UA70280C2 - Thrombin inhibitors precursors, as method for the thrombin inhibitors precursors, as method for the preparation thereof, a pharmaceutical composition preparation thereof, a pharmaceutical composition based thereon and a method for the treatment based thereon and a method for the treatment - Google Patents

Abstract

There is provided compounds of formula (I): R1O(O)C-CH2(R)Cgl-Aze-Pab-R2, wherein R1 and R2 have meanings given in the description, which are useful as prodrugs of inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

Description of the invention

According to the invention, pharmacologically useful precursors of pharmacologically active compounds, 2 which, in particular, are competitive inhibitors of trypsin-like serine proteases, especially thrombin, the use of precursors as therapeutic agents, pharmacological compositions containing them, and synthetic methods of their preparation are proposed.

Blood coagulation is a key process that includes hemostasis (i.e. prevention of blood loss from damaged vessels) and thrombosis (i.e. formation of blood clots in blood vessels, which sometimes leads to 70 occlusion of blood vessels).

Coagulation is the result of a complex of enzymatic reactions. One of the leading stages of this series is the reaction of converting the proenzyme prothrombin into the active enzyme thrombin.

It is known that thrombin plays a central role in coagulation. It activates platelets, which leads to their aggregation, converts fibrinogen into fibrin monomers, which spontaneously polymerize into fibrin polymers, and 12 activates the factor XII, which creates a mesh structure of the polymer with the formation of insoluble fibrin. In addition, fibrin activates factors M and MIII, which leads to positive feedback in the production of thrombin from prothrombin.

By inhibiting platelet aggregation and fibrin formation and cross-linking, effective thrombin inhibitors would be expected to exhibit antithrombotic activity. In addition, antithrombotic 20 activity can be expected to enhance the effectiveness of inhibition of the positive feedback mechanism.

The development of low-molecular-weight thrombin inhibitors has been covered by Siiaezzop (Viosa Soadi!. Ribhip (1994) 5 411).

In Viotrask she is ai. (9.SiIp.IarIpmevi. (1969) 24 zvyurri. 107, 59) thrombin inhibitors are shown, which are based on the amino acid sequence located around the cleavage site of the fibrinogen chain Aa. In the discussion regarding the amino acid sequence, these authors support the tripeptide c 29 sequence of Rpe-Ma!I-Ago as the most effective inhibitor. Gee)

Low-molecular peptide-based thrombin inhibitors have sequences disclosed, for example, in

US Patent 4346078; international patent applications UUO 93/11152, UMO 94/29336, UMO 93/18060; European patent applications 648780, 468231. 559046, 641779, 185390, 526877, 542525, 195212, 362002, 354344, 530167, 293881. patent applications M/O 95/23609, M/O 95/35309, UMO 96/25426 and UMO 94/29336.

In particular, peptide derivatives В 200С-СНо-(К)СаИ-Аге-Пар-Н, where КУ-Н, benzyl cm or C. valkyl, have been disclosed in recent applications. | "c) 35 Although it is known that these active compounds exhibit significant antithrombotic activity, it would be desirable to improve their pharmacokinetic properties when administered orally and parenterally. Examples of pharmacokinetic properties that are desirable to improve include: (a) ensuring and improving absorption from the gastrointestinal tract in order to reduce inter- and/or intra-individual variability in the bioavailability of active compounds; 20 (b) equalization of the plasma concentration dependence (i.e., reduction of the peak/background ratio of the plasma concentration during the dosing interval), in terms of reducing the risk of exceeding the therapeutic interval and side effects caused by high concentration peaks (for example, bleeding) , and also caused by low concentration (for example, the formation of blood clots); and (c) increasing the duration of action of the active compound.

Moreover, oral and parenteral use of active thrombin inhibitors can lead to unwanted local bleeding (for example, when administered intraperitoneally or subcutaneously) as a result of high local concentrations. (c) Finally, orally active thrombin inhibitors, which also inhibit trypsin and other serine proteases in the gastrointestinal tract, may have additional side effects, including dyspepsia (eg, if trypsin is inhibited in the intestinal cavity). (ee) Although some M-benzoylcarbonyl derivatives of the above-mentioned active compounds are also disclosed as thrombin inhibitors in international patent application MUO 94/29336, it was not indicated that these derivatives could be useful as precursors. In fact, M/O 94/29336 does not mention suitable precursors of active compounds.

We have found that the above-mentioned problems can be solved by using compounds according to the second invention, which, being inactive when administered orally and/or parenterally, are converted in the body to give active thrombin inhibitors, including the above-mentioned ones.

ГФ) According to the invention, a compound of the formula име) is proposed

V'F(Os-SNo-(B)Cai-Age-Rar-8 2 ! 60 in which

IN! - With or A'EES(V Z or A"'E(FOOV;

AND! - S. valkylen;

IN? (which replaces one of the hydrogen atoms in the amidino group Par-H) - OH, OS(О В 9, сС(0ООВ, or 65 ФОСН(ВЗОС(ОВУ; 23 - H, Suralkyl, or C. alkylphenyl) (the last group, as an option, substituted with C 4. valkyl, Si valkoxyl,

nitro group or halogen);

V'Ta in? independently - H, C; valkyl, phenyl, 2-naphthyl, or when BC! - A'E(O)M(B7) BZ, together with the nitrogen atom to which they are attached, form pyrrolidinyl or piperidinyl; 29 -- C. 47 alkyl, phenyl or 2-naphthyl (each of which is optionally substituted with C. alkyl or halogen);

B - 2-naphthyl, phenyl or C. alkylphenyl (in which the last three groups, as an option, are replaced by C 4 alkyl,

C, falkoxyl, nitro group or halogen), or C12alkyl (the last group is optionally substituted

Si vacyloxyl, Si valkoxyl or halogen); 28 - H or S. dalkil; and BO - 2-naphthyl, phenyl, C valkoxyl or Su valkyl (the last group, as an option, is substituted with C 1 vacyloxyl,

C, valkoxyl or halogen); provided that when B" is KZ, KZ is benzyl, methyl, ethyl, n-butyl or n-hexyl, and B2-C(ООВ 7, then B/ is not benzyl; or its pharmaceutically acceptable salts (further denoted as compounds according to the invention).

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds according to the invention may have one or more asymmetric carbon atoms, therefore may exhibit optical and/or diastereoisomerism. All diastereoisomers can be separated by conventional methods, for example, chromatography or fractional crystallization. Different stereoisomers can be obtained by separation from a racemic or other mixture of compounds using conventional methods such as fractional crystallization or high performance liquid chromatography. On the other hand, the desired optical isomers can be prepared by reaction of acceptable optically active starting materials under conditions that do not lead to racemization or epimerization, or by derivatization, for example, with a homochiral acid, followed by separation of the diastereoisomeric derivatives by conventional methods (for example, high-performance liquid chromatography on dioxide silicon). All stereoisomers are included within the scope of the invention.

According to a further aspect of the invention, it is proposed to use the compound of formula I, defined above, but without comments, as a precursor.

Alkyls КЗ, Б", К5, К9, К/ and КЗ can be linear or, with a sufficient number of carbon atoms, "3 branched, cyclic or partially cyclic, saturated and unsaturated, include oxygen atoms in the chain and/or be substituted or terminated by the OH group, provided that this group is not attached to the CO carbon atom or combined with another oxygen atom.

Partially cyclic alkyl refers to a group such as CHNoc-hexyl. at

Alkyls 28, Kb, c" and EZ can be substituted, can be linear or, with a sufficient number of carbon atoms, branched, saturated and unsaturated, include oxygen atoms in the chain. -

The alkyl part of alkylphenyls B and EZ can be linear or, with a sufficient number of carbon atoms, branched and/or saturated and unsaturated.

Alkylenes A" can be linear or, with a sufficient number of carbon atoms, branched and/or "saturated and unsaturated. Then Alkoxyls KU, B" and KE? can be substituted, can be linear or, with a sufficient number of atoms a , У У щ , У У "at ds carbon, branched and/or saturated and unsaturated. :c" Acyloxyls B" and BO can be substituted, can be linear or, with a sufficient number of carbon atoms, branched and/or saturated and unsaturated.

Abbreviations are given at the end of the explanation. -1 According to a further aspect of the invention, a compound of formula I, defined earlier, is proposed, with additional comments: o (a) B! is not A!S(OOVU;

GI (b) B7Ta B? is not independent of H; for 2 (c) VZ is not Smualkil when B? - OS (OVU,

According to a further aspect of the invention, a compound of formula I is proposed, in which: (ze) (a) B! -A AA'(O00B; (b) B"Ta 2? independently - H; (c) 29 - C. 47alkyl, when K2 - PERSON,

When! - A'ESOM(V ZV, the best compounds according to the invention are those in which: (F. A! - S. zalkilen;

Ge V - H or Si valkyl;

Vo - C. alkyl or C. cycloalkyl; or in B" and B? together - pyrrolidinyl.

When! - A'C(FOOV, the best compounds according to the invention are those in which:

AND! - Si valkylene;

In - Su valkil v. When! - VU, the best compounds according to the invention are those in which VZ is H, Siloalkyl (the last group can be linear or, with a sufficient number of carbon atoms, branched and/or cyclic or partially cyclic),

or C. alkylphenyl (the last group can be optionally substituted, can be linear or, with a sufficient number of carbon atoms, branched).

The best compounds according to the invention are those in which B2 is OH, OS(O)VZU (in the latter case, BO is, as an option, substituted phenyl, C. 47alkyl (the last group can be linear or, with a sufficient number of carbon atoms, branched, be cyclic or partially cyclic and/or be saturated or unsaturated)), SiO)OK 7 (in the last case B" - as an option, substituted phenyl, C. 1o2alkyl (the last group can be linear or, with a sufficient number of carbon atoms, branched , be cyclic or partially cyclic and/or be saturated or unsaturated), or C. alkylphenyl (the last group may optionally be substituted, may be 70 linear or, with a sufficient number of carbon atoms, branched)), or SIPHOSN(VESOS (OBZ (in the last case, BZ is H, methyl, and KZ is phenyl, or C alkyl (the last group can be optionally substituted, can be linear or, with a sufficient number of carbon atoms, branched and/or cyclic or partially cyclic )).

The best compounds according to the invention are those in which:

В - H, linear Su.zralalkyl, branched C3.ralalkyl, partially cyclic Suzoalkyl, C isocycloalkyl, alternatively, substituted linear C. alkylphenyl, alternatively, substituted branched C alkylphenyl, A'E(OM(B)? ( in the last case A! - C alkylenyl, B? - H or C. alkyl, and KE? - Co alkyl or Cv cycloalkyl, or B" and BK? together - pyrrolidinyl) or A"C(FO)OB 7 (in the last case A! - Su valkylenyl, and B" - Ci dalalkyl); 2 - on, OS(O (in the last case KV - as an option, substituted phenyl, linear C. alkyl, branched 20 Czalalkyl, or cis-oleyl), C (FOOV' (in the last case B - optionally substituted and/or optionally unsaturated linear C.i.alkyl or alternatively substituted and/or optionally unsaturated branched

C3-alkyl, alternatively, substituted phenyl, or alternatively, substituted linear C4-alkylphenyl, or alternatively, substituted branched C-alkylphenyl), or C(IOOOSN(KU)OC(OB (in the latter case, BZ - H or methyl, and 9.phenyl, C17cycloalkyl, linear C17alkyl, branched C17alkyl, or partially cyclic C1alkyl).c 25 Particularly preferred compounds according to the invention are those in which

B - linear C 1 -alkyl, C 1 -cycloalkyl, or, alternatively, substituted linear C 1 -alkylphenyl; v2 - on. ос(Ов5 (in the last case, KZ is a linear Si zalkil or a branched Szalkil), С(ООВ (in the last case B" - as an option, a substituted linear C .dalkil or, as an option, a substituted branched by 30 Szdalkil, a substituted linear C; alkylphenyl, or branched Salkylphenyl), or c(Fosn(BZOoC(OB (in the last case, BZ is H, and BZ is C5 7cycloalkyl, linear C. .alkyl, or partially cyclic Sualkyl). co

When! - VU, and VZ - as an option, substituted C alkylphenyl, the best options for substituents include C alkyl C (especially methyl). at

When K 2 is C(IFOOK) and v is optionally substituted C 42 alkyl, preferred substituents include halogen 32 (especially chlorine) and C 1 -valoxy (especially methoxy).

When 22 is C(FOV" and cB" is optionally substituted phenyl, preferred substituents include C 4 alkyl (especially methyl), halogen (especially chlorine), and C 4 alkyl (especially methoxy).

When K2 is C(FOOB", and B" is optionally substituted with C /.alkylphenyl, the best options for the substituents include « 20 nitro group. with

The best compounds according to the invention are compounds from examples 1-68. c Even better compounds according to the invention include: :z" ETHOOSCNO-(K)CoI-Age-Par-СООСН БСНАСН"; n-PrРОССН»-(K)CoI-Age-Par-СООСНОСНАСН»; t-BUTOOSSN 5-(K)CoI-Age-Par-SOOSN oSNASN"; -1 ETOOSSN»-(K)SaI-Age-Par-SOOETt;

ETOOSSNO-(K)SaI-Age-Rar-SOOn-But; (ав) M-pyrС(О)СНХСНХСНОССН»-(К)Sa!I-Age-Par-7; with DG KsMnessnoOossNno-(K)SaI-Age-Par-7; (n""PRI»MCe(O)СНоОССН-(К)СоI-Аге-Рар-СоОосСнНосОоСссС(СН»)»; (ог) 50 ETOОССН»-(К)СаоИ-Аге-Rao-СООСН оОСС(СН 3) o ETOOSSN»O-(K)CaoI-Age-Par-SOOSN(CH 3)0OSSN;

Mmerossno-(K)SaI-Age-Rar-OsSphen; merossn»o-(K)SaI-Age-Rar-OH;

ETOOSSNO-(K)SaI-Age-Par-OH;

BnzOOSOSSN 5-(K)CaI-Age-Par-OH;

HF) n-PROOSSN»-(K)SaI-Age-Rab-7; with n-PROOSSN»-(K)SaI-Age-Par-OH; i-PrROOSSN»-(K)CaoI-Age-Par-OH; in t-BUTOOSSN 5-(K)CoI-Age-Par-OH; (n«"PR»МССОСНООСССНО-(К)СоI-Аге-Рар-ОН;

ETOOSSNO-(K)SaI-Age-Rab-OAc; nHOoOSSNo-(K)CaoI-Age-Par-OH; b noOoSsSsNnO-(K)SaI-Age-Rar-O-cis-oleyl;

Cyclooctyl OSSN 5-(K)SaI-Age-Rab-7;

t-BUTOOSSN 5-(K)SaI-Age-Par-7; (2-Me)BnzO0 OSSN 5-(K)SaI-Age-Par-7; ц-ГкеСНЙоОоСссНО-(K)SaI-Age-Par-27; ts-Hkso osSsnH 5-(K)SaI-Age-Rab-7;

Fens(Me)" with OosSSsSNH-(K)SaI-Age-Par-7; (Me2» Sn(Me)2 00 SSNo-(K)SaI-Age-Par-27;

BnzOOSOSSN »-(K)CaI-Age-Par-SOOFen(4-OMe); t-HkeSnJoOosSsSNo-(K)SaI-Age-Par-SOOFen(4-OMe); 70 (2-Me)BnzO0 OSSN 5-(K)CaI-Age-Par-SOOFen(4-OMe);

ETHOOSSNO-(K)SaI-Age-Par-SObOFen(a-Me);

BnzOOSOSSN 5-(K)SaI-Age-Par-SOOPheny(4-Me);

BnzOOOSSN »-(K)SaI-Age-Rar-SOO-n-But; i-PrROOSSN"-(K)Co9I-Age-Par-СЯОСНОСНАСН";

ETOOSSNO-(K)SaI-Age-Rar-SOO-i-But;

BnzOOSOSSN 5-(K)SaI-Age-Par-SOO-n-Pr;

ETOOSSN-(K)CaI-Age-Par-СООСН 500С-Ц-Гкс;

ETOOSSNO-(K)SaI-Age-Ra-СООСН ООССН»-Цц-Гкс;

EtOOSSN»O-(K)CaoI-Age-Par-SOOSN(Me)pOsSphen;

ETOOSSN»O-(K)SaI-Age-Ra6-СООСН 50OsSFhen;

BnzOOSSN 5-(K)CaI-Age-Par-SOOSN(Me)OAc;

ETOOSSN»-(K)SaI-Age-Rab-SOoSsnN 50AC; t-BUTOOSSN 5-(K)CoI-Age-Par-СООСН 20АС; mMmeros--SNET)CH OOSCH»-(K)SaI-Age-Par-7; with

MenoOosSsNno-(K)SaI-Age-Par-SOOFen(4-OMe); and

ETOOSSN"-(K)CaI-Age-Par6-СООСН 5ССси". and)

Particularly preferred compounds according to the invention are:

ETOOSSN"-(K)CaI-Age-Par6-СООСН 5ССИ";

BnzOOOSSN »-(K)SaI-Age-Rar-SOO-n-But; o z o nH-PrSNOoOosSsNno-(K)SaI-Age-Rab-2;

CyclooctylС НХОССН»-(K)SaI-Age-Par-7; co

ETOOSSN-(K)CaI-Age-Par-СООСН 500С-Ц-Гкс; with merossn»o-(K)SaI-Age-Par-OH;

ETOOSSNO-(K)SaI-Age-Par-OH; o n-PROOSSN»-(K)SaI-Age-Par-OH; i- i-PrROOSSN»o-(K)CoI-Age-Par-OH;

BnzOOSOSSN 5-(K)CaI-Age-Par-OH; and

ETOOSSNO-(K)SaI-Age-Par-OAcTS.

According to the invention, a method of producing compounds of formula I is also proposed, which includes: "(a) Production of a compound of formula I, in which B 2 is OH, by the reaction of the corresponding compound of formula I, in which 2 is ШЭ with ос(Ов, and КЗ is defined above , with an alkoxide base (including an alkali metal alkoxide), for example, at room temperature in the presence of an acceptable organic solvent (including tetrahydrofuran). , in which K - - OH, by the reaction of the corresponding compound of formula I, in which K -

C(FOOB, and B is defined above, with hydroxylamine or its addition acid salt, for example, at room temperature in the presence of an acceptable base (including potassium carbonate or triethylamine) and an acceptable organic solvent (including tetrahydrofuran or ethanol). o (c) Production of the compound of formula I by the reaction of the corresponding compound of formula II,

H-(B)Sai-Age-Rar-B 2 where is B? defined above, with the compound of formula II, co 7 v'o(os-sno-i o de Y! - a group that is cleaved off, for example, a halide (including bromide) or an alkylsulfonate (including trifluoromethylalkylsulfonate), and B! is defined above, for example, at room or elevated (for example, 402C) temperature in the presence of an acceptable base (including potassium carbonate) and an acceptable organic solvent (two parts of tetrahydrofuran, dimethylformamide, or acetonitrile). ) Production of the compound of formula I, in which B! is H, and B? is OH or C(IFOV", where B! is defined above, by reaction

IF) of the corresponding compound of formula I, in which v' is C. alkyl, or C); alkylphenyl, and 22 - OH or C(FOV, with an alkoxide name) base (including an alkoxide or hydroxide of an alkali metal), for example, at room temperature in the presence of an acceptable organic solvent (including water or methanol). 60 (e) Preparation of the compound of formula I, in which B 2 is OS(O)BZU, and B9 is defined above, by the reaction of the corresponding compound of formula I, in which B2 is OH, with the compound of formula IM, ws(0)-0o-s (ov8 or with a compound of the formula M, vs(0)-OGal in which Hal is SI or Bg, and KZ is defined above, for example, at room temperature in the presence of an acceptable base (including triethylamine, pyridine or M,M- dimethylaminopyridine) and an acceptable organic solvent (including methylene chloride or tetrahydrofuran). (e) Preparation of the compound of formula I, in which B 1 is H, and K2 is OS(O)BZ, and 9 is defined above by reaction

The corresponding compound of the formula MI,

P-(B)Sai-Age-Rar-B2 in which P! - labile acid ester protective group, (including Bnz or t-But), B? -ОС(ОВ, and В? is defined above, with an acceptable acid (including trifluoroacetic acid), for example, at room temperature in an acceptable organic solvent (including methylene chloride). 70 (g) Production of a compound of the formula !, in which B 7 - KZ, Z - C. zralkyl, or C zalkylphenyl, B? - OH or

С(ООВ "where ВЕ" is defined above, by transesterification of the corresponding compound of the formula MI, в'zo(0)С-СНо-(К)Сай-Аге-Рар-К2 in which ВЗ is Su. alkyl, or C. alkylphenyl, that differ from those required, and 22 is defined above, or, alternatively, is a labile alkyl substituent, under conditions well known to those skilled in the art.

Compounds of the formula IYI can be prepared by deprotection of the compound of formula IYI,

VOK-(B)SaI-Age-Rar-B 2 where B2 is defined above, under conditions well known to those skilled in the art.

Compounds of the formulas Mi and MII can be produced similarly to the above-described methods of obtaining compounds of the formula | eternal B! - C. zoalkyl, or Su alkylphenyl.

Compounds of formula MI can be prepared by the reaction of compounds of formula IX,

N-Rar-k? where is B? defined above, with BOK-SadiI-Age-OH, for example, at room temperature in the presence of an acceptable coupling system (including EDH), an acceptable base (including M,M-dimethylaminopyridine) and an acceptable organic solvent (including methylene chloride or acetonitrile). at

Compounds of the formula MI, where K2 is OH, can be prepared by the reaction of the corresponding compound of the formula MI, where B2 is

C(FOOV ", or SIFFOSN(VZOS(OVU), with hydroxylamine or its acid addition salt, for example, at room temperature in the presence of an acceptable base (including potassium carbonate or triethylamine) and an acceptable organic solvent (including tetrahydrofuran or ethanol).

Compounds of the formula MY, where BC? - С(0О)ОВ", or С(ФООСН(ВЗ)ОС(О)В?), can be produced by the reaction with

VOK-(B)Cai-Age-Par-B 2 with the compound of the formula X, sc

I'c(Fshov ha de 1" is a group that is detached (halogen or phenolate), and K 22 is B", or SIOOSN(VZOS(OVO av, hailed by F

335 Defined above, for example, at room temperature or lower in the presence of an acceptable base (including MaOH) and an acceptable organic solvent (including tetrahydrofuran).

Compounds of the formula MIP, in which B2 is ОС(О)ВУ, can be otherwise prepared by the reaction of the corresponding compound of the formula

MI, in which B2 is OH, with a compound of the formula IM defined above, or with a compound of the formula M, for example, at room temperature in the presence of an acceptable base (including triethylamine, pyridine or

M,M-dimethylaminopyridine) and an acceptable organic solvent (including methylene chloride or tetrahydrofuran). h» Compounds of the formula MI, in which 2 - OS(O)B5, can be prepared differently by the reaction BOK-(K)CaiI-Age-Rar-B? with "the compound of the formula XI, v5c(0)-0-0o-K(ov) in which B U is defined above, for example, at room temperature in the presence of an acceptable organic solvent (including tetrahydrofuran). (аv) Compounds of the formula MI, in which 2 is OH, can be prepared by the reaction of the corresponding compound of the formula MI, in which B? with - OS(O, and K5 is defined above) with an acceptable base (including an alkali metal alkoxide), for example, at room temperature in the presence of an acceptable organic solvent (including tetrahydrofuran). Compounds of formula IX are well known from the literature or can be prepared by known methods analogous to the above. For example, compounds of formula IX in which 22 is C(FOOB, or C( FOOSN(VZOS(OB, and B", 8 and BZ are defined above, can be prepared by the reaction of H-Par-H or its protected derivative with the compound of the formula X defined above, for example, at below room temperature in the presence of an acceptable base (in t .parts of MaOnH) two and an acceptable organic solvent (including tetrahydrofuran).

BOK-(B)CoI-Ale-Par-B 2 can be produced by the reaction of H-Par-H or its protected derivative with

F, BOK-SadI-Age-OH, for example, as described above for the compound of formula MP. ime) otherwise BOK-(K)CaI-Age-Par-B2 can be prepared by deprotection of the compound of the formula XI

BOK-(B)SaI-Age-Rar-r 2 60 where P2 is a protecting group, orthogonal to BOK, under conditions well known to specialists.

Compounds of formulas PSH, IM, M, XXI and XIY are either commercially available, or well known in the literature, or can be prepared by known methods (for example, those described above).

From the reaction mixture, compounds according to the invention can be isolated by known methods.

It should be clear to those skilled in the art that when carrying out the above-described method, it may be necessary to protect the functional groups of the intermediates with protective groups.

Functional groups that are preferably protected include hydroxyl, amino, amidino, and carboxyl.

Acceptable hydroxyl protecting groups are trialkylsilyl and diarylsilyl (eg, t-butyldimethylsilyl or trimethylsilyl) and tetrahydrofuranyl. Acceptable protecting groups for the carboxyl are C-alkyl or benzyl esters. Acceptable protecting groups for amino and amidino groups are t-butyloxycarbonyl or benzoyloxycarbonyl. Amidine nitrogen can be mono- or diprotected.

Protecting groups can be removed by known methods such as those described above,

The use of protective groups is fully described in Rgoyesiime Sgotsrz ip Ogdapis Spetivigu, U MU Ye MsOtiev,

Riepyt Rgevzz (1973) and in Rgoiesime Ogocrz ip Ogdapis Spetivigu, 2p40 eayyiop! UMUsSgeepe 5 ROM MUuUshe,

UMieu-Ipiegwsiepse (1991). 70 Compounds according to the invention are useful because they are converted in the body into compounds that exhibit pharmacological activity. Therefore, they are defined as pharmaceutical, in particular, precursors.

By the compounds according to the invention, which are themselves inactive in relation to thrombin, are meant those for which the value of IKeso, according to the following test A, is higher than 1MM.

The compounds of the invention are expected to be useful in situations where thrombin inhibition is desired.

The compounds of the invention therefore provide therapeutic and/or prophylactic treatment of thrombosis and hypercoagulation in the blood and tissues of animals, including humans.

It is known that hypercoagulation can lead to thromboembolic diseases.

Thromboembolic diseases that should be mentioned include those activated by antagonism of protein C, such as factor

M-mutations (factor M Leiden), and for which there is an inherent or acquired deficiency of antithrombin PSh, protein C, protein 5, and Heparin cofactor I. Other known conditions are associated with hypercoagulable and thromboembolic diseases, which include the circulation of antiphospholipid antibodies (anticoagulant lupus), homocysteinemia, heparin-induced thrombocytopenia and impaired fibrinolysis. The compounds of the invention therefore provide therapeutic and/or prophylactic treatment for these conditions.

Compounds according to the invention, in addition, provide for the treatment of conditions in which there is an unwanted excess of thrombin without the ability to hypercoagulate, for example, in such neurodegenerative diseases as Alzheimer's disease. and)

Specific disease states that may be mentioned include the therapeutic and/or prophylactic treatment of venous thrombosis and pulmonary embolism, arterial thrombosis (eg, in myocardial infarction, unstable angina, thrombotic stroke, and peripheral arterial thrombosis), and systemic embolism, which is common for atrial fibrillation or left ventricle after transmural myocardial infarction. co

Moreover, it can be expected that the compounds according to the invention will find use in the prevention of reocclusion with (ie, thrombosis) after thrombolysis, percutaneous transcavitary vascular reconstruction (PCT) and coronary bypass operations; prevention of reocclusion after microsurgery, vascular surgery in general. at

Further use includes therapeutic and/or prophylactic treatment of diffuse intravascular coagulation caused by bacteria, polytrauma, intoxication or other mechanisms; anticoagulant treatment when the blood comes into contact with foreign surfaces in the body, such as vascular grafts, stents, catheters, mechanical and biological prosthetic valves or other medical devices; anticoagulation treatment when the blood comes into contact with medical devices outside the body, such as those that "

Used in cardiovascular surgery, using artificial heart-lungs or hemodialysis. c c In addition to influencing coagulation processes, thrombin is known as an activator of a large number of cells (such as neurophils, fibroblasts, endothelial and smooth muscle cells). Therefore, the compounds according to the invention can also be useful in the therapeutic and/or prophylactic treatment of idiopathic and juvenile respiratory distress syndrome, pulmonary fibrosis secondary to radiation or chemotherapy treatment, septic shock, septicemia, inflammatory response including but not limited to dropsy, such as acute or chronic atherosclerosis, such as coronary, peripheral, or cerebral arterial disease, reperfusion injury, and restenosis after percutaneous transcavitary vascular reconstruction (PCA). Compounds of the invention that inhibit trypsin and/or thrombin may also be useful in the treatment of pancreatitis.

According to a further aspect of the invention, a method of treating a condition requiring thrombin inhibition is proposed, which includes the administration, by a person suffering from or predisposed to such conditions, of a therapeutically effective amount of a compound of formula I, defined above, or a pharmaceutically acceptable salt thereof.

The compounds of the invention can be conventionally administered orally, buccally, rectally, dermally, nasally, tracheally, bronchially, or by any other parenteral route or by inhalation, in the form of pharmaceutical preparations comprising a precursor or its pharmaceutically acceptable non-toxic addition salt of an organic or inorganic acid , in a pharmaceutically acceptable dosage form. Depending on (F, the disorder, the route of administration and the patient being treated, the compositions can be used in different doses. The compounds according to the invention can also be combined and/or used together with any such antithrombotic agents with different mechanisms of action, such as antiplatelet acetylsalicylic acid, because ticlopidine, clopidogrel, inhibitors of thromboxane receptors and/or synthetases, antagonists of fibrinogen receptors, mimetics of prostacyclin and phosphodiesterase inhibitors and antagonists of ADP receptors (RT).

The compounds according to the invention can also be combined and/or used in combination with any such thrombolytic agents as tissue plasminogen activator (natural or recombinant), streptokinase, urokinase, prourokinase, non-isolated complex of stereokinase plasminogen activators 65 (NKASP), animal plasminogen activators salivary glands, etc., in the treatment of thrombotic diseases, in particular, myocardial infarction.

According to a further aspect of the invention, there is proposed a pharmaceutical formulation comprising the above-described compound of formula I or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable excipients, diluents and carriers.

Acceptable daily doses of the compounds according to the invention in the therapeutic treatment of humans are approximately 0.001-100mg/kg of body weight when administered orally and 0.001-5O0mg/kg when administered parenterally.

The compounds according to the invention have the advantage that they can improve such pharmacokinetic properties as the above, when administered orally and parenterally, when compared with compounds of the formula 7/0

КгО(0)С-СНо-(К)СаИ-Аге-Рар-Н in which KU? defined above, and especially, compounds in which KZ - H.

The compounds according to the invention are inactive to thrombin, trypsin and other serine proteases. Thus, the compounds remain inactive in the gastrointestinal tract, thus preventing potential complications 75 of oral anticoagulants that are active per se, such as bleeding and indigestion caused by trypsin inhibition.

In addition, the use of compounds according to the invention can avoid local bleeding caused by parenteral use of active thrombin inhibitors.

Compounds according to the invention also have the advantage that they may be more effective, less toxic, longer acting, have a wider spectrum of activity, cause fewer side effects, are more easily absorbed or have other beneficial pharmacological properties compared to previously known compounds.

Biological tests

Test A Determination of the time of formation of a thrombin clot (CTU)

Human thrombin (T 6769, Zidta Spet So, final concentration 1.4 MiN-units/ml) in 100 ml buffer solution with pH 7.4 and 100 ml inhibitor solution was incubated for 1 minute. Then 100 ml of human plasma combined with o normal citrate was added and the time of cork formation was determined on an automatic device (KS 10,

Ateishipo).

The time of plug formation was compared with the concentration of the inhibitor, and IKeochCHU was determined by interpolation.

IKeochU is the inhibitor concentration that doubles the time of formation of a thrombin plug in human plasma. (av)

Test B Determination of thrombin time in plasma ex mimo

Inhibition of thrombin after oral or parenteral use of the compounds according to the invention was studied in conscious rats, which were equipped with a catheter on the carotid artery a day or two before the experiment to collect seven samples. Compounds dissolved in a mixture of ethanol-ZoCl2-water (5:5:90) were administered on the day of the experiment, and blood samples were isolated for a certain time in plastic tubes containing 1 part of a 0.13M sodium citrate solution and 9 parts of blood Tubes were centrifuged to obtain pure plasma, which was used to determine - thrombin time as described below. 100 ml of plasma with citrate was diluted with 100 ml of 0.995 physiological solution and coagulation was initiated by adding human thrombin (T 6769, Zidta Spet Co, OBA) to 100 ml of a buffer solution with a pH of 7.4. The time of traffic jam formation was determined on an automatic device (KS 10, AteiYishpa).

Concentrations of the active thrombin inhibitor HO(O)C-SNo-(K)CaI-Age-Par-H (see the international patent application - with MO 94/29336) in the plasma of rats were estimated by the standard curve of dependence between the thrombin time in the combined with normal plasma citrate and a known concentration of the above-mentioned active inhibitor -» thrombin, dissolved in physiological solution.

Based on the estimated concentration in plasma of the active thrombin inhibitor HO(OYUU СНо-(К)CaI-Age-Par-N.: in rats (assuming that the prolongation of thrombin time is caused by the above-mentioned compound) curve after oral and/or parenteral use precursor was calculated (AOSpd) according to the trapezoidal rule and data extrapolated to infinity.

The bioactivity of the active thrombin inhibitor HO(О0)С-ХН-(К)SadI-Age-Par-H after oral and/or parenteral use of the precursor was calculated as indicated below: со 50 МАМсСпд/dose)у(АМсСактив.,в) .iv./dose)|Хх1009о where APsSaktiv.iv. - AOS obtained after intravenous administration to conscious rats c2 HO(0)C-CHO-(K)CaI-Age-Rab-H, as described above.

Test B Determination of thrombin time in urine ex mimo

The amount of active thrombin inhibitor HO(O)C-CHo-(K)CaI-Age-Par-H, which was excreted in the urine after oral and/or parenteral use of the compounds according to the invention, dissolved in a mixture of ethanol-ZoiYcio! tm-water o (5:5:90), was evaluated by determining the thrombin time in urine ex mimo (assuming that the prolongation of the thrombin time is caused by the above-mentioned compound). Conscious rats were placed in metabolic cages with separate collection of urine and feces for 24 hours after oral administration of the compounds of the invention. Thrombin time in collected urine was determined as described below. 100 ml of plasma combined with normal citrate was incubated with concentrated or saline-diluted rat urine for one minute. Plasma coagulation was initiated by adding human thrombin (T 6769,

Zidta Spet Sotrapu) in 100 ml of a buffer solution with a pH of 7.4. The time of traffic jam formation was determined on an automatic device (KS 10, AteiYishpa). b5 Concentrations of the active thrombin inhibitor HO(O)C-SNo-(K)CaoI-Age-Par-H in the urine of rats were estimated by the standard curve of dependence between the thrombin time in plasma combined with normal citrate and the known concentration of the above-mentioned active thrombin inhibitor, dissolved in concentrated or diluted saline solution urine of rats. By multiplying the total rat urine obtained in 24 hours by the estimated concentration of the above-mentioned active inhibitor excreted in the urine, it is possible to calculate the amount of active inhibitor in the urine (Kpd).

The bioactivity of the active thrombin inhibitor HO(О0)С-СНХ-(К)SadI-Age-Par-H after oral and/or parenteral use of the precursor was calculated as indicated below; ((Kpd/dose)(Kactiv., i.v./dose)|Хх10090о where Kactiv., i.v. - K, the amount passed into the urine after intravenous administration to conscious rats of ХО(О)С-СНо- (K)CaI-Age-Par-H, as described above. 70 Test G Determination of HO(O)C-SNo-(K)CaI-Age-Par-H in urine | by C-M5 analysis

The amount of active thrombin inhibitor HO(O)C-SNo-(K)CaI-Age-Par-H, which was excreted in the urine after oral and/or parenteral use of the compounds according to the invention, dissolved in a mixture of ethanol-BoyIcio! tm-water (5:5:90), determined by I C-M5 analysis as indicated below.

Animals were treated as described above in Method B. Urine samples were collected and frozen at -207C until 7/5 Use in the analysis.

Urine samples were analyzed for the content of HO(O)C-СНо-(К)CaI-Age-Par-H in the following manner:

Thawed urine samples were mixed and, if necessary, centrifuged. Tubes for solid-phase extraction (Apamisnet Vopa Ash Mo1210-2059) were activated with 1.0 ml of methanol and conditioned with 1.00 ml of acetonitrile with water (50:50), followed by 1.0 ml of 0.195 formic acid. 50 ml of internal standard (2 OMmol/l) was added to each tube. 50 ml of the standard solution was added to the urine standards. 200 ml of sample, or for urine standards, pure urine, was added to each tube and then withdrawn by gravity or careful vacuuming.

Residual urine was washed with 1.0 ml of 2MM ammonium acetate before elution with 1.0ml (35:65) acetonitrile-ammonium acetate (2MM). The collected eluate was transferred to autosampler glasses. ZOMl of the extract was introduced into a liquid chromatographic column (Niregsii WHO-C18; ZMm; 75 mmXa4 mm; Nemek-Raskaga Mo7992603-354), eluting with 1.3 mm ammonium-acetate buffer with 4095 acetonitrile and 0.1; with formic acid at 0.75 ml/minute. The flow was divided so that ZOMl/min. were included in the source of electrosprayed ions of the R-E-5sieh ARI-3 mass spectrometer. at

HO(O)C-CHno-(K)CaI-Age-Par-H and HO(O)C-CHO-(K)CaiI-Pho-Par-H (internal standard) have retention times of approximately 1.5 minutes. their molecular ion (MAN)" was determined at t/2 430.2 and 444.2, respectively. Urea standards of two levels, one at the limit of quantification, were used for calibration based on the av) peak ratio. HO(O) C-CH 5-(K)CaI-Age-Par-H to the internal standard. The linearity of the method was checked in the range of 0.050-20 Mmol/l. The dispersion coefficient was 1-296 at 20 Mmol/l and 7956 at 0.50 Mmol/l The limit of determination is -0.050 Mmol/l He!

Multiplying the total rat urine obtained for 24 hours by the estimated concentration

НО(О)С-СНО-(К)CaI-Age-Par-H in the urine can be used to calculate the amount of the active inhibitor excreted in the urine (Kpd). M.

The bioactivity of the active thrombin inhibitor was calculated as described above in method B.

The invention is illustrated by the following examples.

General experimental operations "

Mass spectra were taken on a Rippidap MAT T50 triple quadrupole mass spectrometer equipped with a surface electrospray. - with TN NMR and "ZS NMR was obtained on spectrometers VVOKERV. ASR 300 and Magiap OMITU riiv 400 and 500 at "» frequency for "Н 300.13, 399.96 and 499.82 m"z, and for 130 - 75 ,46, 100.58 and 125.69mHz. Chemical shifts are given in " units 5.

Production of starting reagents

BOK-(K)CaI-Age-Rar-H, BOK-(K)CaI-Age-Rarhnei, H-««QUAge-Rab-2, H-««QUAge-Par-2xHNeY, - BnzO(0)C -CH»-(K)CaI-Age-Par-7, BOK-(K)CoI-Age-Par-7, VOK-(K)CaoI-Age-Par-OH, and Par-2xHNSii were obtained by the methods described in international patent application UHO 94/29336.

Example 1 ETOOSSN.b-(K)CaI-Age-Par-SOOoSnNhSnNAsSNn" o (OBOK-(K)CaI-Age-Par-СООСН СН-СНОо

Go) 50 To a solution of 6.1 g (1 mmol) of BOK-(K)CaI-Age-Par-H in 125 ml of tetrahydrofuran and 7 ml of 2M (140 mmol) Mahon, 1.7 g (14 mmol) of allyl(chloroformate) was added dropwise at 0"C. . After stirring for an hour at 07 o'clock, the reaction mixture was concentrated, 100 ml of water was added, and the formed aqueous phase was extracted three times with 100 ml of methylene chloride. The combined organic phase was concentrated, obtaining 6.4 g of crude product, which was purified by flash chromatography with ethyl acetate-tetrahydrofuran-triethylamine ( 68:29:3) as eluent.22 Concentration gave 5.8 g (8195) of the desired compound as a white solid.

HF) TN NMR (500 mHz, SOSI»z): 5 8.19 (fer.t, 1H), 7.78 (d, 2H), 7.26 (d, 2H), 6.02-5.92 (m, 1H), 5.32 (d, 9-17 t Hz, 7), 5.18 (d, 9-10 Hz, 71H), 5.06 (d, 9-7 Hz, 1H), 4 .82 (width, 1H), 4.61 (d, 9-6 Hz, 2H), 4.58-4.48 (m, 1H), 4.38-4.27 (m, 2H), 4.14-4.03 (m, 1H), 3.77-3.68 (m, 1H), 2.60-0.90 (m, 24H). in 136 NMR (125 mHu, SOSI3) carbonyl and amidine signals: δ 172.70, 170.74, 168.02, 164.54, 155.98. (her) NA«YUSa9I-Age-Rar-SOOSnNhSnNASnNokhHg FO

15 ml of trifluoroacetic acid was added to a solution of 2.03 g (3.65 mmol) of BOK-(K)CaI-Age-Rao-СОосСНнНЬСнН-СсСнН" from operation (i) in 15 ml of methylene chloride at 07С, stirred at external temperature for 3 hours, followed by concentration and obtaining 2.8 g of the desired compound in the form of a white solid. 65 "IN NMR (500 MHz, Meon (04)): 5 7.80 (5, 2M), 7.57 (d, 2H), 6.02 (m, 1H), 5.45 (d, 9- 17 Hz, 1H), 5.33 (d,

U-10 Gu, 7), 5.91-4.80 (m, ZN), 4.56 (s, 2H), 4.38 (width, 9-8 HZ, 1H), 3.71 ( d, 9-7 Hz, 1H), 2.76-2.6O(m,

1H), 2.35-2.20 (m, 1H), 1.9-1.0 (m, 11H). (her) ETOOSSNO-(K)SaoI-Age-Rar-SOOSN SNASNo

The mixture is 649 mg (0.95 mmol). H««(K)SaI-Age-Rar-SOOSsSnNoSnNASN»X2TFOo from operation (ii), b5bmg (4.8 mmol) KSO»,

100 ml of water and 100 ml of tetrahydrofuran were stirred at 40°C for 2 hours, followed by the addition of 119 mg (1.14 mmol) of ethyl (bromoacetate) in ml of tetrahydrofuran. After stirring at 40°C for 4 hours and an external temperature of 14 hours, the reaction mixture was filtered, concentrated and flash purified - chromatography with ethyl acetate-tetrahydrofuran-triethylamine (68:29:3) as an eluent to obtain 244 mg (4795) of the desired compound as a white solid. "IN NMR (400 MHz, SOSI"): 5 8.46 Gbrir.t, 1H), 7.81 (d, 2H), 7.35 (d, 2H), 6.08-5.94 (m, 1H), 5.35 (d, 9-18

Hz, 1 NN), 5.23 (d, 9-11 Hz, 1 NN), 4.93 (dd, 9-6 and 9 Hz, 1 Н), 4.66 (d, 2Н), 4.62 -4.38 (AB-part

ABH spectrum), 4.16-4.04 (m, 4H), 3.20 (d, 2H), 2.86 (d, 1H), 2.64-2.45 (m, 2H), 2 ,0-1.0 (m, 17Н). 136 NMR (100 mHz, SOSI3) carbonyl and amidine signals: 5 175.33, 172.24, 170.72, 168.19, 164.35.

Example 2 n-PROOSSN.b-(K)CaI-Age--ar-СООСНСНАSN»o

The required compound was obtained by the method according to example 1(ii) with 50 µMg (0.74 mmol)

H-(K)SaI-Age-Rar-SOOSNOSNASNoh2TFO, see operation (iii), and 160 mg (0.88 mmol) of n-propyl(bromoacetate) to give 277 mg (6895) of the desired compound as a white solid. "IN NMR (400 mHz, SOSIz): 5 8.48 Sruer.t, 1H), 7.83 (d, 2H), 7.35 (d, 2H), 6.76 (width, 1H), 6 .02 (m, tn), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.94 (t, 1H), 4.67 (dd, 2H), 4.49 (AB- part of the ABH spectrum), 4.12 (m, 2H), 3.98 (t, 2), 3.24 (AB system, 2H), 2.87 (d, 1H), 2.52 (m, 2H), 1.99 (shird, 2H), 1.80-1.50 (m, 7H), 1.61 (k, 2H), 1.30-1.10 (m, 2H), 1.00 (cd, 2H), 0.90 (t, ЗН). 136 NMR (100 mHu, SOSI»z) carbonyl and amidine signals: 5 175.4, 172.3, 170.7, 167.9, 164.5 .

Example With t-BUTOOSSNO-(K)SaI-Age-Ra6-сСоОосСнньсСнН-сНнь сч

The required compound was obtained by the method according to example 1(ii) with 25 mg (0.42 mmol)

H-(K)SaI-Age-Rar-SOOSNOSNASNoh2TFO, see operation (iii), and 96 mg (0.5O0mmol) of m-butyl(bromoacetate) with (o) obtaining 9Zmg (39905) of the desired compound as a white solid.

TN NMR (500 mHz, SOSIz): 5 8.50 (fer.t, 1H), 7.81 (d, 2H), 7.36 (d, 2H), 6.07-5.97 (m, 1H ), 5.36 (d, 9-16

Hz, 71H), 5.22 (d, 9-10 Hz, 71H), 4.93 (dd, 9-9 and 6 Hz, 1), 4.76 (d, 9-6 Hz, 2H), 4 ,57-446 (m, 2n), is 4.18-4.04 (m, 2H), 3.19-3.08 (AB spectrum, dUdv-20 Hz, 2H), 2.86 (d, 9-8, 1H), 2.72-2.53 (m, 2H), 2.00-0.90 (m, 23H). 136 NMR (100 mHu, SOSIz) carbonyl and amidine signals: 5 175.28, 171.53, 170.76, 167.81, 1641. so

Example 4 ETOOSSN»-(K)CoI-Age-Par-SOOEt c () BOK-(K)CaI-Age-Par-SOOEt o

The desired compound was obtained by the method according to example 1(i) with 0.0 mg (1.3 mmol) of BOK-(K)CaI-Age-Par-H and 150 mg (1.4 mmol) of ethyl (ichloroformate) to obtain 24 mg (34965) of the desired compound in the form white solid. -

TN nMR (300 mHz, SOS): δ 9.37 (fer.s, 1H), 8.16 (shr.s, 1H), 7.72 (d, 2H), 7.18 (d, 2H), 5.17 (d, 1H), 4.73 (t, 1H), 4.47 (dd, 1H). 4.27 (m, 2H), 4.06 (K, 2H), 3.66 (T, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 1.4-1 .8 (m, 7H), 1.22 (s, 9H), 1.3-0.8 (m, 7H). 136 NMR (75 mHu, SOCI3) carbonyl and amidine signals: δ 172.6, 170.7, 167.9, 164.8, 156.0. From 70 (th). H-(P)Coi-Age-Par-SOOETtx 2HCI s To a solution of 240 mg (0.44 mmol) of BOK-(K)CaI-Age-Par-SOOETt from operation (i) in 200 ml of ethyl acetate was added at 07:3 for 5 minutes of hydrogen chloride, stirred at 0"C for 1 hour with subsequent concentration and obtaining 225 mg (100965) of the desired compound in the form of a white solid. NMR NMR (300 mHz, 020): 5 7.85 (5, 2M), 7, 61 (d, 2H), 4.98 (dd, 1H), 4.60 (s, 1H), 4.44 p, 5H), 3.90 (d, -I 1H), 2.73 (m, 1H), 2.37 (m, 1H), 2.0-1.65 (m, 9H), 1.39 (T, ЗН), 1.4-1.1 (m, 7H), 0.98 (m, 1H). 136 NMR (75 mHu, 029) carbonyl and amidine signals: δ 172.7, 169.4, 166.8, 154.3. o (ii ETOOSSNo-(K)CaI-Age-Par-SOOEt co The required compound was obtained by the method according to example (ii) from 16b0mg (0.3 mmol) H-«(K)CaI-Age-Par-SOOEEth co 50 2VOSY, see . operation 4(ii), and 52.5 mg (0.3 mmol) of ethyl (bromoacetate) to give 10 mg (6195) of the desired compound in the form of a light yellow solid. (ze) IN NMR (300 mHz, SOCI3): 6 8 ... 15-4.05 (m, 4H), 3.21 (AB spectrum, 2H), 2.86 (d, 1H), 2.68 (m, 4H), 2.53 (m, 1H), 1 .96 (width, 2H), 1.90-1.70 (m, 12H), 1.35 (T, ZN). 1.22 (v. 6H). 1.33-0.95 (m. 2H). 29 136 NMR (75 mHz, SOCI3) carbonyl and amidine signals: 5 175.5, 172.2, 170.7, 167.6, 164.9.

HF) Example 5 ETOOSSN.b-(K)CaI-Age-Par-SOO-n-Pr with () BOK-(K)CaI-Age-Par-SOO-n-Pr

The desired compound was obtained by the method according to example 1(i) from 6b.0g (13mmol) BOK-(K)CaI-Age-Par-H and 1.57ml (14mmol) n-propyl(chloroformate). Output 5.4g (76905). 60 TN nMR (400 mHz, SOSIz): 8.25 (lat, 1H), 7.82 (d, 2H), 7.31 (d, 2H), 5.09 (lat, 1H), 4.87 (dd, 1H), 4.58 (dd, 1), 4.39 (dd, 2H), 4.14 (k, 1), 4.10 (t, 2H), 3.79 (t , 1), 2.54 (dm, 2H), 2.21 (s, 1H), 1.87-1.55(m, 8H), 1.33 (s, 9H), 1.45-1.10 ( m, 4H), 0.99 (t, ZN). 136 NMR (100 mHu, SOCI3) carbonyl and amidine signals: δ 172.7, 170.6, 167.8, 165.0, 155.9. 65 (i) N«KYUSa9I-Age-Rar-SOO-n-Prh 21FO

The desired compound was obtained by the method of example (ii) from 2.1 g (3.7 mmol) of BOK-(K)CaI-Age-Par-SOO-n-Pr from operation 5(ii). Exit Z, 7g.

TN nMR (400 MHz, MeOH (04)): δ 7.77 (5, 2M), 7.60 (d, 1H), 4.86 (dd, 1H), 4.56 (AB part of the ABH spectrum , 2H), 4.33 (m, 4H), 3.72 (d, 1H), 3.30 (m, 1H), 2.68(m, 1H), 2.28(m, 1H), 1 ,9-1.7(m, 9H), 1.4-1.1(m, 6H), 1.02(t, ЗН), 136 NMR (100 mguz, meon (0,)) carbonyl and amidine signals : 5 172.7, 169.3, 168.0, 161.4. (ii) Et-«K)SaoI-Age-Rar-SOO-n-Pr

The desired compound was obtained by the method of example (ii) from 472 mg (0.69 mmol) of НУК)СаI-Аге-Рар-СОО-н-Прх 2ТФО, see operation (iii), and 138 mg (0.83 mmol) of ethyl (bromoacetate) to give 0.22 mg (5890) of the desired compound as a white solid.

TN NMR (400 mHz, SOSIz): 5 8.46 C (abbr.t, 1H), 7.82 (d, 2H), 7.32 (d, 2H), 4.92 (dd, 1H), 4 ,49 (AV-part

AV spectrum, 2H), 4.10 (m, 6H), 3.23 (AV spectrum, 2H), 2.80 (dm, 2H), 1.98 (lat, 2H), 1.74 (k, 2H), 1.63 (dd, 2H), 1.52 (m, 1H), 1.21 (t, ЗН), 1.20-1.10 (m, 2H), 0.98 ( t, ZN). 136 NMR (100 mHu, SOSI»z) carbonyl and amidine signals: δ 175.3, 172.2, 170.7. 167.6, 164.8.

Example 6 MEOOOSSNO-(K)SaI-Age-Par-SOO-n-Pr

The desired compound was obtained by the method of example 1(ii) with Zb5mMg (0.53mmol)

H-«(r)SaI-Age-Rar-SOO-n-Prkh2T FO, see operation (iii), and 9 mg (0.64 mmol) of methyl(bromoacetate) to give 114 mg (4196) of the desired compound as a white solid. "IN NMR (400 mHz, SOSIz): 5 8.44 Sruer.t, 1H), 7.82 (d, 2H), 7.32 (d, 2H), 7.04 (width, 1H), 4 ... .24 (s, 2H), 2.87 (d, 1H), 2.65 (m, 71), 2.52 (m, 1H), 2.01 (width, 1H), 1.96 (width .d, 2H), 1.75 (k, 4H), 1.663 (width, dd, 2H), 1.53 (m, 1), 1.3-1.1 (m, 5H), 0.99 ( t, ZN).136 NMR (100 mHz, SOSIS) carbonyl and amidine signals: δ 175.3, 172.5, 170.7, 167.6, 165.0.

Example 7 ETOOSSN.b-(K)CoI-Age-Par-SOOSN oSNOMe He (OBOK-(K)CaI-Age-Par-SOOSN 5SNOMe o

The required compound was obtained by the method of example 1(i) from 6b.0g (13mmol) BOK-(K)CaI-Age-Par-H and 1.94g (14mmol) of 2-methoxyethyl(chloroformate). Exit Z, 9g (5296). "IN NMR (400 mHz, SOSIz): 8.24 (width, 1H), 7.83 (d, 2H), 7.31 (d, 2H), 5.08 (width, 1H), 4.87 (dd, 1H), 4.58 (dd, 1H), 4.39 (dd, 2H), 4.30 (t, 2H), 4.15 (m, 1H), 3.79 (width .t, 1H), 3.68 (t, 2), 340 (s, Z), F 2.65-2.45 (m, 2H), 2.20 (width, 1H), 1.9- 1.55 (m, 6H), 1.34 (s, 9H), 1.3-0.95 (t, 6H). со 136 NMR (100 mGu, СОСИ»z) carbonyl and amidine signals: 5 172, 7, 170.7, 167.8, 164.6, 155.9.

The desired compound was obtained by the method according to example (ii) from 1.71 g of BOK-"K)CaI-Age-"Par-SOO-SOOSNOSNoOMez in operation 7(i). Yield 1.89g (8896).

TN NMR (400 mgc6, meon (04)): 5 7.77 (5, 2M), 7.59 (d, 2H), 4.85 (dd, 1H), 4.56 (d, 2H), 4 .49 (m, 2H), - 4.37 (m, 1H), 4.28 (m, 1H), 3.70 (m, ЗН), 3.37 (s, ЗН), 2.68 (m , 1H), 2.28 (m, 1H), 1.9-1.7 (m, 7H), 1.4-1.1 (m, 6H). 136 NMR (100 MHz, MmeOnH (0))) carbonyl and amidine signals: δ 172.7, 169.3, 168.0, 154.6. (ii) Et-«(K)SaI-Age-Rar-SoOOSsnhSsSnNhHOMe «

The desired compound was obtained by the method according to example 1(iii) from 487 mg (0.9 mmol) of sv) with H-(K)CaI-Age-Par-СООСН.ОСнNoОМех2ТфоО, see operation 7(iii), and 138 mg (0.8 mmol) of ethyl (bromoacetate) with

And obtaining a crude product, which was purified by flash chromatography, using tetrahydrofuran-methylene chloride (3:1) as an eluent. Yield 0.1 mg (3490) of the desired compound as a white solid.

TN nMR (400 mHz, SOS): 5 8.46 (fer.t, 1H), 7.83 (d, 2H), 7.32 (d, 2H), 7.21 (shr, 1H), 4, 92 (dd, 1H), 4.49 (AB part of the AVX spectrum, 2H), 4.30 (T, 2H), 4.12 (K, 2H), 4.07 (k, 2H), 3, 68 (t, 1H), 3.40 (s, ЗН), 3.24 -I (s, 2H), 2.62 (m, 71H), 2.52 (m, 71H), 2.07 (width .m, 1H), 1.97 (width, 1H), 1.8-1.5 (m, 5H), 1.3-1.1 (m, 6H), about 1.05-0, 95 (m, 2H). 136 NMR (100 mHu, SOCI3) carbonyl and amidine signals: δ 175.3, 172.2, 170.7, 167.8, 164.6. Example 8 МЕОССН»-(K)CaI-Age-Par-СООСН оСНОМе о 20 The desired compound was obtained by the method of example 1(iii) with 490 mg (0.7 mmol)

H-(K)Sa9I-Age-Rard-SOOSNOSnNoOMeh 2T1FO, see operation 7(iii), and 128 mg (0.84 mmol) of ethyl(bromoacetate) with me, obtaining a crude product, which was purified by flash chromatography using tetrahydrofuran-methylene chloride (3:1) as eluent. Yield 155 mg (4196) of the desired compound as a white solid.

TN nMR (400 mHz, SOSI»z): 5 8.44 Srubr.t, 1 N). 7.83 (d, 2H), 7.91 (d, 2H), 4.92 (dd, 1H), 4.49 (AB part 59 of the ABH spectrum, 2H), 4.30 (t, 2H) , 4.13 (m, 2H), 3.68 (t, 2H), 3.63 (s, ЗН), 3.39 (s, ЗН), 3.25 (s, 2Н), 2.87

GF) (d, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 1.96 (width, d, 1H), 1.8-1.5 (m, 6H), 1.3-1.1 (m, 5H), 1.00 (K, 2H).

HF 136 NMR (100 mHu, SOSI»z) carbonyl and amidine signals: δ 175.2, 172.6, 170.7. 167.8, 164.5.

Example 9 ETOOSSN»-(K)CaI-Age-Par-SOO-n-But in () BOK-(K)CaI-Age-Par-SOO-n-But

The required compound was obtained by the method of example 1(i) from 1.01 g (2.1 mmol) of BOK-(K)CaI-Age-Par-H and 0.32 g (24 mmol) of n-butyl(chloroformate). After stirring at external temperature for 1.5 hours, the reaction mixture was concentrated and extracted three times with methylene chloride. The combined organic phase was washed with water, dried over sodium sulfate and concentrated to give 1.0 g (83965) of a white solid. 65 "YAN nMR (300 mHz, SOSIz): 9.81-9531 (b, 1H), 8.36-8.20 (m, 1), 7.82 (d, 2H), 7.35 ( d, 2H), 7.84 (d, 2H), 6.78-6.43 (width, 1H), 5.05-4.82 (m, 2H), 4.69-4.15 ( m, ZN), 4.15-4.08 (m, ZN), 3.86-3.70 (m, 1H),

2.68-2.42 (m, 2H), 1.92-0.88 (m, 25H). 136 NMR (125 mHu, SOSI»z) carbonyl and amidine signals: δ 172.5, 170.7, 167.9, 164.9, 156.0.

EAV-M5: (ti1)-571 (t/z2) (Her) N«K)SaI-Age-Rar-SOO-n-Buth2 NSI

The desired compound was obtained by the method according to example 4(ii) from 2.5 g (44 mmol) BOK-(K)CaI-Age-Par-SOO-n-But from operation 4(i). Output 2.4g (10096).

TN NMR (400 mGHz, MmeOn (04)): δ 7.78-7.60 (w, 2M). 4.66-4.49 (m, 2H). 4.49-4.35 (m, ZN), 4.35-4.22 (m, 1H). 3.75 (d, 1H), 1.92-1.67 (m, 8H), 1.56-1.07 (m, 8H). The proton signal partially overlaps with the SOZON signal. 13C NMR (100 mGu, Meon (05)) carbonyl and amidine signals: δ 172.7, 169.3, 167.9, 154.7. (her) Et-«(K)SaI-Age-Rar-SOO-n-But

The required compound was obtained by the method of example 1(iii) with 400 mg (0.74 mmol)

N-«(r)SaI-Age-Rar-SOO-n-Buth2NSII, see operation C(iii), and 147 mg (0.88 mmol) of ethyl (bromoacetate). The product was purified by flash chromatography with methylene chloride and ethanol as eluent (gradient 0.15 » 212,890) to give 29mg (7095) of a white solid.

TN nMR (300 mHz, SOSIz): δ 9.70-9.36 (fer.s, 1H), 8.47 (t, 1), 7.81 (d, 2H), 7.32 (d, 2H ), 7.07-6.73 (width, 1H), 4.97-4.87 (dd, 71H), 4.62-4.35 (m, 2H), 4.20-3.98 (m, 6H), 3.27-3.12 (m, 2H), 2.84 (s, 1H), 2.70-2.40 (m, 2H), 2.03-0.85 (m , 22H). 136 NMR (75 mGu, SOSI") carbonyl and amidine signals: 5 175.3, 172.3, 170.8, 167.9, 165.0.

Example 10 М-pyrС(СО)СНХНСНоОосСсСНо-(К)СаI-Аге-Рар-С0О0-7 ()

A mixture of 4.0 g (46.5 mmol) of G-butyrolactone and 6.0 g (92.8 mmol) of pyrrolidine was stirred for 2.5 hours at room temperature. The product was concentrated in a vacuum, obtaining 14.5 g (10095) of the product in the form of a yellow oil.

TN NMR (300 mHz, MeOn (04)): δ 3.58 (T, 2H), 3.50 (T, 2H), 3.40 (T, 2H), 2.42 (T, 2M), 2, 06-1.75(ts, 6H). i) (i) M-pyrI(O)СНьСНьСНьООСсСНОВg

4 ml (45.8 mmol) of bromoacetyl bromide was added dropwise to a mixture of 7.2 g (45.8 mmol) of M-pyrC(O)SNOSNINONE from operation 10(i) and 5.bg (45 mmol) of DMAP in methylene chloride at 0"C. stirring for 1.5 hours at room temperature, another 1.Oml (11.4 mmol) of bromoacetyl bromide and 1.4 g (11.4 mmol) of DMAP were added and the reaction was continued under reflux for 1.5 hours.Water was added and extracted three times with O9 methylene chloride. The organic phase was dried over sodium sulfate and concentrated to give 10.3 g (81950) M of product as a yellow oil.

TN nMR (400mHz, SOSIz): δ 4.15 (T, 2M), 3.75 (p, 2H), 3.40-3.31 (m, 4H), 2.84 (s, 1H), 2.30 (t, 2H), about 1.98-1.83 (m, 4H), 1.81-1.73 (m, 2H). - (her) M-pyr((О)СНьСНьСНьOOоСсСН»-(К)СаИ-Аге-Рац()

The required compound was obtained by the method according to example (iii) from Bg (104 mmol) H-(K)CaI-Age-Par-7 and 3.5 g (124 mmol) M-pyrS(O)СНХСНСНоООССН»Вг from operation 10 (ии). The crude product was purified by flash chromatography with heptane-ethyl acetate-isopropanol (1:22) as eluent to obtain 4.2 g, which was then purified by reversed-phase preparative high-performance liquid chromatography with 4495 acetonitrile in 001 M o, with MNAOH as eluent to obtain 2 .64g (36905) of product as a white solid. » TN o NMR (500 mHz, SOSI5): 5 9.80-9.22 (rer.s, 71Н), 8.36 (t. 71), 7.96-7.58 (m, ZN), 7.45 (d , 2H), 7.37-71.22 (m, 5H), 5.20 (s, 2H), 4.95-4.88 (dd, 1H), 4.72-4.29 (m, 2H ), 4.15-4.04 (m, 2H), 4.04-3.88 (m, 2H), 3.40 (t, 2H), 3.34 (t, 2H), 3.28- 3.17 (m, 2H), 2.85 (d, 1H), 2.67-2.48 (m, 1H), 2.23 (T, 2H), 2.14-0.93 (m, 18H). -1 15 136 NMR (125 mHz, SOS) carbonyl and amidine signals: 5 175.3, 172.4, 170.9, 170.4, 168.2, 164.6.

EAV-M5: (ti1)-703(t/z2) («c) Example 11 cHxsMne()cSnyooOssHno-(K)CaI-Age-Ra6-CO0O-7 with () cHxMne(oO)SnNion

A mixture of 9.9 g (99.8 mmol) of cyclohexylamine and 3.0 g (25.9 mmol) of 2,5-dioxo-1,4-dioxane was stirred for 2.5 h. . (ee) hours at 1007"C. The product was concentrated, obtaining 8.1 g (10095) of the product as a brown solid.

TN nMR (500mGHz, meon (04)): δ 3.92 (p, 2M), 3.75-3.65 (m, 1H), 1.90-1.58 (m, 5H), 1.43 -1.07 (m, 5Н).

The signal of two protons partially overlaps with the SOZON signal. 136 NMR (125mHz, Meon (04)): carbonyl and amidine signals: 5 174.0 62.5, 33.7, 26.5, 26.1, 26.0.

The signal of one carbone partially overlaps with the signal of СОз3О0. o (its) tsgsSmMNnNSeSOSNhSnoOsSSsNOVg ko To a mixture of 8.0g (50.9mmol) cHxMNOS(O)SNHON from operation 11 (i) and 6b2g (50O9mmol) DMAP in 8Oml of methylene chloride at 0"С, 4ml (45.8mmol) of bromoacetyl bromide was added dropwise. After stirring for 1.5 60 hours at room temperature, another 1.0 mL (11.4 mmol) of bromoacetyl bromide and 1.4 g (11.4 mmol) of DMAP were added and the reaction was continued under reflux for 1.5 hours.Water was added and the aqueous phase was extracted three times with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and concentrated to give 10.3 g (7390) of product as a brown solid.

TN nMR (400 MHz, SOSIz): 5 6.12-6.00 Sbrer.s, 71H), 4.62 (s, 2H), 3.90 (s, 2H), 3.84-3.76 ( m, 1), because 1.95-1.86 (m, 2H), 1.75-1.65 (m, 2H), 1.65-1.56 (m, 1H), 1.43-1.29 (m, 2H), 1.24-1.10 (m, ZN). (its) nГгкссСМмне(Оо)СнНоОсСссН»-(К)СаоИ-Аге-Раб(2)

The desired compound was obtained by the method according to example (iii) from Bg (104 mmol) H-(K)CaI-Age-Par-7 and 3.5 g (124 mmol) cHxMne(O0)СНоООСссСНноВг from operation 11 (ии). The crude product was purified by flash chromatography with heptane-ethyl acetate-isopropanol (5:2:2) as eluent followed by concentration and then purified by reversed-phase preparative high-performance liquid chromatography with 5095 acetonitrile in 01M

MNAON as an eluent. Concentration and freezing gave 2.bg (3695) of product as a white solid.

TN nMR (500 mHz, SOSIz): 5 9.78-9.25 (fer.s, 1H), 7.90 (t, 1H), 7.78 (d, 2H), 7.44 (d, 2H ), 7.38-7.24 (m, 9H), 6.66 (t, 1H), 5.20 (s, 2H), 4.90-4.83 (dd, 1H), 4.60- 4.45 (m, 2H), 4.18-3.93 (m, 4H), 3.73-3.62 (m, 1H), 70. (d, 1H), 3.23, 3.44 (AB, 2Н), 2.87, 2.65-2.08 (m, ЗН), 1.98-0.93 (m, 22Н). 136 NMR (125 mHu, SOCI3) carbonyl and amidine signals: 5 175.1, 171.1, 170.7, 168.8, 166.1, 164 4.

EAV-M5: (t1)-703 (t/2).

Pshklad 12(n-PRI.»MS(OSNOSOSSN»-(K)CoI-Age-Par-СООСnNoООоСссС(СН 3)3 () (n--«Пр» MEKKO)SNНОН

A mixture of 1 mL (36.5 mmol) of di-n-propylamine and 2.02 g (17.4 mmol) of 2,5-dioxo-1,4-dioxane was heated for one hour at 50°C and 66 hours at 90°C. Toluene was added and excess di-n-propylamine was removed in vacuo. The residue was purified by flash chromatography with 1095 methanol in methylene chloride as eluent to give 4.18 g (66905) of the desired product.

TN NMR (300 mHz, SOSIz): 5 4.1 (5, 2M), 3.65 (t, 1H), 3.25-3.35 (m, 2H), 2.9-3.0 (m , 2H), 1.45-1.6 (m, dn), 0.8-0.95 (m, 6H). (i) (n-«Pr»Me(0)СНооОосСсСН»оВг

A mixture of 0.743 g (4.7 mmol) (n-PR»MO(O)OHNOOH from operation 142(i), 0.951 g (4.6 mmol) of DCHK and 0.7 g (5.1 mmol) of bromoacetic acid in 15 ml of methylene chloride was stirred for 1 .5 hours at room temperature. The precipitate was separated by filtration, and the solvent from the filtrate was removed under vacuum. Distillation of the residue with 29 gave 0.6 bg (5095) of the desired compound. Ge) "IN NMR (400 mHz, SOSI"z): 5 4.8 (r. 2M), 4.0 (s, 2H), 3.2-3.3 (m, 2H), 3.05-3.15 (m, 2H), 1.5-1, 7 (m.4H), 0.8-1.0 (dt.bH). (iii) Pivaloyloxymethyl(4-nitrophenylcarbonate) o 30 A mixture of 7.5g (25mmol) argentum pivalate and 7.99g (25mmol) iodmethyl(4 -nitrophenyl carbonate) (Alekhapaeg ei a!I., U.Meda.Spet. (1988) 31, 318) was heated under reflux for 2 hours in 50 ml of benzene. Benzene 0 was removed under vacuum and the residue was dissolved in toluene. Purification by flash chromatography with toluene as eluent afforded 4.00 g (5490) of the desired compound.

T"H NMR (300mGu, SOSi3): 5 8.25 (5, 2M), 7.40 (d, 2H), 5.85 (s, 2H), 1.2 (s, 2H). o 35 136 NMR (75 mGu, SOSI") carbonyl and amidine signals: 5 176.7, 155.06. cha (IM) BOK-(K)CaoI-Age-Par-CsoOSnNooOosSS(CH 3)

A solution of 1.18 g (4 mmol) of pivaloyloxymethyl (4-nitrophenyl carbonate) from operation 142(ii) in 20 ml of methylene chloride was added at room temperature to a solution of 1.88 g (4 Ammol) of BOK-(K)CaoI-Age-Par-H and O0.6 bbml (4.75 mmol) of triethylamine in 20 ml of methylene chloride. After one hour, the methylene chloride was replaced with ethyl acetate and the mixture was purified by flash chromatography with ethyl acetate. We received 1.27g (5095) of the desired product. - s TN NMR (300 mHz, SOSIz): 5 9.5 (fer.s, 1H), 8.25 (t, 1H), 7.8 (d, 2H), 7.3 (d, 2H), 7.0 (width, 1H), "» 5.0-4.8 (m, 2H), 4.65-4.5 (m, 1H), 4.5-4.35 (m, 2H ), 4.2-4.05 (m, 71), 3.75 (t, 1H), 2.7-24 (m, 2H), 1.9-145 " (m, 5H), 1.45 -0.8 (m, 24N). (M) NA(KUO)SaI-Age-Par-СООСnNoООоСсС(СН 3)3 45 Z27mg (0.52mmol). BOK-(K)CaI-Age-Par-СОоОосСнНоОООСсС(СН3И)z from operation 12 (iM) was dissolved in a mixture of bml - methylene chloride and 1.2 ml of trifluoroacetic acid. After 2 hours, the reaction mixture was concentrated in vacuo, and acetonitrile was added the solvent was again removed in vacuo, obtaining the crude desired product, which was further used without purification in the next operation. ime) (miHn-Pru»2Me(0)СНооОосСсСН»-(К)СоI-Аге-Рар-СООСнНоООоСссС(СН 3)3 оо 20 The residue from operation 12(m) was mixed with 150 mg (0.5 Zmmol) (n-Pr )2 gMS(O)СНоООСссСССН»ОВг from operation 12(iii) and 480 mg (3.5 mmol) of K»СО»z in 5 ml of tetrahydrofuran were heated for 3 hours at 40"С. The reaction mixture was filtered and "2 concentrated in vacuo, obtaining a crude product , which was further purified by reverse-phase preparative liquid chromatography, obtaining 78 mg (2195) of the desired product. , 1H), 7.95-8.15 (width, 1H), 7.85-7.95 (d, 2H), 7.2-71.3 (d, 2H), 5.8 (s , 2H), 4.8-4.9 (dd, 1H), 4.5-4.7 (m, ЗН), 4.0-44 (m, ЗН), 2.8-3.4 (m , BN), 2.2-2.7

HF) (m, ZN), 1.75-1.3 (m, 9H), 1.3-1.0 (m, 14H), 1.0-0.7 (M.7H). 7 136 NMR (75mHz, SOCI3) carbonyl and amidine signals: 5 177.24, 175.30, 171.85, 170.79, 168.78, 165.82, 163.14. in Example 13 ETOOSSNO»-(K)CoI-Age-Par-СООННОООСсС(СН 3)3

The desired compound was obtained by the method according to example 12 (chmi) from a solution of 0.41 g (0.65 mmol) in 1 ml of acetonitrile

BOK-(K)SaI-Age-Rar-SOOSN OO SS(SNUI)Zz from operation 12 (im). After stirring overnight at room temperature, the solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, the combined organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The residue was purified by flash chromatography with methylene chloride-methanol as eluent.

84 mg (2190) of the desired compound was obtained by freeze-drying from glacial acetic acid.

"YAN YaYaMeR (300 MHz, SOSI3): 65 9.9 Sper.s, 1H), 8.5 (t, 1H), 7.35 (d, 2H), 5.85 (s, 2H), 5, 90 (dd, 1H), 4.6-4.35 (m, 2H), 4.15-4.0 (m, 4H), 3.2 (s, 2H), 2.85 (d, 1H) , 2.7-2.45 (m, 2), 2.0-1.9 (m, 2H), 1.8-1.45 (m, 5H), 1.3-0.9 (m, 18H).136 NM (75 mHz, SOSI3) carbonyl and amidine signals: 5 177.23, 175.48, 172.29, 170.80, 168.78, 168.85, 163.14.

Example 14 ETOOSSN.b-(K)CoI-Age-Par-COOS(CH 3)0ОСССН У () BOK-(K)CaI-Age-Par-COOS(СНООССН with

A solution of 3.05 g (12 mmol) of 1-acetoxyethyl (4-nitrophenyl carbonate) (Alekhapdeg ei ai., 9U.Med4.Spet. (1988) 31, 70 318), 6.38 g (13.5 mmol) BOK-(K)CaI -Age-Par-H and 1.95 ml (14 mmol) of triethylamine in 40 ml of methylene chloride were stirred at room temperature for 16 hours and ethyl acetate was added. The solution was slightly concentrated and washed with aqueous 1095 sodium carbonate, concentrated to give the crude product, which was purified by flash chromatography with ethyl acetate as eluent. We received 5.59 g (77905) of the desired product. "IN NMR (300 mHz, SOSIz): 5 9.5 (ubr.s, 1H), 8.25 (t, 1H), 7.85 (d, 2H), 7.35 (d, 2H), 6 .95 (k, 1H), 6.7 (width, 1H), 5.0-4.85 (m, 2H), 4.65-4.5 (m, 1H), 4.5-4 .25 (m, 2H), 4.2-4.05 (m, 71), 3.75 (t, 1H), 2.65-2.45 (m, 2H), 2.05 (s, ЗН ), 1.9-1.45 (m, 11H), 1.45-0.8 (m, 12H). 136 NMR (75mHz, SOCI3) carbonyl and amidine signals: 5 172.61, 170.80, 169 ,54, 168.91, 162.50, 156.02.

The desired crude product was prepared by the method of operation 12(m4) from 2.21 g (368 mmol)

BOK-(Y)Sdi-Age-Ra-SooSs(CH 3)0OSSN from operation 14(i). (ii ETOOSSNO-(K)CaoI-Age-Par-SOOS(CH 3)0ОССН with

The crude product from operation 14(i) was dissolved in 150 ml of methylene chloride. The mixture was washed with aqueous 1095 sodium carbonate, the organic phase was dried with potassium carbonate and filtered. 756 bmg (5.bmmol) of potassium carbonate and 7900mg (3.0mmol) of ethyl ((O-trifluoromethanesulfonyl)-glycolate in bml cm of methylene chloride were added to the solution. The reaction mixture was stirred for 5-10 minutes at room temperature and concentrated under vacuum . The residue was dissolved in ethyl acetate and the mixture was filtered through brownmillerite. The filtrate was subjected to flash chromatography with ethyl acetate as eluent, followed by high performance liquid chromatography to give 475 mg (2295) of the desired product. NMR (300 MHz, SOSI3): 5 9.5 (rer.s, 1H), 8.3 (t, 1H), 7.7 (d, 2H), 7.2 (d, 2H) , 6.85 (k, 12H), 4.8 (t, 1H), 4.45-4.25 (m, 2H), 4.1-3.Р85 (m, 4H), 3.1 (s, 2H ). 2.75 (s, 1H), 2.5-2.3 (m, 2H), 1.95 (s, ЗН), 1.9-1.8 so (m, 1H), 1.7 -1.25 (m, 8H), 1.25-1.75 (m, 8H). ch 136 NMR (75mHz, SOCI3) carbonyl and amidine signals: 5 175.26, 172.34, 170.81, 169.49 , 168.80, 162.43.

Example 15 MEOOSCH.b-(K)CaI-Age-Par-OS Fen o (OBOK-(K)CaI-Age-Par-СООС(CH 3)0ОССН У -

556mg (2.3mmol ) of dibenzoyl peroxide in 1 Oml of tetrahydrofuran.

After stirring for 24 hours at 20"C, the reaction mixture was concentrated and the obtained crude product was subjected to high-performance reverse-phase preparative liquid chromatography. 124 mg (1095) of the desired white solid compound were obtained. - with T"H NMR (500 mHu, SOCI3): 5 8 .26 (sun, 1H), 8.09 (m, 2H), 7.72 (m, 2H), 7.59 (m, 1H), 7.48 (m, 2H), 7.36 (d, "» 2H), 5.13 (s, 2H), 4.87-4.98 (m, 2H), 4.54-4.61 (m, 1H), 4.33-4.47 (m, 2H), 4.13-4.19 (m, 1H), 3.81 (t, 1H), " 2.53-2.3 (m, 2H), 1.73-1.86 (m, ЗН ), 1.66-1.72 (m, 2H), 1.36 (s, 9H), 0.968-1.28 (m, 6H). 136 NMR (100 mHu, SOSI»z) carbonyl and amidine signals: δ 172.7, 170.6, 163.9, 157.0, 155.9. - 15 I C-M8: (t/z2) 599 (MaN)(t/2) 614 (MaMa"). 0.0 mmol) of BOK-(K)CaI-Age-Par-Phen from operation 15(i) was added to 114 ml of methylene chloride at 207"C with 18 ml of trifluoroacetic acid. After 14 hours of stirring, the reaction mixture was concentrated and the obtained crude product was partitioned between ethyl acetate and 0.1M Mahon solution. The phases were separated and the organic (ee) 50 layer was dried with sodium sulfate and evaporated. 48Omg (9695) of a white solid compound was obtained. o T"H NMR (500 mGu, SOSI3): 5 8.18 (t, 2M), 7.77 (m, 2H), 7.64 (m, 1H), 7.52 (m, 2H), 7 .43 (d, 2H), 4.75-4.81 (m, 71), 4.50 (s, 2H), 4.18-4.34 (m, 2H), 3.12 (d, 1H ), 2.57-2.68 (m, 1). 2.23-2.33 (m, 1H), 1.88-1.96 (m, 1H), 1.73-1.84 (m , 2H), 1.59-1.71 (m. 2H), 1.45-1.57 (m. 1H), 0.80-1.34 (m, 5H).

And S-M8: (t/2) 494 (MAN U); (t/2) 514(Ma-Ma").

F) 177 mg (1.1 mmol) of methyl ( bromoacetate). After stirring at 207 for 14 hours, the reaction mixture was filtered, concentrated to obtain a crude product, which was purified by preparative high-efficiency reversed-phase liquid chromatography to obtain 269 mg (4996) of the desired compound in the form of a white solid.

T"H NMR (500 mGu, SOSI3): 5 8.43 (t, 1M, MH), 8.09 (m, 2H), 7.69 (m, 2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.27 (s, 2H), 4.93 (dd, 1H), 4.59 (dd, 1H), 4.40 (dd , 1H), 4.12 (m, 2H), 3.65 (s, ЗН), 2.87 (d, 1H), 2.712-2.63 (m, 1H), 2.55-2.48 ( m, 7H), 1.96 (m, 1H), 1.74 (m, 2H), 1.67 (d, 1H), 1.59 (d, 1H), 1.56-1.50 (m , 65 1H), 1.29-1.08 (m, 4H), 1.04-0.94 (m, 1H). 136 NMR (100 mHu, SOSI»z) carbonyl and amidine signals: 5 175.1 , 172.5, 170.6, 164.0, 1571.

And 6-mM5: (t/2) 564 (MAN q).

Example 16 MEOOSSN.b-(K)CaI-Age-Par-OH

1.bml of a 0.29M solution (0.4bmmol) of KOMe was added to a solution of 26bO0mg (04bmmol) of meorossnH»o-(K)CaI-Age-Par-OOStFen from operation 15(it) in 4.bml of tetrahydrofuran at 207C. After 15 minutes of stirring, the reaction mixture was concentrated and purified by reverse-phase preparative high-performance liquid chromatography to obtain 109 mg (5295) of the desired white solid compound. 34 (d, 2H), 4.83 (s, 2H), 4.82-4.76 (m, 1H), 4.48 (d, 1H), 4.33 (d, 1H), 4.15 -4.30 (m, 2H), 3.64 (s, ЗН), 3.04 (d, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 1.95 ( m, 1H), 1.75 70. (m, 2H), 1.58-1.70 (m, 2H), 1.53 (m, 1H), 1.31-1.10 (m, 4H) , 1.04 (m, 1H). 136 NMR (100 mHz, meon-da,)) carbonyl and amidine signals: δ 175.9, 174.3, 172.7, 155.2.

And C-M8: (t/2) 460 (M.N); (t/2) 482 (MaeMa").

Example 17 ETHOOSSNO-(K)CaI-Age-Par-OH

120mg (1.72mmol) of hydroxylamine hydrochloride and 0.vml (5.7mmol) were added to a solution of 184mg (0.3mmol) ETOOSCH. of triethylamine in 4.0 ml of 9595 ethanol and stirred the mixture at room temperature for 4 days, then concentrated and purified by preparative high-performance liquid chromatography with reversed phases to obtain 85 mg (5895) of the desired compound.

TN nMR (300 mgc6, Meon-a;): δ 7.6 (5, 2M), 7.35 (d, 2H), 4.85-4.75 (m, 1H), 4.48 (d, 1H), 4.4-4.55 (m, 2H), 4.0-4.35 (m, 4H), 3.35 (d, 2H), 3.05 (d, 1H), 2.5 -2.65 (m, 71Н), 2.2-2.35 (m, 1Н), 1.9-2.05 (m, 1Н), 1.4-1.85 (m, 5Н), 0 .85-1.35 (m, 8H). 136 NMR (75.5 MHz, Meon-d)) carbonyl and amidine signals: δ 175.97, 173.91 172.72, 155.23.

And 6-mM5: (t/2)474(t 1). high school

Example 18 BnzOoOOsSsSN»-(K)CaI-Age-Par-OH

To a solution of 320 mg (4.59 mmol) of hydroxylamine hydrochloride and 1.7 ml (12.24 mmol) of triethylamine in ethanol o) was added 1 g (1.52 mmol) of Bn;zОССсСН»-(K)CaI-Age-Par-7 and the mixture was stirred at at room temperature for 40 hours, then concentrated and the crude product was purified by preparative reverse-phase high-performance liquid chromatography to obtain 0.34 g (4295) of the desired compound. o z o I 6-mM5: (t/2)536(t1).

Example 19 n-PROOSSN-(K)CaI-Age-Par-7 so

The desired compound was obtained by the method according to example (ii) with 700 mg (1.2 mmol) of H-«(K)CaI-Age-Par-2X2NeY and 268 mg (1.45 mmol) of n-propyl(bromoacetate). Output 259mg (35905).

EAV-M5: (ti1)-606 (pti/z). at

Example 20 n-PROOSSN»b-(K)CaI-Age-Par-OH them

The required compound was obtained by the method of example 18 from 182 mg (0.3 mmol of nH-PROOSCHN»-(K)CaI-Age-Par-7 from example 19. The crude product was purified by preparative reversed-phase high-performance liquid chromatography with 4095 acetonitrile in 0.1 M MNAOH as an eluent to obtain 74 mg (5195) of the desired compound. ON

The desired compound was obtained by the method according to example 18 from 590 mg (0.7 mmol of i-PrPOOSSsSnH»-(K)CaI-Age-Par-7 from :c» of the following example 39. Yield 110 mg (3290) of the desired compound.

And C-mM5: (t1)-488(t/z).

Example 22 t-BUtTOOSSN»-(K)CaI-Age-Par-OH -1 The required compound was obtained by the method of example 18 from 738mg (1.2 mmol of i-PrPOOSsSsH»o-(K)CaI-Age-Par-7 from the following of example 37. Yield of 29mg (48905) of the desired compound. o I 6-mM5: (t1)-502(t/lz). d) Deposit 23 (H-PRI»MSOSNIOOSSN»-(K)CaI-Age-Par-OH () NOOSSNO-(K)CoI-Age-Par-0O-BOK bo Solution 67Omg (1.5 mmol) NOOSSNO-(K)CaI-Age-Par-OH from example 28, 6b54mg (Zmmol) (BOI»O and 92mg (0.75 mmol) of DMAP in tetrahydrofuran-water (10:11) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse-phase preparative high-performance liquid chromatography. 112 mg (1290) of the desired compound was obtained by freeze-drying.

And C-mM5: (t1)-643 (t/lz). (yHn-PRrr»a-MSOSnNyoOosSsSN2-(K)CaI-Age-Par-0O-BOK (F) Solution of 1000 mg (0.15 mmol) NOOSSNO-(K)CoI-Ale-Par-OH from operation 23 (), 27 mg (0.17 mmol) co (n-"Pr)2MCOScCHnOOH, 4 mg (0.21 mmol) EDH and 10 mg (0.075 mmol) DMAP in 5 ml acetonitrile, stirred at room temperature for 4 days. The reaction mixture was concentrated, purified by preparative high-performance liquid chromatography with reversed phases and freeze-drying yielded 21 mg (1895) of the desired compound.

And 6-mM5: (tya1)-787 (t/lz). (yyHn-"Pr.a7MSOSnNooOosSsSNo-(K)SaI-Age-Par-OH

A solution of 20 mg (0.025 mmol) of (n-"Pr)"MCOScCH"-(K)CaI-Age-Par-O-BOK in trifluoroacetic acid-methylene chloride v5 (1:11) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, purified by preparative high-performance liquid chromatography with reversed phases and freeze-drying from water and acetonitrile to obtain 5 mg (3490) of the desired compound.

And 6-mM5: (t1)-587 (t/z).

Example 24 cHgEsSMnSOoSsnNyoOoSsSsNnO-(K)SaI-Age-Par-OH

The desired compound was obtained by the method according to example 18 from 118 mg (0.17 mmol) dHxMnSOosSnooOosSsnH»o-(K)CaI-Age-Ra-2 from example 11(iii). Output 1.8 mg.

And C-m5: (t1)-585(t/z).

Example 25 MemnSOosnNooOsSSsNn»-(K)SaI-Age-Par-OH

The desired compound was obtained by the method according to example 18 from 81 mg (0.12 mmol) /o MemneosnooosSsnH»-(K)CaI-Age-Par-727 from the following example 36. Yield 1Omg (1690).

And 6-mM5: (tya1)-517(t/z).

Example 26 ETOOSSN.b-(K)CaI-Age-Par-cSAc () NIA(K)CaI-Age-Par-SAcC

The required compound was obtained by the method according to example 27), (its) and (ii), using /5 acetic anhydride instead of propanoic acid. Output 1Omg (1690).

And C-mM5: (t1)-430 (t/z). (i) N«KYUSaI-Age-Rar-sAts

The desired compound was obtained by the method of example (ii) with 37 mg (0.5 mmol) of NU(K)CaI-Age-Par-OAc and 105 mg (0.6 mmol) of ethyl (bromoacetate). Output b7mg (22905).

And C6-mM5: (tya1)-516(t/z).

Example 27 ETOOSSNO-(K)CaI-Age-Par-OS(Oe:t () BOK-(K)CaI-Age-Par-OH

1 g (1.52 mmol) was added to a solution of hydroxylamine hydrochloride and triethylamine in ethanol

BOK-(KI)CaI-Age-Par-727 and the mixture was stirred at room temperature for 40 hours, then it was concentrated and the crude product was purified by preparative high-performance reversed-phase liquid chromatography.

And C6-M5(ti1)-488(t/z). i) (its) BOK-(K)SaI-Age-Rar-OS(O)e;t

A solution of 50 mg (0.9 mmol) BOK-(K)CaI-Age-Par-OH from operation 27(i) and propanoic anhydride was stirred at room temperature for 45 minutes, then concentrated and the crude product was purified by preparative high-performance liquid chromatography with reversed phases with 5095 acetonitrile in 0.1M

MNaUOH as an eluent to obtain 26bmg (54965) of the desired compound. co

And 6-mM5: (t1 )-544 (ti/lz). s (ii) NA«(YUYU)SaoI-Age-Rar-ssS(Ojet

The desired compound was obtained by the method according to example (ii) from 238 mg (0.44 mmol) of VOK-(K)CaI-Age-Par-OS(OEET from operation 2 7(ii)). Output 290mg (10096). M

And 6-mM5: (t1 )-444 (ti/lz). (METHOOSSN-(K)CoI-Age-Par-OS(O)e;t

To a solution of 300 mg (0.45 mmol) of H-(K)CaI-Age-Par-OS(O)Et from operation 27(iii) and Zovmg (2.233 mmol) of KSO" in bml of methylene chloride at 0"C, 105 mg was added dropwise (0.45 mmol) of ETHOSCHN 505053, prepared from pPis anhydride and ethyl glycolate. After stirring for 1 hour at room temperature, the reaction mixture with c was washed with water, citric acid with water, dried over sodium sulfate and concentrated. The crude product was purified by preparative high-performance liquid chromatography with inverted phases from 45905 and? with acetonitrile in 0.1 M MNAOH as an eluent to obtain bZmg (27905) of the desired compound.

And C-mM5: (t1)-530 (t/z).

Example 28 NOOSSN»-(K)CaI-Age-Par-OH -I () t-BuUtTOOSSNO-(K)CaI-Age-Par-boSten

The desired compound was obtained by the method according to example (ii) with 250 mg (O0.5 mmol). H-(K)CaI-Age-Par-bOsSphene from operation 15(ii) and 119 mg (0.bmmol) of t-butyl(bromoacetate). Output 211mg (6996).

GI and C-mM5: (t1)-606 (pt/z). (its NOOSSNO-(K)CaI-Age-Par-OOsSten co The desired compound was obtained by the method of example 1 from 233 mg (0.3 mmol) of t-BUTOOSCHN 5-(K)CaI-Age-Par-bOsSphene from operation 28 (i ). Output b5mg (37905).

And 6-mM5: (t1)-550 (t/z). (ii, NOOSSNO-(K)SaI-Age-Par-OH

A solution of bomg (0.1 mmol) HOOSCH»-(K)CaI-Age-Par-bOstene from operation 28(iii) and O2M KOMe (0.2 mmol) in 10 ml of tetrahydrofuran and 1.5 ml of methanol was stirred at room temperature for 5 minutes, then concentrated and

F) by freeze-drying from water and acetonitrile, 28 mg (6390) of the desired compound were obtained. ka I C-mM5: (t1)-446 (t/lz).

Example 29 NOOSSNO-(K)Sa!I-Age-Par-O-cis-oleyl 60 () t-BUTOOSNo-(K)CaI-Age-Par-7

A solution of 1.7 g (2.8 mmol) of t-BuUTOOSNo(K)CaI-Age-Par-7 from Example 37 below, 672 mg (33.08 mmol) (BOYU»O and b8 mg (0.5 mmol) of DMAP in 30 ml of tetrahydrofuran was stirred at at room temperature for 24 hours. At 5"C, another 305 mg (1.4 mmol) of (BOK)"O was added. After 24 hours, the reaction mixture was concentrated and purified by preparative reversed-phase high-performance liquid chromatography. 587 mg 65 (3095) of the desired compound was obtained.

ES-M5: (t1)-720(t/2).

(i) t-BuUtTOOSSNo-(K)SaI-Age-Par-OH

The required compound was obtained by the method of example 18 from 580 mg (0.8 mmol) of t-BUTOSOSCHN'-(K)CaI-Age-Par-7 from operation 29(i). Output Z41mg (7195).

ES-M5: (t1)-602 (t/2). (iii) t-BuUtTOOSSNO-(K)SaI-Age-Rar-O-cis-oleyl

A solution of 34mg (0.5bmmol) t-ButoOOCCsCH.o-(K)SadI-Age-RTar-OH from operation 29(i), 17mg (0.5bmmol) cis-oleyl chloride and 62mg (0.bmmol) in methylene chloride was stirred at at room temperature for 5 minutes, the reaction mixture was concentrated and purified by preparative high-performance liquid chromatography with 76 reverse phases. 32bmg (6795) of the desired compound was obtained.

ES-M5: (t1)-867(t/2). (m) NOOSSNO-(K)SaI-Age-Par-O-cis-oleyl

The desired compound was obtained by the method of Example 1 from 223 mg (0.25 mmol) of t-BUTOHCH 5-(K)CaI-Age-Par-O-cis-oleyl from operation 29Kiii).

And C6-mM5: (tya1)-710 (t/z).

Example 30 n-PROOSSN-(K)CaI-Age-Par-7 (i) Cyclooctyl(bromoacetate) 1.9 g (10 mmol) of cyclooctanol and 0.3 g of DMAP were dissolved in methylene chloride, and then 1 ml (12 mmol) of bromoacetyl chloride was added and stirred for 18 hours The reaction mixture was washed with aqueous 2M NaClCO3 and 0.1M HCl, stirred, concentrated and purified by flash chromatography with petroleum ether-methylene chloride as eluent. 1.8 g (7290) of the desired compound was obtained. (i) Cyclooctyl-UOSCHN-(K)CaI-Age-Par-7

The desired compound was obtained by the method according to example (iii) with 70 mg (1.2 mmol) of H-(K)CaI-Age-Par-7x 2HCl and

36bZmg (1.4bmmol) of cyclooctyl(bromoacetate) from operation ZF(i). Output 37Umg (4696). with

EAV-M5: (ti1)-674(t/z).

Example 31 t-ButСНоООСССНХ-(K)SaI-Age-Par-7 o

The required compound was obtained by the method according to example (ii) from 2.5 g (4.3 mmol) of H-«(K)CaI-Age-Par-2xX2HCl and 1.08 g (5.2 mmol) of t-butylmethyl(bromoacetate) from operation ZF( th). Yield 1.87mg (6990).

EAV-M5: (ti1)-634(t/lz). at

Example 32 (2-Me)BnzOOCCsCH»-(K)CaI-Age-Rab-7 (Y) methylbenzyl(bromoacetate) so

The desired compound was obtained by the method according to the example of Zdi(s) from 5 g (41 mmol) of 2-methylbenzyl alcohol and 12.6 g. c (8Omol) of bromoacetyl chloride. 8.2 g (82965) of the desired compound were obtained. (2-Me)BnzOOSnN 5-(K)SaI-Age-Par-7 o

The desired compound was obtained by the method of example (ii) from 580 mg (1 mmol) of H-(K)CaiI-Age-Par-2xX2HCl and 3 mg (1.4 mmol) of 2-methylbenzyl(bromoacetate) from operation C34(i). Output ZOmg (4,595).

And C-mM5: (t1)-668 (t/lz).

Example 33 cHxSSNoOOosSsSN»-(K)SaI-Age-Rab-7

A solution of 1.41 g (1.7 mmol) of BnzOOCCsSn-(K)CaI-Age-Par-7 and 1 mL of cyclohexylmethyl alcohol in 474 mL of triethylamine and 3 mL of methylene chloride was refluxed for 4 days. The reaction mixture was worked up to give the crude product, which was purified by flash chromatography with methylene chloride-methanol (95:5) as eluent. 801 mg (7190) of the desired compound was obtained. "» EAV-M5: (t-1)-660 (t/2).

Example За4цЧксООССсСHO-(K)CaI-Age-Par-7 (Y) cyclohexyl(bromoacetate) -i The required compound was obtained by the method of example 34 (i) from 1 g (10 mmol) of cyclohexanol and ml (12 mmol) of bromoacetyl chloride. o (i) cgKso oSsSn-(K)CaI-Age-Par-7ka The desired compound was obtained by the method according to example (ii) from 2.5 g (4.32 mmol) H-««(K)CaI-Age-Par-2X2HCi and 1.5 g of 5p (5.2 mmol) cyclohexyl(bromoacetate). Output 1.7g (6090). for EAV-M5: (tti)-646(t/2). o Example 35 Fens(Me)»D» сОСсСсСНо-(К)СаИ-Аге-Рап-7 () 2-phenyl-2-propyl(bromoacetate)

The desired compound was obtained by the method of ZOF(i) with 3 g (22 mmol) of 2-phenyl-2-propanol and 4.16 g (2 mmol) of bromoacetyl chloride. Output 1.2g (4490). (its) Fens("Me»D" ООССНО-(K)CaI-Age-Par-7 iF) The required compound was obtained by the method according to example (ii) from 1.2 g (2.2 mmol) of H-(K)CaI-Age -Par-7x 2HCl and cob4Omg (2.5 mmol) of 2-phenyl-2-propyl(bromoacetate). Output 1.3g (86905). "IN nMR (500 MHz, SOSI"): 5 9.3 (fer.C, 1H), 8.35 (t, 1H), 7.75 (d, 2H), 7.45 (d, 2H), 7.30-7.05 (m, 10 or 60 011 H), 5.15 (s, 2H), 4.78 (T, 71H), 4.40-4.30 (AB part of the ABH spectrum. 2H), 3.95 (k, 1H), 3.74 (k, 1H), 3.26-3.19 (AB spectrum, 2H), 2.72 (d, 71H), 2.43 (k , 2H), 1.93 (width, 1H), 1.75-1.60 (m, 9 or TON), 1.54 (d, 1H), 1.49-1.40 (m, 1H), 1.25-1.0 (m, 4H), 0.92 (k, 1H).

Example 36 MEeMNnNSOSNoOOSOSSN»-(K)SaI-Age-Rab-7

The required compound was obtained by the method according to example |(iii) from 1.2 g (2.2 mmol) of NU(K)CaI-Age-Par-2X2HCl and 649 mg 65 (2.5 mmol) of MemMmnsosnOOsSsSNoOVg, prepared by the method according to example 11 (i), ( (ii) and (ii) using methylamine instead of cyclohexylamine. Output 1Omg (1696).

EAV-M5: (t1)-635 (t/2).

Example 37 t-BUTTOOSNO-(K)SaI-Age-Rab-7

The desired compound was obtained by the method according to example |(iii) with 500 mg (1.0 mmol). NU«(K)CaI-Age-Par-2X2NeCl and 231 mg (1.2 mmol) of t-butyl(bromoacetate). Output 420mg (6995).

And C-mM5: (t1)-620 (t/z).

Example 38.

The desired compound was obtained by the method according to example (iii) from 787 mg (1.4 mmol) H-(K)CaI-Age-Par-7x 2HCl and

Zbamg (1.63 mmol) of 2,3-dimethyl-2-butyl(bromoacetate). Output 590 mg (67905). 70 EAV-M5: (ti1)-648(pt/z).

Example 39 and--ProOosSsnN»n-(K)SaI-Age-Rab-7

The desired compound was obtained by the method according to example |(iii) with 700 mg (1.2 mmol). H««(K)CaI-Age-Par-2X2HeCl and 262 mg (1.5 mmol) of isopropyl(bromoacetate). Output 225mg (3190).

EAV-M5: (t-1)-606 (t/2).

Example 40 BnzossSsnNo-(K)CaI-Age-Par-SOOFen(4-OMe) () BOK-(K)CaI-Age-Par-SOOFen(4-OMe)

The desired compound was obtained by the method of example 103 3 BOK-(K)CaI-Age-Par-H and 4-methoxyphenyl(ichloroformate). Yield b5mg (3790).

EAV-M5: (t1)-622 (t/z2). (th). NAYA(K)CoI-Age-Rar-SOOFen(4-OMe)x2 CARRIERS

The desired compound was obtained by the method of example 4(iii) from BOK-(K)Ca9I-Age-Par-SOOFen(4-OMe) from operation 401). (iii) Bn!si OSSNo-(K)SaI-Age-Ra»-SbOFen(4-OMe)

The required compound was obtained by the method according to example 1(ii) from 85 mg (Obmmol) of 25.H-«(K)CaI-Age-sar-SOOFen(4-OMe)x2HCl from operation 4Fii) and 9Omg (0.2 mmol) of benzyl ( bromoacetate). Output bOmg (5690). i9)

EAV-M5: (t1)-670 (t/l2).

Example 41 cHxSSnNoOOosSsCH»-(K)CoI-Age-Par-SOOFen(4-OMe)

The desired compound was obtained by the method according to example 1(ii) with 554 mg (Vol. 4 mmol)

H-«(K)CaI-Age-Rao-SOOFen(d-OMe) x gne from operation 4) and 165 mg (1.5 mmol) of cyclohexylmethyl (bromoacetate). Exit Zamg (8965). co

EAV-M5: (t1)-676 (t/2). Ge

Example 42.

The desired compound was obtained by the method according to example 1(iii) with 522 mg (immol) of

H-«(QU)CaI-Age-Par-SOOFen(4-OMe)x2HCl from operation 40(iii) and Zb5mg (1.5 mmol) of 2-(methyl)benzyl(bromoacetate). h«

Output 158mg (2396).

And C-m5: (t1)-684(t/lz).

Example 43 ETHOOSSNO-(K)CaI-Age-Ra»-SOOFen(4-Me) « () BOK-(K)CaI-Age-Par-SOOFen(4-Me)

The desired compound was obtained by the method according to example 1(i) from 1.96 g (4.5 mmol) of BOK-(K)CoI-Age-Par and 8 BOmg 0 s (4.99 mmol) of 4-tolyl(chloroformate). Output 1.39g (5596). ts EAV-M5: (t-1)-606 (t/2). "" (i) N«KYU)Sa9I-Age-Rar-SOOFeni(4-Me)

The required compound was obtained by the method of example 4(i) with 388 mg (0.64 mmol) of BOK-(K)

SaI-Age-Rar-SOOFen(4-Me) from operation 43(i). Exit 29Zmg (9196). -I EAV-M5: (ti1)-506 (pt/z). (iii ETOOSSNoO-(K)CaI-Age-Par-SOOFen(4-Me) o The required compound was obtained by the method according to example (iii) from 288 mg (0.bmmol) NU(K)CaI-Age-Par-SOOFen(4- Me) co from operation 43(iii) and 114 mg (0.7 mmol) of ethyl (bromoacetate).Yield 81 mg (24905).

EAV-M5: (t1)-592 (t/z2). co Example 44 BnasSnNyoOOoSsSsSNo-(K)CaI-Age-Par-SOOFen(4-Me) c The desired compound was obtained by the method of example 1(ii) with 272 mg (0.54 mmol)

H-«()CaI-Age-Par-SOOFen(4-Me) x 2HCl from operation 43(ii) and 147 mg (0.bmmol) of benzyl(bromoacetate). Yield 107mg (3196).

EAV-M5: (t--1)-654 (t/lz). o Example 45 BniSsSNoOOSSsSNo-(K)SaI-Age-Par-SOO-n-But

The required compound was obtained by the method according to example 1(ii) from 400 mg (0.74 mmol) of imi) H-"(Kyu)CaI-Age-Par-SOO-H-But2HCY from operation Ch(ii) and 210 mg (0.88 mmol) benzyl(bromoacetate). Output 220 mg (48905).

EAV-M5: (t1)-620 (t/z). 60 Example 46 i-PrOOosSsSNnNo(K)CoI-Age-Rrar-CoOosSsnoBsSsnAsSno

The desired compound was obtained by the method of example 1(ii) with 456 mg (0.67 mmol)

H-(K)CaI-Age-Par-СООСНоОСнНАСнН»оХ2ТФFO from operation (ii) and 145 mg (0.8 mmol) of isopropyl (bromoacetate). Output 294mg (79965).

EAV-M5: (ti1)-556(pt/z). 6E Example 47 ETOOSSNO-(K)CaI-Age-Rarb-i-But () BOK-Rar-SOO-i-But

To a solution of 500 mg (2.0 mmol) of BOK-Par-H, prepared from Rab-7 and (BOK)»O (with the formation of BOK-Par-2), followed by hydrogenation at Ra/C, and 400 mg (4.0 mmol) 27 mg (2.2 mmol) of isobutyl(ichloroformate) was added to triethylamine in 10 ml of methylene chloride at 0"C. After 5 hours of stirring, water was added, the organic phase

It was dried with sodium sulfate and concentrated, obtaining 53 Ωg (7695) of the desired compound. "IN NMR (500 mHz, SOSIz): 5 9.5 C (abbr.s, 1H), 7.82 (d, 2H), 7.91 (d, 2H), 6.6 (sh.s, 1H ), 5.00 (W, 1H), 4.33 (W, 2H), 3.93 (D, 2H), 2.04 (m, 1H), 1.45 (s, 9H) , 0.97 (d, 6H).

The required compound was obtained by the method according to example 4iii) from 520 mg (1.5 mmol) BOK-Rar-SOO-i-But from operation 70. AT). Output 430 (8896).

TN NMR (500 mGu, SOSI»a): δ 7.89 (5, 2M), 7.75 (d, 2H), 4.30 (s, 2H). 4.17 (d, 2H), 2.11-2.05 (m, 1H). 1.02 (d, bN). (ii) BOK-(K)SoI-Age-Rar-SOO-i-But

Add 480 mg (1.4 mmol) VOK-(K)CaI-Age-OH to the solution; 27Omg (1.4mmol) of EDH was added to 40mg (1.3mmol) of H-Par-SOO-i-But from operation 47(ii) and 50mg (5.3mmol) of DMAP in 20ml of acetonitrile. The reaction mixture was stirred at room temperature for 15 days, concentrated, dissolved in water and ethyl acetate, and the organic phase was washed

MansSoO»z, dried with sodium sulfate, concentrated and purified by flash chromatography, with ethyl acetate as eluent, to obtain 510 mg (52965) of the desired compound. (m) NA(YUYUSo9I-Age-Rar-SOO-/-Buth2 NSI

The desired compound was obtained by the method according to example 4(ii) with 5X0Omg (0.8v8mmol) VOK-(K)CaI-Age-Par-SOO-i-But 20 from operation 47(ii). Yield 360 mg (879605).

EAV-M5: (ti1)-506(pt/z). (M) ETOOSSNO-(K)SaI-Age-Par-SOO-i-But

The desired compound was obtained by the method according to example (iii) from 288 mg (0.bmmol) H-«(K)CaI-Age-Par-SOO-i-Buth 2NOI from operation 47 (im) and 110 mg (0.b4mmol) ethyl (bromoacetate ). Output 14Omg (47905). p. 25 EAV-M5: (ty1)-558(pt/z). heh)

Example 48 BniuSNoOOOSSNO-(K)SaI-Age-Par-SOO-n-Pr

The desired compound was obtained by the method of example 1(ii) with 902 mg (1.3 mmol)

H-««(KU)Ca9I-Age-Par-SOO-n-Prx2TFO from operation (iii) and 362 mg (1.bmmol) of benzyl(bromoacetate). Output 199mg (25960). NMR (400 mHz, SOSIz): 5,843 (fer.s, 1H), 7.78 (d, 2H), 7.38-7.27 (m, 7H), 5.05 (s, 2H) . (k, 1H), 3.33-3.22 (AB spectrum, 2H), o 2.85 (d, 1H), 2.65-0.94 (m, 19H).

Example 49 ETOOSSNO-(K)CaI-Age-Par-СООССН 500С-цГкКе сч () ETZSOОССНООС-цГкКС ав)

To a solution of 15.6 g (45.6 mmol) tetrabutylammonium hydrosulfate and 5.85 g (4 mmol) cyclohexanecarboxylic acid 39 in methylene chloride was added 9.1 ml of 10 M (bdmmol) Mason solution at 0"C. The reaction mixture was stirred for 5 minutes, filtered, washed and concentrated , dissolved in water and ethyl acetate, the organic phase was washed with methylene chloride, dissolved in toluene, concentrated | dissolved in tetrahydrofuran, obtaining tetrabutylammonium cyclohexanecarbonate. 4 g (25.9 mmol) was added to this solution at room temperature.

ETZSOOSSNOSI (see BoiKtapp apa I ipa, 9U. Zupievziz (1990) 1159). The reaction mixture was stirred at room temperature for 12 hours, concentrated and purified by flash chromatography. 2.57 g (4090) of the desired compound were obtained. :z» IN NMR (400 mGu, SOSI»5): diagnostic peaks 5 5.80 (s, 2H, O-CH»-O), 2.85 (k, 2H, СНо-5). (her) SISOSSNYOOS-tsGks

3.18 g (23.6 mmol) of 505Si was added dropwise to 2.9 g (11 dmmol) of ETZSOOSSNOOOS-TsGKxe from operation (i) at room temperature. The reaction mixture was stirred for 30 minutes and concentrated. 1.82 g (70905) of the desired compound were obtained. o tn NMR (400mHz, SOS"): diagnostic peaks 8 5.82 (s, 2Hn, O-SnH»o-O). (ii) ko BOK-(K)So!I-Age-Par-СООССН ,0Ос-цГкс

The required compound was obtained by the method according to example 1(i) with 750 mg (1.59 μmol) VOK-(K)CaI-Age-Par-H and 46 Омг

Co (2.mmol) CISOSSNOOS-cHx from operation 449(iii). The crude product was purified by high-performance preparative 2 reversed-phase liquid chromatography. Output Z55mg (9905).

EAV-M5: (ti1)-656 (pti/z). (m) NA(KYU)Sa9I-Age-Rar-СООССНОСОС-цГксх2Т ФО

The required compound was obtained by the method according to the example (it) with VOK-(K)CaI-Age-Par-СООССнНХООСс-цГкКс from operation 49). o (M) ETOOSSNO-(K)CaiI-Age-Par-СООССН 500ОС-ццГкс ko The required compound was obtained by the method of example 1(ii) from 193 mg (0.35 mmol)

H-«(K)CaI-Age-Par-СОО-СООССН 50ОС-цГксх2Т ФО from operation 49 (im) and 8Zmg (0.35 mmol) of ethyl (trifluoroacetate). 60 Output 87mg (3995).

TN NMR (400 MHz, SOSIz): δ 8.48 Srer.t, 1H), 7.83 (d, 2H), 7.37 (d, 2H). 5.86 (c, 2H). 4.95 (dd. 1H), 4.15-4.39 (AB-part of the ABH spectrum, 2H), 4.18-4.05 (m. 5H), 3.26-3.17 (AB- spectrum, 2H), 2.87 (d, 1H), 2.75-0.95 (m. 29H).

Example 50 ETOOSSNO-(K)CaI-Age-Par-СООССН ООССНо-цГкКс b5 The desired compound was obtained by the method of Example 49, starting with cyclohexaneacetic acid instead of cyclohexanecarboxylic acid Yield 74 mg (1790)

EAV-M5: (tti)-656 (t/lz).

Example 51 ETOOSSNO-(K)CaI-Age-Par-SPYOSSN(IMe)OOSphen

The desired compound was obtained by the method of example 49, starting with ET2CO-OSCH(SNUZ)CI (obtained from

SISOSSN(SNUZ)SI and Et5N according to the method of RoiYiktapp apa GI tsypa, uU. Zupieviz (1990) 1159) instead of ETZSOOSSNSI.

Output 7Omg (2396).

EAV-M5: (t1)-650 (t/2).

Example 52 ETOOSSNO-(K)CaI-Age-Par-SOOSSN OOSFen

The desired compound was obtained by the method of example 49, using benzoic acid instead of 70 cyclohexanecarboxylic acid. Output 7Omg (23965). "IN NMR (300 mHz, SOSIz): 5 9.73-9.25 Sr.s, 1H), 8.45 (t, 1H), 8.05 (d, 2H), 7.83 (d, 2H ), 7.60-7.10 (m, b6H), 6.10 (s, 2H), 4.96-4.84 (dd, 1H), 4.62-4.30 (АВХ, 2H), 4.20-3.93 (m, 4H), 3.25 (s, 2H), 2.84 (d, 1H), 2.73-2.A1 (m, 2H), 2.41-0, 87 (m, 15H).

Example 53 BnzosOsSsNo-(K)SaI-Age-Rbao-SOOSSnN(Me)OAcC

The required compound was obtained by the method according to example 1(iii), from 108 mg (0.21 mmol)

H-(K)Ca9I-Age-Par-COOSCH(MeEUS(O)CH 3z from operation 14(ii) and 3 mL (0.233 mmol) of benzyl(bromoacetate). Yield 41 mg (3096).

EAV-M5: (ti1)-650 (pt/z).

Example 54 ETOOSSNO-(K)CaI-Age-Ra6-СООССН 5ОАЦц () НА(КУСОИ-Аге-Рар-СОосСссСнNoОАЦцц х271FO

The desired compound was obtained by the method according to example 14(i) and (ii) using acetoxymethyl(4-nitrophenylcarbonate) obtained by the method according to example 142(ii) using argentum acetate instead of pivalate. The desired compound obtained without purification was used in the next step. (Y) ETOOSSNO-(K)SaI-Age-Par-SOOSSsSN OAC with

The desired compound was obtained by the method according to example 1(ii), with o, 8Zmmol o

H-(K)CaI-Age-Par-SOOSCHN 2OAcx2TFO obtained in operation 54(i) and 2.2 mmol of ethyl (bromoacetate). Output 286 mg.

EAV-M5: (t1)-574 (t/l2).

Example 55 t-BUTOOCSNO-(K)CaI-Age-Par6-СООССсСН 2ОАЦцав)

The desired compound was obtained by the method according to example 1(iii), with 0.313 mmol

H-(K)Ca9I-Age-Par-СООССН 2ОАЦХ2ТФFO, obtained in operation 54(i) and 7Zmg (2.2 mmol) of t-butyl(bromoacetate). co

Output 15 bmg (83965). with

EAV-M5: (t1)- 602 (t/lz). at

Example 56 BnzoOsSsNo-(K)CaI-Age-Rar-boOossNn 0Os-t-But

The required compound was obtained by the method according to example 1(iii), with 379 mg (0.313) mmol of

H-(K)Ca9I-Age-Par-SOOSCHN 500c-t-But obtained in operation 12(y) and 135 ml (0.85 mmol) of benzyl(bromoacetate).

Output 146 bmg (3096).

EAV-M5(t1)-678(t/2). "

Example 57 ETOOSSNO-(K)CaI-Age-Par-СООСН 5ССИз () BOK-(K)CaI-Age-Ra6-СООСНХСССИз shi c The desired compound was obtained by the method of example 1), from 1.0 g (2.12 mmol) of VOK -(K)CaI-Age-Rab-H, 11.7 ml of 2 M m Mahon and 494 mg (2.33 mmol) of trichloroethyl(chloroformate). Output 1.08g (7990). » (i) NA«(YUYUSa9I-Age-Rar-СООСНІССИz

The desired compound was obtained by the method of example 10, with 1.0 g (2.12 mmol)

Sh VOK-(K)SaI-Age-Rar-SOOSN 5SSIz obtained in operation 57(i). Output 1.43g (99965).

Sh- TN nMR (500 mGHz, СО3О0): δ 7.79 (5, 2M), 7.61 (d, 2H), 5.10 (s, 2H), 4.87-4.81 (m, 2H ), 4.63-4.52 (Kk, o 2H), 4.41-4.34 (m, 1H), 4.30-4.24 (m, 1H), 3.72 (d, 1H) , 2.72-2.63 (m, 1H), 2.32-2.25 (m, 1H), 1.88-1.10 (m, 14H). (iii ETOOSSNOo-(K)CaI-Age-Par-СООСН 5ССИ3 o The desired compound was obtained by the method of example 10, with 400 mg (0.52 mmol)

Ho) 20 H«(B)CoI-Age-Par-COOSN 2CSiIz obtained in operation 57(ii) and 95 mg (0.57 mmol) of ethyl (bromoacetate). Yield mg (2396). with TN NMR (300 MHz, SOSIz): 5 8.47 (fer.t, 1H), 7.83 (d, 2H), 7.48 (sh.s, 1H), 7.31 (d. 2H) . 24 (s, 2H), 2.87 (d, 1H), 2.65-2.59 (m, 1H), 2.56-2.48 (m. 1H), 2.10-0.95 ( m, 16H). 59 Example 58 MEOOSS(-SET)SNOOSSN»-(K)CaI-Age-Par-7

10.1 g (174 mmol) of propionaldehyde was added dropwise to a solution of 10 g (11 mmol) of methyl acrylate and 1.3 g (11 mmol) of 1,4-diazobicyclo(|2,2,2-octane) |. The reaction mixture was stirred at room temperature for 14 days, 1500 ml of ethyl acetate was added, the organic phase was washed with water and brine, dried with sodium sulfate, filtered and concentrated to obtain 15.5 g (93965) of the desired compound. "IN NMR (400 mHz, SOCI3) : 5 6.24 (p, 1M), 5.81 (s, 1H), 4.34 (T, 1H), 3.78 (s, ЗН), 2.82 (width s, 1H), 1 .69 (m, 2H), 0.95 (t, ЗН). (i) meOOсСсС(-SET)СНоВг 65 b.5ml 4895 НГ at 0"С was added dropwise to 13g (20.8 mmol) of MeОо-ОСС(- CH)C(ONIETT from operation 58(i). After 5 minutes, bml of concentrated sulfuric acid was added dropwise. The reaction mixture was stirred at room temperature for 12 hours, the phases were separated and the upper layer was diluted with ether, washed with water and a solution

MansSoO»z, dried with sodium sulfate and activated carbon, concentrated and purified the residue by flash chromatography, yield 1.7 g (40905).

TN NMR (400mHz, COzO0): 5 6.97 (T, ЗМ), 4.23 (р, 2Н), 3.8 (с, ЗН), 2.32 (m, 2Н), 1.13 (mt , ZN). (iii) t-:ButTOOSSsSNo-(K)SaI-Age-Par-7

The desired compound was obtained by the method according to example (ii), from 2.1 g (33.bmmol) H-(K)CaI-Age-Par-7 and 780 mg (4.0mmol) of t-butyl(bromoacetate). Output 1.73Zg (7890). (m) NOOSSNO-(K)CaI-Age-Rabf-7 70 A solution of t-BUTOOSSNO-(K)CaI-Age-Par-7 from operation 58(iii) and trifluoroacetic acid in methylene chloride was stirred at room temperature for 3 hours, the reaction the mixture was concentrated, freeze-dried from water and 1 Equiv. conc. NOSE (M) MeSOSS(yaSET)SNOOSSN»-(K)CoI-Age-Par-7

A solution of 26 µg (0.41 mmol) of t-BUTOOSCHN-(K)CaoI-Age-Rab-7 from operation 58(im), 1.239 ml of 1M Mahon and 4 ml of water 75 was freeze-dried, bBbml of dimethylformamide was added, then 10 µg (0 ,49bmmol) mMeross(-SET)CH»OVg from operation 58(iii), the reaction mixture was stirred at room temperature for 24 hours, diluted with 5 ml of toluene, washed with water, dried over sodium sulfate, concentrated and the residue was purified by flash chromatography with ethyl acetate-methanol ( 95:5) as an eluent. Output 95mg (3395).

EAV-M5: (t1) - 690 (t/lz).

Example 59 Men OSCH»-(K)CoI-Age-Par-SOOFen(4-OMe) () Men OSsCHnOVg

The required compound was obtained by the method of Example 30(i) with 15 mmol of Menon and 12 mmol of bromoacetyl chloride.

Output 1.5g (5496). (i) Men OSCHno-(K)SoiI-Age-Par-SOOFen(4-OMe) c

The required compound was obtained by the method according to example 1(ii), from 521 mg (immol) of

H-«(K)CaI-Age-Par-SOOFen(4-OMe) obtained in operation 4F(ii) and 416 mg (1.5 mmol) MenoOoSsnH»OVg from operation 59(i). Exit Zbmg (595).

EAV-M5: (ti1)-718(t/z).

Example 60 t-BuUTOOSSNo-(K)SaI-Age-Par--SOOSSN 00s-n-Pr av)

The desired compound was obtained by the method according to example 1(iii), with 575 mg (0.837) mmol

H-(K)Ca9I-Age-Par-СООССН 50Os-n-Pr, obtained in operation 5(iii), and 196 ml (1.01 mmol) of t-butyl(bromoacetate). 09

Output 110mg (2396). Ge

And 6-mM5: (t1)-572 (t/lz).

Example 6 MENOOSSN»-(K)SaI-Age-Par-7 o

The desired compound was obtained by the method of example (iii), from 0.7 g (1.21 mmol) of H-(K)CaI-Age-Par-7 and 400 mg of Her (145 mmol) MenoosSsenH»VH from operation 59(i). Exit ZZOmg (3895).

EAV-M5: (ti1)-702(t/z).

Example 62 BnzOSOSSN»O-(K)CaI-Age-Par-SOO-Bnz(4-MO 2) " () VOK-(K)CaI-Age-Par-Bnz(4-MO")

The desired compound was obtained by the method according to example 1(i) from 1.03 g (2.18 mmol) BOK-(K)CoI-Age-Par-H, 24 ml 2 M 2 s Mahon ha 518 mg (2.4 mmol) 4-MO»-benzyl ( chloroformate). Output 1.32g (93905). ts EAV-M5: (t1)-651 (t/2). "" (i) N«KYUSa9I-Age-Rar-Bnz (4-MO»)

The required compound was obtained by the method according to example 4(ii) from 1.32 mg (2.03 mmol) of BOK-(K)CaI-Age-Par-Bnz(4-MO»), obtained in operation 64). Output 1.Og (79965) - I EAV-M5: (t1)-551 (t/2). (its) Bn!s OSSNO-(K)CaI-Age-Rab-SOO-Bnaz(4-MO 5) o The desired compound was obtained by the method according to example (iii) with 500 mg (0.80 mmol) of H-(K)CaI- Age-Par-Bnz(4-MO"), which was obtained in operation 64iii), and 220 mg (0O0.90 mmol) of benzyl(bromoacetate). Output 1.0g (79905).

EAV-M5: (ti1)-699(t/lz).

Co. Example 63 ETOOSSNO-(K)CaI-Age-Par-SOO-Bnz(4-MO 5) 2 The desired compound was obtained by the method according to example (its) from 211 mg (0.3v8mmol) H-(K)CaI-Age-Par -Bnz(4-MO"), obtained in operation 64(iii), and 47 ml (0.42 mmol) of ethyl (bromoacetate). Output 44 mg (1890). NMR (300 mHz, SOS): 5 9.55 (fer.s, 1H), 8.50 (lat.t, 1H), 8.20 (d, 2H), 7.80 (d, 2H) . - spectrum, 2H), 4.18-4.04 (m, 5H),

Gee! 3.27-3.15 (AB spectrum), 2.87 (d, 1H), 2.75-2.60 (m, 1H), 2.57-2.45 (m, 1H), 2, 00-0.95 (m, 16H).

Example 64 M-pyrS(O)СНоОосСсСНо-(К)СаИ-Аге-Ра6-СОО-7 о () M-pyrС(О)СНН

A mixture of 2.0 g (17 mmol) of 2,5-oxo-1,4-dioxane and vml (9/mmol) of pyrrolidine was heated for 1 hour with a reflux condenser. Excess pyrrolidine was removed under vacuum. Yield 4.4g (99965).

EAV-M5: (ti1)-130 (pt/z). (i) M-pir((О)СНиООССсСНОВg

To a solution of 0.4 g (3.0 mmol) of M-pyrSCO)SNON from operation 64(i) in 15 ml of dimethylformamide at 0"C, 0.63g (33.1 mmol) of bromoacetyl bromide was added dropwise. After stirring for 1.5 hours at 0"C and 0.63 g (33.1 mmol) of bromoacetyl bromide was added at 65°C for an hour at room temperature and the mixture was heated to 80°C.

Stirred for 12 hours at room temperature and concentrated to give 32Omg (41965) of product.

EAV-M5: (t1)-252 (t/z2). (ii) M-pyrS(O)СНьOOоССсСН-(K)SaI-Age-Rats(2)

The required compound was obtained by the method according to example (iii) from 580 mg (Immol) H-(K)CaI-Age-Par-7 and 100 mg (1.2 mmol) M-pyrC(O)СНоООСССН»ВГ from operation 64 (ии). Yield 40mg (6095) of product as a white solid.

EAV-M5: (t1)-675(t/z).

TN NMR (500 MHz, SOSIz): 5 9.66-9.42 Srer.s, 1H), 8.64-8.56 (m, 1H), 8.03-7.93 (d, 2H), 7.89-7.66 (width, 1), 7.45 (d, 2H), 7.45-7.25 (m, 5H), 5.20 (s, 2H), 4.98- 4.92 (dd, 71Н), 4.82-4.74 (m, 1Н), 4.62, 4.58 (AB spectrum, 2Н), 4.26-4.05 (m, ЗН), 3.47-3.16 (m, 6H), 2.95 (d, 1H), 2.78-2.68 (m, 1H), 2.54-2.42 (m, 1H), 70. 2, 03-1.95 (m, 16H).

Example 65 (2-Me)BnzOOSSsCH»-(K)CaI-Age-Rab6-SOO-Bnz(4-MO 5)

The desired compound was obtained by the method according to example (iii) from 500 mg (0.80 mmol) of H-(K)CaI-Age-Par-Bnz(4-MO"), obtained in operation 64 (iii), and 234 mg (0.9 mmol) (2-methyl)benzyl(bromoacetate) obtained in operation C2(i).

Output 528mg (9296).

TN YaMe (400 MHz, SOSIz): 5 9.34 (fer.s, 1H), 8.38 (t, 1H), 8.09 (d, 2H), 7.72 (d, 2H), 7, 48 (d, 2H), 7.37 (width, 1), 7.23 (d, 2H), 7.17-7.05 (m, 4H), 5.18 (s, 2H), 5 ... 93-3.86 (k, 1H), 3.27-3.17 (AB spectrum, 2H), 2.79 (d, 1H), 2.54-2.35 (m, 2H), 2, 22 (s, 3H), 1.91-1.84 (width, 1H), 1.71-1.39 (m, 5H), 1.19-0.84 (m, 4H).

Example 66 MEOOSSN.b-(K)CoI-Age-Par-SOO-Et

The desired compound was obtained by the method according to example (ii) from ZO05 mg (0.69 mmol) of H-(K)CaI-Age-Par-SOO-Et, obtained in operation 4 (ii), and 126 mg (0.83 mmol) of methyl (bromoacetate) , received in operation Z324(i). Output 188mg (5396).

And o-M5(tai1)-516(t/z).

Example 67 (n-""Pr"Me(OСnNooossNn"-(K)SaI-Age-Par-SOO-Bnz(4-MO 5) c () (n--"PRr"Me(X0)СНоОоОССНІСІ)

A mixture of 244 mg (1.53 mmol) of (n-Pr)»MS(O)CHNOOH from operation 12(i) and 27 mg (1.72 mmol) of bromoacetyl chloride was stirred for 12 hours at room temperature. The mixture was poured into aqueous ManHsCO3 and extracted with methylene chloride. The organic phase was washed with (2M aqueous KNHSO) and brine, dried and concentrated.

EAV-M5: (ti1)-237(t/z). at

TN nMR (400 mHz, SOSIz): δ 4.82 (r. 2H), 4.22 (s, 2H), 3.26-3.91 (T, 2H), 3.10-3.15 (t , 2H), 1.52-168 (m, with 2H), 0.86-1.97 (m, 6H). (i) (n-"Pr"Me(F0)СНоОосСсСНо-(К)СаИ-Аге-Рар-СОО-Бнз(4-МО 5) с

The desired compound was obtained by the method of example 1(ii) with 343mMg (0.b2mmol) "with

N«R)SaI-Age-Rar-SOO-Bnz(4-MO 5), obtained in the operation of the tank), and 160 mg (0.6v8mmol) 3o (n-"PR»MOe(O)SNOOSSN'SI, obtained in the operation 67 (i). Output 8U9mg (19965). -

EAV-M5: (t1)-750 (t/l2).

Example 68.

The required compound was obtained by the method according to example 1(ii) with ZvOmg (0.71 mmol)

Н-««К)CaI-Age-Par-СООСН 500Os-t-But, obtained in operation 12(iii), and 215 mg (0.88 mmol) C 50 of (2-methyl)benzyl(bromoacetate), obtained in operation C32 (and). Output Z7mg (7,590). with EAV-M5: (ti1)-692(t/lz).

From" Example 69

The compounds from examples 1-68 were examined by the above test A, it was found that the ICbO value exceeds 1.0 MM (that is, they are inactive in relation to thrombin by themselves; for comparison, the active inhibitor NOOSSNO-(K)CoI-Age-Par -H has ICso TT 0.01MM). it. Example 70 av | Compounds from Examples 1-68 were tested by one, two or all of the above tests B, B and/or D, and were found to be orally and/or parenterally bioavailable in rats as an active inhibitor of NOOSSNO-(K)CaI-Age-Par- H in the form of a free acid and/or one or more of its ethers. Based on the assumption that NOOSSNO-(K)CaI-Age-Par-H is formed in rats, bioavailability was calculated using the formulas described in tests B, B and/or D as acceptable. c Abbreviation:

Ac - acetyl

BOK - t-butyloxycarbonyl 29 (BOY»O - di-t-butyldicarbonate

HF) Bnz - benzyl

But - butyl o DMAP - M,M-dimethylaminopyridine

DCHK - dicyclohexylcarbodiimide 60 EDH - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Ethyl

Me - methyl

Men - (1K,25,5K)mentyl

Pivaloyl - 2,2-dimethylacetyl and Pr - propyl

M-pyr - M-pyrrolidine

TFO - trifluoroacetic acid cHke - cyclohexyl

Ae - 3-azetidine-2-carboxylic acid

Ca - cyclohexylglycine

H-RabB-H - 1-amidino-4-aminomethylbenzene

H-Rab-2 - 4-aminomethyl-1-(M-benzyloxycarbonylamidino)benzene

Par-OH - 4-aminomethylbenzamidoxime (4-aminomethyl-1-(aminohydroxyiminomethyl)benzene 70 7 - benzyloxycarbonyl n, c, and and T mean normal, secondary, iso and tertiary, in NMR spectra c, d, t, Kk and broad stand for singlet, doublet, triplet, quartet, and broad, respectively.Amino acid stereochemistry is 5 unless otherwise noted.

Claims (59)

19 Formula of the invention 1. The compound of the formula ВВ'ФЮ(О)С-СНо-(К)Сай-Аге-Рар-Б2, and in which В! - VZ or A'YESOM(V U) V? or А"'С(ООВ; А! - Si valkylene; 2 (which replaces one of the hydrogen atoms in the amidino group Pар-Н) - ОН, ОС(ОВ 9, сС(0О0ОВ' or с(ФфОСН(В ZОС(ОВУ; c 29 23 - H, C 4 alkyl or C 1 alkylphenyl (the last group, as an option, substituted by C 1 alkyl, C 1 alkyl, He) with a nitro group or halogen); B and BK? independently - H, C alkyl, phenyl, 2 -naphthyl or, when K! - A'E(O)M(B7) BZ, together with the nitrogen atom to which they are attached, form pyrrolidinyl or piperidinyl; of which, as an option, is substituted with C alkyl or halogen); B! - 2-naphthyl, phenyl or C 1 alkylphenyl (in which the last three groups are optionally substituted with C /4 alkyl, so C. valkoxyl, nitro group or halogen), or C)..12alkyl (the last group, as an option, substituted C 16" with acyloxyl, Ci valkoxyl or halogen); 28 - H or S. dalkil; and o 3 ВО - 2-naphthyl, phenyl, C valoxyl or Su valkyl (the last group, as an option, is replaced by C 1 vacyloxyl, v. S. valkoxyl or halogen); provided that when B! - KU, BZ - benzyl, methyl, ethyl, i-butyl or i-hexyl, and K2 - C(IFOOOV", B" is not benzyl; or its pharmaceutically acceptable salts. " yu 2. The compound according to claim 1, which differs in that when VE! - A'ES(O)M(V VU, A! - Si zalkilen. - with 3. The compound according to claims 1 or 2, which differs in that when B! - A"'S(OM(V VU, V - H or S. valkil. . 4. A compound according to any of claims 1 - C, which differs in that when B! - А'Е(О)М(В В, Vo - Su alkyl, и? С, cycloalkyl. 5. Compound according to any of claims 1 - C, which differs in that when B! - A'E(OM(B VU, B and B? together - pyrrolidinyl. - 6. A compound according to any of claims 2 - 5, which is characterized by the fact that A1 is C alkylene, B7 is H or C alkylene, and 5 - o C. alkyl or C» cycloalkyl, or B and KZ together - pyrrolidinyl. with 7. The compound according to claim 1, which differs in that when B! - A!S(O)OV 7, Ah! - Su valkylen. 8. Compound according to claims 1 or 7, which differs in that when VK! - A"'S(FOOV, V - S. valkil. so 9. A compound according to claims 7 or 8, which is distinguished by the fact that A1 is Su valkylene, and S. ldalkyle. with 10. The compound according to claim 1, which differs in that when B! - KZ, KZ - H, C. 4alkyl (the last group can be linear or, with a sufficient number of carbon atoms, branched and/or cyclic or partially cyclic), or C) alkylphenyl (the last group can be optionally substituted, can be linear or, with a sufficient number of carbon atoms, branched). 11. Compound according to claims 1 or 10, which is distinguished by the fact that В - Н, linear Su. C 10 alkyl, branched C 10 alkyl, or partially cyclic C 10 alkyl, C 10 cycloalkyl, optionally substituted linear C 10 alkylphenyl, or optionally substituted branched C 10 alkylphenyl. 12. The compound according to claim 11, which is characterized by the fact that B is linear C. alkyl, C. cycloalkyl or, alternatively, 60-substituted linear C. alkylphenyl. 13. A compound according to any of claims 1 - 12, which is distinguished by the fact that in2 - on. 14. A compound according to any of claims 1 - 12, which differs in that when B? - OS(ОВЕ, 85 - as an option, substituted phenyl, C. 17 alkyl (the last group can be linear or, with a sufficient number of carbon atoms, branched, be cyclic or partially cyclic and/or be saturated or unsaturated). bo 15. The compound according to claim 14, which is distinguished by the fact that 25 is optionally substituted phenyl, linear C ..dalkyl, branched Cz.dalkyl, or cis-oleyl. 16. The compound according to claim 15, which differs in that RK is linear S. .salkyl, branched Szalkyl. 17. The compound according to any of claims 1 - 12, which differs in that when B? - C(OOV', B! - alternatively, substituted phenyl, C. 12 alkyl (the last group can be, alternatively, substituted, linear or, with a sufficient number of carbon atoms, branched, be cyclic or partially cyclic and/or be saturated or unsaturated), or C. alkylphenyl (the last group can be, as an option, substituted, can be linear or, with a sufficient number of carbon atoms, branched). 18. The compound according to claim 17, which is characterized by the fact that B is alternatively substituted and/or alternatively unsaturated 70 linear C. dalkil, or alternatively substituted and/or alternatively unsaturated branched C 1 -alkyl, or optionally substituted phenyl, or optionally substituted linear C 1 -alkylphenyl, or optionally substituted branched C -alkylphenyl. 19. The compound according to claim 18, which is distinguished by the fact that B is optionally substituted linear C. alkyl, or alternatively substituted branched C. alkyl, optionally substituted linear C. alkylphenyl, or branched 719 Szalkylphenyl. 20. The compound according to any of claims 1 - 12, which is characterized by the fact that when B2 - C(OOOSN(VZOS(OVU, 8 - H or methyl. 21. The compound according to any of claims 1 - 12 or 20, which is characterized by the fact that when 2 - (FOSN(VZOoS(OB, in - phenyl or C. dalkyl) (the last group can be optionally substituted, can be linear or, with a sufficient number of carbon atoms, branched and/or cyclic or partially cyclic). 22. The compound according to claims 20 or 21, which differs in that BZ is H or methyl, and B? - phenyl, C 1 -C 4 cycloalkyl, linear C 3 -C 4 alkyl, branched C 3 -C 4 alkyl or partially cyclic C 3 -C 4 alkyl. 23. The compound according to claim 22, which is distinguished by the fact that e8-H,az-Sv/cycloalkyl, linear Su. valkyl or partially saturated Cyclic Su-valkyl. 24. The compound according to any of the previous clauses, which is distinguished by the fact that when C. alkylphenyl is optionally substituted with C. alkylphenyl, the selected substituent is C. alkyl. 25. The compound according to claim 24, which is characterized in that the substituent is methyl. 26. A compound according to any of the previous clauses, which in/dr/removed by the fact that when B? - SIFOOV, and B" - as an option, (ав) substituted C. 42 alkyl, the substituent is chosen from halogen and C. valkoxyl. 27. The compound according to claim 26, which is characterized in that the substituent is selected from chlorine and methoxyl. co 28. The compound according to any of the previous clauses, which differs in that when B2 is C(IFOOV", and B" is, alternatively, C substituted phenyl, the substituent is selected from C. alkyl, C. alkyl, and halogen. o 29. The compound according to claim 28, which is characterized in that the substituent is selected from methyl, methoxy or chlorine. Zo 30. A compound according to any of the previous clauses, which differs in that when B? - C(IIOOOV, and B" - as an option, it is substituted C). alkylphenyl, the selected substituent is a nitro group. 31. The compound according to claim 1, which is characterized by the fact that it is ETOOSSN"-(А)CaI-Age-Par-СООСНОБСНАСН"; "AproOossNn"o-(A)C9I-Age-Rar-SOOSNSNASN"; 7-BUTOOSSN 5-(A)CaI-Age-Par-COOSNOBSNASN"; With c ETOOSSN»-(A)SaI-Age-Par-SOOETt; "» ETOOSSNO-(K)SaI-Age-Rab-SOO i-But; " Pyrr(оО)сСнсНньсСнНооссНн»-(A)SaI-Age-Par-27; cHesMnesosnooossNn»-(A)SaI-Age-Par-27; (А-ПРИМОС(О)СНоОССН»-(А)СОИ-Аге-Рар-СООосСнНооОсс(СН 3); - ЕТООССН»-(АК)СаI-Аге-Ra-СООСНосОСС(СН З)»; -(A)CaI-Age-Par-СООСН(CH 3)ООСН with; Mmerossn»-(Kk)CaI-Age-Par-OOs Phen; o Mmerossn»-(k)CaI-Age-Par-OH; o 50 EtOOSSN»-(A)CaI-Age-Par-OH; BnzOOOSSsSNo-(K)CaI-Age-Par-OH; me, A-ProOossHno-(K)CaI-Age-Rab-7; A-ProOossHno-(Kk )SaI-Age-Par-OH; -ProOossnNo-(K)SaI-Age-Par-OH; 59 7-BUTOOSSN»5-(k)SaI-Age-Par-OH; (K)CaI-Age-Par-OH; d-HesMmnsSOoSsnooOosSsH"-(K)CaI-Age-Par-OH; where ETOOSSN"-(A)CaI-Age-Par-OAc; HOoOSSN»-(K)CaI- Age-Par-OH; 6o HOOSCHN"-(K)C9I-Age-Par-O- cis-oleyl; cyclooctyl OSCHN 5-(K)CaI-Age-Par-7; 7-BUtCHniOOCSN"-(AK)CaI- Age-Par-7; (2-Me)BnzOOSsSN 5-(K)CaI-Age-Par-27; c-HkesSnoOosSsNo-(K)CaI-Age-Par-27; bo c-HxoosSsNo-(K)CoI- Age-Rarb-7; Fens(Me)»D» ООССНХ-(K)SaI-Age-Par-27; (Me CHnC(Me)20ОССН»-(А)СаI-Аге-Rab-27; БнзООСОССН 5-(Кк)СоИ-Аге-Рар-СООФен(4-OMe); Rar-SOOFen(4-OMe); (2-Me)BnzO0OSCHN 5-(Kk)CaI-Age-Rar-SOOFen(4-OMe); ETHOOSSNO-(K)CaI-Age-Rar-SOOFeny(4-Me) ; BnzOOSOSSN 5-(Kk)CoI-Age-Par-SOOPheny(4-Me); BnzOOSOSSN y-(K)CaI-Age-Par-SOO-A-But; 70 -ProOossHno-(K)CaI-Age-Par -СООСНОЬСНн-сСнН"; ETOOSSNO-(K)CaI-Age-Rab-СОО- -But; BnzOOСОССН н-(К)CaI-Age-Par-СОО- А-Pr; ETOОССН»-(K)CaI-Age- Pa6-СООСНООС-d-Гкс; ETОССН»-(K)CaI-Аге-Ра6-СООСНоСОССН»-д-Гкс; ETООССН»-(К)САИ-Аге-Рар-СООСН(Me)rOsSphen; ETОССН»-(К )SaI-Age-Par-СООСН OS Phen; BnzOOСН 5-(АК)СаI-Age-Рар-СООСН(Me)ОАц; ETOОССН»-(К)СаI-Аге-Раб6-СооОССнН 5ОАСц; 7-Buto оОсСсСН ь- (Kk)CaI-Age-Par-SOOSN oOAC; mmeros-CsS-CsSNET)CH o СОССН»-(A)CaI-Age-Par-27; MenoOosSsnNo-(K)SaI-Age-RTar-SOOFen(4-OMe) and EtOOSSN»-(AK)CaI-Age-Par-SOOSN about Csiz. 32. The compound according to claim 1, which is distinguished by the fact that it is ETOOSSN"-(AK)CaI-Age-Par-SOOSN about SS"; with БнзООСОССН ю-(К)СаИ-Аге-Рар-СОО-А-Бут; A-ProOssNno-(K)SaI-Age-Rab-7; i) cyclooctyl-UOSCH»-(AK)CaI-Age-Par-7; ETOOSSN»-(K)SaI-Age-Ra6-СООСНООС-d-Гкс; Mmerossn»-(k)SaI-Age-Par-OH; o z ETOOSSN»-(A)SaI-Age-Par-OH; А-PрРООсССССН»-(K)SaI-Age-Par-OH; co -ProOossnNo-(K)SaI-Age-Par-OH; with БнзОООССССН и-(K)CaI-Age-Par-OH and ETHОССН»-(А)CaI-Age-Par-оАцц. at 33. The compound according to claim 1, which is rejected by the fact that B! is not A!S(FOOV. cha 34. The compound according to claim 1, which differs in that B and 25 are not independently H. 35. The compound according to claim 1, which differs in that B is not C. 117 alkyl, when 2 is osv, 36. The compound according to claim 1, which differs in that K! - A'S(O)OV. " 37. Compound according to claim 1, which differs in that B and 5 are independent of N. - 70 38. The compound according to claim 1, which differs in that 5 is C 17 alkyl, when K 2 is ОС(ОВ, с 39. The compound of formula 1, defined according to any of the preceding claims 1-38, or its pharmaceutically acceptable salt :z" for use as a pharmaceutical. 40. A compound of formula 1 as defined in any of the preceding claims 1-38, or a pharmaceutically acceptable salt thereof for use in the treatment of conditions requiring thrombin inhibition. and - In and - 41. A compound of formula 1 as defined in any of the preceding claims 1-38, or a pharmaceutically acceptable salt thereof for use in the treatment of thrombosis. (av) 42. A compound of formula 1 as defined in any of the preceding claims 1-38, or a pharmaceutically acceptable salt thereof for use as an anticoagulant. 43. A compound of formula 1 defined according to any of the previous claims 1-38, or a pharmaceutically acceptable salt thereof, (ee) which is useful in that it is used as an active ingredient in the manufacture of medicaments for the treatment of conditions that require thrombin inhibition. 44. The compound of formula 1 according to claim 43, which is distinguished by the fact that the condition is thrombosis. 45. The compound of formula 1 according to claim 43, which is characterized by the fact that the condition is hypercoagulability in blood and tissues. 46. The compound of formula 1, defined according to any of the previous claims 1-38, or its pharmaceutically acceptable salt, GF) which is distinguished by the fact that it is used as an active ingredient in the production of an anticoagulant. GI 47. A compound of formula 1 as defined in claim 1, provided that when B" is unsubstituted C 1 alkylphenyl, then B" is not one of two: 60 a) C devZ-H, C 1-6 alkyl or unsubstituted C. alkylphenyl or b) A'E(FOOV, where B - H or C. dalalkyl and A! - C. alkylene. 48. The compound of the formula v'Fu(O)c-cSNo-(B)Soi-Age-Par-B2, and in which 65 V! - Z or A'YESOM(V Z or A"'E(FOOV; A! - Si valkylen; 2 (which replaces one of the hydrogen atoms in the amidino group Rar-H) - OH, OS(ОВ9, сС(0О0ОВ' or с(ФфОСН(В ZОС(ОВУ; ВЗ - H, Su .zralkyl or Si alkylphenyl) (the last group, alternatively, substituted by C/alkyl, C/alkyl, nitro group or halogen); B and BK? independently - H, C. alkyl, phenyl, 2-naphthyl or, when K! - A'E(O)M(B7) BZ , together with the nitrogen atom to which they are attached, form pyrrolidinyl or piperidinyl; vb- C..4alkyl, phenyl or 2-naphthyl (each of which, as an option, is replaced by C.alkyl or halogen); 70 V! - 2- naphthyl, phenyl or C 1 -alkylphenyl (in which the last three groups are optionally substituted with C /4 alkyl, C. valkoxyl, a nitro group or a halogen), or C)..12alkyl (the last group, as an option, is replaced by C 4.6 acyloxyl, C 4.6 valkoxyl or a halogen); 28 - H or S. dalkil; and BO - 2-naphthyl, phenyl, C valkoxyl or C valkyl (the last group, as an option, is substituted with C 1 vacyloxyl, 75. S. valkoxyl or halogen); or its pharmaceutically acceptable salts, which differs in that it is used as a prodrug. 49. A pharmaceutical composition comprising a compound of formula 1 defined by any of the preceding claims 1-38, or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 50. A method of treating a condition requiring thrombin inhibition, which comprises administering a therapeutically effective amount of a compound of formula 1 as defined in any of the preceding claims 1-38, or a pharmaceutically acceptable salt thereof, to a person susceptible to, or suffering from, such a condition. 51. The method of claim 50, wherein the condition is thrombosis. 52. The method according to claim 50, which is characterized by the fact that the condition is hypercoagulability in blood and tissues. with 53. The method of obtaining the compound of formula 1, which includes: o for the compound of formula I, in which B 2 is OH, the reaction of the corresponding compound of formula I, in which 2 is OSOB, and vo is defined in claim 1, with an alkoxide base. 54. The method of obtaining the compound of formula 1, which includes: for the compound of formula I, in which B 2 is OH, the reaction of the corresponding compound of formula I, in which 22 is C(IOOB and B! o is defined in claim 1, with hydroxylamine or its salt addition of acid 55. The method of obtaining the compound of formula 1, which includes: obtaining the compound of formula I, by the reaction of the corresponding compound of formula II, with НА(КУСаI-Аге-Рар-ВБ2, II o de B? defined in claim 1, with the compound of formula II, m in "d(os-sn"-1 7, where I is the group that is split off, and VK! is defined in claim 1. 56. A method of obtaining a compound of formula 1, which includes: for a compound of formula I, in which B! - H, and KB? - OH or C(FOOOV'", where B" is defined in claim 1, the reaction of the corresponding "compound of formula I, in which VK! - C is alkyl or C. alkylphenyl, and B2 is OH or C(IFOOOV "U, with a base. - with 57. The method of obtaining the compound of formula 1, which includes: h" for the compound of formula I, in which B 2 is ОС(ОУ, and in is defined in claim 1, the reaction of the corresponding compound of formula I, in which B 2 is OH, with the compound of the formula IM v5s(0)-0-sK(O85 M or with a compound of the formula M V. ZS(0)-OGal, M ("in") in which Gal is SI or Vg, and vo, in both cases, is defined in claim 1. with 58. A method for obtaining a compound of formula I, which includes: obtaining a compound of formula I, in which BV! - H, and KB? - OS(OBU, and K5 is defined in claim 1, the reaction of the corresponding compound of the formula MI about P'OYU(O)C-СНо-(АК)CaiI-Age-Par-B2, MI in which P! is a labile acid ester protective group, and 2 - PERSONS, where VZ is defined in claim 1, with an acceptable acid. 59. A method of obtaining a compound of formula 1, which includes: o for a compound of formula !, in which B! - KZ, KZ - S. zdalkyl or S. zalkylphenyl, V? - ОН or С(ФОВ", where В! is defined in claim 1, transesterification of the corresponding compound of the formula МИЙ about к'2О(0)0-СНо-(АК)С9и-Аге-Рар-В2, МИЙ in which Ба - Si 4-alkyl or C 1-alkylphenyl, different from the required ones, or, otherwise, is a labile or alkyl substituent, and B2 is defined in claim 1. Official Bulletin "Industrial Property". Book 1 "Inventions, Useful Models, Topographies of Integrated Microcircuits", 2004, M 10, October 15, 2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine.