(Me).

Preferably, R15represents carboxy, sulfo, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Reor

-P(O)(ORe)(Rf),where R eand Rfindependently selected from C1-4the alkyl, or R15represents a group of formula (IC) (which is shown above).

R15more preferably represents a carboxy, sulfo, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from methyl or ethyl, or R15represents a group of formula (IC) (which is shown above).

R15preferably represents carboxy, sulfo, phosphono, P(O)(OEt)(OEt), -P(O)(Ot-Bu)(Ot-Bu), -P(O)(OH)(OEt),

-P(O)(Oh)IU) or-P(O)(OEt)(Me), or R15represents a group of formula (IC) (which is shown above).

In one aspect of this invention R15preferably represents a group of formula (IC) (which is shown above).

In another aspect of the present invention, preferably, R15is not a group of the formula (IC) (which is shown above).

The following aspect of the present invention, preferably, R15represents carboxy.

In another aspect of the present invention, preferably, R15represents sulfo.

The following aspect of the present invention, preferably, R15represents-P(O)(OH)(OEt).

In another aspect of the present invention, preferably, R15represents-P(O)(The H)(OMe).

In another aspect of the present invention, preferably, R15represents-P(O)(OEt)(Me).

In one aspect of the present invention, preferably, R24represents hydrogen.

In another aspect of the present invention, preferably, R24represents a C1-4alkyl.

Preferably, R25represents hydrogen.

Preferably, R26represents carboxy.

Preferably, p is 1 or 2; and R13may be the same or different.

In one aspect of the present invention, more preferably, p is 1.

In another aspect of the present invention, more preferably, p is 2; and R13may be the same or different.

In another aspect of the present invention, more preferably, R takes the value 3, and the values of R13may be the same or different.

In one aspect of the present invention, preferably, q is 0.

In another aspect of the present invention, preferably, q is 1.

In one aspect of the present invention, preferably, r is 0.

In one aspect of the present invention, more preferably, r takes the value 1.

In another aspect of the present invention, more preferably, prinimaet value 2, and the values of R14may be the same or different.

In another aspect of the present invention, more preferably, r takes the value 3; and R14may be the same or different.

Preferably, m is 0.

In another aspect of the present invention, preferably, m is 0 or 1.

Preferably, n is 1.

In another aspect of the present invention, preferably, n is 1 or 2.

Preferably, z is 1.

A group of the formula (IA') is a group, in which R7represents hydrogen, methyl or phenyl, n is 1, ring a is a phenyl, thienyl or indolyl; where ring a is optionally substituted by one or more substituents selected from halogen, hydroxyl or trifloromethyl, m is 0, and R9represents carboxy, -P(O)(OH)(ORcor a group of the formula (IB).

A group of the formula (IA) is a group in which:

D represents-O - or-S-;

ring a represents a phenyl, thienyl or indolyl; where ring a is optionally substituted by one or more substituents selected from halogen, hydroxyl, methoxy or trifloromethyl;

R7represents hydrogen, methyl or phenyl;

R 8represents hydrogen or methyl;

R9represents hydrogen or methyl;

R10represents hydrogen;

m takes a value from 0 to 2, and R10may be the same or different; and

R11represents carboxy, -P(O)(OH)(OEt) or a group of the formula (IB) (which is presented in paragraph (1);

A group of the formula (IB') is a group, in which R10represents hydrogen, hydroxymethyl or phenyl, R is 1 or 2; and R10may be the same or different, and R11represents carboxy or sulfo.

A group of the formula (IB) is a group in which:

R12represents hydrogen or methyl;

R13represents hydrogen, methyl, ethyl, butyl, phenyl, or R23; where R13is optionally substituted by one or more substituents selected from R20; R20represents hydroxyl, methylthio, methoxy, amino, imidazolyl or mercapto; where R20may be independently optionally substituted on carbon by one or more hydroxyl groups; R23represents carboxy;

X represents-NH - or-NHC(O)-;

R14selected from hydrogen, methyl or phenyl; where the specified methyl or phenyl may be optionally substituted one and the multiple substituents, selected from hydroxyl;

R15represents carboxy, sulfo, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from methyl or ethyl, or R15represents a group of formula (IC) (which is presented in paragraph (1);

p value is from 1 to 3, and R13may be the same or different;

q takes a value from 0 to 1; and

r takes a value from 0 to 3, and R14may be the same or different.

A group of the formula (IC) is a group in which

R24represents hydrogen;

R25represents hydrogen;

R26represents carboxy; and

z takes a value of 1;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Thus, in another aspect of the present invention proposed a compound of the formula (I'), which is presented above, where

R1and R2independently selected from ethyl, or butyl;

R3and R6represents hydrogen;

R4selected from halogen, C1-4alkoxygroup or1-4S(O)awhere and takes the value from 0 to 2; and R4may be optionally substituted on carbon by one or more R16; where R16the independent is selected from hydroxyl and N,N-(C 1-4alkyl)2amino;

R5represents a group of formula (IA');

ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17; where

R17selected from halogen, hydroxyl or With the1-4of alkyl; R17may be optionally substituted on carbon by one or more R21; where

R21selected from halogen;

R7represents hydrogen, C1-4alkyl or carbocyclic;

R11represents carboxy, -P(O)(OH)(ORcor a group of the formula (IB') (which is shown above);

R13represents hydrogen, C1-4alkyl or carbocyclic; where R13is optionally substituted by one or more substituents selected from R20; where

R20represents a hydroxyl;

R15represents carboxy or sulfo;

p is 1 or 2; and R13may be the same or different;

m is 0; and

n takes a value of 1;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Thus, in an additional aspect of the present invention proposed a compound of the formula (I'), which is shown above, where:

R1and R2both PR is astavliaut a butyl or one of R 1and R2represents ethyl, and the second represents a butyl;

R4represents methylthio;

R5represents a group of formula (IA') (which is shown above);

R3and R6represent hydrogen;

ring a represents a phenyl;

R7represents hydrogen;

R11represents a group of formula (IB') (which is shown above);

R13represents hydrogen or hydroxymethyl;

R15represents carboxy or sulfo;

p is 1 or 2; and R13may be the same or different;

m is 0;

n takes a value of 1;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Thus, in yet another additional aspect of the present invention proposed a compound of formula (I"), which is shown above, where:

R1and R2independently selected from ethyl, or butyl;

R3and R6represent hydrogen;

R4selected from halogen, C1-4alkoxy or1-4S(O)awhere and takes the value from 0 to 2; where R4may be optionally substituted on carbon by one or moreR16; and where R16independently selected from hydroxyl and N,N-(C1-4alkyl)2amino;/p>

R5represents a group of formula (IA");

ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17;

R7represents hydrogen, C1-4alkyl or carbocyclic;

R8represents hydrogen or methyl;

R9represents hydrogen or methyl;

R11represents carboxy, -P(O)(OH)(ORcor a group of the formula (IB') (which is shown above);

X represents-NH - or-NHC(O)-;

R12represents hydrogen or methyl;

R13represents hydrogen, C1-4alkyl or carbocyclic; where R13is optionally substituted by one or more substituents selected from R20;

R14represents hydrogen;

R15represents carboxy or sulfo;

R17selected from halogen, hydroxyl, C1-4alkyl or C1-4alkoxy; where R17may be optionally substituted on carbon by one or more R21;

R20represents hydroxyl, carboxy, carbocyclic or amino; where R20may be optionally substituted on carbon by one or more R22;

R21selected from halogen;

R22represents a hydroxyl;

p prin who takes a value from 1 to 3; and the values of R13may be the same or different,

q takes a value from 0 to 1;

r takes a value from 0 to 3; and R14may be the same or different; and when q is 1, r is not 0;

m takes a value from 0 to 2; and

n takes values from 1 to 3;

or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Thus, in yet another additional aspect of the present invention proposed a compound of formula (I), which is presented above, where

RVand RWboth represent hydrogen;

R1and R2independently selected from C1-6of alkyl;

Rxand Ryboth represent hydrogen;

Rzselected from halogen, amino, C1-6of alkyl, C1-6alkoxycarbonyl or N'-(C1-6alkyl)ureido;

v is 0 or 1;

R3and R6represent hydrogen;

one of R4and R5represents a group of formula (IA) (presented above), and the other is selected from hydrogen, halogen, C1-4alkoxygroup or1-4S(O)awhere and takes the value from 0 to 2; specified R4or R5may be optionally substituted on carbon by one or more R16; where R16independently selected from hydroxyl, carboxy, and N,N-(C1-4 alkyl)2amino;

D represents-O - or-S-;

R7represents hydrogen, methyl or phenyl;

R8represents hydrogen or methyl;

ring a represents an aryl or heteroaryl; and ring a is optionally substituted by one or more substituents selected from R17; where R17selected from halogen, hydroxyl, C1-4the alkyl or C1-4alkoxy; and R17may be optionally substituted on carbon by one or more R21; where R21selected from halogen;

R9represents hydrogen or methyl;

R10represents hydrogen;

R11represents carboxy, -P(O)(OH)(ORc), where Rcselected from C1-4the alkyl or a group of the formula (IB) (presented above);

R12represents hydrogen or methyl;

X represents-NH - or-NHC(O);

R13represents hydrogen, C1-4alkyl, carbocyclic or R23; where R13is optionally substituted by one or more substituents selected from R20; where R20represents hydroxyl,1-4S(O)awhere and takes the value 0, C1-4alkoxy, amino, carbocyclic, heterocyclyl or mercapto; where R20may be independently optionally substituted on carbon by one or n is the number of R 22; R22selected from hydroxyl; and R23represents carboxy;

R14selected from hydrogen, C1-4the alkyl or carbocyclic; where specified With1-4alkyl or carbocycle may be optionally substituted by one or more substituents selected from R20; and R20represents a hydroxyl;

R15represents carboxy, sulfo, phosphono, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-4of alkyl; or R15represents a group of formula (IC)(presented above);

R24represents hydrogen;

R25represents hydrogen;

R26represents carboxy;

p value is from 1 to 3; where R13may be the same or different;

q takes a value from 0 to 1;

r takes a value from 0 to 3; where R14may be the same or different;

m takes a value from 0 to 2; where R10may be the same or different;

n takes a value from 1 to 2; where R7may be the same or different;

z takes a value from 0 to 1, where values of R25may be the same or different;

or its pharmaceutically acceptable salt, MES, MES such salts and the and the prodrug.

In accordance with another aspect of the present invention, the preferred compounds of this invention are any compounds of examples, or their pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs.

In one aspect of the present invention proposed a compound of formula (I), selected from examples 8, 9, 46, 56, 59, 60, 61, 62, 66 and 69 or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In another aspect of the present invention proposed a compound of formula (I), which represents a connection example 73, 74, 95, 96, 97, 98, 99 and 100 or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In another aspect of the present invention preferred compounds of this invention are any connection examples 43, 50, 51 and 52 or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In yet another additional aspect of this invention the preferred compounds of this invention are any compounds of examples 43, 46, 50, 51, 56, 58, 59, 61, 62, 63, 69, 81, 83, 85, 94, 97, 98, 108, 109, 110, 111 or 117.

Preferred aspects of this invention are the aspects that relate to the compound of formula (I) or its pharmaceutically acceptable salt.

Another aspect of this from the retene offers a method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salt, the MES, the MES of such salts or prodrugs, this method (if not specified other conditions that are affected groups take the values defined in formula (I)includes:

Method 1):oxidation benzodiazepine formula (II):

Method 2): for connections formu (I), where D represents-O-, -NRaor-S-; the interaction of the compounds of formula (IIIa) or (IIIb):

with the compound of the formula (IV):

where L represents a substitutable group;

Method 3): the interaction of the acid of formula (Va) or (Vb):

or its activated derivative with an amine of formula (VI):

Method 4): for compounds of formula (I), where R11represents a group of formula (IB); the interaction of the compounds of formula (I), where R11represents carboxy, amine of formula (VII):

Method 5): for compounds of formula (I), where R11represents carboxy; removing the protective group in the compound of formula (VIIIa):

or (VIIIb):

where RRrepresents a C1-4alkyl;

Method 6): for compounds of formula (I), where R11 represents a group of formula (IB) and R15represents carboxy, removing the protective group of the compounds of formula (IXa):

or (IXb):

where Rprepresents a C1-4alkyl;

Method 7):for compounds of formula (I)where one of R4and R5independently selected from C1-4alkylthio, optionally substituted on carbon by one or more R16; the interaction of the compounds of formula (Xa) or (Xb):

where L represents a substitutable group, with a thiol of the formula (XI):

where Ryrepresents a C1-4alkylthio, optionally substituted on carbon by one or more R16;

Method 8): for compounds of formula (I), where R15represents a group of formula (IC), the interaction of the compounds of formula (IXa) or (IXb), where Rprepresents hydrogen, with a compound of formula (XII):

Method 9) for compounds of formula (I), where R11represents a group of formula (IB), R15represents a group of formula (IC) and R26represents carboxy; removing the protective group from compounds of formula (XIIIa):

or (XIIIb):

and Rprepresents a C1-4alkyl;

Method 10)for the compounds of formula (I), where X represents-N(Rq)C(O)-; the interaction of the compounds of formula (XIVa):

or (XIVb):

with the compound of the formula (XV):

and then, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

A qualified specialist will also be understood that similar methods corresponding to the above-described methods can also be used to obtain compounds of formula (I') or compounds of formula (I)in which group definitions may vary.

L is a substituted group, suitable values for L are, for example, halogen or sulfonyloxy, and in particular, chlorine, bromine, methansulfonate - or toluene-4-sulfonyloxy-group.

Rprepresents a C1-4alkyl. Preferably, Rprepresents methyl or ethyl. More preferably, Rprepresents methyl.

Specific conditions for carrying out the above reactions are the trail of the existing conditions.

Method 1): Benzodiazepine formula (II) can undergo oxidation under standard conditions the oxidation of sulfur, for example using hydrogen peroxide and triperoxonane acid at temperatures in the range of 0aboutC to the boiling point of the solvent, preferably at room temperature or a temperature close to the room.

The compounds of formula (II) can be obtained in accordance with Scheme I, compounds of formula (I), where Rxand Ryrepresent hydrogen. Qualified it is clear that when Rxand Ryare not hydrogen, the above scheme of the synthesis should be carried out in accordance with standard well-known techniques.

Scheme I

where L represents a substitutable group, which is defined above, for example, halogen.

The compounds of formula (IIa) and (IIc) are commercially available compounds or they are described in the literature or can be obtained by known standard methods.

Method 2):Alcohols of formula (IIIa) or (IIIb) may be subject to interaction with compounds of the formula (IV) in the presence of a base, for example, inorganic bases such as sodium carbonate, or organic bases, such as base Hangs (Hunigs base), in the presence of a suitable dissolve the La, such as acetonitrile, dichloromethane or tetrahydrofuran, at a temperature in the range from 0°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent or close to it.

The compounds of formula (IIIa) or (IIIb) can be obtained analogously to compounds of formula (II) (in which R4or R5represents a hydroxyl group), followed by a stage of oxidation (Method 1).

The compounds of formula (IV) are commercially available compounds or they are known from the literature or can be obtained by known standard methods.

Mode 3, Mode 4, Mode 8) and Method 10): Acids and amines can be contacted in the presence of a suitable coupling reagent. Suitable binding reagents can be used in standard peptide binding reagents that are known in the art, or, for example, carbonyldiimidazole and DICYCLOHEXYL-carbodiimide, optionally, in the presence of a catalyst, such as dimethylaminopyridine or 4-pyrrolidinedione, optionally in the presence of a base, such as triethylamine, pyridine, or 2,6-dialkylphenol, such as 2,6-lutidine or 2,6-distritbution. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The reaction mix can be the t conveniently be carried out at a temperature in the range from -40 to 40 aboutC.

Suitable activated derivatives of the acids include halides, for example acid anhydrides, active esters, for example, a complex of pentafluorophenyl esters. The interaction of compounds of these types with amines is well known in this field, for example, they can interact in the presence of a base, such as described above, in a suitable solvent, such as described above. The reaction may conveniently be carried out at a temperature in the range from -40 to 40aboutC.

The compounds of formula (Va) or (Vb), where D represents-O-, -NRa- or-S-, can be obtained in accordance with scheme 2.

Scheme 2

where L represents a substitutable group, as defined above.

The compounds of formula (Va) and (Vb), where D represents-SO - or-SO2-can be obtained by oxidation of compounds of formula (Va) and (Vb), synthesized by the method shown in Scheme 2, where D represents-S-.

The compounds of formula (Va) or (Vb), where D represents-CH2-can be obtained in accordance with Scheme 3.

Scheme 3

The compounds of formula (XIVa) or (XIVb) can be obtained by any of the methods described in this invention, where R11represents a group of formula (IB), but when (IB) is sobo is a group of the formula (XVI):

The compounds of formula (Vc), (VI), (VII), (XII), (XV) and (XVI) are commercially available compounds or they are known in the literature, or they get known standard methods.

Method 5, Method 6) and Method 9): esters of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) protective groups can be removed under standard conditions, such as the conditions described below, for example, the protective group can be removed using sodium hydroxide in methanol at room temperature.

Esters of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) can be obtained in accordance with any of the techniques described above to obtain compounds of formula (I)in which R11, R15or R26represents a C1-4alkoxycarbonyl.

Method 7): the compounds of formula (Xa) and (Xb) may be subject to interaction with thiols of the formula (XI) in the presence of a base, for example, inorganic bases such as sodium carbonate or organic bases, such as base Hangs, in the presence of a suitable solvent, such as DMF or THF, at a temperature in the range of 0aboutC to the boiling point of the solvent.

The compounds of formula (Xa) and (Xb) can be obtained in accordance with any of the techniques described above to obtain compounds of formula (I), where R4and R5presented AET L. a

The compounds of formula (XI) are commercially available compounds or they are known from the literature or can be obtained by known standard methods.

It should be understood that some of the various substituents in the ring in the compounds of this invention can be administered by standard reactions of aromatic substitution or entered by standard modifications of functional groups either before or immediately after the implementation of the methods described above, these reactions are themselves included in the aspect of the method of the present invention. Such reactions and modifications include, for example, introduction of a substituent by using the reaction of aromatic substitution, restoration of substituents, alkylation of substituents and oxidation of substituents. Reagents and conditions for carrying out reactions such techniques are well known in the field of chemistry. Specific examples of reactions of aromatic substitution include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, allhelgona and Lewis acid (such as trichloride aluminum) in the conditions of the Friedel -; introduction of an alkyl group using alkylhalogenide and Lewis acid (such as trichloride aluminia) in conditions of Friedel crafts; and the introduction of the group of halogen. Specific examples of modifications of the function of the national groups include the restoration of the nitro group to the amino group, for example, by catalytic hydrogenation with a Nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of ancilliary to alkylsulfanyl or alkylsulfonyl group.

You should also understand that some of the reactions described in this invention, it may be necessary/desirable to protect any sensitive groups in the compounds. Examples of when protection is necessary or desirable, and appropriate protection methods known to the skilled in this field specialist. Can use standard protective groups in accordance with the standard in practical ways (see, for example, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reagents include groups such as amino, carboxy or hydroxyl group, it may be desirable to protect the group in some of the described reactions.

A suitable protective group for the amino - and alkylamino is, for example, acyl group, for example alcoolica group, such as acetyl, alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, armletaccessory group, for example, benzyloxycarbonyl, or arolina group, for example benzoyl. Conditions for the removal of these protective groups need different type the ü depending on the choice of protective groups. So, for example, acyl group, such as alkanoyl or alkoxycarbonyl, or arolina group can be removed, for example, by hydrolysis with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium. Alternatively, the acyl group, such as tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid, or triperoxonane acid, and arkitekturmuseerna group, such as benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example, Tris(trifurcation) boron. A suitable alternative protecting group for a primary amino group is, for example, calolina group, which can be removed by treatment with alkylamines, for example, dimethylaminopropylamine or hydrazine.

A suitable protecting group for a hydroxyl group is acyl group, for example, alcoolica group, such as acetyl, arolina group such as benzoyl, or arylmethylidene group, such as benzyl. Conditions for the removal of these protective groups must be changed depending on the selection of protective groups. So, acyl group, such as alkanoyl or aroyl may be removed, for example, guide what Alison with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium. Alternatively, allmerica group such as benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

A suitable protecting group for a carboxyl group is, for example, a group forming an ester, such as methyl or ethyl group, which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or tert-bucilina group, which can be removed, for example, by treatment with an acid such as organic acid, such as triperoxonane acid, or benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

The protective group can be removed at any stage of the synthesis using standard methods well known to the skilled chemist.

As stated above, the compounds defined in the present invention have inhibitory activity against IBAT. These properties can be analyzed quantitatively, for example,in vitroquantitative determination of the effect on the absorption of bile acids in IBAT-transfection cells (Smith L., Price-Jones M. J., Hugnes K.T., Jones N.R.A.; J. Biomolecular Screening, 3, 227-230) or in vivo study of the effect on absorption in mice/rats, bile acids, ecenas radioactive isotope (Lewis M.C., Brieaddy LE, Root, C.,J., J. Lip Res., 1995, 36, 108-1105).

In accordance with an additional aspect of the present invention, the proposed pharmaceutical composition that includes a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined above, in combination with a pharmaceutically acceptable excipient or carrier.

The composition may be in the form suitable for oral administration such as tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular introduction or injection), such as a sterile solution, a sterile suspension or emulsion, for topical application, such as an ointment or cream or for rectal administration, such as a candle.

Typically, these compositions can be obtained in a standard way using traditional fillers.

The compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, is usually to be introduced warm-blooded animal in standard doses in the range of 5 to 5000 mg per square meter body size of the animal, i.e. approximately 0.1 - 100 mg/kg or 0.01-50 mg/kg, and this normally provides a therapeutically effective dose. Dosage form standard dose, such as a tablet or capsule will usually contain, for example, 1 - 250 m of the active ingredient. Preferably it is applied daily dose in the range of 1 to 50 mg/kg In another aspect of the applied daily dose in the range of 0.02 - 20 mg/kg, However, the daily dose should be selected depending on the organism to be treated, and especially depending on the method of administration and the severity of the disease to be treated. Thus, the optimal dosage can be determined by the physician who treats each patient.

In accordance with an additional aspect of the present invention, the proposed compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined for use in a method of prophylactic or therapeutic treatment of warm-blooded animal such as man.

The applicants of the present invention it was found that the compounds defined in the present invention, or their pharmaceutically acceptable salt, MES, MES such a salt or prodrug, is an effective IBAT inhibitors and therefore are of interest in the quality of medicines in the treatment of painful conditions associated with States of hyperlipemia.

Thus, in accordance with this aspect of the invention, the proposed compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prole the arstvo, as defined for use as a medicine.

In accordance with another distinctive feature of the invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicinal product for the purpose of obtaining IBAT-inhibitory effect in the organism of warm-blooded animal such as man.

In accordance with another distinctive feature of the invention, the application of compound (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicinal product for use in the treatment of conditions of hyperlipemia warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above in the manufacture of a medicine for use in the treatment of dyslipidemic conditions and disorders (dyslipidemic conditions and disorders, such as hyperlipemia, hyperglyceridemia, hyperbetalipoproteinemia (high levels of LDL), hyperprebetalipoproteinemia (high contents VLL), hyperchylomicronemia (hyperchylomicronemia), the decrease in the content of lipoproteins in the blood (hypolipoproteinemia), hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (content decreased HDL) in a warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicine for use in the treatment of various clinical conditions such as atherosclerosis, the narrowing of the arteries, arrhythmia, hyperchromatism status, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction, angina, peripheral vascular diseases, inflammation, cardiovascular tissues, such as heart valve, vascular network, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, macrophage, and/or macrobiotically infiltration, thickening of the inner lining of blood vessels, medial thinning, infectious and surgical trauma, and vascular thrombosis, shock and temporary bouts of ischemia in warm-blooded animal such as man.

In soo is according to another distinctive feature of the invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicinal product to be used for the treatment of atherosclerosis, coronary heart disease, myocardial Leonarda, angina, peripheral vascular disease, stroke and transient episodes of ischemia in a warm-blooded animal such as man.

In accordance with another distinctive feature of this aspect of the invention, a method for obtaining inhibitory effect against IBAT warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with another distinctive feature of this aspect of the invention, a method of treatment giperhloremiceski conditions in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with yet another distinguishing feature of the top is the aspect of the invention, a method of treatment dyslipidemic conditions and disorders, such as hyperlipemia, hyperglyceridemia, hyperbetalipoproteinemia (high levels of LDL), hyperprebetalipoproteinemia (high content of VLDL), hyperchylomicronemia, the reduced content of lipoproteins in the blood, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (content decreased HDL) in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with another distinctive feature of this aspect of the invention, a method is proposed for the treatment of various clinical conditions such as atherosclerosis, the narrowing of the arteries, arrhythmia, hyperchromatism status, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart disease, cardiovascular disease, myocardial infarction, angina, peripheral vascular diseases, inflammation, cardiovascular tissues, such as heart valves, vascular network of arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocyte, macrophage, and/or macrobiotically infil the acidity, seal the inner lining of blood vessels, medial thinning, infectious and surgical trauma, and vascular thrombosis, shock and temporary bouts of ischemia, when the need for such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with another distinctive feature of this aspect of the invention, a method for treatment of atherosclerosis, coronary heart disease, myocardial infarction, angina, peripheral vascular disease, stroke and transient episodes of ischemia in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

It is proved that the IBAT inhibitor is potentially useful in the treatment and/or prevention of biliary concretions. In accordance with an additional distinguishing feature of this aspect of the invention, a method of treatment and/or prevention of biliary concrements in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount is of the compounds of formula (I) or its pharmaceutically acceptable salt, the MES, the MES of such salts or prodrugs.

The magnitude of the dose required for therapeutic or prophylactic treatment will necessarily vary from organism to be treated, the route of administration of the medicinal product and the severity of the disease to be treated. Standard single dose, which is provided for this purpose, is in the range of, for example, 1 to 100 mg/kg, preferably 1 to 50 mg/kg

Inhibitory activity against IBAT defined above, can be used as the sole therapeutic agent or in addition to the compound of the present invention may include one or more other substances and/or treatments. Such joint treatment may be simultaneous, sequential or separate introduction of the individual components of treatment. In accordance with this aspect of the invention, the proposed pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined above, and additional compounds having inhibitory activity against IBAT, as defined above, and additional gipolipidemicheskoe medicine for joint treatment hyperlipemia.

In another aspect of the present invention with the unity of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug can be administered in combination with an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs. Suitable inhibitors of HMG Co-a reductase inhibitors, their pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs are statins and well known in this field. Examples of statins are fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, tseriwastatina, bervastatin, dalvastatin, mevastatin and (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S) - for 3,5-dihydrogen-6-ANOVA acid (rosuvastatin - rosuvastatin), or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug. Specific statin is atorvastatin (atorvastatin) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug. More specific statin is the calcium salt of atorvastatin. Another specific statin is (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S) - for 3,5-dihydrogen-6-ANOVA acid (rosuvastatin - rosuvastatin or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug. Preferred specific statin is the calcium salt of rosuvastatin.

In an additional aspect of this invention the compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug can be administered in combination with an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and/or a compound that binds bile acids, thereby eliminating the potential risk of the presence of excess bile acids in the intestine, caused by inhibition of the transport of bile acids in the ileum. Excess bile acids in visceral content can cause diarrhea. Thus, this invention provides for the treatment of patients possible side effect such as diarrhea, during the course of therapeutic treatment, comprising the compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Inhibitor of HMG CoA reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug is through his action to reduce the amount of endogenous cholesterol available for the synthesis of bile acids, and to provide additional effect in combination with the compound of the formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug to a decrease in the content l is pidof.

Suitable substances, bile acid binding, for such combination therapy are resins, such as cholesterin and holestipol. One of the advantages is that the dose of a substance that binds bile acids, may be reduced compared to a therapeutic dose for the treatment of cholesterolemia using only substances that bind bile acids. The reduction of the dose of a substance that binds bile acids, may also lead to the elimination of any possible side effects caused by impaired tolerance of the patient to a therapeutic dose.

Therefore, in an additional distinctive characteristic of the present invention, a method for obtaining inhibitory effect against IBAT in the body of warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate introduction of an effective amount of an inhibitor of HMG Co-A reductase inhibitor, its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

Thus, in an additional distinctive characteristic of the present invention, a method for obtaining inhibited the future actions against IBAT warm-blooded animal, for example the person in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate introduction of substances, bile acid binding.

Therefore, in an additional distinctive characteristic of the present invention, a method for obtaining inhibitory effect against IBAT in the body of warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate introduction of an effective amount of an inhibitor of HMG Co-A reductase inhibitor, its pharmaceutically acceptable salt, MES, MES such salts or prodrugs while simultaneously, sequentially or separately added substances, bile acid binding.

Therefore, in an additional distinctive characteristic of the present invention, a method of treatment giperhloremiceski conditions in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal is the effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, the MES, the MES of such salts or prodrugs with the simultaneous, sequential or separate administration with an effective amount of an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

Thus, in an additional distinctive characteristic of the present invention, a method of treatment giperhloremiceski conditions in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate administration with an effective amount of a substance that binds bile acids.

Therefore, in an additional distinctive characteristic of the present invention, a method of treatment giperhloremiceski conditions in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate administration with an effective amount of an inhibitor of HMG Co-A reductase inhibitor or a pharmaceutical the ski acceptable salt, the MES, the MES of such salts or prodrugs and the simultaneous, sequential or separate introduction of substances, bile acid binding.

In accordance with an additional aspect of the present invention, the proposed pharmaceutical composition that includes a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, in combination with a pharmaceutically acceptable diluent or carrier.

In accordance with an additional aspect of the invention, the proposed pharmaceutical composition that includes a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and a substance that binds bile acids, in combination with a pharmaceutically acceptable diluent or carrier.

In accordance with an additional aspect of the present invention, the proposed pharmaceutical composition that includes a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug, an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and a substance that binds bile acids in combination with f is rmaceuticals acceptable diluent or carrier.

In accordance with an additional aspect of the present invention, a kit comprising a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In accordance with an additional aspect of the present invention, a kit comprising a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and substance, bile acid binding.

In accordance with an additional aspect of the present invention, a kit comprising a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug, an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and substance, bile acid binding.

In accordance with an additional aspect of the present invention, a kit including:

a) compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a first standard dose;

b) an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard is the first dose; and

c) the container as the container for the specified first and second dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a first standard dose;

b) a substance that binds bile acids in the form of a second standard dose; and

c) the container as the container for the specified first and second dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a first standard dose;

b) an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard dose;

c) a substance that binds bile acids in the form of a third of the standard dose;

d) the container as the container for the specified first, second and third dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in which Oceanie with a pharmaceutically acceptable diluent or carrier in the form of a first standard dose;

b) an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard dose; and

c) the container as the container for the specified first and second dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in combination with a pharmaceutically acceptable diluent or carrier in the form of a first standard dose;

b) a substance that binds bile acids in the form of a second standard dose; and

c) the container as the container for the specified first and second dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in combination with a pharmaceutically acceptable diluent or carrier in the form of a first standard dose;

b) an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard dose;

c) a substance that binds bile acids in the form of a third of the standard dose; and

d) the container as the e packaging for these first, the second and third dosage forms.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug and inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the manufacture of a medicinal product for the purpose of obtaining inhibitory effect against IBAT warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs and substances that bind bile acids in the production of medicines for use in order to obtain inhibitory effect against IBAT warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs, an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs and connections linking the VC is nye acid, in the manufacture of a medicinal product to receive inhibitory effect against IBAT warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug and inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the manufacture of a medicine for use in the treatment of giperhloremiceski conditions in a warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, a method of applying the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs and acceptor bile acids in the manufacture of a medicine for use in the treatment of giperhloremiceski conditions in a warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs, an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES t is some salts or prodrugs and connections, bile acid binding, in the manufacture of a medicine for use in the treatment of giperhloremiceski conditions in a warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, a method of combined treatment, including the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of the inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

In accordance with another distinctive feature of the present invention, a method of combined treatment, including the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate the conducting connection, bile acid binding, optionally in combination with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

In accordance with another aspect of the present invention, a method of combined treatment, including the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination in a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of the inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, and the simultaneous, sequential or separate introduction of effective amounts of compounds, bile acid binding, optional in combination with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

In accordance with another aspect of the present invention, a method of combined treatment, including the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, the MES, the MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of one or more drugs selected from:

inhibitor of protein transfer esters of cholesterol (cholesteryl ester transfer protein - SER), for example, from inhibitors to which reference is made and which is described in WO 00/38725 (page 7, line 22 to page 10, line 17), are included in this description by reference;

antagonist cholesterol absorption, for example, azetidinone, such as SCH 58235, and those described in U.S. patent No. 5767115, which is included in this description by reference;

inhibitor of protein transfer microsomes, for example, described in the publication Science, 282, 751-54, 1998, which is incorporated in this description by reference;

- fibre-forming derivative of the acid; for example, clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrat;

is a derivative of nicotinic acid, for example, nicotinic acid (Niacin), acipimox and niceritrol;

- phytosterolemia connection, for example, stanilov;

- probucol (probucol);

connections that are used to combat obesity, such as orlistat (EP 129748) and sibutramine (UK Application No. 2184122 and U.S. Patent No. 4929629);

connection with its hypotensive is Tami, for example, the inhibitor of the angiotensin converting enzyme (angiotensin converting enzyme (ACE), antagonist of angiotensin II receptor, beta-adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, diuretic or a vasodilator;

- insulin;

- sulfonation, including glibenclamide, tolbutamide;

- Metformin; and/or

- akabueze;

or their pharmaceutically acceptable salts, MES, MES such salts or prodrugs optionally in combination with a pharmaceutically acceptable diluent or carrier are warm - blooded animal, such as man, in need of such therapeutic treatment.

Specific ACE inhibitors or pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs, including active metabolites, which can be used in combination with the compound of the formula (I)include, but are not limited to, the following connections: alacepril, elatioris, altoprev, altoprev calcium, uncovered, benazepril, benazepril hydrochloride, benazeprilat, benzoyltartaric, captopril, captopril-cysteine, captopril-glutathione, ceronapril, ceronapril, ceronapril, cilazapril, zilazaprilata, delapril, delapril-dikelola, enalapril, enalaprilat, enapril, epicardial, proximit the n, fosinopril, fosinopril, fosinopril sodium, fosinopril, fosinopril sodium, fosinoprilata, fosinoprilat acid, glycopeel, hamartin-4, atapryl, imidapril, indrapuri, indrapala, dibenzepin, lisinopril, licien And, licien In, missapril, moexipril, moexiprilat, multiperil, mortein And, Murzin In, Murzin With, pentopril, perindopril, perindoprilat, pivaloyl, pivotal, inapril, inapril hydrochloride, FinePrint, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spirapril, spirapril, spirapril hydrochloride, temocapril, temocapril hydrochloride, carotid, trandolapril, trandolaprilat, ulibarri, saucepan, sailpilot, zofenopril and zofenoprilat. Preferred ACE inhibitors for use in this invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Preferred ACE inhibitors for use in this invention are ramipril and ramiprilat.

Preferred antagonists of angiotensin II, their pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs for use in combination with the compound of the formula (I) include, but are not limited to, the following connections: candesartan, candesartan, cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan, eprosartan. Especially preferred ant what honestly of angiotensin II or its pharmaceutically acceptable derivatives for use in this invention are candesartan and candesartan cilexetil.

In another aspect of this invention the compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug can be administered in combination with a PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs are well known in the art. They include compounds described in the publications WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170 and publications J.Med. Chem., 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular, the compounds described in the patent applications listed on page 634) and J. Med. Chem., 2000, 43, 527, which are included in this description by reference. In particular, PPAR alpha and/or gamma agonist is WY-14643, clofibrate, fenofibrate, benzafibrate, GW 9578, troglitazone, pioglitazone, rosiglitazone, agitaton, troglitazone, BRL-49634, KRP-297, JTT-501, SB 213068, GW-1929, GW 7845, GW-0207, L-796449, L-165041 and GW 2433. In particular, PPAR alpha and/or gamma agonist is (S)-2-ethoxy-3-[4-(2-{4-methysulfonylmethane}aoxi)phenyl]propanoic acid and its pharmaceutically acceptable salts.

Thus, in an additional distinctive characteristic of the present invention, a method for obtaining IBAT inhibitory effect in alocalname animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate introduction of an effective amount of PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

Thus, in an additional distinctive characteristic of the present invention, a method of treatment hyperlipidemics conditions in a warm-blooded animal, for example, a person in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs with the simultaneous, sequential or separate introduction of an effective amount of PPAR alpha and/or gamma agonist, its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with an additional aspect of the present invention, the proposed pharmaceutical composition that includes a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and PPAR alpha and/or gamma agonist, or E. what about the pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in combination with a pharmaceutically acceptable diluent or carrier.

In accordance with an additional aspect of the present invention, a kit comprising a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug and PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

In accordance with an additional aspect of the present invention, a kit including:

a)a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a first standard dose;

b) PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard dose; and

c) the container as the container for the specified first and second dosage forms.

In accordance with an additional aspect of the present invention, a kit including:

a) a compound of formula (I) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in combination with a pharmaceutically acceptable diluent or carrier in the form of a first standard dose;

b) PPAR alpha and/or gamma agonist or its pharmaceutically pickup is acceptable salt, MES, MES such a salt or a prodrug in the form of a second standard dose; and

c) the container as the container for the specified first and second dotirovannyh dosage forms.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula I or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs and PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the manufacture of a medicinal product for the application to obtain inhibitory effect against IBAT warm-blooded animal such as man.

In accordance with another distinctive feature of the invention, a method of applying the compounds of formula (I) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs and PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug in the manufacture of a medicine for use in the treatment of giperhloremiceski conditions in a warm-blooded animal such as man.

In accordance with an additional aspect of the present invention, a method of combined treatment, including the introduction of an effective amount of the compound fo the formula (I) or its pharmaceutically acceptable salt, the MES, the MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of an effective amount of PPAR alpha and/or gamma agonist or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, optionally in combination with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

In addition to the use in therapy, the compounds of formula (I) or their pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs are also useful as pharmacological tools for the improvement and standardization of systems biological testsin vitroandin vivoto assess the validity of the IBAT inhibitor in the bodies of laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

Many of the intermediates described in this invention are new compounds and, thus, provide an additional distinctive feature of the present invention. For example, the compounds of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) exhibit inhibitory activity against IBAT when tested in on what isanna above experience in vitro and, therefore, the claimed as an additional object of the present invention.

Thus, an additional aspect of the present invention is a compound of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such a salt or a prodrug.

Thus, in accordance with an additional aspect of the present invention, the proposed pharmaceutical composition that includes a compound of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.

Thus, in accordance with an additional aspect of the present invention, the proposed compound of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined above, for use in a method of prophylactic or therapeutic treatment of warm-blooded animal such as man.

Thus, in accordance with this aspect of the invention, the proposed compound of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such a salt or prodrug, as defined above, for use as a medicine

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicinal product for the purpose of obtaining inhibitory effect against IBAT warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, the proposed use of the compounds of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs as defined above, in the manufacture of a medicine for use in the treatment of giperhloremiceski conditions in a warm-blooded animal such as man.

In accordance with another distinctive feature of the present invention, a method for obtaining inhibitory effect against IBAT warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In accordance with yet another distinguishing feature of the top is the aspect of the invention, a method of treatment giperhloremiceski conditions in a warm-blooded animal, such as man, in need of such treatment, the method includes the introduction of a specified animal an effective amount of the compounds of formula (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb) or its pharmaceutically acceptable salt, MES, MES such salts or prodrugs.

In the above-described pharmaceutical composition, process, method, use and distinguishing the manufacture of medicines are also used alternative and preferred embodiment of the compounds of this invention.

Examples

Hereinafter the invention will be further described with reference to the following examples, which do not limit the scope of the present invention and in which, when it comes, can be used standard techniques known to the skilled chemist, and methods similar to those described in these examples;

if not specified other conditions:

(i) the evaporation was carried out using a rotary evaporator under vacuum after removal by filtration of solid residues, such as dehumidifiers;

(ii) all reactions were carried out in an inert atmosphere at room temperature, typically in the range of 18 - 25°using solvents with a purity acceptable for HPLC, unless other conditions;

(iii)column is a chromatography (flash method) was performed on silica gel 40-63 μm (Merck);

(iv) the outputs are given for illustration only and are not necessarily the maximum possible;

(v) the structure of the final products of the formula (I) were confirmed by the method of nuclear (generally proton) magnetic resonance (NMR) and mass spectroscopy; the values of chemical shift magnetic resonance were determined in deuterated CDCl3(if you do not specify another solvent) on the Delta scale (ppm, relative to tetramethylsilane); the data of proton magnetic resonance, unless other conditions; spectra were recorded on a spectrometer Varian Mercury-300 MHz Varian Unity plus 400 MHz, Varian Unity plus 600 MHz or Varian Inova 500 MHz, and if not specified other conditions, the data were recorded at 400 MHz; a plurality of peaks are indicated as follows: s - singlet, d - doublet; DD, double doublet; t - triplet; TT, triple triplet; kV - Quartet; TCEs - triple Quartet, m - multiplet; ush. - broadened signal; Avcw - AB Quartet; Rth - AB doublet; AVDD - AB doublet of doublets; dvcv - doublet of AB Quartet; IHMS recorded on a Waters ZMD, LC column x-Terra MS C8(Waters), detection with HP 1100 MS-detector, equipped with a diode antenna; mass spectrum (MS)(loop) recorded on a VG Platform II (Fisons Instruments) with HP 1100 MS-detector, equipped with a diode antenna; if not specified other conditions given mass ion is a (MH+); if the text is not given more than the detailed description, analytical high performance liquid chromatography (HPLC) was performed on Prep LC 2000 (Waters), Cromasil C8, 7 μm (Akzo Nobel); MeCN and 10 mm ammonium acetate in deionized water as mobile phase with a suitable composition;

(vii)intermediates were not fully characterized, and the purity was determined by thin-layer chromatography (TLC), HPLC, IR, MS and NMR analysis.

(viii) drying solutions as desiccant was used sodium sulfate;

(ix) if the column is marked as "ISOLUTE", this means that the column contains 2 g of silicon dioxide, and silicon dioxide were placed in 6 ml syringe and deposited on a porous disk with a pore size 54Å obtained from International Sorbent Technology called "ISOLUTE"; "ISOLUTE" is a registered trade mark;

(x) can be used the following abbreviations

DHM - dichloromethane

DMF - N,N-dimethylformamide;

TBTU - o-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate;

EtOAc is ethyl acetate;

MeCN is acetonitrile;

TFUC - triperoxonane acid;

IPA isopropanol;

DIPEA - diisopropylethylamine;

THF is tetrahydrofuran.

Example 1

11 Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-methoxycarbonylethyl)carbamoylmethyl]-,3,4,5-tetrahydro-1,5-benzothiazepine (method 29; 300 mg, 0.46 mmol) dissolved in methanol (5 ml). To the solution was added NaOH (100 mg in 0.2 ml water) and the mixture is stirred at room temperature for 1 hour. Add acetic acid (0.3 ml). The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. Layer DHM is separated, dried and evaporated under reduced pressure, obtaining specified in the header connection: 270 mg (92%). NMR, (500 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,1 (s, 3H) 3,2 (users, 2H), 3,6-3,8 (m, 2H), 4,6 (s, 2H), 5,6 (d, 1H), and 6.6 (s, 1H)and 6.9-7.5 (m, 11H), and 7.8 (d, 1H).

Examples 2-9

Below obtain the connection according to the method of example 1 using the appropriate source materials.

Example

No.
ConnectionNMRSource.

in-VA
2(300 MHz, CD3OD) 0,9-0,95 (m, 6H), of 1.05 to 1.3 (m, 8H), is 1.4-1.6 (m, 4H), 2,2 (s, 3H), of 3.25 (s, 2H), 3,75 (users, 2H)and 4.65 (DD, 2H), and 5.2 (s, 1H), 6,7-to 7.3 (m, 10H), and 7.4 (s, 1H)method

30
3(300 MHz, CD3OD) of 0.75 to 0.85 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,2 (s,3H), 3,75 (users, 2H), 3,25 (s, 2H), 4,6-4,7 (m, 2H), 5,7 (s, 1H), 6,7 (s, 1H), 6,9-to 7.3 (m, 8H), and 7.4 (s, 1H)method

31
4(300 MHz, CD 3OD) of 0.75 to 0.9 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,2 (s, 3H), of 3.25 (s, 2H), 3,75 (users, 2H), 4,6-4,8 (m, 2H), of 5.45 (s, 1H), 6,7 (s, 1H), 6,95 of 7.3 (m, 5H) of 7.4 (s, 1H), 7,6 (s, 4H)method

32
5(500 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 12H), 3,2 (users, 2H) 3,6 (users, 2H), 4,48 (m, 2H), 5,0 (s, 1H), 6,5 (d, 1H), 6,7-of 7.4 (m, 10H), and 7.9 (s, 1H)method

39
6(DMSO-d6) of 0.7-0.8 (m, 6H), of 0.9 to 1.6 (m, 12H), 3,2 (users, 2H), 3,7 (users, 2H), 4,6-4,8 (m, 3H), and 6.6 (d, 2H), 6,9-to 7.3 (m, 8H) to 7.4 (s, 1H) and 8.3 (d, 1H)method

40
7M/z=768,9method

67
81(300 MHz, CD3OD) of 0.75 to 0.9 (m, 6H), 1,0-1,25 (m, 4H), is 1.4-1.6 (m, 4H), of 2.15 (s,3H), 3,1-3,3 (m, 4H), 3.5 to 3.8 (m, 5H), 4.75 in (Avcv, 2H), of 5.45 (s, 2H), 6.75 in (s, lH), 6,95 is 7.5 (11H); M/z 711,3method

42
9(500 MHz, DMSO-d6) of 0.7-0.8 (m, 6H), of 0.9 to 1.6 (m, 12H), 2,2 (s, 3H) of 3.2 to 3.8 (m, 8H), 4,8 (Avcv, 2H), 5,6 (d, 1H), 6,7 (s, 1H), 6,8-7,5 (m, 11H), 7,8 (users, 1H), and 8.6 (d, 1H), 8,8 (t, 1H)method

69
1Instead of methanol using ethanol purification preparative HPLC using MeCN and acetate-ammonium buffer (55:45) as eluent.

When is EP 10

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{1-[N-((R)-1'-phenyl-l'-carboxymethyl)carbarnoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{1-[N-((R)-1'-phenyl-1'-methoxycarbonylethyl)carbarnoyl]ethoxy}2,3,4,5-tetrahydro-1,5-benzothiazepine (method 33; 103 mg, 0.15 mmol) dissolved in a mixture of THF and H2O (2:1, 3 ml). Add LiOH (7 mg, 0.3 mmol) and the mixture is stirred for 7 hours at room temperature. A large part of the solvent is removed under reduced pressure and the crude product is purified preparative HPLC (eluent: a mixture of MeCN and acetate-ammonium buffer, 45:55), receiving specified in the title compound, 97 mg (96 %). NMR (DMSO-d6) 0,60-0,80 (m, 6H), from 0.90-1.60 (m, 11H), 3,15 is-3.45 (m, 2H), 3,50-3,90 (m, 2H), 4.95 points-of 5.25 (m, 2H), 6,85-of 7.55 (m, 12H), 8,55-8,95 (m, 1H).

Examples 11-16

Below obtain the connection according to the method of example 10, using the appropriate source materials.

Example

No.
ConnectionNMRSource.

in-VA
11((CD3)2CO) 0,70-0,90 (m, 6H), of 0.95 and 1.35 (m, 4H), 1,40 is 1.75 (m, 4H), 3,15-to 3.35 (m, 2H), 3,80 (users, 2H), of 5.40 (d, 1H), 5,90-6,15 (2s, 1H), 6,95 to 7.75 (m, 18H)method

34
12 (CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), 3,60 (s, 3H), 3,75 (users, 2H), 4,60 (Avcv, 2H), of 5.40 (s, 1H), 6,50 (s, 1H), 6,95 was 7.45 (m, 10H), 7,55 (s, 1H)method

35
13(CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), 3,55 (s, 3H), 3,75 (users, 2H), 3,90 (Avcv, 2H), 4,60 (Avcv, 2H), ceiling of 5.60 (s, 1H), 6,50 (s, 1H), 6,95 was 7.45 (m, 10H), 7,55 (s, 1H)method

36
14(CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-to 1.60 (m, 4H), 3,20 (s, 2H), 3,60 (s, 3H), 3,75 (users, 2H), 4,55 (Avcv, 2H), of 5.55 (s, 1H), 6,50 (s, 1H), 6,95 was 7.45 (m, 9H), to 7.50 (s, 1H)method

37
15(CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-to 1.60 (m, 4H), of 2.15 (s, 3H), 3,25,(s, 2H), 3,75 (users, 2H)and 4.65 (Avcv, 2H), ceiling of 5.60 (s, 1H), 6,70 (s, 1H), 6.90 to was 7.45 (m, 10H)method

38
16NMR (CD3OD) of 7.55-7,41 (3H, m), 7,35-7,20 (5H, m), 7,15-was 7.08 (3H, m),? 7.04 baby mortality-6,98 (1H, m), 5,48-5,32 (1H, m), 4.80 to 4,60 (2H, m), 4.00 points of 3.56 (4H, m), 3.27 to up 3.22 (2H, m), 1,61-1,00 (11H, m), 0,83-to 0.74 (6H, m)method

70

Example 17

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]|-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1

'-phenyl-1'-methoxycarbonylmethylene]-2,3,4,5-tetrahydro-l,5-benzothiazepine (method 46; 60 mg, 0,091 mmol) dissolved in THF (1 ml) and added to a solution of lithium hydroxide monohydrate (12.6 mg, 0.29 mmol) in water (1 ml). The mixture is stirred several times within 30 minutes. Add 2M HC1 solution (0.3 ml) and the aqueous layer was extracted with DHM. The organic layer was washed with saturated salt solution, dried, filtered and evaporated under reduced pressure, obtaining specified in the header of the connection 48 mg (82%). NMR (CD3OD) 0,73 is 0.84 (m, 6H), of 1.0 to 1.6 (m, 8H), 3.27 to (users, 2H), 3,60-3,,90 (m, 2H), 4,71 (Avcv, 2H), 5,47-of 5.55 (m, 1H), 7,02 (ushort, 1H), 7,08-7,17 (m, 3H), 7,25-7,46 (m, 7H), 7,52 (s, 1H), 8,43 (d, NH); m/z 643,5.

Examples 18-21

Below obtain the connection according to the method of example 17 using the appropriate source materials.

Example

No.
ConnectionNMR or m/zSource.

in-VA
181M/z 670 (m+NH4+)method

43
192NMR (CD3OD) 0,70-0,90 (m, 6H), from 1.0 to 1.32 (m, 4H), 1,32 is 1.70 (m, 4H), of 2.15 (s, 3H), 2,85 (users, 3H), 3,23 (users, 2H), 3,53-3,93 (m, 2H), 4,99 (Avcv, 2H), 6,27 (s, 1H), of 6.71 (s, 1H), 6,94 (t, 1H), 7,07 (d, 2H), 7,25 (m, 2H), 7,3-7,47 (m, 6H); m/z 625,3method

62
20 NMR (CD3OD) of 0.75 is 0.84 (m, 6H), 1,0-of 1.29 (m,4H), 1,36-of 1.65 (m,4H), of 2.15 (s, 3H), 2,82-of 2.97 (m, 2H), 3,22 (users, 2H), 3,6-of 3.85 (m, 2H), 4,66 (Avcv, 2H), 5,43 (t, 1H), of 6.71 (s, 1H), of 6.96 (t, 1H), to 7.09 (d, 2H), 7,2-7,38 (m, 7H), 7,40 (s, 1H); m/z 625,4method

112
21NMR (600 MHz, CD3OD) of 0.77-to 0.88 (m, 6H), from 1.0 to 1.32 (m, 4H), 1,39 is 1.70 (m, 4H), of 2.16 (s, 3H), 2,88 (users, 3H), 3,25 (users, 2H), 3,52-3,93 (m, 2H), 5,03 (Avcv, 2H), 6,28 (s, 1H), 6.73 x (s, 1H), of 6.96 (t, 1H), 7,09 (userd, 2H), 7,27 (t, 2H), 7,32-7,46 (m, 6H)method

79
12.2 equivalent of LiOH mixture of THF/water (4/1)

2Purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5/95 to 100/0).

Example 22

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-l,5-benzothiazepin

Specified in the title compound synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-methoxycarbonylethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 61) in accordance with the method of example 17, with the difference that the aqueous layer was extracted with EtOAc. The product was then purified preparative HPLC (eluent gradient: MeCN/acetylneuraminic the buffer from 5:95 to 100/0) NMR 0,75-of 0.83 (m, 6H), 1,0-1,25 (m, 4H), 1.32 to of 1.52 (m, 3H), 1,55-1,70 (m, 1H), 3,20 (Avcv, 2H), 3,65-a 3.83 (m, 2H), 4,62 (Avcv, 2H), of 5.68 (d, 1H),? 7.04 baby mortality-to 7.15 (m, 4H), 7,3-7,5 (m, 8H), 7,87 (userd, 1H); m/z 63,1.

Example 23

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(N-{(S)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-l,5-benzothiazepin ammonium salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 17; 48 mg, of 0.075 mmol) and 2-aminoethanesulfonic acid (17 mg, 0.14 mmol) dissolved in DMF (2 ml) and DIPEA (0,052 ml, 0.30 mmol). The mixture is stirred for 15 minutes at pritemperature 60°C. Add TBTU (31 mg, 0,097 mmol) and the mixture is stirred for 2 hours at a temperature of 60°C. the Solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5/95 to 100/0). Lyophilization results specified in the title compound, 4 mg (7%). NMR (CD3OD) of 0.75 or 0.83 (m, 6H), 0,95-of 1.65 (m, 8H), 2,85-3,0 (m, 2H), 3.27 to (users, 2H), of 3.5-3.9 (m, 4H), 4.72 in (Avcv, 2H), 5,48 (s, 1H), 7,02 (ushort, 1H), 7,09-to 7.15 (m, 3H), 7,25-7,52 (m, 8H); m/z 750,3.

Examples 24-37

The compounds below are obtained by the same technique. Acid (1 EQ.) dissolved in THF (1 ml) and added to a solution of lithium hydroxide monohydrate (12.6 mg, a 2.9-6.6 EQ.) in water (1 ml). The mixture was occasionally stirred and after 1,5-6 hours removing the protective group is terminated (in accordance with LC-MS). Add 2M aqueous HCl (0.3 ml).

When the career 24-33

The reaction mixture is selected syringe, which contains hydramatrix®. Product elute DHM. DHM dried, filtered and evaporated under reduced pressure. The product was then purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5:95 to 100:0)

Examples 34-37

The aqueous layer was twice extracted with DHM. The organic layer is dried, filtered and evaporated under reduced pressure.

Example

No.
ConnectionNMR(CD3OD)m/zOutcome.

in-VA
240,75-0,84 (m, 6H), 1,0-1,25 (m, 4H), 1,37-of 1.65 (m, 4H), 3,20 (users, 2H), 3,55-3,90 (m, 5H), 4,58 (Avcv, 2H), 5,33 (s, 1H), 6,51 (s, 1H), 6,97 (ushort, 1H), 7,12 (userd, 2H), 7,2-7,33 (m, 5H), 7,41 (userd, 2H), 7,54 (s, 1H)595,4method

47
250,73-of 0.85 (m, 6H), 1,0-1,3 (m, 4H), 1,35-of 1.65 (m, 4H), 2,17 (s, 3H), 3,23 (users, 2H), 3,55-3,90 (m, 2H), 4,71 (Avcv, 2H), 5,49-5,52 (m, 1H), 6.73 x (s, 1H), of 6.96 (ushort, 1H), 7,10 (userd, 2H), 7.23 percent was 7.45 (m, 8H), at 8.36 (userd, NH)611,2method

48
260,74 is 0.84 (m, 6H), 1,0-1,3 (m, 8H), 1,37-and 1.54 (m,4H), 3,28 (users, 2H), 3,65-of 3.85 (m, 2H), 4.72 in (Avcv, 2H);5,49-5,52 (m, 1H),? 7.04 baby mortality (ushort, 1H), 7,09-to 7.18 (m, 3H), 7,28-7,46 (m, 7H), 7,52 (s, 1H), 8,45 (ears the forth, NH)671,2method

49
270,74 is 0.84 (m, 6H), 1,0-1,3 (m, 4H), 1,35-of 1.65 (m,4H), 3,21 (users, 2H)and 3.59 (s, 3H), 3,62-3,90 (m, 2H), 4,62 (Avcv, 2H), 5,49 (s, 1H), 6,50 (s, 1H) 6,98 (ushort, 1H), 7,12 (userd, 2H), 7.24 to the 7.43 (m, 7H), 7,54 (s, 1H)595,3method

50
280,74-of 0.85 (m, 6H), 0,85-of 1.65 (m, 14H), 3,21 (users, 2H), 3,6-3,9 (m, 2H), 4,25 is 4.36 (m, 1H), 4.53-in-of 4.66 (m, 2H), 5,49 (s, 1H), 6,47 (s, 1H) 6,91-7,0 (m, 1H),? 7.04 baby mortality-7,16 (m, 2H), 7,22-7,46 (m, 7H), 7,51 (s, 1H)623,3method

51
290,73-of 0.85 (m, 6H), 0,85-of 1.65 (m, 8H), 3,24 (users, 3H), 3,34 (users, 2H), 3,6-3,95 (m, 2H), 4,8-of 4.95 (m, 2H), 5,52 (s, 1H), 7,06 (ushort, 1H), 7,17 (userd, 2H), 7,27-7,40 (m, 5H), 7,40-to 7.50 (m, 3H), of 7.69 (s, 1H)643,3method

52
300,74 is 0.84 (m, 6H), 0,85-of 1.55 (m, 12H), 3,24-to 3.33 (m, 2H), 3,65-of 3.85 (m, 2H), 4,65-4,78 (m, 2H), 5,50 (users, 1H), 6,99 to 7.2 (m, 4H), 7,25-of 7.48 (m, 7H), 7,51 (s, 1H)671,2method

53
310,72 is 0.84 (m, 6H), 0,85-of 1.65 (m, 8H), 3.27 to (users, 2H), 3,54 to-3.9 (m, 2H), 4,70 (Avcv, 2H), 5,70 (s, 1H), 6,63-6,69 (m, 1H), of 6.71-6,77 (m, 2H), 7,02 (ushort, 1H), 7,08-7,17 (m, 3H), 7,30 (ushort, 2H), 7,52 (s, 1H)675,4method

54
320,72 is 0.84 (m, 6H), 0,98-to 1.67 (m, 8H), 3,21 (users, 2H) 3,54 to-3.9 (m, 5H), 4,62 (Avcv, 2H), to 5.57 (s, 1H), 6,51 (s, 1H), 6,59-of 6.73 (m, 3H), 6,97 (ushort, 1H), 7,12 (userd, 2H), 7,28 (ushort, 2H), 7,56 (s, 1H)627,5method

55
330,73 is 0.86 (m, 6H), 1,0 by 1.68 (m, SH), are 2.19 (s, 3H), 3,24 (users, 2H), 3,55 to-3.9 (m, 2H), 4,71 (Avcv, 2H), of 5.53 (s, 1H), 6,60-of 6.73 (m, 3H), 6.75 in (s, 1H), of 6.96 (ushort, 1H), 7,10 (userd, 2H), 7,27 (ushort, 2H), 7,44 (s, 1H)643,4method

56
340,74 is 0.86 (m, 6H), 1,0-1,3 (m, 8H), 1,35-of 1.57 (m,4H), are 2.19 (s, 3H), 3,23 (users, 2H), 3,62-of 3.85 (m, 2H)and 4.65 (Avcv, 2H), 5,28 (s, 1H), 6,72 (s, 1H), 6,94-7,05 (m, 3H), 7,12 (userd, 2H), 7,28 (ushort, 2H), 7,39 (s, 1H), the 7.43 (DD, 2H)657,3method

57
350,75 is 0.86 (m, 6H), 1,0-1,3 (m, 8H), 1,35-of 1.55 (m, 4H), for 2.01 (s, 3H), 3,11-3,26 (Avcv, 2H), 3,6-3,8 (m, 2H), 4,58 (d, 1H), 4,70 (d, 1H), 5,64 (s, 1H), 6,62 (s, 1H), 6,91-7,0 (m, 2H), 7,01 for 7.12 (m, 3H), 7.23 percent-7,33 (m, 4H), 7,37 (s, 1H), 7,69 (userd, 1H)to 678.4method

58
360,76 is 0.84 (m, 6H), 1-0-1,3 (m, SH), 1,36-of 1.53 (m,4H), 3,21 (users, 2H), to 3.64 (s, 3H), 3,67-a 3.87 (m, 2H), 4,57 (Avcv, 2H), 5,31 (s, 1H), 6,50 (s, 1H), 6,95-7,06 (m, 3H), 7,14 (userd, 2H), 7,28 (ushort, 2H), 7,38-7,46 (m, 2H), 7,51 (s, 1H)641,4method

59
37the 0.75-0.87 (m, 6H), 1,0-1,3 (m, 8H), 1,34-of 1.53 (m,4H), 3,18 (Avcv, 2H), 3.27 to (s, 3H), 3,65-of 3.85 (m, 2H), to 4.52 (d, 1H)and 4.65 (d, 1H), to 5.66 (s, 1H), 6.30-in (s, 1H), 6.90 to-7,02 (m, 2H), 7.03 is-7,16 (m, 3H), 7.23 percent-7,34 (m, 4H), to 7.50 (s, 1H), to 7.59 (userd, 1H)662,4method

60

Example 38

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-3-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 22; 50 mg, 0,078 mmol) dissolved in DMF (1.5 ml). Add meantioned sodium (20 mg, 0.29 mmol) and the mixture is stirred for 1.5 hours at a temperature of 50°C. Add acetic acid (40 mg) and the solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55), receiving specified in the title compound, 29 mg (61%). NMR (DMSO-d6): of 0.7-0.8 (m, 6H), of 0.9 to 1.6 (m, 8H), 2,2 (s, 3H), 3,1-3,7 (m, 4H), 4,6-4,8 (m, 3H), 6,7 (s, 1H), 6,8-7,4 (m, 11H), and 8.3 (d, 1H).

Example 39

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-l,5-benzothiazepin (example 22; 50 mg, 0,078 mmol), ethane the IOL (99 mg, to 1.59 mmol) and cesium carbonate (253 mg, 0.78 mmol) is added to DMF (5 ml) and the mixture is stirred for 30 hours at a temperature of 44°C. the Solution is filtered and evaporated under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55). The residue is purified column chromatography (eluent: DHM/methanol, 100:15), receiving specified in the title compound, 15 mg (31%). NMR (300 MHz, CD3OD) 0,7-0,85 (m, 6H), 1,0-1,6 (m, 11H), to 2.65 (q, 2H), 3,2 (s, 2H), 3,7 (users, 2H), 4,6 (kV, 2H), 5,3 (s, 1H), 6.75 in (s, 1H)and 6.9-7.5 (m, 11H).

Example 40

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(2-hydroxyethylthio)-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 22; 50 mg, 0,078 mmol), 2-mercaptoethanol (281 mg and 3.59 mmol) and cesium carbonate (228 mg, 0.7 mmol) is added to DMF (5 ml) and the mixture is stirred for 9 hours at a temperature of 70°C. the Solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55). The collected fractions liabiliry, getting mentioned in the title compound, 20 mg (40%). NMR (300 MHz, CD3OD) of 0.75 to 0.85 (m, 6H), of 1.0 to 1.6 (m, 8H), 2,9 (t, 2H), 3,2 (s, 2H), 3,55 (t, 2H), 3,7 (users, 2H)and 4.65 (q, 2H), 5,3 (s, 1H), 6,9 (s, 1H), 6,95-7.5 (m, 11H).

Example 41

1,1-Dioxo-3-bout the l-3-ethyl-5-phenyl-7-(2- N',N'-dimethylaminoethyl)-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 22; 50 mg, 0,078 mmol), dimethylaminoethanol hydrochloride (99 mg, of 0.94 mmol), potassium carbonate (129 mg, of 0.94 mmol), DIPEA (100 mg, 0.77 mmol) and sodium borohydride (35 mg, of 0.93 mmol) is added to DMF (10 ml) and the mixture is stirred for 24 hours at a temperature of 85°C. the Solution is filtered and evaporated under reduced pressure. The residue is twice purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55). The collected fractions liabiliry, getting mentioned in the title compound 15 mg (30%). NMR (300 MHz, CD3OD) of 0.75 to 0.85 (m, 6H), 1,0-of 1.65 (m, 8H), to 2.65 (s, 6H), was 3.05 (t, 2H), 3,2 (t, 2H), 3,3 (s, 2H), 3,75 (users, 2H), and 4.75 (s, 2H), and 5.2 (s, 1H), 6,95 to 7.4 (m, 11), and 7.5 (s, 1H).

Example 42

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropylthio-8-[N-((R)-l'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 22; 50 mg, 0,078 mmol), 2-propandiol (126 mg, of 1.65 mmol), cesium carbonate (152 mg, 0.47 mmol), sodium borohydride (25 mg, 0.66 mmol) is added to DMF (5 ml) and the mixture is stirred for 5 minutes at temperature° C. the Solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55). The collected fractions liabiliry getting mentioned in the title compound, 15 mg (30%). NMR (300 MHz, DMSO-d6) 0,7-0,85 (m, 6H), 0,95-of 1.65 (m, 14H), and 3.3 (s, 2H), 3,7 (users, 2H), and 4.75 (DD, 2H), of 5.05 (users, 1H), 6.75 in to 7.4 (m, 12H), 8,5 (users, 1H).

Example 43

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(tert-butoxycarbonylmethyl)carbarnoyl]IU-Teal}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 63; 120 mg, 0,17 mmol) dissolved in DHM (2 ml). Add TFOC (0.7 ml) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50), receiving specified in the title compound, 95 mg (85%). NMR (300 MHz, DMSO-d6) NMR (300 MHz, DMSO-d6) of 0.7-0.8 (m, 6H), of 0.9 to 1.6 (m, 12H), 2,2 (s, 3H) 3,2-3,3 (m, 2H), 3.5 to 3.8 (m, 4H), 4,8 (Avcv, 2H), 5,6 (d, lH), 6,7 (s, 1H), 6,8-7,5 (m, 11H), 8,5-to 8.7 (m, 2H).

Examples 44-49

Below obtain the connection according to the method of example 43, using an appropriate source materials.

Example 50

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin ammonium salt

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 22; 150 mg, 0.30 mmol) and 2-((2'R)-2'-amino-2'-phenylethanolamine)econsultancy acid (method 28; containing DIPEA hydrochloride, 150 mg, 0.36 mmol) dissolved in DMF (6 ml). Add DIPEA (0.2 ml, 1.15 mmol) and TBTU (114 mg, 0.36 mmol) and the mixture is stirred for 2 hours at room temperature. The solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5:95 to 100:0), getting mentioned in the title compound, 73 mg (32%). NMR (CD3OD) of 0.75 to 0.85 (m, 6H), 1,0-1,3 (m, 8H), 1.3 to 1.6 (ra, 4H), of 2.16 (s, 3H), 2,85-3,0 (m, 2H), 3,24 (users, 2H) 3,5-of 3.85 (m, 4H), 4,70 (Avcv, 2H), vs. 5.47 (s, 1H), of 6.71 (s, 1H), 6,97 (ushort, 1H), 7,11 (userd, 2H), 7.23 percent was 7.45 (m, 8H); m/z 746,2.

Example 51

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin ammonium salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 17; 49 mg, 0.10 mmol) and 2-((2'R)-2'-amino-2'-phenylethanolamine)econsultancy acid (method 28; containing DIPEA hydroch Oric; 52 mg, 0.12 mmol) dissolved in DMF (2 ml). Add DIPEA (0,071 ml, 0.41 mmol) and TBTU (39 mg, 0.12 mmol) and the mixture is stirred for 2 hours at room temperature. The solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5:95 to 100:0), getting mentioned in the title compound, 59 mg (78%). NMR (CD3OD) 0,74-of 0.90 (m, 6H), 0,98-1,3 (m, 4H), 1,35-to 1.67 (m, 4H), of 2.16 (s, 3H), 2,85-to 3.02 (m, 2H), 3,23 (users, 2H) 3,52-3,90 (m, 4H), 4,70 (Avcv, 2H), vs. 5.47 (s, 1H), of 6.71 (s, 1H), of 6.96 (ushort, 1H), 7,09 (userd, 2H), 7,21-of 7.48 (m, 8H); m/z 718,4.

Example 52

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N(ethoxycarbonylmethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-l,5-benzothiazepine (method 72; 44 mg, 0,063 mmol) dissolved in a mixture of THF:H2O (1:1, 2 ml) and add NaOH (1 M, 0,126 mmol). The mixture is stirred at room temperature during 1 hour. The reaction mixture was acidified with HCl (1 M), diluted to 10 ml and extracted with DHM (3x10 ml). The combined organic layers are dried(MgSO4) and the solvent is evaporated, getting mentioned in the title compound (33 mg, 78%). NMR (300 MHz) 0,78-of 0.85 (m, 6H), 1,02 is 1.70 (m, 8H), of 2.20 (s, 3H), 3.15 in/3,21 (Avcv, 2H), 3,78 (m, 2H), 3,94/4,20 (duvcw, 2H), with 4.64 (q, 2H), 5,91 (d, 1H), 6,6 (s, 1H), 6,98-7,52 (m, 11H), 8,17 (d, 1H).

Example 53

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N-(1"-carboxy-1"-phenylmethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'- [N-( 1"-l-1"-phenylmethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 73) in accordance with the procedure of example 52. NMR (500 MHz) 0,76 is 0.84 (m, 6H), 1,05-of 1.73 (m, 8H), and 2.14 (s, 3H), and 3.16 (m, 2H), 3,74 (m, 2H), 4,48 (m, 2H), of 5.53 (d, 2H), 5,96 (d, 2H), 6,63 (s, 1H), 6,97-of 7.48 (m, 13H), 7,86 (m, 1H), 8,17 (m, 1H).

Example 54

1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{1-[N-((R)-α-carboxybenzoyl)carbarnoyl]ethoxy}-2,3,4,5-tetrahydro-l,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{1-[N-((R)-1'-phenyl-1'-carboxymethyl)carbarnoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 10, 0,050 g, 7,6x10-5mol) in DMF (4 ml) add diameterat sodium (0,021 g, 3,0xl0-4mol) and the solution stirred for 4 hours at room temperature. The mixture is concentrated and the residue partitioned between water and ether. The aqueous phase is extracted two more times with ether and the combined organic extracts dried (MgSO4), concentrate and purify HPLC. Get 0,30 g (63%) indicated in the title compound as a solid which CSOs white matter. NMR (CD3OD) 0,75-0,90 (m, 6H), 1,00-1,30 (m, 4H), 1,40-1,70 (m, 7H), of 2.15 (d, 3H), 3,10-3,30 (m, 2H), 3,55-3,95 (m, 2H), 4.80 to of 4.95 (m, 2H), and 5.30 (d, 1H), 6,70 is 7.50 (m, 12H); m/z 625,3.

Example 55

1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{α-[N-((R)-α-carboxybenzoyl)carbarnoyl]benzoyloxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{α-[N-((R)-α-carboxybenzoyl)carbarnoyl]benzoyloxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 11; 0,018 g, 2,5x10-5mol) in DMF (3 ml) add diameterat sodium (0,007 g, 1,0x10-4mol) and the solution stirred for 4 hours at room temperature. The mixture is concentrated and the residue partitioned between water and ether. The aqueous phase is extracted two more times with ether and the combined organic extracts dried (MgSO4), concentrate and purify HPLC. Get listed in the title compound (0.015 g, 99 %) as a white solid. NMR (CD3OD) 0,70-0,85 (m, 6H), 1,00-1,25 (m, 4H), 1,35-of 1.65 (m, 4H), of 2.20 (d, 3H), of 3.10-3.20 (m, 2H), 3,50-of 3.85 (m, 2H), and 5.30 (d, 1H), 5,80 (d, 1H), 6,70 (s, 1H), 6.90 to-the 7.65 (m, 16H).

Example 56

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino} econsultancy acid (method 80; 32,5 mg, 0,119 mmol) is mixed with DMF (4 ml) and N-methylmorpholine (30 μ l, 0,272 mmol). Get clear solution and several portions successively added 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 22; 50 mg, 0,099 mmol) and TBTU (38 mg, 0,119 mmol). The reaction mixture was stirred at room temperature for 30 minutes and remove DMF. The crude product is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 1:1). Lyophilization results in 55 mg specified in the title compound (71%). NMR (500 MHz, MeOD) 0,78 is 0.86 (m, 6H), 1,0-1,3 (m, 8H), is 1.4-1.6 (m, 4H), of 2.15 (s, 3H), 2,85-3,00 (m, 2H), 3,25 (s, 2H), 3,55-3,68 (m, 2H), 3,75 (users, 2H) 4,65 (Avcv, 2N) are 5.36 (s, 1H), 6,70 (s, 1H), 6.75 in (d, 2H), 6,98 (t, 1H), 7,12 (d, 2H), 7,22 (d, 2H) 7,28 (m, 2H) and 7.4 (s, 1H); m/z 762.

Examples 57-58

Below obtain the connection according to the method of example 56 from the corresponding starting compounds with the difference that the reaction is carried out in a period of 64 hours (example 57), or for 2 hours (example 58) and the product purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 45:55 to 60/40).

Example

No.
ConnectionNMR or m/zSource.

in-VA
44NMR (300 MHz) of 0.7-0.9 (m, 6H), 1,0-1,7 (m, SH), 3,2 (m, 2H), 3,75 (users, 2H), 3,9-4,0 (m, 1H), 4,15-of 4.25 (m, 1H), 4,5-4,7 (m, 2H), 5,75-5,9 (m, 1H), 7,05 to 7.2 (m, 4H), 7,25 to 7.4 (m, 5H), 7,45-of 7.55 (m, 3H), of 8.2 (d, 1H)method

64
45NMR (CD3OD) 0,70-0,90 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), 3,55 (s, 3H), 3,75 (users, 2H), 3,80-4,00 (m, 2H), 4,40-4,70 (m, 3H), 5,65 (s, 1H|, of 6.50 (s, 1H), 6,95 is 7.50 (m, 10H), 7,55 (s, 1H)method

41
46(300 MHz, CD3OD) of 0.75 to 0.85 (m, 6H), of 1.05 to 1.3 (m, 8H), is 1.4-1.6 (m, 4H), 2,2 (s, 3H), of 3.25 (2H), 3,7-3,95 (m, 4H), 4,7 (Avcv, 2H), 5,5 (s, 1H), 6,7 (s, 1H), 6.75 in-7,35 (m, 9H), and 7.4 (s, 1H)method

65
47783,5method

66
48802,7method

68
49(500 MHz, CD3OD) 0,82 (ushort, 6H), 1,05-of 1.26 (m, 8H), 1,42-of 1.56 (m, 4H), 3.27 to (users, 2H), 3,6-of 3.75 (m, 2H), 4,58 (Avcv, 2H), 5,41 (s, 1H), 6.73 x-PC 6.82 (m, 3H), of 7.0 (d, 2H), 7,05 (DD, 1H), 7,25 was 7.36 (m, 3H), 7,41 (userd, 2H), of 7.48 (d, 1H); m/z 608,3method

119
Example

No.
ConnectionNMR (CD3OD) or m/zSource.

in-VA
57< / br>
Enantiomer 1
0,75-0,84 (m, 6H) 1,00-of 1.27 (m, 4H), 1,37-of 1.64 (m, 4H) and 2.14 (s, 3H), 2,8'6-3,00 (m, 2H), up 3.22 (s, 2H), 353-3,68 (m, 2H), 3,85 userd, 2H), 4,68 (Avcv, 2H), 5,35 (s, 1H), 6,70 (s, 1H), 6.75 in (d, 2H), 6,95 (t, 1H), was 7.08 (d, 2H), 7,20-7,29 (m, 4H), 7,37 (s, 1H); m/z751 (M+NH4+)method

23
58< / br>
Enantiomer 2
0,77-of 0.85 (m, 6H) 1,06-of 1.27 (m, 4H), 1,40-of 1.62 (m, 4H) 2,17 (s, 3H), 2,87-3,00 (m, 2H), 3,24 (s, 2H), 3,56-3,68 (m, 2H), 3,75 (userd, 2H), 4,71 (Avcv, 2H), lower than the 5.37 (s, 1H), 6,72 (s, 1H), 6,77 (d, 2H), 6,97 (t, 1H), 7,10 (d, 2H), 7.23 percent (d, 2H), 7,28 (m, 2H), 7,40 (s, 1H); m/z 751 (M+NH4+)method

24

Example 59

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-N'-(2-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; 66,8 mg, 0,109 mmol) and compound ethyl ester β-alanine hydrochloride (23,0 mg, 0.15 mmol) dissolved in DHM (2.5 ml) and addN-methylmorpholin (0,07 ml, 0.64 mmol). The mixture is stirred at room temperature for 5 minutes, then add TBTU (of 45.6 mg, 0,142 mmol) and the resulting mixture is stirred for 2 hours. The reaction mixture was filtered through a small column and concentrate. The crude ester was dissolved in THF (1.5 ml) and add water (1.5 ml) and NaOH (1 M, 0.20 mmol). The mixture is stirred at room temperature for 1 hour, the reaction quenching is 1 M HCl. The reaction mixture was diluted with water (10 ml) and extracted with DHM (3 x 5 ml). The organic layers are concentrated and purified preparative HPLC, getting mentioned in the title compound (60 mg, 81%). NMR (300 MHz) to 0.80 (m, 6H), 1.00 and is 1.70 (m, 8H), 2,17 (s, 3H), 2,48 (m, 2H), 3,17 (Avcv, 2H), 3,35 (m, 1H), only 3.57 (m, 1H), 3,70 (m, 2H), 4,62 (Avcv, 2H), 5,77 (d, 1H), only 6.64 (s, 1H), 6,98 (t, 1H), 7,06 (d, 2H), 7,28 (m, 4H), 7,42 (m, 3H), 7,56 (m, 1H), 8,10 (m, 1H).

Examples 60-63

Below obtain the connection according to the method of example 59, using an appropriate source materials.

Example

No.
ConnectionNMRSource.

in-VA
600,81 (m, 6H), 1.00 and-of 1.95 (m, 10H), 2,22 (s, 3H), 3,37 (m, 2H), 3,18 (Avcv, 2H), 3,48 (m, 2H, in), 3.75 (m, 2H), 4,66 (kV, 2H), of 5.75 (d, 1H), to 6.67 (s, 1H), 7,00 (t, 1H), to 7.09 (m, 2H), 7,20 (m, 1H) 7,30 (m, 4H), 7,44 (m, 2H), 8,25 (m, 1H)example

38
61NMR (300 MHz, DMSO-d6) to 0.74 (m, 6H), 0.95 to-1,50 (m, 12H), of 2.16 (s, 3H), 2,28 (t, 2H), 3,24 (m, 2H), 4,74 (kV, 2H), 5,33 (d, 1H), 6,69 (m, 2H), 6,85 (t, 1H), 6,99 (m, 2H), 7,16 (m, 4H), 8,33-to 8.45 (m, 2H)example

2
62(300 MHz) 0,81 (m, 6H), 1.00 and-of 1.74 (m, 14H), 2,22 (s, 3H), 2,31 (m, 2H) 3,10-to 3.35 (m, 4H), to 3.73 (m, 2H), 4,62 (Avcv, 2H), 5,64 (d, 1H), 6,39 (users, 1H), to 6.67 (s, 1H), 6,9-7,10 (m, 3H), 7,25-of 7.48 (m, 7H), 8,21 (d, 1H)example

38
630,81 (m, 6H), 1,03-of 1.55 (m, 12H), are 2.19 (s, 3H), by 2.55 (m, 2H), 3,18 (m, 2H), 3.46 in (m, 1H), to 3.58 (m, 1H), 3,74 (m, 2H), with 4.64 (Avcv, 2H), 5,80 (m, 1H), only 6.64 (s, 1H), 7,01 (t, 1H), was 7.08 (d, 2H), 7,30 (m, 5H), 7,44 (m, 3H), 8,11 (m, 1H)example

1

Example 64

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-methoxybenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-l,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(tert-butoxycarbonyl)-4-hydroxybenzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 78; 48 mg, 0,070 mmol), bromacil(trimethylammonium) (57 mg, 0,230 mmol), tetrabutylammonium bromide (3 mg, 0,009 mmol) and Cs2CO3(71 mg, 0.22 mmol) are added to CH3CN (1.0 ml) and the reaction mixture refluxed overnight. The solvent is evaporated and the residue is transferred into water (10 ml), extracted with DHM (3 x 5 ml) and dried (MgSO4). The crude ester is dissolved in DHM (2.5 ml), add TFOC (0.3 ml) and the reaction mixture was stirred at room temperature overnight. The solvent is evaporated and the crude product is purified preparative HPLC, getting mentioned in the title compound (23 mg, 51 %). NMR (DMSO-d6) to 0.74 (m, 6H), 0,94 is 1.60 (m, 8H), 2,17 (s, 3H), of 3.25 (m, 2H), 3,69 (s, 3H), 4,70 (Avcv, 2H), 4.95 points (users, 1 is) of 6.71 (s, 1H), 6,83 (m, 3H), 6,97 (d, 2H), 7,20 (m, 4H), 7,27 (s, 1H), of 8.37 (users, 1H).

Example 65

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(α-[N'-(2-sulfoethyl)carbarnoyl]-α-methylbenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin ammonium salt

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(α-carboxy-α-methylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 18; 27 mg, 0,041 mmol) dissolved in DHM (2 ml). Successively added taurine (taurine) tetrabutylammonium salt (45 mg, 0,123 mmol) and TBTU (16 mg, 0,050 mmol) and the mixture is stirred for 5 hours at room temperature. The solvent is evaporated and the product purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). Lyophilization results specified in the title compound (20 mg, 62%). NMR shows that 16% of the product remains in the form of tetrabutylammonium salt. NMR (500 MHz) of 0.75 to 0.9 (m, 6H), 1,0-1,3 (m, 8H), 1.3 to 1.6 (m, 4H), of 1.95 (s, 3H), 2,1 (s, 3H), 2,9 (users, 2H), 3,05 (users, 2H), 3,55 (Rth, 2H), 3,75 (users, 2H), 4,55 (Avcv, 2H), and 6.6 (s, 1H), 6,9-7,6 (m, 12H), of 8.2 to 8.3 (users, 1H); m/z 777 (M+NH4+).

Examples 66-67

Below obtain the connection according to the method of example 65, using an appropriate source materials.

Example

No.
ConnectionNMR (CD3OD) or m/z Source.

in-VA
66777 (M+NH4+)example

1
670,75-0,85 (m, 6H), of 1.02 (t, 12H), of 1.05 to 1.3 (m, 4H), 1.3 to 1.7 (m, 20H), 2,17 (s, 3H), 2,85-to 2.99 (m, 2H), 3,19-3,26 (m, 10H), 3,52-to 3.92 (m, 4H), 4,71 (Avcv, 2H), vs. 5.47 (s, 1H), 6,72 (s, 1H), of 6.96 (t, 1H), 7,09 (userd, 2H), 7.23 percent-7,44 (m, 8H); m/z 735,2 (M+NH4+)example

25

Example 68

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{α-[N'-(carboxymethyl)carbarnoyl]-α-methylbenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{α-[N'(methoxycarbonylmethyl)carbarnoyl]-α-methylbenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 44; 20 mg, 0,028 mmol) dissolved in 2.5 ml of a mixture of THF/water (4/1). Add LiOH (2 mg, 0,084 mmol) and the mixture is stirred for 1 hour at room temperature. Specified in the title compound purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). MeCN is evaporated and the remaining buffer acidified with acetic acid. Lyophilization results in 10 mg of product (51%). NMR of 0.7-0.9 (m, 6H), from 1.0 to 1.35 (m, 8H), of 1.35 to 1.6 (m, 4H), 2,0 (s, 3H), 2,2 (s, 3H), 3,2 (users, 2H), 3,65-3,85 (users, 2H), 3,9-4,1 (d, 2H), 4,5-4,7 (Avcv, 2H), and 6.6 (s, 1H), 6,8 (users, 1H), and 6.9-7.5 (m, 11H), 8,1 (s, 1H) ;m/z 727 (M +NH 4+).

Example 69

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{α-[N'-( 2-sulfoethyl)carbarnoyl]-2-terbisil}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[α-carboxy-2-terbisil]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 15; 20 mg, 0,030 mmol), taurine tetrabutylammonium salt (20 mg, 0,054 mmol) and DIPEA (25 mg, 0,19 mmol) dissolved in DMF (0.4 ml). Added TBTU (15 mg, 0,047 mmol) and the mixture is stirred for 30 minutes at room temperature. The product isolated from the reaction mixture preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). Get 7 mg (29%) specified in the connection header. M/z = 764,5.

Example 70

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-(R)-{α-[N'-(R)-{α-[N-(carboxymethyl)carbarnoyl]benzyl}carbamoyl)methylcarbamoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)- 1'-phenyl-1'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 43; 35 mg, 0,050 mmol) and (R)-α-[N-(tert-butoxycarbonylmethyl)carbarnoyl]benzylamine (method 86; 20 mg, 0,076 mmol) dissolved in DHM (2 ml) and added 2,6-lutidine (of 0.03 ml, 0.26 mmol). The mixture is stirred at room temperature for 5 minutes, then add the TBTU (20 mg, 0,062 mmol) and stirring is continued for 3 hours. The reaction mixture was filtered through a column (eluent: DHM/EtOAc, 3:1). Tert-Butyl ether then dissolved in DHM (6 ml) and add TFOC (1 ml). The mixture is stirred at room temperature overnight and the solvents evaporated. Add toluene and evaporated it, and repeat this procedure. Get listed in the title compound (40 mg, 93 %), which does not require additional purification. NMR (500 MHz, DMSO-d6) to 0.75 (m, 6H), 0.95 to-1,50 (m, 12H), of 2.16 (s, 3H), of 3.25 (m, 2H, in), 3.75 (m, 2H), 3,90 (DD, 1H), 4,73/4,84 (Avcv, 2H), 5,54 (m, 2H), to 5.58 (d, 1H), of 6.68 (s, 1H), 6,85 (t, 1H), 6,99 (d, 2H), 7.18 in-7,46 (m, 13H), 8,51-8,73 (m, 4H).

Example 71

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-(S)-{α-carboxy-4-hydroxybenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 22; 61 mg, 0.12 mmol) and methyl (2S)-amino(4-hydroxyphenyl)acetate hydrochloride (31 mg, 0.14 mmol) dissolved in DHM (4 ml) and added 2,6-lutidine (0.04 ml, 0.34 mmol). The mixture is stirred at room temperature for 5 minutes, then add TBTU (53 mg, 0,17 mmol) is added and stirring is continued for 2 hours. The reaction mixture was filtered through a small column. The crude methyl ester was dissolved in THF (1.5 ml) and add water (1.0 ml) and NaOH (aq., 1 M to 0.39 mmol). Rea is operating, the mixture is stirred at room temperature for 8 hours, the reaction is quenched with HCl (1 M) and extracted with DHM (3 x 5 ml). The collected organic layers are concentrated and purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50), receiving specified in the title compound (57 mg, 72 %). NMR (500 MHz, CD3OD) 0,81 (m, 6H), 1,05-of 1.26 (m, 8H), 1,40-of 1.55 (m, 4H), 2,17 (s, 3H), 3,24 (users, 2H), 3,74 (users, 1H), 4,66 (Avcv, 2H), 6,70 to 6.75 (m, 3H), of 6.99 (t, 1H), 7,11 (d, 2H), 7,22-7,30 (m, 4H), 7,40 (s, 1H).

Example 72

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-(S)-{α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin ammonium salt

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxy-4-hydroxybenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 71; 31 mg, 0,047 mmol) and tetrabutylammonium taurine (57 mg, 0,155 mmol) dissolved in DHM (2 ml). The mixture is stirred at room temperature for 5 minutes, then add TBTU (24 mg, of 0.075 mmol) and stirring is continued for 6 hours. The solvent is evaporated and the residue purified preparative HPLC (twice, for deletes all tetrabutylammonium salt) (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55), receiving specified in the title compound (6 mg, 16%). M/z 762,2.

Examples 73-74

1,1-Dioxo-3-(R/S)-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-(R)-{α-[N'-(R)-(2-imidazol-5-yl-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-who enzodiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; of 56.4 mg, 0,092 mmol) and methyl-D-histidinate the dihydrochloride of 25.2 mg, 0.104 g mmol) are added to DHM (3 ml). Then add N-methylmorpholine (0.05 ml, 0.41 mmol) and TBTU (40 mg, 0.12 mmol). The reaction mixture is stirred at a temperature of 4°C for 1.5 hours and at room temperature for 3 hours. Add a further quantity of TBTU (15 mg, 0,047 mmol) and DIPEA (of 0.025 ml, 0.14 mmol) and the reaction mixture was stirred at room temperature for an additional 30 minutes. The solvent is evaporated and the residue filtered through a small column (eluent: MeOH). The crude methyl ester was dissolved in THF (1.0 ml) and add water (1.0 ml) and NaOH (aq., 1 M, 0.15 mmol). The reaction mixture was stirred at room temperature for 2 hours and the reaction quenched with HCl (1 M). The solvent is evaporated, the residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer). Connection elute as two peaks, which explains the presence of two diastereomers. The first peak (10 mg, 14%). The second peak (16,8 mg, 24%).

First peak: NMR (DMSO-d6) to 0.74 (m, 6H), of 0.95 is 1.60 (m, 8H), 2,17 (s, 3H), 2,82 (m, 2H), 3,23 (m, 2H), 4,27 (m, 1H), 4,80 (Avcv, 2H), ceiling of 5.60 (d, 1H), 6,55 (users, 1H), 6,70 (s, 1H), at 6.84 (t, 1H), of 6.96 (d, 2H), 7,14-7,28 (m, 6H), 7,33 (s, 1H), 7,44 (users, 1H), 8,54 (d, 1H), 8,60 (users, 1H); m/z 748,4.

The second peak NMR (DMSO-d 6) to 0.74 (m, 6H), of 0.95 is 1.60 (m, 8H), 2,17 (s, 3H), 2,92 (duvcw, 2H), 3,23 (m, 2H), to 4.41 (m, 1H), 4,79 (Avcv, 2H), ceiling of 5.60 (d, 1H), 6,70 (s, 1H), 6,78 (s, 1H), at 6.84 (t, 1H), of 6.96 (d, 2H), 7,16-7,34 (m, 6H), 7,40 (m, 2H), 7,55 (s, 1H), 8,55 (d, 1H), 8,71 (d, 1H); m/z 748,4.

Example 75

1,1-Dioxo-3,3-dibutil-5-(4-tert-butylphenyl)-7-methylthio-8-(N-{(R)-α-[N'-(carboxymethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound isolated as a side product in the synthesis of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 43). Approximately 1 g of this compound purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50), receiving specified in the title compound (32 mg). NMR (500 MHz, DMSO-d6) to 0.73 (m, 6H), 0,90-G,40 (m, 12H), 1,24 (s, 9H), of 2.16 (s, 3H), 3,23 (m, 2H), 3,65/3,75 (duvcw, 2H), 4.72 in/4,82 (Avcv, 2H), ceiling of 5.60 (d, 1H), 6,65 (s, 1H), 6,97 (d, 2H), 7.23 percent-to 7.35 (m, 6H), was 7.45 (d, 2H), 8,58 (d, 1H), to 8.62 (t, 1H).

Example 76

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(N-((R)-α-carboxybenzoyl)carbamoylmethyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 81; 38 mg, 0,080 mmol) and methyl ester of D-phenylglycine hydrochloride (24 mg, 0.12 mmol) dissolved in DHM (2 ml) and add N-methylmorpholine (0.05 ml, 0.42 mmol). The mixture is stirred pikantnoi temperature for 5 minutes, then add TBTU (44 mg, 0.14 mmol) and stirring is continued for 2 hours. The reaction mixture was filtered through a small column. The obtained product is dissolved in THF (1 ml), add water (1 ml) and NaOH (aq., 0.2 ml, 1 M) and the reaction mixture was stirred at room temperature for 2 hours. The reaction is quenched by addition of HCl (1 M), dilute the mixture with water (10 ml) and extracted with DHM (3 x 3 ml). Purification preparative HPLC results indicated in the title compound (40 mg, 82 %). NMR (DMSO-d6) to 0.75 (m, 6H), 0,96 is 1.60 (m, 8H), up 3.22 (m, 2H), 3,56 (Avcv, 2H), with 3.89 (s, 3H), to 4.81 (d, 1H), 6,78 (t, 1H), 6,83 (d, 2H), 6.89 in (s, 1H), 7,11-of 7.23 (m, 7H), 7,31 (s, 1H), of 8.37 (m, 1H).

Example 77

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-[N-(α-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonylmethyl-8 carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 82; 21 mg of 0.038 mmol) and methyl ester of phenylglycine hydrochloride (12 mg, 0.061 mmol) was dissolved in DHM (1.5 ml) and add N-methylmorpholine (0,02 ml to 0.19 mmol). The mixture is stirred at room temperature for 5 minutes, then add TBTU (18 mg, 0,056 mmol) and stirring is continued for 2 hours. The reaction mixture was filtered through a small column. Raw fluids dissolved in THF (1 ml) and add water (1 ml) and NaOH (aq., 0.1 ml, 1 M). The reaction mixture p is remediat at room temperature for 2 hours, quenched with HC1 (1 M), diluted with water (10 ml) and extracted with DHM (3x3 ml). The collected organic layers are concentrated and purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 30:70 to 40:60), receiving specified in the title compound (20 mg, 80%). NMR (CD3OD) to 0.80 (m, 6H), of 1.03-1.26 in (m, 4H), 1,38-of 1.65 (m, 4H), to 1.96 (s, 3H), 3,20 (s, 2H), 3,44 (s, 2H), 3,67 (users, 1H), 3,76 (users, 1H), 4,67 (Avcv, 2H), from 5.29 (s, 1H), 6.89 in (s, 1H), 6,92 (t, 1H), 7,05 (d, 2H), 7,19-7,32 (m, 5H), 7,41 (s, 1H), 7,45 (d, 2H).

Example 78

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(R)-(α-{N'-[(R)-N-(2-hydroxy-1-carboxyethyl)carbamoylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 43; 50 mg, 0,072 mmol), tert-butylo-(tert-butyl)-D-serinate hydrochloride (22 mg, 0,087 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) dissolved in DHM (1 ml). Added TBTU (29 mg, 0,090 mmol) and the mixture is stirred for 1 hour at room temperature. The reaction mixture is evaporated and the residue filtered through a small column (eluent: DHM/EtOAc, 1:4). The resulting substance (˜60 mg) is dissolved in DHM (1 ml). Add TFOC (0,59 g, 5.2 mmol) and the mixture is stirred for 2 hours at room temperature. The solvent is evaporated and the residue cleaned the t preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). Obtain 38 mg (72%) specified in the connection header. NMR (300 MHz, DMSO-d6) of 0.7-0.8 (m, 6H), 0,9-1,5 (m, 12H), 2,2 (s, 3H), 3,2-a 3.9 (m, 10H), 4.2V (users, 1H), 4,8 (Avcv, 2H), 5,6 (d, 1H), 6,7 (s, 1H), 6,8-7,5 (m, 11H), or 8.0 (d, 1H), and 8.6 (d, 1H), 8,7 (t, 1H).

Example 79

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(R)-(α-{N'-[(S)-N-(2-hydroxy-1-carboxyethyl)carbamoylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-l'-phenyl-l'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 43; 50 mg, 0,072 mmol),tert-butylO-(tert-butyl)-L-serinate hydrochloride (22 mg, 0,087 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) dissolved in DHM (1 ml). Added TBTU (29 mg, 0,090 mmol) and the mixture is stirred for 1 hour at room temperature. The reaction mixture is evaporated and the residue filtered through a small column (eluent: DHM/EtOAc, 1:4). The resulting substance (˜ 60 mg) is dissolved in DHM (1 ml). Add TFOC (0,44 g, 3.9 mmol) and the mixture is stirred for 18 hours at room temperature. The solvent is evaporated and the residue purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). Get 33 mg (63%) specified in the connection header. NMR (300 MHz, DMSO-d6) of 0.7-0.8 (m, 6H), 0,9-1,5 (m, 12H), 2,2 (s, 3H), 3,2-a 3.9 (m, 10H), 4,2 (m, 1H), 4,8 (Avcv, 2H), 5,6 (d, 1H), 6,7 (s, 1H), 6,8-7,5 (m, 11H), 7,9 (d,1H), to 8.6 (d, 1H), 8,7 (t, 1H).

Example 80

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(1,1-dicarboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; 50 mg, 0,082 mmol), dimethylaminomethyl (60 mg, 0.13 mmol) and N-methylmorpholine (55 μl,0.5 mmol) dissolved in DHM (3 ml), added TBTU (42 mg, 0.13 mmol) and the mixture is stirred for 15 minutes. The solvent is evaporated under reduced pressure. The residue is dissolved in ethanol (95%) (2 ml) and add a solution of NaOH (80 mg, 2 mmol) in water (80 ml). The reaction mixture is stirred for 4 hours. The mixture is neutralized with acetic acid. The solvent is evaporated under reduced pressure and the residue purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 50:50). The collected fractions liabiliry, receiving 4 mg (7%) specified in the connection header. NMR (300 MHz, CD3OD) of 0.75 to 0.9 (m, 6H), 1,0-1,3 (m, 4H), 1,4-of 1.65 (m, 4H), of 2.15 (s, 3H) of 3.25 (s, 2H) 3,7 (users, 2H), 4,65 of 4.8 (m, 2H), of 5.75 (s, 1H), 6.75 in (s, 1H), 6,9-of 7.55 (m, 11H).

Examples 81-87

Below obtain the connection according to the method of example 80 from the appropriate starting compounds, but with the difference that instead of N-methylmorpholine using 2,6-lutidine and changes the ratio of the components MeCN/centroamerica buffer (45:55). Slightly change the duration of each stage.

Example

No.
ConnectionNMR (300 MHz, CD3OD)Source.

in-VA
81(500 MHz) 0,8-0,95 (m, 6H), 1,05-1,35 (m, 4H), 1,4-1,7 (m, 4H), 2,2 (s, 3H), of 3.25 (s, 2H), of 3.7-3.9 (m, 4H), 4,4-of 4.45 (m, 1H), 4,7-4,8 (m, 2H), 5,7 (s, 1H), 6.75 in (s, 1H), 6,95-to 7.6 (m, 11H)example

38
820,75-0,9 (m, 6H), of 1.05 to 1.3 (m, 4H), is 1.4-1.6 (m, 4H), of 2.15 (s, 3H), of 3.25 (s, 2H), 3,7-3,95 (m, 4H), 4,25-4,3 (m, 1H), 4.75 in (Avcv, 2H), 5,65 (s, 1H), 6.75 in (s, 1H), 7.95 is-at 7.55 (m, 11H)example

38
830,75-0,9 (m, 6H), 1,05-1,35 (m, 8H), is 1.4-1.6 (m, 4H), of 2.15 (s, 3H), of 3.25 (s, 2H), of 3.7-3.9 (m, 4H), 4,35 is 4.45 (m, 1H), 4,7 (Avcv, 2H), 5,7 (s, 1H) 6.75 in (s, 1H), 6,95-of 7.55 (m, 11N)example

1
8410,75-0,9 (m, 6H), of 1.05 to 1.3 (m, SH), is 1.4-1.6 (m, 4H), of 2.15 (s, 3H), of 3.25 (s, 2H), of 3.7-3.9 (m, 4H), 3,3-3,4 (m, 1H), 4,7 (Avcv, 2H), 5,65 (s, 1H), 6,7 (s, 1H), 6,95-of 7.55 (m, 11H)example

1
8520,75-0,9 (m, 6H), of 1.05 to 1.3 (m, 8H), is 1.4-1.6 (m, 4H), of 3.25 (s, 3H), 3,6-3,9 (m, 6H), a 4.3 to 4.5 (m, 2H), 4,7 (Avcv, 2H), 5,65 (s, 1H), 6,7 (s, 1H), 6,95-7.5 (m, 11H)example

83
8630,75-0,9 (m, 6H), of 1.05 to 1.3 (m, 8H), is 1.4-1.6 (m, 4H), of 2.15 (s, 3H), of 3.25 (s, 2H), 3,6-3,9 (m, 6H), 4,35 to 4.5 (m, 2H), 4,7 (Avcv, 2H), 5,6 (s, 1H), 6,7 (s, 1H), 6,95-of 7.55 (m, 11N)example

83
8740,75-0,9 (m, 6H), of 1.05 to 1.3 (m, 8H), is 1.4-1.6 (m, 4H), 2,2 (d, 3H), 3,15-to 3.35 (m, 5H), 3,5-of 3.85 (4H), 4.4 to 4.5 (m, 1H), 4,6-4,7 (m, 2H), 5,6 (s, 1H), 6,7 (s, 1H), 6,95-of 7.55 (m, 11N)example

1
1The ratio of the eluent components equal to 55:45;

2Elution with a gradient;

3The ratio of the components of eluent is 50:50;

4The ratio of the components of eluent is 60:40.

Example 88

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzoyl)l-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-methoxycarbonylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 87; of 55.2 mg, 0,064 mmol) dissolved in THF (2 ml) and 0.5 ml of water. Add LiOH (3.1 mg, to 0.127 mmol) and the mixture is stirred for 1 hour. Add water (1 ml), the mixture is acidified with 0,1M HCl and extracted with DHM (3 x 2 ml). Phase DHM dried and concentrated. The solid product is evaporated in diethyl ether and dissolved in water (grade: pure HPLC). Lyophilization results specified in the title compound as white solid (28 mg, 68%). NMR 0,77-of 0.85 (m, 6H), 1,03-1,25 (m, 8H), 1,34-of 1.57 (m, 4H) of 2.16 (s, 3H), 3,18 (users, 2H), 3,75 (users, 2H)and 4.65 (Avcv, 2H), 5,7 (d, 1H), 6,63 (s, 1H), 7,0 (t, 1H), and 7.1 (d, 2H), 7,26-of 7.48 (m, 8H), the 7.85 (d, 1H); m/z 639.

Example 89

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-{(S)-α-[N'-(carboxymethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-{(S)-α-[N'(methoxycarbonylmethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 88; 19 mg, or 0.027 mmol) hydrolyzing with LiOH (1.3 mg, 0,054 mmol) in THF (1 ml) and water (0.3 ml). After 1 hour, add water (3 ml), the mixture is acidified using 0,1M HC1, and extracted with DHM (3 x 3 ml). The organic layer is dried and evaporated, receiving 16 mg (82%) specified in the connection header. NMR 0,77-of 0.85 (m, 6H), 1,0-1,3 (m, 8H), 1,34-of 1.57 (m, 4H), 2,17 (s, 3H), 3,18 (s, 2H), 3,75 (users, 2H), 3,90-4,20 (m, 2H)and 4.65 (Avcv, 2H), by 5.87 (m, 1H), 6,63 (s, 1H), 6,98 is 7.50 (m, 12H), 8,12-to 8.20 (m, 1H); m/z 696.

Example 90

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-{(S)-α-[N'-(2-sulfoethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin sodium salt

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 88; 41 mg, 0,064 mmol) dissolved in 3 ml DHM. Add tetrabutylammonium salt of taurine (70 mg, 0,191 mmol) and TBTU (25 mg, 0,078 mmol) and see what camping is stirred over night at room temperature. The solvent is evaporated and the product purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 45:55 to 55:45). Lyophilization of the collected fractions and then ion-exchange chromatography on 4 g of Amberlite CG-120 (form Na+) results specified in the title compound (42 mg, 85%). NMR of 0.7-0.8 (m, 6H), is 0.9-1.2 (m, 8H), 1.3 to 1.5 (m, 4H), 2,0 (s, 3H), 2,9-3,2 (m, 2H+2H), and 3.3 to 3.8 (m, 2H+2H), 4,4-4,7 (m, 2H), 5,6 (m, 1H), to 6.57 (s, 1H)and 6.9-7.5 (m, 11H), 7,8 and 8.1 (m, 2H); m/z 746.

Example 91

Below the connection receive in accordance with the method of example 90 from the appropriate starting compounds, but with the difference that the product was then purified using the buffer as eluent with a gradient from 40/60 to 70/30, and subsequent lyophilization results in ammonium salt.

Example

No.
ConnectionNMR (CD3OD) or m/zSource.

in-VA
910,76 is 0.84 (m, 6H), 1,03-of 1.27 (m, 8H), 1,38-of 1.55 (m, 4H), of 2.15 (s, 3H), 2.95 and (t, 2C), 3,24 (s, 2H), to 3.58 (dt, 2H), 3,75 (users, 2H), 3,85 (AVDD, 2H), 4.72 in (Avcv, 2H), 5,51 (s, 1H), 6,70 (s, 1H), 6,97 (t, 1H), 7,11 (d, 2H), 7,25-7,40 (m, 6H), 7,46 (d, 2H); m/z 803example

43

Example 92

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-[N-{(R)-α-[N'-(carboxymethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzol is azepin sodium salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin, sodium salt (WO 01/66533; 120 mg, 0,278 mmol)dissolved in DHM (4 ml)are added to a solution α-[N-(tert-butoxycarbonylmethyl)carbarnoyl]benzylamine (method 86; 90%, 150 mg, 0,511 mmol) in DHM (3 ml). Add 2,6-dimethylpyridin (65 ml, 0,559 mmol) and TBTU (137 mg, 0,427 mmol) and the reaction mixture was stirred at room temperature overnight. The solution is filtered through a column (eluent: DHM/EtOAc, 8:2). The solvent is evaporated. Add DHM (4 ml) and TFOC (0.6 ml) and the mixture is stirred over night. The solvent is evaporated and the crude product is purified preparative HPLC on a column filled with Chromasil C18as the mobile phase ispolzut a mixture of MeCN/ammonium acetate-ammonium buffer with a gradient from 50:50 to 100:0). MeCN is evaporated, and lyophilization results specified in the title compound (62 mg, 36%). NMR 0,73-of 0.82 (m, 6H), 1.00 and is 1.23 (m, 4H), 1.30 and of 1.65 (m, 4H), 3,05-3,18 (m, 2B), 3,65 (users, 2H), 3,75 (AVDD, 2H), 4,46 (Avcv, 2H), 5,70 (d, 1H), 6,79-of 7.24 (m, 10H), was 7.36 (d, 2H), 7,46 (d, 1H), 7,83 (d, 1H), 8,00 (users, IB); m/z 622.

Example 93-94

Below obtain the connection according to the method of example 92 from the appropriate starting compounds, but with the difference that HPLC carried out on a column filled with Chromasil C8(lilloana gradient: from 45/55 to 60/40).

Example

No.
ConnectionNMR (CD3OD) or m/zSource.

in-VA
93< / br>


Enantiomer 1
0,75-0,84 (m, 6H) 1,00-of 1.27 (m, 4H), 1,38-of 1.66 (m, 4H) to 2.15 (s, 3H), up 3.22 (s, 2H), 3,75 (users, 2H), 3,83 (AVDD, 2H), 4,69 (Avcv, 2H), ceiling of 5.60 (s, 1H), of 6.71 (s, 1H), of 6.96 (t, 1H), to 7.09 (d, 2H), 7.23 percent-7,37 (m, 5H), 7,39 (, 1H), 7,46 (d, 2H); m/z 668method

23;

method

86
94< / br>


Enantiomer 2
0,78-of 0.85 (m, 6H) 1,04-of 1.27 (m, 4H), 1.41 to of 1.65 (m, 4H) 2,17 (s, 3H), 3,24 (s, 2H), 3,68 (users, 2H), 3,89 (AVDD, 2H), 4.72 in (Avcv, 2H), 5,62 (s, 1H), 6.73 x (s, 1H), 6,97 (t, 1H), 7,11 (d, 2H), 7,26-7,38 (m, 5H), 7,41 (, 1H), of 7.48 (d, 2H); m/z 668method

24;

method

86

Example 95

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(ethoxy)(methyl)phosphoryl]ethyl}carbarnoyl)benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv.Chim.Acta; GE; 75; 8; 1992; 2545-2552; 16 mg, 0,106 mmol) in DHM (2 ml) at a temperature of 0°C in an atmosphere of argon added 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; 50 mg, 0,082 mmol), DIPEA (42 mg, 0,328 mmol) and TBTU (34 mg, 0,106 mmol). The reaction mixture was stirred at room temp is the temperature for 110 minutes then add DHM and the solution washed with NaHCO3(aq., the feast upon.) and a saturated solution of salt. The organic layer is dried and the solvent is evaporated under reduced pressure. The residue is purified by chromatography, elwira product mixture DHM/methanol (100:5). Obtain 43 mg (71%) specified in the connection header. NMR (500 MHz) 0,78-of 0.85 (m, 6 H), 1,02-and 1.54 (m, 12H), 1,6-1,75 (user., 1H), 1,8-2,10 (m, 3H), of 2.21 (s, 3H), 3,10-of 3.25 (m, 2H), 3,51-a-3.84 (m, 4 H), 3,9-to 3.99 (m, 1H), 4,01-4.09 to (m, 1H), 4,54-4,69 (DD, 2H), 5,51 (d, 1H), of 6.68 (s,1 H), of 6.96-7,02 (m, 1H), 7.03 is-to 7.18 (m, 3H), 7,25-7,42 (m, 6H), 7,43-of 7.48 (m, 2H), 8,05-of 8.15 (m, 1H).

Examples 96-97

Below obtain the connection according to the method of example 95, using an appropriate source materials.

Example

No.
ConnectionNMR and m/zSource.

in-VA
96from 0.76 to 0.85 (m, 6H), 1.00 and-of 1.52 (m, 12H), 1,55-1,75 (m, 1H), 1,95-2,12 (user., 1H), measuring 2.20 (s, 3H), 3,10-of 3.25 (m, 2H) 3,55-of 3.85 (m, 4H), 3,85-4,00 (m, 2H), 4,03 is 4.13 (m, 2H), 4,6 (kV, 2H), 5,64 (d, 1H), 6,66 (s, 1H), 7,78 (user., 1H), 6,95-7,10 (m, 3H), 7.23 percent-7,40 (m, 6H), 7,43-7,49 (m, 2H), 8,07 (d, 1H); m/z 760,3example

38
97(600 MHz) 0.75 to about 0.82 (m, 6H), 1,0-1,4 (m, 13H), 1,64 (users, 1H), 2,18 (s, 3H) is 3.08-3.24 in (m, 2H), 3,50-a-3.84 (m, 4H), a 3.87-4,13 (m, 2H), 4,54-and 4.68 (m, 2H), 5,56-5,62 (m, 1H), 6,63 (s, 1H), 6.87 in-7,10 (m, 3H), 7.24 to 7,40 (m, 7H), 7,43 7,49 (m, 2H), ,98-8,05 (m, 1H); m/z 730,5example

38

Example 98

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[{gdaxi)(methyl)phosphoryl]ethyl}carbarnoyl)benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(ethoxy)(methyl)phosphoryl]ethyl}carbarnoyl)benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 95; 27 mg, being 0.036 mmol) in ethanol (1.5 ml) at a temperature of 0°C is added 2 M aqueous NaOH solution (to 0.22 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for 24 hours. Add acetic acid (0.2 ml). The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. Layer DHM is separated, washed with saturated salt solution, dried and evaporated under reduced pressure. Recrystallization of the residue from a mixture of DGM/ether/petroleum ether yields a specified title compound (23 mg, 89%). (600 MHz) 0,74-of 0.82 (m, 6H), 1,0 is 1.70 (m, 11H), 1,90-of 2.09 (m, 2H), 2,16 (s, 3H), 3,05-3,24 (m, 2H), 3,40-of 3.85 (m, 4H), 4,50 with 4.65 (DD, 2H), of 5.55 (d, 1H), 6,63 (s, 1H), 6,93-7,07 (m, 3H), 7,20 is 7.50 (m, 9H), 8,10 (d, 1H); m/z 716,3.

Example 99

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[(hydroxy)(ethoxy)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-Dioxo-3-butyl-3-e of the Il-5-phenyl-7-methylthio-8-[ N-((R)-α-{N'-[(diethoxy)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-l,5-benzothiazepine (example 96; 13 mg of 0.017 mmol) in MeCN (0.5 ml) added dropwise 1 M aqueous LiOH solution (0,171 ml, 0,171 mmol). The reaction mixture was stirred at room temperature for 3 days. Add acetic acid and the solvent is evaporated under reduced pressure. The crude product is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 45:55), receiving specified in the header of the connection 11 mg (88%). NMR (600 MHz, CD3OD) of 0.77 is 0.84 (m, 6H), 1,00-1,30 (m, 7H), 1,40-of 1.65 (m, 4H), 2,17 (s, 3H), 3,23 (users, 2H), 3,51 (d, 2H), 3,6-of 3.85 (m, 4H), 4,70 (DD, 2H), to 5.57 (s, 1H), 6,72 (s, 1H), of 6.96 (t, 1H), to 7.09 (d, 2H), 7,25-7,31 (m, 3H), to 7.32 and 7.36 (m, 2H), 7,40 (s, 1H), 7,45 (d, 2H); m/z 732,4.

Example 100

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[(hydroxy)(methyl)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[(ethoxy)(methyl)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 97; 85 mg, 0.12 mmol) in MeCN (2.4 ml) at a temperature of 0°C added dropwise 1 M aqueous LiOH solution (1,17 ml of 1.17 mmol). The reaction mixture was stirred at room temperature for 20 hours. Add acetic acid and the solvent is evaporated under reduced pressure, the NII. The crude product is purified column chromatography (eluent: DHM/MeOH/Et3N; 100:15:0.2 and 100:30:0,2), getting mentioned in the title compound (62 mg, 76%). NMR (CD3OD) of 0.75 is 0.84 (m, 6H), 1,0 is 1.70 (m, 11H), of 2.15 (s, 3H), 3,22 (users, 2H), 3,35 (d, 2H), 3,60-3,90 (m, 2H), 4,70 (DD, 2H), 3,55 (s, 1H), of 6.71 (s, 1H), of 6.96 (t, 1 H), to 7.09 (d, 2H), 7.23 percent-7,38 (m, 5H), 7,40 (s, 1H), 7,46 (d, 2H); m/z 702,3

Example 101

Below obtain the connection according to the method of example 100 using the appropriate source materials.

Example

No.
ConnectionNMR (600 MHz, (CD3OD) and m/zSource.

in-VA
1010,76-of 0.83 (m, 6H), of 1.05 to 1.55 (m, 15H), 1,91 of 1.99 (m, 2H), of 2.15 (s, 3H), 3,24 (users, 2H), 3,40-to 3.50 (m, 2H), 3,66-3,86 (m, 2H), 4,69 (DD, 2H), 5,42 (s, 1H), 6,70 (s, 1H), 6,92 (t, 1H), 7,11 (d, 2H), 7,25-7,39 (m, 6H), the 7.43 (d, 2H); m/z 744,3example

104

Example 102

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[di-(tert-butoxy)l}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; 80 mg, 0,131 mmol) and di(tert-butoxy)phosphorylethanolamine (Tet. Lett.; EN; 33; 1; 1992; 77-80; 37 mg, 0,164 mmol) in DHM (5 m is added 2,6-lutidine (28 mg, 0,262 mmol) and TBTU (53 mg, 0,164 mmol). The reaction mixture was stirred at room temperature for 2 hours and 50 minutes. The solvent is evaporated under reduced pressure and the crude product is purified column chromatography (eluent: DHM/MeOH, 100:4), getting mentioned in the title compound (92 mg, 86%). NMR (500 MHz) of 0.77 is 0.86 (m, 6H), 1,03 is 1.75 (m, 26H), 2,22 (s, 3H), 2,10-of 2.25 (m, 2H), 3,45-3,90 (m, 4H), br4.61 (DD, 2H), 5,52 (d, 1H), 5,94 (users, 1H), to 6.67 (s, 1H), 7,0 (t, 1H), 7,07 (d, 2H), 7,26-of 7.48 (m, 8H), 8,12 (d, 1H); m/z 704,22 [M-2(tert-butyl)+2H].

Example 103

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[di(hydroxy)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N'-[di-(tert-butoxy)phosphorylmethyl]carbarnoyl}benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 102; 72 mg, 0,088 mmol) in DHM (4 ml) at a temperature of 0°C add TFOC (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. The organic layer is separated, washed with saturated salt solution, dried and evaporated under reduced pressure. The residue is suspended in ether and the crystals are filtered, getting mentioned in the title compound (60 mg, 97%). NMR (500 MHz, DMSO-d6) 0,70-0,80 (m, 6H), 0,99-to 1.61 (m, 8H), to 2.18 (s, 3H), 2,80 to 4.0 (m, 6H), 4,80 (DD, 2H), 5,65 (d, 1H), of 6.71 (s, 1H), 6,80-7,02 (m, 3H), 7,15-7,35 (m, 6H), of 7.48 (d, 2H), 8,50-9,20 (m, 2H); m/z 704,3

Example 104

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbarnoyl)benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-l'-phenyl-l'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 1; 60 mg, 0,094 mmol) and 2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 20 mg, 0,132 mmol) at a temperature of 0°C in argon atmosphere added 2,6-lutidine (20 mg, 0,19 mmol) and TBTU (39 mg, 0,121 mmol). The reaction mixture was stirred at room temperature for 70 minutes, then add DHM and the solution washed with water and saturated salt solution. The organic layer is dried and the solvent is evaporated under reduced pressure. The residue is purified column chromatography (eluent: DHM/MeOH, 100:5), receiving specified in the title compound (67 mg, 92%). NMR (300 MHz) 0,74-86 (m, 6H), from 1.0 to 1.60 (m, 18H), 1,80-2,05 (m, 2H), measuring 2.20 (s, 3H), 2,17 (s, 2H), 3,47-of 3.80 (m, 4H), 3,8S-4,10 (DD, 2H), 5,52 (d, 1H), 6,65 (s, 1H), 6,95 for 7.12 (m, 3H), 7,13-7,42 (m, 7H), 7,43-7,49 (m, 2H), 8,05-8,16 (m, 1H); m/z 772,4.

Example 105

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-mercapto-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-Deeb the Il-5-phenyl-7-methylthio-8-[ N-((R)-α-{N'-[2-(triphenylmethyl)-1-(tert-butoxycarbonyl)ethyl]carbarnoyl}bsil)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 91; 37 mg, being 0.036 mmol) in DHM (1 ml) in an argon atmosphere was added when the temperature 0°C add TFOC (1 ml). The ice bath is removed and add triethylsilane (42 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 2 hours and then the solvent is evaporated under reduced pressure. The crude product is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 40:60 to 60:40), receiving specified in the title compound (16 mg, 59%). NMR (500 MHz, CD3OD) from 0.76 to 0.85 (m, 6H), of 1.05 to 1.60 (m, 12H), 2,17 (s, 3H), 2.77-to of 2.92 (m, 2H), 3,24 (users, 2H), 3,61-3,88 (m, 2H), 4,56 (t, 1H), 4,70 (DD, 2H), 5,65 (s, 1H), of 6.71 (s, 1H), 6,98 (t, 1H), 7,12 (d, 2H), 7,25-the 7.43 (m, 6H), to 7.50 (d, 2H); m/z 742,4.

Example 106

The connection shown below are in accordance with the method of example 105, using an appropriate source materials.

Example

No.
ConnectionNMR (500 MHz, CD3OD) and m/zSource.

in-VA
1060,77-of 0.85 (m, 6H), 1,03 of 1.28 (m, 8H), 1,38 is 1.58 (m, 4H), of 2.15 (s, 3H), 2,87-3,5 (m, 2H), 3,25 (s, 2H), 3,75 (users, 2H), 4,55 (s, 1H), 4,71 (DD, 2H), to 5.66 (s, 1H), of 6.71 (s, 1H), 6,98 (t, 1H), 7,12 (d, 2H), 7,25-the 7.43 (m, 6H), 7,49 (d,2H); m/z 742,28method

93

Example 107

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(carboxy)benzyl]carbarnoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(tert-butoxycarbonyl)benzyl]carbarnoyl}aoxi)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 90; 77 mg, to 0.108 mmol) in DHM (3 ml) at a temperature of 0°C add TFOC (0.75 ml). The reaction mixture was stirred at room temperature for 2 hours and 45 minutes. The solvent is evaporated under reduced pressure and the crude product is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 40:60 to 50:50), receiving specified in the title compound (60 mg, 82%). NMR (500MHz, CD3OD) of 0.75 to 0.85 (m, 6H), 1,0-1,25 (m, 4H), 1,40-of 1.64 (m, 4H), of 2,75 2,90 (m, 2H), 3,26 (s, 2H), 3,50-3,90 (m, 2H), 4,30-to 4.41 (m, 2H), 5,43 (s, 1H), 6,99 (t, 1H), 7,05-7,13 (m, 3H), 7.23 percent-7,34 (m, 5H), was 7.45 (d, 2H), 7,52 (s, 1H); m/z 658.

Example 108

The connection shown below are in accordance with the method of example 107 using the appropriate source materials.

Example

No.
ConnectionNMR (500 MHz, CD3OD) and m/zSource.

in-VA
1080,78-of 0.85 (m, 6H), 1,02-of 1.30 (m, 8H), 1,38 is 1.58 (m, 4H), to 1.87 (s, 3H), 2,15 (who, 3H), 2.77-to and 2.83 (m, 1H), 2,87-to 2.94 (m, 1H), 3,24 (s, 2H), 3,74 (users, 2H), 4.53-in-4,59 (m, 1H), and 4.68 (DD, 2H), to 5.66 (s, 1H), of 6.71 (s, 1H), 6,98 (t, 1H), 7,12 (d, 2H), 7,25-7,31 (m, 3H), to 7.32 and 7.36 (m, 2H), 7,40 (, 1H), 7,49 (d, 2H); m/z 756,23method

92

Example 109

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbarnoyl)-4-hydroxybenzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 2; 80 mg, 0,122 mmol) and 2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv. Chim. Acta; GE; 75; 8; 1992; 2545-2552; 24 mg strength of 0.159 mmol) in DHM (2 ml) under argon atmosphere added 2,6-lutidine (26 mg, 0,244 mmol) and TBTU (51 mg, strength of 0.159 mmol). The reaction mixture was stirred at room temperature for 60 minutes, then diluted DHM. The solution is washed with water, saturated salt solution, dried and the solvent is evaporated under reduced pressure. The residue is purified column chromatography (eluent: DHM/MeOH; 100:7), receiving specified in the title compound (67 mg, 92%). NMR (600 MHz), 0,74 is 0.80 (m, 6H), from 1.0 to 1.55 (m, 18H), 1,82-1-98 (m, 2H), of 2.15 (s, 3H), 3,14 (users, 2H), 3,40 of 3.56 (m, 2H), 3,70 (users, 2H), 3,89-was 4.02 (m, 2H), 4,51 (DD, 2H), 5,33 (t, 1H), is 6.61 (s, 1H), 6,65-6,72 (m, 2H,), to 6.95 (t, 1H), 7,03 (d, 2H), 7,12-7,19 (m, 3H), 7,22-7,26 (m, 2H), 7,32 (s, 1H), 8,11 (t, 1H); m/z 788,56.

Example 110

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-2-[(methyl)(hydroxy)phosphoryl]ethyl}carbarnoyl)-4-hydroxy-benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbarnoyl)-4-hydroxybenzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 104; 37 mg, 0,047 mmol) in a mixture of MeCN/MeOH (4 ml, 1:1) was added 1 M aqueous LiOH solution (0.8 ml, 0.8 mmol). The reaction mixture was stirred at room temperature for 40 minutes. Add acetic acid and the solvent is evaporated under reduced pressure. The crude product is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer, 40:60 to 45:55), receiving specified in the title compound (35 mg, 96%). NMR (500 MHz, CD3OD) 0,78-of 0.85 (m, 6H), 1,06 of 1.28 (m, 11H), 1,39-of 1.57 (m, 4H), 1,72-of 1.85 (m, 2H), 2,16 (s, 3H), 2,24 (s, 2H), 3,40-to 3.50 (m, 2H), 3,65-a-3.84 (m, 2H), 4,69 (DD, 2H), are 5.36 (s, 1H), of 6.71 (s, 1H), 6,76 (d, 2H), 6,99 (t, 1H), 7,13 (d, 2H), 7,22-7,33 (m, 4H), 7,39 (s, 1H); m/z 760,27

Example 111

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N'-(2-methylsulfinyl-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound isolated as a side product of the synthesis of example 108. NMR (500 MHz, CD3OD) 0,78-of 0.85 (m, 6H), 1,02-to 1.60 (m, 12H), of 2.16 (d, 3H), 2,53 (d, 3H), is 3.08-3,18 (m, 1H), 3,24 (s, 2H), 3,35 (v user., 1H), 3,75 (v user., 2H), 4,62 (v user., 1H), 4,71 (DD, 2H), ceiling of 5.60 (d, 1H), 7,71 (s, 1H), 6,98 (t, 1H), 7,12 (d, 2H), 7,25-7,42 (m, 6H), 7,47 (d, 2H); m/z 772,25.

Example 112

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N'To(3-m is tilty-2-carboxypropyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N'-(3-methylthio-2-methoxycarbonylpropionyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 94; 68 mg, 0,087 mmol) in ethanol (5 ml) is added NaOH (9 mg in 0.4 ml of water) at a temperature of 0°C. the Reaction mixture was stirred at room temperature for 2.5 hours. Add acetic acid and the solvent is evaporated under reduced pressure. The crude product is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 40:60 to 60:40), receiving specified in the title compound (52 mg, 76%). NMR (500 MHz, CD3OD) 0,79 is 0.86 (m, 6H), 1,05-of 1.29 (m, 8H), 1,40 is 1.58 (m, 4H), 1,84-of 1.93 (m, 4H), 2,01-of 2.21 (m, 5H), 2.26 and-of 2.34 (m, 1H), 3,26 (s, 2H), 3,76 (users, 2H), to 4.52-4,58 (m, 1H), 4,70 (DD, 2H), 5,61 (s, 1H) 6.73 x (s, 1H), 7,0 (t, 1H), 7,14 (d, 2H), 7,27-the 7.43 (m, 6H), 7,49 (d, 2H); m/z 770,16.

Example 113

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N'-(2-methylthio-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N'-(2-mercapto-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 106; 15 mg, 0.02 mmol) in methanol (1.5 ml) in an atmosphere of nitrogen was added sodium methoxide (in 0.104 mmol of 0.14 ml of methanol) and methyliodide (0.16 mmol). The reaction mixture was stirred at the room for the Noah temperature for 50 minutes. Add acetic acid. The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. The organic layer is separated, washed with saturated salt solution, dried and evaporated under reduced pressure, obtaining mentioned in the title compound (4 mg, 26%). NMR (500 MHz, CD3OD) of 0.75-8,30 (m, 6H), 1,03-of 1.57 (m, 12H), 2,10 (s, 3H), 2,17 (s, 3H), 2,83-of 2.30 (m, 1H), from 3.0 to 3.25 (m, 1H), 3,26 (s, 2H), of 3.77 (users, 2H), 4,58-4,63 (m, 1H), 4.72 in (DD, 2H), 5,64 (s, 1H), 6,72 (s, 1H), 7,0 (t, 1H), 7,12 (d, 2H), 7,28-7,52 (m, 8H); m/z 756,25.

Example 114

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-[N-{(R)-α-[N'-(carboxymethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-[N-{(R)-α-[N'-(tert-butoxycarbonylmethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 102; 129 mg, 0,164 mmol) in DHM (5 ml) in nitrogen atmosphere at a temperature of 0°C add TFOC (1.5 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the crude product is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer, from 40:60 to 50:50), receiving specified in the title compound (77 mg, 63%). NMR (500 MHz, CD3OD) is 0.84 (t, 6H), 1,10-1,22 (m, 8H), 1,35-1,45 (m, 4H), of 2.34 (s, 3H), 3,19-of 3.27 (m, 2H), 3,55 (s, 2H), a 3.87 (DD, 2H), 4,67 (DD, 2H), 5,61 (s, 1H), 7,09-to 7.15 (m, 3H), 7,7-7,37 (m, 6H), 7,47 (d, 2H); m/z 748,03 (M+NH3).

Example 115

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-[N-{(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 118; 0,050 g, 0,105 mmol) in DMF (4 ml) is added 2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}econsultancy acid (method 80; 0.037 g, is 0.135 mmol) andN-methylmorpholin (0,040 ml, 0,363 mmol). The mixture is stirred for 10 minutes and then added TBTU (0,044 g, 0,137 mmol). The reaction mixture is stirred for two days, after which the solvent is removed under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer), receiving specified in the header connection (0,042 g, 55 %) as a white solid. NMR (DMSO-d6) 0,60-0,80 (m, 6H), of 1.05 to 1.50 (m, SH), of 2.15 (s, 3H), 2,45 is 2.55 (m, 2H), 3,05-of 3.80 (m, 6H), 4,70 (Rth, 1H), 4,80 (Rth, 1H), 5.25 in (d, 1H), 6,65 to 6.75 (m, 3H), 6,80-7,05 (m, 3H), 7,10-7,25 (m, 4H), 7,30 (s, 1H), 8,20-8,30 (m, 1H), 8,45 (d, 1H).

Example 116

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-[N-{(R)-α-[N'-(carboxymethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 118; 0,050 g, 0,105 mmol) vdhm (4 ml) is added (R)-α -[N-(tert-butoxycarbonylmethyl)carbarnoyl]benzylamine (method 86; 0.036 g, 0.136 mmol) andN-methylmorpholin (0,040 ml, 0,363 mmol). The mixture is stirred for 5 minutes and then added TBTU (0,044 g, 0,137 mmol). The reaction mixture is stirred for two days, then add TFOC (1.5 ml). After 1.5 hours, the solution was diluted with toluene, and then the solvent is removed under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer), receiving specified in the header connection (0,020 g, 29 %) as a white solid. NMR (DMSO-d6) 0,60-0,80 (m, 6H), of 1.05 to 1.50 (m, 8H), of 2.15 (s, 3H), 3,10-of 3.80 (m, 6H), 4,70 (Rth, 1H), 4,85 (Rth, 1H), ceiling of 5.60 (d, 1H), 6,70 (s, 1H), 6,80-7,05 (m, 3H), 7,15-to 7.50 (m, 8H), 8,35 (users, 1H), 8,55 (d, 1H).

Example 117

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-[N-{(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 6; 0,020 g, 4,h-5mol) in DMF (4 ml) is added 2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}absoltuley acid (method 80; 0,014 g, 5,10 x 10-5mol) andN-methylmorpholin (0,020 ml, 1,h-4mol). The mixture is stirred for 10 minutes and then added TBTU (0,016 g, 4,h-5mol). The reaction mixture is stirred for 3 hours and then the solvent daring is t under reduced pressure. The residue is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer), receiving specified in the header connection (0,023 g, 75 %) as a white solid. NMR (500 MHz, DMSO-d6) 0,65-0,80 (m, 6H), 0,80-1,50 (m, 12H), 2,40-2,60 (m, 2H), 3.15 and is-3.45 (m, 4H), of 3.60 (s, 3H), 3,65 (users, 2H), 4,60 (Rth, 1H), 4,70 (Rth, 1H), 5.25 in (d, 1H), 6,50 (s, 1H), 6,70-7,25 (m, 10H), 7,35 (s, 1H), 8,20-8,30 (m, 1H), and 8.50 (d, 1H), 9,40 (users, 1H).

Example 118

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-[N-{(R)-α-[N'-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 115; 0,020 g, 4,h-5mol) in DMF (4 ml) is added 2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}econsultancy acid (method 80; 0,017 g, 6,20x10-5mol) andN-methylmorpholin (0,016 ml, 1,h-4mol). The mixture is stirred for 10 minutes and then added TBTU (0,019 g, 5,h-5mol). The reaction mixture is stirred overnight and then the solvent is removed under reduced pressure. The residue is purified preparative HPLC (eluent: a mixture of MeCN/ammonium acetate-ammonium buffer), getting mentioned in the title compound (0.008 g, 24 %) as a white solid. NMR (500 MHz, DMSO-d6) 0,65-0,80 (m, 6H), 0,80-1,60 (m, 8H), 2.40 a is 2.55 (m, 2H), 3,20-3,40 (m, 4H), 3,65 (users, 2H)and 4.65 (Rth, 1H), 4,70 (Rth, 1H), 5.25 in (d, 1H), 6,65 was 7.45 (m, 13H), 8,20-8,30 (m, 1H), at 8.60 (d, 1H), 9,40 (users, 1H).

Example 119

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-[N-(α-(R)-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound synthesized from 1,1-dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-[N-(α-(R)-l)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 45) in accordance with methods method 109. NMR (CD3OD) 0,81 (ushort, 6H), of 1.03 to 1.3 (m, 8H), 1.32 to to 1.59 (m, 13H), 3,24 (users, 2H), 3,57-of 3.77 (m, 2H), br4.61 (users, 2H), 5,51 (s, 1H), 6,83 (d, 1H), between 7.0 and 7.1 (m, 3H), 7,26-the 7.43 (m, 7H), 7,49 (d, 1H); m/z 708,5.

Example 120

1,1-Dioxo-3,3-dibutil-5-[4-(N'-tert-butylurea)phenyl]-8-[N-(α-(R)-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-(N'-tert-butylurea)phenyl)-8-[N-(α-(R)-l)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 111; 30 mg, 0,042 mmol) dissolved in THF (1.5 ml), H2O (0.5 ml) and added LiOH (42 mg, 0,064 mmol, monohydrate) are added. The mixture is stirred for 2 hours. The product was then purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5:95 to 100:0), getting mentioned in the title compound (24 mg, 82%). NMR (CD3OD) 0,81 (ushort, 6H), 1,05-of 1.26 (m, 8H), of 1.35 (s, 9H), 1,38-of 1.57 (m, 4H), 3,25 (users, 2H), 3,6-of 3.77 (m, 2H), br4.61 (Avcv, 2H), of 5.45 (s, 1H), at 6.84 (d, 1H), 7,01-7,11 (m, 3H), from 7.24 (d, 2H), 7,26-7,37 (m, 3H), 7,37-7,42 (m 2H), to 7.50 (d, 1H); m/z 707,5.

Obtain the original substance

Source materials for the examples described above, are either commercially available or can be easily obtained by standard methods from known materials. The following reactions are illustration, but not limitation, some of the original substances, used in the above reactions.

Method 1

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1'-(etoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0,300 g, 0,663 mmol) in MeCN (10 ml) is added sodium carbonate (0,30 g, and 2.83 mmol), ethyl ester 2-bromopropane acid (0,145 g coefficient was 0.796 mmol) and tetrabutylammonium bromide (0,022 g, 0.07 mmol). The suspension is refluxed over night. The solvent is evaporated and the crude mixture was extracted (DHM/H20), dried (MgSO4), evaporated and purified flash chromatography (hexane:EtOAc to 5:1), obtaining specified in the header connection (0,346 g, 95 %) as a white solid. NMR 0,70-0,85 (m, 6H), 1.00 and is 1.75 (m, 8H), of 1.35 (t, 3H), of 1.70 (d, 3H), 3,05-of 3.25 (m, 2H), 3,55-3,90 (m, 2H), 4,20 is 4.35 (m, 2H), 4,80 (kV, 1H), 7,00-7,10 (m, 3H), 7,15 (s, 1H), 7,25-7,35 (m, 2H), 7,45 (s, 1H).

Method 2

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1'-carboxymethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-d is oxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1-(etoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 1; 0,050 g 0,090 mmol) in EtOH (4 ml, 95 %) is added sodium hydroxide (0,045 g, 1.13 mmol) and the resulting mixture is refluxed for 1.5 hours. Add AcOH (0.2 ml) and most of the solvent is removed under reduced pressure. The crude product is extracted (DHM/H20), dried (MgSO4) and evaporated, getting mentioned in the title compound (0,031 g, 65 %) as a white solid. NMR (500 MHz, CD3OD) 0,70-0,85 (m, 6H), 0.95 to-1,25 (m, 4H), 1,35 is 1.70 (m, 4H), to 2.65 (d, 3H), 3,10-to 3.35 (m, 2H), 3,45-3,95 (m, 2H), 4,70 (kV, 1H), 6.90 to-7,35 (m, 6H), was 7.45 (s, 1H).

Method 3

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1'-phenyl-1'-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0,200 g, 0,442 mmol) in MeCN (6 ml) is added ethyl α-bromophenylacetate (0,139 g), Na2CO3(0,200 g) and tetrabutylammonium bromide (0,034 g). The suspension is refluxed overnight, then the solvent is removed under reduced pressure. The crude product is extracted (DHM/H20) and purified flash chromatography (hexane:EtOAc-5:l) receiving specified in the header connection (0,256 g, 94 %) as a white solid. NMR 0,65-0,85 (m, 6H), 0,95-of 1.65 (m, 8H), 3.00 and is 3.15 (m, 2H), 3,50-of 3.80 (m, 2H), 3,70-of 3.80 (2s, 3H), ceiling of 5.60 (s, 1H), 5,65 (d, 1H) 7,00-of 7.60 (m, 17H), 8,05-8,20 (2D, 1H).

Method 4

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1'-phenyl-1'-carbox is methoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1'-phenyl-1'-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 3; 0,244 g, 0,397 mmol) in a mixture of THF/H2O (2/1, 3 ml) is added lithium hydroxide (0,019 g). After 2 days the solvent is removed under reduced pressure and the crude mixture purified HPLC, getting mentioned in the title compound (0,215 g,92 %) as a white solid. NMR (CD3OD) 0,60-0,80 (m, 6H), 0,90-1,25 (m, 4H), 1,30-1,60 (m, 4H), 3,05-3,30 (m, 2H), 3,40-3,90 (m, 2H), of 5.55 (s, 1H), 6,85-of 7.70 (m, 12H).

Method 5

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesized in accordance with the method of publication W09616051 for the corresponding 3-butyl-3-ethyl analogue; 0.400 g, 0,927 mmol) in MeCN (10 ml) add ethylbromoacetate (0,13 ml), Na2CO3(0.40 g) and tetrabutylammonium bromide (0,030 g). The suspension is refluxed overnight, then the greater part of the solvent is removed under reduced pressure. The crude product is extracted (DHM/H2O) and filtered through a column of small height with silicon dioxide (DHM:EtOAc to 1:4), receiving specified in the header connection (0,476 g, 99 %). NMR 0,65-0,85 (m, 6H), 0,95-of 1.65 (m, 8H), 3.00 and is 3.15 (m, 2H), 3,50-of 3.80 (m, 2H), 3,70-of 3.80 (s, 3H), ceiling of 5.60 (s, 1H), 5,65 (d, 1H) 7,00-of 7.60 (m, 17H), 8,05-to 8.20 (d, 1H).

M is TOD 6

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 5; 0,448 g, 0,865 mmol) in a mixture of THF/H2O (2/1, 6 ml) is added lithium hydroxide (0,062 g). After 1 hour add AcOH (0.5 ml), add and most of the solvent is removed under reduced pressure. The crude product is purified HPLC (MeCN), receiving specified in the header connection (0,408 g, 96 %) as a white solid. NMR (CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), the 3.65 (s, 3H), 3,70 (users, 2H), 4,50 (s, 2H), 6,50 (s, 1H), 6.90 to-7,30 (m, 5H), 7,40 (s, 1H).

Method 7

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (WO 9616051; 1.0 g), ethylbromoacetate (0.50 g), sodium carbonate (1.2 g) and tetrabutylammonium bromide (60 mg) in MeCN (15 ml) is refluxed overnight. The solvent is removed under reduced pressure and the residue extracted (DHM/H2O). The organic layer is separated and the solvent is removed under reduced pressure. The residue is purified by chromatography (DHM/EtOAc, 90:10), receiving specified in the title compound (1.2 g, 98%). NMR (CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), the 3.65 (s, 3H), 3,70 (users 2H) 4,50 (s, 2H), 6,50 (s, 1H), 6.90 to-7,30 (m, 5H), 7,40 (s, 1H).

Method 8

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

A mixture of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0.3 g), ethylbromoacetate (0.14 g), sodium carbonate (0.3 g), tetrabutylammonium bromide (0.02 g) in MeCN (10 ml) is refluxed for 4 hours. The solvent is removed under reduced pressure. The residue is partitioned between DHM/H2O and the organic layer separated. The solvent is evaporated and the residue purified by chromatography (DHM/EtOAc, 90:10), receiving specified in the title compound (0.34 g, 95%). NMR (500 MHz) of 0.7-0.9 (m, 6H), of 1.0 to 1.8 (m, 11H), 3,2 (m, 2H), 3,6-3,8 (users, 2H), 4,3 (kV, 2H), 4,7 (s, 2H), between 7.0 and 7.1 (m, 3H), 7,15 (s, 1H), and 7.3 (m, 2H), and 7.4 (s, 1H).

Method 9

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 8; 0.34 g) and sodium hydroxide (0.3 g) is dissolved in ethanol and the mixture refluxed for 1 hour. Add acetic acid (1 ml) and the solvent is removed under reduced pressure. The residue is partitioned between DHM/H2O and the organic layer separated and dried. Rubbing the residue with n-hexane results specified in the header connect the deposits (0.29 grams, 90%) as a solid. NMR (500 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.7 (m, 8H), 3,1-3,2 (m, 2H), 3,6 (users, 2H), 4,6 (s, 2H), 6,9-7,1 (m, 4H), 7,2 (m, 2H), and 7.5 (s, 1H).

Method 10

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 7; 1.2 g) dissolved in ethanol (20 ml). To the resulting solution was added sodium hydroxide (0.5 g)dissolved in H2O (1 ml), the reaction mixture is heated to 40°C and kept at this temperature for 30 minutes. Add acetic acid (1 ml) and the solvent is removed under reduced pressure. The residue is partitioned between DHM/H2O and the organic layer separated and dried. Rubbing the residue with n-hexane results specified in the title compound (1.1 g, 97%) as a solid. NMR 0,75-0,85 (m, 3H), and 0.9 (t, 3H), of 1.0 to 1.7 (m, 8H), and 3.2 (q, 2H), the 3.65 (s, 3H), 3,65-of 3.85 (m, 2H), 4,7 (s, 2H), 6,4 (s, 1H), 7,0 (t, 1H), and 7.1 (d, 2H), and 7.3 (t, 2H), and 7.5 (s, 1H).

Method 11

1,1-Dioxo-3,3-dibutil-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (synthesized in accordance with the method of publication W09616051 for the corresponding 3-butyl-3-ethyl analogue; 2.0 g, 4,16 mmol), ethylbromoacetate (0.84 g, of 5.03 mmol), sodium carbonate (2,0 is, 189 mmol) and tetrabutylammonium bromide (80 mg, 0.25 mmol) are added to MeCN (20 ml). The mixture is refluxed for 2 hours and then evaporated under reduced pressure. The residue is extracted with a mixture of DGM/water. Layer DHM separated and evaporated under reduced pressure. The residue is purified column chromatography. Product elute with a mixture DHM/EtOAc (90:10), receiving specified in the title compound (2.2 g, 93%). NMR of 0.7-0.8 (m, 6H), 1,0-1,6 (m, 15H), 3,2 (users, 2H), 3,7 (users, 2H), 4,3 (kV, 2H), 4,7 (s, 2H), 7,0-to 7.3 (m, 6H), and 7.4 (s, 1H).

Methods 12-13

The compounds below are synthesized in accordance with methods method 11 using the appropriate acid and amine (when the substance is commercially available, source not specified).

Method

No.
ConnectionM/zSource.

in-VA
12< / br>


Enantiomer 1
538method

83
13< / br>


Enantiomer 2
538method

84

Method 14

1,1-Dioxo-3,3-dibutil-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,,5-tetrahydro-1,5-benzothiazepine (method 11; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). To the resulting solution was added NaOH (0.8 g in 1.5 ml water) and the mixture is stirred for 30 minutes at room temperature. Add acetic acid (2 ml). The solvent is evaporated under reduced pressure and the residue extracted with a mixture of EtOAc/water. The EtOAc layer is separated, dried and evaporated under reduced pressure, obtaining mentioned in the title compound (2.0 g, 95%). NMR (500 MHz) of 0.7-0.8 (m, 6N), 1.0 to 1.5 (m, 12H), 3,2 (users, 2H), 3,7 (users, 2H), 4,7 (s, 2H), 7,0-to 7.3 (m, 6H), and 7.4 (s, 1H).

Method 15

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropoxy-8 carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

Isopropyl alcohol (12 ml) is added sodium (115 mg, 5 mmol), then the temperature increases to 80°C and forms a salt form of alcohol. After all the sodium has dissolved, one portion add 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 9; 100 mg, 0.2 mmol). After that the reaction mixture is refluxed overnight, then cooled to room temperature and quenched with acetic acid. The solvent is then removed under reduced pressure and the residue is dissolved in a mixture of water and MeCN (70/30) and partially purified HPLC. The residue is dissolved in ethylene glycol and add NaOH (500 mg). The resulting reaction mixture is heated to 125°C and maintained at the same temperature during the night, then cooled to room temperature, quenched with acetic acid and add EtOAc (100 ml). The ethylene glycol is removed by washing the organic layer acidified water three times. The organic layer is then concentrated and the residue is again cleaned, as described above, receiving specified in the title compound (40 mg, 41 %). NMR (300 MHz) of 0.7-1.0 (m, 6H), of 1.0 to 1.8 (m, 15H), and 3.2 (q, 2H, in), 3.75 (m, 2H), 4,3 (m, 1H), 4,6 (s, 2H), 6.35mm (s, 1H), 6,95 to 7.2 (m, 3H), 7,2-7,4 (m, 2H), 7,55 (s, 1H).

Method 16

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 25; 500 mg, 1.2 mmol) is added MeCN (30 ml), tetrabutylammonium bromide (30 mg, 0.08 mmol), anhydrous sodium carbonate (500 mg, 4.7 mmol), ethylbromoacetate (0,14 ml of 1.26 mmol) and cesium carbonate (20 mg, 0.06 mmol). The reaction mixture is then stirred overnight at a temperature of 80°C. Then the solvent is removed under reduced pressure, water is added and DHM and the aqueous phase is extracted three times DHM. The combined organic phases are then dried, concentrated and purified flash chromatography [DHM/EtOAc; 1:0, 9:1], getting listed in the title compound (600 mg, 99%). NMR (300 MHz) of 0.8-1.0 (m, 6H), of 1.0 to 1.8 (m, 11H), 2,2 (s, 3H), 3,2 (kV, 2H) 3,75 (userc, 2H), 4,3 (kV, 2H), and 4.75 (s, 1H), 6,7 (s, 1H), 6,95 (t, 1H), 7,05 (d, 2H), 7,25 (m, 2H), and 7.3 (s, 1H).

Method 17

1,1-di the CSR-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 16; 478 mg, 0.95 mmol) is added THF (15 ml), water (3 ml) and LiOH (34 mg, 1.4 mmol). After that the reaction mixture is stirred for 1 hour, then add acetic acid (0.2 ml), water (10 ml) and DHM (10 ml). The aqueous layer was extracted three times DHM. The combined organic phases are dried and concentrated, obtaining mentioned in the title compound (450 mg, 99%). NMR of 0.7-0.9 (m, 6H), of 1.0 to 1.7 (m, 8H), 2,2 (s, 3H), 3,2 (kV, 2H), and 3.7 (m, 2H), and 4.8 (s, 2H), 6,65 (s, 1H), 6,95 (t, 1H), 7,05 (d, 2H), 7,25 (m, 2H), 7,35 (s, 1H), 8.4V (users, 1H).

Method 18-19

The compounds below are synthesized in accordance with methods Method 17, using the appropriate acid and amine (when connections are commercially available, source not specified), with the difference that use two equivalent of LiOH and extraction is carried out using EtOH after 2 hours of reaction.

Method

No.
ConnectionM/zSource.

in-VA
18< / br>


Enantiomer 1
510method

12
19< / br>


Enantiomer 2
510method

13/td>

Method 20

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8 ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 16; 122 mg, 0.24 mmol) is added DHM (3 ml), water (3 ml) and potassium carbonate (120 mg, 0.87 mmol). The reaction mixture was cooled to 0°C and one portion add m-chloroperoxybenzoic acid (160 mg, 0.51 mmol). After 5 hours the reaction is quenched by adding DHM and a saturated solution of sodium bicarbonate. The aqueous phase is extracted three times DHM. The combined organic phases are dried, concentrated and purified flash chromatography [DHM/EtOAc, 9:1], getting mentioned in the title compound (46 mg, 35%). NMR of 0.7-0.8 (m, 6H), 1,0-of 1.65 (m, 11N), and 3.2 (q, 2H), and 3.3 (s, 3H), 3,7 (users, 1H), 4,25 (kV, 2H), and 4.8 (s, 2H), between 7.0 and 7.1 (m, 3H), 7,2-7,3 (m, 2H), 7,5 (s, 2H).

Method 21

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8 carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8 ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 20; 46 mg of 0.085 mmol) is added THF (5 ml), water (1 ml) and LiOH (10 mg, 0.4 mmol). The reaction mixture is stirred for 1 hour and then the reaction quenched with excess acetic acid. Add water and DHM, and the aqueous phase is extracted three times DHM. The combined organic phases are dried and concentrated, the floor is th specified in the title compound (40 mg, 91%). NMR 0,7-0,85 (m, 6H), of 1.0 to 1.7 (m, 8H), 3,2 (m, 2H), and 3.3 (s, 3H), and 3.8 (s, 2H), 4,9 (s, 2H), 5,0 (users, 1H), 7,05-to 7.15 (m, 3H), 7.3 to 7.4 (t, 2H), and 7.5 (s, 1H), and 7.6 (s, 1H).

Method 22 (Method of obtaining 1)

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 14; 500 mg of 0.93 mmol) dissolved in DMF (10 ml). Add meantioned sodium (200 mg, 2,85 mmol) and the mixture is stirred for 2 hours at a temperature of 50°C. Add acetic acid (0.4 ml) and the solvent is evaporated under reduced pressure. The residue is extracted with a mixture of EtOAc/water. An ethyl acetate layer is separated, dried and evaporated under reduced pressure, obtaining mentioned in the title compound (450 mg, 96%). NMR (300 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,2 (s, 2H), 3,2 (users, 2H), 3,7 (users, 2H), and 4.8 (s, 2H), and 6.6 (s, 1H), 6,9-7,1 (m, 3H), of 7.2 to 7.4 (m, 3H).

Method 22 (Method of obtaining 2)

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-etoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 114; 15,45 g, 28,71 mmol) in EtOH (160 ml) add a solution of NaOH (4,67 g, 116 mmol) in water (10 ml). The solution is stirred for 30 minutes at room temperature. The solvent is removed under reduced pressure and the residue partitioned between EtOAc and 1.0 M HCl. Water is the additional layer is extracted two times with EtOAc and the combined organic extracts washed with saturated salt solution and concentrate, receiving specified in the header of the connection (of 14.28 g, 98 %) as a white powder. NMR (500 MHz, DMSO-d6) NMR (500 MHz, DMSO-d6) 0,65-0,80 (m, 6H), 0,90-1,50 (m, 12H), of 2.20 (s, 3H) of 3.25 (s, 2H), 3,65 (users, 2H), 4,80 (s, 2H), 6,70 (s, 1H), 6,80-7,30 (m, 6H), 13,20 (s, 1H).

Method 23-24

The compounds below are synthesized in accordance with methods method 22 (method of obtaining 1), using the appropriate acid and amine (when connections are commercially available, source not specified), with the difference that the reaction was performed at room temperature and in Method 24 for a longer period of time.

Method

No.
ConnectionM/zSource.

in-VA
23< / br>


Enantiomer 1
478method

18
24

< / br>
Enantiomer 2
478method

19

Method 25

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1.5-benzothiazepin

To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (W9616051; 600 mg, 1,29 mmol) is added DMF (5 ml) and meantioned sodium (450 mg, 6.42 per mmol). The reaction mixture is heated to 60°C is kept at this temperature for 1 hour. Then the oil bath is heated to 120°C and incubated the mixture at this temperature for 4 hours. To stop the reaction temperature was lowered to room temperature and quickly add an excess of acetic acid. The reaction mixture was kept under a stream of nitrogen passing over sodium hypochlorite, for 2 hours. Add water and EtOAc and the aqueous phase three times extracted with EtOAc. The combined organic phases are washed with water, dried and concentrated under reduced pressure. The residue is purified flash chromatography [DHM/EtOAc, 9:1], getting mentioned in the title compound (0.5 g, 92%). NMR of 0.65-0.8 (m, 6H), of 0.95 to 1.6 (m, 8H), 3,1 (kV, 2H), 3,6 (userc, 2H), 6.75 in (s, 1H), 6,8 (t, 1H), 6,9 (d, 2H), 7,15 (t, 2H), 7,55 (s, 1H).

Method 26

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To 1,1-dioxo-3,3-dibutil-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesized in accordance with the method of publication W9616051 for the corresponding 3-butyl-3-ethyl analogue; 40 mg, 0.08 mmol) is added DMF (2 ml), meantioned sodium (60 mg, 0.85 mmol) and sodium borohydride (60 mg, 1.6 mmol). The reaction mixture was kept overnight at a temperature of 60°C. Add an additional amount of sodium borohydride (60 mg, 1.6 mmol) and methanolate sodium(60 mg, 0.85 mmol) and the temperature was raised to 120°C. the Reaction mixture vyderjivaut this temperature for 4 hours and then cooled to room temperature. Add acetic acid and kept under a stream of nitrogen passing through the sodium hypochlorite, during the night. Add water and EtOAc and the aqueous phase three times extracted with EtOAc. The combined organic phases are washed with HCl (1M), dried and concentrated under reduced pressure. The residue is purified flash chromatography [EtOAc/heptane, 1:4], getting mentioned in the title compound (0.34 g, 93%). NMR of 0.7-0.9 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,2 (s, 3H), 3,1 (s, 2H), 3,4 (s, 2H), 3,7 (users, 2H), 6,7 (s, 1H), 6,85-7,05 (m, 2H), 7,2-7,4 (m, 2H).

Method 27

Ammonium salt of 2-[(2'R)-2'-(tert-butoxycarbonylamino)-2'-phenylethanolamine]econsultancy acid

2-Aminoethanesulfonic acid (740 mg, 5,91 mmol) and (2R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1,09 g, 4,34 mmol) dissolved in DMF (20 ml). Add DIPEA (2.8 ml, at 16.1 mmol) and TBTU (1,53 g, 4,78 mmol) and the mixture is stirred for 2 hours at a temperature of 60°C. the Solvent is evaporated under reduced pressure. The residue is purified preparative HPLC (eluent gradient: MeCN/ammonium acetate-ammonium buffer from 5:95 to 100:0), getting mentioned in the title compound (589 mg, 32%). NMR (CD3OD) was 1.43 (s, 9H), 2,85-3,0 (m, 2H), 3,53-3,68 (m, 2H), 5,1 (users, 1H), 7,25 was 7.45 (m, 5H).

Method 28

Ammonium salt of 2-((2'R)-2'-amino-2'-phenylethanone)econsultancy acid

Ammonium salt of 2-[(2'R)-2'-(tert-butoxycarbonylamino)-2'-phenylethanolamine]econsultancy acid is (method 27; 589 mg, 1.57 mmol) was dissolved in EtOAc (20 ml) and the mixture of ohlazhaaut in an ice bath. Gaseous hydrogen chloride bubbled through the reaction mixture in the ice bath removed and the reaction mixture is left for 30 minutes at room temperature. The solvent is evaporated under reduced pressure. The residue re-dissolved in EtOAc (20 ml) and ohlazhaaut in an ice bath. Gaseous hydrogen chloride is again bubbled through the reaction mixture in the ice bath removed and the reaction mixture is left for 30 minutes at room temperature. The solvent is evaporated under reduced pressure. Add DIPEA in DHM and the mixture is evaporated under reduced pressure. The method was repeated twice. The mixture liabiliry, getting mentioned in the title compound (563 mg, 85%)containing 1 equivalent of diisopropylethylamine. NMR (D2O) 1,35-to 1.38 (m, 15H), 2,96-of 3.12 (m, 2H), 3,21 (kV, 2H), 3,50-of 3.80 (m, 4H), 5,11 (users, 1H), 7,45-of 7.55 (m, 5H).

Method 29

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-methoxycarbonylethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 22; 250 mg, 0.49 mmol), methyl ester (R)-2-phenylglycine hydrochloride (120 mg, of 0.60 mmol) and DIPEA (300 mg, 2.3 mmol) dissolved in DHM (10 ml) and the mixture stirred for 5 minutes at room temperature. We use the t TBTU (210 mg, of 0.65 mmol) and the mixture is stirred for 30 minutes at room temperature. The solvent is evaporated under reduced pressure and the residue is transferred into the column. Product elute DHM/EtOAc (90:10), receiving specified in the title compound (306 mg, 95%). NMR (500 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,1 (s, 3H) 3,2 (users, 2H), 3,6-3,8 (m, 5H), 4,6 (Avcv, 2H), 5,6 (d, 1H), and 6.6 (s, 1H)and 6.9-7.5 (m, 11N), and 7.9 (d, 1H).

Methods 30-45

The compounds below are synthesized in accordance with methods method 29, of the appropriate acid and amine (when substances are commercially available, source not specified), but with the difference that in some methods, the reaction time is increased to 2 hours.

Method

No.
ConnectionNMR or m/zSource.

in-VA
30(300 MHz, CD3OD) to 0.8-0.9 (m, 6H), l,l to 1.6(m, 12H),2,2(s, 3H), 3,3 (s, 2H), 3,75 (users, 5H), 4,7-4,8 (m, 2H), of 5.45 (s, 1H), 6,7 (s, 1H), 6,8-of 7.3 (m, N) was 7.45 (s, 1H)method

22
31(300 MHz, CD3OD) 0,75-0,95 (m, 6H), 1.0 to 1-6 (m, 12H), 2,1 (s,3H),3,2(s,2H),and 3.7(s,5H)and 4.65 (s, 2H), to 5.85 (s, 1H), 6,7 (s, 1H), from 6.9 to 7.4 (m, 9H)method

22
32(300 MHz, CD3OD) of 0.75 to 0.9 (m, 6H), of 1.0 to 1.6 (m, 12H), 2,2 (s,3H), 3,2 (s, 2H, in), 3.75 (s, 5H), 4,7 (users, 2H), 5,7 (s, 1H), 6,7 (s, 1H), from 6.9 to 7.4 (m, 6N) 7,55 one-7.8 (m, 4H)method

22

and

method

71
330,70-0,85 (m, 6H), of 0.95 is 1.75 (m, 8H), 1,55-1,75 (2D, 3H), 3,05-3,30 (m, 2H), 3,55-3,90 (m, 2H), 3,70-of 3.80 (2s, 3H) 4,75-4,90 (2Q, 1H), ceiling of 5.60 (d, 1H), 7,00-of 7.55 (m, 12H), 7,80-to 7.95 (m, 1H)method

2
340,65-0,85 (m,6H), 0,95-of 1.65 (m, 8H), 3.00 and is 3.15 (m, 2H), 3,50-of 3.80 (m, 2H), 3,70-of 3.80 (2s, 3H), ceiling of 5.60 (s, 1H), 5,65 (d, 1H) 7,00-of 7.60 (m, 17H), 8,05-8,20 (2D, 1H)method

4
35(CD3OD) of 0.75 to 0.85 (m, 6H), 1,00-1,30 (m, 8H), 1,35-of 1.55 (m, 4H), 3,20 (s, 2H), 3,55 (s, 3H), 3,70 (s, 3H), 3,75 (users, 2H), 4,60 (Avcv, 2H), of 5.55 (s, 1H), 6,50 (s, 1H), 6,95-7,40 (m, 10H), to 7.50 (s, 1H)method

6
36707,4example

12
370,75-0,85 (m, 6H), 1,00-1,60 (m, 12H), 3,20 (s, 2H), 3,60 (s, 3H), 3,75 (users, 2H, in), 3.75 (s, 3H), 4,55 (Avcv, 2H), to 5.85 (d, 1H), 6,40 (s, 1H), 6,95 was 7.45 (m, 9H), 7,55 (s, 1H), with 8.05 (d, 1H)method

6
380,75-0,85 (m, 6H), 1,00-1,60 (m, 12H), of 2.20 (s, 3H), 3,20 (s, 2H), 3,75 (users, 2H), 3,80 (s, 3H), 4,60 (Avcv, 2H), 5,90 (d, 1H), 6,65 (s, 1H), 6,95 was 7.45 (m, 10H), to 7.95 (d, 1H)method

22/td>
39(500 MHz) of 0.7-0.8 (m, 6H), 1.0 to 1.5 (m, 12H), 3,2 (m, 2H), of 3.7-3.8 (m, 5H), 4,6 (Avcv, 2H), 5,6 (d, 1H), 6,8-7,4 (m, 10H), and 7.5 (s, 1H)method

14
40(300 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 12H), 3,2 (users, 2H), of 3.7-3.8 (m, 5H), 4,6 (Avcv, 2H), 5,6 (d, 1H), 6,8 (d, 2H), 7,0-7,4 (m, 8H), 7,9 (d, 1H)method

14
41766,4 (M-(tert-butyl)+2N)example

12
42739,3example

38
43667method

22
44724example

18
45722,5method

109

Method 46

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1'-phenyl-l'-methoxycarbonylmethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 9; 50 mg, 0,098 mmol) dissolved in DHM (2 ml). To the resulting solution was added methyl (2S)-amino(phenyl)ACE is at (19 mg, 0.12 mmol) and DIPEA (0,068 ml to 0.39 mmol) and the reaction mixture stirred for 2 minutes. Added TBTU (42 mg, 0.13 mmol) and the mixture is stirred for 1.5 hours at room temperature. The mixture is transferred into a column filled with ISOLUTE and elute with 10 ml of a mixture DHM/EtOAc (8:2), getting mentioned in the title compound (60 mg,93%). M/z 657,5.

Methods 47-62

The compounds below are synthesized in accordance with methods method 46 (but the reaction is carried out in the course of the night) from the appropriate acid and amine (when substances are commercially available, source not specified).

Method

No.
ConnectionNMR or m/zSource.

in-VA
47609,4method

10
48625,4method

17
49685,3method

14
50609,4method

10
51637,4method

15
52 657,4Method

21
53685,3method

14
540,73-of 0.95 (m, 6H), 0,98-of 1.78 (m, 8H), 3,12 of 3.28 (m, 2H), 3.6 and 4.0 (m, 5H), 4,60 (Avcv, 2H), 5,79 (d, 1H) 6,0 (users, 1H), is 6.54 (DD, 1H), 6,83 (t, 1H), 6,95 (DD, 1H), 7,0-7,5 (m, 7H), 8,43 (d, NH), to 9.32 (users, 1H)method

9 and

method

74
550,75-0,9 (m, 6H), 1,0-of 1.78 (m, 8H), 3,10-3,26 (m, 2H), 3,63-a 3.87 (m, 8H), 4,56 (Avcv, 2H), USD 5.76 (d, 1H), 5,99 (users, 1H), 6,38 (s, 1H), 6,51 (DD, 1H), for 6.81 (t, 1H), 6,93 (DD, 1H), 7,0-to 7.15 (m, 3H), 7.23 percent to 7.4 (m, 2H), 7,55 (s, 1H), 8,54 (d, NH), 9,45 (users, 1H)method

10 and

method

74
560.76 to 0.87 (m, 6H), of 1.0 to 1.8 (m, 8H), of 2.23 (s, 3H), 3,1-of 3.25 (m, 2H), 3,6-3,95 (m, 5H), br4.61 (Avcv, 2H), 5,79 (d, 1H), 6,0 (users, 1H), is 6.54 (DD, 1H), 6,65 (s, 1H), 6,83 (t, 1H), 6,92 to 7.1 (m, 4H), 7.23 percent to 7.4 (m, 3H), of 8.37 (d, NH), 9,35 (users, 1H)method

17 and

method

74
57(CD3OD) from 0.76 to 0.85 (m, 6H), of 1.02 to 1.3 (m, 8H), 1,36-of 1.56 (m, 4H), of 2.16 (s, 3H), 3,24 (users, 2H), 3,66-of 3.80 (m, 5H) 4,71 (Avcv, 2H), to 5.57 (s, 1H), of 6.71 (s, 1H), 6,98 (t, 1H), 7,06-7,14 (m, 4H), 7,28 (ushort, 2H), 7,37 was 7.45 (m, 3H)method

22 and

method

75
58 (CD3OD) from 0.76 to 0.85 (m, 6N), 1,02 of 1.28 (m, 8H), 1,36-of 1.56 (m, 4H), to 1.96 (s, 3H), 3,24 (users, 2H), 3,6-3,8 (m, 5H), 4,73 (Avcv, 2H), USD 5.76 (s, 1H), 6,63 (s, 1H), 6,94? 7.04 baby mortality (m, 2H), 7,07-to 7.15 (m, 3H), 7,27 (t, 2H), 7,31 (s, 1H), 7,37 (d, 1H), 7,42 (s, 1H), 7,56 (d, 1H)method

22
59(CD3OD) 0,80 (ushort, 6H), from 1.0 to 1.28 (m, 8H), 1,36-and 1.54 (m, 4H), 3,22 (users, 2H), 3,61 (s, 3H), 3,69 to 3.8 (m, 5H), 4,62 (Avcv, 2H), 5.56mm (s, 1H), of 6.49 (s, 1H), 6,99 (ushort, 1H), 7,07-7,16 (m, 4H), 7,29 (ushort, 2H), 7,37-the 7.43 (m, 2H), 7,52 (s, 1H)method

6 and

method

75
60(CD3OD) of 0.75 is 0.84 (m, 6H), 1,0-of 1.29 (m, SH), 1,35-and 1.54 (m, 4H), 3,20 is 3.23 (m, 5H), 3,65 to 3.8 (m, 5H), with 4.64 (Avcv, 2H), 5,74 (s, 1H), 6,34 (s, 1H), 6,95? 7.04 baby mortality (m, 2H), 7,09-to 7.15 (m, 3H), 7.24 to 7,31 (m, 3H), 7,37 (d, 1H), 7,50-rate of 7.54 (m, 2H)method

6
6110,74-of 0.83 (m, 6H), 0,98 to 1.7 (m, 8H), 3,18 (Avcv, 2H), 3,60-3,90 (m, 5H), 4,59 (Avcv, 2H), 5,67 (d, 1H), 7,0-7,2 (m, 4H), 7,2-of 7.55 (m, 8H), to $ 7.91 (d, NH)method

9
62639,4method

17 and

method

76
1elution with fractional gradient: DHM/EtOAc, 100:0, 9:1, 8:2.

Method 63

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N- {(R)-1'-phenyl-1'-[N'-(tert-butoxycarbonylmethyl)carbarnoyl]ethyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 1; 110 mg, 0,17 mmol), tert-butyl ester of glycine (30 mg, 0.23 mmol) and DIPEA (120 mg, of 0.93 mmol) dissolved in DHM (2 ml). The mixture is stirred for 5 minutes at room temperature. Added TBTU (72 mg, 0.22 mmol) and the mixture is stirred for 1 hour at room temperature. The solvent is evaporated under reduced pressure, the residue is transferred into the column and elute the product with a mixture DHM/EtOAc (90:10), receiving specified in the title compound (122 mg, 94%). NMR (300 MHz) of 0.7-0.8 (m, 6H), 1,0-1,6 (m, 21H), 2,2 (s, 3H) 3,2 (s, 2H), 3,7-4,0 (m, 4H), 4,6 (Avcv, 2H), 5,6 (d, 1H), 6,4 (t, 1H), and 6.6 (s, 1H)and 6.9-7.5 (m, 11H), and 8.1 (d, 1H).

Methods 64-69

The compounds below are synthesized in accordance with methods method 63 of the appropriate acid and amine (when substances are commercially available, source not specified).

Method

No.
ConnectionNMR or m/zSource.

in-VA
64756,1example

22
65(CD3OD) of 0.75 to 0.85 (m, 6H), of 1.1-1.3 (m, 8H), and 1.4 (s, 9H), 1,45-1,55 (m, 4H), of 2.15 (s, 3H), of 3.25 (s, 2H), 3,75 (users, 1H), 3,85 (s, 2H), 4,7 (Avcv 2H), 5,5 (s,lH), 6,7 (s,lH), 6,75-7,35 (m, 9H), and 7.4 (s, 1H)example

2
66937,9 (M-H)-example

2
67796,4example

1
68example

1
69example

1

Method 70

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{N-[(S)-1'-phenyl-1'-{detoxifaction]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 9) and diethyl(S)-amino(phenyl)methylphosphonate in accordance with the method of example 33. NMR (600 MHz) To 7.77-7,72 (N), m), 7,47-7,42 (3H, m), of 7.36-7,27 (5H, m), 7,14 (1H, s), 7,10-7,03 (2H, m), 5,55-of 5.48 (1H, m), 4.63 to-4,51 (2H, m), 4,14-was 4.02 (2H, m), 3,99-to 3.92 (1H, m), 3,81-of 3.60 (3H, m), 3,22-3,10 (2H, m), 1,65-1,25 (8H, m), 1,19-of 0.95 (6H, m), 0,78-to 0.73 (6H, m).

Method 71

4-Trifluoromethyl-α-methoxycarbonylbenzyl

4-Trifluoromethyl-α-carboxymethylamino (1.4 g, to 1.83 mmol) and thionyl chloride are added to a methanol (8 ml) and the mixture refluxed for 2 hours. Rast is oritel is evaporated under reduced pressure. The residue is suspended in diethyl ether, the product is filtered, washed with ether and dried, obtaining mentioned in the title compound (0.34 g, 69%). NMR (300 MHz, DMSO-d6) 3,3 (s, 1H), the 5.45 (s, 1H), 7,7-7,9 (m, 4H), 9,25 (users, 3H).

Method 72

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-N(ethoxycarbonylmethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38; 52 mg, 0,082 mmol) and ethyl ester of glycine hydrochloride (18 mg, 0,129 mmol) dissolved in DHM (2 ml) and added dropwise DIPEA (0,70 ml, 0.42 mmol). The mixture is stirred at room temperature for 5 minutes, add TBTU (34 mg, 0.11 mmol) and again stirred for 2 hours. The solvent is evaporated and the residue purified flash chromatography (elution: DHM/EtOAc, 10:3), getting mentioned in the title compound 50 mg (88%). NMR (500 MHz) 0,86 (m, 6H), 1,10-of 1.75 (m, 8H), of 1.28 (m, 3H), of 2.23 (s, 3H), 3,19 (kV, 2H, in), 3.75 (m, 2H), 3,99-of 4.25 (m, 4H), with 4.64 (q, 2H), 5,64 (m, 1H), 6.35mm (users, 1H), 6,69 (s, 1H), 7,03 (t, 1H), to 7.09 (d, 1H), 7,29-7,52 (m,7H), 8,10(d, 1H).

Method 73

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-{(R)-1'-phenyl-1'-[N-(1"-methoxycarbonyl-1"-formethylcarbamoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specified in the title compound is synthesized according to the method of method 72 of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[ N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (example 38) and methyl (2R)-amino(phenyl)acetate hydrochloride.

Method 74

1-(1'-Methoxycarbonyl-1'-aminomethyl)-2,3-dihydroxyphenyl hydrochloride

1-(1'-Carboxy-1'-aminomethyl)-2,3-dihydroxyphenyl (40 g, 0,218 mmol) is mixed with methanol (230 ml). Gaseous HCl bubbled through the solution. The mixture is refluxed for 2 hours. The solvent is evaporated under reduced pressure. The product is crystallized from methanol/EtOAc/diethyl ether to obtain 35.5 g (70 %) specified in the connection header. NMR (600 MHz, CD3OD) 3,76 (s, 3H), 5,19 (s, 1H), 6,68-6-75 (m, 2H), 6,85 (DD, 1H).

Method 75

(R)-1-(1'-Methoxycarbonyl-1'-aminomethyl)-4-forfinal hydrochloride

(2R)-Amino(4-forfinal)acetic acid (570 mg, 2.77 mmol) was dissolved in methanol (5 ml) and the resulting solution cooled in an ice bath. Added dropwise thionyl chloride (2 ml) and the mixture allowed to warm to room temperature. After 5 hours the mixture is evaporated under reduced pressure. This processing is repeated and then the reaction mixture was stirred over night. The mixture is evaporated under reduced pressure, obtaining mentioned in the title compound in quantitative yield. NMR (500 MHz, CD3OD) of 3.84 (s, 3H), of 5.26 (s, 1H), 7,26 (t, 2H), 7,53 (DD, 2H).

Methods 76-77

Compounds represented by the s below synthesized in accordance with methods method 75 from the appropriate acid and amine (when substances are commercially available, source not specified).

Method

No.
ConnectionNMRSource.

in-VA
76(S)-α-methylamino-α-methoxycarbonylbenzyl(CD3OD) 2,63 (s, 3H), 3,81 (s, 3H), of 5.15 (s, 1H), 7,45-of 7.55 (m, 5H)(S)-α-methylamino-α-carboxybenzene
771α-methoxycarbonyl-N-methyl, benzylamine hydrochloride(D2O) to 2.65 (s, 3H), 3,81 (s, 3H), of 5.15 (s, 1H), 7,45-of 7.48 (m, 2H), 7,52-to 7.59 (m, 3H)(methylamino)

(phenyl)uksousnokisloy
1The total reaction time is 5 days

Method 78

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-αtert-butoxycarbonyl)-4-hydroxybenzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

tert-Butyl (2R)-amino(4-hydroxyphenyl)acetate (104 mg, 0.47 mmol) and 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 17; 185 mg, 0,39 mmol) dissolved in DHM (5 ml) and the resulting solution was added lutidine (0,09 ml, 0.77 mmol). The mixture is stirred at room temperature for 5 minutes, the m added o-(7-asobancaria-1-yl)- N,N,N',N'-tetramethyluronium hexaflurophosphate (208 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Purification with flash chromatography (elution gradient: DHM:EtOAc; 10:1→5:1) results specified in the title compound (175 mg, 66 %). NMR (300 MHz) 0,81 (m, 6H), 1,05-of 1.65 (m, 8H), of 1.42 (s, 9H), of 2.21 (s, 3H), 3,17 (Avcv, 2H), 3,74 (m, 2H), 4,60 (Avcv, 2H), 5,22 (users, 1H), 5,49 (d, 1H), to 6.67 (s, 1H), 6,79 (m, 2H), 7,00 (t, 1H), 7,07 (d, 2H), 7.23 percent-7,30 (m, 3H), 7,40 (s, 1H), 7,82 (userd, 1H).

Method 79

The compounds below are synthesized in accordance with methods method 78 of the appropriate starting materials.

Method

No.
ConnectionM/zVhodnu-VA
79639,3method 17 method 77

Method 80

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}econsultancy acid

N-Boc-4-hydroxyphenylglycine (1,00 g is 3.21 mmol) dissolved in DMF (5 ml) and the resulting solution was added tetrabutylammonium taurine (2,36 g, 6.42 per mmol) with additional DMF (5 ml). The resulting suspension is cooled in an ice bath and added TBTU (1.24 g, of 3.85 mmol) is added. The ice bath is removed after 30 minutes and the mixture is stirred for 2 hours, then filter the display and concentrate. In the reaction mix add TFUK in DHM (20%, 20 ml) and the resulting mixture is stirred over night. Add ethanol (20 ml) and the solvents evaporated. The crude product is refluxed in ethanol (100 ml) for 1 hour. After filtration of pure connection specified in the header, in the form of a white solid (626 mg, 71%). NMR (DMSO-d6) of 2.4 to 2.6 (m, 2H), 3,2-3,4 (m, 2H), 4,79 (s, 1H), 6,78 (d, 2H), 7.23 percent (d, 2H), by 8.22 (t, 1H), 8.4V (users, 3H), and 9.7 (s, 1H).

Method 81

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (113 mg, 0.24 mmol), Cs2CO3(170 mg, 0.52 mmol) and ethyldiglycol (to 0.060 ml, 0.54 mmol) in DMF (4.0 ml) is subjected to a microwave irradiation apparatus Smith at a temperature of 80°C for 3 minutes and then at a temperature of 90°C for 8 minutes. The reaction mixture dabavliaiut water (250 ml), extracted with DHM (5 x 10 ml) and the combined organic fractions are dried (MgSO4), concentrate and purify but small column height (elution gradient: petroleum ether:EtOAc 4:1→2:1). The obtained product is dissolved in THF (2 ml), add water (2 ml) and NaOH (aq., 0.5 ml, 1 M) and the reaction mixture was stirred at room temperature for 2 hours. The reaction is quenched by addition of HCl (1 M), and the reaction with the ect diluted with water (10 ml) and extracted with DHM (3 x 3 ml). Purification preparative HPLC results indicated in the title compound (58 mg, 59 %). NMR (300 MHz, CD3OD) 0,81 (m, 6H), 1.00 and is 1.70 (m, 8H), 3,21 (m, 2H), 3,42 (m, 2H), 3,71 (m, 2H), 3,92 (s, 3H), to 6.88 (m, 2H), 7,02 (m, 2H), 7.23 percent (t, 2H), 7,40 (s, 1H).

Method 82

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonylmethyl-thio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 9; 50 mg, 0,098 mmol) and CS2CO3(51 mg, 0.15 mmol) is added to DMF (2.0 ml) and to the resulting solution add ethyldiglycol (0,02 ml, 0.15 mmol). The reaction mixture was subjected to microwave irradiation apparatus Smith at a temperature of 150°C for 5 minutes. The reaction mixture was diluted with water (100 ml), acidified with HCl (1 M), extracted with DHM (3 x 10 ml) and the combined organic layers are dried (MgSO4) obtaining specified in the title compound as a crude product (54 mg). M/z 550,2.

Method 83 and Method 84

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (enantiomer 1):

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (enantiomer 2)

Two enantiomers of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051) are razdeleniem corresponding racemic mixtures IP is the use of preparative HPLC (column: Chiralpak AD (20 x 250 mm, 10 μm); mobile phase: heptane/IPA 90/10). Inject the racemate (17.3 mg) in IPA (1 ml) elute with a volumetric flow rate of 10 ml/min, the chromatogram appears in UV light at 285 nm. Total share of 260 mg of the racemate to obtain 121 mg of enantiomer of the first elution (enantiomer 1) and 115 mg of enantiomer second elution (enantiomer 2). The total yield of 91%. Each of the two enantiomers are obtained from the output of 99.4%.

Method 85

(R)-N-Benzyloxycarbonyl-α-[N'-(tert-butoxycarbonyl-methyl)carbarnoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-carboxymethylamino (10 g, 35,0 mmol) and tert-butylglycol hydrochloride (6.3 g, or 37.4 mmol) dissolved in DHM (200 ml) and added 2,6-lutidine (8,2 ml of 70.4 mmol). The resulting mixture was stirred for 5 minutes at a temperature of 0°C, added TBTU (12.4 g, and 38.6 mmol) and stirring is continued for 1 hour 30 minutes at a temperature of 0°C and 3 hours 45 minutes at room temperature. The reaction mixture was washed with water (2 x 100 ml), dried (MgSO4) and purified flash chromatography (elution gradient: DHM:EtOAc 7:1→5:1), obtaining mentioned in the title compound (13 g, 94 %). NMR (500 MHz) of 1.45 (s, 9H), of 3.84 (d, 1H), 4,00 (DD, 1H), 5,10 (m, 2H), 5,28 (users, 1H), 6,13 (users, 1H), 6,23 (users, 1H), 7,30-7,44 (m, 10H).

Method 86

(R)-α-[N-(tert-Butoxycarbonylmethyl)carbarnoyl]benzylamine

(R)-(N-Benzyloxycarbonyl-α-[N'-(tert-is ethoxycarbonyl-methyl)carbarnoyl]benzylamine (method 85; 12.8 g, to 32.2 mmol) was dissolved in EtOH (99%, 200 ml) and toluole (50 ml). Add Pd/C (10%, 0.65 g) and carry out the hydrogenation at atmospheric pressure for 5 hours 30 minutes at room temperature. The reaction mixture is filtered through diatomaceous earth, then the solvent is evaporated, getting mentioned in the title compound (8,4 g, 99 %). NMR (600 MHz) of 1.45 (s, 9H), 3,93 (m, 2H), 4,54 (s, 1H), 7,31-7,42 (m, 5H), 7,51 (users, 1H).

Method 87

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-methoxycarbonylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 22; 50 mg, 0,099 mmol) dissolved in DHM (2 ml). Add methyl ester (S)-phenylglycine hydrochloride (24,8 mg, 0,123 mmol) and diisopropylethylamine (70 μl, 0,401 mmol). The mixture is stirred for 15 minutes, then added TBTU (38 mg, the amount of 0.118 mmol). The reaction is finished after 1.5 hours (LC/MS). The crude product was purified flash chromatography (elution: chloroform/EtOAc, 8/2), receiving specified in the header connection (88,6%; 55,2 mg, 0,064 mmol). M/z 653.

Method 88

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-{(S)-α-[N'(methoxycarbonylmethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzoyl)carbamoylmethyl]-2,3,4,5-tet is ahydro-1,5-benzothiazepine (example 88; 25 mg 0,039 mmol) and methyl ester of glycine (7.5 mg, 0,059 mmol) dissolved in DHM (2 ml). To the mixture sequentially add diisopropylethylamine (27 μl, 0,158 mmol) and TBTU (15 mg, 0,047 mmol) and the mixture is stirred for 2 hours at room temperature. The crude product was purified flash chromatography (elution: DHM/EtOAc, 8/2), getting mentioned in the title compound (22 mg, 79%). M/z 710.

Method 89

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxymethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

Sodium hydroxide (38 mg, 0.95 mmol) dissolved in ethanol (2.5 ml) and added 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (WO 96/16051; 200 mg, 0,443 mmol). The mixture is stirred at room temperature for 5 minutes, add 3-bromopropionic acid (68 mg, 0,443 mmol) and the reaction mixture is refluxed for 20 hours. Add acetic acid. The solvent is evaporated under reduced pressure and the residue is extracted with EtOAc/water. The organic layer was separated, washed with water, dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM/MeOH, 100:5), receiving specified in the title compound (89 mg, 38%). NMR (CD3OD) of 0.75 or 0.83 (m, 6H), 1,0-1,25 (m, 4H), 1,38-of 1.65 (m, 4H), 2,82 (m, 2H), 3,26 (s, 2H), 3,50-3,90 (m, 2H), 4,33 (t, 2H), 6,99 (t, 1H), 7,07-7,13 (m, 3H), 7,28 (m, 2H), 7,53 (s, 1H).

Method 90

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(tert-butoxycarbonyl)benzyl]carbarnoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxymethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 89; 70 mg, 0,134 mmol) and (R)-α-(tert-butoxycarbonyl)benzylamine (J. Amer. Chem. Soc.; EN; 117; 44; 1995; 10879-10888; 35 mg, 0,169 mmol) in DHM (2.5 ml) is added 2,6-lutidine (29 mg, 0,268 mmol) and TBTU (56 mg, 0,174 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, the ZAT diluted DHM. The solution was washed with NaHCO3(aq., the feast upon.), water, dried and the solvent is evaporated under reduced pressure. The remainder suspension in a mixture of ether/petroleum ether and the crystals are filtered, getting mentioned in the title compound (85 mg, 89%). (500 MHz) 0,79 is 0.86 (m, 6H), 1.04 million of 1.28 (m, 4H), 1,35-of 1.56 (m, 11H), 1.60-to 1.77 in (m, 2H), 2,82 (t, 2H), 3,13-of 3.25 (m, 2H), 3.72 points users, 2H), 4,35-of 4.44 (m, 2H), 5,54 (d, 1H), 6,95 (d, 1H),? 7.04 baby mortality (t, 1H), was 7.08 (d, 2H), to 7.15 (s, 1H), 7,29-the 7.43 (m, 6H), 7,52 (s, 1H).

Methods 91-94

The compounds below are synthesized according to the method of example 104 from the corresponding starting compounds (specified source Amin, when he is no longer commercially available).

/table>

Method 95

3,3-Dibutil-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

A mixture of 3,3-dibutil-4-oxo-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 95/04534; 1.0 g, 2.5 mmol), 4-bromchlorenone (4,78 g, 24,98 mmol), copper bromide (36 mg, 0.25 mmol) and potassium carbonate (0.35 g, 2.5 mmol) is refluxed for 20 hours. The reaction mixture was loaded into the column and elute the product with a mixture of 5% EtOAc/petroleum ether (0.8 g, 63%). NMR (500 MHz) 0,86 to 0.92 (m, 6H), of 1.16 and 1.35 (m, 8H), 1,45-of 1.65 (m, 4H), and 3.16 (s, 2H), 3.96 points (s, 3H), 7,06-7,10 (m, 2H), 7,19 (s, 1H), 7,29 (s, 1H), 7,33-7,38 (m, 2H). M/z 511.

Method 96

1,1-Dioxo-3,3-dibutil-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a mixture of 3,3-dibutil-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 95; 0,67 g, 1,304 mmol), DHM (34 ml), water (34 ml) and potassium carbonate (0,554 g, 4.0 mmol) at a temperature of 0°C one portion add m-chloroperoxybenzoic acid (0,78 g, 3.2 mmol). The reaction mixture is stirred at a temperature of 0 °C for 10 hours and then at room temperature for 14 hours. Add DHM (100 ml) and NaHCO3(aq., the feast upon.; 150 ml). The organic layer is separated, washed with saturated salt solution, dried and evaporated under reduced pressure, obtaining mentioned in the title compound (0.68 g, 96%). NMR (600 MHz) of 0.7 to 0.92 (m, 6H), from 1.0 to 1.60 (m, 10H), 1.70 to of 1.92 (m, 2H), 2,30-3.7 m, 2H), 3,99 (s, 3H), 7,16-7,20 (m, 2H), 7,24 (s, 1H), 7,34-7,37 (m, 2H), 7,44 (s, 1H); m/z 543.

Method 97

1,1-Dioxo-3,3-dibutil-4-oxo-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 96; 0.66 g, 1,22 mmol) in anhydrous DMF (11 ml) under nitrogen atmosphere add meantioned sodium (0,43 g, between 6.08 mmol). The reaction mixture was stirred at room temperature for 72 hours. The solvent is evaporated under reduced pressure and the residue extracted with trichloromethane and water. The organic layer is separated, washed with saturated salt solution, dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM), receiving specified in the header connection 0.6 g (96%). NMR (500 MHz) of 0.80 to 1.0 (m, 6H), 1,10-1,6 (m, 10H), 1.70 to 2,0 (m, 2H), 2,28 (s, 3H), 3,37-3,70 (m, 2H), Android 4.04 (s, 3H), of 6.65 (s, 1H), 7,25-7,30 (m, 2H) 7,35-7,42 (m, 3H); m/z 510,4.

Method 98

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-4-oxo-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 97; 0,41 g of 0.79 mmol) in anhydrous ether (15 ml) under nitrogen atmosphere add LiAlH4(0.15 g, of 3.97 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. Reactional flask is Hledat to 0° C and the excess LiAlH4quenched by addition of water (0.3 ml) and 2 M aqueous NaOH solution (0.3 ml). The mixture is filtered and the filtrate is dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM), receiving specified in the header connection (0,265 g, 68%). NMR (300 MHz) 0.8 to about 0.90 (m, 6H), 1.0 to about 1.47 (m, 12H), of 2.33 (s, 3H), 3,17 (s, 2H), 3,70 (s, 2H), 3,93 (s, 3H), 7.03 is-was 7.08 (m, 3H), 7.23 percent-to 7.32 (m, 3H); m/z 496.

Method 99

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 98; 0.26 g 0.52 mmol) in anhydrous DHM (10 ml) under nitrogen atmosphere add tribromide boron (2,63 g, 10,48 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction flask is cooled to 0°C, add water (20 ml) and hydrazine monohydrate (0.5 ml). The organic layer is separated, dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM/EtOAc, 100:5 and 100:10), receiving specified in the title compound (0.20 g, 80%). NMR (500 MHz) of 0.85 (t, 6H), 1,03 of 1.28 (m, 8H), 1,35 of 1.46 (m, 4H), 2,39 (s, 3H), 3,21 (s, 2H), of 3.73 (s, 2H),? 7.04 baby mortality (d, 2H), 7,29-7,34 (m, 3H), 7,44 (s, 1H); m/z 482.

Method 100

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a mixture of 1,1-dioxo-3,3-dibutil--(4-chlorophenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 99; 0,194 g, 0,402 mmol), anhydrous Na2CO3(0,192 g, is 1.81 mmol) and tetrabutylammonium bromide in MeCN (5 ml) add ethylbromoacetate (0,101 g, 0,604 mmol). The reaction mixture is refluxed for 3.5 hours. The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. The organic layer is separated, dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM/EtOAc, 100/5 and 100/10), receiving specified in the header connection (0,197 g, 86%). NMR (300 MHz) 0,80-to 0.89 (m, 6H), from 1.0 to 1.45 (m, 15H), was 2.34 (s, 3H), and 3.16 (s, 2H), 3,68 (s, 2H), 4,30 (kV, 2H), 4,71 (s, 2H), 7,05-7,11 (m, 3H), 7,19 (s, 1H), 7,29-7,35 (m, 2H).

Method 101

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 100; of € 0.195 g, 0,343 mmol) in ethanol (8 ml) is added NaOH (1,03 mmol in 0.5 ml water). The reaction mixture was stirred at room temperature for 70 minutes and then quenched by addition of acetic acid (0.3 ml). The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. The organic layer is separated, washed with saturated salt solution, dried and evaporated under reduced pressure, obtaining specified in the header connection (0,169 g, 91%). NMR (500 M is C, CD3OD) 0,86 (t, 6H), 1,11-of 1.28 (m, 8H), 1,37-of 1.44 (m, 4H), of 2.33 (s, 3H), of 3.25 (s, 2H), 3,55 (s, 2H), to 4.73 (s, 2H), 7,10-to 7.15 (m, 3H), 7,26 (s, 1H), 7,28-to 7.32 (m, 2H).

Method 102

1,1-Dioxo-3,3-dibutil-5-(4-chlorophenyl-7-methylthio-8-[N-{(R)-α-[N'-(tert-butoxycarbonylmethyl)carbarnoyl]benzyl}carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a solution of 1,1-dioxo-3,3-dibutil-5-(4-chlorophenyl)-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 101; 100 mg, 0.185 mmol) and (R)-α-[N-(tert-butoxycarbonylmethyl)carbarnoyl]benzylamine (method 86; 56 mg, 0,213 mmol) in DHM (4 ml) is added 2,6-lutidine (40 mg, and 0.37 mmol) and TBTU (89 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, then add EtOAc and the solution washed with water. The organic layer is separated, dried and evaporated under reduced pressure. The crude product is purified column chromatography (elution: DHM/MeOH, 100:3), receiving specified in the header connection (0,129 g, 89%). NMR (600 MHz) 0,78-82 (m, 6H), 1,01 is 1.23 (m, 8H), 1.30 and of 1.42 (m, 13H), 2,32 (s, 3H), 3,10 -, and 3.16 (m, 2H), 3,62-3,68 (m, 2H), 3,81-a 3.87 (m, 1H), 3.95 to a 4.03 (m, 1H), to 4.52 (DD, 2H), to 5.57 (d, 1H), 6,27 (t, 1H), 7,01-7,07 (m, 3H), 7,20-the 7.43 (m, 8H), 8,02 (d, 1H).

Method 103

3,3-Dibutil-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

3.3-dibutil-4-oxo-8-methoxy-2,3,4,5-tetrahydro-l,5-benzodiazepine (synthesized in accordance with the method of publication WO9616051 for the corresponding 3-BU the Il-3-ethyl analogue; 2.9 g, 9.0 mmol) is added p-nitrophenolate (24 g, 119 mmol), K2CO3(1.6 g, 12 mmol) and CuI (180 mg, 0.95 mmol). The reaction mixture is heated to 200°C and kept at this temperature during the night. The mixture is allowed to cool to room temperature and the resulting solid is purified by chromatography (lilloana: DHM). The fractions containing the product are concentrated under reduced pressure and add EtOH (95%) and insoluble p-nitrophenylamino filtered. The residue is again purified flash chromatography (elution: DHM). The product still is not clean, so the residue then purified flash chromatography (elution: EtOAc/heptane, 1:9), receiving specified in the header connection (to 2.57 g, 64%). NMR (600 MHz) of 0.77-0.87 (m, 6H), of 1.12 to 1.31 (m, 8H), is 1.4-1.6 (m, 4H), 3,09 (users, 2H) 3,79 (s, 3H), 6,72-6,83 (m, 2H), 7.18 in-7,27 (m, 3H), 8.3 (l, 2H).

Method 104

1,1-Dioxo-3,3-dibutil-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

3.3-dibutil-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 103; to 2.57 g, 5.8 mmol) is added DHM (130 ml), water (130 ml) and Ka2CO3(2,44 g, 17.6 mmol). The reaction mixture was cooled to 0°C and one portion add m-chloroperoxybenzoic acid (3.42 g, a 13.9 mmol). The reaction mixture is left overnight, giving her the opportunity to slowly warm to room temperature. After that add aq. NaHCO 3(feast upon.) and separate the two layers. The aqueous layer was extracted three times DHM. The combined organic layers dried, filtered and evaporated under reduced pressure. The product was then purified flash chromatography (elution: DHM), getting mentioned in the title compound (2.4 g, 87%). M/z 475,4.

Method 105

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To LiAlH4(USD 5.76 g, 151 mmol) is added THF (200 ml). The reaction mixture was cooled to 0°C and slowly with a syringe type H2SO4(4,06 ml, 76 mmol). After complete addition, the reaction mixture is stirred for 10 minutes. Then at a temperature of 0°C add 1,1-dioxo-3,3-dibutil-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 104; to 2.57 g of 5.06 mmol)dissolved in THF (50 ml). After vigorous stirring for 1 hour the cooling bath is removed, the reaction mixture is heated to 40°C and kept at this temperature during the night. After this, in the specified order type Na2SO4·10H2O (3-4 teaspoons), water (8 ml), NaOH (15%, aq.) (8 ml), water (25 ml) and MeOH (30 ml) is added. The precipitate is removed by filtration and Prodavat DHM/MeOH. The solvent is dried, filtered and concentrated under reduced pressure. The residue is purified flash chromatography (elution: DHM/EtOAc, 9:1 then 3:1), getting listed is in the title compound (0.6 g, 27%). M/z that amount to 431,3.

Method 106

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 105; 918 mg, 2,13 mmol) dissolved in DMF (dry, 20 ml). To the resulting solution add thiamethoxam sodium (810 mg, 11.6 mmol). The reaction mixture is treated at a temperature of 100-120°C for four days, then at room temperature overnight. To the obtained mixture is added acetic acid (3 ml), the mixture is blown with nitrogen (Gator.) and the gas is passed through the flask with sodium hypochlorite for decomposition of the resulting mercaptan. Add water and the aqueous layer was twice extracted with EtOAc. The combined organic layers washed with saturated salt solution, dried, filtered and evaporated under reduced pressure. Add mixture containing DMF, toluene and a saturated solution of salt (do not dissolve). The aqueous layer was twice extracted with toluene. The combined organic extracts washed with a saturated solution of salt. Long funnel was washed with EtOAc to dissolve any residue. Toluene and an ethyl acetate solutions are combined, dried, filtered and evaporated under reduced pressure. The residue is purified flash chromatography (elution: DHM/EtOAc, 7:3), getting mentioned in the title compound (0.6 g,27%). M/z 417,4.

The method is 107

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 106; 600 mg, 1.44 mmol dissolved in THF (10 ml). Add di-tert-BUTYLCARBAMATE (314 mg, 1.44 mmol) and the mixture is stirred at a temperature of 60°C for two hours and at room temperature for 3 days. The solvent is evaporated under reduced pressure. Add EtOAc and the organic layer washed with a solution of KHSO4(0,3M aq.) and saturated salt solution, dried, filtered and evaporated under reduced pressure. The residue is purified flash chromatography (elution: DHM/EtOAc, 9:1), obtaining specified in the header connection (0,597 g, 80%). M/z 517,3.

Method 108

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 107; 597 mg, of 1.16 mmol) dissolved in MeCN (20 ml), add K2CO3(480 mg, 3.5 mmol), tetrabutylammonium bromide (54 mg, 0,17 mmol) and ethylbromoacetate (167 μl, 1.5 mmol). The mixture is heated to 60°C and kept at this temperature during the night. The solvent is evaporated under reduced pressure. Add EtOAc and water and the aqueous layer was twice extragear who have EtOAc. The combined organic extracts washed with saturated salt solution, dried, filtered and evaporated under reduced pressure, obtaining specified in the header connection (0,617 g, 89%). M/z 603,3.

Method 109

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 108; 607 mg, 1.0 mmol) dissolved in THF (6 ml), add H2O (6 ml) and LiOH (127 mg, to 3.02 mmol, monohydrate). The mixture is stirred for 1 hour. After that, the mixture was poured into water and the solution acidified using aqueous solution of HCl (1M). The aqueous layer was twice extracted with EtOAc. The combined organic extracts washed with saturated salt solution, dried, filtered and evaporated under reduced pressure, obtaining specified in the header connection (0,571 g, 99%). M/z 575,4.

Method 110

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-tert-butoxycarbonylamino)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 45; 562 mg, 0.78 mmol) dissolved in DHM (18 ml). Add TFOC (4 ml) and the reaction mixture is stirred for 3 hours. Dissolve the ü is evaporated under reduced pressure. The residue is partitioned between EtOAc and aqueous solution of NaOH (1M). The aqueous phase is extracted again EtOAc. The combined organic extracts washed with saturated salt solution, dried, filtered and evaporated under reduced pressure, obtaining mentioned in the title compound (440 mg, 91%). M/z 622,5.

Method 111

1,1-Dioxo-3,3-dibutil-5-[4-(N'-tert-butylurea)phenyl]-8-[N-(α-(R)-l)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3,3-dibutil-5-(4-AMINOPHENYL)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 110; 40 mg, 0,064 mmol) dissolved in DMF (1 ml). Add tert-utilizationa (8,3 μl, 0,071 mmol). The reaction mixture is stirred at a temperature of 60-80°C during the night. Add tert-utilizationa (20 µl, 0,171 mmol). The reaction mixture is stirred at a temperature of 60-80°C for 2 days and then at room temperature for several days. The solvent is evaporated under reduced pressure. The product was then purified preparative HPLC (elution gradient: MeCN/ammonium acetate-ammonium buffer from 5/95 to 100/0), getting mentioned in the title compound (30 mg, 65%). M/z 721,6.

Method 112

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-(α-methoxycarbonylmethyl-benzyl)carbamoylmethyl]-2,3,4,5-tetrahydro-1,5-benzothiazepin

Specify the OU in the title compound synthesized from 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 17) and methyl 3-amino-3-phenylpropionate (Helv. Chim. Acta; EN; 83; 6; 2000; 1256 - 1267) in accordance with the method of example 56. M/z 639,4.

Method 113

tert-Butyl D-(S-trityl)cysteinate hydrochloride

To a suspension of S-trityl-D-cysteine (2.0 g, 5.5 mmol) in tert-butyl acetate (35 ml) with vigorous stirring, added dropwise 70% HClO4(1.6 ml). The reaction mixture was stirred at room temperature for 70 minutes, then add EtOAc (50 ml) and NaHCO3(aq., the feast upon.) to pH 8.0. Sediment unreacted S-trityl-D-cysteine, is removed by filtration. The organic layer was separated, washed with 0.5 M HCl (2 x 75 ml) and saturated salt solution, dried and evaporated, getting mentioned in the title compound (2,02 g, 81%). NMR (500 MHz): USD 1.43 (s, 9H), 2,83-2,95 (m, 2H), 3,41-of 3.48 (m, 1H), 7,21-7,37 (m, 9H), 7,46 (d, 6H).

Method 114

1,1-Dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-etoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a suspension of 1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 26; is 12.85 g, 28,71 mmol) in MeCN (150 ml) add ethylbromoacetate (of 3.85 ml, 34.6 mmol), tetrabutylammonium bromide (0,925 g 2,869 mmol) and sodium carbonate (12,85 g, 121,2 mmol). The mixture is refluxed for 5 hours. The solvent is removed under reduced pressure and the residue partitioned between DHM and 0.5 M HCl. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrate. Chromatogra the Oia (elution: DHM/EtOAc, 9:1) leads to the desired product (15,45 g) as a dark oil. NMR 0,70-0,85 (m, 6H), 1.00 and-of 1.55 (m, 15H), of 2.15 (s, 3H), 3,10 (s, 2H), 3,70 (users, 2H), 4,25 (kV, 2H), 4,70 (s, 2H), 6,65 (s, 1H), 6.90 to-7,30 (m, 6H).

Method 115

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (method 116; 0,48 g, 1.04 mmol) dissolved in ethanol (10 ml). Add NaOH (0,30 g, 7.5 mmol) and the mixture refluxed for 30 minutes. Add acetic acid (1 ml). The solvent is evaporated under reduced pressure and the residue extracted with a mixture DHM/water. Layer DHM is separated, dried and evaporated. Gain of 0.44 g (97%) specified in the connection header. NMR (300 MHz) of 0.7-0.8 (m, 6H), of 1.0 to 1.6 (m, 8H), 3,1-3,3 (m, 2H), 3.5 to 3.8 (m, 2H), 4,6 (s, 3H), of 6.8 to 7.3 (m, 7H), and 7.5 (s, 1H).

Method 116

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To MeCN (10 ml) is added 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (WO9616051; 0.40 g, 1.07 mmol), ethylbromoacetate (0,23 g, 1.38 mmol), sodium carbonate (0.50 g, 4.7 mmol) and tetrabutylammonium bromide (30 mg, 0,093 mmol). The mixture is refluxed for 18 hours and then evaporated under reduced pressure. The residue is extracted with a mixture of DGM/water. Layer DHM separated and evaporated under decreased the pressure. The residue is purified column chromatography (elution: DHM/EtOAc, 90:10). Get to 0.480 g (97%) specified in the connection header. NMR (300 MHz) 0,7-0,85 (m, 6H), 1,0-1,7 (m, 11H), 3,1-3,3 (m, 2H), 3,6-3,8 (m, 2H), 4,3 (kV, 2H), 4,6 (s, 2H), 6,9-to 7.3 (m, 7H), 7.5 (d, 1H).

Method 117

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a suspension of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (obtained in accordance with the methodology publication WO 96/16051 using identical stages of synthesis, but with the difference that the original substance is selected with the aim of obtaining depoprovera, instead of butyl/ethyl derivative; 0,756 g of 1.62 mmol) in DMF (40 ml) was added NaSMe (0,605 g, 8.20 mmol, 95 %), and the mixture is stirred overnight at a temperature of 120°C. the Solvent is removed under reduced pressure and the residue partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted two more times with EtOAc and the combined organic extracts dried (MgSO4) and concentrate. Get listed in the title compound (0,665 g, 98 %). NMR (500 MHz, DMSO-d6) NMR (500 MHz, DMSO-d6) 0,60-0,80 (m, 6H), of 1.05 to 1.50 (m, 8H), of 2.15 (s, 3H), 3,20 (s, 2H) 3,65 (users, 2H), 6,65 (s, 1H), 6.75 in-to 6.95 (m, 3H), 7,10-7,25 (m, 2H), 7,30 (s, 1H), and 10.5 (s, 1H).

Method 118

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepin

To a suspension of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-is ethylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 117; 0,665 g, was 1.58 mmol) in MeCN (10 ml) add ethylbromoacetate (0,262 ml of 2.35 mmol), tetrabutylammonium bromide (0,051 g, 0,158 mmol) and sodium carbonate (0,870 g, 8,21 mmol). The mixture is stirred overnight at a temperature of 80°C. the Solvent is removed under reduced pressure and the residue partitioned between EtOAc and 0.5 M HCl. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrate. The residue is filtered through a column of small height, filled with silica (elution: DHM/EtOAc, 9:1), concentrated and dissolved in EtOH (10 ml). Add a solution of NaOH (0.25 g, of 6.25 mmol) in water (1 ml) and the resulting mixture is stirred over night at room temperature. The solvent is removed under reduced pressure and the residue partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted two times with EtOAc, the combined organic extracts washed with saturated salt solution and concentrated. The crude product is purified preparative HPLC (eluent: MeCN/ammonium acetate-ammonium buffer), receiving specified in the header connection (0,441 g, 58%) as a white solid. NMR (DMSO-d6of 0.55 to 0.75 (m, 6H), of 1.05 to 1.50 (m, 8H), of 2.15 (s, 3H), 3,20 (s, 2H), 3,65 (users, 2H), 4,50 (s, 2H), 6,65 (s, 1H), 6,80-7,00 (m, 3H), 7,15 (s, 1H), 7,15-7,25 (m,2H).

Example 121

The following compositions are typical examples of pharmaceutical dosage forms containing the compound of formula (I) or its headlight is asepticheski acceptable salt, MES, MES such a salt or a prodrug (compound X), for therapeutic or prophylactic use in humans:

MethodConnectionNMR (500 MHz) and m/zSource.

in-VA
91 0,77 is 0.86 (m, 6H), 1,03-of 1.62 (m, 21H), of 2.21 (s, 3H), 2,32 (DD, 1H), 2,54 (DD, 1H), 3,14 (s, 2H), 3,74 (users, 2H), 4,48-a 4.53 (m, 1H), 4,60 (DD, 2H), to 5.57 (d, 1H), 6,33 (d, 1H), to 6.67 (s, 1H), 7,01 (t, 1H), 7,09 (d, 2 H), 7,17-7,40 (m, 21H), to 7.50 (d, 2H), 8,10 (d, 1H); m/z 1040,83example

1;1
920,78 is 0.86 (m, 6H), of 1.05 to 1.27 (m, 8H), 1,36 is 1.58 (m, 13H), of 1.78 (s, 3H), of 2.23 (s, 3H), 2.77-to of 2.92 (m, 2H), 3,19 (s, 2H), 7,75 (users, 2H), with 4.64 (DD, 2H), 4,72-of 4.77 (m, 1H), of 6.68 (s, 1H), for 6.81 (d, 1H), 7,01 (t, 1H), to 7.09 (d, 2H), 7,27-7,42 (m, 6H), to 7.50 (d, 2H), 8,16 (d, 1H); m/z 812,23example

1;2
930,74 is 0.81 (m, 6H), from 1.0 to 1.22 (m, 8H), 1,29-of 1.62 (m, 13H), to 2.13 (s, 3H), 2,50-of 2.64 (m, 2H), 3,14 (s, 2H), 3,69 (users, 2H), 4,42-4,48 (m, 1H), 4,58 (DD, 2H), of 5.45 (d, 1H), 6,13 (d, 1H), 6,62 (s, 1H), of 6.96 (t, 1H),? 7.04 baby mortality (d, 2H), 7,17-7,21 (m, 3H), 7.23 percent-7,37 (m, 18H), 7,41 (d, 2H), and 8.0 (d, 1H)example

1;

method

113
940,81-0.87 (m, 6H), 1.06 a-of 1.29 (m, 8H), 1,39-to 1.61 (m, 4H), 1,78 (users, 2H), was 1.94 (s, 3H), 2,07-2,17 (m, 1H) 2,20-of 2.27 (m, 4H), and 3.31 (s, 2H), of 3.77 (users, 2H), 3,80 (s, 3H)and 4.65 (DD, 2H), 4,76-4,82 (m, 1H), 5,65-5,70 (m, 1H), 6,69 (s,lH),? 7.04 baby mortality (t,lH), 7,12 (d,2H), 7,29-7,44 (m, 7H), 7,52 (d, 2H), 8,16 (d, 1H)example

1
1tert-Butyl L-(S-trityl)cysteinate hydrochloride: Org. Pre. Proced. Int.; 1999, 31:571-572

2tert-butyl ester S-methyl-L-cysteine: Pestic. Sci.; EN; 45; 4; 1995; 357-362
(a) Tablet Img tablet
Compound X100
Lactose (Ph.Eur)182,75
Sodium crosscarmelloseto 12.0
Pasta corn starch (5% wt./about.)2,25
Magnesium stearate3,0

(b) Tablet IImg tablet
Compound X50
Lactose (Ph.Eur)223,75
Sodium crosscarmellose6,0
Corn starch15,0
Polyvinylpyrrolidone (5% wt./about.)

Pasta
2,25
Magnesium stearate3,0

(C) Tablet IIImg tablet
Compound X1,50
Lactose (Ph.Eur)93,25
Sodium crosscarmellose4,0
Pasta corn starch (5% wt./about.)0,75
Magnesium stearate1,0

(d) Capsulemg/capsule
Compound X10
Lactose (Ph.Eur)488,5
Magnesium stearate1,5

(e)Injection I50 mg/ml
Compound X5,0% wt./about.
0.1 M hydrochloric acid(to bring the pH to 7.6)
The polyethylene glycol 4004.5% wt./about.
Water for injectionUp to 100%

(f)Injection II10 mg/ml
Compound X1.0% wt./about.
Sodium phosphate BP3,6% wt./about.
0.1 M solution of sodium hydroxide15,0% V/V
Water for injectionUp to 100%

(g) Injection III(1 mg/ml buffer, pH 6)
Compound X1.0% wt./about.
Sodium phosphate BPof 2.26% wt./about.
Citric acid0,38% wt./about.
The polyethylene glycol 400a 3.5% wt./about.
Water for injectionUp to 100%

Note

Presents the preparations can be obtained by standard methods, well known in the pharmaceutical field. The tablets (a) - (C) standard methods can be covered intersolubility coating, for example a coating of cellulitecellulite.

1. The compound of formula (I):

where RVand RWindependently selected from hydrogen or C1-6of alkyl;

R1and R2independently selected from C1-6of alkyl;

Rxand Ryindependently selected from hydrogen or C1-6valkila, or one of Rxand Ryrepresents hydrogen or C1-6alkyl and the other represents hydroxyl or C1-6alkoxy;

Rzselected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-6of alkyl, C2-6alkenyl,2-6the quinil, C1-6alkoxy, C1-6alkanoyl,1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanolamine, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl,1-6S(O)andwhere and takes the value from 0 to 2, C1-6alkoxide the onila, C1-6alkoxycarbonyl, ureido, N'-(C1-6alkyl)ureido, N-(C1-6alkyl)ureido, N',N'-(C1-6alkyl)2ureido, N'-(C1-6alkyl)-N-(C1-6alkyl)ureido, N',N'-(C1-6alkyl)2-N-(C1-6alkyl)ureido, N-(C1-6alkyl)sulfamoyl and N,N-(C1-6alkyl)2sulfamoyl;

v takes a value from 0 to 5;

one of R4and R5represents a group of formula (IA):

R3and R6and second of R4and R5independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)andwhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl, and R3and R6and second of R4and R5may be optionally substituted on carbon by one or more R16;

D represents-O-, -N(Ra)-, -S(O)b- or-CH(Ra)-, where Rarepresents a hydrogen is whether C 1-6alkyl, b takes the value from 0 to 2;

ring a represents an aryl or heteroaryl, and ring a is optionally substituted by one or more substituents selected from R17;

R7represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic, and R7is optionally substituted by one or more substituents selected from R18;

R8represents hydrogen or C1-4alkyl;

R9represents hydrogen or C1-4alkyl;

R10represents hydrogen, C1-4alkyl, carbocyclic or heterocyclic, and R10is optionally substituted by one or more substituents selected from R19;

R11represents carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rdor

-P(O)(ORc)(Rd), where Rcand Rdindependently selected from C1-6of alkyl; or R11represents a group of formula (IB):

where X represents-N(Rq)-, -N(Rq)C(O)-, -O -, and-S(O)awhere and takes the value from 0 to 2, and Rqrepresents hydrogen or C1-4alkyl;

R12is dared or C 1-4alkyl;

R13and R14independently selected from hydrogen, C1-4of alkyl, carbocycle, heterocyclyl or R23and specified With1-4alkyl, carbocyclic or heterocyclyl may be independently optionally substituted by one or more substituents selected from R20;

R15represents carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Reor

-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-6of alkyl; or R15represents a group of formula (IC):

where R24selected from hydrogen or C1-4of alkyl;

R25selected from hydrogen, C1-4of alkyl, carbocycle, heterocyclyl or R27and specified With1-4alkyl, carbocyclic or heterocyclyl may be independently optionally substituted by one or more substituents selected from R28;

R26selected from carboxy, sulfo, sulfine, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rgor

-P(O)(ORg)(Rh), where Rgand Rhindependently selected from C1-6of alkyl;

p value is from 1 to 3; where R13may be the same or RA is generated;

q takes a value from 0 to 1;

r takes a value from 0 to 3; where R14may be the same or different;

m takes a value from 0 to 2; where R10may be the same or different;

n takes values from 1 to 3; where R7may be the same or different;

z takes a value from 0 to 3; where R25may be the same or different;

R16, R17and R18independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxy, C1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)andwhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl and N,N-(C1-4alkyl)2sulfamoyl; where R16, R17and R18may be independently optionally substituted on carbon by one or more R21;

R19, R20, R23, R27and R28independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxy, carbamoyl, mercapto, sulfamoyl,1-4 of alkyl, C2-4alkenyl,2-4the quinil,1-4alkoxy, C1-4alkanoyl,1-4alkanoyloxy, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkanolamine, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)2carbamoyl,1-4S(O)andwhere and takes the value from 0 to 2, C1-4alkoxycarbonyl, N-(C1-4alkyl)sulfamoyl, N,N-(C1-4alkyl)2sulfamoyl, carbocycle, heterocyclyl, sulpho, sulfine, amidino, phosphono, P(O)(ORa)(ORb), -P(O)(OH)(ORa),

-P(O)(OH)(Ra) or-P(O)(ORa)(Rb), where Raand Rbindependently selected from C1-6of alkyl; and R19, R20, R23, R27and R28may be independently optionally substituted on carbon by one or more R22;

R21and R22independently selected from halogen, hydroxyl, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifloromethyl, cryptomelane, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethinyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesila, N-methylcarbamoyl and N,N-dimethylsulphamoyl;

or its pharmaceutically acceptable salt, MES or with ivat of such salt.

2. The compound of formula (I) according to claim 1, where Rvand Rwboth represent hydrogen, or its pharmaceutically acceptable salt, MES or MES of such salt.

3. The compound of formula (I) according to claim 1 or 2, where R1and R2independently selected from ethyl, propyl or butyl, or its pharmaceutically acceptable salt, MES or MES of such salt.

4. The compound of formula (I) according to any one of claims 1 to 3, where Rxand Ryboth represent hydrogen, or its pharmaceutically acceptable salt, MES or MES of such salt.

5. The compound of formula (I) according to any one of claims 1 to 4, where Rzselected from halogen, amino, C1-6of alkyl, C1-6alkoxycarbonyl or N'-(C1-6alkyl)ureido, or its pharmaceutically acceptable salt, MES or MES of such salt.

6. The compound of formula (I) according to any one of claims 1 to 5, where v is 0 or 1, or its pharmaceutically acceptable salt, MES or MES of such salt.

7. The compound of formula (I) according to any one of claims 1 to 6, where R3represents hydrogen, or its pharmaceutically acceptable salt, MES or MES of such salt.

8. The compound of formula (I) according to any one of claims 1 to 7, where R4or R5that is not a group of formula (IA)selected from hydrogen, halogen, C1-4alkoxy or1-4S(O)andwhere and takes the value from 0 to 2; and the specified R4and the and R 5may be optionally substituted on carbon by one or more R16; where R16independently selected from hydroxyl, carboxy, and N,N-(C1-4alkyl)2amino, or its pharmaceutically acceptable salt, MES or MES of such salt.

9. The compound of formula (I) according to any one of claims 1 to 8, wherein R5represents a group of formula (IA) (1) and R4represents methylthio, or its pharmaceutically acceptable salt, MES or MES of such salt.

10. The compound of formula (I) according to any one of claims 1 to 9, where R6represents hydrogen, or its pharmaceutically acceptable salt, MES or MES of such salt.

11. The compound of formula (I) according to any one of claims 1 to 10, where a group of formula (IA)

D represents-O - or-S-;

ring a represents a phenyl, thienyl or indolyl; where ring a is optionally substituted by one or more substituents selected from halogen, hydroxyl, methoxy or trifloromethyl;

R7represents hydrogen, methyl or phenyl;

R8represents hydrogen or methyl;

R9represents hydrogen or methyl;

R10represents hydrogen;

m takes a value from 0 to 2, and R10may be the same or different; and

R11PR is dstanley a carboxy, -P(O)(OH)(OEt) or a group of the formula (IB), presents in claim 1,

or its pharmaceutically acceptable salt, MES or MES of such salt.

12. The compound of formula (I) according to any one of claims 1 to 11, where a group of formula (IB)

R12represents hydrogen or methyl;

R13represents hydrogen, methyl, ethyl, butyl, phenyl, or R23and R13is optionally substituted by one or more substituents selected from R20where R20represents hydroxyl, methylthio, methoxy, amino, imidazolyl or mercapto, and R20may be independently optionally substituted on carbon by one or more hydroxyl; R23represents carboxy;

X represents-NH - or-NHC(O)-;

R14selected from hydrogen, methyl or phenyl, with the specified methyl or phenyl may be optionally substituted by one or more substituents selected from hydroxyl;

R15represents carboxy, sulfo, phosphono,

-P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from methyl or ethyl, or R15represents a group of formula (IC), presents in claim 1;

p value is from 1 to 3, where the values of R13can biodiscovery or different;

q takes a value from 0 to 1; and

r takes a value from 0 to 3, where the values of R14may be the same or different;

or its pharmaceutically acceptable salt, MES or MES of such salt.

13. The compound of formula (I) according to any one of claims 1 to 12, where a group of formula (IC)

R24represents hydrogen;

R25represents hydrogen;

R26represents carboxy; and

Z takes a value of 1;

or its pharmaceutically acceptable salt, MES or MES of such salt.

14. The compound of formula (I) according to any one of claims 1 to 3, where

RVand RWboth represent hydrogen;

R1and R2independently selected from C1-4of alkyl;

RXand Ryboth represent hydrogen;

RZselected from halogen, amino, C1-6of alkyl, C1-6alkoxycarbonyl or N'-(C1-6alkyl)ureido;

v is 0 or 1;

R3and R6represent hydrogen;

one of R4and R5represents a group of formula (IA), presents in claim 1, and the second is selected from hydrogen, halogen, C1-4alkoxy or1-4S(O)andwhere and takes the value from 0 to 2; and specified R4and R5may be optionally substituted n is the carbon one or more R 16where R16independently selected from hydroxyl, carboxy, and N,N-(C1-4alkyl)2amino;

D represents-O - or-S-;

R7represents hydrogen, methyl or phenyl;

R8represents hydrogen or methyl;

ring a represents an aryl or heteroaryl; where ring a is optionally substituted by one or more substituents selected from R17; where R17selected from halogen, hydroxyl, C1-4the alkyl or C1-4alkoxy, and R17may be optionally substituted on carbon by one or more R21; where R21selected from halogen;

R9represents hydrogen or methyl;

R10represents hydrogen;

R11represents carboxy, -P(O)(OH)(ORc), where Rcselected from C1-4the alkyl or a group of the formula (IB) (1);

R12represents hydrogen or methyl;

X represents-NH - or-NHC(O);

R13represents hydrogen, C1-4alkyl, carbocyclic or R23; where R13is optionally substituted by one or more substituents selected from R20; where R20represents hydroxyl,1-4S(O)andwhere and takes the value 0, C1-4alkoxy,amino, carbocyclic, heterocyclyl or mercapto; where R20may be independently optionally substituted on carbon by one or more R22where R22selected from hydroxyl; and R23represents carboxy;

R14selected from hydrogen, C1-4the alkyl or carbocyclic; where the specified C1-4alkyl or carbocycle may be optionally substituted by one or more substituents selected from R20where R20represents a hydroxyl;

R15represents carboxy, sulfo, phosphono,

-P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re) or-P(O)(ORe)(Rf), where Reand Rfindependently selected from C1-4of alkyl; or R15represents a group of formula (IC), presents in claim 1;

R24represents hydrogen;

R25represents hydrogen;

R26represents carboxy;

p value is from 1 to 3; where R13may be the same or different;

q takes a value from 0 to 1;

r takes a value from 0 to 3; where R14may be the same or different;

m takes a value from 0 to 2; where R10may be the same or different;

n takes a value from 1 to 2; where values Rsup> 7may be the same or different;

z takes a value from 0 to 1, where values of R25may be the same or different;

or its pharmaceutically acceptable salt, MES or MES of such salt.

15. The compound of formula (I) according to any one of claims 1 to 14, selected from the group including:

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(carboxymethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbarnoyl]methyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N - {(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-carboxyethyl)carbarnoyl]benzyl}carb is olmetec)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(carboxyethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(5-carboxypentyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N - {(R)-α-[N'-(2-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N{α-[N'-(2-sulfoethyl)carbarnoyl]-2-terbisil}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N - [(R)-α-(N'-{(R)-1-[N"-(R)-(2-hydroxy-1-carboxyethyl)carbarnoyl]-2-hydroxyethyl}carbarnoyl)benzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N{α-[N'-(carboxymethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N'-(ethoxy)(methyl)phosphorylmethyl)carbarnoyl]benzyl}carbarnoyl-methoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbarnoyl)benzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-methylthio-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbarnoyl)-4-hydroxybenzyl]carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N - [(R)-α-(N'-{2-[(methyl)(hydroxy)phosphoryl]ethyl})carbarnoyl)-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N'-(2-methylsulfinyl-1-carboxyethyl)carbarnoyl]benzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; and

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-[N-{(R)-α-[N'-(2-sulfoethyl)carbarnoyl]-4-hydroxybenzyl}carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

or its pharmaceutically acceptable salt, MES or MES of such salt.

16. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 1: oxidation benzodiazepine formula (II):

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

17. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 2): for compounds of formula (I), where D represents-O-, -NRaor-S-; the interaction of the compounds of formula (IIIa) or (IIIb):

with the compound of the formula (IV):

where L represents a substitutable group;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

18. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 3: interaction of the acid of formula (Va) or (Vb):

or its activated derivative with an amine of formula (VI):

and further, if necessary or desirable:

i) PR is the rotation of the compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

19. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 4): for compounds of formula (I), where R11represents a group of formula (IB); the interaction of the compounds of formula (I), where R11represents carboxy, amine of formula (VII):

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

20. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 5): for compounds of formula (I), where R11represents carboxy; removing the protective group in the compound of formula (VIIIa):

or (VIIIb):

where Rprepresents a C1-4alkyl;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

p num="1254"> iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

21. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

method 6): for compounds of formula (I), where R11represents a group of formula (IB) and R15represents carboxy, removing the protective group from compounds of formula (IXa):

or (IXb):

where Rprepresents a C1-4alkyl, and the other values of the radicals defined above;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

22. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

for compounds of formula (I)where one of R4and R5independently selected from C1-4alkylthio, optionally substituted on carbon by one or more R16; the interaction of the compounds of formula (XA) or (Xb):

where L represents a substitutable group, and other values radicals ODA is defined above, with a thiol of the formula (XI):

where Ryrepresents a C1-4alkylthio, optionally substituted on carbon by one or more R16;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

23. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

for compounds of formula (I), where R15represents a group of formula (IC), the interaction of the compounds of formula (IXa) or (IXb), where Rprepresents hydrogen, with a compound of formula (XII):

where the values of the radicals defined above;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

24. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

for compounds of formula (I), where R11represents a group of formula (IB), R15pre is is a group of formula (IC) and R 26represents carboxy; removing the protective group from compounds of formula (XIIIa):

or (XIIIb):

and Rprepresents a C1-4alkyl, and the other values of the radicals defined above;

and further, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

25. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 15, which includes

for the compounds of formula (I), where X represents-N(Rg)C(O)-; the interaction of the compounds of formula (XIVa):

or (XIVb):

with the compound of the formula (XV):

where the values of the radicals defined above;

and then, if necessary or desirable:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups;

iii) obtaining a pharmaceutically acceptable salt, MES, MES or MES of such salt.

26. The compound of formula (I) or f is matemticas acceptable salt, MES or MES such a salt according to any one of claims 1 to 15 as an active ingredient of the medicinal product, suitable for receiving inhibitory effect against IBAT warm-blooded animal such as man.

27. The method of obtaining inhibitory effect against IBAT warm-blooded animal, such as man, in need of such treatment, comprising the introduction of a specified animal an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or MES such a salt according to any one of claims 1 to 15.

28. Pharmaceutical composition having inhibitory activity against IBAT, which includes a compound of formula (I) or its pharmaceutically acceptable salt, MES or MES such a salt according to any one of claims 1 to 15 in combination with a pharmaceutically acceptable diluent or carrier.

29. The pharmaceutical composition according p, which further includes an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES or MES of such salt.

30. The pharmaceutical composition according p, which additionally contains a substance, bile acid binding.

31. The pharmaceutical composition according p, which further includes an inhibitor of HMG Co-A reductase inhibitor or its pharmaceutically acceptable salt, MES or MES such salts and substance, vyzyvayuschee bile acids.

32. The composition according to clause 29 or 31, where the inhibitor of HMG Co-A reductase represents atorvastatin or its pharmaceutically acceptable salt, MES or MES of such salt.

33. The composition according to clause 29 or 31, where the inhibitor of HMG Co-A reductase is a rosuvastatin or its pharmaceutically acceptable salt.

34. The pharmaceutical composition according p, which additionally contains alpha and/or gamma PPAR agonist or its pharmaceutically acceptable salt.

35. The composition according to clause 34, where alpha and/or gamma agonist PPAR represents (S)-2-ethoxy-3-[4-(2-{4-methysulfonylmethane}ethoxy)phenyl]propanoic acid or its pharmaceutically acceptable salt.

36. A compound selected from compounds of the formulas (VIIIa), (VIIIb), (IXa), (Xb), (XIIIa) and (XIIIb)

and Rprepresents a C1-4alkyl, and the other values of the radicals defined in claim 1, or its pharmaceutically acceptable salt, MES or MES of such salt.



 

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The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

Thrombin inhibitors // 2178796

The invention relates to medicine, namely to methods of producing biologically active substances with immunoregulatory properties, and may find application in medicine,veterinary medicine and experimental biochemistry

The invention relates to medicine, namely to methods of producing biologically active substances with immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry

The invention relates to new N-(-substituted pyridinyl)caronel-dipeptides, which have activity as inhibitors of the enzyme that promotes the conversion of angiotensin
The invention relates to a method of crystallization by cooling methyl ester of alpha-L-aspartyl-L-phenylalanine (hereinafter AWS), which is likely to find wide application as a low-calorie zacharopoulou substance because it has the sweetness of high quality and is approximately 200 times sweeter than sugar

The invention relates to the synthesis of biologically active compounds, in particular to new derivatives of N-phenylglycinate formula

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the way they are received and to farbkomposition based on them

FIELD: organic chemistry, medicine, biology.

SUBSTANCE: invention relates to novel derivatives of thiazole that are strong antagonists, agonists or partial agonists of cannabinoid CB1 receptors. Compounds show the general formula (I): wherein R and R1-R4 have values given in the invention claim. Also, invention relates to using compounds of the formula (I) or their stereoisomers for preparing a pharmaceutical composition. Also, invention relates to intermediate compounds of the formula (V): wherein R2 and R8 have values given in the invention claim.

EFFECT: valuable medicinal and biological properties of compounds.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of phenoxy-N-[4-(1,1-dioxoisothiazolidin-2-yl)-valeramide and describes compounds of the formula (I): wherein E represents phenyl or isoquinoline each of that is monosubstituted with group R1 wherein R1 represents -CN, amidino-group, halogen atom, -NH2, -CH2NH2 or compound of the formula: W represents -OCHAr', -OCHA, -NHCHAr', -NHCHA, -NHCOOCHAr', -NHCONHCHAr' or piperidine-1,2-diyl; Ar' represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; A represents alkyl with 1, 2, 3, 4, 5, 6 or 7 C-atoms; X represents -CONH; Y represents Ar-diyl; T represents group -(CH2)3; Ar represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; Hal represents fluorine (F), chlorine (Cl), bromine (Br) or iodine (J) atoms. These compounds are the coagulation factor Xa inhibitors. Also, invention relates to a method for synthesis of compounds of the formula (I), a medicinal agent containing these compounds and using compounds of the formula (I) for preparing a drug used in treatment of thrombosis, myocardium infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, restenosis after plastic surgery in vessels, intermittent lameness, migraine, tumors, tumor diseases and/or tumor metastasis and a kit (set). Also, invention relates to intermediate compounds of the formula (I-1): wherein R1 represents -NO2 or -NH2; R represents methyl, chlorine atom or trifluoromethyl and their salts. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 14 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes substituted benzoylpyrazoles of the general formula (I): wherein Q means oxygen atom (O); R1 means alkyl with 1-6 carbon atoms; R2 means hydrogen atom; R3 and R4 mean independently of one another hydrogen atom, halogen atom, alkyl with 1-4 carbon atoms substituted with halogen atom; R5 means hydrogen atom, alkyl with 1-6 carbon atoms; Y means hydrogen atom; Z means alkoxyamino-group with 1-6 carbon atoms, alkylamino-group with 1-6 carbon atoms, substituted alkoxy-group with 1-4 carbon atoms, N-alkylalkoxyamino-group with 1-4 carbon atoms, phenyl substituted with halogen atom, monocyclic heterocyclyl, heterocyclylamino-group, group -N=(heterocyclyl) chosen from the group: furyl, tetrahydrofurylmethylamino-group, isoxazolyl, dihydroisoxazolyl (isoxazolinyl), tetrahydroisoxazolyl (isoxazolidinyl), tetrahydro-(2H)-1,2-oxazine-2-yl, dihydrothiazolyl (thiazolinyl), oxadiazolylamino-, thiadiazolylamino-group, piperidinyl, piperidinylamino-group, 2-oxo-1,3-diazacyclohexyl, morpholinyl, morpholinylamino-group, respectively, and substituted if necessary with alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms involving their all possible tautomeric forms and possible salts. Also, invention describes a herbicide agent based in proposed compounds. Proposed compounds possess herbicide activity.

EFFECT: valuable properties of compounds and agent.

4 cl, 5 tbl, 77 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes novel derivatives of thiazole that able for effective binding and activating PPARα and/or PPARγ simultaneously and, respectively, combine antiglycemic effect caused by activation of PPARγ with anti-dyslipidemic effect caused by activation of PPARα. Also, the claim describes compounds of the formula (I): wherein substitutes from R1 to R10 as well as X and Y are determined in the description and invention claim, and their pharmaceutically acceptable salts and esters also. Also, the proposed invention describes pharmaceutical compositions possessing antagonistic activity with respect to PPARα and/or PPARγ comprising compound of the formula (I) as an active component and pharmaceutically acceptable carrier and/or additive. Except for, the invention proposes claimed compounds as therapeutically active substances for treatment and/or prophylaxis of diseases mediated by agonists of PPARα and/or PPARγ, such as diabetes mellitus, non-insulin dependent diabetes mellitus, elevated blood pressure, increased level of lipids and cholesterol, atherosclerotic diseases, metabolic syndrome, endothelial dysfunction, procoagulant state, dyslipidemia, ovary polycystic syndrome, inflammatory or proliferative diseases.

EFFECT: valuable medicinal properties of compounds.

27 cl, 140 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to using compounds represented by the general formula (II): wherein Ra and Rb are chosen independently from hydrogen atom, alkyl, cycloalkyl, aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)n-aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)nC(O)OR3; Z is chosen independently from -C(R3)(R4)-; R3 and R4 are chosen independently from hydrogen atom, alkyl and 6-membered cycle with nitrogen atom as a heteroatom; n has values 0, 1 or 2; X and Y are chosen independently from =O, =S and =N(R3). These compounds are active component in preparing a pharmaceutical composition designated in treatment of diseases wherein glycogen synthase-kinase 3-beta (GSK-3) is involved. Also, invention relates to compounds represented by the general formula (II) wherein Ra is chosen from -CH2Ph, -CH2CO2Et, 4-OMePh, 4-MePh and 4-BrPh; Rb is chosen from Me and -CH2CO2Et; X and Y represent =O. Also, invention relates to a pharmaceutical composition possessing GSK-3-inhibitory activity and containing compound of the general formula (II) as an active component. Invention provides using heterocyclic inhibitors of glycogen synthase-kinase-3β.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

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