UA77209C2 - Benzothiazepine and benzothiadiazepine derivatives inhibiting bile acid ileal transfer, their use for treatment of hyperlipidaemia, method for their manufacture (variants), pharmaceutical composition (variants) - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein Rv, R1, R2, Rx, Ry, M, Rz, v, R3, R4, R5 and R6 are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described. , (I)

Description

C 71209 4 alkyl)gamino, C1i-Cv-alkyl(O)z, where a represents d' in HF) ze Y Vi

M is selected from -M- or -CH-; on the day of St

AB: selected from halogen, nitro group, cyano group, from SHIELD of hydroxyl group, amino group, carboxyl de group, carbamoyl, mercapto group, sulfamoyl, (C)

C-Cv-alkyl, C-Cv-alkenyl, C-Cv-alkynyl, C1-Cv- (IV) -alkyl)amino, M,M-(C1-Cv-alkyl)gamino, C1-Cv- M represents -M(B7)-, -M(VUZS(0)-, - alkanoylamino, M-(C1-Cv -alkyl)ucarbamoyl, M,M-(С1- M(ВС(ОСеЗАОЗМ(ВЙ)С(0)-, -О- and -З(О)а-); where a

C-Cv-alkyl)carbamoyl, C-Cv-alkyl(O) a, where a represents 0-2, m represents 1-2, B: and B! independently 0-2, C1-C8-alkoxycarbonyl, /M-(C1-C1- independently selected from hydrogen or C1-C1-alkyl, neoalkyl) usulfamoyl and M,M-(C1-C1- substituted Re, and B" represents hydrogen or alkyl)sulfamoyl; Ci-Ca-alkyl; m represents 0-5; VD" represents hydrogen or Ci-Ca-alkyl; one of P" and KE? is a group of formula (IA): BZ and B! are independently selected from hydrogen, C1-C6-alkyl, carbocycle, or heterocycle; and when 4 is 0,

B" can additionally be selected from the hydroxyl group; where "From Her B!" is not necessarily independently substituted by one or more substituted M ps selected from 220; d | B! represents is a carboxyl group, a sulfo group, a sulfino group, a phosphono group,

RIFHONHONU), -RIOHONUI(KU) or -RIOHONHN, (IA) de Re and V! independently selected from C1-Segalkilu;

VAZ and Re and another of P" and EZ are independently selected from hydrogen, and A can be a halogen, a nitro group, a cyano group, a hydroxyl group, an amino group, a carboxyl group, a carbamoyl group are 0-3, where B'E values can be LU, mercaptogroup, sulfamoyl, C1i-Cα-alkyl, Co- the same or different:

C.4-alkenyl, C2-Ca-alkynyl, C-C-alkoxy, C1-C4- t is 0-2; where the values of Vo can be alkanoyl, C-C-alkanoyloxy, M-(C1-C4- the same or different: alkyl)amino, M,M-(C1-Ca-alkyl)gamino, C-C4-n is 1- 3; where the values of B7 can be alkanoylamino, M-(C1-Cα-alkyl)ucarbamoyl, M,M-(C1-) the same or different:

Ca-alkyl)zcarbamoyl, C1-C6-alkyl(O)»a, where a represents the ring B is a heterocycle connected to the 0-2 atom of Ci-Ca-alkoxycarbonyl, the nitrogen atom substituted near of a carbon atom with one alkyl sulfamoyl I 8. in g. and sh4 c. in M a group selected from 23, and optionally additionally alkyl)sulfamoyl; some Kk and the other from Kv are not substituted near the carbon atom by one or several can necessarily be substituted near the carbon atom 24; and in which, if the heterocycle is specified,

If there is a penob or several Vo or -CH(B2)-: bound to a nitrogen atom, contains the -МН- part, then it is -0-, "М(Б2Х., -З(О)х- or CH( NUU; where that nitrogen atom may optionally be substituted

Be represents hydrogen or C1-C8-alkyl and B represents a group selected from B25; itself 0-2; | B"E, B" and B!8 are independently selected from halogen, nitrogen

Ring A is aryl or heteroaryl; where rup, cyano group, hydroxyl group, amino group, ring A is optionally substituted with one or more carboxyl group, carbamoyl, mercapto group, with any substituents selected from K g sulfamoyl, C1i-Ca-alkyl, Co-Ca-alkenyl, C2-C4 -

A" represents hydrogen, C1-C6-alkyl, carbocycle alkynyl, C1-C6-alkyl, C1-C6-alkanoyl, C1-C6- or heterocycle; where B" is an optionally substituted alkanoyloxy M-(C1-C6-alkyl )amino M M-(Si-Ca- with one or more substituents selected from alkyl)gamino 'Si-Ca-alkanoylamino "MA(Si-Ca-' or alkyl/ucarbamoyl, M,M-(C1-Ca-alkyl/ 2-carbamoyl,

M is free or fused C-C-alkyl5(O)a, where a is 0-2, C1-C4- and d is Prado; alkoxycarbonyl, /M-(C1-Ca-alkyl)usulfamoyl |i

A" represents hydrogen, C1-C6-alkyl, carbocycle M,M-(C1-C6-alkyl)xsulfamoyl; where P/E, VI? and VIV or a heterocycle; where EC"? optionally substituted independently may optionally be substituted by one or more substituents selected from near the carbon atom by one or more B";

Dy represents a carboxyl group, sulfogroup A", At, B" Its RUs are independently selected from halogen, sulfinogroup, phosphonogroup, -P o oVa(ove ! nitro group, cyano group, hydroxyl group, amino-

In rupu, rug U. RO in another group, carboxyl group, carbamoyl, mercapto-

RIOHONHONOU, "ROHONHNU or ROHOVuv and groups, sulfamoyl, C1-C6-alkyl, C0-C4-alkenyl, where. В A" are independently selected from C-Sehapkyl; or C2-Ca-alkynyl, C-C-alkoxy, C-C-alkanoyl, C-

A" is a group of the formula (IV) or (IC); -(C1-C4-alkyl/ucarbamoyl, M,M-(C1-Ca-alkyl/2-carbamoyl,

Ci-Ca-alkyl5(O)a, where a represents 0-2, Ci1-C4- alkoxycarbonyl, M-(C1-C-alkyl)usulfamoyl,

М,М-(С1-Са-alkylsulfamoyl, carbocycle, hete-

71209 6 rocycle, benzyloxycarbonylamino, (C1-C4- t represents 0; alkyl)psylyl, sulfogroup, sulfinogroup, amide- A" represents a carboxyl group, a fornogroup, a phosphonogroup, -RIOHOVHORE), /- mule (IV) (as shown above) or a formula group

RIFONHOVU), -P(IOHON)(B2U) or -P(IFHOV2) (RU), (IS) (as shown above), in which: where Va and EE? independently selected from Ci-Cv-alkyl; where B": represents hydrogen or Ci-Ca-alkyl;

VU, VO, IDD? | Вб independently can optionally be 1 or 2; be replaced near the carbon atom by one or more VAZ is hydrogen or C-Cv-alkyl, optionally B22; strangely substituted РВ2О, where is 2? is a hydroxy-

B22 is independently selected from halogen, hydroxyl group, carbamoyl, amino group, benzyloxycar group, cyano group, carbamoyl, ureido group, bonylamino, C1-1-C-alkyl(O)a, where a is 0, amino group, nitro group, carboxyl group, car- or (C1-Ca-alkyl)zylyl; bamoyl, mercapto group, sulfamoyl, trifluoro-B" represents a hydrogen or hydroxyl group, a methyl group, a trifluoromethoxy group, methyl, or Ci-Cv-alkyl; where B!" may optionally be ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, meso-substituted with one or more substituents, toxiccarbonyl, formyl, acetyl, formamido selected from 220; acetylamino, acetoxy, methylamino, dimethylami- M represents -M(A")С(О0)-, where КЕ" represents no, M-methylcarbamoyl, M,M-dimethylcarbamoyl, hydrogen; methylthio, methylsulfinyl, mesyl, M-d represents 0 or 1; methylsulfamoyl and M,M-dimethylsulfamoyl; r is 0 or 1;

VAZ represents a carboxyl group, a sulfogroup, B!5 represents a carboxyl group or a sulfo-sulfino group, a phosphonogroup, -P'('ODOVZHOV), - rupa;

RIFHONHONVU), -P(IXHON) (VU) or -P(IOCHOVUI(B"), B" represents a hydroxyl group; and where 5 and B" are independently selected from C1i-C6-alkyl; B2O is selected from a hydroxyl group;

IN? selected from C1i-Cv-alkyl, C1-Cv-alkanoyl, C1- ring B is pyrrolidin-1-yl or azetid-

C-alkylsulfonyl, C-C-alkoxycarbonyl, carnyl substituted near the carbon atom by one group, bamoyl, M-(Ci-Cv-alkyl)ucarbamoyl, -M,M-(C1-Cv- selected from B23), and neoob optionally additionally substituted alkyl/ucarbamoyl, benzyl, benzyloxycarbonyl, substituted near the carbon atom by one or more benzoyl and phenylsulfonyl; B; where BZ is a carboxyl group and B. or a pharmaceutically acceptable salt thereof, the solvate is a hydroxyl group; or a solvate of such salt. or its pharmaceutically acceptable salt, solvate or 2. The compound of formula (I) according to point 1, in which KU is a solvate of such a salt. is hydrogen, or its pharmaceutically acceptable salt, solvate or solvate of such a salt. 10. The compound of formula (I) according to item 1, in which: 3. The compound of formula (I) according to item 1 or 2, in which A" is hydrogen;

IN! and B2 both represent butyl, or its far- B and E2 both represent butyl; a pharmaceutically acceptable salt, solvate or solvate of Ah and VU both represent hydrogen; such salt. M represents -M-; 4. The compound of formula (I) according to any of items 1-3, m represents 0; in which EH and KU both represent hydrogen, or its VZ and 25 represent hydrogen; a pharmaceutically acceptable salt, solvate or so- B" represents bromine, methyl or methylthio; and the levate of such a salt. 4, (carboxyme- in which M is -M-, or its pharmaceutically tyl)carbamoylIbenzyl)carbamoylmethoxy, /-M-(A)- an acceptable salt, solvate or solvate of such a salt. and 4m- 6. Compound of formula (I) according to any of items 1-5, in which m is 0, or its pharmaceutic equivalent (arboxymeb) M-(including a salt, solvate or solvate of such a salt. tylucarbamoyl|benzylcarbamoylmethoxy, -()- 7. The compound of formula (I) according to any of clauses 1-6, o (M-(2-sulfoethyl)carbamoyl|-4- in which EC? and P? are hydrogen, or its pharma- hydroxybenzyl)carbamoylmethoxy, /M -(A)- 9 -(M- a pharmaceutically acceptable salt, solvate or solvate of ((8)-1-carboxy-2- such a salt. hydroxyethyl)ucarbamoyl|benzyl)carbamoylmethoxy, 8. The compound of formula (I) according to any from points 1-7, d(vu. About tm /(2u.4- nak ! М-А()- 7 МАМ-(5)-1 in which K" represents bromine, met l or methylthio, carboxyethyl)carbamoyl|benzyl)carbamoylmethoxy, or a pharmaceutically acceptable salt, solvate or a solvate of such a salt. as Y 9. The compound of formula (I) according to any of clauses 1-8, - in which o of the formula PA) (as zo- propyl)ucarbamoyl|benzylcarbamoylmethoxy, /- M-(A)- fermented in item 1), in which: 0 -IM-(P)-1-carboxy-2-

X represents -O-; methylthio ring A is phenyl, optionally methyl)carbamoyl|benzylcarbamoylmethoxy, /-M-(HA)- substituted with one or more substituents, selected OK DM-((5)-1-carboxy-2-carbamoyl - by them with B"; ethyl)carbamoyl|benzylcarbamoylmethoxy, -M-(B)- looks like one: "7M-(-sulfoethyl)carbamoyl 4-

VZ is hydrogen; hydroxybenzyl)carbamoylmethoxy, М-А(()- У -|(М-

VAZ is hydrogen; (carboxymethyl)carbamoyl|-4-

hydroxybenzyl)carbamoylmethoxy, /M-(B)- E -(M- dimethylbu- Y Y ((5)-1-carboxyethyl)carbamoyl|-4- tyl)ucarbamoyl|benzyl)carbamoylmethoxy, /-M-(HA)- hydroxybenzylcarbamoylmethoxy, (/ M-(B)- E -G(M- o. MAK) -carboxy-3,3- ((5)-1-carboxy-2-hydroxyethyl)carbamoyl|-4- dimethylbutyl)carbamogl|- 4-4 hydroxybenzylcarbamoylmethoxy, M-(B)- E -/M-(2- hydroxybenzyl)carbamoylmethoxy, MAN) -(M- sulfoethyl)carbamoylIbenzyl)carbamoylmethoxy, (5)-1-carboxy-2-(trimethylsilyl)ethyl| carbamoyl-m-((вВ)-9-IM-((8)-1-carboxy-2-(В)-4-hydroxybenzyl)carbamoylmethoxy or M-(В)-Е - hydroxypro- (М-КА)- 1-carboxy-2-Pyl)ucarbamoyl|benzylcarbamoylmethoxy, (/- M-(B)- (trimethylsilyl)ethyl|carbamoyl)-4- o. M-((8)-1-carboxy-2-hydroxybenzyl)carbamoylmethoxy;

And "car b tpib b . or its pharmaceutically acceptable salt, solvate or methypropyl) car amoyl|benzylcarbamoylmethoxy, solvate of such a salt.

MAC) 7 PIT). 1-carboxy-3-Y 11. The compound of formula (I) according to item 1, selected from: methylbutyl)carbamoyl|benzyl)carbamoylmethoxy, 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 -(M-

M-((c)-95 (M-(1-(8)-1-carboxy-2-(5)-2-cv)-9-IM-((B)-1-carboxy-2-methylbutyl) carbamoyl|benzylcarbamoylmethoxy, methylthioethyl)carbamoyl|-4-

M-(B)- 0 -carboxy-4-hydroxybenzylcarbamoylmethoxy)-2,9,4,5- hydroxybenzyl)carbamoylmethoxy, (/-M-(B)- 9 -(M- tetrahydro-1,2,5-benzothiadiazepine ; ((5)-1-carboxy-4-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-aminobutyl)carbamoylIbenzylcarbamoylmethoxy, (v. 0. -IM-( 5U1 -carboxy-2-(B)-

Mm-(B)- and -M-(8)-1-carboxy-4-hydroxypropyl)carbamoyl-4- (benzyloxycarbonylami-Phydroxybenzylcarbamoylmethoxy 28lB: b b tpib b « M- tetrahydro-1,2,5-benzothiadiazepine; but ) utilikar amoyl) enzilukar amoylmethoxy, 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-

I()- Я -((5)-2-carboxypyrrolidine-1-y: ((B)- Y -|M- methylpropyl)carbamoyl|-4- (carboxymethyl)-M- Y hydroxybenzylcarbamoylmethoxy)-2,3,4,5- methylcarbamoyl|benzyl)carbamoylmethoxy, M-(A)- tetrahydro-1 ,2,5-benzothiadiazepine; ok DM-(1-(8)-2-(8)-1-carboxy-1-hydroxyprop-2-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M - yl)ucarbamoyl|benzyl)icarbamoylmethoxy, M-cV)- - (c)- 0 -(IM-((5)-1-carboxybutyl)carbamoyl|-4-

IM- hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- (sulfome-tetrahydro-1,2,5-benzothiadiazepine; tyl)carbamoyl|Ibenzylcarbamoylmethoxy, /- M-(B)- 1,1-dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-(M-0.carboxybenzyl)carbamoylmethoxy, /-M-(B)- 9 - cvB)- 9 1M-((8)-1-

IM-((5)-1-carboxy-2-(H)-hydroxypropyl)carbamoyl|- carboxypropyl-4-hydroxybenzyl)carbamoylmethoxy, /-M-(B)- 9 -|M- pylucarbamoylIbenzyl)carbamoylmethoxy)-2, 3,4,5- ((5)-1-carboxy-2-methylpropyl)carbamoyl|-4-tetrahydro-1,2,5-benzothiadiazepine; hydroxybenzylcarbamoylmethoxy, m-CV)- 9 -(M- 1 "dioxo Z. dibutyl-5-phenyl-7-methylthio 8 (M. ((8)-1-carboxybutyl)carbamoyl|-4- KH). -IM- (8)-1- hydroxybenzyl)carbamoylmethoxy, m-cV)- 9 -IM- brownoxyvy e ((8)-1-carboxypropyl)carbamoyl-4- tylucarbamoylIbenzylcarbamoylmethoxy)-2,3,4,5- y y y tetrahydro- 1,2,5-benzothiadiazepine; pdroxybenzylcarsamoylmethoxy, 6 and Chm-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-c)-1-carboxy-"methylthioethyl)car amoyl|- and ctSh- 4M-(8)-1-carboxy-2-(B)- hydroxybenzylcarbamoylmethoxy, M-(()- Ux -(M- hydroxypro- ((5)-1-carboxypropyl)carbamoyl|)- 4- phenyl)ucarbamoyl|benzyl)carbamoylmethoxy)-2,3,4,5- hydroxybenzylcarbamoylmethoxy, M-cV)- -(IM- tetrahydro-1,2,5-benzothiadiazepine; 1(5)-1-(M- ((5)-2-hydroxy-1-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M- carboxyl -sulfoethyl)carbamoyl|-4-thyl)carbamoyl|propyl)ucarbamoyl|benzyl)carbamoyl hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- methoxy, M-cV)- -(2-(5)-2-( carboxy)-4-(H)-4-tetrag hydro-1,2,5-benzothiadiazepine; (hydroxy)pyrrolidine-1-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-ylcarbonylbenzyl)carbamoylmethoxy, M-(B)- E -(2- cv)- 9-IM-((8)-1-carboxyethyl)carbamogly|-4-(5)-2-(carboxy)azetidine-1-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-ylcarbonylbenzyl)carbamoylmethoxy, M- (B)- 9 -(M- tetrahydro-1,2,5-benzothiadiazepine; ((8)-1-IM-((8)-1- 1,1-dioxo-3,3-dibutyl-5-phenyl -7-methylthio-8-(M-carboxyev-cv)-I IM-(B)-1-carboxy-2-yl)carbamoyl|ethylcarbamoyl|benzylcarbamoyl methylthio-ethoxy, m-(B)-9-IM-( (B)-1-carboxy-3,3-thyl)carbamoyl|benzyl)icarbamoylmethoxy)-2,3,4,5-dimethylbut-tetrahydro-1,2,5-benzothiadiazepine; tyl)carbamoyl|benzyl)carbamoylmethoxy, /- M-(B)- 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M- 0 -IM-((5)- 1 -carboxy-3,3- (- 0 -IM-((5)-1 -IM-((5)-2-hydroxy- 1 -

9 71209 10 carboxyl- o boju la boju l tyl)carbamoyl|propyl)ucarbamoyl|rensylucarbamoyl osn В в! in ZM ov! methoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine ve v and B and M vx and M V 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio- 8-(M- and B B ; C what

Cv)-9-IM-((5)-1-carboxy-2-methylpro- (c), (5 pyl)ucarbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-(mo)tetrahydro-1,2, 5-benzothiadiazepine; (Ma) , or its pharmaceutically acceptable salt, solvate or its activated derivative with an amine of the formula or a solvate of such a salt. (M): 12. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or solvate of such a salt according to any of items 1 - 11 for use as a medicinal product. МН 13. The compound of formula (I) or its pharmaceutically acceptable salt, solvate or solvate of such a salt according to any of items 1 - 11 for use in the form of prophylaxis or therapeutic treatment of a warm-blooded animal, such as a person. and then, if it is necessary or desirable: 14. The method of obtaining a compound of formula (I) by i) converting a compound of formula (I) into another compound by any of items 1-11, in which X represents -O-, ku formulas (1); -MAg or -5-; or its pharmaceutically acceptable i) removal of any protective groups; , a salt, a solvate or a solvate of such a salt, which includes) the formation of a pharmaceutically acceptable salt, tea: a solvate or a solvate of such a salt. the reaction of the compound of formula (Ia) or (NAME): 16. The method of obtaining the compound of formula (Y) according to any of clauses 1-11, in which B'! is

Wo Oh / Nh Oy / formula group (IV); or its pharmaceutically acceptable

Z-M in! ZM of a salt, solvate or solvate of such a salt, which includes: in the reaction of a compound of formula (I), where E!! is

Н M where where: M where a carboxyl group, with an amine of the formula (MI):

In VU In VU d'i dz (B, (B This (Mu) . (Pa) , (pr) and then, if it is necessary or desirable: with the compound of the formula (II): i) conversion of the compound of the formula (I) into another compound of formula (1); iii) removal of any protective groups; c) formation of a pharmaceutically acceptable salt,

M solvate or a solvate of such a salt. "Ве | n 17. The method of obtaining a compound of formula (I) according to Ве /В/ any of items 1-11, in which one of P" and E? independently selected from Ci-Cv-alkylthio, which is optionally (I) substituted near the carbon atom by one or where I is a displacing group; by several AT or its pharmaceutically acceptable and then, if necessary or desirable: a salt, a solvate or a solvate of such a salt, which includes : teas: compounds of the formula (I) in another reaction of compounds of the formula (Mia) or (M): i) removal of any protective groups; vo i o, u v o, u iii) the formation of a pharmaceutically acceptable salt, ZM ovi and Z-M V! solvate or a solvate of such a salt. 15. The method of obtaining the compound of the formula (I) according to any of items 1-11 or its pharmaceutically acceptable salt, solvate or solvate of such a salt, which includes: the reaction of the acid of the formula (IMa ) or (MB): (well (ve, (Ua) ; (MI)

11 71209 12 where I. represents a group that is displaced; with the body I" yaz t . o o formulas (MIP): then Ets x BD ,

A"-H, (MIP) yayu re r, Ma am . . m in which KE" is a C-Cv-alkylthio, which is necessarily substituted near the carbon atom by one or in In several B/5: and then, if necessary or desirable: (BZ, i) conversion of a compound of formula (I) into another compound of formula 0; | in which P together with the group -OS(O)-, to which it accepts) removal of any protective groups; And | dnany, forms a complex ester; iii) the formation of a pharmaceutically acceptable salt, and then, if necessary or desirable: a solvate or solvates of such a salt. i) conversion of the compound of formula (I) into another compound 18. The method of obtaining the compound of formula (I) according to formula (1); any of items 1-11, in which B'! represents i) removal of any protective groups; carboxyl group; or Its pharmaceutically acceptable salt) formation of a pharmaceutically acceptable salt, soluble salt, solvate or solvate of such a salt, solvate or solvate of such a salt which includes: | 20. The method of obtaining a compound of the formula (I) by deprotection of a compound of the formula (IXa): by any of items 1-11, in which B'I represents ВО; ' - in the 8th group of the formula (IV) and MSH(K")C(O)-; or its pharmacists-

But where is the technically acceptable salt, solvate or solvate of a large salt, which includes: ve 7x Mch reaction of the acid of the formula (Xia):

Ge) Ge) v3 VU where u

In ohm / and about in? vya Vod Zm v' (ve | I g

M M ih M y (ha) y ". y I I, I or (IHB): dz i b ve o o kh v o, M ud that 5- to t as We (khiv) ve . otv shk zbo (Khi ); (O)-, to which it is added, forms an ester; and then, if necessary or desirable: kiv) (83), i) conversion of a compound of formula (I) into another compound or its activated derivative with amine of the formula ku formula (1); (XI)): ii) removal of any protective groups; where i) formation of a pharmaceutically acceptable salt, solvate or solvate of such a salt. M 19. The method of obtaining the compound of formula (I) according to any of items 1-11, in which B'! is a ve group of the formula (IV) and 25 is a carboxyl (XI) group; or its pharmaceutically acceptable salt, I I E I solvate or solvate of such a salt, which includes: and then, if necessary or desirable: deprotection of the compound of formula (Xa): i) conversion of the compound of formula (I) into another compound to / to the formula (1); o Ve ovo Ve B 5-M Vi ) removal of any protective groups; And ve | and ii) formation of a pharmaceutically acceptable salt,

VO x) m M their MA solvate or solvate of such a salt. ' and R ve because her o iv! in: Vu 21. Use of a compound of formula (I) or its dye, a pharmaceutically acceptable salt, a solvate or a solvate of such a salt according to any of items 1 - 11 for the preparation of a medicinal product for inhibiting (ha) transfer of bile acids in the ileum or (Xb): (IVAT) in a warm-blooded animal, such as a human. 22. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or solvate of such a salt according to any of points 1 - 11 for inhibition of transfer of bile acids in the ileum (IVAT) in a warm-blooded animal, such as a human 27. Pharmaceutical composition containing a compound of formula (I) or its pharmaceutically acceptable 23. Method of inhibiting transfer of bile acids, solvate or solvate of such a salt according to any of the lots in the ileum (IVAT) in a warm-blooded animal - points 1 - 11 th inhibitor of NMO CoA reductase or us, such as a person who needs such treatment, its pharmaceutically acceptable salt, solvate or which includes the introduction of the specified animal another effective agent is a solvate of such a salt and a substance that binds the bile of a certain amount of a compound of formula (I) or its pharmaceutical acid, in combination with a pharmaceutically acceptable salt, solvate or solvate soluble solvent or carrier. which salts according to any of items 1 - 11. 28. The composition according to item 25 or 27, in which the inhibitory an acceptable tine or a pharmaceutically acceptable salt thereof, salt, solvate or solvate of such a salt according to any of the levates or solvates of such a salt. items 1 - 11 in combination with a pharmaceutically acceptable 29. The composition according to item 25 or 27, in which the inhibitory solvent or carrier. tor NMO CoA reductase is a dewy 25. Pharmaceutical composition containing spolutin or its pharmaceutically acceptable salt. part of the formula (I) or its pharmaceutically acceptable 30. A pharmaceutical composition that contains a co-salt, solvate or solvate of such a salt according to any part of the formula (I) or its pharmaceutically acceptable items 1 - 11 and an inhibitor of NMO CoA reductase or a salt , solvate or solvate of such a salt according to any of its pharmaceutically acceptable salt, solvate or items 1 - 11 and PPRA agonist alpha and/or gamma solvate of such salt in combination with pharmaceutically or its pharmaceutically acceptable salt in a co-acceptable solvent or carrier. compatible with a pharmaceutically acceptable solvent 26. A pharmaceutical composition containing a compound or a carrier. of formula (I) or its pharmaceutically acceptable 31. The composition according to item 30, in which the PPAK agonist salt, solvate or solvate of such a salt according to any of alpha and/or gamma is (5)-2-ethoxy-3-| 4 - items 1 - 11 and a substance that binds bile acid - (2--4-methanesulfonyloxyphenyl)ethoxy)feta, in combination with pharmaceutically acceptable nil|Ipropionic acid or its pharmaceutically presolvent or carrier. fine salt

The present invention relates to derivatives of benzothiazide simvastatin and fluvastatin, or treatment with dozapine and benzothiadiazepine, or their pharmaceutical adjuvants, substances that bind bile acids, acceptable salts, solvates, solvates such as resins. Commonly used substances, leu and their prodrugs. These benzothiazepines and benzothiadiazepines, which bind bile acid, are foams that have an inhibitory effect on, for example, cholestyramine and cholesterol. The latter is carrying bile acids in the ileum (IVAT) and, at times, another approach to the treatment has been proposed - thus, are valuable in the treatment of painful vans (Vie Asii5 apa Girorgoivip Mesaroijist: a conditions associated with hyperlipemic conditions, and these Vepaizzapse The compounds are useful in methods of treating the heat of a blood animal, such as a human being. provides for methods of obtaining the indicated derivatives of substances that have an inhibitory effect on benzothiazepine and benzothiadiazepine, pharmaceuticals, in relation to the transfer of bile acids in them, compositions that contain them, and their use for ileum (IVAT). preparation of drugs for inhibition The reabsorption of bile acids from bile acid transfer in the ileum of the gastrointestinal tract is (IVAT) in a warm-blooded animal such as man.normal th physiological process that takes place

Currently, it is well known that hyperlipemics occur mainly in the ileum with the help of conditions associated with increased concentrations of bile acid transfer mechanism in the ileum of total cholesterol and low ileum lipoprotein (ILL). IVAT inhibitors can be applied to us, cholesterol, are the main risk factors for the treatment of hypercholesterolemia | see, for example, in cardiovascular atherosclerotic diseases, "Ipiegasiop oi Bie asiaz apa spoiev5tegoi m/yp ryuvakh (for example, "Sogopagu Neagp Oizeavze: popzuzietis adepiv Pamipd Nurospoiesiegoiaetis

Vedysipd She VizkK; and UUopamide Miem" Av5tap a., rgorepiev", Viospetisa ei Viorpuvzis Asia, 1210

Saptepa A. SyPep R. and others; Sigsshayop 1999, 100, (1994) 255-287). Thus, acceptable compounds, 1930-1938 and "Oiare(ez apa Sagaiomazciag Oizease: And which have such inhibitory activity in relation to

Ziaietepi g Neainsage Rgoiezviopaie ilot She nyu to IVAT, are also suitable for treatment

Ategpsap Neap Avzosiaiop" Stpypau 5, Vepiatip I., hyperlipemic states. Substituted compounds that have

Viike A., etc.; Sixmianop, 1999, 100, 1134-46). There was such an inhibitory activity in relation to it was found that violations of the circulation of bile acids, IVAT, described, see, for example, hypolipemic fat in the intestinal cavity reduces the level of cholesluca, described in international applications UMO 93/16055, terin. Known approaches to treatment for reducing cholesterol concentration include, for example, treatment with inhibitors 98/38182, UMO 99/35135, UMO 98/40375, UMO

NMOa-CoA reductase, mainly statins, such as 99/35153, UUO 99/64409, UMO 99/64410, MO

71209 16 00/01687, UUO 00/47568, UMO 00/61568, UMO pi, hydroxyl group, amino group, carboxyl 01/68906, OE 19825804, UMO 00/38725, MO group, carbamoyl, mercapto group, sulfamoyl, 060,2/387 UO 00/38727, MO 00/38728, MO of Ci-Cv-alkyl, Co-Cv-alkenyl, Co-Cv-alkynyl, C1-Cv- 00/38729, UMO 01/68906 and ER 0864582. Alkoxy, Ci-Cv -alkanoyl, Si-Cv-alkanoyloxy, M-

A further object of this invention is the formation of compounds according to the invention for the treatment of dislyalkanoylamino, M-(C1- Св-alkylcarbamoyl, М,М-(С1- epidemic conditions and disorders, such as hyperlipemia, Св-alkyl)гcarbamoyl, С1-Св-alkyl(О)а, where a pre-hypertriglyceridemia, hyperbetalipoproteinemia represents 0-2, С1 -S-Alkoxycarbonyl, M-(C1- (increased content of low-density lipoproteins), C-Alkyl)usulfamoyl and 00 M, M-(C-Sbv- /-al- hyperprebetalipoproteinemia (increased content of kyl)dsulfamoyl; very low-density lipoproteins ), hyperchylomic- m represents 0-5; ronemia, hypolipoproteinemia, hypercholesterolemia, one of KE" and 25 represents a group for- hyperlipoproteinemia and hypoalphalipoproteinemia of mule (IA): (decreased content of high-density lipoproteins).

In addition, it is assumed that these compounds are useful for the prevention and treatment of various clinical conditions, such as atherosclerosis, arteriosclerosis, arrhythmia, hyperthrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary artery disease blood vessels, heart and vascular diseases, myocardial infarction, angina pectoris, diseases of peripheral vessels, (A) inflammation of cardiovascular tissues, such as the heart, valves, vascular network, arteries and veins, aneurysms, VZ and 25 and the other P" and Ex independently selected from vostenosis, restenosis, formation of plaques on the walls of the day, halogen, nitro group, cyano group, hydroxyl vessels, formation of strips of fatty deposits on the no group, amino group, carboxyl group, vessel walls, infiltration leukocytes, monocybamoyl, mercaptogroup, sulfamoyl, C1-C4- cells and/or macrophages, thickening of the inner alkyl, Co-Ca-alkenyl, Co-Ca-alkynyl, Si-Si- vascular lining, reduction of the thickness of the middle alkoxy, Si- Sa-al canoyl, C-C--alkanoyloxy, M- vascular sheaths, infections and surgical injuries and trom- (C1-Cα-alkyl)damino, M,M-(C-Cα-alkyl)gamino, C1-C4- blood vessels, stroke and temporary disorders of cerebral alkanoylamino, M-(С1-Са-alkylcarbamoyl, М,М-(С1-) blood circulation. Ca-alkyl)carbamoyl, Ci-Ca-alkyl(O)a, where a pre-

The present invention is based on the discovery that C-C-Alkoxycarbonyl, M-(C1-) certain benzothiazepine and benzothiadiazepine C4-alkyl)usulfamoyl and M,M-(C1-C4- compounds unexpectedly inhibit IVAT. It is assumed that alkyl) gsulfamoyl; where Ж and РЭ and other Р" and 25 something- such properties are valuable for the treatment of хво- necessarily can be substituted near the atom of erosive conditions associated with hyperlipemic leci with one or more В 5; conditions. Х represents itself -O-, -M(H2g)-, -5(O)h- or -

Thus, the present invention relates to the compound CHn(Vg)-; where Kg is hydrogen or C of formula (1): C-alkyl and P is 0-2; ring A is aryl or hetero-

From o to aryl; where ring A is optionally substituted by one or several substituents selected from B"; and B' is hydrogen, Ci-Ca4-alkyl, carbocycle or heterocycle; where B" is optionally substituted by M вх is replaced by one or several substitutes, vyb VU is replaced by B'8;

Kk VAZ is hydrogen or Ci-Ca--alkyl;

AND? is hydrogen or CgCa4-alkyl;

IN!? represents hydrogen, Ci-Ca-alkyl, (ge), . 10' carbocycle or heterocycle; where KK" is optionally substituted by one or more substituents, 0) selected from B"; in which A" is a carboxyl group, . , sulfogroup, sulfinogroup, phosphonogroup, -

WU is selected from Y, hydrogen, or Ci-Cv-alkyl; AND RIFOOVU(OHU), -P(IFONHOVU), -Pn(IFONHVU or one of KA selected from hydrogen, C-Se-alkyl -RIOHOVU(VU), where B: and VU are independently selected from Si- or C2-Cv- alkenyl, and the other is selected from C1-C6-C6-alkyl; or B1 represents a for-alkyl or C2-C6-alkenyl group; mule (IV) or (IS):

Ah and EU are independently selected from hydrogen, a hydroxyl group, an amino group, a mercapto group, a C-Cv-alkyl, a group of

Ci-Cv-Alkoxy, M-(C1-Cv-alkylamino, -M,M-(C1-Cv- |. ' Sh o | J. alkyl)gamino, Ci-Cv-alkyl5(O)z, where a represents ved St: self 0-2; I shi di

M is selected from -M- or -CH-; Ve

A: selected from halogen, nitro group, cyanogroup- av) ps)

17 71209 18

RIFON)(B2) or-P(FOHOVU) (RU), where Ez and RE? in which: independently selected from Ci-Cv-alkyl; where VZ, VO, dya and do

U represents -M(B")-, -M(A")C(O)-,. - m(АЗС(ОХСААЗММ(АИ)С(О)-, -0О-, and -(О)а-) can be substituted independently, optionally, where a near the carbon atom is one or more 22; represents 0-2, m represents 1-2, B? Its 222 are independently selected from halogen, hydro-

VAZ ii V! independently selected from hydrogen or C1-C4- strong group, cyano group, carbamoyl, ureidogru-alkyl, optionally substituted B29, and B" predp, amino group, nitro group, carboxyl group, is hydrogen or C-Ca-alkyl; carbamoyl, mercaptogroup, sulfamoyl, trypto-

IN? represents hydrogen or C-C4-rmethyl group, trifluoromethoxy group, methyl, alkyl; ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, me-

VAZ and B" are independently selected from hydrogen, C1-Cb- toxiccarbonyl, formyl, acetyl, formamido, alkyl, carbocycle, or heterocycle; and when 4 do- acetylamino, acetoxy, methylamino, dimethylamino- 0, B" may additionally be selected from hydrono, M-methylcarbamoyl, M,M-dimethylcarbamoyl, xyl group; where VZ | B!" is not necessarily independent of methylthio, methylsulfinyl, mesyl, M- can be substituted by one or more methylsulfamoyl and M,M-dimethylsulfamoyl; substituents selected from 20; BZ is a carboxyl group,

B!5 is a carboxyl group, a sulfo group, a sulfino group, a phosphono group, - a sulfo group, a sulfino group, a phosphono group, - P(IFOVUKHOV"), - ("OHOHOHON), -P(OHOHON) (NU) or

P(IFHOVUKHOVI), -P(IFHONHOV), -P(IFOHON) (VU) or -P(IFOVZ)I(B"), where R and E" are independently selected from Si- -P(IFHONU) (P), where R: and R! independently selected from C1-C1-alkyl;

Sev-alkyl; IN? selected from Ci-Cv-alkyl, Ci-Cv-alkanoyl, p represents 1-3; where the values of BZ may be the same or different; carbamoyl, M-(C1-Cv-alkyl)ucarbamoyl, M,M-(C1-Cv- 4 represents 0-1; alkyl/ucarbamoyl, benzyl, benzyloxycarbonyl, r represents 0-3; where the value of B" mo - benzoyl and phenylsulfonyl; may be the same or different; or a pharmaceutically acceptable salt thereof, the salt represents 0-2; where the value of B, a solvate of such a salt or its prodrugs may be the same or different; According to another embodiment , and represents 1-3; where the value B" my invention relates to the compound of formula (1): must be the same or different; R a bot

Ring B is a heterocycle, a link | I Her zany with a nitrogen atom, substituted near a carbon atom. We fly with one group selected from P23, and optional i Ide kovo is additionally substituted near the carbon atom in Besai m-n by one or more P2-; and in which, if the indicated B heterocycle bound to a nitrogen atom contains the -MH- part, then that nitrogen atom is not necessarily "and can be replaced by a group selected from БЕ25; ve

B'!E, B" and B!8 are independently selected from halogen, nitro- (KU, trogroup, cyano group, hydroxyl group, amino group, carboxyl group, carbamoyl, mercapto-O) group, sulfamoyl, C1i-C4a- alkyl, C2-C4-alkenyl, Sh

Co-C4-alkynyl, C-C-Alkoxy, C-C-alkanoyl, C1-Uyka:

C.-alkanoyloxy, M-(C1-Ca-alkyl)amino, M,M-(C1-Ca- BU selected from hydrogen or Ci-Cv-alkyl; alkyl)gamino, Ci-Ca-alkanoylamino, (/- M -(С1-Са- one of КК" and B? selected from hydrogen or С1-Св-alkyl)ucarbamoyl, /- M,M-(Си-Са-alkyl)уcarbamoyl, alkyl, and the other selected from Си-Св- alkyl;

Si-Ca-alkylU(O)a, where a represents 0-2, Si-Ah and its KU are independently selected from hydrogen, hydroxyl-

C.-Alkoxycarbonyl, M-(C1-Ca-alkyl)usulfamoyl and other groups, amino groups, mercaptogroups, C-Cv-alkyl,

M,M-(C1-Ca-alkyl)ugsulfamoyl; where B", B" and 8 C-Cv-alkoxy, /M-(Ci-Cv-alkyl)amino, -M,M-(C1-Cv- can independently optionally be substituted by alkyl)gamino, C-Cv -alkyl(O)g, where a is represented near the carbon atom by one or more P2!; itself 0-2;

B, B2o, some and 26 are independently selected from halo- M is selected from -M- or -CH-; well, nitro group, cyano group, hydroxyl group, B: selected from halogen, nitro group, cyano group, amino group, carboxyl group, carbamoyl, merpa, hydroxyl group, amino group, carboxyl capto group, sulfamoyl, C-Ca-alkyl, C2-C4- group, carbamoyl, mercapto group, sulfamoyl, alkenyl, Co-Ca-alkynyl, Ci-Ca-alkoxy, C1-Ca-Ci-Cv-alkyl, Co-Cv-alkenyl, Co-Cv-alkynyl, C1-Cb-alkanoyl, Ci-Ca-alkanoyloxy, M-(C1-Ca-alkanoyl, Ci-Cv-alkanoyloxy, M-(C1-Cv-alkyl)amino, M,M-(Ci-Ca-alkyl)gamino, Ci-Ca-alkyl )amino, M,M-(C1-Cv-alkyl)gamino, C1-Cv- alkanoylamino, M-(Ci-Cv-alkyl)carbamoyl, M,M-(C1- alkanoylamino, M-(C1-Cv-alkyl) )ucarbamoyl, M,M-(C1-

Ca-alkyl)»arbamoyl, Ci-Ca-alkyl(O)z, where a represents Cn-alkyl)gcarbamoyl, Ci-Cv-alkyl(O)a, where a represents 0-2, Ci-Ca -Alkoxycarbonyl, M-(C1- represents 0-2, C-Cv-Alkoxycarbonyl, M-(C1-

Ca-alkyl)sulfamoyl, M,M-(C1-Ca-Ce-alkylsulfamoyl and M,M-(C1-Cv-alkyl)gsulfamoyl, carbocycle, heterocycle, be-alkyl)gsulfamoyl; nyloxycarbonylamino, (Ci-Ca-alkyl)zylyl, sum represents 0-5; alpha groups, sulfino groups, amidino groups, phospho- one of K" and P? represents a group of phornogroup, -RIOHOV2DOVE), -RIODONHOVU), - mule (IA):

by one or more substitutes chosen from EK o B! represents a carboxyl group, x- a sulfo group, a sulfino group, a phosphono group, - t UKH P(IFOVUHOVI), -P(IFOCOHOHVU), -P(IOCHONH VU) or ve | -RIFOHOVU)B)), where P: and E ! are independently selected from C1- to OB C1-alkyl; p represents 1-3; where the values of BZ- (A) may be the same or different; 4 represents 0-1;

VZ and 25 and the other B and 25 independently selected from vog represents 0-3; where the value of B" of a mod, halogen, nitro group, cyano group, hydroxyl can be the same or different; of a group, amino group, carboxyl group, the card represents 0-2; where the value of B" bamoyl, mercapto group, sulfamoyl, C1-C4- can be the same or different; alkyl, Co-Ca-alkenyl, Co-Ca-alkynyl, /-Ci-n represents 1-3; where the value of VC" can

Salkoxy, Ci-Ca-alkanoyl, Ci-C«-alkanoyloxy, M- may be the same or different; (Ci-Ca-alkyl)amino, M,M-(C1-Ca-alkyl)gamino, C1-Ca- A, A" and K!8 are independently selected from halogen, ni- alkanoylamino, M-(C1-C4- alkyl) ucarbamoyl, M, M-(С1- trogroup, cyano group, hydroxyl group, amino-

Ca-alkyl)gcarbamoyl, Ci-Ca-alkyl(O)z, where a is the precursor, carboxyl group, carbamoyl, mercaptog- represents 0-2, Ci-C-- alkoxycarbonyl, M-(C1- group, sulfamoyl , C-Ca-alkyl, C-Ca-alkenyl,

C4-alkyl)sulfamoyl and M,M-(C1-Ca4-C2-C4-alkynyl, C-C-alkoxy, C-C-alkanoyl, C-alkyl)gsulfamoth; where BZ and c and the other P and P are non-C.-alkanoyloxy, M-(C1-Ca-alkyl)amino, M,M-(C1-Ca- can necessarily be substituted near the carbon atom-alkyl)gamino, Ci-C.-alkanoylamino, M-(C1-C4-lecnium with one or more P 5; alkyl/ucarbamoyl, M,M-(C1-Ca-alkyl/2-carbamoyl,

X is -O-, -M(H2)-, -5(O)u- or - Si-Cl-alkyl(O)a, where a is 0-2, Ci-

CH(B2)-; where B2 is hydrogen or C1-C6-alkylcarbonyl, M-(C1-C6-alkyl)usulfamoyl and

St-alkyl and b is 0-2; M,M-(C1-Ca-alkyl)gsulfamoyl; where B, B" and B ring A is aryl or hetero- independently optionally substituted aryl; where ring A is optionally substituted one near the carbon atom by one or more K"!; or several substituents selected from B"; BZ and 220 independently selected from halogen, nitrogen

B" represents hydrogen, C1-Cα-alkyl, carboxyl, cyano group, hydroxyl group, amino group, rbocycle or heterocycle; where B" is not necessarily a carboxyl group, carbamoyl, mercapto group, substituted with one or more substituents, selected sulfamoyl, C1i-Ca-alkyl, C-C-alkenyl, C2-C4- starting with B"8; alkynyl, C-C-alkoxy, C-C-alkanoyl, C1-C4-

VAZ is hydrogen or Ci1i-Ca-alkyl; alkanoyloxy, /M-(C1i-Ca-alkyl)damino, /-M,M-(C1-Ca4-

AND? is hydrogen or C1i-Ca-alkyl; alkyl)amino, C-C4-alkanoylamino, M-(C1-Ca4-

IN? represents hydrogen, C1-Ca-alkyl, alkyl)ucarbamoyl, /- M,.M-(C1-Ca-alkyl)gcarbamoyl, carbocycle or heterocycle; where BO is optionally C1-Cα-alkyl(O)a, where a represents 0-2, C- is substituted by one or more substituents, C1-Cα-alkyl, M-(C1-Cα-alkyl)usulfamoyl, selected from B" М,М-(С1-Са-alkylsulfamoyl, carbocycle, hete-

A"! is a carboxyl group, a ring, a sulfo group, a sulfino group, an amidino group, a sulfo group, a sulfino group, a phosphono group, - p, phosphono group, -P(IFOVUCHONU), -

Р(IFOVU(ONU), -I«FOHONHOVU), -Р««OHON) (VU) or RIFONHOV2), -RIOHON)I(B2) or -P(IFHOV2(RU), -RIFOHOVU(VU), where B : and VU are independently selected from C, where Re and RE" are independently selected from Ci-Cv-alkyl; where KZ

St-alkyl; or B!! represents a group of phor- and 129 may independently be zamymulas (IV): dogs near the carbon atom by one or more dags; in VZ about B? Its 222 independently selected from halogen, hydro-

And! i | D of a strong group, cyano group, carbamoyl, ureidopea, etc.; PM py, amino group, nitro group, carboxyl group, carbamoyl, mercapto group, sulfamoyl, trifluoromethoxy group, methyl, (IV) ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido , in which: acetylamino, acetoxy, methylamino, dimethylami-

U represents -M(B")-, -Ш(А")C(O)-, -O-, but, M-methylcarbamoyl, M,M-dimethylcarbamoyl, and -5(O)a-; where a represents 0-2 and B" represents methylthio, methylsulfinyl, mesyl, M- represents hydrogen or C-Ca-alkyl; methylsulfamoyl and M,M-dimethylsulfamoyl;

IN? is hydrogen or C-C4- or its pharmaceutically acceptable salt, alkyl salt; cotton wool, a solvate of such a salt or its prodrugs.

VIZ and vyya are independently selected from hydrogen, C1-C4- According to another embodiment, da-alkyl, carbocycle or heterocycle; where BZ and V the invention relates to the compound of formula (1): optionally, independently, they can be substituted to B or by several substituents selected from B"; it and II B" represents hydrogen, Ci-Ca-alkyl, rbocycle or heterocycle; where B" is optionally substituted with one or more substituents selected from M including B"8; and VU VZ represents hydrogen or Ci-Ca--alkyl;

Kk V? represents hydrogen or C2-C--alkyl;

IN!? represents hydrogen, Ci-Ca-alkyl, (ve) carbocycle or heterocycle; where B!9 is optional

U is substituted with one or more substituents selected from B"; 0) B"! is a carboxyl group,

What sulfogroup, sulfinogroup, phosphonogroup, -

Quib Y bo ss No RIFOVU(ONVU), "-RIOHONHONU", -RIUHONuVU or vyorani from hydrogen aso St7ov'alkyl; -RIFOHOV-X(VU), where R: and I are independently selected from Si- opkluaishiy selected Sa 000SolKlu; 960 KU is a group of forwards.

The BU atoms are independently selected from hydrogen, hydroxyl (IV) or (0): no group, amino group, mercapto group, Ci-Cv-alkyl, hydrogen

Ci-Cv-Alkoxy, M-(Ci-Cv-alkyl)amino, -M,M-(C1-Cv-or alkyl)gamino, Ci-Cv-alkyl(O)a, where a represents ved Shchi, Seh itself 0-2; SHI

M is selected from -M- or -CH-; di:

B: selected from halogen, nitro group, cyanogroup, hydroxyl group, amino group, carboxyl group, carbamoyl, mercapto group, sulfamoyl, in which:

Ci-Cv-alkyl, Co-Cv-alkenyl, Co-Cv-alkynyl, C1-Cv- U represents -M(B")-, -M(B")C(O)-,. - alkoxy, Ci-Cv-alkanoyl, Ci-Cv-alkanoyloxy, M- M(B")C(OSVeVOUM(B)C(O)-,. -O- І -B(O)a- where a (С1и1 -Cv-alkyl)amino, M,M-(C1-Cv-alkyl)gamino, C1-Cv- represents 0-2, Y represents 1-2 alkanoylamino, M-(C1-Cv-alkylcarbamoyl, M,M -(C1- Ve i v are independently selected from hydrogen or Si-si- sizvlya 02, Sb oleiunykorbonnu MS 0Sail, optionally substituted B, I pred,

St-alkyl)s lfamoyl ! Mche "svst represents hydrogen or C-C4-alkyl; apkylrsupfametlu. U and 1796 B? represents hydrogen or C-C4- ' alkyl; m represents 0-5; 3; I one of B and Vo represents group for-v and Vie are independently selected from hydrogen, C1-C1-alkyl, carbocycle or heterocycle; and when 4 dorimules (IA): 0, B!" can additionally be selected from the hydroxyl group; where V"Z and VE!? are not necessarily immediately adjacent to Z and can be replaced by one or more substituents selected from 220;

Co. . АХ ик В'5 is a carboxyl group,

Bi Mrya sulfogroup, sulfinogroup, phosphonogroup, - o re vv v? P(IFOVUHOVI), -P(IFOTSONHONVU), -P(IOHONH VU) or in ' -P(IFOHONVUE)), where P: and P! independently selected from C- (id) C-alkyl; and p represents 1-3; where the short-circuit value can

VZ Her 25 and another RE: and 2? independently selected from the group, halogen, nitro group, cyano group, hydroxyl group, amino group, carboxyl group, carg represents 0-3; where the value of B" may be bamoyl, mercapto group, sulfamoyl, C1-C4- must be the same or different, 10 alkyl, C2-Ca-alkenyl, C2-Ca-alkynyl, C1-C4- is 0-2; where the value and: alkoxy, C1-C-alkanoyl, C1i-C--alkanoyloxy, M- can be the same or different, 7 (C1-Ca-alkyl)amino, M,M-(C1-Ca-alkyl)gamino, Si -C4-n represents 1-3, where the values of VC mole-alkanoylamino, M-(C1-C4-alkylcarbamoyl, M,M-(C1-) must be the same or different;

Ca-alkyl)»carbamoyl, Ci-Ca-alkyl(O)a, where a represents Ring B is a heterocycle, represents 0-2, C1i-Ca-alkoxycarbonyl, M-(C1- by a nitrogen atom substituted near a carbon atom

Cα-alkyl)sulfamoyl and M,MI-(C-Salec) by one group selected from KU, and optional alkyl)"-sulfamoyl; where VZ and NE and another R | VZ is somehow additionally substituted. near the carbon atom can necessarily be replaced near the carbon atom by one or several a "I! in which, if the pointer is one or several B; the heterocycle bound to the nitrogen atom contains

X represents -O-, -M(Neg)-, -Z(O)p- or - -MH- part, then that nitrogen atom is not necessarily

CHn(Wag)-; where Kg represents hydrogen or Si- can be replaced by a group selected from .

St-alkyl and b is 0-2; inv and! Kk are independently selected from halogen, Ni: ring A is an aryl or hetero group, a carboxyl group, a carbamoyl mercaptog. aryl; where ring A is optionally substituted by one rup, sulfamoyl, C1-C6-alkyl, C0-C8-alkenyl,

23 71209 24

C2-C4-alkynyl, C-C4-alkoxy, C-C-alkanoyl, C1-

C.-alkanoyloxy, M-(C1-Cα-alkyl)amino, M,M-(C1-Cα4- iod. alkyl)gamino, C1-C.-alkanoylamino, M-(C1-C4- If optional substituents are chosen from alkyl/ucarbamoyl, M,M-(C1-Ca-alkyl/2-carbamoyl), "one or more" groups, then under this have on

C1i-Ca-alkyl(O)a, where a represents 0-2, Si- means that this definition includes all substituents,

C4-Alkoxycarbonyl, M-(C1-Ca-alkyl)sulfamogyl and which can be selected from one of the specified groups,

M,M-(C1-Ca-alkyl)hesulfamoyl; where БЭ, В!" and ВВ or substituents that can be selected from two or independently can optionally be substituted by more than the specified groups. near the carbon atom by one or more K2!; "Heteroaryl" is a completely non-

ВЗ, Во, дя and Б26 are independently selected from a halogenated, mono- or bicyclic structure, which contains a nitro group, a cyano group, a hydroxyl group, etc. 3-12 atoms, of which at least one atom is selected from an amino group, a carboxyl group, carbamoyl, measured from nitrogen, sulfur or oxygen, which can, if captogroup, sulfamoyl, Ci-Ca-alkyl, C2-C4- not specifically indicated otherwise, be connected to alkenyl, Co-Ca-alkynyl, Ci- Ca-Alkoxy, C1-C4 - a carbon or nitrogen atom. Preferably, "hetero-alkanoyl, C1i-C-alkanoyloxy, M-(C1-C4- aryl)" refers to fully unsaturated, monocyclyl-alkyl)amino, M,M-(C1-Ca-alkyl)gamino, C1-b4- structure containing 5 or 6 atoms, or bialkanoylamino, M-(C1-Cα-alkylcarbamoyl, M,M-(C1-) cyclic structure containing 9 or 10 atoms, with

Ca-alkyl)»carbamoyl, Ci-Ca-alkyl(O)a, where a is preceded by at least one atom selected from nitrogen, sulfur represents 0-2, Ci-C4-alkoxycarbonyl, M-(C1- or oxygen, which may, unless specifically stated

C.4-alkyl)sulfamoyl, M,M-(C1-C4- otherwise, be bound to a carbon atom or azo-alkyl)sulfamoyl, carbocycle, heterocycle, beta. Examples and suitable values for ponsyloxycarbonylamino, sulfo group, sulfinogen "heteroaryl" are thienyl, isoxazolyl, imidazolyl, rup, amidino group, phosphono group, - pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyranyl,

P(IFHOVUKHONU), - (YUONHOV), -P(FONU(B2) or indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl and -RIFOVU) (RU), where B and EE? independently selected from Siquinolyl. Mostly, the concept of "heteroaryl"

St-alkyl; where "Y, 820, dya and Web are independently not required to be thienyl or indolyl. may necessarily be substituted near the carbon atom. "Aryl" represents a completely unsaturated or several 22; chen, mono- or bicyclic carbon structure,

IN?! Is she 22? independently selected from halogen, hydrogen containing 3-12 atoms. Predominantly, "aryl" of a strong group, cyano group, carbamoyl, ureido group is a monocyclic structure containing 5 or 6 atoms, or a bicyclic structure containing carbamoyl, mercapto group, sulfamoyl, trifto - contains 9 or 10 atoms. Suitable values for rmethyl group, trifluoromethoxy group, methyl, for "aryl" are phenyl or naphthyl. In particular, the "aryl" of ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, me- is phenyl. toxiccarbonyl, formyl, acetyl, formamido, "Heterocycle" is a saturated, acetylamino, acetoxy, methylamino, dimethylami- partially saturated or unsaturated, mono- or bi-, M-methylcarbamoyl, M,M-dimethylcarbamoyl, cyclic structure that contains 3-12 atoms, of which methylthio, methylsulfinyl, mesyl, M- at least one atom selected from nitrogen, sulfur or methylsulfamoyl and M,M-dimethylsulfamoyl; oxygen, which can, if not specifically indicated

BZ is a carboxyl group, otherwise, it can be bound to a carbon atom or an azo-sulfo group, a sulfino group, a phosphono group, - the one where the -СНо- group can optionally be substituted

RIFHOVZHON"), -I(YUDONHONU), -P(FONHNAU) or not by the group -C(0)-, or the ring sulfur atom of non- -RIFHOHONZU)(A"), where z and E" are independently selected from Si- can necessarily be oxidized to 5-oxides.

St-alkyl; Mostly "heterocycle" is sati-

A selected from Ci-Cv-alkyl, Ci-Cv-alkanoyl, chen, partially saturated or unsaturated, mono-

C1i-Cv-alkylsulfonyl, C1-Cv-alkoxycarbonyl, or a bicyclic structure that contains 5 or 6 atocarbamoyl, M-(C1-Cv-alkyl)ucarbamoyl, M,M-(C1-Cv-miv), of which at least one atom selected from nitrogen, alkyl/ucarbamoyl, benzyl, benzyloxycarbonyl, sulfur, or oxygen, which may, unless specifically benzoyl and phenylsulfonyl; otherwise specified, be bonded to a carbon atom or a pharmaceutically acceptable salt, salt, or nitrogen atom thereof, wherein The -СНо- group may optionally be cotton, a solvate of such a salt or its prodrugs, replaced by a -С(0)- group, or a ring sulfur atom

In this invention, the concept of "alkyl" includes both optionally oxidized to a 5-alkyl group with a straight chain, and branched oxide(s). Examples and suitable meanings of chained, but with respect to specific alky- for the term "heterocycle" is thiazolidinyl, pyrrolidyl groups such as "propyl" are meant nyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, groups only with a direct chain. For example, "C1-2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl,

C1-C6-alkyl" includes C1-Ca4-alkyl, C1-C3-alkyl, propyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4- isopropyl and tert-butyl. However, with regard to specific triazolinyl ), 2-oxazolidinonyl, 5,6- alkyl groups such as "propyl" are meant for dihydrouracilyl, 1,3-benzdioxolyl, 1,2,4- straight-chain groups only, and for oxadiazolyl, 2-azabicyclo (2.2.1|)heptyl, 4- individual alkyl groups with a branched chain, thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, such "isopropyl" mean only groups with a tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, ben- branched chain. Similar the condition zastothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3- also applies to other radicals, for example, dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1- "phenylCi-Cv-alkyl" may include phenylC1-Cv-dioxothiomorpholino, tetrahydropyranyl, 1,3- alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. Under podioxolanil, homopiperazinyl, thienyl, isoxazolyl,

imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-ethyl)amino and M-ethyl-M-methylamino. Examples of triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimi- "Co-C6-alkenyl" and "Co-C6-alkenyl" are vinyl, allyl and 1-dil, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4- propenyl. Examples of "C2-C6-alkynyl" and "Co-C4- pyridonyl, quinolyl, and 1-isoquinolonyl. alkynyl" are ethynyl, 1-propynyl, and 2-propynyl. "Heterocycle bound to a nitrogen atom" prefixes "M-(C1-C8-alkyl)usulfamoyl" and "M-(C1-C4- represents a saturated, partially saturated or alkyl)usulfamoyl" are M- (C1-C6-alkyl)usulfamoyl, an unsaturated, mono- or bicyclic structure that is M-(methyl)sulfamoyl and M-(ethyl)usulfamoyl. Prik- contains 3-12 atoms, of which at least one atom in the order "M-(C1-Cv-alkyl)isosulfamoyl" "M-(C1-Cv- represents nitrogen and a heterocycle connected to alkyl)isosulfamoyl" is M, M-(dimethyl)sulfamoyl and the carbonyl group of the formula (IS) with the help of M-(methyl)-M-(ethyl)usulfamoyl. Examples of "M- of this nitrogen atom, which may additionally contain (C1-C8-alkyl)ucarbamoyl" and "M-(C1-C4- additional heteroatoms selected from nitrogen, sulfur or alkyl/ucarbamoyl)" are methylaminocarbonyl and ethylamioxygen, where the -СНо- group can optionally be nocarbonyl. Examples are "М,М-(С1-Св- replaced by a group -С(0)-, or ring sulfur atom of alkyl/)ggarbamoyl" and "М,М-(С1- Ca-alkyl)carbamoyl" can optionally be oxidized to 5-oxides. There are dimethylaminocarbonyl and methylethylaminocarbo-

Preferably "heterocycle bound to a nitrogen atom" is nil. Examples of "Ci-Cv-alkylsulfonyl" are mesyl and are saturated, partially saturated ethylsulfonyl. Examples of "(C1-C4-alkyl)silyl" or an unsaturated, mono- or bicyclic structure include trimethylsilyl and methyldiethylsilyl. which contains 5 or 6 atoms, of which at least one A suitable pharmaceutically acceptable salt represents a nitrogen and a heterocycle bound to a bow according to the invention represents, for example, a carbonyl group of the formula (IS) by means of an acid-addition salt of a compound according to the invention, which is of this nitrogen atom, which may additionally contain quite basic, for example, acid-additive additional heteroatoms selected from nitrogen, sulfur or salt, for example, with inorganic or organic oxygen, where the -СНо- group may optionally be an acid, e.g. , salt, hydrogen bromide- replaced by the group -С(0)-, or ring atom of sulfur, sulfur, phosphorus, trifluoroacetate, lin- can optionally be oxidized to 5-oxides. monic, acetic or maleic acid. Except

Examples and suitable values for the concept of a suitable pharmaceutically acceptable salt "heterocycle bound to a nitrogen atom" are morpholy- compounds according to the invention, which are sufficiently acidic, but, pyrrolidin-1-yl, imidazol-1-yl, pyrazolidin- 1-yl is an alkali metal salt, for example, piperidin-1-yl and piperazin-1-yl. In particular, "heteroclade, sodium or potassium salt, alkaline earth salt - a ring bound to a nitrogen atom" represents a gold metal, for example, a calcium or magnesium pyrrolidin-1-yl. salt, ammonium salt, or salt with an organic base, "Carbocycle" is a saturated part that forms a physiologically acceptable cation, supersaturated or unsaturated, mono- or bicyclic example, a salt with methylamine, dimethylamine, a single carbon structure, which contains 3-12 atoms; trimethylamine, piperidine, morpholine, or where the -CNeo- group can optionally be replaced by tris-(2-hydroxyethyl)amine. group -С(0)-. Predominantly, the "carbocycle" represents compounds of the formula (I) can be introduced into a monocyclic structure that contains 5 or 6 atoms, or a bicyclic structure that contains us or animals to obtain a compound of the formula 9 or 10 atoms. Suitable values for "ca- (I). Examples of prodrugs include carbocycle esters" are cyclopropyl, cyclobutyl, 1- compounds of formula (I), which are capable of hydrolysis to the umomo- oxocyclopentyl, cyclopentyl, cyclopentenyl, wah ip mimo, and amides of the compound of formula (1), which are capable of cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetra- to hydrolysis under conditions of i mimo. linyl, indanyl or 1-oxoindanyl. In particular, the "carbo- Ether of the compound of formula (I), which is a cyclic" represents a cyclopropyl, cyclobutene before hydrolysis under conditions of i mimo, containing a cartil, 1-oxocyclopentyl, cyclopentyl, boxyl or hydroxyl group, represents cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl by itself, for example, pharmaceutically acceptable or 1-oxoindanyl. complex ester, which is hydrolyzed in the human body

Examples of "Ci-Cv-alkanoyloxy" and O/"C1-C4- dines or animals with the formation of the starting acid of alkanoyloxy" are acetoxy. Examples of "C1-C6- or alcohol. Suitable pharmaceutically acceptable alkoxycarbonyl" Its 0/0 "Ci-C4-Alkoxycarbonyl" esters for the carboxyl group include include include methoxycarbonyl, ethoxycarbonyl, n- and C1-C6-Alkoxymethyl esters, for example, tert -butoxycarbonyl. Examples of "Ci-C-Alkoxy" and methoxymethyl, C1i-Cv-alkanoyloxymethyl compounds - "Ci-C4--Alkoxy" include methoxy, ethoxy and propane ethers, for example, pivaloyloxymethyl, phthaloxy. Examples of "Ci-Cv-alkanoylamino" and "C1-Ca4-lidyl ethers, C3-Cv-alkanoylamino" include formamido, acetamido, and cycloalkoxycarbonyloxyCi1-Cv-alkyl compound propionylamino. Examples of "Ci-Cv-alkyl(O)a, where a is ethers, for example, 1-cyclohexylcarbonyloxyethyl; represents 0-2" and "C1-C.--alkyl(O)a, where a is 1,3-dioxolene- 2-onylmethyl ethers, representing 0-2" include methylthio, ethyl, for example, 5-methyl-1,3-dioxolen-2-onylmethyl; and Silthio, methylsulfinyl, ethylsulfinyl, mesyl, and ethyl N-Alkoxycarbonyloxyethyl esters, nasulfonyl. Examples of "Ci-Cv-alkanoyl" and "C1-Cv- example, 1-methoxycarbonyloxyethyl, and can alkanoyl" include propionyl and acetyl. Be attached to any carboxyl group di "M-(C1-C6-alkyl)amino" and "M-(C1-C6-alkyl)amino" compounds according to the present invention. include methylamino and ethylamino. Examples The complex ester of the compound of formula (I), which is "M,M-(C1-Cα-alkyl)gamino" and "M,M-(C1-C4-) is susceptible to hydrolysis under the conditions of imo, containing hyd-alkyl )ugamino" include di-M-methylamino, di-(M-hydroxyl group, includes inorganic complex ethers

27 71209 28 ry, such as phosphate esters and os- B" represents bromine, methyl or methyl acyloxyalkyl ethers and corresponding compounds, ltio. that as a result of splitting the ether during hydrolysis in A? represents a group of the formula (IA), (as the conditions of the ip mimo form the starting hydroxyl shown above), in which: group Examples of c-acyloxyalkyl simple ethers include acetoxymethoxy and 2,2- ring A is phenyl, optionally dimethylpropionyloxy -methoxy. Examples of groups that are substituted by one or more substituents, which form complex esters capable of hydrolysis in us, selected from B"; under the following conditions, the hydroxyl group is alkanoyl, n is 1; benzoyl, phenylacetyl and substituted benzoyl and phenyl- BA" represents hydrogen; cetyl, alkoxycarbonyl (to obtain alkylcarb- AB represents hydrogen; bonate esters), dialkylcarbamoyl and M- BZ represents hydrogen; (dialkylaminoethyl)-M-alkylcarbamoyl ( for oder- t represents 0; the choice of carbamates), dialkylaminoacetyl and carboxy- BA" represents a group of the formula (IV), (as acetyl. Examples of substituents near benzoyl are shown above), in which: morpholino and piperazino, connected with ring atom B": represents hydrogen; a nitrogen atom with the help of a methylene group in the 3rd p represents 1 or 2; or the 4th position of the benzoyl ring. BZ represents hydrogen;

A suitable value for the amide of the compound fo-4 is 0; rmula (I), which is capable of hydrolysis under conditions of ip g is 0; mimo containing a carboxyl group is, for example, VZ is a carboxyl group

M-Ci-Cv-alkyl or M,M-di-Ci-Cv-alkylamide, such as or a sulfo group; and

M-methyl, M-ethyl, M-propyl, M,M-dimethyl, M-ethyl- B" represents a hydroxyl group.

M-methyl or M,M-diethylamide. o represents M-A(A)-o-|M-

Some compounds of formula (I) may have chira- (carboxyl centers and/or geometrically isomeric centers (E- and tyl)carbamoyl|benzyl)carbamoylmethoxy, M-(A)-o-2- isomers), and it is meant , that the invention covers IM- all such optical forms, diastereoisomers and geomet- (carboxymeric isomers that have an inhibitory effect on the relative -(2-sulfoethyl)carbamoyl|-4- intestine (IVAT). hydroxybenzyl)carbamoylmethoxy.

The invention relates to any and all tautomers - VAZ is a group of formula (IA), (such as forms of compounds of formula (I), which have inhibitory shown above), in which: action in relation to the transfer of bile acids - X represents - AT-; lot in the ileum (IVAT). ring A is phenyl, optionally

It is also implied that certain compounds focally substituted with one or more substituents (I) can exist in the form of solvates, and we, selected from B"; also in the form of unsolvated forms, such as, n represents 1; for example , hydrated forms. Also has on B" represents hydrogen; keep in mind that the scope of the invention includes all such Ag represents hydrogen; solvated forms that have an inhibitory effect on A? represents hydrogen; in relation to the transfer of bile acids in t is 0; ileum (IVAT). IN! is a carboxyl group,

Preferred values are as follows. Such a group of the formula (IV), (as depicted above) or group of chen may be used, according to the formula (IS), (as depicted above), in which: any definitions, clauses of the formula or variant- B? represents hydrogen or C-C4-ts of the implementation of the invention, indicated earlier in given-alkyl; of the invention or hereafter. p represents 1 or 2;

VU is hydrogen. VAZ is hydrogen or C-C4-

B' Her 22 is C-C-Alkyl. alkyl, optionally substituted by E2O, where 229 pre-

IN! and 22 are both butyl. is a hydroxyl group, carbamoyl, ami-

One of B! and 2? is ethyl, and another group, benzyloxycarbonylamino or C-C4, is butyl. alkyl(O)a where a is 0;

One of EH and VU represents hydrogen, and B!" represents hydrogen or hydroxyl; the other represents a hydroxyl group. lin group;

Ah and BU both represent hydrogen. 4 represents 0;

M represents -M-. r represents 0 or 1;

M represents -CH-. B!5 is a carboxyl group and mu is 0 or 1. or a sulfo group; m represents 0. B" represents a hydroxyl group; i

B: is a C1-Ca-alkyl. ring B is pyrrolidin-1-yl,

VZ and 9 represent hydrogen. substituted near the carbon atom by one group,

B" represents methylthio or bromide selected from 23; where 23 represents carboxy-

BA" is a methylthio strong group.

IN? is halogen, Ci1-Ca-alkyl vo is M-((BA)-o-AlIM- or Ci-C-alkyl(O)a where a is 0. (carboxyme-

tyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o- X represents -O-;

IM-ring A is phenyl, optionally (carboxymethyl substituted with one or more substituents-ethyl)carbamoyl|benzyl)carbamoylmethoxy, M-(B)-oms selected from B";

IM-(2-sulfoethyl)carbamoyl|-4-p is 1; hydroxybenzylcarbamoylmethoxy, M-((A)-o-(M-((5)-B" represents hydrogen; 1-carboxy-2-BZ represents hydrogen; hydroxyethyl)/carbamoyl|benzylcarbamoylmethoxy, A? represents hydrogen;

M-((B)-o-(M-((8)-1-t) represents O; carboxyethyl)carbamoyl|benzyl)carbamoylmethoxy, H" represents a carboxyl group,

M-((B)-o-(M-((8)-1- group of formula (IV), (as depicted above) or carboxypro- group of formula (IC), (as depicted above), in which: pil) ucarbamoyl|benzylcarbamoylmethoxy, M-(B)-o- represents hydrogen or Si-Ca- (M-(B)-1-carboxy-2-methylthio-alk; ethyl)carbamoyl|benzyl)carbamoylmethoxy, -M-( B) - p represents 1 or 2; - BZ represents hydrogen or C-Sbv-o-|M-((5)-1-carboxy-2-carbamoyl-.bov and i vo ho ethyl)carbamoyl|benzyl) carbamoylmethoxy, -M-(A)- alkyl, optionally substituted "where . pred-

ЧМ-(2-sulfoethyl)carbamoyl|-4- is a hydroxyl group, carbamotl, amyl. group, benzyloxycarbonylamino, C1-C4- hydroxybenzyl)carbamoylmethoxy, MA om. alkyl(O)a, where a is 0, or (C1-C4- (carboxymethyl)carbamoyl|-4- alkyl)zsilyl; hydroxybenzylcarbamoylmethoxy, M-((A)-o-(M-((5)- in) is hydrogen or hydroxy-1-carboxyethyl)carbamoyl-4- group or C-C-alkyl, where B" is optional hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)- may be substituted with one or more 1-carboxy-2-hydroxyethyl)carbamoyl|-4- substituents selected from 220; hydroxybenzyl) icarbamoylmethoxy, MA (A)-o-(M-(2- M) is -M(B")C(0)-, where B" presulfoethyl)carbamoyl|benzylcarbamoylmethoxy represents hydrogen;

M-((A)-o-(M-((5)-1-carboxy-2-(H)-4 represents 0 or 1; hydroxyprog represents 0 or 1; phenyl)ucarbamoyl|benzylcarbamoylmethoxy, M -(A)-o- B! represents a carboxyl group (m-((5)-1-carboxy-2- or sulfo group; methylpropyl)carbamoylIbenzyl)carbamoylmethoxy, B" represents a hydroxyl group; and

M-((A)-o-(M-((5)-1-carboxy-3-B? selected from the hydroxyl group; methylbutyl)carbamoyl|benzylcarbamoylmethoxy, ring B is pyrrolidin-1-yl or

M-((A)-o-(M-(1-(5)-1-carboxy-2-(5)-2-azetidinyl, substituted near the carbon atom by one methylbutyl)carbamoyl|benzylcarbamoylmethoxy group selected from E23, and optionally additionally

M-(BA)-o-carboxy-4- substituted near the carbon atom by one or decyl-hydroxybenzyl)carbamoylmethoxy, M-((A)-o-|M-((5)- koma KE"; where KZ is a carboxyl 1-carboxy-4- group and 22" represents a hydroxyl group. aminobutyl)carbamoyl|benzyl)carbamoylmethoxy, vo represents M-(A)-o|M-

M-(A)-o-(M-((5)-1-carboxy-4- (carboxymethyl- (benzyloxycarbonylmethyl)carbamoyl|benzyl)carbamoylmethoxy, M-(A)-o-no)butyl|carbamoyl) benzyl) carbamoylmethoxy, -M- IM-

I(A)-o-(5)-2-carboxypyrrolidine-1-(carboxymethylcarbonyl)benzyl|carbamoylmethoxy, /-M-(B)-o-|M- tyl)carbamoyl|benzyl)carbamoylmethoxy, M-( A)-os-(carboxymethyl)-M-(M-(2-sulfoethyl)carbamoyl|-4- methylcarbamoyl|benzyl)carbamoylmethoxy, M-(B)- hydroxybenzyl)carbamoylmethoxy, M-(A)-o-(M -((5)- o0-(M-(1-(8)-2-(8)-1-carboxy-1-hydroxyprop-2-1-carboxy-2-yl)ucarbamoyl|benzylcarbamoylmethoxy, /- M- (B)-o-hydroxyethyl)/ucarbamoyl|benzylcarbamoylmethoxy,

IM-MAV) -o-(M-()-1- (sulfome-carboxyethylcarbamoylbenzylcarbamoylmethoxy, tyl)carbamoyl|benzyl)carbamoylmethoxy, M-((A)-o- M-A(A)-o-(M-( (5)-1-carboxybenzyl)carbamoylmethoxy, M-((A)-o-(M- carboxypro- ((5)-1-carboxy-2-(B)-hydroxypropyl)carbamoyl-4- pylucarbamoylIbenzyl)carbamoylmethoxy, M -(A)-o- hydroxybenzyl)carbamoylmethoxy, M-(A)-o-|M-((5)- (M-((A)-1-carboxy-2-methylthio-1-carboxy-2-methylpropyl )carbamoyl|-4-ethyl)carbamoyl|benzyl)carbamoylmethoxy, M-(B)- hydroxybenzyl)carbamoylmethoxy, M-((B)-o-(M-((8)- o-(M-((5) -1-carboxy-2-carbamoyl-1-carboxybutyl)carbamoyl-4-ethyl)carbamoyl|benzyl)carbamoylmethoxy, -M-(A)- hydroxybenzyl)carbamoylmethoxy, M-((B)-o-(M-(( 8). B)-a-IM- (carboxymethyl)carbamoyl|-4- ((8)-1-carboxy-2-methylthio-ethyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-(A)-o-|M- ((5)- hydroxybenzylcarbamoylme toxic 1-carboxyethyl)carbamoyl|-4-

AND? is a group of formula (IA), (as hydroxybenzyl)carbamoylmethoxy, M-((A)-o-|M-((5)- shown above), in which: 1-carboxy-2-hydroxyethylcarbamoyl|-4-

31 71209 32 hydroxybenzylcarbamoylmethoxy, /-M-((A)-o-(IM-(2-B?) is a group of the formula (IA). sulfoethyl)carbamoylIbenzylcarbamoylmethoxy, Thus, according to another option

M-(c)-a-IiM-((5)-1-carboxy-2-(B)- implementation, the object of the invention is a compound of the formula hydroxypropyl)/ucarbamoyl|benzyl)icarbamoylmethoxy (I), (as depicted above ), in which: i, M-((B)-o-(m-((5)-1-carboxy-2-AX) represents hydrogen; methylpropyl)carbamoyl|benzyl)carbamoylmethoxy, B! and B? Ci-Ca--alkyl;

M-((B)-o-(M-((5)-1-carboxy-3-Ah and BEU) both represent hydrogen; methylbutyl)carbamoyl|benzylcarbamoylmethoxy, M represents -IM-;

M-((A)-o-|M-(1-(5)-1-carboxy-2-(5)-2-U represents O; methylbutyl)carbamoyl|benzyl)carbamoylmethoxy, A" Re represents hydrogen ; ,

M-((B)-o-carboxy-4-in: is a halogen, C-C4-alkyl hydroxybenzyl)carbamoylmethoxy, M-((A)-o-|M-((5)- or St-Cg- alkyl(O)" where a represents 0; 1-carboxy-4-B? represents a group of the formula (IA), (as aminobutyl)carbamoyl|benzylcarbamoylmethoxy, onov represents o- (be nlooiaoboni box sy-Y ring A represents is phenyl, (optionally) butyl(carbamoylbenzyl)carbamoylmethoxy, -M- we are vyboanines with v or several substituents-

KV)-o-((5)-2-carboxypyrrolidine-1-"in is 1:ylcarbonyl)benzyl|Icarbamoylmethoxy, -M-(A)-o-(M-B" is hydrogen; (carboxymethyl)- M- o BZ is hydrogen, E? is methylcarbamoyl|benzylcarbamoylmethoxy, M-|(A)- is hydrogen, t is 0, o0-(M-(1-(8)-2-(8)-1- carboxy-1-hydroxyprop-2-in is a carboxyl group, yl)ucarbamoyl|benzylcarbamoylmethoxy, /- M-(A)-a- group of formula (IV), (as depicted above) or a group

Im- of formula (IS), (as shown above), in which: (sulfomethyl-VI? represents hydrogen or C-C4-ethyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o-alkyl; carboxybenzyl)carbamoylmethoxy, M-(A)-o-(M-p represents 1 or 2; ((5)-1-carboxy-2-(H)-hydroxypropyl)carbamoyl|-4- BZ represents hydrogen or Si -C1-alkyl hydroxybenzyl)carbamoylmethoxy, M-(A)-o-|M-((5)- optionally substituted BO, where 22? represents 1-carboxy-2-methylpropyl)carbamoyl|-4- is a hydroxyl group , carbamoyl, amino group, hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)- benzyloxycarbonylamino, C-Ca-alkylb(O)a, where a 1-carboxybutyl)carbamoyl|-4- represents is 0, or (C1-C-alkyl)psylyl; hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)-B!") is hydrogen or hydroxy-1-carboxypropyl)carbamoyl| -4- group or Ci-Cv-alkyl; where B" is not necessarily hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-) can be substituted by one or more substituted- ((2)-1- carboxy-2-methylthio-ethyl)carbamoyl|-4- compounds selected from 29; hydroxybenzyl)carbamoylmethoxy, M-(B)-o-(M-((5)- U is -M(A")C( O)-, where K" represents 1-carboxypropyl)carbamoyl|-4- is hydrogen; hydroxybenzyl)carbamoylmethoxy, M-(A)-o-|M-(5)- 4 represents 0 or 1; 1-IM-((8)-2-hydroxy-1-g represents 0 or 1; carboxyl-B!5 represents a carboxyl group of tyl)carbamoyl|propyl)carbamoyl|benzylcarbamoyl or a sulfo group; methoxy, M-((B)-o-(2-(5)-2-(carboxy)-4-(8)-4-A is a hydroxyl group; and (hydroxy)pyrrolidine-1-B is selected from hydroxyl groups; and ylcarbonyl|ibenzylcarbamoylmethoxy, /-M-(B)-o-(2-ring B is pyrrolidine-1ch or (8)-2-(carboxy)azetidine-1-azetidinyl, substituted near the carbon atom by one ylcarbonylbenzyl) ucarbamoylmethoxy, /- M-(B)-o-|M- group selected from K 7, and optionally additionally 4(8)-1-IM-(8)-1- substituted near the carbon atom by one or decyl- where KZ represents a carboxyl tyl)carbamoyl|ethylcarbamoyl|benzyl)carbamoyl group and K"" represents a hydroxyl group; ethoxy, M-((B)-o-(M-(B)-1-carboxy-3,3- vate or a pharmaceutically acceptable salt, salt dimethylbu-"prolycyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o - thus according to another option

HAC) t caroxy 8.5 implementation, the object of the invention is a compound of the formula dimethylou: . (I), (as depicted above), in which: tyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o-VU represents hydrogen;

IM-(8)-1-carboxy-3,3-dimethylbutyl)carbamoyl|-4-B! and b2 are both butyl; hydroxybenzylcarbamoylmethoxy, M-((A)-o-1M4-((5)-Ah and BU both represent hydrogen; 1-carboxy-2-(trimethylsilyl)ethylcarbamoyl)y-4-M represents -M-; ! hydroxybenzyl )carbamoylmethoxy or M-(A)-o-1M-mu represents 0;

I(2)-1-carboxy-2-(trimethylsilyl)ethylI|carbamoyl)y- BZ and 2? are hydrogen; 4-thihydroxybenzyl)carbamoylmethoxy. B" represents bromine, methyl or methyl

IN? is hydrogen. ltis:i

B" is a group of formula (IA). b is M-(B)-o-IM-

(carboxymethyl-1-IM-((5)-2-hydroxy-1-ethyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o-carboxyv-

IM- tyl)carbamoyl|propyl)ucarbamoyl|benzylcarbamoyl (carboxyme- methoxy, M-(A)-o-(2-(5)-2-(carboxy)-4-(A)-4- tyl)carbamoyl|benzylcarbamoylmethoxy , M-(A)-o- (hydroxy)pyrrolidine-1-

IM-(2-sulfoethyl)carbamoyl|-4-ylcarbonyl|benzylcarbamoylmethoxy, /-M-(A)-o-(2-hydroxybenzyl)carbamoylmethoxy, M-(A)-o-(M-((5)- ( 5)-2-(carboxy)azetidin-1-1-carboxy-2-ylcarbonyl|benzylcarbamoylmethoxy, /-M-(A)-o-(M-hydroxyethyl)carbamoyl|benzylcarbamoylmethoxy, 1(5)-1-IM -((5)-1-

M-((A)-o-(IM-((5)-1- carboxyv- carboxyethylcarbamoyl|benzyl)carbamoylmethoxy, tyl)carbamoyl|ethylcarbamoyl|benzyl)carbamoylm

M-((A)-o-|M-((5)-1- ethoxy, M-((A)-o-|M-(A)-1-carboxy-3,3- carboxypro-dimethylbutyl) )ucarbamoyl|brenzilcarbamoylmethoxy, M-(A)-o-ethyl)carbamoyl|benzyl)carbamoylmethoxy, M-(A)-o-

IM-(A)-1-carboxy-2-methylthio- IM-((5)-1-carboxy-3,3-ethyl)carbamoyl|benzyl)carbamoylmethoxy, M-(A)- dimethylbu- o-|M- ((5)-1-carboxy-2-carbamoyl-ethyl)carbamoyl|benzylcarbamoylmethoxy, M-(A)-o-ethyl)carbamoyl|benzyl)carbamoylmethoxy, -M-(A)- IM-(A)-1- carboxy-3,3-dimethylbutyl)carbamoyl|-4-o-IM-(2-sulfoethyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-((A)-o-1M-((5)- hydroxybenzylcarbamoylmethoxy, M -((BA)-o-|M- 1-carboxy-2-(trimethylsilyl)ethyl|carbamoyl)-4- (carboxymethyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy or M-(A)-o-(M- hydroxybenzylcarbamoylmethoxy, M-(A)-o-|M-((8)- Y(A!Y)-1-carboxy-2-(trimethylsilyl)ethyl|carbamoyl)- 1-carboxyethyl)carbamoyl|-4- 4- hydroxybenzyl)carbamoylmethoxy; hydroxybenzyl)carbamoylmethoxy, M-(BA)-o-|M-((5)- or its pharmaceutically acceptable salt, sol-1-carboxy-2-hydroxyethyl)carbamoyl|-4- vate, solvate of such a salt or its prodrugs. hydroxybenzyl)carbamoylmethoxy, / M-(B)-o-(M-(2- According to another variant of the implementation of bis-sulfoethyl)carbamoyl|benzyl)carbamoylmethoxy, the preferred compounds according to the invention are

M-((B)-o-|M-((8)-1-carboxy-2-(B)- any of the compounds described in examples 5, 6, 7, 9, hydroxypropyl)ucarbamoyl|benzyl) icarbamoylmethox 11, 14, 15, 26, 27, 28, 30 or 33 or its pharmaceutically acceptable salt, M-A((B)-o-|M-((8)-1-carboxy-2- solvate, a solvate of such a methylpropyl)carbamoyl|benzyl)carbamoylmethoxy salt, or its prodrugs. , ,

M-((B)-os|(M-((8)-1-carboxy-3- In another embodiment, vy-methylbutyl)carbamoyl|benzyl)carbamoylmethoxy, any of the compounds described in any of pre-

M-(A) o-IM-(1-(5)-1-carboxy-2i5)ulade, or its pharmaceutically acceptable salt, sol-methylbutyl)carbamoyl|benzylcarbamoylmethoxy, . I am a vat, a solvate of such a salt or its prodrugs.

M-(A)-o-carboxy-4-Y Preferred variants of the invention hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)-) are those that relate to the compound of formula (I) or Its 1-carboxy-4-Y and a pharmaceutically acceptable salt.aminobutyl)carbamoyl|benzylcarbamoylmethoxy. Another object of this invention is a method of

M-((A) o-(m-(5)-1-carboxy-4) compound of formula (I) or its pharmaceutically acceptable salt, solvate, solvate of such a salt or no)butylcarbamoyl)benzyl)carbamoylmethoxy , M- its prodrugs, while the method (where changing groups

MA)-o-(5)-2-carboxypyrrolidine-1- have the values given for formula (I), unless ylcarbonyl)benzyl|carbamoylmethoxy, /-M-((B)-o-|M- is not specifically stated otherwise ) provides: (carboxymethyl)-IM- Method 1): for compounds of formula (I), where X is pre-methylcarbamoyl|benzyl)carbamoylmethoxy, M-(B)- represents -O-, -МВ2 or -5-; the reaction of the compound o-(M-(1-(8)-2-(8)-1-carboxy-1-hydroxyprop-2- of formula (Ia) or (PIB): yl)ucarbamoyl|benzylcarbamoylmethoxy, /- M-( A)-oh-

IM- оо оо в (sulfometho DM в о ДЖ тыл)carbamoyl|benzylcarbamoylmethoxy, M-((A)-o- carboxybenzyl)carbamoylmethoxy, M-(A)-o-(M- M M M y ((5 )-1-carboxy-2-(H)-hydroxypropyl)carbamoyl|-4- and В К В ve К hydroxybenzyl) carbamoylmethoxy, M-((A)-o-(M-((5)- t v 1- carboxy-2-methylpropyl)/carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)- (t (KE), 1-carboxybutyl)carbamoyl|-4-hydroxybenzyl) carbamoylmethoxy, M-((A)-o-(M-((5)- (Pa) (tb) 1-carboxypropyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-((B)-o-|M- with the compound of formula (I): (8A)-1-carboxy-2-methylthio-ethyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)-1-carboxyprop )carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy, M-((A)-o-(M-((5)-

which is optionally substituted near the carbon atom by one or more B: c" and Method 5): for compounds of formula (I), where B! schi M n represents a carboxyl group; deprotection from the compound of formula (IXa): in Ov

PI Rezu (o ve 1 9. By AI ve vedu M i VM Od where I is a group that displaces | z sia; Method 2): the reaction of an acid of the formula (IMa) or o 1 | t you same 7-de (meh rr 9. o Dir VU vo 5 u A o h o, r m t N o, uv u cha i o / yuchy kum iv v fa u ha v | v2 (Kk)

You t ХМ du volaka y e VU ge i o "С (ха) (ве), (о, or (ХИБ): (Ма) (мб) у и | | (А у or |Й activated derivative; with amine for- a - o V u Z muly (M): Ve. ry y x X ty - su yii M y xx. Ka M p

AH ve | Kk g

SA vo v r ra Dod v vy VI | id

TYA te un pe, BU ro I ro vo EI, . (KU so ikh " i . 11

Method 3); side of compounds of the Formula U where Kk in which KR together with the group -ОС(О)-, to which it represents the group tk omula (IV); the reactant is attached, forming an ester; compound of formula (I), where is and soru Method 6): for compounds of formula (I), where B" is a carboxyl group, with an amine of formula (MI): is a group of formula (IV) and BZ is a carboxyl group; deprotection of the compound of formula (Xa):

Gee what 74 in: hee! v ro vo V y Mana KI t (M) | MI I. | re Cor:

RO GEN Y nia to m-K

Method 4) for compounds of the formula (I), where one of B" g 5 Y A du and 85 is independently selected from Ci-Sev-alkylthio, which is (5 and is optionally substituted near the carbon atom by one or by several K!"; the reaction of a compound of the formula (Kk, (Mpa) or MIIB): (Ka)

Re x de o. about in about o v y vo ze v Ni zv-d di or (HB): g v Ve "4 gAZ

Me -e Me dona V.V.

V in nan pi ih o a: kny: NI i shchi (pe), (Z, VYNY che ro Ese - (Una) (Miiv) pud aku de I represents a group that is displaced; with the thiol of the formula (MI) : their d'-H (MI) that . not in which B" is a C-Cv-alkylthio, in which RR together with the group -OS(O)-, to which it is attached, forms a complex ether;

Method 7): for compounds of formula (I), where B" is important, EP is methyl. According to the group of formula (IV) and another variant of the invention, Ke represents

M(АС(О)-; the reaction of the acid of the formula (Xia): involves C1-C8-alkyl or phenylC1-C8-alkyl, preferably C1-C4-alkyl or benzyl, more preferably

It is tert-butyl, methyl, ethyl or benzyl. пи: ИН The following are the specific conditions for the above-mentioned reavdo V de ov it Mn ktions.

I. and I | and ry | ры Где Bicyclic structures according to this invention no | Я ей т іт can be obtained according to Scheme Ia or in яй-о вых, G-Я Scheme IU. It is obvious to a person skilled in the art that any of the above intermediate values of B" or "B" or "B" in the following schemes can be replaced by the corresponding group. For example, for the synthesis of a compound

Shk of the formula (Ia) 2" can have the value ХХ in the following scheme. or (ХИБ): АХ бай быных шк 7 zna Y y

Because 0 Ma t R zok as, k) N poly o ie a sta

Z o o o pov i and t Zh

N XX century Bo ha , y) (vi ! with vch h KE sia Kei

Ov v t vv r. dk me K. B v yiv t o v T t z sita still and NI She v no te Jakoovshy kov van y v Rosv ikh po ik ky v as yav tyy (V ke Fi i po ( khiv) U and Z or its activated derivative; with an amine of the formula (XII):

Tey; mil i y ud M TO anis vam she m SCHE "I

Ve i Sho (XI) and then, if it is necessary or desirable: i) conversion of the compound of the formula (I) into another peso compound of the formula (1); i) removal of any protective groups; where ROI represents the functional i) formation of a pharmaceutically acceptable salt, the interconversion of Bg into other values of K" for the presolvate, solvate of such a salt or prodrugs using methods known to a specialist in this field

It represents a group that is displaced, techniques. suitable values for /. are, for example, halo- Compounds of the formula (A) and (0) are commercially dostugen or sulfonyloxy group, for example, chlorine, pnimi, or they are known from the literature, or they are mobrom, methanesulfonyloxy or // toluene-4- should be obtained using traditional sulfonyloxy groups. methods known in the art.

BP together with the group -OS(O)-, to which it is attached, forms a complex ether. It is preferably methyl or ethyl. More re-

pentafluorophenyl ethers are also available. The reaction of compounds of these compounds with amines is well known in this field of technology, for example, they can interact in the presence of a base, such as those indicated above, and in a suitable solution ; a factor such as those indicated above. Reaction of course

ZOROM ayumu i her ivi and sh oo notvoma vk can be carried out at a temperature in the interval

And also from -40 to 4076. Compounds of the formula (ImMa) or (ImBB), in which X: -0- is the eye of MAag, -5-, can be obtained according to

ОТ и ШВИ им Я t Ach se g zt duty Schemes 2: - van v ha V ph o - Ho techn

Fa Zhov nah ue govo SOUND j - ber M vuh be i zy v:

In there FEM KN: and

And Bosh bme) sheya te yah : y 3 Mart shchi ne: oh maso" y : Mesm pshkhov KAK that p Noony otv 0m) shi dy ' (washed p i duv)

GO and we an and ; Mmaboh:

DV YN and I od ve i: va and Sho ad Y mes i same YOU PI ve R: . i yav re Scheme 2: H pe in le i e i E: z

ОЙ т ш Ю В Я de Г. у (Mia) and (MIB) represents a group, en KOH M, ох which is displaced, for example, bromine, chlorine, fluorine,

BUT Nyaz o A

Hey! " mesyl or tosyl and where X is -O-, -5-, etc. MAg (optional for -50- and -502- with the subsequent oxidation step according to Method 1). zlk'ne IV Compounds of formulas (ImMa) and (MB), where X represents It is -50- or -5O2-, these compounds can be obtained by oxidation of the obtained compounds of the formula and reaction U ry U . (IMa) and (IMB) according to Scheme 2, where X represents (IP) in the presence of a base, for example, an inorganic one, is -5- rovy and as Hun's in Lan prep Formulas MU) or SU) in which X is a domestic solvent, such as acetonitrile, ihl represents -СНо- and p represents 1, dricyl, dihu can be obtained according to Scheme 3. rmethane or tetrahydrofuran, at a temperature in the range from 0"С to the temperature of the phlegm, prevails Sh Em at the temperature of phlegm or near the temperature of the mouth

Compounds of the formula (II) are commercially available, semi-precious compounds, or they are known from the literature, or they are known in the literature. : they can be obtained using traditional methods known in the field of technology. that 77

Method 2) and Method 3) and Method 7): Acids and amines and BU can be combined in the presence of a suitable heck coupling reagent. Standard peptide bonds can be used as suitable binding reagents. basic reagents known in the field, or, for example, carbonyldiimidazole and dicyclohexylfuran in M y noya carbodiimide, optionally in the presence of a catalyst and an inhibitor such as dimethylaminopyridine or 4- drrte YAR M screw and pyrrolidinopyridine, optionally in the presence of a pc C base, for example, triethylamine, pyridine or i xx 2,6-di-alkyl-pyridines, such as 2,6-lutidine or vu «a 2.6-di-tert -butylpyridine. Suitable solvents are dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction can usually be carried out at a temperature in the range from -40 to 4070. It is obvious to a specialist in this field that the above reaction scheme can be modified for

Suitable activated acid derivatives are the preparation of compounds of the formula (Ma) or (MB), where n acid halides, for example, chlorides, is 2 or 3. di, and active esters, for example, compounds of the formula (Xia) and (XIB) can be obtained using procedures known to those skilled in the art. Cases where such protection is necessary or necessary in the art, according to the methods described in the desired, as well as acceptable methods for doing so in the present invention. protection known to a specialist in this field of technology. Con-

Compounds of the formula (IMc), (M), (MI), (XII) and (MI) are a specific example when it may be necessary to use commercially available compounds, or they are the application of a protective group, is the protection of the nitrogen atom in mi from the literature , or they can be obtained at the 2nd position of the benzothiadiazepine ring using traditional methods known in this synthesis of certain intermediate products. the field of technology. Conventional protecting groups may apply

Method 4): Compounds of the formula (Mmiia) and (MIIB) can, in accordance with generally accepted practice, be subjected to reaction with thiols of the formula (MIII) in the clade, see T.MU Sgeepe, Rgoiesime OSgocr5 ip the presence of a base, for example, an inorganic base- Ogdapis Zzupipev5i5, dhopp Umieu and 5op5, 1999). Such a base, such as sodium carbonate, or an organic base, if the reactants contain such groups, such as a Hunig base, in the presence of an accessory such as an amino group, a carboxyl group, or a hydroxyl solvent such as DMF or THF at a group, it may be desirable to protect such a group at a temperature in the range from 0°C to the temperature in some of the reactions described in this invention. phlegm. A suitable protecting group for an amino group

Compounds of formula (IIa) and (MB) may be or alkylamino groups are, for example, an acyl group obtained by any of the procedures, for example, an alkanoyl group, such as acetyl, described above for the preparation of compounds of formula (1), alkoxycarbonyl group, for example, methoxy - but in which one of P and E? is I. carbonyl, ethoxycarbonyl or tert-

Compounds of the formula (MI!) are commercially available butoxycarbonyl group, arylmethoxycarbonyl compounds, or they are known from the literature, or a group, for example, benzyloxycarbonyl, or aroone can be obtained using a traditional group, for example, benzoyl. Conditions for removal of the methods known in this field of technology. khistu for the above-mentioned protective groups in

Method 5) and Method c): From esters, for- mainly depend on the choice of protecting group. mule (IXa), (IXB), (Xa) and (XB) can be removed by - So, for example, an acyl group such as an alkanoyl-hist under standard conditions, such as described below, on or an oxycarbonyl group or an aroyl group, for example , they can be deprotected by the group can be cleaved off, for example, by reaction with sodium hydroxide in methanol under hydrolysis with a suitable base, such as hydroxide at room temperature. alkali metal such as lithium hydroxide or

Sodium esters of formula (IXa), (IXB), (Xa) and (XbB). Alternatively, the acyl group, such as can be obtained using any of the tert-butoxycarbonyl group can be cleaved by the procedures described above for the preparation of compounds of the formula (I), for example, by treatment with a suitable acid, but in which B! or 25 represents a group such as a salt, sulfur or phosphorous C-C-Alkoxycarbonyl group. acid or trifluoroacetic acid and aryl metho-

It is also obvious that various substituents in the alkyl carbonyl group, such as benzyloxycarbonyl structures in the compounds according to this wine group, can be cleaved off, for example, can be introduced by standard hydrogenation in the presence of a catalyst, aromatic substitution reactions or such as palladium on carbon, or by treatment obtained by modification of conventional functional Lewis acid, for example, nal groups both before and immediately after boron tris(trifluoroacetate). A suitable alternative to the methods described above, and essentially included in the scope of the native protective group for the primary amino acid of the invention. Such reactions and modifications include, for example, a phthaloyl group, which can be cleaved off by treatment with an alkylamine, an aromatic substitution reaction, reduction, for example, with dimethylaminopropylamine, or from hydrogen substituents, alkylation of substituents and oxidation by infection. avengers Reagents and reaction conditions for such methods are well known in the field of chemistry. Specific examples of the group are, for example, an acyl group, for example, allads of aromatic substitution reactions are a canoyl group, such as an acetyl, an aroyl group, the introduction of a nitro group using a concentrated, for example, a benzoyl group, or an arylmethyl group, na- nitric acid, the introduction of an acyl group by for example, benzyl. The deprotection conditions for the above-mentioned protecting groups (such as aluminum trichloride) under Friedezat conditions will mainly depend on the choice of the protecting group. So, for example, La Kraft; introduction of an alkyl group after an acyl group, such as alkanoyl or aroyl, with alkyl halides and Lewis acids (this group can be cleaved, for example, with aluminum trichloride) under Friedel conditions with the help of hydrolysis with a suitable base, such as

Craft; and introducing a halogen group. Concrete alkali metal hydroxide, for example hydroxide, examples of modifications are the reduction of nitrolithium or sodium. Alternatively, the arylmethyl group to the amino group using, for example, a ca- group, such as a benzyl group, can be split- catalytic hydrogenation with a nickel catalyst lene, for example, by hydrogenation in the presence or treatment with iron in the presence of hydrochloric acid catalyst, such as palladium on coal when heated; oxidation of the alkylthio group to alkyl- A suitable protecting group for carboxyl sulfinyl or alkylsulfonyl. group is, for example, an esterified group, e.g.

It is also apparent that for some reactions, a clade, a methyl or ethyl group that may be described in this invention may need to be cleaved off, for example by hydrolysis with a base/desirable to protect any sensitive groups with such as sodium hydroxide, or for example

tert-butyl group, which can be cleaved off, therapeutic treatment of a warm-blooded animal, for example, by acid treatment, such as a human. organic acid, such as trifluoroacetic We have found that compounds dissolved in acid, or, for example, the benzyl group that this invention, or their pharmaceutically acceptable- can be cleaved, for example, by hydro- to a salt, solvate, solvate of such a salt or their prodrugs, in the presence of a catalyst such as pala- are effective inhibitors of the transfer of bile actions on coal. of acids in the ileum (IVAT), and, accordingly, there is a co-

Protective groups can be cleaved at any time during the treatment of painful conditions, which is related to a suitable stage of synthesis with the help of coils with hyperlipemic conditions. tea methods, well known in the field of chemistry. Another variant of the implementation of this invention is

As mentioned above, the compounds according to this compound of formula (I), or its pharmaceutical derivative, have an inhibitory effect in relation to the soluble salt, solvate, solvate of such a salt or its transfer of bile acids in the ileum of the drug, as described here above , for use as (IVAT). These properties can be evaluated, for example, of a medicinal product. clade, with the help of research under the conditions of ip could Thus, another variant of the implementation of the effect on the absorption of bile acids in IVAT-finding is the use of the compound of formula (I) or its transfected cells (Ztyi GI, Riise-uopev M. of a pharmaceutically acceptable salt , solvate, sol-

U, Nydpe5 K. T. and UChope5 M. K. A.; In Viotoyesshag vatu of such a salt or its prodrugs as described hereinabove,

Zegeepipo, 3, 227-2301| or under the conditions of ip mimo for the preparation of a medicinal product for application - investigation of the effect on the absorption of radioactive labeling to inhibit the transfer of bile oxygenated bile acids in mice/rats (Hemiz M. S, lot in the ileum (IVAT) in a warm-blooded animal -

Vgievadau S. BE. and Kooi S, GI, U Gir Kez 1995, 36, 1098- us, such as a person. 1105). Thus, another variant of the implementation of

According to another embodiment, the present invention is the use of a compound of formula (I), or its invention provides a pharmaceutical composition - a pharmaceutically acceptable salt, solvate, salt, which contains a compound of formula (I), or its derivative of such a salt or its prodrugs, as described above, a pharmaceutically acceptable salt, solvate, solvate thereof for the preparation of a medicinal product for use, a salt or its prodrugs, as described hereinabove, in combination for the treatment of hyperlipemic conditions in combination with a pharmaceutically acceptable solvent blooded animal such as man. or carrier Thus, another variant of the implementation of

The composition may be in a form suitable for use of the compound of formula (I) or suitable for oral administration, for example, in a pharmaceutically acceptable salt, solvate, salt form, tablet or capsule, for parenteral administration of such a salt or its prodrugs , as described above, th administration (including intravenous, subcutaneous - for the preparation of a medicinal product for application, intramuscular, intravascular administration for the treatment of dyslipidemic conditions and dilution or infusion) in the form of a sterile solution, methods such as as hyperlipemia, hypertriglyceridemia, suspensions or emulsions, for local administration, in hyperbetalipoproteinemia (increased lipoprotein content in the form of an ointment or paste, or for rectal injection of low-density proteins), hyperprebetalipoproteinemia, in the form of a suppository. Tnemia (increased lipoprotein content is very low

In general, the above compositions can be thick), hyperchylomicronemia, you are prepared in the usual way with the use of conventional fillers. proteinemia and hypoalphalipoproteinemia (decreased

A compound of formula (I), or its pharmaceutics of high-density lipoprotein content) into a heat-acceptable salt, solvate, solvate of such a salt or its blood animal, such as a human. prodrugs are usually administered to a warm-blooded animal. Thus, another variant of implementation is a standard dose in the range of 5-5000 mg per m? the method is to use the compound of formula (I) or its upper body of the animal, i.e. approximately 0.02- pharmaceutically acceptable salt, solvate, salt - 100mg/kg, preferably 0.02-5Omg/kg and usually it is a wat of such a salt or prodrugs thereof, as described hereinabove, in a therapeutically effective dose. The standard form used for the preparation of a medicinal product, such as a tablet or capsule, for the treatment of various clinical conditions, usually includes, for example, 1-250 mg of an active component such as atherosclerosis, arteriosclerosis, arrhythmia, hypertension. Predominantly used daily dose for rhombic conditions, impaired vascular function, is in the range of 1-50 mg/kg, more severe endothelial function, heart failure 0.1-10 g/kg. According to another option, pregnancy, coronary vessel disease, heart palpitations, the daily dose is in the range of 0.02 - vascular disease, myocardial infarction, steno- 20mg/kg. However, the daily dose primarily depends on rdia, diseases of peripheral vessels, inflammation of the organism that is treated, the characteristics of cardiovascular tissues, such as the heart, the origin of the route of administration and the severity of the disease, which valves, vascular network, arteries and veins, aneurysms, amenable to treatment. Therefore, the optimal dose of stenosis, restenosis, the formation of plaques on the walls must be determined by the attending physician individually for each patient. vessel walls, infiltration by leukocytes, monocytes

According to another variant of implementation, by dates and/or macrophages, thickening of the inner The invention relates to the compound of formula (I) or its vessel lining, reducing the thickness of the average pharmaceutically acceptable salt, solvate, salt vessel lining, infections and surgical injuries and trom - cotton wool of such a salt or its prodrugs, as described above, blood vessels, shock and temporary disorders of the brain for use in the method of prevention or circulation in a warm-blooded animal, such as any

dyne. sclerosis, diseases of coronary vessels, heart attacks

Thus, another variant of implementation of myocardial tortuosity, angina pectoris, peripheral diseases is the use of the compound of formula (I) or its vessels, stroke and temporary disorders of cerebral pharmaceutically acceptable salt, solvate, salt circulation in a warm-blooded animal, such as an individual of such a salt or its prodrug, as described hereinabove, in need of such treatment, which includes for the preparation of a medicinal product for administration to said animal an effective amount for the treatment of atherosclerosis, diseases of the compound of formula (I), or its pharmaceutical of coronary vessels, myocardial infarction, angina pectoris, soluble salt, solvate, solvate of such a salt or its diseases of peripheral vessels, stroke and timcha- prodrugs. It is also obvious that the inhibitor of the transfer of an animal such as a person. of bile acids in the ileum (IVAT) potentially

According to another embodiment, it may be suitable for treatment and/or prophylaxis, the finding provides a method of inhibiting the transfer of gallstones. According to another bile acids in the ileum (BAT) in a warm-blooded animal, such as a human, in need of a method of treatment and/or prevention of biliary conc- such treatment, which includes the introduction of the indicated rements in a warm-blooded animal, such as a human, to an animal of an effective amount of a compound of formula (1) in need of such treatment, which includes the administration of or its pharmaceutically acceptable salt, solvate, giving said animal an effective amount of a co-solvate of such a salt or its prodrugs. of formula (I), or its pharmaceutically acceptable

According to another embodiment, a salt, a solvate, a solvate of such a salt, or a prodrug thereof. The finding provides a method of treating hyperlipemic The amount of the dose required for therapeutic conditions in a warm-blooded animal, such as a person, or prophylactic treatment of a specific that needs such treatment, which includes in- a diseased condition necessarily depends on the organization of the specified animal, the effective amount of spolunism , which is subject to treatment, the route of administration of formula (I) or its pharmaceutically acceptable and the severity of the disease that is subject to treatment. salt, solvate, solvate of such a salt or its prodrugs. The applied standard dose is in

According to another variant of implementation, the range, for example, 1-5Omg/kg, preferably 0.1- finding provides a method of treatment of dyslipidemic 10mg/kg. conditions and disorders, such as hyperlipemia, hypertri- Inhibitory action in relation to the transfer of glyceridaemia, hyperbetalipoproteinemia (increased bile acids in the ileum (IVAT), as a description of the content of low-density lipoproteins), hyperprene- here above, can be used in in the form of beta-lipoproteinemia (increasing the content of night therapy or can be used, in addition to very low-density lipoproteins), hyperchylo- to the compound according to the invention, one or more ronemia, hypolipoproteinemia, hypercholesterolemia, other substances and/or treatments. Such a complex hyperlipoproteinemia and hypoalphalipoproteinemia treatment can be carried out by simultaneously (reducing the content of high-density lipoproteins) in the body, sequential or separate introduction of an individual - a warm-blooded animal, such as a person, who has the right components, which are used to treat such treatment, which includes input. According to this version of the implementation, the animal of an effective amount of the compound of the invention is provided with a pharmaceutical product, which (I), or its pharmaceutically acceptable salt, contains a compound of the formula (I), or its pharmaceutically solvated, solvated of such a salt or its prodrugs. an acceptable salt, solvate, solvate of such a salt or thereof

According to another embodiment, the drugs as described hereinabove, and further, the invention provides a method for the treatment of various clinical conditions that inhibit bile acid transport in colons, such as atherosclerosis, arteriosclerosis, large intestine (IVAT), such as described here above, and in addi- arrhythmia, hyperthrombotic conditions, functional disorders hypolipemic agent for complex vascular sion, endothelial function disorders, cardiac treatment of hyperlipemia. insufficiency, disease of coronary vessels, According to another variant of the implementation of vy- cardiovascular diseases, myocardial infarction, finding, a compound of the formula (Her), or its pharmaceutical- angina pectoris, diseases of peripheral vessels, but an acceptable salt, solvate, solvate of such a salt or inflammation of cardiovascular tissues, such as silver prodrugs, can be administered in combination with inhibition, valves, vascular network, arteries and veins, aneurysm of NMO Co-A reductase, or their pharmaceutical changes, stenoses, restenoses, formation of plaques on acceptable salts, solvates, solvates on vessel walls, the formation of strips of fatty deposits of salts or their prodrugs. Suitable inhibitions on the walls of vessels, infiltration by leukocytes, frames of NMO Co-A reductase, their pharmaceutics by monocytes and/or macrophages, thickening by internally acceptable salts, solvates, solvates of the vascular lining, reducing the thickness of these salts or their prodrugs are statins, vascular lining, infections and surgical tra- known in this field. The preferred statins are strokes and vascular thrombosis, stroke and temporary disorders of fluvastatin, lovastatin, pravastatin, simvastatin, cerebral circulation in warm-blooded animals, tatin, atorvastatin, cerivastatin, bervastatin, which as a person who needs such treatment as dalvastatin, mevastatin and (E)-7-(4-(4-fluorophenyl)- involves administering to the indicated animal an effective b-isopropyl-2- amount of the compound of formula (I) or its pharmaceutically acceptable salt , solvate, a solvate of such a salt of il|c3K,55)-3,5-dihydroxyhept-b-enoic acid (ro- or its prodrug. suvastatin), or its pharmaceutically acceptable salt,

According to another embodiment, the dasolvate, a solvate of such a salt, or a prodrug thereof. The present invention provides a method of treating an atherogenic statin, namely atorvastatin, or its pharmaceutical

a pharmaceutically acceptable salt, solvate, solvate such as to require such treatment, which includes salts or prodrugs thereof. A more preferred statin to administer to said animal in an effective amount is atorvastatin calcium. Also, the preferred compound of formula (I) or its pharmaceutic pristatin is (E)-7-I4-(4-fluorophenyl)-6-isopropyl-2-one salt, solvate, solvate of such a salt or its

Imethyl(methylsulfonyl)amino|pyrimidine-5- prodrugs with simultaneous, sequential or il|!c3K,55)-3,5-dihydroxyhept-b-enoic acid (ro- separate administration with a substance that binds bile - suvastatin) , or a pharmaceutically acceptable acid thereof. a salt, a solvate, a solvate of such a salt, or a prodrug thereof. So, according to the additional option

A more preferred statin is the calcium salt of the invention, a method of inhibiting suvastatin is provided. transfer of bile acids in the ileum

According to an additional variant of implementation (IVAT) in a warm-blooded animal, such as a person of the invention, a compound of formula (I), or its pharmacist, which requires such treatment, which includes an intradermally acceptable salt, solvate, solvate of such a salt of administration to the specified animal, an effective amount or its prodrug can be administered in combination with an inhibitory compound of formula (I), or its pharmaceutically acceptable NMO Co-A reductase inhibitor, or its pharmaceutically acceptable salt, solvate, solvate of such a salt, or its pharmaceutically acceptable salt, solvate, prodrug solvate with simultaneous, sequential or such salt or its prodrugs, and/or a substance that separate administration of an effective amount of inhibitor binds bile acid, thus avoiding HMa Co-A reductase, or its pharmaceutically possible risk of excess bile acids in an acceptable salt, a solvate, a solvate of such a salt, or the colon caused by the inhibition of the sys- its prodrugs, with simultaneous, sequential, or topic transfer of bile acids. Excess of separate administration with a substance that binds bile - the concentration of bile acids in the internal acid content. those can cause diarrhea. Thus, this Therefore, according to an additional variant, the invention also provides treatment for possible implementation, the invention provides a method for treating side effects, such as diarrhea, in patients during hyperlipemic conditions in a warm-blooded animal, treatment that includes a compound of formula (I), or her such as a person in need of such treatment, a pharmaceutically acceptable salt, a solvate, a solvate that includes the administration of an effective salt or its prodrug to the indicated animal. amount of the compound of formula (I), or its pharmaceutical

An inhibitor of NMO CoA-reductase, or its pharmaceutically acceptable salt, solvate, solvate of such a pharmaceutically acceptable salt, solvate, solvate of such a salt or its prodrugs with simultaneous, sequential salt or its prodrugs will be removed due to their action or separate administration of an effective amount of inhibitor - chew the availability of endogenous cholesterol for the thorum of NMO Co-A reductase, or its pharmaceuticals- synthesis of bile acids and have an additional effect in chno acceptable salt, solvate, solvate of such a salt in combination with the compound of formula (I), or its pharma- or its prodrugs. ceutically acceptable salt, solvate, solvate. Therefore, according to an additional variant of such a salt or its prodrugs to reduce concentration, the invention provides a method of treatment of lipid concentration. hyperlipemic conditions in a warm-blooded animal,

Suitable substances that bind bile acids, such as a person in need of such treatment, acids, for such a joint treatment are resins, which includes the administration of the specified animal to effective- such as cholestyramine and cholesterol. One of the advantages of the compound of formula (I) or its pharmaceuticals is that the dose of the substance that binds the bile of an acid-acceptable salt, solvate, solvate of such a lot may be less than the therapeutic dose of the salt or its prodrugs at the same time, sequentially for the treatment of cholesterolemia with a separate drug- or separate administration of an effective amount of the substance using only a substance that binds wines that binds bile acid. bile acid. By reducing the dose of the substance, therefore, according to the additional option that binds bile acid, it is also possible to avoid the implementation, the invention provides a method of treating the occurrence of any side effects caused by hyperlipemic conditions in a warm-blooded animal, insufficient sensitivity of the patient to therapeutic drugs, such as humans , which needs such treatment, no dose. which includes the introduction to the specified animal of effective

Therefore, in accordance with an additional variant of the amount of the compound of formula (I) or its pharmaceutical implementation of the invention, a method of inhibitively acceptable salt, solvate, solvate of such a transfer of bile acids in ileal acid or its prodrugs with simultaneous, sequential administration is provided (IVAT) in a warm-blooded animal, such as humans- or by the separate administration of an effective amount of inhibin- that requires such treatment, which includes the torus of NMO Co-A reductase, or its pharmacists- administration to the specified animal of an effective amount of an acceptable salt, solvate, solvate such a salt of the compound of formula (I), or its pharmaceutical preparation or its prodrugs, with simultaneous, sequential administration of a distinct salt, solvate, solvate of such a salt or its or separate administration with a substance that binds prodrugs with simultaneous, sequential or bile acid. separate administration of an effective amount of the inhibitor According to another embodiment, the

NMOa Co-A reductase, or its pharmaceutical composition provides a pharmaceutical composition, which is an acceptable salt, solvate, solvate of such a salt, or contains a compound of formula (I), or its pharmaceutically prodrug. an acceptable salt, solvate, solvate of such a salt or thereof

Therefore, according to an additional variant of the prodrug, and the NMO Co-A reductase inhibitor, or its implementation of the invention, a method of inhibiting the transfer of bile acids in the ileum is provided. - shchi (IVAT) in a warm-blooded animal, such as a human-therapeutically acceptable solvent or carrier.

According to another variant of implementation, given in a single dosage form; and the invention provides a pharmaceutical composition- a) a container containing the specified pepper, which contains the compound of formula (I), or its minced meat, the second and third dosage forms. a pharmaceutically acceptable salt, solvate, solvate of such According to another embodiment, a salt or its prodrug, and a substance that binds bile, the invention provides a kit that contains: an acid, in combination with a pharmaceutically acceptable a) compound of the formula ( I), or its pharmaceutical solvent or carrier. an acceptable salt, solvate, solvate of such a salt or thereof

According to another variant of implementation, daprodrugs, together with a pharmaceutically acceptable different invention provides a pharmaceutical component or carrier, in the first unit dosage, which contains the compound of formula (I) or its pharmaceutical form; a pharmaceutically acceptable salt, solvate, solvate thereof B) an inhibitor of NMO Co-A reductase, or its phase or its prodrugs, and an inhibitor of NMO Co-A reductase, a pharmaceutically acceptable salt, solvate, solvate or its pharmaceutically acceptable salt, solvate, such salts or its prodrugs, in the second single do- solvate of such a salt or its prodrugs, and a substance that is in the so-called form; and binds bile acid, in combination with pharmaceu- c) a container in which the specified per- by an acceptable solvent or carrier are contained. the first and second dosage forms. According to another

According to another variant of implementation, yes- a variant of implementation, the present invention provides a kit that contains a compound a kit that contains: formula (I), or its pharmaceutically acceptable salt, a) a compound of formula (I), or its pharmaceutically acceptable solvate , a solvate of such a salt or its prodrug, and an inhibitory-acceptable salt, solvate, solvate of such a salt or its tor NMO Co-A reductase, or its pharmaceutical prodrug, together with a pharmaceutically acceptable variously acceptable salt, solvate, solvate of such a salt or factor or carrier, in the first unit dose - its prodrug. her form;

According to another variant of the implementation, d) the substance that binds bile acid, the second invention provides a kit that contains the compound of gij in a single dosage form; and formula (I), or its pharmaceutically acceptable salt, c) a container containing the specified persolvate, solvate of such a salt or its prodrugs, and second and second dosage forms. According to another wine that binds bile acid. embodiment, the present invention provides

According to another embodiment, the kit containing: the present invention provides a kit containing a compound a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, an acceptable salt, a solvate, a solvate of such salt or its solvate, a solvate of such a salt or its prodrug, and inhibitory prodrugs, together with a pharmaceutically acceptable solvent of NMO Co-A reductase, or its pharmaceutical factor or carrier, in the first unit dose, an acceptable salt, solvate, solvate such a salt or its form; its prodrugs and a substance that binds bile acid B) an inhibitor of NMO Co-A reductase, or its falot. pharmaceutically acceptable salt, solvate, solvate

According to another embodiment, such a salt or its prodrug, in the second unit, the present invention provides a kit that contains: the so-called form; and a) a compound of formula (I), or its pharmaceutical c) a substance that binds bile acid; into a three-acceptable salt, solvate, solvate of such a salt or its single dosage form; and prodrugs, in the first single dosage form; a) a container in which the specified per-

B) inhibitor of NMO Co-A reductase, or its phase, second and third dosage forms. pharmaceutically acceptable salt, solvate, solvate Thus, in another embodiment of this salt or its prodrug; the second unit of the invention is the use of a compound of the formula (I), or its so-called form, and a pharmaceutically acceptable salt, solvate, salt (c) a container containing the indicated pervates of such a salt or its prodrugs, and an inhibitor of NMO Co- And the second dosed form. According to another reductase, or its pharmaceutically acceptable embodiment, the present invention provides a salt, a solvate, a solvate of such a salt, or a prodrug thereof, which contains: pharmaceutical use for inhibiting the transfer of biliary acceptable salt, solvate, solvate of such a salt or its acids in the ileum (IVAT) in warm-blooded tva- prodrugs, in the first single dosage form; ryna such as a human being. p) a substance that binds bile acid; In other words, another variant of the invention is a single dosage form; and the use of the compound of formula (I), or its pharmaceutical form) a container containing the indicated perceutically acceptable salt, solvate, solvate tasha and the second dosage form. In accordance with another salt or its prodrugs, and a substance that binds bile- variant implementation, the present invention provides chonic acid, for the preparation of a medicinal product, a kit that contains: for use in inhibiting the transfer a) a compound of formula (I), or of its pharmaceutical bile acids in the ileum (IVAT) into a heat-accepting salt, a solvate, a solvate of such a salt or its blood animal, such as a human. prodrugs, in the first single dosage form; Thus, another variant of the implementation of

B) an inhibitor of NMO Co-A reductase, or its fan, is the use of a compound of formula (I), or its pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt, solvate, salt of such a salt or its prodrug; in the second single dose of such a salt or its prodrugs, and the inhibitor of NMO Co-A in the so-called form; reductase, or its pharmaceutically acceptable c) a substance that binds bile acid; in tres- salt, solvate, solvate of such a salt or its pro-

kiv, and a substance that binds bile acid, for him, by sequential or separate administration of an effective drug preparation for the use of an amount of NMO Co-A reductase inhibitor, to inhibit the transfer of bile acids in or its pharmaceutically acceptable salt, solva-hip intestine (IVAT) in a warm-blooded animal, a father, a solvate of such a salt or its prodrugs, indispensable as a person. together with a pharmaceutically acceptable semi-

Thus, another variant of the implementation of the agent, with simultaneous, sequential or separate application, is the use of the compound of formula (I), or its introduction of an effective amount of a substance that binds a pharmaceutically acceptable salt, solvate, salts bile acid, necessarily necessarily together with a farvate of such a salt or its prodrugs, an inhibitor of NMO Co-A with a pharmaceutically acceptable solvent or reductase carrier, or its pharmaceutically acceptable warm-blooded animal, such as a person, who shakes the salt, solvate, solvate of such a salt, or ingests it such treatment. kiv, for the preparation of a medicinal product for the so- So, according to an additional variant of application for the treatment of hyperlipemic conditions in the implementation, the invention provides a combined medicine- a warm-blooded animal, such as a person. tation, which includes the introduction of an effective amount

Thus, another variant of the implementation of the compound of formula (I) or its pharmaceutical preparation is the use of the compound of formula (I) or its soluble salt, solvate, solvate of such a salt or its pharmaceutically acceptable salt, solvate, prodrug salt, optionally together with a pharmaceutical cotton of such a salt or its prodrugs, a substance that is compatible with an acceptable solvent or carrier, with simultaneous bile acid, for the preparation of medicinal them, sequential or separate administration of one agent for use in the treatment of hyperlipe- or several of the following substances selected from ruminal states in a warm-blooded animal such as a magpie, which includes: dill. - inhibitors of CETP (a protein that transfers

Thus, another embodiment is a cholesterol ester), for example, those for which the compound of formula (I) is used, or it is referred to and which are described in (application MUO 00/38725 pharmaceutically acceptable salt, solvate, salt .7 line 22 - page 10, line 17|, which are included in the cotton wool of such a salt or its prodrugs, an inhibitor of NMO Co-A this invention by reference; reductase, or its pharmaceutically acceptable - antagonists of cholesterol absorption, for example, salt, solvate, a solvate of such a salt or its prolaclad azetidinones, such as 5СН 58235 and those of opik, and a substance that binds bile acid, for sleds in patent O5 5,767,115, which are included in this preparation of a medicinal product for the use of the invention by reference; for the treatment of hyperlipemic states in warm-blooded - MTP (microsomal transport animal, such as human. protein) inhibitors, for example, those described in IZsiepse,

Therefore, according to the additional option 282, 751-54, 19981, which are included in the present invention implementation, the invention provides a combined treatment- by reference; treatment, which includes the introduction of an effective amount - derivatives of fibrous acid; for example, clofib - a compound of the formula (I), or its pharmaceutical preparation, gemfibrozil, fenofibrate, ciprofibrate and its salt, solvate, solvate of such a salt or its afibrate; prodrugs, optionally together with pharmaceutical derivatives of nicotinic acid, for example, a nicotinic-acceptable solvent or carrier, with single-component acid (niacin), acipimox and niceritrol; by them, sequential or separate administration of an effect - a phytosterol compound, for example, ethanols; tive amount of NMO Co-A reductase inhibitor, - probucol; or a pharmaceutically acceptable salt thereof, a solvate - a compound for the treatment of obesity, for example, a solvate of such a salt or its prodrugs, orlistat (EP 129,748) and sibutramine (OB 2,184,122 and zkovo together with a pharmaceutically acceptable solution 4,929,629) ; factor or carrier to a warm-blooded animal, such as - an antihypertensive compound, for example, inhibi- a person in need of such treatment. torus of angiotensin-converting enzyme, anti-

Therefore, according to an additional variant of the angiotensin II receptor agonist, adrenergic implementation, the invention provides a combination treatment-blocker, alpha-adrenergic blocker, beta-administration, which includes the administration of an effective amount of an adrenergic blocker, a mixed alpha/beta compound of formula (I), or its pharmaceutical para-adrenergic blocker, adrenergic stimulant salt, solvate, solvate of such a salt or its torus, calcium channel blocker, diuretic prodrug, optionally together with pharmaceutical or vasodilator; an acceptable solvent or carrier, with simultaneously - insulin; by them, sequential or separate administration of effective sulfonylureas, including glibenclamide, a tive amount of a substance that binds bile cystolbutamide; lotu, optionally together with pharmaceutical metformin; and/or an acceptable solvent or warm-blooded carrier - acarbose; to an animal, such as a human, in need of such treat- or a pharmaceutically acceptable salt, solvate, treatment thereof. a solvate of such a salt or its prodrug, optionally

Therefore, according to an additional variant, together with a pharmaceutically acceptable solvent, the invention provides a combined drug or carrier to a warm-blooded animal, such as a human, which includes the administration of an effective amount that requires such treatment. compounds of the formula (I), or its pharmaceutically acceptable ACE inhibitors or their pharmaceutical salts, solvates, solvates of such salts or its pharmaceutically acceptable salts, solvates, prodrugs, optionally together with pharmaceutically acceptable salts of such salts or their prodrugs , including an acceptable solvent or carrier, with simultaneously active metabolites that can be used in combination with the compound of formula (I) include, but are not limited to, methanesulfonyloxyphene, the following compounds: alazepril, nil)ethoxy)phenyl|propionic acid and its pharmaceuticals - alatriopril, altiopril of calcium, ancovenin, biotically acceptable salts. Additional suitable nazepril, benazepril hydrochloride, benazepri- PRAC alpha and/or gamma agonists are lat, benzoylcaptopril, captopril, captopril- MM622/Ragaglitazar and BM5 298585. cysteine, captopril-glutathione, ceranapril, cera- Therefore, according to an additional option nopril, ceronapril, cilazapril, cilazaprilat, implementation, the invention provides a method of inhibiting delapril, delapril-diacid, enalapril, ena- transfer of bile acids in the ileum laprilat, enapril, epicaptopril, foroxymitin, (IVAT) in a warm-blooded animal, such as a human, fosphenopril, fosenopril , fosenopril sodium, which requires such treatment, which includes vvefosinoril, fosinopril sodium, fosinoprilat, a day for the indicated animal in an effective amount of spolufosinoprilic acid, glycopril, hemorphin-4, of the formula (I), or ITS pharmaceutically acceptable idrapril, imidapril, indolapril, indolaprilat, salts, solvate, solvate of such a salt or its prodrugs, libenzapril, lisinopril, lyciumin A, lyciumin B, at the same time, to the investigational or individual mixanpril, moexipril, moexiprilat, movelty - administration of an effective amount of the PRAK agonist alpril, muracein A, muracein B, muracein C, pentofa and/or gamma, or its pharmaceutical equivalent - pril, perindopril, perindoprilat, pivalopril, noy salt, solvate, solvate of such a salt or its pivopril, quinapril, quinapril hydrochloride, quinaprolic. rylate, ramipril, ramiprilat, spirapril, hydrochlo- Therefore, according to an additional variant of spirapril, spiraprilat, spiropril, hydrochlo- implementation, the invention provides a method of treatment of spiropril, temocapril, hydrochloride hyperlipemic conditions in a warm-blooded animal, temocapril, teprotide, trandolapril, trandola - such as a person in need of such treatment, prilat, utibapril, zabicipril, zabiciprilat, which includes the administration of the specified animal to the effective- fenopril and zofenoprilat. Preferable inhibited amount of the compound of formula (I) or its ACE pharmaceuticals for use according to this topically acceptable salt, solvate, solvate of this invention are ramipril, ramiprilat, lisinopril, salts or its prodrugs with simultaneous, sequential enalapril and enalaprilat . More preferred or separate administration of an effective amount of ACE inhibitor agonists for use according to the present invention is ramipril and ramiprilat. of a technically acceptable salt, solvate, such a solvate

The preferred antagonists of angiotensin HER, their salts or its prodrugs. pharmaceutically acceptable salts, solvates, according to another variant of implementation, solvates of such salts or their prodrugs for the invention provides a pharmaceutical composition, which in combination with a compound of formula (I) contains a compound of formula (I) or its pharmaceutical composition but not limited to them, the compounds: cande-acceptable salt, solvate, solvate of such a salt or a sartan thereof, candesartan cilexetil, losartan, valproic, and an alpha and/or gamma agonist of PPRA, or a sartan thereof, irbesartan, tazosartan, telmisartan and ep- pharmaceutically acceptable salt, solvate, solvate rosartan. More preferred antagonists of such a salt or its prodrug, in combination with pharma-angiotensin II or their pharmaceutically acceptable solvent or carrier. derivatives for use according to this invention. According to another embodiment, the product is candesartan and candesartan cilexetil. The present invention provides a kit comprising a compound

According to another embodiment of the formula (I), or a pharmaceutically acceptable salt thereof, the invention, a compound of the formula (I), or its pharmaceutical solvate, a solvate of such a salt or a prodrug thereof, and an agonistically acceptable salt, solvate, solvate of such a salt or PPAE alpha and/or gamma, or its pharmaceutically prodrugs, may be administered in combination with an agonist, an acceptable salt, solvate, solvate of such a salt or

PRAK alpha and/or gamma, or their pharmaceutical prodrugs. acceptable salts, solvates, solvates According to another embodiment, data of such salts or their prodrugs. Suitable agonists of the invention provide a kit that contains:

PRAC alpha and/or gamma, their pharmaceutically acceptable a) compound of formula (I), or its pharmaceutically acceptable salts, solvates, solvates of such or salts thereof, their acceptable salt, solvate, solvate of such a salt or prodrugs are well known in this field. Such a combination of prodrugs, in the first single dosage form; which are the compounds described in international applications B) PPRA agonist alpha and/or gamma, or its

MO 01/12187, MO 01/12612, MO 99/62870, MO pharmaceutically acceptable salt, solvate, solvate 99/62872, MO 99/62871, UMO 98/57941, MO of such a salt or its prodrugs; in the second single dosage form; and therapeutic patents, 10 (5), 623-634, in particular, c) a container containing the specified compounds described in the patent applications, enumerated and second dosage forms. According to another no on page 6341 and In May Speth, 2000, 43, 527, which variant implementation, the present invention provides all incorporated by reference. a set that contains:

Preferable agonists of PRAK alpha and/or gamma are a) the compound of formula (I), or its pharmaceuticals-

MUu-14643, clofibrate, fenofibrate, bezafibrate, any acceptable salt, solvate, solvate of such a salt

SMU 9578, troglitazone, pioglitazone, rosiglitazone, or its prodrugs, together with a pharmaceutically acceptable eglitazone, proglitazone, VKI-49634, KAR-297, UTT- tive solvent or carrier, in the first unit 501, 58 213068, SMU 1929, SUMU 7845 , CM 0207, 1 - dosage form; 796449, I -165041 and SM/ 2433. More preferred B) PPRAK alpha and/or gamma agonist, or its PPRAK alpha and/or gamma agonist is (5)-2-ethoxy-3- pharmaceutically acceptable salt, solvate, solvate

I4-(2-4-) of such a salt or its prodrug, in the second single do-

71209 56 form, and an acceptable solvent or carrier. c) a container that contains the specified first and second dosage forms. , the object of this invention is a compound of the formula

Thus, another variant of the implementation of (IXa), (IXB), (Xa) or (XB), or its pharmaceutical composition, is the use of a compound of formula (I), or its acceptable salt, solvate, solvate of such a salt or its pharmaceutically acceptable salt, solvate, salt-prodrug, as described above, for use in cotton wool of such a salt or its prodrugs, and a PRAK agonist method of prevention or therapeutic drug-alpha and/or gamma, or its pharmaceutical administration to a warm-blooded animal, such as a human . of a specific salt, solvate, solvate of such a salt or Thus, according to this variant of its prodrugs, for the preparation of a medicinal product, the object of the invention is a compound of the formula for use in inhibiting the transfer of (IXa), (IXB), (Xa) and ( HB), or its pharmaceutical bile acids in the ileum (BAT) into a heat-absorbing salt, solvate, solvate of such a salt or its blood animal, such as a person. medicine, as described hereinabove, for use as

Thus, another variant of the implementation of the medicinal product. invention is the use of a compound of the formula (I), or its Another variant of the invention is the use of a pharmaceutically acceptable salt, solvate, saltation of a compound of the formula (IXa), (IXB), (Xa) or cotton wool of such a salt or its prodrugs, a PPAK agonist al- (XB), or its pharmaceutically acceptable salt, sulfa and/or gamma, or its pharmaceutically acceptable, solvate of such a salt or its prodrugs, as described above, for the preparation of a medicinal product of a prodrug, for the preparation of a medicinal product for the use of inhibiting the transfer of the use of the treatment of hyperlipemic states of bile acids in the ileum (IVAT) in warm- and warm-blooded animals such as humans. a blood animal such as a human.

Therefore, according to an additional variant Another variant of the invention is the application, the invention provides a combined treatment of a compound of the formula (IXa), (IXb), (Xa) or vana, which includes the introduction of an effective amount (XB) or its pharmaceutically acceptable salts, salts of compounds of the formula (I), or its pharmaceutics, a solvate of such a salt or its prodrugs, as described in the available salt, solvate, solvate of such a salt or its above, for the preparation of a medicinal product of a prodrug, optionally together with pharmaceutically for use in the treatment of hyperlipemics with an acceptable solvent or carrier, from simultaneous use in a warm-blooded animal, such as a human. by it, sequential or separate administration of effective According to an additional variant of the feasible amount of PPRA agonist alpha and/or gamma, nia, the invention provides a method of inhibiting transfer or its pharmaceutically acceptable salt, solvation of bile acids in the ileum (IVAT) in that, a solvate of such a salt or its prodrugs, not necessarily a warm-blooded animal, such as a human being, who, together with a pharmaceutically acceptable solution, dissolves such a treatment, which includes the introduction of an indicator or a carrier to a warm-blooded animal, such as an animal of an effective of the amount of the compound form- a person who needs such treatment. whether (IXa), (IXB), (Xa) or (XB), or its fbarmaceutical

In addition to their use in a therapeutically acceptable salt, solvate, solvate of such a salt or medicine, compounds of formula (I), or their pharmaceuticals and prodrugs. technically acceptable salts, solvates, solvates of such According to an additional variant of the implementation of salts or their prodrugs, also useful as a pharmaceutical, the invention provides a method of treating hyperlipetic agents for the development and standardization of testomic conditions in a warm-blooded animal, such as systems under the conditions of ip myco and ip mimo to evaluate the dyna requiring such treatment, which includes the action of bile acid transfer inhibitors in the beak- administration of the indicated animal in an effective amount to the large intestine (IVAT) in laboratory animals, such as compounds of formula (IXa), (IHB), (Xa) or (HB), or its cats, dogs, rabbits, monkeys, rats and mice, for a pharmaceutically acceptable salt, solvate, salt- search for new therapeutic agents. cotton wool of such a salt or ITS prodrugs.

Many of the intermediates described in this In other embodiments of the above-mentioned pharmaceutical invention are novel and, therefore, they are the object of the composition, method, method, application and of this invention. For example, the compounds of the formula for the preparation of the medicinal product, also used (IXa), (IXB), (Xa) and (XB) show an inhibitory effect on the alternative and preferred variants of the action on the transfer of bile acids in the compounds described in this invention . ileum (IVAT), when studied in the above-mentioned studies in the conditions of ip mio, and therefore they Further, the invention is illustrated by the following are applied as one of the preferred options by means that do not limit its scope, in which the invention can be dreamed. standard techniques known to a person skilled in the art will be applied

Thus, according to an additional variable in the field of chemistry, and methods similar to those described in the above implementation, the object of the invention is a compound of the formulas of this invention, if they correspond to the formulas (IXa), (IXB), (Xa ) or (XB), or its pharmaceuticals, and in which, unless specifically indicated otherwise: a technically acceptable salt, solvate, solvate of such a salt () evaporation is carried out on a rotary or its prodrugs. evaporator in a vacuum and the processing procedure is carried out

According to an additional option, the invention provides a pharmaceutical composition, such as dried, by filtration; tion, which contains a compound of the formula (IXa), (IXB), (Xa) (i) all reactions are carried out in an inert atmosphere or (Xp), or its pharmaceutically acceptable salt, at ambient temperature, a bisolvate, a solvate of such a salt or its prodrugs, as usual in the range of 18-257С, with solvents of the level and sano here above, in combination with pharmaceutical HPLC in anhydrous conditions, unless specifically indicated otherwise; tetrahydro-1,2,5-benzothiadiazepine (ii) column chromatography (using To solution 1,1-dioxo-3,3-dibutyl-5-phenyl-7- flash method) is carried out on silica gel cobromine-8- carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-pots 40-63 μm (MegskK); of benzothiadiazepine (Method 2; 0.020g, 3.71710zmol) (m) the yields are presented for illustration purposes only. reached butoxycarbonylmethyl)carbamoyl|benzylamine maximum values; (Method 5; O.013g, 4.82710 mol) and M- (M) structure of the final products of formula (I), methylmorpholine (0.015ml, 1.4810mMol). 5 min and then added (as a rule, proton) magnetic resonance Tvta (0.015g, 4.82"10 zmMol). The reaction mixture of pe- (NMR) and mass spectral methods; value was chemically stirred overnight and then TFC (1.5 ml) was added. after 1 hour, the solution was diluted with toluene, made with deuterium COzO0 (unless specifically, the solvent was removed under reduced pressure. otherwise indicated) on the delta scale (parts per million, The residue was purified by preparative HPLC, relative to tetramethylsilane); reported data using Mesm/ammonium tones as an eluent, unless specifically stated otherwise; spectra in acetate buffer and freeze-dried, recorded on a Magiap Megs spectrometer, adding 0.026g of the title compound (96905)

ZOOMHz, Magiap Opyu riy5-400MHz, Magiap Opyu in the form of a white solid substance. NMR (400MHz, riih-6EOMHz or on Magiap Ipoma-500MHz; and dmMoo-ab peaks) 0.60-0.80 (t, 6H), 0.80-1.60 (t, 12H), multipeptities were presented in the following method: 5, 3.30 (aa (AB), 1H), 3.45 (a4 (AB), 1H), 3.85 (rg5, 2H), siglet; a, doublet; yes, a doublet of doublets; Her, triplet; 4.70 (a (AB), 1H), 4.75 (a (AB), 1), 5.60 (a, 1n),

H, triple triplet; a, quartet; (4, triple qua- 6.90-7.50 (t, 12H), 8.00-8.10 (t, 1H), 8.55 (a, 1H). rtet; t, multiplet; bg, wide ;

Sv(Umaieg5), recorded with a set of equipment- (M-((B)-o--I(M-) HP 1100 M5-detector semiconductor- (carboxyme diode; mass spectrometry (M5) (loop) rear) carbamoyl(benzyl)carbamoylmethoxy)-2,3,4,5- was registered on the US Rianogt II (Rizopv5 devices) with tetrahydro-1,2,5-benzothiadiazepine with the equipment set NeP-1100 M5- To a solution of 1,1-dioxo-3,3 -dibutyl-b-phenyl-7- detector semiconductor diode; unless methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro- is specifically indicated otherwise, the mass ion was designated 1,2,5-benzothiadiazepine (Method 3, 0.016g, 3.16710- as (MNU); 5mol) in DCM (4ml) was added (P)-o-|M-(tert- (m) if not specified in more detail in the text, butoxycarbonylmethyl)carbamoyl|benzylamine analytical highly effective liquid chromatography (Method 5; 0.012 g, 454710 5 mmol) and HPLC (HPLC) were carried out on Rger I.S 2000 (Umayegv), methylmorpholine (0.015 ml, 1.48"10'mol). The mixture

Kgtotavii St., 7mkm, (AK?2o More); Mesm and deionization were stirred for 10 minutes and then 100 mM ammonium acetate (0.015 g, 4.82105 mol) was added. The reaction mixture is used as a mobile phase with a suitable composition; was stirred overnight and then TFC (1.5 ml) was added. (mi) intermediate products, as a rule, were not After 1 hour, the solution was diluted with toluene, until fully characterized and the purity was determined by removing the solvent under reduced pressure. using thin-layer chromatography (TLC), The residue was purified by preparative HPLC,

HPLC, infrared (IR), M5 or NMR analyses; using as an eluent Mesm/ammonium- (mium) if the solutions were dried, as a desiccant acetate buffer and dried by freezing, ode- used sodium sulfate; rusting 0.018 g of the title compound (82 95) (XM) if the column reference is given as a white solid. NMR. (400 MHZ, "ISOGITE", this means that the circle DMSO-аv) 0.65-0.80 (t, 6Н), 0.85-1.60 (t, 12Н), nka contains 2 g of silicon dioxide, silicon dioxide 2.10 (5, ЗН), 3.65 (da (АВ), 1Н), 3.75 (aa (АВ), 1), is in a 6 ml disposable syringe and supported by 3, 85 (рг5, 2Н), 4.65 (а (АВ), 1Н), 4.75 (а (АВ), 1Н), washed with a membrane with pore sizes 54А, obtained 5.60 (а, 1Н), 6 ,55 (5, 1H), 6,90-7,50 (gl, 11), 8,45 well from Ipiegpaiop! Zogrepi Tesppoiodu under hire (d, 1H), 8.50-8.60 (t, 1). "ISOGITE" numentation; "IZVOGITE" is an example with a registered trademark; 1 -Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-(M-0) the following abbreviations can be used above and further : hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-

DCM dichloromethane; | tetrahydro-1,2,5-benzothiadiazepine

DMFA M,M-dimethylformamide; To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-

TFC / trifluoroacetic acid; Bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5-

TVTI of tetrafluoroborato-benzotriazol-y-yl-benzothiadiazepine (Method 2; 0.050g, 9.277105mol)

M,M,M',M'-tetramethyluronium; 2-((28)-2-amino-2-(4-

Es ethyl acetate, and hydroxyphenyl)ethanol|aminoethanesulfonic acid

MesmM acetonitrile. lotu (Method 6; 0.033g, 1.2010imole) and M-

Example 1 | methylmorpholine (0.04 mL, 3.72710'"mol). The mixture of 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-(M-) was stirred for 10 min and then added

CA)-o-|M- tTvTIi (0.039g, 1.21710mol). The pecarboxy reaction mixture was stirred overnight and the solvent was removed under reduced pressure. The residue was purified by pre-

59 71209 60 parative HPLC, using Example 6 as an eluent

MesMm/ammonium acetate buffer and freeze-dried 1,1-Dioxo-3,3-Dibutyl-5-Phenyl-7-methylthio-8-, obtaining 0.039 g of the title compound (M-((A)-o- (M-((5)-1) compounds (53905) in the form of a white solid. carboxypro-

NMR (400MHz, DMSO-ab6) 0.60-0.80 (t, 6H), 0.80- pylucarbamoyl|benzylcarbamoylmethoxy)-2,3,4,5- 1.60 (t, 12H), 2.40 -2.60 (t, 2H), 3.10-3.50 (t, 2H), tetrahydro-1,2,5-benzothiadiazepine 3.85 (rg5, 2H), 4.70 (a (AB), 1Hn), 4.75 (a (AB), 1H); Solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7- 5.25 (a, 1H), 6.70 (c, 1H), 6.75 (c, 1H), 6.85- 7.80 (t, methylthio-8-|M-(A)-o-

TON), 8.15-8.25 (t, 1H), 8.45 (y0, 1H), 9.40 (riv, 1H). carboxybenzyl)carbamoylmethoxy1|-2,3,4,5-

Example 4 of tetrahydro-1,2,5-benzothiadiazepine (Example 25; 1,1-Dioxo-3,3-Dibutyl-5-Phenyl-7-methylthio-8- 0.055g, 0.086mmol), butyric acid, 2-amino -, (M-((A)-o-(M-((5)-1-carboxy-2-1,1-dimethylethyl ether, hydrochloride, hydroxyethyl)/carbamoyl|benzylcarbamoylmethoxy)- (25)- (0.020g , 0.102 mmol) and M-methylmorpholine 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (0.035 ml, 0.316 mmol) in DCM (5 ml) were mixed

A solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7- at room temperature for 10 minutes, after methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro was added TVTI (0.036g, 0.112 mmol). Through 1,2,5-benzothiadiazepine (Method C; 0.050 g, 19 hours, butyric acid, 2- 0.099 mmol), tert-butyl h-K28)-2-amino-2-amino-, 1,1- dimethylethyl ester, hydrochloro-phenylethanoyl|-o-(tert-butyl)-I-serinate (Method, (25)-(0.020g, 0.102mmol), M-methylmorpholine 14; 0.042g, 0120mmol) and M-methylmorpholine ( . After 68 hours, the transformation was completed at room temperature for 10 minutes, after which it was dissolved; It/72: 781.5. TFC (2ml) was added and TVTIi (0.041g, 0.128mmol) was added to the reaction. This mixture was stirred for 7 hours and after 8 hours the transformation was complete; t/: 839.7. TFC (2 ml) was additionally added to it. In 18 hours

TFC (2ml) was added and the reaction mixture was stirred - the reaction ended. The solution was transferred to dividing wells for 12 hours. The solution was transferred to a funnel and washed twice with water, and then a concentrator funnel and washed twice with water and then concentrated. The residue was purified by preparative centrifugation. The residue was purified by preparative HPLC using a gradient of 40-6095 MesCM in tive HPLC using a gradient of 40-6095 0.1M ammonium acetate buffer as eluent. Oder-

Mesm in 0.1 M ammonium-acetate buffer as eluted 0.026 g of the compound indicated in the title (41905) ent. 0.045 g of the compound specified in the title was obtained as a white solid. NMR (400MHz, bows (63905) in the form of a white solid. NMR DMSO-α): 0.65 (ZH, 9, 0.65-0.80 (6Н, t), 0.85-1.75 (400MHz , DMSO-aiv): 0.60-0.80 (6H, t), 0.85-1.60 (14H, t), 2.10 (ZH, 5), 3.80 (2H, Bg5), 3.95-4.10 (1H, (12H, t), 2.10 (ZH, 5), 3.40-3.65 (2H, t), 3.85 (2H, t), 4.65 (1H, a(AB)), 4.75 (1H, a(AB)), 5.65 (1H, 9), rgv5), 4.10-4.20 (1H, t), 4.70 ( 1H, "4(AB)), 4.75 (1H, 6.55 (1H, 5), 6.85-7.50 (12H, t), 8.50 (1Na), 8.60

I(AB)), 5.70 (1H, a), 6.60 (1H, 5), 6.85-7.50 (12H, t), (1H.a); t/2 781.5. 8.50 (IN, 4), 8.60 (1H, a); t/2: 839.7. Example 7

Example 5 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (M-( (A)-o-IM-(A)-1-carboxy-2- (M-((A)-o-(M-((5)-1- methylthio-carboxyl-yl)carbamoylbenzyl)carbamoylmethoxy)-2 ,3,4,5- tyl)carbamoylIbenzyl)carbamoylmethoxy)-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine tetrahydro-1,2,5-benzothiadiazepine Solution 1,1-dioxo-3,3 -dibutyl-5-phenyl-7-

1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-((B)-o-methylthio-8-|M-((A)-o-carboxybenzyl)carbamoylmethoxy) solution |-2,3,4,5- carboxybenzyl)carbamoylmethoxy!|-2,3,4,5- tetrahydro-1,2,5-benzothiadiazepine (Example 25; tetrahydro|-1,2,5-benzothiadiazepine (Example 25 ; 0.055g, 0.08bmmol), tert-butyl ether 8- 0.055g, 0.08bmmol), I-alanine, 1,1-methyl-i-cysteine (Reviis. 5si.; EM; 45; 4; 1995; 357-dimethylethyl ester, hydrochloride 362; 0.020g, 0105mmol| and M-methylmorpholine (0.017g, 0.098mmol) and M-methylmorpholine (0.035ml, 0.317mmol) in DCM (5ml) were stirred (0.028ml, 0.254mmol) in DCM (5ml) was stirred at room temperature for 10 min, then at room temperature for 10 min, after which TVTI (0.036g, 0.112mmol) was added. Then TVTIO (0.033g, 0.10Zmmol) was added. After 19 hours, additional tert-butyl was added ether 16 hours, the transformation is complete; t/l: 767.4. 8-methyl-!-cysteine (0.020g, 0.105mmol), M-

TFC (2.5 ml) was added and the reaction mixture was mixed with methylmorpholine (0.035 ml, 0.317 mmol) and the TVT was stirred for 2 hours. The solution was diluted with toluene (0.036 g, 0.112 mmol). After 68 hours, it was transformed and then concentrated. The residue was cleaned and the process was completed; pt/h: 811.6 (M-1). It was added by preparative HPLC using TFA (1.5 ml) and the reaction mixture was stirred in a gradient of 40-6095 Mesm in 0.1 M ammonium acetate for 7 hours and TFA (1.5 ml) was additionally added. buffers as eluent. Received 0.044 g of indicated in After 18 hours, the reaction ended. The solution of the title compound (7290) in the form of a white solid was carried into a separatory funnel and washed twice with water and substances. NMR (400MHz): 0.70-0.85 (6H, t), 0.90- then concentrated. The residue was purified by 1.70 (12H, t), 1.30 (ZH, a), 2.10 (ZH, 5), 3.95 (2H, preparative HPLC using a 40-bg5 gradient), 4.25- 4.40 (1H, t), 4.60 (1H, 4(AB)), 4.65 (1H, 6095 MesmM in 0.1M ammonium acetate buffer as

Jaa(AB)), 5.60 (1H, 5), 6.60 (1H, 5), 6.95-7.50 (11H, t); eluent 0.042 g of the compound (65 95) indicated in the title t/2: 7674 was obtained in the form of a white solid.

NMR (400MHz, DMSO-av): 0.65-0.80 (6H, t), 0.85-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- 1.60 (12H, t), 1, 85 (ZH, 5), 2.10 (ZH, 5), 2.60-2.80 tetrahydro-1,2,5-benzothiadiazepine (2H, t), 3.80 (2H, Bg5), 4.20 -4.35 (1H, t), 4.65 (1H, 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-

ЧЯ(АВ)), 4.75 (1Н, а(АВ)), 5.65 (1Н, 4), 6.55 (1Н, 5), IM-(А)-o-carboxy-4-6, 85-7.50 (12H, t), 8.45 (IN, 4), 8.65 (1H, a). hydroxybenzyl)carbamoylmethoxy!1-2,3,4,5-

Example 8 Tetrahydro-1,2,5-benzothiadiazepine (Example 18; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-50 mg, 0.076 mmol) was dissolved in DCM (4 ml). Then- (M-(A)-o-(M-((5)-1-carboxy-2-glycine carbamoyl tert-butyl ether) (12 mg, 0.091 mmol), 2,6-lutidine (20 μl, til )carbamoyl|benzylcarbamoylmethoxy)-2,3,4,5- O.15mmol) and TVTO (ZOmg, 0.091mmol). After 3 hours of tetrahydro-1,2,5-benzothiadiazepine, DMF (2ml) was added and proso-

M-Methylmorpholine (0.034 ml, 0.314 mmol), liquid solution. Tert-butyl ether gly-

Tvty (0.033g, 0.10 mmol) and I-asparagine, 1,1-tin (0.04 mmol), 2,6-lutidine (0.15 mmol) and TVTIO

Dimethylethyl ester, monohydrochloride (2x0.03mmol) and the mixture was stirred additionally (0.021g, 0.093mmol) was sequentially added to the solution over 3 hours. The reaction mixture was concentrated to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- and then extracted between aqueous KNBZO" (0.05M,

IM-(A)-o-carboxybenzyl)carbamoylmethoxy|-rn) and EU6As (2x20ml). The organic phase was washed with 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (applied with saline, dried and concentrated) in DCM (5 ml). After 2 g, the starting material and the ester of the title compound were still present, yielding an oil containing tert-butyl diene. M/7: 769 and 786 additionally added M-methylmorpholine (0.035ml, (Ma18 (MNag)). DCM (4ml) and TFC (1.5ml). 0.314mmol) and TVTI (0.033g, 0.10Zmmol) were added. After 12 hours, the mixture was stirred for 2 hours and then the conversion was complete; t/2: 810.5. centered and purified by preparative method

The solution was diluted with water (-5 ml) and then ext-HPLC three times on a C8 column (50x250 mm) using ether. The combined organic phases were dried in a gradient (20/80 to 50/50) Mesm/0.1M, ammoniated over magnesium sulfate and concentrated. of acetate buffer as an eluent. During lyophilization

The residue was dissolved in a mixture of DCM (5ml) and TFC to obtain the title compound (yield (2.5ml) and the solution was stirred for 21 hours - 52965) (28mg). NMR (400 MHz) 0.8 (I, 6H), 1.0-1.2 (t, ni. The solution was transferred to a separatory funnel and washed with 6H), 1.25-1.4 (t, 2H), 1 ,4-1.5 (t, 2H), 1.55-1.7 (t, li water and then concentrated. The residue was purified- 2H), 2.1 (5, ЗН), 3.9 (АВа, 2Н ), 3.95 (rg5, 2H), 4.6 l by preparative HPLC using (АВа, 2H), 5.45 (5, 1H), 6.6 (5, 1H), 6.75 (y, 2H), 7.05 gradient 40-6095 Mesm in 0.1M ammonium acetate (, 1H) 7.15-7 4 (t, 7H); t/2: 730 (Man18 (MNa). buffers as an eluent. 0.022 g of the title compound (37 95) indicated in Example 11 was obtained in the form of a white solid 1,1-Dioxo-3,3-dibutyl-5-phenyl-7- methylthio-8- substances. NMR (400 MHz, DMSO av): 0.60-0.80 (VN, (M-((A)-o-|(M-(85)-1-carboxyethyl)carbamoyl-4- t), 0.80-1.60 (12H, t), 2.10 (ZH, 5), 2.25-2.70 (2H, hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- t) , 3.80 (2H, bBi5), 4.35-4.45 (IN, t), 4.65 (1H, tetrahydro-1,2,5-benzothiadiazepine 4(AB)), 4.75 (1H, (AB), 5.60 (1Н, 4), 6.55 (1Н, 5). ), 8.55-8.70 (1H, t); using the method described in example 10, t/2 810.5. starting with 3,0001.1-dioxo-3,3-dibutyl-5-phenyl-7-

Example 9 | | methylthio-8-(M-((B)-os-carboxy-4-

Ammonium salt 1,1-dioxo-3,3-dibutyl-5-phenyl-hydroxybenzyl)carbamoylmethoxy!|-2,3,4,5-7-methylthio-8-(M-((A)-o-|M -(2-tetrahydro-1,2,5-benzothiadiazepine (Example 18; sulfoethyl)carbamoyl|-4-5Omg, 0.076 mmol) and tert-butyl I-alaninate hydroxybenzyl)carbamoylmethoxy)-2,9,4,5 - chloride. The preparation of the intermediate tetrahydro-1,2,5-benzothiadiazepine product - tert-butyl ether indicated in the order was confirmed

The compound indicated in the title was synthesized, the catch of the compound. M/727: 783 and 800 (Ma18 (MNakh)). Using the method according to example 3, hydrolysis and purification by preparative HPLC yielding 3 /001,1-dioxo-3,3-dibutyl-5-phenyl-7-, the title compound was obtained as polymethylthio-8-carboxymethoxy-2 ,3,4,5-Tetrahydrote 20mg (yield 3795). NMR (400 MHz) 0.8 (ii, 6H), 1,0-1,2,5-benzothiadiazepine (Method 3; 4Zmg, 1.2 (t, 6H), 1.25-1.4 (t, 2H ), 1.3 (a, ЗН), 1.4-1.5 (t, 0.085 mmol). The solvent was evaporated after 3 h - 2Н), 1.55-1.7 (t, 2Н), 2.1 (5, ЗН), 3.95 (рг5, 2Н), 4.35 dyne and the crude product was purified by pre- (а, 1Н), 4.6 (АВЯ, 2Н), 5.45 (5, 1Н), 6.6 (5, 1H), 6.75 parative HPLC (C8 column, 50x250mm), used (a, 2H), 7.05 (1 1) 7.15-7.4 (t, 7H); t/2: 744. forming a gradient (40/60 to 60/40) Mesm/0.1mM Example 12 ammonium acetate buffer as eluent. During lyophilization, 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-zation yielded Zd8mg (yield 5790) specified in the order- (M-((B)-o-|M-( (5)-1-Carboxy-2-ol compound. NMR (400 MHz): 0.8 (Hi, 6H), 1,0-1,2 hydroxyethyl)carbamoyl|-4- (t, 6H), 1.25 -1,4 (t, 2H), 1,4-1,5 (t, 2H), 1,55-1,7 hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- (t, 2H), 2 ,1 (5, ZH), 2.8-3.0 (t, 2H), 3.55-9.7 (t, tetrahydro-1,2,5-benzothiadiazepine 2H), 3.95 (ri5, 2H ), 4.6 (АВа, 2Н), 5.35 (5, 1Н), 6.6 The title compound was synthesized, obtained (5, 1Н), 6.75 (а, 2Н), 7.05 ( 5 1) 7.15-7.4 (t, 7H), using the method described in example 10, 8.15 (5 1H); t/2: 763. starting from 3 00001,1-dioxo-3,3-dibutyl-5-phenyl-7-

Example 10 | | methylthio-8-|M-(A)-os-carboxy-4-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxybenzyl)carbamoylmethoxy!|-2,3,4 ,5- (M-(A)-o-I(M-(carboxymethyl)carbamoyl|-4-

tetrahydro-1,2,5-benzothiadiazepine (Example 18; compound in yield 61905 (Zbmg). NMR (400MHz) 0.8 50mg, 0.076mmol) and tert-butyl hydrochloride 0o-(I, 6H), 0.9 ( a, ZN), 1.0-1.2 (t, 6H), 1.25-1.4 (t, 2H), (tert-butyl)-I-serinate. The intermediate ester was confirmed to be 1.4-1.5 (t, 2H), 1.55-1.7 (t, 2H), 2.1 (5, ЗН), 3.95; t/2: 755. At (rg5, 2H), 4.15-4.25 (t, 1H), 4.35 (y, 1Hn), 4.6 (АВа, hydrolysis and purification by preparative HPLC 2H), 5.65 (5, 1H), 6.6 (5, 1H), 7.05, 1H), 71 (a, 2H), the title compound was obtained in the amount of 7.15-7.4 (t, 6H), 7.5 (8, 2H); t/2: 741. those 19mg (output 3390). M/7: 743 (M--1). NMR (400 MHz): Example 15 0.8 (B 6H), 1.0-1.2 (t, 6H), 1.25-1.4 (t, 2H), 1.4-1.5 1, 1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (t, 2H), 1.55-1.7 (t, 2H), 2.1 (in, 3H), 3, 65-3.8 (t, (M-((A)-o-(M-((5)-1-carboxy-2-2H), 3.95 (rg5, 2H), 4.33 (i, 1H), 4.6 (АВа, 2Н), 5.5 (5, methylpro- 1Н), 6.6 (5, 1Н), 6.75 (a, 2Н), 7.05 (Her, 1Н) 7 ,15-7,4 (t, pilucarbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-tn).tetrahydro-1,2,5-benzothiadiazepine

Example 13 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-

Ammonium salt 1,1-dioxo-3,3-dibutyl-5-phenyl-IM-(A)-o-carboxybenzyl)carbamotylmethoxy|- 7-methylthio-8-(M-((A)-o-|M- (2-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example sulfoethyl)carbamoylbenzylcarbamoylmethoxy)- 25; 50 mg, 0.078 mmol) was dissolved in 2 ml of DMF. 2,3,4,5-tetrahydro-1 .

IM-(A)-o-carboxybenzyl)carbamoylmethoxy|- 0.154 mmol) and the mixture was stirred for 20 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example minutes. TVTIi (ZOmg, 0.093 mmol) was added ) and dissolved 25; 50 mg, 0.07 in 8 mol) in 3 ml of DCM. The addition was stirred all night. Additionally, tetrabutylammonium taurine (38 mg, 0.236 mmol), methylmorpholine (Zmcl, 0.078 mmol) and TVTI (3x5 mg) were additionally added, and the mixture was stirred for 30 minutes. Add- 0.047 mmol) and the mixture was stirred overnight and TVTIi (30 mg, 0.093 mmol) and the mixture was stirred. The residue was purified by flushing overnight. The solution was concentrated and purified by chromatography (2g) using EAs:hexane by preparative HPLC using C8 (3:7) as eluent. The collected fraction was washed with a 595 column (50x250 mm). Gradient (20/80 to 60/40) Mansoz (10 ml), 0.1 M KNZO»x (15 ml) and saline

Mesm/0.1M ammonium acetate buffer was used before drying and concentration. was used as an eluent. During lyophilization, it was confirmed that the intermediate product was obtained - 4 mg of a mixture of products, which was purified by flash tert-butyl ether chromatography (5 g), using a 3-2095 k gradient; t/2: 812 (Ma-18 (МНе)). DCM (4ml) and mMeon in DCM as eluent were added. Fractions containing the indicated TFC (1.5 ml) and the mixture were stirred overnight, concentrated in the title compound, collected and concentrated. were poisoned and purified by preparative HPLC

Meon and water were added, and during lyophilization, the product was placed on a C8 column (50x250 mm). The gradient (20/80 - 60/40) was 17 mg (2995 output). NMR (400MHz) 0.8 (1, 6H), Mesm/0.1M ammonium acetate buffer was used - 1.0-1.2 (t, 6H), 1.25-1.4 (t, 2H), 1.4-1.5 (t, 2H), used as an eluent. During lyophilization, 1.55-1.7 (t, 2H), 2.1 (5, ЗН), 2.85-3.0 (t, 2H), 3.5- the title compound was obtained in a yield of 3195 3 .7 (t, 2H), 3.95 (ri5, 2H), 4.6 (АВа, 2H), 5.45 (5, (18mg). NMR (400MHz) 0.65-0.85 (t, 12H), 0.95-1.2 1), 6.6 (5, 1), 7.05 (5 1) 7.15-7.45 (t, (t, 6H), 1.25-1 .4 (t, 2H), 1.4-1.5 (t, 2H), 1.55-1.7 10H); t/2:747. (t, 2H), 2.0-2.2 (t, 1H), 2.1 (5, ЗН), 3.95 (rg5, 2H),

Example 14 4,3 (9, 1H), 4,6 (АВа, 2Н), 5,65 (5, 1Н), 6,6 (5, 1Н), 1,1-Dioxo-3,3-dibutyl- 5-phenyl-7-methylthio-8- 7.05 (i, 1H), 7.2 (a, 2H), 7.25-7.4 (t, 6H), 7.5 (a, 2H); (M-((A)-o-(M-((5)-1-carboxy-2-(A)- t/2: 739. hydroxypro- Example 16 pyl)ucarbamoyl|benzyl)carbamoylmethoxy)-2,3 ,4,5- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-tetrahydro-1,2,5-benzothiadiazepine (M-((A)-o-|M-( (5)-1-carboxy-3-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-methylbutyl)carbamoyl|benzylcarbamoylmethoxy-

IM-(A)-o-carboxybenzyl)carbamoylmethoxy|- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example of the Indicated in the title, the compound was synthesized from 25; 50 mg, 0.078 mmol) was dissolved in 1 ml of DMF and according to the method given in example 15, 1 ml of DCM. O-tert-butyl ether from 1,1-dioxo-3,3-dibutyl-5-phenyl-7-butyl-(I)-threonine (22 mg, 0.095 mmol) and M-methylthio-8-| M-((A)-o-methylmorpholine (17 µL, 0.154 mmol) and a mixture of per-carboxybenzyl)carbamoylmethoxy|-2,3,4,5- were stirred for 20 minutes. TVT of tetrahydro-1,2,5-benzothiadiazepine (Example 25; (3 mg, 0.093 mmol)) was added and the solution was stirred for 2 hours and concentrated. DCM (21 mg, 0.095 mmol) was added. DMF was removed and 20 ml of EtOAc (20 ml) and the solution was washed with 10 ml of saline, added and washed with MnSOO (595, 10 ml), 0.1 M dried and concentrated to 3 ml. Confirm with KNBZO"x (15 ml) and salt solution, before obtaining the intermediate ester; t/l: dried and concentrated. The precipitate obtained was 853. TFC (0.5 ml) was added and the solution was stirred and purified by flash chromatography as described overnight. Additionally, 0.5 ml of TFC was added and through Z no. The intermediate product was confirmed and the mixture was concentrated and purified by the preparative HPLC indicated in the title with t-butyl ether on a C8 column (50x250mm). compounds; t/7: 826 (Ma-18 (MNa)). During hydrolysis and

Gradient (20/80 - 60/40) MesmM/0.1M ammonium - purified by preparative HPLC - receiving acetate buffer was used as an eluent. whether the compound specified in the header at output 2195

During lyophilization, the indicated in the title (12mg) was obtained. NMR (400 MHz) 0.7 (yes, 6H), 0.75-0.85 (t,

6H), 0.95-1.2 (t, 6H), 1.25-1.7 (t, 9H), 2.1 (5, 3H), 1,1-Dioxo-3,3-dibutyl- 5-phenyl-7-methylthio-8- 3.95 (riv, 2H), 4.3-4.4 (t, 1H), 4.6 (ABa, 2H), 5.55 (5, (M- ((P)-o-|(M-((5)-1-carboxy-4-1H), 6.6 (5, 1H), 7.05(1), 7.2 (a, 2H), 7.25-7.4 (t, aminobutyl)carbamoyl|benzylcarbamoylmethoxy)- 6H), 7.5 (9, 2H); t/2: 753. 2,3,4,5-tetrahydro-1,2,5 -benzothiadiazepine

Example 17 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-IM-(A )-o-1M-(8)-1-(tert-butoxycarbonyl)-4- (M-((A)-o-(M-(1-(5)-1-carboxy-2-(5)- 2- (benzyloxycarbonylamimethylbutyl)carbamoyl|benzylcarbamoylmethoxy)-no)butylcarbamoylbenzyl)carbamoylmethoxy|- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepine (Method 8;

The compound indicated in the title was synthesized from 0O.00bmg) was dissolved in DCM (0.2ml), TFC was added according to the method given in example 15 (1ml) and the reaction mixture was stirred at room temperature, leaving 30/001.1-dioxo -3,3-dibutyl-5-phenyl-7-th temperature for 1 hour. DCM and FC methylthio-8-|M-((A)-o-) were removed under reduced pressure and the residue was purified carboxybenzyl)carbamoylmethoxy|-2,3,4,5- by preparative HPLC using tetrahydro-1,2,5- of benzothiadiazepine (Example 25; Mesm/MNa. 50/50 buffer as eluent. Acetonitrile 50 mg, 0.078 mmol) and tert-butyl (I()-iso-leucinate) were evaporated and upon lyophilization, the indicated (21 mg, 0.095 mmol) was obtained. DMF was removed and 20 ml EAs in the title compound in yield 3790 (21.9 mg).

KNBZO»x (15ml) and brine, before Example 20 was dried and evaporated. 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 was not purified using flash chromatography. Subt- (M-((A)-o-(M-((5)-1-carboxy-4-) obtained the intermediate product - (Ibenzyloxycarbonylami-tert-butyl ether of the compound indicated in the title) butylcarbamoylbenzyl)carbamoylmethoxy|- t/727: 809. Hydrolysis and purification by pre-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine parative HPLC yielded 1,1-Dioxo-3,3-dibutyl- 5-phenyl-7-methylthio-8- compound with a yield of 3795 (22 mg). NMR (400 MHz) IM-(A)-o-1M-((5)-1-(tert-butoxycarbonyl)-4- 0.65 -1.4 (t, 22H), 1.4-1.5 (t, 2H), 1.5-1.7 (t, 2H), (benzyloxycarbonylami- 1.75-1.85 (t, 1H ), 2.1 (5, ЗН), 3.95 (рга, 2Н), 4.25 (α, no)butyl|carbamoyl)benzyl)carbamoylmethoxy|- 1Н), 4.6 (АВа, 2Н), 5 ,6 (5, 1H), 6,6 (5, 1H), 7,05 (and 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 1H), 7,2 (9, 2H), 7.25-7.4 (t, 6H), 7.45 (y, 2H); t/g: 8; 0.006bmg) was dissolved in DCM (0.1ml), 753. TFC (0, 15 ml) and the reaction mixture was stirred at

Example 18 at room temperature for 1 hour. DCM and 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-TPK were removed under reduced pressure and the residue

IM-(A)-o-carboxy-4- was purified by preparative HPLC using hydroxybenzyl)carbamoylmethoxy|-2,3,4,5-containing Mesm/MH buffer 55/45 as eluent. Aceto-tetrahydro-1,2,5-benzothiadiazepine nitrile was evaporated and, upon lyophilization, 1,1-Dioxo-3,33-dibutyl-5-phenyl-7-methylthio-8- the title compound was obtained in a yield of 3595 (2MG). carboxymethoxy-2,3,4,5-tetrahydro-1,2,5- M/27: 888.7 and 886.7 (M-H). benzothiadiazepine (Method 3; 295 mg, 0.5 in 8 mmol) was dissolved in 10 ml of DCM. 4-(1-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(A)-tert-butoxycarbonyl-1-aminomethyluphenol (M-KA)-o-(( 5)-2-carboxypyrrolidine-1- (Method 7; 160 mg, 0.72 mmol), 2,6-lutidine (140 μl, ylcarbonyl)benzyl|carbamoylmethoxy)-2,3,4,5- 1.20 mmol) and TVTI ( 230 mg, 0.72 mmol). The mixture of tetrahydro-1,2,5-benzothiadiazepine was stirred for 3 hours. Additionally, 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ly 4-(1-(A)-tert-butoxycarbonyl-1- (M-(B)-o- |(8)-2-(tert-butoxycarbonyl)pyrrolidine-1-aminomethyl)phenol (10 mg, 0.04 mmol) and protylcarbonyl|benzylcarbamoylmethoxy)-2,3,4,5- were stirred for 2 hours. Tetrahydro-1,2,5-benzothiadiazepine was added (Method 10; 41 mg,

DCM (20ml) and the solution was washed with MansoOz (5965, 0.052mmol), dissolved in DCM:TFC 4:1 (3ml) and per- 20ml), KNZO: (0.3M; 20ml), stirred with saline solution for 3 hours. The reaction mixture (20 ml) was evaporated under reduced pressure before being dried and concentrated. The remainder of the eye - up to a volume of 10 ml. The preparation of the tertiary compound was confirmed by preparative HPLC using butyl ether of the title compound; using a gradient of acetonitrile/ammonium acetate but/2: 729 (Ma18 (MHg)). TFC (1.3ml) and ferric acid (5/95 to 100/0) were added as eluent. 26.5 mg (7095) of the mixture was stirred for 4.5 hours and a concentration of the title compound was obtained after stirring. The crude product was purified by lyophilization. M/» 737.3034. preparative HPLC, using C8 column Example 22 (5O0x50Omm) and gradient (40/60 to 70/30 for 40 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- minutes) MesSmM/0 ,1M ammonium acetate buffer as (M-(B)-o-|M-(carboxymethyl)-M- eluent. During lyophilization, the title compound methylcarbamoyl|benzyl)carbamoylmethoxy)- was obtained in a yield of 77.595 (302mg). NMR of 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (400 MHz) 0.8 (, 6H), 1.0-1.2 (t, 6H), 1.25-1.4 (t, The title compound was synthesized from 2H), 1.4-1.5 (hl, 2H), 1.55-1.7 (t, 2H), 2.1 (5, 3H), 1,1-dioxo -3,3-dibutyl-5-phenyl-7-methylthio-8-(M- 3.95 (riv, 2H), 4.6 (ABa, 2H), 5.3 (5, 1H), 6.6 (5, 1H), (A)-o-IM-(-tert-butoxycarbonylmethyl)-M- 6.75 (y, 2H), 7.05 (5 1H) 7.15-7.4 (t, 7H ); t/2: 673 methylcarbamoylIbenzylcarbamoylmethoxy)- (My 8(MNa)). 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method

Example 19

11) using the method according to example 714 mg. NMR (500MHz): 0.8 (ry, 6H), 0.96-1.25 (t, 21. NMR (500MHz, 2 rotamers 3:1 mixture): basic 6H), 1.25-1.4 ( t, 2H), 1.42-1.51 (t, 2H), 1.57-1.69 rotamer: 0.8 (rp, 6H), 1.0-1.24 (t, 6H), 1 ,25-1.4 (t, (t, 2H), 2.11 (5, ЗН), 3.8-4.15 (t, 2H), 4.66 (АВа, 2H), 1.4- 1.51 (t, 2H), 1.56-1.68 (t, 2H), 2.09 (5, ЗН), 2H), 5.49-5.53 (t, 1H), 6.61 (5, 1H), 7.06 (i tn), 3.0 (5, ЗН) 3.75-4.21 (t, AN), 4.60 (АВа, 2Н), 6.01 (5, 7.18-7.26 (t, 2H), 7.28-7.45 (t, 8H), 8.35 (y, MH); 1H), 6.58 (5, 1H), 7.05 (i, 1), 7.16-7.28 (t, ZN), 7.3- t/2 640.2. 7.45 (t, 5Н), 7.48 (рга, 2Н) additional peaks for dru- Example 26 urban rotamer at 2.14 (5), 3.0 (5), 4.56 (АБа), 1, 1-Dioxo-3,3-dibutyl-5-Phenyl-7-methylthio-8- 5.81 (5), 6.61 (Bg5); t/2 711.4. (M-((A)-o-(M-((5)-1-carboxy-2-(B)-

Example 23 hydroxypropyl)carbamoyl-4-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- (M-((A) -o-(M-(1-(8)-2-(8)-1-carboxy-1-hydroxyprop-tetrahydro-1,2,5-benzothiadiazepine 2-ylcarbamoyl|benzyl)carbamoylmethoxy)-2,3,4 ,5- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-tetrahydro-1,2,5-benzothiadiazepine IM-(A)-o-carboxy-4-

The title compound was synthesized from hydroxybenzyl)carbamoylmethoxy!|-2,3,4,5-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-|M-tetrahydro-1,2 ,5-benzothiadiazepine (Example 18; ((A)-o-(M-(11-(8)-2-(8)-1-(tert-butoxycarbonyl)-1-100 mg, 0.152 mmol) was dissolved in 3 ml of DMF Hydroxy-prop-2-tert-butyl ether o-tert-butyl-(I)-yl|carbamoylbenzyl)carbamoylmethoxy|-2,3,4,5-threonine (50 mg, 0.21 mmol) and M- tetrahydro-1,2,5-benzothiadiazepine methylmorpholine (Method 12) according to (Za4μl, 0.309mmol) and the mixture was stirred according to the method according to example 21. M/2 for 5 minutes. TVTI /(bomg, 741.3. 0.187 mmol) and the solution was stirred for 30

Example 24 minutes. Formic acid (1-2 drops) was added and

Ammonium salt 1,1-dioxo-3,3-dibutyl-5-phenyl- mixture was extracted between EtOAc and water. The aqueous phase of 7-methylthio-8-(M-(A)-o-|M-(sulfomez) was washed with EtOAc and the combined organic phases of tyl)carbamoyl|benzyl)carbamoylmethoxy-2,3,4,5- washed with 295 MnSOOz, saline solution, tetrahydro-1,2,5-benzothiadiazepine was dried and concentrated. The preparation of 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 tert-butyl ether indicated in the title was confirmed

IM-((B)-o-carboxybenzyl)carbamoylmethoxy compounds; t/2: 869. DCM (3 ml) and TFC 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example (0.5 ml)) were added and the solution was stirred overnight. The mixture con- 25; 50 mg, 0.078mmol), aminomethanesulfonic acid was concentrated and purified by preparative acid (15mg, 0.088mmol) and M-methylmorpholine by HPLC on a C8 column (50x250mm). The gradient (20/80 (17.2 μl, 0.15 mmol) was dissolved in DMF (2 ml). to 50/50) MesSmM/0.1 M ammonium acetate buffer

Tetrabutylammonium hydrogen sulfate was added and used as an eluent. During lyophilization of ode- (35 mg, 0.10 mmol) and the mixture was heated for 15 minutes, the title compound was oxidized at 60°C. 0.93 (a, ZN), TVTI (45 mg, 0.14 mmol) was added. The reaction mixture 1.0-1.22 (t, 6H), 1.25-1.4 (t, 2H), 1 4-1.52 (t, 2H), the mixture was stirred at room temperature 40 1.55-1.7 (t, 2H), 2.1 (5, ЗН), 3.95 (rg5, 2H), 4, 18 minutes, then at 60"C for one hour. 4.25 (t, 1Н), 4.35 (y, 1), 4.63 (АВа, 2Н), 5.53 (в,

After stirring overnight, 1H), 6.57 (5, 1H), 6.75 (y, 2H), 7.03 (y, 1H), 7.2 (y,

With 5 mg TVTI. After 6 hours, 2H was added in small amounts), 7.23-7.37 (t, 5H); t/7: 757. in portions of 29 mg of TVTISH and the reaction mixture was stirred all night. The mixture was evaporated under reduced 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-pressure. The product was purified by preparative (M-((A)-o-(M-((5)-1-carboxy-2-

HPLC using a gradient of acetonitrile-methylpropyl)carbamoyl-4-aryl/ammonium acetate buffer (5/95 to 100/0) as hydroxybenzyl)carbamoylmethoxy-2,3,4,5- eluent. 10 mg (1795) of the indicated compound in the form of an ammonium salt was obtained. NMR The title compound was synthesized using the method described in Example 26, t, 4H), 1.51-1.68 (t, 2H), 2.08 (5, ЗН), 3.7-4.18 (t, leaving Kk! 1,1-dioxo-3,3- dibutyl-5-phenyl-7-2H), 4.24 (y, 1H), 4.39 (y, 1H), 4.62 (АВа, 2H), 5.62 methylthio-8-|M-(А )-c-carboxy-4-(5, 1H), 6.58 (riv, 1H), 7.02 (ry, 1), 7.14-7.23 (t, hydroxybenzyl)carbamoylmethoxy1|-2,3 ,4.5-2), 7.24-7.36 (t, 6H), 7.45 (0, 2H); t/2 732.9. of tetrahydro-1,2,5-benzothiadiazepine (Example 18;

Example 25 70 mg, 0.108 mmol) and tert-butyl (I)-valinate (31 mg, 1,1-Dioxo-3.3-dibutyl-5-phenyl-7-methylthio-8-0.148 mol). Confirmed receipt of intermediate

IM-(A)-o-carboxybenzyl)carbamoylmethoxy product - tert-butyl ether of the compound specified in 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine title. M/7: 811. Hydrolysis and purification of 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- by preparative HPLC yielded (M-KA)-o-(tert- in the title compound in the amount of 5 mg (6990 butoxycarbonyl)benzylcarbamoylmethoxy) - output). NMR (400 MHz) 0.7-0.75 (t, 16H), 0.79 (i, 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 9; 6H), 0.96 -1.24 (t, B6H), 1.25-1.4 (t, 2H), 1.4-1.5 (t, 762 mg, 1.09 mmol) were dissolved in a mixture of TtFK 2H), 1.54- 1.7 (t, 2H), 2.0-2.2 (t, 1H), 2.1 (5, ЗН), (6.65 ml) and triethylsilane (0.350 ml). The reaction mixture was 3.95 (briv, 2H), 4.22 (a, 1H), 4.6 (АВа, 2H), 5.54 (5, the mixture was stirred for one hour and then 1H), 6.58 ( 5, 1H), 6.75 (a, 2H), 7.03 (i, 1H), 7.2 (a, evaporated under reduced pressure, obtaining 2H), 7.23-7.37 (t, 5H); t/2: 755. zanu in the title compound at quantitative output Example 28

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ly at room temperature for 10 minutes, after (M-(A)-o-(M-((5)-1-carboxybutyl )carbamoyl|-4- to which TVTIi (0.048 g, 0.149 mmol) was added. After 1 hour of hydroxybenzylcarbamoylmethoxy)-2,3,4,5-, the transformation into complex tetrahydro-1,2,5-benzothiadiazepine ether was completed. M/7: 829.5. The reaction mixture was diluted with

The title compound was synthesized with hydrochloric acid (15 ml) and stirred using the method described in Example 26 at 50°C for 17 hours. The solution was diluted with toluene, leaving 1,1-dioxo-3,3-dibutyl-5 -phenyl-7- and then concentrated. The residue was purified by methylthio-8-(M-((A)-o-carboxy-4-) by preparative HPLC using hydroxybenzyl)carbamoylmethoxy|1-2,3,4,5-gradient 20-6095 MesM in 0.1 M ammonium acetate tetrahydro-1,2,5-benzothiadiazepine (Example 18; buffer as eluent. 0.070 g of the indicated in

Zbmg, 0.054 mmol) and tert-butyl (I) hydrochloride of the title compound (7995) as a white solid norvalinate (16 mg, 0.076 mmol). Substances were confirmed. NMR (400 MHz, DMSO-α): 0.605-0.80 of intermediate product - tert-butyl (6H, t), 0.80-1.60 (12H, t), 1.85 (ZH, 5), 2.10 (ZH, ether of the title compound. M/2: 811. At 5), 2.60-2.80 (2H, t), 3.85 (2H, Bg5), 4.15-4, 30 (1H, hydrolysis and purification by preparative HPLC, t), 4.65 (1H, a(AB)), 4.70 (1H, a(AB)), 5.50 (1H, a), obtained indicated in the title compound in the amount of 6.60 (1H, 5), 6.60-7.35 (11H, t), 8.30 (1H, a), 8.40 and 23 mg (5695 yield). NMR (400 MHz) 0.7-0.85 (t, 9H), (TN, a), 9.40 (TN, horn). 0.97-1.22 (t, 8H), 1.25-1.4 (t, 2H), 1.4-1.5 (t, 2H), Example 31 1.5-1.8 (t ) (М- 1Н), 4.6 (АВа, 2Н), 5.45 (5, 1Н), 6.58 (5, 1Н), 6.75 (а, (А)-оАИ|М- 2Н), 7.03 (i 1), 7.19 (a, 2H), 7.23-7.37 (t, 5H); t/: (carboxymethyl)carbamoyl|benzyl)carboxymethoxy-2,3, 4.5-

Example 29 Tetrahydro-1,2,5-benzothiadiazepine 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- Solution of 1,1-dioxo-3,3-dibutyl-5-phenyl- 7- (M-((2)-o-IV-((5)-1-carboxypropyl)carbamoyl|-4-methyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,2,5- hydroxybenzyl)carbamotmethoxy)-2,354,5-benzothiadiazepine (Method 5; 0.050g, 0.105mmol), tetrahydro-1,2,5-benzothiadiazepine (A)-o-I|M-(tert-

Solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-butoxycarbonylmethyl)carbamoyl|benzylamine methylthio-8-(M-((A)-o-carboxy-4-) (Method 86 of application UMO 02/50051 ; 0.039g, hydroxybenzyl)carbamoylmethoxy|1-2,3,4,5- 0.148mmol) and M-methylmorpholine (0.046bml, tetrahydro-1,2,5-benzothiadiazepine (Example 18; 0.417mmol) in DCM (4ml) was stirred at room temperature for 20 minutes, after which 1,1-dimethylethyl ether, hydrochloride, TVTI (0.044g, 0.137mmol) was added. After 1 h (25)- (0.031g, 0.16O0mmol) and conversion of M-methylmorpholine into a complex ester (t/2: 721.2 (0.05Oml, 0.457mmol) in DMF (4ml) stirred- (Ma1)) was completed. The solvent was removed at room temperature for 10 min, after reduced pressure and the residue was dissolved in formic acid, to which TVTI (0.048 g, 0.149 mmol) was added. After 1 acid (5 ml), the solution was stirred for 17 hours, the conversion to the complex was completed, and then it was concentrated. The residue was purified with ether. M/72: 797.4. The solution was diluted with toluene and by preparative HPLC, using then concentrated. The residue was dissolved in a gradient mixture of 40-6095 MesM in 0.1 M ammonium acetate

DCM (5ml) and TFC (2ml) and the mixture was stirred in buffer as eluent. Received 0.044 g of the indicated amount in 7 hours. The solvent was removed under reduced heading compound (6395) as a white solid. The residue was purified by preparation. NMR (400MHz, DMSO-av): 0.65-0.80 (6H,

HPLC using a gradient of 20-6095 Mesm in t), 0.85-1.60 (12H, t), 2.10 (ZH, 5), 3.40-3.65 (2H, 0.1M ammonium acetate buffer as an eluent. Oder-t), 3.70 (2H, p5), 4.60 (1H, 4(AB)), 4.70 (1H, a(AB)y), chewed 0.056g of the title compound (6695) 5.595 (1H, a), 6.70 (1H, 5), 6.80-7.50 (12H, t), 8.20- in the form of a white solid. NMR. (400 MHz, 8.30 (1H, t), 8.55 (1H, a).

DMSO-aiv): 0.70 (ZN, O, 0.70-0.80 (6H, t), 0.85-1.75 Example 32 (14H, t), 2.10 (ZN, 5), 3.80 (2H, Bgv), 4.00-4.15 (1H, 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-(M- tu 4.65 (1H , a(AB)), 4.70 (1H, a(AB)), 5.50 (1H, 9), (A)-o-IM-(5)-1-carboxypropyl)carbamoyl|-4- 6 .60 (1H, 5), 6.65-7.40 (11H, t), 8.35 (1H, a), 8.50 hydroxybenzyl)carbamoylmethoxy)-2,3,4,5- (1H, a) 9.40(1 H, Bg5). tetrahydro-1,2,5-benzothiadiazepine

Example 30 Solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-methyl-8-carboxymethoxy-2 ,3,4,5-tetrahydro-1,2,5- (M-((A)-o-|M-(A)-1-carboxy-2-benzothiadiazepine (Method 16; 0.050g, 0.105mmol), methylthioethyl)carbamoyl|-4- (A)-o-(M-((5)-1-(tert-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-butoxycarbonyl)propylcarbamoyl)y-4-tetrahydro-1 ,2,5-benzothiadiazepine of hydroxybenzylamine (Method 19; 0.045g,

A solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-0O.14bmmol) and M-methylmorpholine (0.047 ml, methylthio-8-(M-((A)-o-carboxy-4- 0.427 mmol) in DCM (4 ml) was stirred at chemin-hydroxybenzyl)carbamoylmethoxy!1-2,3,4,5-t temperature for 15 minutes, after which tetrahydro-1,2,5-benzothiadiazepine (Example 18, TVTI (0.044 g, 0.137 mmol). After 17 0.075 g, 0.114 mmol), of tert-butyl ether 5 hours of conversion into a complex ester (t/2: 765.7 methyl-iii-cysteine (Reziis. 5si.; EM; 45; 4 ; 1995; 357- (Ma1)7) was completed. The solvent was removed under reduced pressure and the residue was dissolved in formic (0.05Oml, 0.457mmol) in DMF (4ml) stirring acid (5 ml). The solution was stirred during Z

71 71209 72 days and then concentrated. The residue was purified by 1-ylcarbonyl|Ibenzyl)icarbamoylmethoxy)-2,3,4,5- by preparative HPLC using tetrahydro-1,2,5-benzothiadiazepine (Method 22; gradient 40-6095 Mesm in 0.1M ammonium acetate 27 .5 mg, 0.035 mmol) was dissolved in DCM (3 ml) and added buffer as an eluent. 0.017 g of TFA (ml) was obtained. The reaction mixture was stirred to afford the title compound (2390) as a white solid for 1.5 hours. The solvent was evaporated from the substance. NMR (400MHz, DMSO) 0.60 (ZN, 9, 0.65) under reduced pressure. The product was lyophilized, yielding 0.80 (6Н, t), 0.85-1.75 (14Н, t), 2, 10 (ZH, 5), 3.75 and 25 mg of the title compound. M/72 722.92. (2H, 55), 3.90-4.05 (1H, t), 4.60 (1H, 4 (AB)), 4.65 Example 36 (IN, I(AB)), 5.50 (1H, 4), 6.65-7.30 (11H, t), 8.15 1,1-Dioxo- 3,3-dibutyl-5-Phenyl-7-methylthio-8-(IN, 9), 8.40 (1H, a). (M-((A)-o-(M-1(5)-1 -(M4-((5)-1-

Example 33 carboxy-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethyl)carbamoyl|ethylcarbamoyl|benzylcarbamoyl (M-((A)-o-(M-((5) -1-(M-(5)-2-hydroxy-1-ethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine carboxyl-1,1-Dioxo-3,3-dibutyl- 5-phenyl-7-methylthio-8-ethyl)carbamoyl|propyl)ucarbamoyl|benzylcarbamoyl (M-(A)-o1M-((5)-1-1M-Y(5)-1-(tert-methoxy)- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine butoxycarbo-1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-nyl)ethylcarbamoyl)ethyl)carbamoyl|benzylcarbam (M-((A)-o-(M-((5)-1-(4-(5)-2-(tert-butoxy)-1-(tert-oylmethoxy)-2,3,4,5 -tetrahydro-1,2,5- butoxycarbo- benzothiadiazepine (Method 26; 34 mg, 0.041 mmol) nyl)ethylcarbamoyl)propyl)/ucarbamoyl|benzylcarba was dissolved in a mixture of DXM: TFC (31, 4 ml). Reaction moylmethoxy)-2,3 ,4,5-tetrahydro-1,2,5- mixture was stirred for 2 hours. Benzothiadiazepine solvent (Method 20; 14 mg, 0.015 mmol) was evaporated under reduced pressure. The product was dissolved in a mixture of DCM: TFC (3:1.4 ml ). tive HPLC, the mixture was stirred for 3.5 hours. Dissolving the MeCM/0.1M ammonium-acetate gradient, the buffer was evaporated under reduced pressure. The product was (5/95 to 100/0) as an eluent, obtaining the title compound, 23 mg (7295), which was purified by preparative HPLC. NMR (500 MHz, using a MeSM/O gradient, 1 M ammonium acetate bu- COzOb) 0.81 (ri, 6H), 0.88-1.54 (t, 16H), 1.56-1.71 fer ( 5/95 to 100/0) as an eluent, obtaining indications (t, 2H), 2.11 (5, ЗН), 3.8-4.2 (t, 2H), 4.33-4.42 ( t, well, in the title compound, Zmg (6595). NMR (400MHz): 2), 4.66 (АВа, 2Н), 5.55 (5, 1Н)t 6.61 (в, 1Н), 7.07 0.7-0.83 (t, 9H), 0.9-1.40 (t, 8H), 1.40-1.52 (t, 2H), (b 1), 7.22 (Ba, 2H), 7.28-7.43 (t, 6H), 7.48 (a, 1.52-1.70 (t, ЗН), 1.77-1.88 (t, 1H), 2, 11 (5, ЗН), 2Н); t/2 782.1. 3.8-4.1 (t, 4H), 4.29 (aa, 1), 4.37 (B 1), 4.63 Example 37 (ABa, 2H), 5.57 (5, 1H), 6.60 (5, 1H), 7.04 (ry, 1H), 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 7.20 (rha, 2H), 7.25 -7.40 (t, 6H), 7.47 (0, 2H); t/27 (M-((A)-o-(M-(A)-1-carboxy-3,3-812,3. dimethylbu-

Example 34 Tyl)carbamoyl|benzyl)carbamoylmethoxy)-2,3,4,5-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-tetrahydro-1,2,5-benzothiadiazepine ; and (M-(A)-o-(2-(5)-2-(carboxy)-4-(H)-4-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio -8- (hydroxy)pyrrolidine-1- (M-((A)-o-(M-(A)-1-carboxy-3,3-ylcarbonyl|Ibenzyl)carbamoylmethoxy)-2,3,4,5- dimethylbut-tetrahydro-1,2,5-benzothiadiazepinyl)carbamoyl|benzyl)carbamoylmethoxy)-2,3,4,5- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- Tetrahydro-1,2,5-benzothiadiazepine (M-(A)-o-(2-(8)-2-(methoxycarbonyl)-4-(H)-4-1,1-Dioxo-3,3-dibutyl -5-phenyl-7-methylthio-8-(hydroxy)pyrrolidine-1-IM-(A)-o-carboxybenzyl)carbamoylmethoxy|-ylcarbonyl|Ibenzyl)carbamoylmethoxy)-2,3,4,5- 2,3, 4,5-tetrahydro-1,2,5-benzothiadiazepine (Example tetrahydro-1,2,5-benzothiadiazepine (Method 21; 23 mg, 25; B51 mg, 0.080 mmol) was dissolved in 2 ml of DMF. 0.03 mol) was dissolved in THF: NgO (1:1, Iml). To- sequentially added tert-butyl 4-methyl O,- gave lithium hydroxide (monohydrate, 2mgH, leucinate (Method 27; 23Zmg, 0.114mmol), M- 0.048mmol) and the mixture was stirred for 2 methylmorpholine (18μl, 0.163mmol) and TVTISH (31mg, hours. 50905 of the starting material still remained, 0.097mmol) and the mixture was stirred for 2, then additional lithium hydroxide (Zmg") was added and hours. One drop of formic acid was added and left for an hour. The reaction was still not the mixture was extracted between EtOAc and water. The aqueous phase was completed, therefore additional hydroxide was added (pH-3) and washed with EtOAc. The combined organic lithium (2 mg) and the reaction mixture were stirred overnight. The layers were washed with 595 MnHsSO and saline

The product was purified by preparative HPLC, then dried over Ma»5O4 and evaporated using a Mesm/0.1M ammonium gradient to dryness. The intermediate acetate buffer (5/95 to 100/0) as eluent was confirmed to give the tert-butyl ether product of the title compound, 12 mg (5395). compound trap. M/7: 823. DCM (2 ml) was added and

M/2 753.04. TFC (0.5 ml) and the solution were stirred overnight. Mixture

Example 35 was concentrated and purified using preparative HPLC on a C8 column (50x250mm). East- (M-(A)-o-(2-(5)-2-(carboxy)-azetidine-1- frequent gradient MesmM (20-5095) in 0.1M ammonium-ylcarbonyl|benzylcarbamoylmethoxy)-2,3 ,4,5- acetate buffer was used as an eluent.Tetrahydro-1,2,5-benzothiadiazepine Two diastereomers were separated under these conditions and their were collected and lyophilized separately. Dias- (M-((A)-o-(2-(5)-2-(tert-butoxycarbonyl)azetidine) tereomer, which is eluted first, was obtained in the amount of 5 mg

73 71209 74 (1695 yield) and the diastereomer, which is eluted during 2 hours. One drop of formic acid was added to obtain the amount of Zmg (10905 yield). Absonic acid and then the mixture was extracted between E(OAc and the luteal configuration was established by pouring water. The aqueous phase (pH-3) was washed with ETOAc. the NMR spectrum with related compounds and the combined organic phases were washed with 195 Mansoz, for the diastereomer, which is eluted first, was salt solution and then dried with Ma»bOx and found to be the (K,K)-diastereomer, and for was concentrated. ether. M/7: 813. It was added that it was (K,5)-THF (2ml), water (2ml) and GION (1Omg, 0.418mmol) and diastereomer. M/7: 767. NMR (K ,K)-diastereomer, the mixture was stirred overnight. on C8 6H), 1.25-1.39 (t, 2H), 1.40-1.51 (t, 2H), 1.57-1.68 columns (50x100mm). Gradient from 20 to 5095 Mesm ( t, ЗН), 1.80 (ай, 1НН), 2.08 (5, ЗН), 3.95 (brga, 2Н), in 0.1 M ammonium-acetate buffer was used vuva- 4.47 (aa, tn), 4.63 (Ara, 2H), 5.61 (5, 1H), 6.58 (v, ly as an eluent. The two diastereomers were separated in these 1), 7.04 (i, 1), 7.20 (a, 2H), 7.25-7.35 (t, 6H), conditions and collected separately. During lyophilization, 7.А3-7.47 (t, 2Н) was obtained. I NMR of the (K,5) diastereomer was 8 mg (2495 yield) of the diastereomer, which eluted (400 MHz): 0.7 (5, 9H), 0.79 (i, 6H), 0.99-1.22 ( t, 6H) is the first, and 8.4 mg (2595 yield) of the second, Abso- 1.25-1.39 (t, 2H), 1.40-1.51 (t, ЗН), 1.55- 1.70 (t, lute configurations were determined by comparing 2H), 1.76 (a9, 1), 2.12 (5, ЗН), 3.95 (riv, 2H), 4.35 NMR data of related compounds, and for diastereo- (da, tn), 4.60 (ABra, 2H), 5.54 (5, 1H), 6.60 (5, 1H), the mer eluting first, it was found that 7.04 ( B 1), 7.20 (a, 2H), 7.24-7.37 (t, 6H), 7.39 - it represents the (E.E)-diastereomer, and dias- 7.46 (t, 2H). the tereomer eluting second represents

Example 38 is a (K,5)-diastereomer. M/7: 799. NMR of (K,K)-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- diastereomer (400 MHz): -0.16 (in, 9H), 0.79 (i, 6H), (M-((A)-o-(M-((A)-1-carboxy-3,3- 0.9-1.22 (t, 8H)), 1, 25-1.40 (t, 2H), 1.40-1.52 (t, dimethylbutyl)carbamoyl|-4- 2H), 1.55-1.68 (t, 2H), 2.11 (5, ZH), 3.95 (ri5, 2H), hydroxybenzylcarbamoylmethoxy)-2,3,4,5- 4.29-4.35 (t, 1H), 4.58 (Ara, 2H), 5.45 (5 , 1H), 6.59 tetrahydro-1,2,5-benzothiadiazepine (5, 1H), 6.73 (9, 2H), 7.04 ( 1H), 7.17-7.27 (t, 5H) ,

The title compound was obtained at 7.32 (and 2H); and (K,5)-diastereomer (400 MHz): 0.04 using the method according to example 37, (5, 9H), 0.79 (i, 6H), 1.00-1.22 (t, 8H), 1.25-1.40 (t,

BASED ON 1,1-dioxo-3,3-dibutyl-5-phenyl-7- 2H), 1.40-1.52 (t, 2H), 1.55-1.68 (t, 2H), 2 .08 (in, methylthio-8-(M-(A)-o-carboxy-4-ZN), 3.95 (rg5, 2H), 4.40-4.46 (t, 1H), 4.62 (Aba, hydroxybenzyl)carbamoylmethoxy|-2,3,4,5- 2H), 5.49 (5, 1H), 6.58 (z, 1H), 6.73 (0, 2H), 7.04 ( i, tetrahydro-1,2,5-benzothiadiazepine (Example 18; 1H), 7.14-7.36 (t, 7H). 53mg, 0.081mmol). The production of intermediate tert-butyl ether was confirmed. M/2: 839. Thil- Starting substances for the above examples one of the diastereomers was collected during the purification of virgins are either commercially available, or they can be easily obtained by means of preparative HPLC of the racemic specified in the title compounds. It was obtained in a number of ways from known substances. For example, the following 4mg (1295) and when comparing the NMR data of related reactions are given for the purpose of illustration, but in no way can it be found that it represents a limitation of the scope of the invention, for some starting (A,P)-diastereomer. M/7: 783. NMR (400 MHz): 0.79 substances, and which are used in the above (I, 6H), 0.95 (5, 9H), 0.99-1.22 (t, 6H), 1 ,25-1.39 (t, reactions. 2H), 1.40-1.51 (t, 2H), 1.56-1.68 (t, ЗН), 1.79 (aa, Method 1 1H) . -8- (АБа, 2Н), 5.47 (5, 1Н), 6.58 (5, 1Н), 6.73 (9, 2Н), ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1, 2.5-7.04 (, 1H), 7.19 (a, 2H), 7.24-7.35 (t, 5H). benzothiadiazepine and

Example 39 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2, 3,4 5-tetrahydro-1,2,5- (M-((P)-o-(M-KA)-1-carboxy-2- benzothiadiazepine (trimethylsilyl)ethyl|Icarbamoyl)-4- To suspension 1, 1-dioxo-3,3-dibutyl-5-phenyl-7-hydroxybenzyl)carbamoylmethoxy!1-2,3,4,5-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2, 5-tetrahydro-1,2,5-benzothiadiazepine and benzothiadiazepine (obtained according to the application 1,1-Dioxo-3,3-dibutyl-5-cenyl-7-methylthio-8-ky UMO 98/38182; 0.218g, 5.65"10"Mmol) in DMF (M-(A)-e-(m-((8)-1-carboxy-2- (5ml)) was added Mazme (0.210g, 2.83mmol, 95 90), and (trimethylsilyl)ethyl|carbamoyl)-4- the mixture was stirred for 5 hours at 120"C. hydroxybenzyl)carbamoylmethoxy|-2,3,4,5- The solvent was removed under reduced pressure and tetrahydro-1,2,5- benzothiadiazepine shock was partitioned between EOAc and 0.5 M VEHICLE The aqueous layer of 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- was extracted twice more with EOAc and the combined organic

IM-((B-o-carboxy-4- extracts were dried (Ma5O»4) and concentrated. hydroxybenzyl)carbamoylmethoxy|-2,3,4,5- The residue was dissolved in MesMm (7 ml) and ethyl tetrahydro-1 2,5-benzothiadiazepine (Example 18; lbromoacetate (0.063ml, 5.65710 mol), tet-55MG bromide, 0.084mMmMol) and methyl 3-rabutylammonium (0.018g, 5.65"10 mol) and (trimethylsilyl)alanine carbonate ( Method 28: 19 mg of sodium (0.250 g, 2.3 mmol). The mixture was stirred

0.108 mmol) was dissolved in 3.5 ml of DMF. Continuously overnight at 80°C. The solvent was removed by adding M-methylmorpholine (18 μl, 0.163 mmol) under reduced pressure, and the residue was partitioned between EOAcC and

TVTO (32mg, 0.101mmol) and the mixture was stirred with 0.5M NS. The organic layer was washed with brine

75 71209 76 solution, dried (Md5O»4) and concentrated. pressure and the residue was dissolved in tert-VIOMe

During flash chromatography on silica gel (100 ml). The organic phase was washed with water (20ml) and (NexEAc-6:1) obtained the compounds indicated in the title, then extracted three times with diluted Mmaon in the form of colorless oils: (2x5Oml 0.5M). The combined organic extracts under 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8- were acidified with diluted HCl (7Oml, 1M) (pH 1-2) and with ethoxycarbonylmethoxy-2, 3,4,5-tetrahydro-1,2,5-tim was extracted twice with tert-VIOMe (2 gx5 Oml). benzothiadiazepine, 0.187g (5895). NMR (400 MHz, The ether layer was washed with saline solution,

SOCIv) 0.70-0.80 (t, 6H), 0.90-1.70 (t, 15H), 3.90 were dried over Md5Ox and concentrated. I get (ri, 2H), 4.25 (a, 2H), 4.35 (riv, 1H), 4.65 (5, 2H), 4.694 g (92965) of the required product in the form of 6.95-7 ,40 (t, 7H); and 1,1-dioxo-3,3-dibutyl-o-phenyl-brown oil. NMR (400MHz, CO3O0): 0.70-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5- 0.85 (t, 6H), 1.00-1.25 (t, 6H), 1 ,25-1,50 (t, 4H), tetrahydro-1,2,5-benzothiadiazepine, 0,024g (8905). 1.55-1.70 (t, 2H), 2.10 (5, ZH), 3.90 (rg5, 2H), 4.55

NMR (400 MHz, SOCIz) 0.70-0.85 (t, 6H), 0.90-1.70 (5, 2H), 6.60 (5, 1H), 6.95-7.35 (t , 6H). (t, 15Н), 2.10 (5, ЗН), 3.90 (рг5, 2Н), 4.20 (рі5, 1Н), Method 4 4.25 (а, 2Н), 4.65 (5, 2H), 6.55 (5, 1H), 6.95-7.35 (t, (B)-M-Benzyloxycarbonyl-o-|M-tert-vn). butoxycarbonylmethyl)carbamo'l|benzylamine

Method 2 (gB3- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8- ((Benzyloxy)carbonyl|iaminoXphenyl)acetic acid-carboxymethoxy-2,3,4,5-tetrahydro- 1-2,5-tu (1 g, 35.0 mmol) and tert-benzothiadiazepine butylglycine hydrochloride (6.3 g, 37.4 mmol) were dissolved in DCM

To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7- (200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-stirring for 5 minutes at 02C, 1,2,5-benzothiadiazepine was added (Method 1; 0.184g, 3.24710: TVTIi (12.4g, 38 ,bmmol) and continued pe- "'mole) in EUN (7ml) was added Mahon (0.052g, stir for 1.5 hours at 02C and 3.75g- 1.30mmol) and the mixture was stirred overnight. Solutions at at room temperature. The reaction mixture was removed under reduced pressure and the residue was washed with water (2 x 100 ml), dried (Ma5O4), partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted and purified by flash chromatography, washed twice more with EMOAc and combined organic (DHM:EOAS 7:1-55:1), obtaining the indicated in the title extracts were washed with saline solution and the title compound (13g, 9495). by 1.45 (z, 9H), 3.84 (0, 1H), 4.00 (a9, 1H), 5.10 (t, 2H), preparative HPLC, using as eluent 5.28 (rg5, 1H ), 6.13 (rg5, 1H), 6.23 (bg5, 1H), 7.30-

Mesm/ammonium-acetate buffer and dried at room temperature. 7.44 (t, 10H). by chewing, obtaining 0.173 g of the compound (99905) indicated in the title Method 5 in the form of a white solid. (B)-o-|M-(tert-

NMR (400 MHz, COzOB) 0.70-0.85 (t, 6H), 0.95-1.70 Butoxycarbonylmethyl)carbamoyl|benzylamine (t, 12H), 3.90 (рg5, 2H), 4.50 ( 5, 2H), 6.90-7.40 (t, (B)-M-Benzyloxycarbonyl-o-|M-(tert-7H). .butoxycarbonylmethyl)carbamoyl|benzylamine

Method C and y (Method 4; 12.8 g, 32.2 mmol) was dissolved in EN voesioxo in dibutyl phenyl thuethylthio. (9995, 200 ml) and toluene (50 ml). Ra/C ben oxymethoxy-2,3,4,5-tetrahydro-1,2,5- (1095, 0.65 g) was added and hydrogenation was carried out at atmospheric pressure for 5.5 hours at room temperature.

To the solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7- temperature. The reaction mixture was filtered through methylthio-8-ethoxycarbonyl-methoxy-2,9,4,5-. | diatomaceous earth and solvents were evaporated, and NMR (600 MHz, SOSIz): 1.45 (v, 9H) 3.93 (t 2H), maon (0.007g, 1.80107mmol) and a mixture of stirring- 4.54 (v, 1H) 731- to? (t BN) 7 B (ogv, 1H) " " during the night. The solvent was removed under reduced pressure and the residue was purified by preparative 2-2(28)-2-amino-2-(4-)HPLC using hydroxyphenyl)ethanol|amino) ethanesulfonic acid

Mesm/ammonium acetate buffer and dried by patting. howl! indicated in the title" M-Bos-(0)-4-hydroxyphenylglycine (1.00 g, ku compound o) in the form of a white solid. .

YAM (OM, SOY) Tin OS ilniono st s ony voo (t, 12H), 2710 (5, ZN), 3.90 (ri, 2H), 4.55 (5, 2H), with additional 5 ml of DMF. The obtained suspension 6.60 (5, under vo735 (t,bN). was cooled on ice and TVTI (1.24 g, tovi 3 3-dyb 5 il-7 0-8 3.85 mmol) was added. The ice bath was removed after 30 ; 1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- minutes and the mixture was stirred for 2 hours, carboxymethoxy-2,3,4,5-tetrahydro-1,2,5- before filtered and concentrated. Benzothiadiazepine (alternative preparation) was added to TFC in DCM (2096, 20 mL) and the reaction mixture of 1,1-Dioxo-2-(4-methoxybenzyl)-3,8-dibutyl-5- was stirred overnight. ethanol phenyl-7-methylthio-b-(tert- | (20 ml) and the solvents were evaporated. The crude butoxycarbonylmethoxy)-2,9,4,5-tetrahydro-1,2,5- product was boiled in a reflux flask benzothiadiazepine (Method 25; 6.902 g, 10 mmol) in ethanol (1000 ml) for 1 hour. Dissolved in a mixture of TFC (5 ml) and Eu5Ii (ml) and filtered to obtain the pure indicated in the title, the mixture was stirred for 90 minutes at room temperature - a compound in the form of a white solid substance, 626 mg at room temperature The solvent was removed by lowering (7196). NMR (DMSO-45): 2.4-2.6 (t, 2H), 3.2-3.4 (t,

77 71209 78 2H), 4.79 (5, 1H), 6.78 (9, 2H), 7.23 (y, 2H), 8.22 (y, using DHM:IEHUAc 100:0.95:5 , then 1H), 8.4 (рg5, ЗН), 9.7 (5, 1H). 90:10. The pure fraction was added to the first fraction,

Method 7 obtaining 787 mg (9195) of the title compound 4-(1-(8)-tert-Butoxycarbonyl-1-ol. NMR (400 MHz, SOCl3) 0.78 (Ii, 6H), 0.92-1 ,12 aminomethyl)phenol (t, 4H), 1.12-1.46 (t, 6H), 1.54 (5, 9H), 1.58-1.72

Sulfuric acid (conc., 1 ml) was added to the solution (t, 2H), 2.14 (5, ЗН), 3.8-4.05 (t, 2H), 4.32 (riv, rank 0-( 8)-4-hydroxyphenylglycine (1.0 g, 6.0 mmol) MH), 4.56 (АВа, 2Н), 5.56 (а, 1), 6.56 (5, 1Н), 7.04 in 1 ,4-dioxane (dml), located in the flask (61), 7.10 (ha, 2H) 7.24-7.42 (t, 8H), 7.84 (9, MH);

TeyopF. The flask was cooled to -787C and t/72 694.7 (M-H)U was added. isobutylene (8 g, 142.6 mmol, condensed at - Method 10 78 "C). The flask was placed in an autoclave at room 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- temperature and stirred for 15 hours (M-(A)-o-((5)-2-tert-butoxycarbonyl)pyrrolidine-1-

The autoclave was cooled on ice before opening. Excess isobutylene was added to evaporate tetrahydro-1,2,5-benzothiadiazepine, and the remaining solution was poured into aqueous 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-

Mahon (2M, 20ml) and extracted with diethyl ether-IM-(A)-o-carboxybenzyl)carbamoylmethoxy|- to remove the by-product formed - 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine ( Example 1. The aqueous phase was slightly acidified to give 25; 50mg, 0.078mmol) and tert-butyl I-prolineate rnat0o using 2M HCl and extracted with (15mg, 0.0v8d8mmol) dissolved in DCM (2ml) and added with diethyl ether ( 75 ml). The organic phase was dissolved in M-methylmorpholine (17.2 μl, 0.15 mmol) and washed with saline solution, dried and concentrated (45 mg, 0.14 mmol). The reaction mixture was measured. The obtained product was recrystallized by stirring for 3 hours, then additionally added in diethyl ether/hexane. Weight: 0.55 g (4190). were tert-butyl I-prolinate (15mg, 0.088mmol).

NMR (600MHz, SOCI3) 1.45 (5, 9H), 4.45 (5, 1H), 6.8 The reaction mixture was stirred overnight. (a, 2H), 7.25 (y, 2H); t/2: 224. The reaction mixture was placed directly on the

Method 8 of the IsoYishe bottle (2g, silicon dioxide). The product was eluted using a step gradient, 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-

IM-((A)-o-(M-((5)-1-(tert-butoxycarbonyl)-4- by diluting with DCM: EtOAc 100:0, 95:5, 90:10, then 80:20, (with benzyloxycarbonyl - obtaining the title compound (41 mg, no)butyl Icarbamoylbenzyl)carbamoylmethoxy!|- 6690). M/2 793.2. 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine Method 11 1,1- Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-

IM-(A)-c-carboxybenzyl)carbamoylmethoxy|- (M-((A)-o-|(M-tert-butoxycarbonylmethyl)-M- 2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine (Example methylcarbamoylbenzylcarbamoylmethoxy) - 25; 53mg, 0.08gmmol), tert-butyl M- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (benzyloxy)carbonyl|-I-ornithine (35mg, 1 ,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 0.098 mmol), M-methylmorpholine (0.027 g) was dissolved in IM-(A)-o-carboxybenzyl)carbamoylmethoxy|- in DCM (5 ml ). The mixture was stirred at room temperature.

TvVTI (32 mg, 0.10 mmol) and the reaction mixture of permethylglycinate (15 mg, 0.100 mmol) were dissolved in DCM and stirred for 1.5 hours. The solvent was removed (2 ml) and M-methylmorpholine (17.2 μl, under reduced pressure and the residue was dissolved by 0.15 mmol) and TVTI (45 mg, 0.14 mmol) were added. Reaction chromatography, using DCM:E(OAcS, 5:1) as a mixture was stirred for 4 hours. The reaction eluent, obtaining the title compound, the mixture was placed directly on a column of ISO 57mg (7296). M/2 - 944.7 and 942, 7 (M-H). (2g, silicon dioxide). The product was eluted with additional

Step 9 method using 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-DHMETOAc 100:0, 95:5, 90:10, then 80:20, or - (M-KA)-o-(treating the title compound (ZOmg, 5095). butoxycarbonyl)benzylcarbamoylmethoxy)- M/2 767 4. 2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine Method 12 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2 ,3,4,5-tetrahydro-1,2,5-IM-((A)-o-(M-(11-(8)-2-(8)-1-tert-butoxycarbonyl)-benzothiadiazepine (Method 3; 627 mg, 1.24 mmol) was dissolved in DCM (25 ml), tert-butyl (2K)-yl|carbamoylbenzyl)carbamoylmethoxy!|-2.,3,4,5-amino( phenyl)acetate (308mg, 1.48mmol), 2,6-tetrahydro-1,2,5-benzothiadiazepine dimethylpyridine (288μl, 247mmol) and TwtTi 1,1-Dioxo-3,3-dibutyl-5-phenyl-7- methylthio-8-(477mg, 1.48mmol).The mixture was stirred for 3.5 hours. The reaction mixture was evaporated under 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example under reduced pressure. The product was purified, using 25; 50 mg, 0.078 mmol) and tert-butyl (2E,3K)-3- using an Izoi!she column (10g, silicon dioxide). The amino-2-hydroxybutanoate product (15mg, 0.086bmmol) was eluted using a step gradient, taken up in DCM (2ml) and DMF (ml) and M- was added using DCM: EtOAc 100:0, then 95:5. methylmorpholine (17.2μl, 0.156bmmol) and TvtTi

Approximately 694 mg of the pure compound was collected. Another (45 mg, 0.14 mmol). The reaction mixture was stirred, the fraction was purified a second time, using for 4 hours. The reaction mixture was placed in an Isoiche column (10 g, silicon dioxide). The product was transferred to an IsoYashie column (2g, the dioxide was crystallized using a step gradient, niyu). The product was eluted using a step gradient using DCM:EOAc 100:0, 95:5, (30 mL) and triethylsilane (1.03 g, 8.85 mmol) was added 90:10, then 80:20, giving the title solution 1,1-dioxo-2-(4-methoxybenzyl)-3,3- compound (3Zmg, 53905). M/2 797.3. dibutyl-5-phenyl-7-methyl-8-methoxy-2,3,4,5-

Method 13 of tetrahydro-1,2,5-benzothiadiazepine (Method 15; tert-Butyl M-(28)-2- 0.92g, 1./77mmol) in DCM (2ml). The reaction mixture (Cbenzyloxy)carbonyl|amino)-2-phenylethanoyl)-o- was stirred at room temperature for tert-butyl)-I-serinate for 30 minutes. After concentration of the reaction mixture (28) - the residue was dissolved in diethyl ether (5Oml) and ((Benzyloxy)carbonyl|Iaminophenyl)acetic acid - washed with water (25ml) and sodium bicarbonate (2.0g, 7.0mmol) and tert-butyl O-(tert-butyl)-i - (1095, 25ml). After drying, filtering, and concerinate (2.0 g, 7.9 mmol) and 2,6-lutidine were dissolved in centrifugation, the crude product was subjected to

DXM (ZOml). After stirring for 5 flash chromatography on silica gel (Hexane:E(Ac - minutes at 0"C, TVTI (2.5 g, 7.9 mmol) and 90:10 were added), obtaining 0.58 g of a gray solid. Stirring was continued until 30 minutes at 0"C and 4 hours of a solution (0"C) of this solid in dichloromethane at room temperature. The reaction mixture (30 ml) was added dropwise to VVgz in DCM (1 M and washed with water (2 x 100 ml), dried and purified DCM, 10.2 mL, 10.2 mmol). The reaction mixture was purified by flash chromatography (DCM), allowed to stand at room temperature for 45 minutes, and then washed with sodium bicarbonate

NMR (ZOOMHC): 1.05 (5, 9H), 1.45 (5, 9H), 3.4-3.8 (t, (1095, 25ml) and water (25ml). After drying, 2H), 4.5 (rg5, 1H), 4.85 (5, 2H), 5.1 (5, 2H), 5.4 (5, filtration and concentration of the crude product 1H), 7.25-7.5 (t , 10H). (0.55 g, gray solid) was dissolved in Mesm

Method 14 (ZOml). To the solution was added CoCO3 (0.22 g, tert-Butyl./M-(28)-2-amino-2-phenylethanoyl|-o- 1.58 mmol) and tetra-n-butyl ammonium bromide (1Omg"g) and ( tert-butyl)-I-serinate then ethyl bromoacetate (0.25 g, 1.51 mmol). |iamino)-2-phenylethanoyl)-one and then evaporated under reduced pressure. (tert-butyl)-I-serinate (Method 13; 3.3g, b, dmmol) The residue was dissolved in E(OAc (50ml) and washed with dissolved in EN (9595, 30ml) and catal-MNEeCl (aq., 1095) and salt solution. After the required amount of RO/S (595) (5095 in water) and hydrogenation, drying, filtration and concentration were carried out at atmospheric pressure for 3 hours at room temperature. The reaction mixture (NechEUAs 9:1-8:2), obtaining 0.58 g was incompletely filtered through diatomaceous earth and a white solid solvent. ) and added SON (0.097 g, onion (2.35 g, 98 90). NMR (500 MHz): 1.1 (5, 9H), 1.45 2.31 mmol). The reaction mixture was stirred at (5, 9H), 3.45-3.8 (t, 2H), 4.5 (i, 1H), 4.55 (5, 1H), at room temperature for 40 minutes. Mixture 4.85 (5, 2H), 7.3 -7.5 (t, 5H), evaporated under reduced pressure, dissolved in

Method 15 in water (5Oml) and acidified with 1M NSI. The aqueous layer was extracted twice with diethyl ether. When the solvent was evaporated under reduced pressure, 0.46 g (5595) of the title compound was obtained. NMR

To the cooled solution (-782C) 1,1-dioxo-2- (SO0MHC, acetone-av); 0.70-0.90 (t, 6H), 0.95-1.80 (4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-bromo-8- (t, 12H), 2, 15 (5, ZH), 3.85-4.15 (t, 2H), 4.85 (5, methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 2H), 6, 00 (in, 1H), 6.80 (5, 1H), 6.90-7.05 (t, 1), (Method 23; 2.10g, 3.41mmol) in THF (50ml) according to 7 ,10-7,45 (t, 5H). n-Vigy solution (2.35 ml, 3.75 mmol, Method 17 16M in hexane) was added to the plate. After stirring at -7870 (8)-M-Benzyloxycarbonyl-o-carboxy-4- for 20 minutes, Me! (2.42 g, hydroxybenzylamine 17 Tmol). The mixture was stirred at -787C against (A)-p-Hydroxyphenylglycine (5.00g, 29.9mmol) for 10 minutes and mixed with water (50ml) for 18 hours at room temperature. The temperature was added to the suspension. Diethyl ether (5O0ml) was added and sodium bicarbonate (6.3g, 75.0mmol) and the resulting organic phase was washed with 1095 MNaCl (aq., white suspension after 10 minutes of stirring. With 5Oml) and brine (50ml). After drying, benzyl chloroformate was added in a dropwise funnel, crude (5.1 mL, 33.9 mmol) was added over 20 minutes, and the product mixture was subjected to flash chromatography (Hec- vigorously stirred. After 2 hours, San'EtOAc -95:5 was added) , obtaining 0.4 g (2195) of the indicated water (30 Oml) and the suspension was extracted with ether in the title product in the form of a colorless oil. (200 ml). The white solid was not dissolved and

NMR (300 MHz, SOS"): 0.60-0.70 (t, 6H), 0.70-0.90 additionally gave water and simple ether. And C/M5 (t, 4Н), 0.90-1.35 (t, 8Н), 2.00 (5, ЗН), 3.70 (5, ЗН), indicated that the solid substance represents 3.80 (5, ЗН), 4.00-4.20 (t, 2Н), 4.35-4.60 (t, 2Н), it is a product. The transparent part of the aqueous phase was boiled and acidified until was not formed

BN). white precipitate This mixture was left for the weekend and then

Method 16 was filtered. The remaining aqueous phase, 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-containing undissolved substance, is also acidified- carboxymethoxy-2,3,4,5-tetrahydro-1, 2,5-ly and extracted with EtOAc (3x). Also here, the benzothiadiazepine precipitate remained between the phases. It was collected from organic

To the trifluoroacetic acid solution (0"C) of the first layer. The EUAc phase was evaporated. Toluene was added twice to remove water. Simultaneously, DMF (ml) was added. TVTI (12.5 mg, 0.039 mmol) was added to two fractions of a white solid and recrystallized - and the mixture was stirred for one hour. Dosed in DCM (200ml). The cooled mixture was filtered with tert-butyl hydrochloride O-(tert-butyl)- and treated and obtained 4.77g (5390) of white solid serinate (0.8mg, . a), 7.05-7.50 (7Н, т), 7.90 under reduced pressure and co-evaporated for some time with (НН, а). toluene. The product was purified using ro-

Method 18, a packed column of IZOH ShTE (silicon dioxide, 2g) and (8)-M-Benzyloxycarbonyl-o-1M-((5)-ter-elylated by a step gradient, using butoxycarbonyl)propyl|carbamoyl)-4- toting DCM :EAc 1000 (1Oml) 95:5 (10ml) hydroxybenzylamine 90:10 (10ml) 80:20 (10ml), obtaining 14mg of indicated

A solution of (P)-M-benzyloxycarbonyl-c-carboxin in the title compound. M/2 924.7. 4-hydroxybenzylamine (Method 17; 2.00 g, Method 21 6b,b4mmol), tert-butyl ether (25)-2-amino 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8 - butanoic acid (1.30g, bb4immol) and mM- (M-(A)-o-(2-(5)-2-(methoxycarbonyl)-4-(H)-4- methylmorpholine (2.0g, 19 , dmmol) in DCM (3 mL) (hydroxy)pyrrolidine-1- was stirred at room temperature for ylcarbonyl|benzyl)carbamoylmethoxy)-2,3,4,5- 5 min, after which TVTI (2.60 g, 8.10 mmol) was added . tetrahydro-1,2,5-benzothiadiazepine

The reaction mixture was stirred at 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- ambient temperature overnight. The solvent IM-(A)-o-carboxybenzyl)carbamoylmethoxy|- was removed under reduced pressure and the residue was purified 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example by flash chromatography on silica gel 25; 54mg, 0.084 mmol), methyl hydrochloride (4K)-4- (DHM: Acetone -60:40). The product was crystallized from hydroxy-I-prolineate (18.4 mg, 0 mmol) and M-toluene (20 ml), obtaining 1.85 g of the desired pro-methylmorpholine (13.9 μl, 0.1 mmol) was dissolved in the duct as a white solid. NMR of DMF (2ml). TVTI (32.5 mg, 0.101 mmol) (400 MHz): 0.80 (ZN, 9, 1.45 (9H, 5), 1.50-1.80 (2H) was added, and the mixture was stirred for three hours. t), 4.10-4.20 (1Н, t), 5.05 (1Н, 4(АВ)), 5.15 (1Н, the factor was evaporated under reduced pressure. Product а(АВ)), 6.75 (2Н, а), 7.20-7.40 (7Н, т). was purified twice using packaged co-

Method 19 of ISOGITE (silicon dioxide, 2g) and eluted (B)-o-1M-((5)-1-(tert-) by a step gradient, using

Butoxycarbonyl)propyl|carbamoyl)-4-DHM:'EuAc 100:0, 95:5, 90:10, 80:20 and 60:40, or hydroxybenzylamine chewing 23µg of the title compound. M/2

Mixture /(K)-M-Benzyloxycarbonyl-o-(M-|((5)-1- 767.0. (tert-butoxycarbonyl)propyl|Icarbamoyl)u-4- Method 22 of hydroxybenzylamine (Method 18; 1.80g . (A)-o-(2-(5)-2-tert-butoxycarbonyl)azetidinyl in a hydrogen atmosphere at room temperature 1-ylcarbonyl|benzyl)carbamoylmethoxy)-2,3,4.5- for 2 hours. The reaction mixture was filtered through tetrahydro-1,2,5-benzothiadiazepine through silica gel (2 g) and concentrated. The residue 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- was dissolved in acetone (20 ml) and methanesulfonic acid (0 ,40g, 4.16bmmol). Crystallization- 2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example did not occur and the solvent was removed by reducing 25; 50mg, 0.07v8mmol), tert-butyl (25)-azetidine-2- wife pressure. The crude product was purified carboxylate (17 4mg, 0O,111mmol) and M- by preparative HPLC, using methylmorpholine (10.µl, 0.094mmol) was dissolved in a gradient of 20-5095 MesM in 0.1M ammonium acetate in DMF (2ml). TVTI (ZOmg, 0.094 mmol) was added to the buffer as an eluent. 0.350 g of the indicated substance was obtained and the mixture was stirred for four hours. title compound (2890) as a white solid. The solvent was evaporated under reduced pressure. Pro-substances. NMR (400MHz, DMSOSO-av): 0.75 (ZH, 9, the duct was purified using prepackaged col- 1.40 (9H, 5), 1.50-1.75 (2H, t), 2.70 ( 1H, 5), 4.00-410 nku ISOGITE (silicon dioxide, 2g) and eluted (IN, t), 4.30 (1H, 5), 6.65 (2H, a), 7.15 (2H, a), 8.15 by a step gradient, using (NN, a). DHM:'EUAs 100:0, 95:5, 90:10, 80:20, obtaining

Method 20 27.5 mg of the compound specified in the title. M/2 777.6 1,1-Dioxo-3.3-dibutyl-5-phenyl-7-methylthio-8- (M-H). (M-((A)-o-(M-((5)-1-1M4-((5)-2-(tert-butoxy)-1-(tert- Method 23 butoxycarbo-1,1-Dioxo- 2-(4-methoxybenzyl)-3,3-dibutyl-b-nyl)ethylcarbamoyl)propyl)/ucarbamoyl|benzylcarba phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2, 5-molylmethoxy)-2,3,4,5-tetrahydro-1,2,5- benzothiadiazepine benzothiadiazepine For solution 1,1-dioxo-3,3-dibutyl-5-phenyl-7- 1,1-Dioxo-3 ,3-dibutyl-5-phenyl-7-methylthio-8-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5- (M-((A)-o-|M- ((5)-1- benzothiadiazepine (obtained in accordance with the application - carboxyproka UMO 98/38182; 0.200g, 0.404mmol) in Mesm pil)ucarbamoyl|benzyl)carbamoylmethoxy)-2,3,4,5- (5ml) , where p-methoxybenzyl chloride was added to tetrahydro-1,2,5-benzothiadiazepine (Example 6.15mg, (0.06bml, 0.486bmmol), C5I (0.010g, 0.038mmol) and 0.021mmol), tert-butyl hydrochloride O -(tert- C82CO3 (0.263g, 0.807mmol) and the mixture was stirred with butyl)-I-serinate (5.4mg, 0.021mmol) and M- at 60"C for 4 hours. The solvent was removed with methylmorpholine (4.6μl, 0.042mmol ) was dissolved in at reduced ti sku and the rest were divided between

KIODAs and 0.5 M NSI (aq.). The organic layer was washed 3.80 (5, ЗН), 4.20 (biv, 2Н), 4.50 (рга, 2Н), 4.60 (5, washed with salt solution, dried over Ma5О4 2Н), 6, 45 (in, 1H), 6.75-6.85 (t, 2H), 7.00-7.15 (t, and concentrated. The residue was filtered through silica-ZN), 7.20-7.40 (t , 5H). kagel (DHM:EUAc -9:1), obtaining 0.257 g of the specified compound (quantity) in the title of Method 26 in the form of 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- completely white solid. NMR (400 MHz, (M-(A)-o-(M-((5)-1-(M-((5)-1-(tert-

SOS"): 0.60-0.75 (t, 6H), 0.75-1.20 (t, 8H), 1.25-butoxycarb- 1.45 (t, 2H), 1.80-2 .00 (t, 2H), 3.80 (5, ЗН), 3.90 (5, nyl)ethylcarbamoyl)ethyl)carbamoyl|benzylcarbam

ZN), 4.05-4.30 (t, 2H), 4.45-4.65 (t, 2H), 6.70-7.45 olemethoxy)-2,3,4,5-tetrahydro-1 ,2,5- (t, 11H). benzothiadiazepine

Method 24 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-IM-(A )-o-carboxybenzyl)carbamotylmethoxy|-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine. (Example 1,2,5-benzothiadiazepine 25; 58 mg, 0.091 mmol), tert-butyl I -alanyl-y -

The ointment (0.150 g, 2.033 mmol, 9595) was added to alaninate hydrochloride (27.5 mg, 0.1 mmol) and M-solution of 1,1-dioxo-2-(4-methoxybenzyl)-3,3-methylmorpholine (20 μl, 0.18 mmol) was dissolved in dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-DMFA (2 ml). TVTI (35 mg, 0.18 mmol) and tetrahydro-1,2,5-benzothiadiazepine (Method 23; the mixture was stirred for 2-3 hours. Solution - 0.249 g, 0.404 mmol) in DMF (5 ml) were added. The mixture was evaporated under reduced pressure. The product was stirred at room temperature for 2 hours and purified using a packed column, after which the temperature was raised to ISOCTE (silica, 2g) and eluted at 80°C and Mazme (0.090g, 1.22mmol) was added again. Step gradient using DCM: EAsS

After 20 hours at 80"C, water was added to the mixture at 100:0, 95:5, 90:10, and 80:20, obtaining 34mg (4596) (5ml) and 1M NH (aq.) (pH--4). The solution the title compound was extracted three times. M/: 838.5. was washed with ESO and the combined organic layers were washed by Method 27 with brine, dried over Masoch and tert-Butyl 4-methylleuinate was concentrated. The crude product was purified 4-Methylleucine ( 500mg, 3.44mmol) was suspended by flash chromatography on silica gel in 10ml tert-butyl acetate. the compound in the amount of 0.188 g (8290) was yellowed with a cork and stirred overnight. Analysis of a dark brown solid. NMR (500 MHz, carried out using TLC (DCM: Meon, 9:1;

SOS"): 0.60-0.75 (gl, 6H), 0.75-1.20 (t, 8H), 1.25 - staining with a ninhydrin/EON solution). The solution was poured - 1.40 (t, 2H), 1.80-2.00 (t, 2H), 2.20 (5, ЗН), 3.80 (5, was poured into a flask containing 30 ml of EOAc and 30 ml 595

ZN), 4.20 (ri5, 2H), 4.50 (ri5, 2H), 6.05 (ri5, 1H), Ma?g2SbOz. The aqueous layer was made acidic and 6.75-6.85 (t, ZN), 7.00-7.10 (t, ZN), 7.20-7.35 (t, 2M Mahon was added until the pH value was approx. 4H), 7.50 (5.1H). lyzno 7. The phases were separated and the aqueous phase was washed

Method 25 twice with ZOml EAs. The combined organic phases were washed with 1,1-dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-salt solution, dried with phenyl-7-methylthio-8-(tert-Ma»25O4 An oil was obtained which was co-evaporated with toluene and then with diethyl benzothiadiazepine ether before being placed under vacuum at

To the solution of 1,1-dioxo-2-(4-methoxybenzyl)-3,3- two days. Weight 665 mg (9695 output). NMR (SOCI3): 1,0 dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5- (5, 9H), 1,5 (5, 9H), 1,65-1 .95 (t, 2H), 3.82 (I, 1H). Tetrahydro-1,2,5-benzothiadiazepine (Method 24; Method 28 4.487g, 7.889mmol) in Mesm (100ml) was added Methyl 3-(trimethylsilyl)alanine tert-butyl bromide (0.262g, 0.813mmol), tert-Z - Trimethylsilyl alanine (U. Ogdapotei. Spet., butyl bromoacetate (1.4bml, 9.88Omol) and carbonate 628, (2001), 183-194; 19mg, 0.118mmol) were mixed with potassium (anhydrous, 3.28g, 23, 7mmol) in such a position with Zml VEz-MeonH (1495, 3.7mmol) in a hermetic line. The mixture was heated to 5573 for 2.5 hours and heated to 702C. The analysis was carried out overnight, after which it was cooled to room temperature by TLC (MeOn:DHM 1:9, dyeing from the temperature and left to stir continuously with hydrin in ethanol). The mixture was heated overnight. The solvent was evaporated until there were no hours left and then cooled to the temperature of a yellowish suspension, which was extracted between diets- of the environment. The mixture was poured into a mixture of ether (150 ml) and water (100 ml). Aqueous phase - 3 ml of EOAc and 2 ml of water containing MagSO3. The mixture was washed with ether (100 ml) and combined again with MagSO3 (595 aq.) to a pH value of 7. (2xZml). Combined 100ml), salt solution (100ml) and dried. the organic layers were washed with saline solution

The ether was removed under reduced pressure and the obtained (ml), dried with Ma»5Ox» and evaporated. The off-beige solid was dried while reducing the product in the form of a white film. Mass: 19 mg of pressure for 4 hours (5.355 g, 9995). NMR (9295 output). NMR (SOCI3): 0.1 (5, 9H), 1.2-1.4 (t, (400MHz, SOCI»z): 0.60-1.25 (t, 14Н), 1.25-1 .40 (t, 2H), 3.8 (z, ЗН), 4.2 (riv, 1H). 2H), 1.50 (5, 9H), 1.75-2.00 (t, 2H) , 2.10 (5, ZN),

Computer layout 0. Gaponenko Signature Circulation 26 approx.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, str. Urytskogo, 45, Kyiv, MSP, 03680, Ukraine

SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, Kyiv - 42, 01601