UA61057C2 - Thrombin inhibitors, a method for preparation , a pharmaceutical composition based thereon and a method for treatment - Google Patents

Abstract

There is provided amino acid derivatives of formula (I), wherein p, q, R1, R2, R3, R4, Y, n and é have meanings given in the description which are useful as competitive 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. , (I)

Description

Description of the invention

According to the invention, pharmaceutically useful compounds are proposed, in particular, competitive inhibitors of serine 2 proteases, similar to trypsin, especially thrombin, their use in medicines, pharmaceutical compositions with them and methods of their synthesis.

Blood coagulation is a key process involved in hemostasis (including prevention of blood loss from damaged vessels) and thrombus formation (including the formation of blood clots in a blood vessel or heart, which subsequently leads to vessel blockage). . 70 Coagulation occurs as a result of a series of enzymatic reactions. One of the important stages of this is the conversion of proenzyme prothrombin into 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 monomer, which spontaneously polymerizes into fibrin polymers, and also activates the HIPI factor, which crosslinks the polymer to form insoluble fibrin. In addition, thrombin activates factor 12 M and factor MIP, which leads to a positive feedback loop in the formation of thrombin from prothrombin.

By inhibiting platelet aggregation and fibrin formation and crosslinking, effective thrombin inhibitors would be expected to enhance antithrombotic activity. In addition, it can be hoped that effective inhibition of the positive feedback mechanism will enhance antithrombotic activity.

The development of low molecular weight thrombin inhibitors is described by Ciaezsopp, Viosa Soadia. Ribhypoi (1994) 5411.

Viotrask ey ai. (U. SiIip. ar. Ipmevi. 24 zirri. 107, 59 (1969) showed that thrombin inhibitors are based on an amino acid sequence located around the cleavage site for the fibrinogen A chain.

In the discussion regarding the amino acid sequence, these authors believe that the sequence Ppe-MaI-Aga (PO-P2-P1, hereafter denoted as the sequence PZ-P2-P1) should be the most effective inhibitor | see classification of p. 29 substrate specificity: Zspespiep (FVegdep Viorpuz. Kez. Sottyp. (1967) 27 157; (1968) 32 8981. Ge)

Thrombin inhibitors based on dipeptidyl CO derivatives are - aminoalkylguanidine in position P/1, known from US patent Mo4346078 and international publication MO 93/11152. Similar structurally similar dipeptidyl derivatives were also identified. For example, the international publication UMO 94/29336 discloses compounds, for example, with aminomethylbenzamidines, cyclic aminoalkylamidines and cyclic aminoalkylguanidines - 3o in the Ri position; European patent application 0648780 discloses compounds, for example, with cyclic IS o) aminoalkylguanidines in the P1 position.

Thrombin inhibitors that are based on peptidyl derivatives also having cyclic aminoalkylguanidines in the P position (for example, 3- or 4-aminomethyl-1-aminopiperidine) are known from European patent applications -- 0468231, 0559046 and 0641779.

Thrombin inhibitors, which are based on tripeptidyl derivatives with argininaldehyde in the P1 position, were disclosed for the first time in European patent application 0185390.

Even later, peptidyl derivatives based on argininaldehyde and modified in position

RZ. For example, international publication UUO 93/18060 discloses hydroxy acids, European patent application No. 0526877 discloses des-amino acids, and European patent application No. 0542525 discloses O-methylmandelic acids in the RZ position. with

Serine protease inhibitors (for example, thrombin) based on electrophilic ketones in the P1 position are also known. For example, European patent application 0195212 discloses peptidyl-y-ketoesters and amides, European patent application 0362002 discloses fluoroalkyl amido ketones, European patent application 0364344 discloses a-B-6-triketo compounds, and European patent application 0530167 discloses derivatives -Alkoxyketones in position P1.

Other, structurally different inhibitors of trypsin-like serine proteases based on C-terminal boronic acid and arginine derivatives and their isothiouronium analogs are known from European patent application 0293881. - Even later it was disclosed in European patent application 0669317, 0686642 and 0648780, and also in the international publication UMO 95/35309, UMO 95/23609 and UUO 94/29336.

However, there remains a need for effective inhibition of trypsin-like serine proteases such as thrombin. This is especially necessary for compounds suitable for oral use and selective at

And inhibition of thrombin, stronger than other serine proteases. Compounds that exhibit competitive inhibition of thrombin would be expected to be particularly useful as anticoagulants and therefore useful in the therapeutic treatment of thrombosis and related disorders. 5B According to the invention, a compound of the formula I, i is proposed

F) Oh! co ve AH

M u bo shi sr X v Ye o nan B in which p and 4 are independently equal to 0, 1, 2, Z or 4; because B - H, 2,3 - epoxypropyl, Su. alkyl (in which the last group is optionally substituted or terminated by one or more hydroxyl groups), a structural fragment of the formula Ia sn n,

M o |c) where 70 in which A! - an ordinary bond or C. dalkilene, and ЭХ - H or S. dalkil provided that in the chain ВХ-б-6-А!. no more than six carbon atoms, or, when p is 0, together with B? is a structural fragment of the formula IB, sn, I "tuh: where B" is H or C. alkyl; b2 - H, 8i(Me)z, naphthyl, indolyl, СНЕ2В22 or C. alkyl (in which the last group is optionally substituted or terminated by one or more hydroxyl groups or fluorine atoms), or C3-dicycloalkyl or phenyl (in which the last two groups are optionally substituted or terminated by one or more C1-1 alkyl, C1-dialkyl, halogen hydroxy-, cyano-, nitro- , methylenedioxy-, trifluoromethyl groups, МН), С(О)ОВ2), or when p equals cm

Oh, together with B! is a structural fragment of the IS formula; and)

BZ - H, 5i(Me)z, naphthyl, indolyl, SNK29UB26 or C. alkyl (in which the last group is optionally substituted or terminated by one or more hydroxyl groups or fluorine atoms), or C3 dicycloalkyl or phenyl (in which the last two groups optionally substituted or terminated by one or more C1 alkyl, C1 dialkyl, halogen rch-hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, MSH(H)B2", C(FOOB2B); oyu 827 , 22, 25 and 25 independently - cyclohexyl or phenyl; 223 and B27 independently - H, C-alkyl or C(O)B29; o 227, B28 and E29 independently - H or C. dalalkyl; "-

V - N or S. dalkil;

In - S. dalkylene, optionally substituted with S. lalkyl, hydroxy-, methylene or oxo groups; where n is equal to 0, 1, 2, C or 4; and

B is a structural fragment of the formulas Ma, ИМБ or Имс «- с выз» hna

Ma re m IMe 455. MNN Mn, NM Mn, not Mn, b de vo- H, halogen or S. dalkil; and - X tah? independently - ordinary connection or SN»o; o under the condition that when B", B2, B" - H, p is equal to O, Y - (СН2)", p is equal to 1 а: (а) ЕЗ - unsubstituted phenyl, and: 1 : я 5 : : : ( I) B is a structural fragment of the Ma formula, and K? - H, then d is not equal to 0 or 1; and that (her) B is a structural fragment of the MB formula, and X! and X? both CH", then 4 is not equal to 0; and (c) EZ is unsubstituted cyclohexyl, B is a structural fragment of formula Ma, and B is H, then d is not equal to 0; or a pharmaceutically acceptable salt thereof (hereinafter referred to as "compounds according to the invention"). 22 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 also have one or more asymmetric carbon atoms and therefore may exhibit optical and/or diastereoisomerism. All diastereomers are isolated by separation of racemic or other mixtures of compounds using conventional methods such as fractional crystallization or high performance liquid chromatography. Alternatively, the desired optical isomers can be obtained by reaction of suitable 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 diastereomeric esters by conventional means (e.g., high-performance liquid chromatography, chromatography on silicon oxides). All stereomers are included within the scope of the invention. 65 Alkyl groups B", EX, VU, 2, BZ, 7, 5, 23, 21, B2t, 28 and B? can be, and B, EZ and U can be substituted; cycloalkyl groups K2 and EZ can be; and Alkoxy groups VK? and C can be substituted, be linear or branched, saturated or unsaturated. Alkylene groups A" and B can be saturated or unsaturated.

Halogen groups, which PE can be and which 2 and EZ can be substituted for, include fluorine, chlorine, bromine, and iodine.

The wavy line on the carbon atom in the fragments of the formulas Ia, IB, Ma, IMBb and IMc means the bond position of the fragment.

Abbreviations are listed at the end of the application.

When B is a structural fragment of the formulas Ma, Mc or IM, in the latter of which X and X2 are CHO groups, the desired compounds according to the invention include those in which n is 1.

When B is a structural fragment of the IM formula, in which X is an ordinary connection, and X? - an ordinary bond or CH group", preferred compounds according to the invention include those in which n is equal to 2. vn When B is a structural fragment of the formula Ma, and preferred compounds according to the invention include those in which B?

Preferred compounds of formula I include those in which: v/- H, methyl, 2,3-dihydroxypropyl, or (2,2-dimethyl-1,3-dioxalan-4-yl)methyl; p is equal to 0;

B2 - H, optionally substituted C. dalalkyl or optionally substituted phenyl; d is equal to 0, 1 or 2;

VZ - C. dalkyl, naphthyl, indolyl, optionally substituted cyclohexyl, or optionally substituted phenyl;

M - СНО (СНо)», (СНо)з, СНАСН(СНО)СН», СНоС(:О)СН» or СНоС(-СНО)СН»; V - N.

When B2 is C. dalkyl, preferred substituents optionally include a hydroxy group. Preferably, the hydroxy group is attached to the o-carbon atom relative to the carbon atom attached to the OVC group.

More preferred compounds according to the invention include those in which: p

B - H, methyl; at

B2 - H, methyl, hydroxymethyl or ethyl; 4 equals 0;

BZ - optionally substituted cyclohexyl or optionally substituted phenyl; m zo U - Sn», (СНа)» or СНС(-СНО)СН».

When both VK and 2 are H, BZ is unsubstituted cyclohexyl or unsubstituted phenyl, and d is O or 1, preferred compounds according to the invention include those in which M is CHno or CHNC(-CHNO)CH. at

When KV! - H, EZ - unsubstituted cyclohexyl or unsubstituted phenyl, and 4 is 0 or 1, preferred compounds according to the invention include those in which K2 is methyl, hydroxymethyl or ethyl. -

When R is cyclohexyl or phenyl, preferred optional substituents include hydroxy, fluoro, chloro, methyl, O methoxy, amino, nitro, trifluoromethyl, methylenedioxy, ethoxy, and propoxy groups. Substituents of particular note include hydroxy, mono- and difluoro, chlorine, methyl, methoxy and methylenedioxy groups.

Particularly preferred compounds of the invention include those in which:

In - SNU;

B is a structural fragment of the Ma formula. - c Preferred compounds according to the invention are those in which the carbon atom of the amino acid in the fragment t. aA p 45 -i-h U z XX («c) c 50 o has a 5-configuration. The wave lines on the nitrogen and carbon atoms in the above fragment denote

What is the point of attachment of the fragment.

When both B and 2 are H and p is 0, preferred compounds of the invention include those in which the carbon atom in fragment 19) is

ИЙ has a K-configuration. Wave lines on the carbon atom on the above fragment indicate the place of attachment of the fragment. The preferred compounds according to the invention are: Sp-(K,5)CH(OH)-C(O)-Age-Rab;

Sp(Y)CH(OH)-C(O)-Age-Rab;

RI--BYUSN(OH)-S(O)-Age-Rab;

Ry(3-Me)-(K,5)CH(OH)-C(O)-Age-Rab;

Ry(3-OMe)-(K,5)CH(OH)-C(O)-Age-Rarb;

RA(3,5-diOMe)-(K,5)CH(OH)-C(O)-Age-Rarb;

Ry(3-OMe,4-OH)-(K,5)CH(OH)-C(O)-Age-Rab;

RA-"K,5)C(EO(OH)-C(O)-Age-Rab;

RA-"K,5)C(EC(OH)-C(O)-Pho-Rab; 70 P"-(YUS(OH)-C(O)-Age-Rab;

Ry(3-OMe,4-OH)-(K,5)CH(OH)-C(O)-Pho-Rab;

RI--YUSN(OH)-S(O)-Age-Ras;

RI--YUSN(OH)-C(O)-(K,5)Ris(cis-4-Me)-Rab;

PA(3,4---0-CH»-0-))-(K,5)CH(OH)-C(O)-Age-Rab;

Ry(3-OMe)-(K,5)CH(OH)-C(O)-Pho-Rab;

PA(3,5-diOMe)-(K,5)CH(OH)-C(O)-Pho-Rab;

РИ-«К,5)С(МехоОН)-С(О)-Age-Rarb;

RI-(3,5-diMeX,5)C(OH)-C(O)-Age-Rab;

RA(3-MN.)-(K,5)CH(OH)-C(O)-Age-Rab;

RA(3-MH")-(K,5)CH(OH)-C(O)-Pho-Rab;

Ry(3-MO2")-(K,5)CH(OH)-C(O)-Pho-Rab;

PA(3,4---0-CH»-0-))-(K,5)CH(OH)-C(O)-Pho-Rab;

РНА(3,5-difluoro)-(K,5)CH(OH)-C(O)-Pho-Rab;

РЙ--ЮХСН(О-СН»-(К,5)СН(-О-С(СН 3)2-ОО-СН»-))-С(0)-Аге-Раб; with

Ry-"YUS(Me)HON)-S(O)-Rgo-Rab;

Ry--(5)C(MechoOH)-C(O)-Rho-Rab; and)

РНА(3,4-difluoro)-(K,5)CH(OH)-C(O)-Pho-Rab;

РІ--ЮЮСН(ОН)-С(О)-(К,5)Ris(4-methylene)-Rab;

Ry(3-SI)-(k,5)CH(OH)-C(O)-Age-Rab; изо РА-(К,5)С(-ОО-СК(СН3)5-ОО-СН»-)-С(О)-Age-Rarb;

РА-(К,5)С(-ОО-СК(СН3)2-ОО-СН»-)-С(О0)-Ро-Раб; i am

RA-«К,5)К(СНоОНХОН)-С(О)-Аге-Раб; and about

RA-«К,5)К(СНоОНХОН)-С(О)-Rho-Rab.

According to the invention, a method of producing compounds of formula I is also proposed, which includes: -- (a) interaction of compounds of formula M

In he « 0 СН, (СН) - with and. IY M ;" " in which p, 4, B", B? and EZ is indicated above, with the compound of the formula MI, e

F M

- n-Mm i o X (sna B co b in "M in which VU, U, n and B are indicated above; or (b) the interaction of the compound of the formula MII 4 o B

G54! H

Ф) "it's ей b, І» вв т" о он in which р, а, В", В, В", ЕЗ and У are indicated above, with the compound of formula MI,

NeM-(SNao)d-V UP! b5 Also , . and in which n and B are indicated above; in the presence, for example, of a connecting system (for example, oxalyl chloride y

OME, EOS, OSS or TVTu), a suitable base (for example, pyridine, OMAR or PIREA) and a suitable organic solvent (for example, dichloromethane, acetonitrile or OME).

Compounds of formula M are commercially available, well known in the literature, or can be prepared by known methods.

For example, compounds of the formula U, in which both B and B2 are H, p and d are equal to 0, BZ is naphthyl or phenyl optionally substituted by one or more C1-alkyl, C-alkyl, halogen, hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, MIN)?! or С(ФО)ОВ29), can be prepared by the reaction of an aldehyde of the formula IX in which Va is naphthyl or phenyl optionally substituted by one or more C..alkyl, C. adalkyl, halogen, hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, М(Н)Б2" or С(ФООВ28), and Б?! 75 and К28 are indicated above, with: () compound of formula Х веМ X where K" - H or (CH3/)zz5i, at an elevated temperature (for example, higher than room temperature, but lower than 100"C) in the presence of a suitable organic solvent (for example, chloroform) and, if necessary, a suitable catalytic system (for example, benzylammonium chloride) followed by hydrolysis in the presence of a suitable base (e.g., Mahon); (i) chloroform at, e.g., elevated temperature (e.g., above room temperature but below 10072) in the presence of a suitable organic solvent (e.g., chloroform) and if necessary - a suitable catalytic system (for example, benzylammonium chloride) followed by hydrolysis in the presence of a suitable base (for example, Mahon); (ii) a compound of the formula XI, dm oh cha de M - Mao or M, followed by oxidative cleavage (for example, by ozonolysis or with osmium or ruthenium as a catalyst izers) in conditions well known to specialists; or with (m) tris(methylthiomethane) under conditions well known to those skilled in the art, followed by hydrolysis in the presence of a suitable base.

Compounds of formula M in which both B! - H, K2 -- CHNOOH, p and 4 are equal to 0, and BZ is naphthyl or phenyl, which is optionally substituted by one or more C.alkyl, C.alkyl, halogen, hydroxy-, cyano-, nitro-, (se) methylenedioxy-; with trifluoromethyl groups, М(Н)К2" or С(ОООВ29), can be prepared by the reaction of compounds of the formula XI,

Zas(o)Sonz XI « - s de Ka - defined above, with sodium hypochlorite at, for example, room temperature in the presence of a suitable solvent, for example, water. -» Compounds of the formulas MI and MII are commercially available, well known from the literature, or can be prepared by known methods. For example, compounds of formula MI can be prepared by standard peptide conjugation of compounds of formula XIII, (o)fe

OA o n-m u s 70 He" "M o on

In which E7 and U are defined above, with the above compound of formula MIII, under such conditions as are indicated for the synthesis of the compound of formula |. Similarly, a compound of formula II can be prepared by standard peptide coupling of a compound of formula XIII, described above, with a compound of formula Y, defined above, under such conditions, for example, as described above for the synthesis of a compound of formula I. Compounds of formulas MI, XIX, X, XI, XII, and XII are commercially available, well known in the literature, or can be prepared by known methods. Substituents in the phenyl group of compounds of formulas M, MIII, IX and XIII can be introduced in 60 ways, well known to specialists.

Compounds according to the invention can be isolated from the reaction mixture in conventional ways.

It should be clear to those skilled in the art that the method described above may require protection by protecting groups.

Functional groups that are preferably protected include hydroxyl, amino, amidino, guanidino, and carboxyl. Suitable hydroxyl protecting groups include trialkylsilyl and diarylalkylsilyl (eg, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. O.O'-isopropylidene is suitable for protecting hydroxyl groups attached to neighboring carbon atoms. Tert-butyloxycarbonyl or benzyloxycarbonyl are suitable for protecting amino, amidino, and guanidino groups. The nitrogen of amidino and guanidino groups can be mono- or diprotected. Suitable carboxyl protecting groups include

C. alkyl or benzyl esters.

Protection and deprotection can be done before or after coupling. In particular, compounds according to the invention can be prepared in a way that includes the coupling of an M-acylated amino acid or

M-protected amino acid. When using a protected amino acid, the acyl group can be added after conjugation and deprotection of the nitrogen atom can then be carried out by standard methods after 7/0 of this.

Protecting groups can be removed by methods well known to those skilled in the art, as well as described below.

Some protected intermediates of formula I, in which the nitrogen atoms of amidine and guanidine in group B are protected, and which can be obtained before final deprotection in the preparation of compounds according to the invention, are new compounds.

According to a further aspect of the invention, a compound of the formula ХМ, и о в is proposed

YES

M U hm (sn), (snu her dyna (v) m in which V! is a structural fragment of the formulas Ma, Me or Im shre (8)

M ma ve Me m i-

OM vno? OM many! cm nno: u p" and 02 independently - H or benzylcarbonyl, and p, 4, B", K2, VZ, 7, U, p, 29, X and X?, of course, every time O! and 02 cannot be N. "-

Wavy lines on the carbon atoms of fragments of the formulas Ma, Me or IM'7 indicate the position of the bond of the fragment. (Se)

The use of protective groups is fully described in |"Rgoyesiime sSgoiMyrz ip Ogdapis Spetivigu", edition .) Mu

E. MsOtiev, riepyt Rgezz (1973), as well as "Rgogesiime Sgotsshrz ip Ogdapis Zupipevziz" second edition, T MM SOgeep "R.O

M MUsha, UMipeu-Ipiegvsiepse (1991)). "

It should be appreciated by those skilled in the art that although such protected derivatives of the compounds of formula I may not exhibit pharmacological activity by themselves, when administered orally or parenterally, as a result of metabolism in the body, compounds according to the invention are formed from them, which are pharmacologically active. Therefore, such derivatives can be described as "prodrugs". All prodrugs of compounds of the formula | included in the scope of the invention. Protected derivatives of compounds of formula I that are particularly useful as prodrugs include compounds of formula ХМ.

The compounds of the invention are useful because they exhibit pharmacological activity. Therefore, they are defined as pharmaceutical. (22) According to a further aspect of the invention, it is proposed to use the compounds according to the invention as pharmaceuticals.

In particular, compounds according to the invention can be thrombin inhibitors, as demonstrated, for example, in the tests described below. pg 50 Therefore, the compounds of the invention can be expected to be useful in conditions requiring thrombin inhibition. "m Compounds according to the invention have been so defined in the treatment or prevention of thrombosis and hyperability to blood and tissue coagulation in animals, including humans.

Compounds according to the invention were further indicated in the treatment of conditions in which an unwanted excess of thrombin without signs of hypercoagulability, for example, such neurodegenerative diseases as Alzheimer's disease.

In particular, disease states that may be mentioned include the treatment and/or prevention of venous thrombosis and pulmonary embolism, arterial thrombosis (eg, unstable angina in myocardial infarction, thrombotic attacks, and peripheral arterial thrombosis), and systemic embolism, usually 60 atrial fibrillation or left ventricle after transmural myocardial infarction.

Moreover, it can be expected that the compounds according to the invention will be used in the prevention of reocclusion (i.e. thrombosis) after thrombolysis, percutaneous transcavitary angioplasty, coronary bypass operations, microsurgery and vascular surgery in general.

Other indications include the treatment and prevention of disseminated intravascular coagulation due to b5 bacteria, polytrauma, intoxication, or any other cause; anticoagulation treatment when blood comes into contact with foreign body surfaces such as vascular shunts, catheters and stents, mechanical and biological valve prostheses or any other medical devices outside the body such as artificial heart-lungs used in cardiovascular surgery , and a hemodialyzer.

In addition to this effect on coagulation processes, thrombin is known to activate a large number of cells (such as neutrophils, fibroblasts, endothelial cells, and smooth muscle cells). Therefore, the compounds of the invention may also be useful in the treatment or prevention of idiopathy and juvenile respiratory distress syndrome, pulmonary fibrosis due to radiation or chemotherapy treatment, septic shock, sepsis, inflammation including but not limited to dropsy, acute or chronic atherosclerosis such as coronary -arterial disorders, cerebro-arterial disorders, circulatory disorders, as well as 7/0 restenosis after percutaneous transcavitary angioplasty.

Compounds of the invention that inhibit trypsin and/or thrombin may also be useful in the treatment of pancreatitis.

Further, according to the invention, a method of treating conditions requiring thrombin inhibition is proposed, which includes the administration of a therapeutically active amount of said compound of formula I or a pharmaceutically acceptable salt thereof to a person suffering from or susceptible to such a condition.

The compounds according to the invention can normally be administered orally, transdermally, through the oral cavity, rectally, dermally, through the trachea, bronchial tubes, by any other parenteral route or by inhalation in the form of pharmaceutical preparations comprising the active ingredient in the form of a free base or a pharmaceutically acceptable salt addition of a non-toxic organic or inorganic acid in a form that is pharmaceutically acceptable

DOSES.

The compounds of the invention can also be combined with any such antithrombotic agent with a different mechanism of action, such as antiplatelet agents, acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and/or synthetase inhibitors, fibrinogen receptor antagonists, prostacyclin mimetics and phosphodiesterase inhibitors. high school

Compounds according to the invention can also be combined with such a thrombolytic as tissue plasmogen activator (natural or synthetic), streptokinase, urokinase, prourokinase, non-isolated streptokinase and) plasmogen activator complex (NSPAK), plasminogen activator of animal salivary glands, etc. for the treatment of thrombotic disorders, especially, myocardial infarction.

Further, according to the invention, pharmaceutical formulations are proposed, which include the specified M. zo compound of formula I or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable auxiliary agent, diluent or carrier. at

A suitable daily dose of the compound according to the invention for the therapeutic treatment of humans is approximately (in 0.001 - 100mg/kg of body weight for oral use and 0.001 - 5Omg/kg for parenteral use.

Compounds according to the invention have the advantage of being more effective, less toxic, longer acting, wider ranges of activity, more potential, less side effects, more easily absorbed, or may have other beneficial pharmacological properties in compared with previously known compounds.

Biological tests.

A. Determination of thrombin boiling time (CT). 100 ul of a buffered solution with a pH of 7.4 of human thrombin (T 6769

Zidta Spet So) and 100 μl of the inhibitor solution were incubated for 1 minute. Then 100 cl of human plasma combined with normal citrate was added and the boiling time was determined on an automatic device (KS 10, AteiYishpo). The dependence of the boiling time in seconds on the concentration of the inhibitor was constructed and IKeocht was determined by interpolation. "» IKeochT - the concentration of an inhibitor that doubles the boiling time of thrombin for human plasma.

B. Determination of activated thromboplastin inhibition time (ATP). CHUAT was determined in the combined with

Normal plasma citrate with PTT reagent on Aziotaiyey 5 produced by Ziado. 1Ocdl of the inhibitor solution was (o) added to 9Ocdl of plasma, and then the reagent and calcium chloride solution, CHUAT in the mixture was determined on the KS 1O coagulation analyzer (Ateishpa) according to the instructions of the reagent manufacturer. The dependence of the boiling time in seconds on the concentration of the inhibitor in the plasma was constructed, and IKeochUAT was determined by interpolation. («c) IIKbochCHUAT - the concentration of the inhibitor in human plasma, which doubles the time of inhibition of activated sl 50 thromboplastin.

B. Determination of time of thrombin ip mimo. Inhibition of thrombin by oral or parenteral administration of compounds according to the invention in conscious rats that were catheterized a day or two before the experiment to obtain blood samples from the carotid artery. On the day of the experiment, blood samples were taken at a fixed time after the use of the compound in plastic tubes containing 1 part of a 0.13 M solution of sodium citrate and parts of blood. The tubes were centrifuged to obtain platelet-poor plasma. Plasma was used for thrombin time determination as described below. 100ul of rat plasma combined with citrate was diluted with 100cl of 0.996 saline solution, the beginning of plasma coagulation was induced by adding 100ul of a buffered solution with a pH of 7.4 of human thrombin (T 6769 Zidta Spet So).

Boiling time was determined on an automatic device (KS 10, AteiYishpa). because When using the compound of the formula KHIM, the concentration of the thrombin inhibitor of suitable activity of the formula | in rat plasma was evaluated using a calibration curve relating the dependence of thrombin time in citrate-coupled rat plasma to a known concentration of the corresponding "active" thrombin inhibitor in saline.

D. Determination of the time of thrombin in urine ip mimo. Conscious rats were placed for 24 hours in cells for the study of metabolism, followed by oral administration of the compound according to the invention. Thrombin time was determined in collected urine as described below.

100ul of rat plasma combined with citrate was incubated with concentrated rat urine or in a saline solution, the beginning of plasma coagulation was induced by adding 100 dl of a buffered solution with a pH of 7.4 of human thrombin (T6769 Zidta Spet Co). Boiling time was determined on an automatic device (KS 10, AteiYishpo).

When using a compound of the formula KHIM, the concentration of a thrombin inhibitor of suitable activity of the formula in the urine of rats was estimated using a calibration curve relating to the dependence of thrombin time in the plasma of rats combined with citrate on the known concentration of the corresponding "active" thrombin inhibitor in concentrated rat urine (or in a saline solution). . Based on the total urine production of rats during 24 hours and the determined concentration of the above-mentioned active inhibitor in the urine, the amount of excreted 70 active inhibitor was calculated.

The invention is illustrated by the following examples.

General experimental method. Mass spectra were recorded on a triple quadrupole mass spectrometer

ERippidap MAT T5O 700, equipped with an electro-emissive surface (BAV-M5) and mass spectrometer MO Rianogt Ii, equipped with an electro-emissive surface (! С-М85). NO NMR and C NMR measurements were performed on 75 spectrometers of VVOKEV, ASR 300 and magap OMITMU riiv 400 and 500, which operate at "H frequencies of 300.13, 399.6 and 499.82 MHz, respectively, and 1302 frequencies of 75.46 , 100.58 and 125.69 MHz, respectively.

Example 1. CA-(K,5)CH(OH)-C(O)-Age-Rab x NOI. () Vos-Age-ON. 13.5((7O0mmol) ES was added at room temperature to a mixture of 5.777(57mmol)

I -azetidine-2-carboxylic acid (H-Age-OH) and 6.04 g (57 mmol) of sodium carbonate in bbml of water and 100 ml of TNE.

After 60 hours, TNE was removed in vacuo and the mixture was diluted with water and acidified with 2M potassium hydrogen sulfate solution. Extraction with methylene chloride followed by drying (magnesium sulfate) and evaporation of the solvent gave a residue, which was crystallized from a mixture of methylene chloride and texane, obtaining 10.87 g (95905) of colorless crystals.

TN NMR (Z00MGu, SOSIz): 5 4.85-4.7(s,1), 4.0-3.75(m,2), 2.65-2.35(m,2), 1, 4 (p. 9). p 29 (i) Vos-Age-Rab(7). 13.5 g (70 mmol) EC was added at room temperature to a mixture of 19.87 g ((5a4 mmol) (U

Vos-Age-OH from the above operation), 18.31((57mmol) H-Rab(7) x NOSI, prepared by the method described in the international publication UMO 94/29336, and 9.9((81mmol) OMAR in 27 mL of acetonitrile.After 16 hours, the solvent was removed in vacuo and replaced with ethyl acetate.The mixture was washed with water and aqueous citric acid.

The organic layer was dried (magnesium sulfate) and the solvent was removed under vacuum to obtain a residue from which, after crystallization from a mixture of methylene chloride, toluene, diisopropyl ether, petroleum ether, 17.83 g of

Vos-Age-Rats(2). at

TO NMR (ZO0MHC, СОСсСИ): 85 007.85-7.75(d,1), 7.45-7(m, 7), 52(c2), at), 46-44(m,2), 3.95-3.8("K",1), 3.8-3(k,1), 2.5-2.3(m,2), 1.4(c,9). -- (ii) N-Age-Rab(2). 2.44((5.2 mmol) of Vos-Age-Rab(7) from the above operation(s) were dissolved in a mixture of 10 ml of trifluoroacetic acid and 10 ml of methylene chloride. After 30 minutes, the solvent and trifluoroacetic acid were removed under vacuum, and the residue dissolved in methylene chloride. The organic phase was washed with 1095 sodium carbonate solution and dried (potassium carbonate). Removal of the solvent under vacuum gave a residue from which, after crystallization from methylene chloride, 1.095 g (5790) of H-Age-Rac(7) was obtained in the form of colorless crystals. "

TN NMR (ZOOMHC, SOS): 85 7.85-7.75(d,2), 7.45-7.25(m, 7), 52(s2), 4.5(s2), 4.3Z (d,1), 36b5(k1), C with 3.4-3.3(m,1), 2.7-2.5(m,1), 2.4-2.2(m,1 ). ts (m) Sp-(K,5)CH(OH)-C(O)-Age-Rab was prepared according to the method described by Keiyu 5 I aSoig (Zupii. Sott. 22 "» 859 (1992)). To the solution 0.30 g (1.9 mmol) of (K,5)-hexahydromandelic acid, a catalytic amount of OMAR and 0.31 ((3.bmmol) pyridine in methylene chloride was added dropwise to 0.42 ((3.9 mmol) TM5CI. The mixture was stirred 4 hours at room temperature, then cooled to 0"C and a catalytic amount of OME(С

Ge") drops from a 2 ml pipette) and 0.251 (2.00 mmol) oxalyl chloride. The mixture was stirred for 1 hour at 0"C, a mixture of 0.67 (1.8 mmol) H-Age-Rab(7) from the above operation (ii) and 0.50 g (b, 2 mmol) pyridine was added, allowed to warm to room temperature temperature and stirred overnight. To the mixture was added 1095 ml of a solution of citric acid in av! methanol, and after 30 minutes it was poured into a separatory funnel, diluted with 30 ml of ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, then with brine and and dried with sodium sulfate. After evaporation and flash chromatography on silica gel using a mixture of "I methylene chloride: methanol 99 : 1 to 92 : 8) as an eluent, bomg (69o) of the desired compound was obtained.

TN NMR (300 MHz, SOSIz): 8 1.0-1.9(m, 11H), 2.4-2.7(m, 2H), 3.80(d1H), 4.05-4.25( m,1H), 4.3-4.5(m,2H), 4.85-5.0(m,1H), 5.18(s,2H), 7.1-7.5(m, 7H), 7.65-7.8 (m, 2H), 7.86 (Bi, 1H, a smaller part of the diastereomer and/or rotamer), 8.33 (Bi, 1H, a larger part of the diastereomer and/or rotamer)

Ge) 136 NMR (750MHz, SOSIz) amidine and carbonyl carbons: δ 174.8, 170.6, 168.0 and 164.5. (m) Sp-(K,5)CH(OH)-C(O)-Age-Rab x NS. bomg (0.12 mmol). SP-(K,5)CH(OH)-C(0)-Age-Par from the above operation(s) was dissolved in 5 ml of ethanol and 590 Ra/C and 0.1 ml of concentrated NCI were added. The mixture was hydrogenated at atmospheric pressure for 2 hours. After filtration and evaporation, the product was purified by KRIS with 60 using (0.005M MH .OAc, 0.005M NOAc) : SNZUSM 4 : 1 as an eluent. After freeze-drying, aqueous NS was added and the solution was freeze-dried. The yield of the desired product is 15 mg (3196).

TN o nMR (Z00MHz, 0250): 5 0.7-2.0(m, 11H), 2.25-2.4(m, 1H), 2.65-2.9(m, 1H), 3 ,79(d,1H, of the smaller part), 4,03(D,1H, of the larger part), 4,05-4,15(m,2H, of the smaller part), 4,35-4,45(m,( 6О), 2Н, the greater part), 4.5-4.6 (m, 2Н), 5.20 (m, 1Н, the smaller part, the signal of the greater part overlaps the signal of NOIU), 7.5-7.65 (m , 2H), because 7.75-1.8B(M,?H).

13C NMR (750 MHz, SOSIS) of amidine and carbonyl carbons (diastereomers and/or rotamers): δ 176.3, 175.4.6, 173.7, 173.3, 167.2 and 167.0.

Example 2. SY--KOUSN(OH)-C(O)-Age-Ra x NOI. () Сп-(ЮСН(ОН)-С(О)-Аге-Рац(2). The sub-titled compound was prepared by the method according to example (im), from 0.60 g (3.8 mmol) of (K)-hexahydromandelic acid with with a yield of 0.15 g (10905). 24 mmol) CH-(K)CH(OH)-C(O)-Age-Rac(2) from operation) with a yield of 52mg(5496).

TO nMR (ZO00MHz, 050): 5 0.7-2.0(m, 11H), 2.25-2.4(m, 1H), 2.6-2.9(m, 1H), 3, 79 (d, iH, smaller part), 70 4.02 (D, 1H, larger part), 4.05-4.15 (m, 2H, smaller part), 4.35-4.45 (m, (B5О), 2Н, the greater part), 4.5-4.6 (m, 2Н), 5.19 (m, 1Н, the smaller part, the signal of the greater part overlaps the signal of NOIU), 7.5-7.65 ( m, 2H), 7.715-7.85 (m, 2H). 132 NMR (75 MHz, SOCI3) of amidine and carbonyl carbons (diastereomers and/or rotamers): δ 171.9, 170.2, 169.8 and 163, 8. 12 Example 3. EBSN(OH)-C(O)-Age-Rab x HCl. with example (ii, with EAs saturated with NCI. The reaction mixture was evaporated After half an hour, obtaining

N-Age-Rats(2) x 2HCI with a quantitative output. (its EBSN(OH)-C(O)-Age-Rab(7/). A mixture of 0.13((0.8O0mmol) diethyl glycolic acid, 0.39(0.88mMmol)

H-Age-Rats(2) x 2HCII, 0.281 (0.8 mmol) TVTO in 15 ml of OME was cooled in an ice bath and 0.41 g (3.2 mmol) of OPIREA was added to the reaction mixture, after which it was stirred overnight. The resulting mixture was poured into 500 ml of water and extracted three times with ethyl acetate. The combined organic phase was washed with aqueous sodium bicarbonate and water and evaporated. The crude product was purified by flash chromatography on silica gel with methylene chloride: THP as an eluent. Exit ZOmg (890). with 29 TN nMR (400 MHz, SOSIz): 5 8.04 (BB1H), 7.77 (d, 2H), 7.40 (d, 2H), 7.35-7.2 (m, 5H), 5 ,17(c2H), 4.90 (min), (0 4 Ab(dd,1H), 4.39(dd,1H), 4.3-4.2(m,2H), 2.66(m ,1H), 2.44(m,1H), 1.8-1.5(m,4H), 0.9-0.75(m,6H). )-Age-Rab x NS The title compound was prepared by the method according to example 1(x), with

ZOomg(0.0bZmmol) of EBSN(OH)-C(O)-Age-Rac(2) from operation(s) with a yield of 19mg(7990). M zo IN nMR (ZOOMHCts, 020, the spectrum is complicated by the presence of rotamers): δ 7.8O(d, 2H), 7.65-7.5(m, 2H), 5.43(m 1H, a smaller part of the rotamer), 4.90 (m, 1H, most of the rotamer), 4.6-4.5 (m, ЗН), 4.11 (m/1H, rotamer), about

C.70 (mM, 1H, rotamer), 2.8-2.55 (m, 1H), 2.35-2.15 (m, 1H), 1.9-1.6 (m, 4H), 1.0-0.75 (m, 6H). o 136 NMR (75 MHz, 029) amidine and carbonyl carbon(rotamers): 5 178.3, 177.4, 175.0, 173.5, 167.2.

Example 4. RLSN(OH)-C(O)-Aze-Ra x NOSI. - () EBSN(OH)-C(O)-Age-Rats(7). The sub-title compound was prepared by the method according to example 3(iii), with 0.18 (0.000 mmol) of benzylic acid. Output 0.16g (3595).

TO NMR (ZO00MHz, 020): 8 7.93 (B1), 7.71(d, 2H), 7.54-7.15(m, 17H), 514(c2H), 4.89(M1H) , 4.57(m1H), 4.48(dd 1H), 4.35(dd 1), 3.60 (m.1H), 3.44(m,1H), 2.44(m 1H), 2.23 (m1N). " (its PbCH(OH)-C(O)-Age-Par x CARRIERS. The title compound was prepared according to example 1(x), with 0.16 (0.28 mmol) PbCH(OH)-C(O)- Age-Rats (2) from the previous operation) with an output of ZOmg (6895). o, c TN nMR (400 MHz, 050, the spectrum is complicated by the presence of rotamers): 5 7.65-7.55(m, 2Н), 7.4-7.1(m, 12Н),

From" 5.13 (m, 1H, of a smaller part of the rotamer), 4.77 (m, 1H, of a larger part of the rotamer), 4.43 (d, 1H), 4.4О(d/1H), 4.12( m1H, the larger part of the rotamer), 4.05-3.9(m,1H, plus 1H of the smaller part of the rotamer), 2.55(m,1H, the smaller part of the rotamer), 2.39(m,1H, the larger part of the rotamer ), 2.08(m, 1N). b» 15 136 NMR (75 MHz, 029) amidine and carbonyl carbons(rotamers): 6 175.7, 174.9, 174.6, 173.4, 167 1.

Example 5. n-SeH.iZ(K.5)CH(OH)-C(O)-Age-Ra x NOSI. - (Y) n-"SeNiz(K.5)CH(OH)-C(O)-Age-Rac(2). The sub-titled compound was prepared by the method according to example 3(iii), with 0.13(O .8Omol) of (K,5)-2-hydroxyoctanoic acid. Yield 0.25g (61905). 20 IN NMR (400MHz, SOCI53): 5 8.24 (pc, 1H, one diastereomer), 7.89 (pc, 1H, one diastereomer), about 7.8-7.75 (m, 2H), 7.4-7.45 (m, 2H), 7.35-7.25 (m, 5H), 5.18 ( s, 2H), 4.95-4.85 (m, 1H), 4.55-4.35 (m, 2H),

And 4.2-4.0 (m, ZN), 2.8-2.65 (m, 1H), 2.6-2.4 (m, 1H), 2.0-1.2 (m, TON), 0.9-0.8 (m, ZN). (its) n-"SenNiz(K.5)CH(OH)-C(O)-Age-Ra x NOI. The target compound was prepared by the method according to example 1(m), from 0.140.28 mmol) n-SeNiZ( K,Z)CH(OH)-C(O0)-Age-Rac(2)) from the previous operation (ii) with a yield of 88 mg (7896).

IN nMR (400 MHz, 020): δ 7.7-7.6 (m, 2H), 7.45-7.3 (m, 2H), 5.03 (m. 1H, one diastereomer), 4.74 (m,1H, of one diastereomer overlapping with the water signal), 4.45-4.35 (m,2H), 4.3-4.1 (m,2H), 4.0-3.8 (m, about 1H), 2.65-2.45 (m, 1H), 2.3-2.1 (m, 1H), 1.6-0.9 (m, TON), 0.75-0.65 (m, ZN). co 13C NMR (75MHz, SOSI3) amidine and carbonyl carbons (diastereomers and rotamers): δ 176.8, 176.4, 176.0, 173.5, 173.3, 173.2, 167.2. 60 Example 6. RNACUSN(OH)-C(O)-Age-Rab. () RI(KSN(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared by the method of example Z), from 0.1240, vmmol) (K)-mandelic acid. The crude product (0.315g) was purified by flash chromatography on silica gel with ethyl acetate:T HE (4:6) as an eluent. The yield was 0.128g (3290) in the form of a white powder with a purity of 91.296 (NRI C). NMR (499.803 MHz, SOSIv): 85 8.14 (t, 1), 7.72 (d, H), 7.42 (d, 2H), 7.33 (t, 4H), 7.28 (m, ZN), 7.22 bo (d, 2H), 5.18 (s, 2H), 4.92 (s, 1H), 4.79 (dd, 1H), 4.54 (broad s, 1H), 4.39 (d, 2H), 4.00 (k, 1H), 3.53

(Kk, 1H), 2.48 (m, 1H), 2.24 (m, 1H), 2.19 (broad c, 1H). 136 NMR (125.688 MHz, SOCI3) amidine and carbonyl carbons: δ 173.1, 170.3, 168.1, 164.5. (her) RAIYUSN(ON)-S(O)-Age-Rab. 107 mg (0.214 mmol) RIKYUSN(OH)-C(O)-Age-Rab (72) from the previous operation (i) was dissolved in a TNE:water (2:1) mixture, 37 Ra/C (4 moles) was added and hydrogenated hours The solution was filtered and evaporated to dryness. The obtained white powder was added to 2000 ml of water acidified with 0.42 ml of 1.0 M NH (2 equivalents). The resulting solution was washed with 1 ml of ethyl acetate and 1 ml of diethyl ether and dried twice by sublimation. Yield 72 mg (8490) in the form of a white powder of purity 9195 (NRI C).

TN nMR (399.9968 MHz, 020): δ 7.57 (t, 2H), 7.36 (d, 1H), 7.32 (s, 3), 7.27 (s, 1H), 7.25 (d, 1H), 7.19 70 (d, 1H), 5.17 (s, 1H, most part), 5.09 (s, IN, smaller part), 5.00 (dd, 1, smaller part ), 4.38 (c, 2, major part), 4.20 (dd, 2H, major part), 3.98 (dd, 2H, minor part), 3.97 (m, 1H, major part), 3.75 (dd, 1H), 2.68 (s, IN, smaller part), 2.65 (m, 1H, smaller part), 2.35 (m, 1H, larger part), 2.12 (m , 1H, the greater part), 2.03 (m, 1H, the smaller part). 136 NMR (111.581 MHz, 029) amidine and carbonyl carbons: 5 174.5, 173.2, 172.5, 172 4.

Example 7. RA(4-CE3)-(K.5)CH(OH)-C(O)-Age-Ra x NOI. () RAI(4-СЕ53)-(К,5)СН(ОН)-С(О0)-Аге-Рац(7). The intermediate compound was prepared by the method according to the example of Ziii) from 0.19 g (0.88 mmol) of (K,5)-4-rifluoromethylmandelic acid with purification by flash chromatography on silica gel with methylene chloride.TNE (6:4) as eluent. Output in the form of white powder 0.13g (26965).

IN nMR (ZOOMHz, 020): 5 9.6-9.F2 (w/1H), 8.24 (pc, 1H, diastereomer), 7.9 (pc/1H, diastereomer), 7.7-71, 1 (m, 13H), 5.16 (s, 2H), H), 5.07 (s, 1H, diastereomer), 4.98 (s, 1H, diastereomer), 4.80 (m, 1H), 4.5-4.2 (m, 2H), 4.1-3.5 (m, 2H), 2.5-2.2 (m, 2H). 13C NMR (75 MHz, SOCI3) of amidine and carbonyl carbons (diastereomers): 5 173.3, 172.4, 170.3, 168.3, 164 )CH(OH)-C(O)-Age-Rab x NS. The target compound was prepared by the method of example 1(m), from 133 mg (0.2 mmol) of РНА(4-СЕ3)-(К,5)СН(ОН)-С(О)-Аге-Rаб(7) from the previous operation (i) with a yield of 77 mg o) (7095) in the form of a white crystalline powder.

TN NMR (Z00MHC, 050): δ 8.84 (m, 1H, diastereomer/rotamer), 8.73 (m, 1H, diastereomer/rotamer), 8.52 (m, 1H, diastereomer/rotamer), 7, 8--4 (m, 8H), 5.46, 5.44, 5.30, 5.20 (singlets, 1H, rch- diastereomers/rotamers), 4.96 (m, 1H, overlapping diastereomer/rotamer with NOB signal), 4.6-4.0 (m,

AN), 2.65-2.45 (m, 1H), 2.9-2.5 (m, 1H), 2.4-2.1 (m, 1H). 13C NMR (75 MHz, 020) of amidine and carbonyl carbons (diastereomers and rotamers): δ 173.6, 173.3, 173.1, 173.0, 172.9, 167.0. -

Example 8. PH(4-OMe)-(K.5)CH(OH)-C(O)-Age-Rab x NOI. () PH(A-OMe)-(E.5)CH(OH)-C(O)-Age-Rac(7). The intermediate compound was prepared by the method of Example C(ii) from 018 g (1.00 mmol) of (K,5)-4-methoxymandelic acid with purification by flash chromatography on silica gel with ethyl acetate:methanol (95:5) as eluent. Output in the form of white powder 27 mg (17965).

The ratio of diastereomers is 85:15, signals from the larger diastereomer: "

TN nMR (400 MHz, SOCI8): 5 8.19 (m, 1H), 7.80 (d, 2H), 7.45 (d, 2H), 7.4-7.2 (m, 7H), 7 ... ,9-4.85 (m, 2H, from this a singlet at 4.89 (1H)), 4.6-4.4 (m, 2H), 4.02 (m, 7H), 3.81 (s , ЗН), 3.55 (m, "» 1H), 2.62 (m, 1H), 2.32 (m, 1H). " 13C NMR (100 MHz, SOCI3) amidine and carbonyl carbons: 5 173.6 , 170.3, 167.8, 164.6. i) Pn(A-Ote)xk.5)CH(OH)-C(0)-Age-Par x NOSI. The target compound was prepared by the method of example b" 395 1(9), from 27 mg (O0.05 mmol). RI(4-OMe)-(K,5)CH(OH)-C(O)-Age-Rac(7) from the previous operation () with a yield of 15 mg (68905) in the form of a white powder. -th The ratio of diastereomers is 85:15, signals from the diastereomer that is larger: o To NMR (400 MHz, 020): δ 7.7-7.6 (m, 2H), 7.5-7.3 (m, 4H) , 7.18 (d, 2H, rotamer), 6.97 (d, 2H, 20 rotamer), 6.9-6.85 (m, 2H, rotamer), 5.19 (c, 1H, rotamer), 5.14 (c, 1H, rotamer), 5.01 (m, IN, o rotamer), 4.76 (m, 1H, rotamer), 4.48 (c, 1H, rotamer), 4.3-3 .7 (m, 7H, from this 2 singlets at 3.78, 3.77

I (ZH)), 2.73 (m, 1H, rotamer), 2.46 (m, 1H, rotamer), 2.3-2.0 (m, 1H). 136 YaMe (75MGu, 020) amidine and carbonyl carbons (rotamers): 5 175.5, 174.1, 173.3, 1731, 167.1, 167.0.

Example 9. PH(4-OH)-(K.5)CH(OH)-C(O)-Age-Rab x NOI. () Ry(4-OH)-(K.5)CH(OH)-C(O)-Age-Rab(2). The intermediate compound was prepared by the method according to the example of Ziya),

F, with 0.34 g (2, mol) of (H,5)-4-hydroxymandelic acid with purification by flash chromatography on silica gel with co-ethyl acetate:ethanol (9:1) as eluent. Output in the form of white powder 18 mg (17965). "YAN YaYamer (400 MHz, SOSI5): 5 7.70 (d, 2H, minor part of diastereomer/rotamer), 7.6b4(d, 2H, major part 60 of diastereomer/rotamer), 7.5-7.0 (m . ,30, 5.26, 5.22, 5.21 (singlets, 2H, diastereomers/rotamers), 4.95-4.8 (m, 2H), 4.15-4.05 (m, 2H), 4.0-4.0-3.7 (m, 2H), 2.7-2.5 (m, 2H). (i) RA(4-OH)-(K.5)CH(OH)- C(O)-Age-Rab x HC. The intermediate compound was prepared by the method of Example 65 1(m), with 34 mg (0.18 mmol) of PH(4-OH)-(K,5)CH(OH)-C( O)-Age-Rats(7) from the previous operation (i) yielding 37mg (49905) in the form of a white powder.

TN NMR (600 MHz, 020): 5 7.76, 7.72, 7.71, 7.68, 7.52, 7.47, 7.40, 7.35, 7.25, 7.19, 7 ,11, 6.97, 6.82, 6.76, 6.73, 6.71 (doublets, 8H, diastereomers/rotamers), 5.19 (s, 1H, diastereomer/rotamer), 5.17 (s , 1H, diastereomer/rotamer), 5.14 (s, 1H, diastereomer/rdtamer), 5.01 (m, 1H, diastereomer/rotamer), 4.88 (m, 1H, diastereomer/rotamer, other signals of such protons overlap with NOV signals), 4.6-3.8 (m, 4H), 2.717 (m, 1H, diastereomer/rotamer), 2.62 (m, 71H, diastereomer/rotamer), 2.49 (m , 1H, diastereomer/rotamer), 2.3-2.1 (m, 1H). 13C NMR (75 MHz, 020) of amidine and carbonyl carbons (diastereomers/rotamers): 5 175.9, 174.8, 174.3, 173.3, 173.2, 172.9, 167 1.

Example 10. RA-CH» (K)CH(OH)-C(O)-Age-Ra x HC. () Ry-CH"-"KYUSN(OH)-C(O)-Age-Rab(72). The intermediate compound was prepared by the method of Ziii) from 0.25 g (1.5 mmol) of (H)-phenyllactic acid. After purification by flash chromatography on silica gel with eluent

0.28 g (3695) of the product was obtained.

TN nMR (B500MHz, SOSIz): 8 8.19 (m, 1H), 7.72 (d, 2H), 7.43 (d, 2H), 7.4-7.1 (m, TON), 5 .19 (s, 2H), 4.73 19 (m, 1H), 4.45-4.25 (m, 2H), 4.19 (m, 1H), 3.86 (m, 1H), 3 ,18 (m, 1H), 3.0-2.9 (m, 2H), 2.42 (m, 1H), 2.14 (m, 1H). 136 NMR (125 MGu, SOSI3) amidine and carbonyl carbons: δ 174.5, 170.2, 167.9, 164.3. (i) RA-СНо-К)СН(ОН)-С(О)-Аге-Раб x НС. The target compound was prepared by the method of example (y), from 0.22 g (0.4 mmol). RY-SN-(K)CH(OH)-C(O)-Age-Rac(7) from the previous operation () with a yield of 101.5 mg (57905) in the form of a white powder.

TN NMR (600MGu, 029): 6 7.73 (d, 2H, of the greater part of the rotamer), 7.62 (d, 2H, of the smaller part of the rotamer), 7.5-7.4 (m, 2H), 7, 4-7.2 (m, 5H), 7.10 (m, 2H, a smaller part of the rotamer), 4.71 (m, 1H, a larger part of the rotamer), 4.5-4.4 (m, 2H), 4.34 (m, 1H, of the smaller part of the rotamer), 4.14 (m, 1H), 4.03 (m, 1H), 3.53 (m, 1H), 3.05-2.95 (m, 2H, of the greater part of the rotamer), 2.9-2.7 (m, 2H, of the smaller part of the rotamer), 2.65-2.5 (m, 1H, of the smaller part of the rotamer), 2.5-2.3 (m, 1H, of most of the rotamer), 2.3-2.1 (m, 1H). 136 YaMe (75MGu, 020) amidine and carbonyl carbons (rotamers): 5 175.9, 175.0, 173.7, 173.2, o 167.1, 166.8.

Example 11. CH-(QU)CH(OH)-C(O)-Ris-Rab.

Vos-Ris-OH was prepared according to M. Vodapz2ku 5 A. Vodapz2ku ("Te Rgasive oi Reride |i- 30 Zupipeviv", Zrhipdeg-Megiad), using TNE instead of dioxane. yu

TN NMR (300 MHz, SOSIz): 5 5.0-4.8 (width d,1H), 4.0 (width c1H), 3.0 (width d,1H), 2.20 (d,1H), 1.65 (m, 2H), 1.5-1.3 (stm, 13H). o (i) Vos-Ris-Rab(7). The intermediate compound was prepared by the method according to example (iii), from 2.02 g (8.8 mmol) "-

Vos-Ris-OH from the previous operation (i), 1.59 g (44965) of the product was obtained. 35 EAV-M5 t/ 495 (MA1)7 x,

TN nMR (400 MHz, SOSIz): 5 7.83 (d, 2H), 7.43 (d, 2H), 7.36-7.11 (m, 5H), 6.52 (shs, MH), 5 .20 (s, 2H), 4.81-4.72 (m, 1H), 4.61-4.34 (m, 2H), 4.10-3.90 (m, 1H), 2.70 -2.64 (m, 1H), 2.36-2.25 (m, 1H), 1.7-1.3 (m, 14H). (ii) H-Ris-Rab(7) x 2NSІ. 1.59 g (3.25 mmol) of Bos-Ris-Rab(7) from the previous operation (i) was dissolved in 100 ml of ethyl acetate saturated with NCI. Half an hour later, the reaction mixture was evaporated, obtaining the desired compound in 40 quantitative yield. no) with EAV-M5 t/ 395 (Ma1)7 :z» IN nMR (ZOOMHCts, 0590): 5 7.82 (d, 2H), 7.63-7.41 (m, 7H), 5.47 (c, 2H), 4.69-4.49 (AB- system centered on 5 4.59, 2H), 4.03 (dd, 1H), 3.52 (shd, 1H), 3.10 ( dt, 1H), 2.29 (dd, 1H), 2.08-1.61 (m, 5H). (m) H-Ris-Rac(2) was obtained by dissolving the dichloride from the previous operation (iii) in 2M Mahon with the following

Fu by extracting СНоСи» and evaporating the organic solvent. (m) cSp-(YUDSN(OH)-C(O0)-Ris-Rab(7) was obtained by the method of example C(i), from 0.152g (0.9bmmol) of (K)-hexahydromandelic acid and 0.417g ( 1.0 bmmol) of H-Rys-Rab(7) from the previous operation (im). Using flash chromatography on silica gel with the eluent, first ethyl acetate:toluene (3:2), then ethyl acetate, 9 Omg (1895) of the intermediate product was obtained. 1 IN nNMR (ZOOMHz, SOSI5): 6 7.82 (d, 2H), 7.5-7.2 (m, 7H), 6.63 (t, X-part of the AVX system, MH), 5, 21 (c, "M 2H), 5.14 (d, 1H), 4.46 (ABH-system, 2H), 4.26 (alleged - s, 1H), 3.61 (shd, 1H), 3 .52 (shd, 1H), 3.06 (dt, 1H), 2.30 (shd, 1H), 1.92-1.0 (m, 14H), 0.95-0.8 (m, 1H ). 136 NMR (75MHu, SOSI") amidine and carbonyl carbons: 5 174.8, 170.3, 167.8, 164.6. (mi) CH-SUDSN(OH)-C(O)-Ris-Rab x HC. The target compound was prepared by the method of example 1(x), from 5 µM g o (0.11 mmol) CA-(USCHN(OH)-C(O)-Ris-Rab(7) from the previous operation (m) with a yield 19 mg (4095) in the form of a white powder. name) EAV-M5 t/z 401 (M1)7

TN NMR (400 MHz, 020), the spectrum is complicated by the presence of rotamers: 5 7.91-7.72 (m, the larger and smaller parts of the 60 rotamer, 2H), 7.58 (d, 2H, the smaller part of the rotamer), 7.53 (d, 2H, most of the rotamer), 5.17 (estimated, 2H, most of the rotamer), 4.66-4.28 (m, ZH), 3.96 (shd, 1H, most of the rotamer), 3.26 (pc, 1H, the greater part of the rotamer), 3.05-2.88 (m, 1H, the smaller part of the rotamer), 2.39-2.20 (m, 1H), 2.0-0.75 (m, 16H). 136 NMR (75 MHz, Meord) amidine and carbonyl carbons: δ 175.86, 173.20, 168.53.

Example 12. SP-CH" "Kyu)CH(OH)-C(O)-Ris-Ra x NS. bo () Сп-СН (ЮСН(ОН)-С(О)ОН. A solution of 2.57 g of phenyllactic acid and 0.75 g of rhodium on aluminum in 17/Oml of methanol was hydrogenated in an atmosphere of No at a pressure of 3 atmospheres for 2 days. The mixture was filtered and evaporated to dryness, obtaining the product in quantitative yield.

TN nMR (400MHz, SOSIv): 5 4.23 (w dd, 1H), 3.24 (supposedly son), 1.68 (shd, 1H), 1.63-1.43 (m, bH), 1 ,43-1.31 (m, 1H), 1.21-1.0 (m, ЗН), 0.95-0.75 (m, 2H). (its) Сп-СНХ-(Х)СН(ОН)-С(О)-Рис-Раб(7). The intermediate compound was prepared by the method according to example (s), with

C5Zmg (0.7bmmol) H-Ris-RabB(7) x 2HCI from the previous operation (ii) of example 11, and 159mg (0.91mmol)

Сп-СНО-(ЮСН(ОН)-С(О)ОН) from the previous operation (ii) of this example. Using flash chromatography on silica gel with ethyl acetate-mitolluol (7:3) as an eluent, 92 mg (22965) of the product was obtained.

TN NMR (Z00MHZc, SOCI3): δ 7.72 (d, 2H), 746-7.1 (m, 7H), 6.90 (t, MH), 5.18 (s, 2H), 5.07 (d, 1H), 4.45 (shd, 71H), 4.37 (d, 2H), 3.73-3.47 (m, 2H), 3.10 (pc, 71H), 2.24 ( shd, 1H), 2.15-2.0 (m, 71H), 1.90 (shd, 1), 1.80-1.05 (m, 12H), 1.05-0.75 (m, ZN). 136 NMR (75 MGu, SOSIz) amidine and carbonyl carbons: δ 175.88, 170.43, 168.04, 164.58. (ii) CH-CHN (KISN(OH)-C(O)-Ris-Ra x HCIII.ss 136 NMR (75 MHz, 029) amidine and carbonyl carbons (rotamers): 6 177.10, 173.88, 173, 07, 167.24.

Example 13. RIA-IYUSN(OMe)-C(O)-Age-Rab x NOI. () N-Age-OME x NOSI. 200 ml of MeonN was cooled to -407"C in an argon atmosphere. 47.1g (0.39bmol) of thionyl chloride was added dropwise and the mixture was stirred at -107C for 35 minutes. 10.0g (0.099 mol) H-Ag2e-OH was added and the mixture was stirred at The reaction mixture was then evaporated to give 16.1 g (100965) of the desired compound.

TN NMR (400 MGu, SOSI»z): 5 5.12-5.24 (m, 1H), 4.08-4.29 (m, 2H), 3.84 (s, ЗН), 2.65- 2.87 (m, 2H). (its RAAUCN(OMe)-C(0)-Age-OMe. The intermediate compound was prepared by the method of example (ii), from 0.bOg (3.bmmol) K(-)-y-methoxyphenylacetic acid and 0.55g ( C3,bmmol) H-Age-OMe x NOI from the previous step (i) of this example.0.32g (3495) of the product was obtained.

TN nMR (SO0MHC, SOSIv8): 7.29-7.48 (m, B5H), 4.71-5.08 (m, 2H), 3.92-4.31 (m, 2H), 3.69 -3.83 (m, ZN), o 3.19-3.46 (m, ZN), 2.135-2.65 (m, 2H). (its) RIA-SUSN(OMe)-С(О)-Age-OH. A solution of 0.071g (1.7mmol) of lithium chloride monohydrate in bml of water was added to a solution of 0.32g (1.2mmol) of RA--SUCH(OMe)-C(O)-Age-OMe from the previous operation (ii) in 10ml of TNE . The reaction mixture was stirred for an hour and then evaporated. The residue was dissolved in water and extracted with toluene. The pH of the aqueous layer was adjusted to 3 with aqueous HCl followed by extraction with ethyl acetate (4 times). The combined organic layers were evaporated to give 0.28g (9290) of the desired compound. ("in

TN nMR (300 MHz, SOSIz): 5 7.30-7.50 (m, 5H), 5.18 (s, 2H), 4.95-5.10 (m, 1H), 4.80 (s, 1H), 4.10-4.35 - (m, 2H), 3.40 (s, ЗН), 2.40-2.80 (m, 2H). 3 (m) RIA-IESN(OMe)-C(O)-Age-Rab(7). The intermediate compound was prepared by the method according to example (i), with. (AT

O,Zbg (1.00mmol) H-Rac(2) x HCI and 0.25g (1.00mmol) РЙ-(КЮСН(ОМе)-С(О)-Аге-OH from previous operation (ii) of this example. 0.39 g (7695) of the product was obtained in the form of a white powder.

TN nMR (300 MHz, SOSIz): 5 8.29 (m, 1H), 7.77 (d, 2H), 7.45 (d, 2H), 7.4-7.2 (m, TON), 31 5.22 (s, 2H), « 4.93 (m, 1H), 4.69 (s, 1H), 4.44 (m, 2H), 4.15 (m, 2H), 3.35 ( c, ЗН), 2.69 (m, 1Н), 2.42 (m, 1Н). (y) RA--IYUSN(OMe)-C(O)-Age-Rar x NS. The target compound was prepared by the method according to example 1(x), with 0.15 g (0.29 mmol) of PA--SUUSCH(OMe)-C(O)-Age-Rac(7) from the previous operation (im). 50.4 mg (4190) of the product was obtained

In the form of a white powder.

TN nMR (400MHz, СО3О0): 5 7.8-7.6 (m, 2H), 7.6-7.4 (m, 2H), 7.4-7.1 (m, 5H), 4, 6-44 (m, 2H), 4.3-4.0 15 (m, 2H), 3.29 (s, 3, 2.75-2.5 (m, 1H), 2.4-2, 1 (m, 1H). bu Example 14. RA-(3-YUMe)-(K.5)CH(OH)-C(O)-Age-Ra x NOI. () RA-(3-YUMe)- (K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared by the method according to example - C(its), from 0.27 g (1.5 mmol) (K.5)- of 3-methoxymandelic acid. 0.34 g (4395) of the product was obtained. The ratio of diastereomers was 1:1. 50 EAV-M5 t/z 531 (Ma1)7 1 IN nNMR (400MHz, SOCI5): 5 8.14 (m, 1H, diastereomer), 7.87 (m, 1H, diastereomer), 7.8-7.0 (m, TON), "M 6.9-6.7 (m, ЗН), 5.16 (s, 2H), 4.96 (s, 1H, diastereomer), 4.88 (s, 1H, diastereomer), 4.85-4.7 (m, 1H), 4.4-4.2 (m, 2H) . (m, 71H, diastereomer), 2.5-2.35 (m, 71H), 2.32 (m, 1H, diastereomer), 2.20 (m, 1H, in diastereomer). 136 YaMe (75MGu, SOSIZz ) amidine and carbonyl carbons (diastereomers): 5 173.9, 173.0, 170.5, o 170.4, 168.3, 168.2, 164.5. co (i) Pb-(3-OMe)-(K.5)CH(OH)-C(O)-Age-Rab x HC. The target compound was prepared by the method of Example 1(m), from 0.23 g (0.4 μmol). РИ-(3-ХОМе)-(К,5)СН(ОН)-С(О)-Аге-Рац(2) from the previous operation (i). Received 126bmg 60 (6795) product. The ratio of diastereomers is 1:1.

EAV-M5 t/ 397 (M--1)"

TN NMR (400MGu, 020), the spectrum is complicated by the presence of diastereomers/rotamers and some impurities: 5 7.6-7.1 (m, 5H), 6.9-6.6 (m, ЗН), 5.2-4 .7 (m, 1-2H), 4.4-3.7 (m, 4-5H), 3.63 (s, 3H, diastereomer/rotamer), 3.55 (m, 1H, diastereomer/ rotamer), 2.5-2.3 (m, 1H), 2.2-2.0 (m, 1H). for 136 NMR (75 MHz, 020) amidine and carbonyl carbons (diastereomers): 5 175.8, 175.4, 174.8, 174.6,

168.5.

Example 15. RI-(3-Me)-(K.5)CH(OH)-C(O)-Age-Rabr x NOAc. () (K,5)-3-methylmandelic acid. A mixture of 12.0 g (0.1 mol) of 3-methylbenzaldehyde and 1.23 g (0.005 mol) of benzylthiethylammonium chloride in 1 bml of chloroform was stirred at 56"C. A solution of 25 g of Mahon in 25 ml of water was added dropwise to the mixture. After complete addition, the mixture was stirred for 1 hour, and then diluted with water to 4000 ml and extracted (3 x 5 ml) with diethyl ether. The pH of the mixture was adjusted to 1 with concentrated sulfuric acid and extracted (6 x 50 ml) with diethyl ether. The combined organic layers were dried with magnesium sulfate and evaporated. The crude product was recrystallized from toluene, yielding 8.47 g (5195) of the desired product.

IS-M5 t/ 165 (M-1)7.331 (2M-1)7 "H NMR (600 MGu, CO300): 5 7.10-7.28 (m, 4H), 5.08 (s, 1H), 2.32 (c, ZN). (its) RA-(3-Me)-(K.5)CH(OH)-C(0)-Age-Rab(7). The intermediate compound was prepared according to the method described in example 3(iii), with 0.22 g (1.33mmol) (K,5)-3-methylmandelic acid from the previous operation (iii).

0.37g (54965) of the product was obtained.

IIS-M t/: 515 (MA1)" "YAN nNMR (400MHz, SOSIv),: 8 8.11-8.21 (t, MH), 6.97-7.89 (m, 13Н), 5, 18-5.24 (m, 2H), 4.83-5.00 (m, 2H), 4.37-4.58 (m, 2H), 3.50-4.11 (m, 2H), 2.39-2.71 (m, 2H), 2.27-2.38 (m, ZN). (iii) Ryp-(3-Me)-(K.5)CH(OH)-C(O0)-Age-Rab x NOAc. Mixture 01o5g (0.20mmol)

RI-(3-Me)-(K,5)CH(OH)-C(O0)-Age-Rab(72), 0.012 g (0.20 mmol) of acetic acid and 0.14 g of 596 Ra/C in 12 ml of ethanol titrated at atmospheric pressure for 6 hours. The reaction mixture was filtered, the filtrate was evaporated. The crude product (97 mg) was dissolved in water and freeze-dried to obtain a sticky product, which was dissolved in NOAc and freeze-dried again to obtain a product without any improvement. The product was dissolved in water, passed through an NRI C-filter and 7 mg (7695) of the target compound was obtained by freeze-drying.

IS- M t/2 381 (MA)! ch 29 TN nMR (400 MHz, 020): δ 6.89-7.72 (m, 8H), 4.79-5.23 (m, 2H), 3.76-4.51 (m, 4H), 2.38-2.82 (m, 2H), He) 2.15-2.27 (m, ZN). 13C NMR (75.5 MHz, 050, complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons (diastereomers): 5 181.21, 175.43, 174.38, 173.94, 173.23, 172.16, 167, 00 m 20 Example 16. PA-(3-OE0-(K.5)CH(OH)-C(O)-Age-Ra x HOAc. () (B,5)-3-ethoxymandelic acid. 0.712g (4 .23 mmol) of (B.,5)-33-hydroxymandelic acid was dissolved in 15 ml of acetonitrile M. 2.34 g (16.94 mmol) of KSO" was added and 1.0 ml (12.71 mmol) of ethyl iodide was added dropwise.

The reaction mixture was refluxed for 2 hours and evaporated. The residue was dissolved in 25 ml of HNO and 1 ml of acetone and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated to obtain aqueous solution (the second layer was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with an aqueous solution of KNOZ, and water was added until the formed salts dissolved. The aqueous solution was extracted three times with ethyl acetate. The combined organic layer was washed with water, dried with NaClO); and evaporated. The residue was treated with KRIS (2595 acetonitrile:7595 0.1 M HOdAs) and fractions with the desired product were evaporated. The obtained aqueous solution was extracted three times with ethyl acetate. The combined organic layer was washed with water, dried with Ma»5O; and evaporated. « 20 The yield of the intermediate compound is 182 mg (2296). w-v s IIS-M5 t/ 195 (M-1)7.391 (2M-1)7.587 (3ZM-7)7 and "H NMR (400MGu, СО30О0): 5 6.89-7.27(m, 4H), 5.08 (s, 1H), 3.99-4.13 (m, 2H), 1.34-1.40 (t, ZN). "" (i) RIA-(3-YAYUOEDO- (K.5)CH(OH)-C(O)-Age-Rab (7). The intermediate compound was prepared according to the method described in example C(iii) from 0.178 g (0.907 mmol) (K.5) -Z-ethoxymandelic acid from the previous operation (iii).

259 mg (5295) of the product were obtained. (22) IIS-M t/: 545 (MA1)" - "YAN nMR (400 MHz, SOSI8),: 5 6.77-7.77 (m, 13Н), 5.16-5.21 (d, 2Н ), 4.78-4.99 (m, 2H), 4.27-4.51 (m, 2H), 3.53-4.07 (m, 4H), 2.21-2.60 (m , 2H), 1.29-1.41 (m, ЗН). (in (iii) RI--3-OEO-(K.5)CH(Ot-C(O)-Age-Par x NOAc. The target compound was prepared according to the method with 20 described in example 15(ii) , with 0.182g (0.3Zmmol) RIIA-(3-YUE0-(K,5)CH(OH)-C(O)-Age-Rab(7) from the previous operation (ii). Yield 157mg (10096). "m EAV-M5 ti/z 411 (MA1)7

TN nMR (400MHz, SOZON): 5 7.71-7.79 (m, 13H), 7.49-7.60 (m, 2H), 7.19-7.30 (m, 1H), 6, 94-7.02 (m, 2H), 6.81-6.90 (m, 1H), 5.09-5.18 (m, 71H), 4.74-4.81 (m, 1H), 4.39-4.62 (m, 2H), 3.93-4.35 (m, 4H), 2.21-2.60 (m, 29 2H), 1.29-1.41 (m, ZN).

HF) 13C NMR (100.6 MHz, 050, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbon (diastereomers): 5 180.68, 174.30, 173.50, 173.07, 172.44, 172.26.

Example 17. PA-(3-Orgk(n))-(K.5)CH(OH)-C(O)-Age-Ra x NOAc. in () (K,5)-3-allyloxymandolic acid. 0.504 g (3Z,Omol) of (K,5)-3-hydroxymandelic acid was dissolved in 2Bml of dry acetone. 0.907 g (7.5 mmol) of allyl bromide and 1.037 g (7.5 mmol) of dry K»CO3 were added, and the mixture was stirred under a nitrogen atmosphere for 16 hours, and then evaporated. The residue was dissolved in 25 ml of water and 1 ml of acetone and the mixture was stirred for 2 hours (followed by NRI C treatment). The mixture was evaporated and the resulting aqueous layer was extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 2 with an aqueous solution of KNHZO") and extracted three times with ethyl acetate. The combined organic layer was washed with water, dried (H2SO4) and evaporated. The yield of intermediate compound 65 was 175 mg (2895).

"H NMR (500 MGu, SOSIz): 5 6.87-7.30 (m, 4H), 5.97-6.10 (m, 1H), 5.26-5.44 (m, 2H), 5 .20 (c, 1H), 4.51-4.55 (d, 2H). Rab(7). The intermediate compound was prepared according to the method described in example C(ii) from 0.167 g (000.8 mmol) of (K,5)-3-allyloxymandolic acid from the previous operation (i). Yield 26 0mg (58905 ) of the product.

TN nMR (B500MHz, SOSIz): 85 8.09-8.17 (t, MH), 6.79-7.87 (m, 13H), 5.94-6.09 (m, 1H), 5, 20-5.44 (m, 4H), 4.86-5.02 (m, 2H), 4.32-4.62 (m, 4H), 3.54-4.15 (m, 2H), 2.30-2.74 (m, 2H). (ii) RI-(3-ORn))-(K.5)CH(OH)-C(O)-Age-Par x NOAc. The target compound was prepared according to the method described in Example 15(ii) from 0.0 bg (0.1 mmol) of Ry-(3-ORG(iso))-(K,5)CH(OH)-C(O) -Age-Rab(7) from the previous 70 operation (ii). Output 47mg (97960).

IIS-M5 t/ 425 (M--1)-,423 (MAT)

TN NMR (B5O0MHC, 020), 5 6.70-7.71 (m, 8H), 4.70-5.25 (m, 2H), 3.78-4.53 (m, 6H), 2, 05-2.80 (m, 2H), 1.56-1.75 (m, 2H), 0.82-0.95 (m, ZN).

Example 18. RA-(3-OR (iso))-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. 12 (i) (K,5)-3-isopropoxymandelic acid. The intermediate compound was prepared according to the method described in example 16(i) from 0.70 g (4.16 mmol) of (K,5)-3-hydroxymandelic acid, 5.87 g (16.65 mmol) of C5»CO»3 and 1 .25 Mml g (12.49 mmol) of isopropyl iodide. Received 6b2mg (7905) of product.

IS-M5 t/ 209 (M-1)"

TN NMR (400 MHz, COzO0): 5 6.81-7.25 (m, 4H), 5.08 (s, 1H), 4.53-4.64 (m, 1H), 1.28-1 ,32 (d, 6H). 720 (her). RA-(3-OR piso))-(K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared according to the method described in example C(iii) from 0.063 g (0.3 mmol) of (K,5)-3-isopropoxymandelic acid from the previous operation (I). Output bOmg (3490) of the product.

IIS-M t/: 559 (МА1)" sch

TN nMR (400MHz, SOSIz): 5 6.75-7.79 (m, 13H), 5.18-5.24 (m, 2H), 4.81-4.99 (m, 2H), 4, 31-4158 (m, ZN), 3.97-4.15 (m, 1H), 3.55-3.77 (m, 1H), 2.24-2.64 (m, 2H) 1.23 -1.33 (m, 6H)., i) (her) | PA-(3-ORiso))-(K.5)CH(OH)-C(O)-Age-Par x NODAs. The target compound was prepared according to the method described in Example 15(ii) from 0.05 g (0.090 mmol) of Rpy-(3-Org(iso))-(-k,5)CH(OH)-C(O) -Age-Rats(7) from the previous operation (ii). Output 41mg (9496). h-

I c-MZt/2425(Ma1)7

TN nMR (400 MHz, CO3O0): 5 6.81-7.80 (m, 8H), 5.08-5.18 (m, 1H), 4.74-4.80 (m, 1H), 4 ,53-4.64 (m, 2H), yuyu 4.41-4.51 (m, 1H), 3.93-4.35 (m, 2H), 2.23-2.60 (m, 2H ), 1.25-1.32 (m, 6H). av) 13C NMR (100.6 MHz, 050, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and "-carbonyl carbons (diastereomers): 5 181.10, 173.60, 173.15, 172.48, 166.39 .

Example 19. PA-(2-OMe)-(K.5)CH(OH)-C(O)-Age-Ra x NOAc. (Se) (). RA-(2-OMe)-(K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared according to the method described in example Ziii) from 0.18 g (1.00 mmol) of (K,5)-2-methoxymandelic acid. Received 8Omg (17905) of the product.

TN NMR (500 MHz, SOSIv): 5 8.16-8.22 (t, MH), 6.81-7.85 (m, 13H), 5.16-5.20 (m, 2H), 4 ,79-4.91 (m, 1H), « 4.35-4.49 (m, 2H), 4.02-3.84 (m, 2H), 3.63-3.80 (m, ЗН ), 3.32-3.56 (m, 1H), 2.21-2.57 (m, 2H). (i) Ri--2-OMe)-(K.5)CH(OH)-C(O)-Age-Par x NOAc. The target compound was prepared according to the method C c described in example 15(iii), with O0.08 g (0.15 mmol) Ry-(2-OMe)-(K,5)CH(OH)-C(0)- Age-Rab(7) from the previous one

From" operation (ii). 45mg (7195) of the product was obtained.

EAV-M5 t/ 397 (M--1)"

TN NMR (BOOMHC, 020): 5 6.83-7.70 (m, 8H), 4.71-4.97 (m, 1H), 4.34-4.51 (m, 2H), 4, 22-3.87 (m, ZN), p 75 367-375 (M, ZN), 2.74-2.0 (m, 2H). 13C, NMR (75.5 MHz, 02O, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 179.96, 176.28, 174.97, 174.50, 173.44, 173.39, 173.29, 173.10, 167.12. o Example 20. RII-(3.5-diOMe)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. 50 (). PA-(3.5-diOMe)-(K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared according to the method 1 described in example C(iii) from 0.21 g (1.00 mmol) of (K,5)-3,5-dimethoxymandelic acid, prepared according to the "M method described in (Zupipeziv (1974) 724), 0.31 mg (62905) of product were obtained.

ТN NMR (5О00МГцц, СОСИ3),;: 5 8.11-8.16 (t, МН), 7.17-7.86 (m, 9Н), 6.41-6.49 (m, ЗН), 5.21-5.24 (d, 2H), 4.84-5.03 (m, 2H), 4.29-4.66 (m, 2H), 4.17-3.67 (m, 8H ), 2.32-2.72 (m, 2H). (i) PA-(3.5-dioMe)-(K.5)CH(OH)-C(O)-Age-Par x NOAc. The target compound was prepared according to the method described in Example 15(ii) from 0.15 g (0.27 mmol) of Rp-(3,5-diOoMe)-(K,5)CH(OH)-C(O0)- Age-Rab(7) from the previous one

IF) operation (s). 120Omg (10095) of product was obtained. name) "YAN nMR (500 MHz, 050): 5 7.34-7.75 (w 4H), 6.44-6.66 (m, ЗН), 4.67-5.12 (m, 1H), 3.97-4.55 (m, 5H), 3.79 (s, ЗН), 3.71-3.74 (m, ЗН), 2.14-2.85 (m, 2Н). 60 13С NMR (75.55 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 181.17, 174.85, 173.92, 173.53, 173.09, 172.98, 182.90 , 166.77.

Example 21. RA-(3-OMe.4-OH)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. () RA-(3-OMe.4-0OH)-(K.5)CH(OH)-C(OH)-Age-Rab(7). The intermediate compound was prepared according to the method described in example C(iii) from 0.20 g (1.Omol) (K,5)-4-hydroxy-3-methoxymandelic acid. Received 8U9mg bo (16905) of product.

IIS-M5 t/ 547 (M--1)7,545 (M-1)7

TN nMR (400 MHz, SOCI8): 5 8.07-8.15 (m, MH), 6.64-7.86 (m, 12H), 5.20-5.27 (m, 2H), 3 .57-5.00 (m, OH), 2.31-2.74 (m, 2H). (its PA-(3-OMe.4-0OH)-(K.5)CH(OH)-C(O)-Age-Rav och HOAc. The target compound was prepared according to the method described in example 15(iii) , with 0.085 g (0.1 mmol) Ry-(3-OMe,4-0H)-(K,5)CH(OH)-C(O)-Age-Rac(7) from the previous operation (iii). Obtained 57 mg (78905) of product.

EAV-M5 t/ 413 (M--1)k "YAN yaYAMe (400MGu, 020), the spectrum is complicated by the presence of diastereomers/rotamers: 5 6.66-7.83 (m, 8Н), 70 5.25-4, 8 (m, 2H), 4.59-3.88 (m, 4H), 3.68-3.88 (m, 3H), 2.85-2.10 (m, 2H). 13C NMR (75 ,55 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 182.01, 175.56, 174.43, 174.04, 173.20, 173.05, 166.90, 166.85.

Example 22. RA-(2-E.5-CE3)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. (). RA-(2-E.5-CE53-(K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared according to the method described in example C(iii), with O,Zg (1.2 mmol) of (K,5)-2-fluoro-5-trifluoromethylmandelic acid, prepared according to the method described in Ogo. Zupij. SOII. 336. 0.32 g (5195) of the product were obtained.

EAV-M5 t/ 587 (Ma1)7

TN nMR (400 MHz, SOSIz): 85 7.15-7.87 (m, 12H), 5.19-5.30 (m, 2H), 4.87-5.00 (m, 1H), 4 .36-4.60 (m, ЗН), 4.05-4.20 (m, 1Н), 3.60-3.73 (m, 1Н), 2.32-2.72 (m, 2Н) . (i) RA-(2-E.5-CE3)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. The target compound was prepared according to the method described in example 15) , with 0.15 g (0.2 mmol) RI-(2-E,5-CE3)-(«K,5)CH(OH)-C(O0)-Age-Rab(7) from the previous operation (i) 110mg (9095) of the product was obtained.

NN NMR (500 MHz, 020): 65 7.28-7.83 (m, 7H), 5.43-5.65 (m, 1H), 5.18-4.82 (m, 1H), 4, 56-3.97 (m, 4H), sch 2.85-2.14 (m, 2H).

Zb NMR (75.5 MHz, 02O, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and o carbonyl carbons: 5.173.61, 173.33, 173.06, 172.83, 172.68, 172.62, 166, 86, 164.27, 161.15, 160.92.

Example 23. RA-(«K.5)SCHEO(OH)-C(O)-Age-Ra x NOAc. () RA-(K.5)SSEC(OH)-C(0)-Age-Rab(7). The intermediate compound was prepared by the method of example C(her), 3 parts of 0.18 g (1.Omol) (P,5)-2-hydroxy-2-phenylbutanoic acid. Received 7U9mg (15965) of product.

IIS-M ti/z 529 (Ma-1)7,527 (M-1)k yu

TN nMR (400 MHz, SOCI3);: 8 7.27-7.86 (m, 14H), 5.22 (s, 2H), 4.82-4.93 (m, 1H), 4.39-4 .57 (m, 2H), Ф 3.84-3.98 (m, 2H), 2.02-2.64 (m, 4H), 0.86-0.93 (m, ЗН). "-- (its RA-(K.5)SSECO(OH)-C(O)-Age-Par x NOAc. The target compound was prepared by the method according to the example

From 15(i), with 0.08g (01bmmol) RI-(K,5)C(EC(OH)-C(O)-Age-Rab(7) from the previous operation (). 6b2mg re) was obtained (90905 ) of the product.

TN nMR (400 MHz, 020): δ 7.27-7.84 (m, 9H), 5.35-4.83 (m, 1H), 4.60-3.89 (m, 4H), 2, 40-2.61 (m, 1H), 1.95-2.30 (m, ЗН), 0.78-0.95 (m, ЗН). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 182.09, 175.79, 175.48, 173.53, 173.23, 167.05. c Example 24. RA-(К.5)С(МехОН)-С(О)-Аге-Рах НОАс. :z» () RA-(K,Z)C(MechoOH)-C(0)-Age-Rab(2). The intermediate compound was prepared by the method of Ziii) from 0.2 g (1.2 mmol) of (K,5)-2-hydroxy-2-phenylpropanoic acid. 0.17g (3195) of the product was obtained.

TN NMR (5О0МГц, СОСИ3);: 5 8.04-8.14 (m, МН), 7.17-7.80 (m, 14Н), 5.20 (s, 2Н), 4.76-4 .86 (m, 1H),

F 4.31-4.50 (m, 2H), 3.76-3.94 (m, 2H), 2.19-2.44 (m, 2H), 1.70 (s, ЗН). (its Ry-«K,5)C(MechOH)-C(O)-Age-Rar x NOAs. The target compound was prepared by the method according to example - 15(iii), from O08g (0.1 mmol) RIA-(K,5)C(MekhOH)-C(0)-Age-Rab(7) from the previous operation (I). 48 mg o (7890) product was obtained. The ratio of diastereomers is 85:15. sl 50 TN NMR (500 MHz, 020): δ 7.30-7.79 (m, 9H), 4.82-3.99 (m, 5H), 2.09-2.74 (m, 2H), 1.70-1.77 (m, ZN). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl "m carbons: 5 176.90, 176.34, 173.89, 173.48, 167.00.

Example 25. RA--YUSN(OH)-C(O)-Age-Ras x NOAc. () Vos-Age-O5y. A mixture of 5g (25mmol) Vos-Age-OH and 2.88g (25mmol) NOBZ in 25ml TNE was cooled in an ice bath and 4.3ml (25mmol) EOS was added, the solution was stirred overnight, then evaporated and dissolved

F! in ethyl acetate, washed with aqueous 04 M KNHSO), then 1095 Ma»CO3, dried with Mo9504 and evaporated.

Recrystallization from ethyl acetate:petroleum ether gave 3.78 g (5195) of the intermediate compound. o TN nMR (SO0MHZc, 020): δ 4.89 (m, 1H), 4.07 (m, 1H), 3.95 (m, 1H), 2.85 (s, 4H), 2.67 ( m, 1H), 2.45 (m, 1H), 1.42 (c, 9H). 60 (th) Vos-Age-Ras(7). A mixture of 0.2 ml (1.44 mmol) of triethylamine, 0.194 g (0.bbmmol) of Vos-Age-O5Y and 0.277 g (0.6 mmol) of H-Ras(72) x 2HCl in 100 ml of TNE was stirred at room temperature for 18 hours, then evaporated and the residue was dissolved in ethyl acetate. It was filtered through a brownmillerite briquette and chromatographed on a silica gel column with ethyl acetate:TNE (2:11). The eluent was evaporated, the residue was dissolved in ethyl acetate, washed with water, dried (Mao) and evaporated to give 0.250 g (8190) of the intermediate compound. 65 "YAN iNMR (Z00MHz, SOSI8): 5 7.4-7.2 (m, 5H), 5.05 (s, 2H), 4.55 (pc, 1H), 3.85 (shk, 1H ), 3.72 (shk, 1H),

3.2-3.0 (m, 2H), 2.4-2.2 (m, 2H), 2.10 (m, 1H), 1.9-1.7 (m, 4H), 1, 5-1.3 (m, 11Н, their s at 1.37, 9Н), 1.0-0.8 (m, 2Н). (iii) H-Age-Ras(2). The intermediate compound was produced by the method of example C(i), from Vos-Age-Ras(7) from the previous operation (ii) followed by alkaline extraction treatment. (m) RAAYUDSN(OOTVOM5)-S(O)-Age-Ras(2). The intermediate compound was prepared by the method according to example (iii), from 0.236 g (0.869 mmol) of RA--IIHUCHN(OTVOM5)-C(OOH, prepared by the method described by Natada et al. in U. At. Spets. os. (1989 )111,669, and 0.25 g (0.53 mmol) of H-Age-Ras(2) from the previous operation (iii), previously activated by stirring for 30 minutes in СНоСи».trifluoroacetic acid (1:1, 1 Oml). Yield 1 bOmg (48965).

TN about NMR (B5O00MHz, SOSI5);: 5 7.44-7.2 (m, 1OH), 5.22 (s, 1H), 5.16-5.06 (m, 2H), 4.90- 4.80 (m, 1H), 70 4.43-3.92 (m, 2H), 3.12-2.88 (m, 2H), 2.60-2.35 (m, 2H), 2 ,10-1.25 (m, 1OH), 0.94-0.84 (m, 9H), 0.15-0.00 (m, 6H). (m) РА--"ЮСН(ОН)-С(О)-Аге-Ras x HOAc. The target compound was prepared by the method of Example 15III) from 0.16 g (0.25 mmol) of RIA-ЮСН(ОТВОМ5)-С( O0)-Age-Raf(7) from the previous operation (im) with purification of KRI C 15 mg (14905) of the product was obtained.

EAV-M5 t/2 373(M1)7

Example 26. RA-SKYUSN(OH)-C(O)-Age-Rid x NOAc. (Y) Vos-Age-Rid (7). The intermediate compound was prepared by the method according to example (iii), from 1.03 g (5.12 mmol)

Vos-Age-OH, see example 1(i), and 0.25 g (0.5Z3mmop) of H-Ryd(7) x 2HCII, prepared in the manner described in the international publication UUO 94/29336. Output 1.24g (5196).

TN nMR (400 MHz, SOSIz);: 8 7.43-7.27 (m, 5H), 5.12 (s, 2H), 4.67-4.60 (t, 1H), 4.26-4 ,16 (d, 2H), 3.86-3.95 (m, 1H), 3.82-3.74 (m, 1H), 3.30-3.11 (m, 2H), 2.89 -2.78 (m, 2H), 2.52-2.33 (shs, 1H), 1.83-1.71 (m,

ЗН), 1.44 (с, 9Н), 1.29-1.15 (m, 2Н). (i) H-Age-Reed(2) x 2CARRIERS. 1.2 g (2.53 mmol) of Vos-Age-Rid(7) from the previous operation () was mixed in 7 bml of ethyl acetate saturated with HCl at room temperature for 1 hour, then evaporated and the residue was diluted with water and extracted with ethyl acetate. The aqueous layer was dried by sublimation, obtaining 1.085 g (9690 s) of the target compound. at

TN nMR (BO0MHz, СО53О0): δ 7.46-7.32 (m, 5H), 5.28 (s, 2H), 5.05-4.99 (t, 1H), 4.16-4, 08 (d, 2H), 3.99-3.91 (m, ЗН), 3.25-3.13 (m, 4H), 2.88-2.79 (m, 1H), 2.57- 2.47 (m, 1H), 1.96-1.82 (m, ЗН), 1.26-1.40 (m, 2H). (ii) RAIYUSN(OTVOM5)-S(O0)-Age-Raf(7). The intermediate compound was prepared by the method of example 25(ih), from 0.401 g (1.5 mmol) of RIA--YUSN(OTVOM5)-C(O)OH and 0.672 g (1.5 mmol) of H-Age-Rid(7) with previous operation(s). in

Exit ZBOmg (4695). yu

IIS-M5 t/ 508 (M.-1)7.530 (MaeMa)" (m) RA--KYUSN(O)-C(OH)-Age-Rid(7) x NOAc. The target compound was prepared by the method of Example 15iii ) from 0.1 g (0.197 mmol) RA-IIUDSN(OTVOM5)-C(O)-Age-Rid(2) from the previous operation (ii) with KRIS purification. 81 mg (9595) of the product was obtained.

IS-M5 t/2 374 (MAT) and

TN nMR (400MHz, CO3O0): δ 7.25-7.50 (m, 5H), 5.15 (s, 2H), 4.65-4.75 (m, 1H), 4.25-4, 35 (m, 1H), 3.80 4.00 (m, ЗН), 2.95-3.50 (m, 4H), 2.05-2.50 (m, 2H), 1.75-1 .90 (m, ZN), 1.15-1.30 (m, 2H).

Example 27. RA-(K)CHNO)-C(O)-Pho-(K.5)Niide x HOAc. « 20 () NeK.Z) Nid x 2NSI. The intermediate compound was prepared by the method according to example C(1), from Bos-(K,5)Nido(2), Uc was prepared according to the method described in the international publication UUO 94/29336. (its RAATAVIOUSN(OTVOM5)-C(O0)-Pho-OVp. The intermediate compound was prepared by the method according to example (ii), from 2.0 g:z" (8.2 mmol) of I-proline benzyl ester hydrochloride and 2.0 g ( 7.51 mmol) RA-(IYUSN(OTVOM5)-С(ООН, prepared by the method described by Nataaa ei ai. in 9). At. Spect. 5os. (1989) 111 669. Yield 2.0 g (59905).

TN nMR (B5O00MHZc, SOSIv);: 8 7.22-7.55 (m, 10OH), 5.45 (s, 1H), 4.45-4.55 (m, 1H), 3.70-3 .82 (m, 1H), b 3.05-3.15 (m, 1H), 1.65-2.15 (m, 4H), 1.83-1.71 (m, ЗН), 0, 85-1.05 (m, 9H), 0.00-0.22 (m, 6H). (its RIA-"YUSN(OTVOM5)-C(0)-Rho-OH. A mixture of 1.9 g (419 mmol) RA-"YUSN(OTVOM5)-C(0)-Rho-OVp o/z - previous stage (its ) and 0.21 g of 1095 Ra/C in 8 Oml of ethanol were hydrogenated at atmospheric pressure for 3 hours, filtered through brownmillerite and the filtrate was evaporated. The yield of the desired compound was 1.36 g (0.91965). sl 50 IS-M5 t/ 362 (M -1)"

TN about NMR (B5O00MHz, СО53О0): 5 7.20-7.50 (m, 5H), 5.45 (s, 1H), 4.30-4.40 (m, IN), 3.30-3 .70 (t, 2H), which is 1.75-2.30 (t, 4H), 0.85-1.00 (m, 9H), 0.00-0.20 (m, 6H). (m) RNNIIUDSN(OOTVOM5)-С(О)-Рго-(К.5)НИиЯя(2). The intermediate compound was prepared by the method of example 25(im), with 0.36 bg (100 mmol). RA--KYUSN(OTVOM5)-C(0)-Rho-OH from the previous operation (ii) and 0.3 bg (1.00 mmol)

H-(K,5)Nid x 2HCI from the previous operation (i). The yield of the raw product, which was used without further purification in the next operation, was 0.63 Zg.

IS-M5 t/2 636(MAT) and 136 NMR (100.5 MGu, SOSI3) amidine and carbonyl carbons: 5 171.57, 171.20, 163.79, 159.22. (M). RA--KYUSN(OH)-C(O)-Pho-(K.5)NiYA(2). Mixture 0.63g (Immol). RI--(K)CH(OTVOM5)-C(O)-Pho-(K,5)Nid(2) from 60 of the previous operation (m) and 1 Oml of 2095 TEA solution in dichloromethane were stirred for 3 hours at room temperature. The pH of the reaction mixture was adjusted to 9 with aqueous K»CO» and successively extracted with dichloromethane.

The combined organic layer was dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography on a column with silica gel (40 g) with eluent: 00 ml of dichloromethane, 100 ml of dichloromethane:ethanol (95:5) and 300 ml of dichloromethane:ethanol (9:1). The yield of the intermediate compound was 138 mg (2695). because IS-M8 t/h 522("MA)"

136 NMR (100.5 MHz, SOCI3) amidine and carbonyl carbons: δ 172.21, 171.20, 163.64, 159.11. (E). RA--KYUCHN(OH)-C(O)-Pho-(K.5)Nid x NOAc. The target compound was prepared by the method of Example 15(iii) from 0.071 g (0.14 mmol). РІ--«KH)CH(OH)-C(O0)-Pho-(K.5)Nid(7) from the previous operation (m). 49mg (8095) of product was obtained.

IS-M5 t/2 Z388(M 1)

TN NMR (400 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers): δ 7.32-7.56 (m, 5H), 5.37-5.52 (m, 1H), 4.32-4.64 ( m, 1H), 3.57-3.75 (m, 2H), 3.24-3.56 (m, 4H), 2.89-3.15 (m, 2H), 1.25-2, 80 (m, 9H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl 70 carbons: δ 181.92, 174.92, 173.69, 173.03.

Example 28. PA-""K)CH(OH)-C(O)-Pho-Oide x HOAc. by example 25(im), with 0.23 g (0.608 mmol) PA--IIUSN(OTVOM5)-C(O)-Pho-OH, see example 27(ii), and 0.14 g (0.507 mmol) H-bid (2), see international publication MO 94/29336 Yield of crude product used without further purification in 12 subsequent operations, Z16bmg.

And C-M5 t/2 622(M1)" (its RAAEZCHN(OH)-C(O)-Pho-Oid(2). Up to 0.315g (0.50 bmmol) RA-IK)CH(OTVOM5)-C( O)-Rho-Oide (7) from the previous operation (i) was added at 0"C with 2095 ml of a solution of hydrofluoroacetic acid in dichloromethane, the mixture was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 8 with aqueous KSO" and extracted with dichloromethane. The organic layer was washed with aqueous Massey, dried over sodium sulfate and evaporated. 250 mg of the crude product was purified by flash chromatography on a silica gel column with the eluent: dichloromethane:methanol (9:1).

Intermediate compound yield 18Omg (7090). NMR (400 MHz, SOSI8): 5 7.25-7.39 (m, 10OH), 5.32-5.37 (shs, 1H), 5.08-5.19 (m, 2H), 4.40-4.49 (m, 1H), 4.21-4.35 (m, 2H), 3.87-4.03 (m, 2H), 3.71-3.79 (m, 2H ), 3.18-3.32 (m, 2H), 3.00-3.10 (m, 1), 2.61-2.73 (m, cm 1H), 2.14-2.24 ( m, 1H), 1.62-2.07 (m, 8H). (o) (its) RA-IIUDSN(OH)-C(O)-Pho-OiId x HOAc. The target compound was prepared by the method of example 15iii ) from 0.14g (0.27bmmol) of RA-IIHUCHN(OH)-C(O)-Rho-Oide(2) from the previous operation (ii). 112 mg (9495) of product was obtained.

TN nMR (400MHz, СО53О0): δ 7.27-7.44 (m, 5H), 5.34 (s, 1H), 4.29-4.35 (m, 1H), 4.17-425 ( m, 2H), chn zo 375-383 (m, 2H), 3.63-3.73 (m, 1H), 3.25-3.34 (m, 1H), 3.08-3.23 ( m, 2H), 2.79-2.90 (m, 1H), 1.71-2.10 (m, 6H). 136 NMR (75.5 MHz, СО3О0) amidine and carbonyl carbons: δ 174.79, 173.26, 158.16. at

Example 29. RI-)CH(OH)-C(0O)-(6K or 5)Ris(cis-4-Me)-Par x NOAs and RI-P)CH(OH)-C(0)-(5 or F

Yuriis(ips-4-Me)-Ra x NOAs. (). (K.5)-M-Os-Rys(cis-4-Me)-Rab(7). The intermediate compound was prepared by the method according to example (ii), with - 0.88 g (4.1 mmol) of (K,5)-M-Boc-Rys(cis-4-Me)-OH, prepared by the method described in 9). Oh Spent (se) (1990) 55 738. Output 405mg (1990).

EAV-M5 t/2 509 (IM1)7

TN NMR (400MHz, SOSIz);: 5 7.25-7.90 (m, 9H), 5.20 (s, 2H), 4.45-4.50 (m, 2H), 4.30-4 .40 (m, 1H), « 3.15-3.70 (m, 2H), 1.70-2.00 (m, 4H), 1.45 (s, 9H), 1.30-1, 15 (m, 1H), 0.90-1.05 (m, ZN). () H-(K.5)Ris(cis-4-Me)-RabB(2). 040 g (0.79 mmol) of (K,5)-M-Voc-Rys(cis-4-Me)-Rab(7) from operation (1) was dissolved in 5 ml of dichloromethane, 5 ml of trifluoroacetic acid was added and the mixture was stirred 0, 5 hours, then evaporated and the residue was dissolved in dichloromethane, washed with aqueous NaCl, dried with magnesium sulfate and evaporated. The crude product was purified by flash chromatography on a silica gel column with dichloromethane:methanol (95:5) and dichloromethane:methanol (9:1) as eluent. Yield of intermediate compound ZOOmg (94905).

EAV-M8 t/: 409("MA1)

Me. "No NMR (500 MHz, cСОr300): δ 7.25-7.85 (m, 9H), 5.15 (s, 2H), 4.35-445 (m, 2H), 2.55-3.60 (m, ЗН), - 1.85-2.05 (m, 1Н), 1.35-1.65 (m, 2Н), 0.90-1.20 (m, 5Н). OTVOM5)-C(O0)-(K,5)Ris(cis-4-Me)-Rab(7). The intermediate compound was prepared by the method of example C(i), with 0.290 g (0.7 mmol) of H- (K,5)Ris(cis-4-Me)-RabB(7) from the previous operation (iii) and 0.189 g of sl 20 (0.71 mmol) PH-IIUDSN(OOTVOM5)-C(O)OH, prepared by the method , described by Natadaa ei ai. in U. At. Spet. os. (1989) 111 669. The yield of the crude product, which was used without purification in the next operation, 0.40 Og.

What (im) RIA-"ISN(OH)-C(O)-(K,Z)Ris(cis-4-Me)-Rats(2). 0.40 g raw

РА--CH(ОТВОМ5)-С(О)-(К,)Ris(cis-4-Me)-Rab(7) from the previous operation (ii) was treated from 2090 with a solution of trifluoroacetic acid in dichloromethane. The mixture was evaporated and the residue was purified 29 by flash chromatography on a silica gel column with eluent: dichloromethane:imethanol (95:5) and

HF) dichloromethane:methanol (98:2, 95:5, 9:1). The yield of the intermediate compound was 45 mg (11 95). (m) Ry-"TOCH(OH)-C(O)-(K or 5)Ris(cis-4-Me)-Rab x NOAs and Ry-"YUSN(OH)-C(O0)-(5 or URIis(cis-4-Me)-Rab x o NOAc. Mixture 0.045g (0.083mmol). RA-(QU)CH(OH)-C(O)-(K,5)Ris(cis-4-Me )-Rab(7) from the previous operation (im) and

O,Obg 595 Ra/C in ml of ethanol was hydrogenated for 2.5 hours at atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated. The crude product was subjected to preparative KRI C (0.1 M MNH.AOAc; 3095 acetonitrile), while diastereomers were separated. The yield of compound 29A with a diastereomer ratio of 299:1 was 7 mg, and compound 29B with a diastereomer ratio of 98:2 was 11 mg.

Compound 29A

I C-M5 t/2 409(M1)7, 407(M-1)7 b5 TN nMR (BO00MHz, 020): δ 7.20-7.80 (m, 9H), 5.65 (s, 2H ), 4.65-5.35 (m, 1H), 4.40-4.55 (m, 2H), 3.85-4.00

(m, 1H), 3.65-3.75 (m, 1H), 2.65-3.15 (m, 2H), 2.05-2.20 (m, 1H), 1.05-1 .75 (m, 2H), 0.70-0.90 (m, ЗН).

Compound 29B

IIS-M5 t/2 409(M-1)7, 407(M-1)7

TN nMR (B5O0MHC, 020): 5 7.25-7.80 (m, 9H), 4.55-5.75 (m, 2H), 4.35-4.50 (m, ЗН), 3, 75-3.85 (m, 1H), 2.70-2.80 (m, 1H), 1.80-2.20 (m, 1H), 0.70-1.70 (m, 6H).

Example 30. RA-"CH2)"-(K)CH(OH)-C(O)-Age-Rab x HC. () РА-(СНО"-"ЮСН(ОН)-С(О)-Аге-Рац(2). The intermediate compound was prepared by the method according to example Ж), from 0.434 g (0.988 mmol) of H-Аге-Rabf(7 /) x 2HCl from the previous operation (iii) and 0.162g (0.898mmol) 10. (K)-(-)-2-hydroxy-4-phenylbutyric acid, 0.433g (1.348mmol) TVTIi and 0.363g (3.59mmol ) of M-methylmorpholine in 15 ml of OME with a yield of 105 mg (2296).

IIS-M5 t/2 529(M-1)7, 527(M-1)7

TN NMR (500 MHz, SOSIv);: 8 8.17-8.25 (m, MH), 7.05-7.72 (m, 14H), 5.16-5.22 (m, 2H), 4 .71-4.88 (m, 1H), 4.32-4.41 (m, 2H), 3.92-4.04 (m, 2H), 3.79-3.88 (m, 1H) , 2.62-2.86 (m, 2H), 229-2.57 (m, 2H), 1.80-1.98 (m, 2H). (i) RA-ISNO»-(K)CH(OH)-C(O)-Age-Rab x NOI. The target compound was prepared by the method of Example 1(x) from 0.112 g (0.212 mmol). RA-"CH")"-(KYUCHN(OH)-C(O0)-Age-Rab(7) from the previous operation (iii). 77 mg (8496) of the product was obtained.

IIS-M5 t/2 395(M'-1)7, 393(M-1)7

TN nMR (400 MHz, CO300): δ 7.77-7.77 (m, 9H), 4.73-5.19 (m, 1H), 4.40-4.62 (m, 2H), 3, 92-4.34 (m, ЗН), 2.48-2.84 (m, ЗН), 2.09-2.33 (m, 1Н), 1.85-2.05 (m, 2Н). 13C NMR (100.6 MHz, 0250, the spectrum is complicated by the presence of rotamers) amidine and carbonyl carbons: δ 175.66, 174.80, 172.56, 172.49, 166.14, 165.87.

Example 31. 2-Naphthyl-"K,5)CH(OH)-C(O)-Age-Par x NOAc. c () (K,5)-2-naphthylglycolic acid. The intermediate compound was prepared by the method of example 15) from 15.6 g (10 mmol) of 2-naphthaldehyde with a yield of 12.37 g (61965). at

IS-M5 t/ 201 (M-1)7, 403(2M-1)7

TN NMR (500MHz, COzO0): δ 7.43-7.98 (m, 7H), 5.29-5.35 (m, 1H). (i) 2-naphthyl-"(K.5)CH(OH)-C(0)-Age-Rac(7). The intermediate compound was prepared by the method according to the example of Ziii), - from 0.162 g (0.vmmol) (B,8)-2-naphthyl glycolic acid from the previous operation (i) with a yield of 26 bmg (6096). yu

II6-M t/2 551(Ma1)7

TN nMR (400 MHz, SOSIz8): δ 7.18-7.91 (sh 716Н), 4.86-5.26 (m, ЗН), 4.05-4.60 (m, ЗН), 3.52 -3.78 (m, 2H), about 2.24-2.73 (m, 2H). "- (ii) 2-naPhtyl-"K,5)CH(OH)-C(O)-Age-Par x NOAc. The target compound was prepared by the method of the example

From 15(ii) with 0.266 g (0.48 mmol) of 2-naphthyl-(K,5)CH(OH)-C(O)-Age-Rab(7) from the previous operation (ii). 202 mg of yi-oi (88905) product was obtained.

II6-M8 t/2 417(0МА1)7

TN NMR (500 MHz, COzO0): 5 7.28-7.96 (m, 11H), 5.30-5.40 (m, 1H), 3.95-4.82 (m, 5H), 2, 09-2.59 (m, 2H). " 20 Example 32. Z-indolyl-СНо(К,З)СН(ОН)-С(О)-Аге-Rаб x NOAc. with (Y) 3-indolyl-CH-"(K,5)CH(OH)-C(0)-Age-Rac(7). The intermediate compound was prepared by the method of example C(ii), from 0.21 g (1.Omol) of (K,5)-3-(3-indolyl)lactic acid with a yield of 22Omg (4596). ;" ТН о NMR (B5О00МГЦц, СОСИ3): 8 6.57-7.80 (m, 14Н), 5.24 (s, 2Н), 4.59-4.83 (m, 1Н), 4.19-4 .51 (m, ZN), 3.69-3.99 (m, 2H), 3.03-3.36 (m, 2H), 2.31-2.56 (m, 2H). (her). C-indolyl-CHN-(K,5)CH(OH)-C(0)-Age-Par o x NODAs. The target compound was prepared according to

He") by example 15(ii) with 0.11 g (0.20 mmol) of 3-indolyl-CH"-(K,5)CH(OH)-C(0)-Age-Rab(7) from the previous operation (1 ). with 75 mg (8095) of the product obtained.

EAV-M5 t/2 420(M1)7 ("c) TN NMR (BOOMHCts, 0250): 8 7.00-7.75 (m, 9H), 4.61-4.71 (m, IN), 3.74-4.51 (m, 5H), 3.00-3.28 (m, 2H), sl 50 1.95-2.42 (m, 2H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl "m carbons: 5 179.38, 176.19, 175.56, 173.06, 166.78.

Example 33. (СНиз3)» СНА(Ю)СН(ОН)-С(О)-Аге-Раб х NOАс. () (Snza»cSnNuU«yuUsCH(OH)-C(O0)-Age-Rac(7). The intermediate compound was prepared by the method according to the example of Ziii), from 29 0.12g (1.0mmol) (K)-2- of hydroxyisovaleric acid with a yield of 8 mg (1690).

HF) TN NMR (300 MHz, SOSI5): 5 8.25-8.40 (t, MH), 7.15-7.90 (m, 9H), 5.20 (s, 2H), 4.85- 4.95 (m, 1H), 4.30-4.55 (m, 2H), 4.05-4.25 (m, 2H), 3.75-3.90 (m, 1H), 1, 65-2.75 (m, ZN), 0.70-1.05 (m, 6H). o (its (SNU CH-U(K)CH(OH)-C(O)-Age-Par x HOAc. The target compound was prepared by the method of Example 15iii) from O.13g (0.27 mmol) (CH3i). CH -Kyu)CH(OH)-C(O)-Age-Rats(72) from the previous operation (i). Received 1Zmg (23905) 60 products.

TN nMR (30 MHz, 0250): 5 7.45-7.80 (m, 4H), 4.85-5.25 (m, 1H), 4.30-4.40 (m, 1H), 3, 80-4.10 (m, 2H), 2.60-2.80 (m, 1H), 2.20-2.35 (m, 1H), 1.90-2.05 (m, 1H), 0.70-1.00 (m, 6H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of rotamers) amidine and carbonyl carbons: 5 65 182.37, 176.34, 175.38, 173.84, 173.26, 167.16.

Example 34. (Cs»CsHn-ASNoI)»-(K.5CH(OH)-C(O)-Age-Par x HOAc. (i)

(SnzsHn-(CHo)»-(K.Z)CH(OH)-C(O)-Age-Rab(2). The intermediate compound was prepared by the method according to the example of Ziii), from 0.12 g (0.8 in 8 mmol) ( K,5)-isoleucine acid with a yield of 15O0mg (36965).

TN NMR (Z00MHZc, SOCI5): 5 7.15-7.80 (m, 9H), 5.20 (s, 2H), 4.85-4.95 (m, 1H), 4.35-4 .55 (m, 2H), 3.85-4.20 (m, ЗН), 2.40-2.80 (m, 2H), 1.75-2.10 (m, 1H), 1.20 -1.55 (m, 2H), 0.75-1.00 (m, 6H). (its (Snz»sn-(CHo)»-(K.5)CH(OH)-C(0)-Age-Rav x NOAc. The target compound was prepared by the method according to example 15iii) from 0.13 g (0.27 mmol ) (CHNaz)»CH-(CH»)»-(K,Z)CH(OH)-C(O0)-Age-Rac (7) from the previous operation (1).

110mg (10095) of the product was obtained. (its (CHO.»CsHn-A(CH3az)»-(K.Z)CH(OH)-C(0)-Age-Rav x HOAc. The target compound was prepared by the method of Example 70 15(iii) with O0, 13g (0.27 mmol) (CHNaz)»CH-(CH»)»-(K,Z)CH(OH)-C(O0)-Age-Rac (7) from the previous operation (1).

110mg (10095) of the product was obtained.

TN NMR (400 MHz, 050) 5 7.36-7.69 (m, 2H), 7.37-7.46 (m, 2H), 4.72-5.12 (m, 1H), 440-446 (m, 2H), 4.17-4.31 (m, 2H), 3.90-4.02 (m, 1H), 2.50-2.69 (m, 1H), 2.11-2 .27 (m, 1H), 1.12-1.72 (m, ЗН), 0.61-0.85 (m, 6H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl 75 carbons: 5 176.97, 176.80, 176.61, 176.19, 173.84, 173.38, 173.28 , 173.17, 173.10, 166.78, 182.02.

Example 35. РНА(3-ОН)-(К.5)СН(ОН)-С(О)-Про-Раб x НС. () Vos-Rgo-Rab(7) x NOSI. The intermediate compound was prepared by the method according to example (i), from 10.2 g (47.4 mmol) of Bos-Rho-OH and 15.9 g (49.mmol) H-Rabz(72) x HCI with a yield of 21.74 g (95.59 ).

EAV-M5 ti/z 481 (M1)7

TN nMR (400MHz, СО3О0): δ 8.0-7.8 (m, 2H), 7.5-7.25 (m, 7H), 5.17 (s, 2H), 4.6-4, 15 (m, ЗН), 3.6-3.35 (m, 2Н), 2.3-2.1 (m, 1Н), 1.8-2.1 (m, ЗН), 1.3- 1.5 (two broad singlets of Bos rotamers, 9H), 0.75-1.00 (m, 6H). (i) N-Rgo-Rats (7). The intermediate compound was prepared by the method of example C(i) with Bos-Pho-Rac(7) x NOSI from the previous operation (ii) with subsequent alkaline extraction treatment. rya (ii) Ry(Z3-OH)-(K.5)CH(OH)-C(O)-Rho-Rac(2). The intermediate compound was prepared by the method according to the example of Ziii) cm from 025 g (1.5 mmol) of (K,5)-3-hydroxymandelic acid and 0.63 g (1.665 mmol) of H-Pho-Rab(7) from the previous (o) operation ( iii) with a yield of 51 mg (690).

EAV-M5 t/z 531 (Ma1)7 (m) RA(3-OH)-(K.5)CH(OH)-C(O)-Pho-Rab x NOSI. The target compound was prepared by the method according to example 1(x) M with 0.05 g (0.094 mmol of PH(3-0OH)-(K,5)CH(OH)-C(O)-Pho-Rab(7) from the previous operation (iii). ZOmg (7490) of the product was obtained. IF)

EAV-M5 t/2 397(M1)7 o 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 175.36, 175.13, 172.92, 167.13. --

Example 36. PA(3.5-diOMe)-(K,5)CH(OH)-C(O0)-Pho-Rab x HOAc. co () RA(3.5-diOoMe)-(K.5)CH(OH)-C(O)-Pho-Rac(2). The intermediate compound was prepared by the method according to the example

C(its) with 0.08g (0.3v8mmol) (K,5)-3,5-dimethoxymandelic acid, prepared by the method described in Zupipeziv (1974) 724, and 0.16g (0.42mmol) H-Pho- Slave(7), see example C5(iii) with a yield of 1mg (2895).

TN about NMR (B5О00МГЦц, СОСИ): 5 7.70-7.80 (t, МН), 7.08-7.50 (m, 9Н), 6.30-6.50 (m, ЗН), 5.20 (s, 2H), « 40 ...5.00-5.10 (m, 1H), 4.25-4.70 (m, ZH), 3.60-3.80 (m, 6H), 3.35-3.55 (m, 1H), 2.95-3.25 (m, 1H), 1.70-2.25 (m, 4H). - c (its PA(3.5-diOoMe)-(K.5)CH(OH)-C(O)-Pho-HTav x NODAs. The target compound was prepared by the method of example 15(iii) with 0.0 bg (0 ,1 ommol RI(3,5-dioMe)-(K,5)CH(OH)-C(0)-Pho-Rab(7) from the previous operation (i) with a yield of 35mg (72905) of the product. "YAN nMR (500 MHz, 050): δ 7.23-7.80 (w, 4H), 6.41-6.65 (m, ЗН), 5.35-5.45 (m, 1H), 4.35 -4.60 (m, ZN), 3.80 (s, ZN), 3.10-3.75 (m, 5H), 1.70-2.35 (m, 4H). ia Zb NMR (75 ,5 MHC, 02O, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and -k carbonyl carbons: 5 175.28, 175.05, 174.03, 173.46, 172.80, 172.73, 167.11, 166.95.

Example 37. PH(3-OMe)-(K.5)CH(OH)-C(O)-Pho-Par x NOAc. o () Pn(Z-OMe)-(K.5)CH(OH)-C(O)-Pho-Rac(7). The intermediate compound was prepared by the method according to the example of Ziii) cl 20 from 027 g (1.5 mmol) of (K,5)-33-methoxymandelic acid and 0.57 g (1.5 mmol) of H-Pho-Rac(2), see example of Z5IiYi), with . with a yield of 158 mg (2090). with EAV-M5 t/2 545(M1)7

TN nMR (400 MHz, SOSIz): 5 7.77-7.84 (w 2H), 7.01-7.48 (m, 8H), 6.80-6.91 (m, ZN), 5, 20-5.24 (m, 2H), 5.06-5.11 (m, 1H), 4.30-4.72 (m, ЗН), 3.68-3.79 (m, ЗН), 3.38-3.57 (m, 1H), 2.91-3.17 (m, 1H), 1.68-2.31 (m, 4H). (i) Pn(Z3-OMe)-(K.5)CH(OH)-C(O)-Pho-Rab x NOAc. The target compound was prepared by the method of the example

HF) 15(ii) with 0.0 bg (0.11 mmol) RNAi(3-OMe)-(K,5)CH(OH)-C(0)-Pho-Rac(7) from the previous operation (i) with with a yield of 39 mg g) (7590) of the product.

I0o-M5 t/2 411(M-1)7, 409(M-1)7 in TN NMR (400MHz, 020): 5 6.81-7.84 (m, 8Н), 6.41-6, 65 (m, ЗН), 5.47 (s, 1Н), 4.35-4.59 (m, ЗН), 3.60-3.88 (m, 4Н), 3.07-3.29 ( m, 1H), 1.74-2.37 (m, 4H).

Example 38. PI(3.4---0-CH»-O-)-(K.5)CH(OH)-C(O)-Age-Par x NOAc. (). PH(3.4---0-CH"-O0-)-("K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared by the method according to example C(ii), from 0.20 g (1.0 mmol) of (K,5)-3,4-methylenedioxymandelic acid, prepared by the method described in 65 U Zupipev (1974) 724, with a yield of 22 Omg ( 4490).

TN nMR (400 MHz, acetone-iv): δ 6.68-8.12 (m, 12H), 5.94-6.05 (m, 2H), 5.18 (s, 2H), 3.81- 5.12 (m, 6H),

2.30-2.54 (m, 2H). (its) Ri(3.4---0О-СНХ-О-)-(К.5)СН(ОН)-С(0)-Аге-Рабую x NOAc. The target compound was prepared by the method according to example 15(iii) from 0.11 g (0.20 mmol) of PH(3,4---0-СНХ-0-)-(К,5)СН(ОН)-С(О0 )-Age-Rab(7) from the previous operation (Y) with a yield of 72 mg (7695) of the product.

TN NMR (B5О0МГЦц, 020): 5 6.64-7.80 (m, 7Н), 5.91-6.01 (m, 2Н), 4.80-5.24 (m, 2Н), 3, 88-4.57 (m, 4H), 2.11-2.84 (m, 2H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: δ 176.03, 175.70, 175.07, 174.82, 168.86.

Example 39. RiY(3-OMe.4-OH)-(K.5)CH(OH)-C(O)-Pho-Rab x NOAc. () PH(Z-OMe.4-0OH)-(K.5)CH(OH)-C(O)-Pho-Rab(7). The intermediate compound was prepared by the method according to example C(i) from 040 g (2.Omol) of (K,5)-4-hydroxy-3-methoxymandelic acid and 0.76 bg (2.Omol)

N-Rgo-Rats (7), see example of ZHia), with a yield of 132 mg (1296).

EAV-M5 t/2 561(M1)7

TN NMR (400MHz, SOSIz);: 5 6.62-7.84 (m, 12H), 5.20-5.25 (m, 2H), 4.15-5.08 (m, ЗН), 3 ,42-3.84 (m, 4H), 2.91-3.25 (m, 1H), 1.66-2.37 (m, 4H). (its Pn(3-OMe.4-OH)-(K.5)CH(OH)-C(O)-Pho-Par x NODAs. The target compound was prepared by the method according to example 15iii) with 0.048 g (OH0.09 mmol ) RA(3-OMe,4-OH)-(K,5)CH(OH)-C(O)-Pho-Rab(72) from the previous operation (i) with a yield of 2 Zmg (5590) of the product.

EAV-M5 t/2 427(Ma)"

TN nMR (400 MHz, 020): δ 6.72-7.83 (m, 7H), 5.42 (s, 1H), 4.38-4.68 (m, ЗН), 3.55-4, 10 (m, 4H), 3.09-3.29 (m, 1H), 1.72-2.37 (m, 4H). 136 NMR (75.5 MHz, 029) amidine and carbonyl carbons: 5, 175.12, 173.25, 167.09. high school

Example 40. RA-(K.5)SSEO(OH)-C(O)-Pho-Rab x NOAc. () RA-(K.5)SSEV(OH)-C(O)-Pho-Rab(7). The intermediate compound was prepared by the method according to the example of Ziii) with i) 0.3 bg (2.00 mmol) of (P,5)-2-hydroxy-2-phenylbutanoic acid and 0.7 bg (2.00 mmol) of H-Pho-Rab(7 ), see example

C5(ii), with a yield of 57 mg (595).

EAV-M5 t/2 543(M1)7 -

TN nMR (400 MHz, SOSIv);: 8 7.24-7.88 (m, 14H), 5.23 (s, 2H), 4.48-4.81 (m, ЗН), 2.98-3 .25 (m, 2H), 1.49-2.32 (m, 6H), 0.85-0.95 (m, ZN). o (its RA-(K.5)C(ED(OH)-C(O)-Pho-Par x NOAc. The target compound was prepared by the method according to example (3 15(its) with 0.055 g (0.1 mmol) RA-(K,5)C(EC(OH)-C(0)-Rho-Rac(7) from the previous operation (ii) with the yield Zamg (72965) of the product. -

EAV-M5 t/:2 409(M-1)7 (Se)

TN nMR (400 MHz, 020): δ 7.33-7.82 (m, 9H), 4.38-4.60 (m, ЗН), 3.19-3.71 (m, 2H), 1, 54-2.34 (m, 6H), 0.73-0.90 (m, ZN). 13C NMR (75.55 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 182.05, 176.42, 175.73, 175.59, 174.70, 174.47, 167 ,18.

Example 41. RA(3.5-diMe)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. With c () (K,5)-3.5-dimethylmandelic acid. The intermediate compound was prepared by the method according to example 15) with

From" 5.0 g (3/mmol) of 3,5-dimethylbenzaldehyde with a yield of 2.8 g (42965). "H NMR (400MGu, COzO0): δ 7.05 (s, 2H), 6.94 (s, 1H), 5.04 (s, 1H), 2.28 (s, 6H), 0.73- 0.90 (m, ЗН). 15 (i) RA(3.5-diMe)-(K.5)CH(OH)-C(O)-Age-Rab(7). The intermediate compound was prepared by the method according to the example

Fu C(i), with 0.27 (1.5 mmol) (K,5)-3,5-dimethylmandelic acid with a yield of 40 Zmg (5195).

EAV-M5 t/:2 529(M1)7 - TN nMR (B500MHz, SOSIz): 5 6.85-7.88 (m, 12H), 5.22-5.26 (m, 2H), 4, 84-5.003 (m, 2H), 4.43-4.62 (m, 2H), about 3.57-4.13 (m, 2H), 2.25-2.74 (m, 8H). 50 (its) RA(3.5-diMe)-(K,5)CH(OH)-С(О)-Age-Par x NODAs. The target compound was prepared by the method of example 15(ii) from 0.102 g (0.194 mmol) of РНА(3,5-diMe)-(«K,5)CH(OH)-C(O)-Age-Rab(7) from the previous operation (ii) "M with a yield of 74 mg (84905) of the product.

EAV-M5 t/:2 395(M1)7

TN NMR (500MHz, 020): 5 6.76-7.82 (m, 7H), 4.80-5.27 (m, 2H), 3.87-4.62 (m, 4H), 2, 20-2.87 (m, 8H). 13C NMR (75.55 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and o carbonyl carbons: 5 182.07, 175.60, 174.49, 174.37, 173.96, 173.23, 173 ,09, 173.05, 172.93, 166.98, 166.90.

Example 42. RA(3-MH)-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. (Y) RAI(3-MO2)-(K.5)CH(OH)-C(0)-Age-Rats(7). The intermediate compound was prepared by the method of Ziii) from 0.30 g (1.5 mmol) of (K.5)-3-nitromandelic acid with a yield of 400 mg (4895). 60 IS-M5 t/2 545(iMAT)"

TN nMR (400 MHz, SOCI3): 85 7.16-8.22 (m, 1Z3H), 5.18-5.23 (m, 2H), 4.85-5.15 (m, 2H), 4, 08-4.60 (m, ZN), 3.65-3.81 (m, 1H), 2.31-2.71 (m, 2H). (its) RA(3-MH")-(K.5)CH(OH)-C(O)-Age-Rab x NOAc. The target compound was prepared by the method of example 15(ii) from 0.102 g (O0.19U9mmol) РНА(3-МО»)-(К,5)CH(OH)-C(O)-Age-Rac(2) from the previous operations (iii) with a yield of 74 mg bo (89905) of product.

IIS-M5 t/2 382(0MAT)"

TN NMR (400 MGu, 020): 5 6.58-7.82 (m, 8H), 4.80-5.25 (m, 2H), 3.60-4.60 (m, 4H), 2, 12-2.88 (m, 2H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: δ 181.96, 175.27, 174.25, 173.84, 173.19, 173.01, 166.93.

Example 43. RA(3-MO»)-(K.5)CH(OH)-C(O)-Age-Par x NOAc.

0.03 g (0.27 mmol) of anisole and 0.138 g (0.92 mmol) of trifluoromethanesulfonic acid were added to the mixture

O.100g (0.18mmol) PH(3-MO")-("K,5)CH(OH)-C(O)-Age-Rab(7), see operation 42(i) and 1Oml of dichloromethane.

The reaction mixture was stirred for 10 minutes at room temperature. Water was added, bringing the pH of the solution to 9 with a solution of Ma»CO3. Dichloromethane was removed under vacuum and the remaining aqueous layer was extracted three times per bml with diethyl ether, followed by drying by sublimation. The crude product was subjected to preparative KRIS to obtain, after drying by sublimation, b2mg (6095) of the target product.

TN NMR (400 MGu, 020): 5 7.38-8.31 (m, 8H), 4.83-5.50 (m, 2H), 4.03-4.57 (m, 4H), 2, 17-2.86 (m, 2H).

Zb NMR (75.5 MHz, 02O, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 181.5, 173.84, 173.39, 173.15, 173.04, 172.96, 172.80, 166.85.

Example 44. PA(3-MH)-(K,5)CH(OH)-C(O)-Pho-Rab x NOAc. (Y) RAI(3-MO2)-(K,5)CH(OH)-C(O0)-Pho-Rac(7). The intermediate compound was prepared by the method according to the example of Ziii) from 0.30 (1.5 mmol) (K,5)-3-nitromandelic acid and 0.75 g (1.6 mmol) H-Rho-Rab(/) x 2HCl with a yield 0.61 g (73905).

IIS-M5 t/2 56FC(M1)

TN o nMR (400 MHz, SOSIz): δ 7.26-8.23(m, 13H), 5.20-5228(m, ZN), 4.33-4.73(m, ZN), 3.46 -3.68(m, 1H), 2.92-3.14(m, 1H), 1.79-2.33(m, 4H). (its) PA(3-MH)-(K,5)CH(OH)-C(O0)-Pho-Rabr x NOAc. The target compound was prepared by the method according to the example of compound 15(Y) with 0.104 (019 mmol) PA(3-MO»2)-(K,5)CH(OH)-C(O)-Pho-Rab(7) from the previous operations) with a yield of 4 mg (7695) of product. and)

II6-M t/:2 396(M1)7

TN NMR (400MHz, 020): 5 6.74-7.82(m, 8H), 5.34-5.40(m, 1H), 4.35-4.58(m, ЗН), 3, 09-3.78(m, 2H), 1.75-2.35(m, 4H). 13C NMR (75.5 MHz, 0250, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl (/(h- carbons: 5 182.04, 175.38, 175.18, 173.12, 173.04, 167.07 oh

Example 45. PNH(3-MO»2)-(K or 5)CH(OH)-C(O)-Pho-Rab x NOAc.

The target compound was prepared by the method of example 15(i) with 0.117 (021 mmol) (F

Ry(3-MO»)-(K,5)CH(OH)-C(O)-Rho-Rab(7), see operation 44(i). Some fractions were concentrated and "- 23 mg (4596) of the compound with a ratio of diastereomers" of 99: 1 was obtained.

I6-M5 t/2 424(M-1)7, 426(Ma1)7 x,

TN NMR (500MGu, 0520): 5 7.31-8.35(m, 8H), 5.50-5.71(m, 1H), 3.64-4.57(m, 4H), 3, 24-3.32(m, 1H), 1.76-2.42(m, 4H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of rotamers) amidine and carbonyl carbons: δ 175.21, 173.98, 172.58, 172.18, 167.12, 166.82. "20 (The first fractions were concentrated to obtain an epimer of the above-mentioned compound with a ratio of -c diastereomers" 99: 1).

Example 46. ПНА(3,4---0-CH»-O-)-(K,5)CH(OH)-C(O)-Pho-Par x HOAc. (i) :z» Ry(3,4---0-CH»-0-)-(K,5)CH(OH)-C(0)-Pho-Rab(7). The intermediate compound was prepared by the method according to the example

C(i), with 0.20 g ((1.0 mmol) (K,5)-3,4-methylenedioxymandelic acid, prepared by the method described in U zupipeziz (1974) 724, and 0.35 (0.9 mmol) H- Rgo-Rats(72) x 2HNSI, see example C4(ii), with a yield of 8Omg(16905).

Ф ТН о nNMR (B5О0MHz, СОСИ3): δ 6.69-7.89(m, 12Н), 5.91-6.04(m, 2Н), 4.30-5.28(m, 2Н), 3.00-3.61(m, bH), with 1.95-2.35(m, 4H). (i) РНА(3,4---0-CH».O-)-(K,5)CH(OH)-C(0)-Pho-Par x HOAc. The target compound was prepared by the method according to av! by example 15(ii) with 0.08 (0.14 mmol) РНА(3,4---0-CHN-0-)-("K,5)CH(OH)-C(0)-Pho-Rac( 7) from the previous operation)

With a yield of 48 mg (7390) of product. n EAV-M5 t/2 425(M1)7 that CHNO NMR (5O00MHz, 050): 5 6.81-7.85(m, 7H), 5.90-6.05(m, 2H), 5, 33-544(m, МН), 4.37-4.90(m, ЗН), 3.62-3.77(m, 1Н), 3.13-3.28(m, 1Н),1, 80-2.36 (m, 4H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl 22 carbons: 5 175.37, 175.09, 173.66, 173.66, 173.08, 173.00, 167.03 .

HF) Example 47. RI(3,5-difluoro)-(K,5)CH(OH)-C(O0)-Pho-Rab x NOAc. () PH(3Z,5-difluoro)-(K,5)CH(OH)-C(0)-Pho-Rab(7). The intermediate compound was prepared by the method of example C(iii) from 0.28 g ((1.5 mmol) (K,5)-3,5-difluoromandelic acid and 0.75 ((1.65 mmol) H-Pho-Rac( 2) x 2NOI, see example C5(ii) with a yield of 0.42 g (51906). 60 Ib-M5 t/2 549("M-7)7, 5B. (MA)

TN NMR (400MHz, SOCI3),;: 8 6.72-7.84(m, 12H), 5.22(s, 2H), 5.08(s, 1H), 4.34-4.73( m, ЗН), 3.41-3.60(m, 1Н), 2.96-3.19(m, 1Н), 1.80-2.34(m, 4Н). (i) PA(3,5-difluoro)-(K,5)CH(OH)-C(O)-Pho-Tar x NOAc. The target compound was prepared by the method of Example 15(ii) with 0.104 (0.1 μmol of РА(3,5-difluoro)-(К,5)CH(OH)-C(O)-Pho-Rab(7) from the previous operations) with an output of 79 mg (8895).

IS-M5 t/2 415(M-1)7417(M1)7

TN NMR (400MHz, 0250): δ 6.86-7.80(m, 7H), 5.50(s, 1H), 3.58-4.72(m, 4H), 3.19-3, 32(m, 1H), 1.80-2.37(m, 4H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl o carbons: 5 181.87, 175.21, 174.98, 174.12, 172.57, 172.12, 171.97 , 167.10, 165.24.

Example 48. РА-(КУ)СН(О-СНо-(К,5)СН(ОН)-СННО)-С(О)-Аге-Rаб x NOAc. () RA--KYUSN(OH)-С(О)ОВp. 3.0 g ((19.7 mmol) of (P)-mandelic acid was dissolved in 500 ml of OME and 3.214 (9.8 mmol) of cesium carbonate was added. The reaction mixture was stirred at room temperature overnight.

The mixture was diluted with 200 ml of water and the aqueous layer was extracted with ethyl acetate. After separation, the organic layer 70 was washed with Masi brine, dried with Ma»5O)4 and evaporated. The yield of the intermediate compound was 4.2 g (88965).

IIS-M5 t/2 265(MaMa)" "H NMR (400MHu, SOSI»z): 5 7.17-7 44(m, 10H), 5.12-5.27(m, ZN). (i) RY-"KYUSN(O-SNSNASNo)-S(O)OVp. A mixture of 1.0(4.1Zmmol) RI-K)CH(OH)-C(O)OVp from the previous operation), 0.1sh(0.8Zmmol) of magnesium sulfate and 2.58g ((11.2mmol) of argentum oxide (!) in 25 ml of petroleum ether (bp. 40 - 60 "С) was stirred at room temperature in the dark under a layer of nitrogen. 0.75 g (6.19 mmol) of allyl bromide was added dropwise, and then in two portions 2.581 (11, 2 mmol) of argentum(I) oxide. The reaction mixture was stirred at room temperature overnight, then filtered through brownmillerite and the filtrate was evaporated to give 1.143g (98905) of the intermediate compound. 20 TN NMR (400MGu, SOCI»z): 5 7.20 -7.50(m, 10OH), 5.89-5.99(m, 1H), 5.09-5.31(m, 4H), 4.99(s, 1H), 4.03-4 ,11(m, 2H). (ii) RA--KYCHN(O-CHNo-(K,5)CH(OH)-CHNHON)-C(OOOVp. Mixture 0.74 (2.62 mmol)

RI-"YUSN(O-SNYO-SNASN")-C(O)OVp from the previous operation(s), 0.4251 (3.15 mmol) of M-methylmorpholine-M-oxide and 0.0027 g (0.01 mmol) of tetraoxide osmium in 10 ml of a mixture (2 : 1) of water-acetone was stirred at room temperature for 2 days. 1.5 (7.89 mmol) of sodium pyrosulfite was added and the mixture was stirred for 1 hour, after which it was filtered through 25 g through brownmillerite and the filtrate was evaporated to give 0.51 g (6295) of the intermediate compound.

IN NMR (400MHz, SOS"): 5 7.16-7 44(m, 1OH), 5.09-5.20(m, 2H), 4.96(s, 1H), 3.55-3, 97 (m, 5H). o (im) РА--ЮСН(О-СНо-(К,5)СН(-О-С(СН 3)5-0-СН»-))-С(О)О8Вп. 0.51 (1.61 mmol)

RI-"YUSN(O-CH"-(K,5)CH(OH)-SNNH)-C(O)OVp from the previous operation (ii) was dissolved in 20 ml of acetone. 0.007 (0.037 mmol) of p-toluenesulfonic acid monohydrate was added and stirred at room temperature for 24 hours to 30 hours. After adding 0.09 g of potassium carbonate, the reaction mixture was stirred at room temperature for 1 hour, then filtered through brownmillerite and the filtrate was evaporated to give 0.55941 (97905) of the intermediate compound. Av

TN NMR (400 MHz, SOSIsh): 85 7.18-7.48 (m, TON), 5.01-5.21 (m, ZN), 4.27-4.40 (m, 1H), 4, 02-4.11(m, 1H), 3.76-3.90(m, 2H), 1.34-1.41(m, EN). - 35 (m РА--ЮСН(О-СН»-(К,5)СН(-О-С(СН 3)5-0-СНо-))-Ф(ООН. 0.183g (0.5immol) is

RI-"ЮСН(О-СН»-(К,5)СН(-О-С(СН 3)2-0О-СНо-))-С(О)ОВp from the previous operation (im) was dissolved in TOml of ethanol, added 0.09g59Uu Ra/C and hydrogenated the mixture at atmospheric pressure for 1 hour, after which it was filtered through brownmillerite and the filtrate was evaporated, obtaining 0.137g (10095) of the intermediate compound. "

IS-M5 t/2 265(M-1)7 40 CH NMR (400MHz, СО3О0): 5 7.28-7.48(m, 5Н), 4.97(s, 1Н), 4.25-4 ,35(m, NN), 4.01-4.09(m, 1H), c) with 3.72-3.84(m, 1H), 3.43-3.65(m, 2H), 1.30-1.37 (m, 6H). "from (m). РІ-СІСН(О-СНо-(К,5)СН(-О-С(СН 3)5-0О-СН»-))-С(О0)-Аге-Раб(7) The intermediate compound was prepared by the method of example C(ii) with 0.165 ((0.b2mmol) РА-(«КУ)СН(О-СНО-(К,5)СН(-О-С(СН 3)5- 0О-СН»-))-С(О)OH.: from the previous operation (m) with a yield of 0.20 g (5295). 45 IS-M8 t/g 613(M-17)7 b15(MA)

F TO NMR (500MHz, SOS): 85 7.22-7.88(m, 14Н), 5.22(s, 2Н), 4.87-4.95(m, 2Н), 3.40-4 .54 (m, OH), - 2.36-2.76 (m, 2H), 1.22-1.42 (m, 6H). o (mi) РІ-СІСН(О-СНо-(К,5)СН(-О-С(СН 3)2-ОО-СН»))-С(О0)-Age-Par x HOAc. The desired compound was prepared by method 50 according to example 15 (ii) with 0.20 mg (0.325 mmol) of РІ-"ЮСН(О-СН»-(К,5)СН(-О-С(СН 3)2-0О- СНОо-))-С(О0)-Аге-Раб(/) from the previous operation (mi) with a yield of -Ч 0.1794100905).

I S-M5 t/2 479(M-1)7481(M1)7

TO NMR (BO0MHC, 020): 5 7.33-7.80(m, 9H), 4.81-5.31(m, 2H), 3.94-4.59(m, bH), 3, 25-3.80(m, ZN), about 2.16-2.88(m, 2H), 1.29-1.44(m, 6H). o 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 181.99, 173.12, 172.93, 172.18, 166.84. co (mii) RA--KYUSN(O-CHO-(K,5)CH(OH)-CHNON)-C(O)-Age-Par x NOAc. 0.0944sh0.17mmol)

RI-"YUSN(O-СНОо-(К,5)СН(-О-С(СН 3)2-ОО-СНОо-))-С(О0)-Аге-Рай x NOAs from the previous operation (my) was dissolved in 60 1 Oml of a mixture of acetic acid and water (4:1), the reaction mixture was stirred at room temperature for 24 hours.

The mixture was evaporated and the residue was dissolved in water and dried by sublimation to yield 85 mg of the target compound (10090).

IS-M5 t/2 439(M-1)7, 441(Ma1)7

TN NMR (500MHz, 020): 5 7.32-7.78(m, 9H), 4.81-5.28(m, 2H), 3.28-4.56(m, 9H), 2, 15-2.90(m, 2H), v5 13C nMR (100.6 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 179.14, 172.93, 172.89, 172.51, 171.96, 166.54.

Example 49. RI-USN(O-CHN-(K,5)CH(OH)-SNNH)-C(O)-Pho-Rab x NOAc. () РеРА-"ЮИСН(О-СНо-(К,5)СН(-О-С(СН 3)20-СН»-))-С(О)-Рго-Раб(7). The intermediate compound was prepared by the method of example C(iii) from 0.108 g (0.4 mmol) of RA--"K)CH(O-CH"o-(K,5)CH(-O-C(CH 3)2- О-СН»-))-С(О)OH, see example 48(m), and 0.202 (0.4 mmol) H-Rho-Rabz(7) x 2HCl, see example Хх(ii), with a yield of 0.10 g (40965).

IIS-M5 t/2 627(M-1)7, 629(M-1)7, 6B1(MaeMa)"

TN nMR (B5О0МГЦц, СОСИв);: 5 7.23-7.87(m, 14Н), 5.03-5.27(m, ЗН), 3.34-4.64(m, ТОН), 1 .71-2.39(m, 4H), 1.23-1.41(m, 6H). (its) RIA--ЮСН(О-СНо(,5)СН(-О-С(СН 3)5-ОО-СН»))-С(О0)-Pho-Par x HOAc. The desired compound was prepared by method 70 according to example 15) from 0.100 g (0.159 mmol)

RI-"YUSN(O-OH"O-(K,5)CH(-O-C(CH 3)5-0O-CH"-))-C(O0)-Pho-Rats (72) from the previous operation (i) with a yield of 85 mg (9695).

I6-M5 t/2 493(M-1)7, 495(Ма1)7

CHNO NMR (500MHz, 020): 5 7.30-7.82(m, 9H), 5.22-5.38(m, 1), 4.32-4.62(m, 4H), 4, 01-4.11(m, 1H), 3.22-3.83(m, 5H), 1.78-2.22(m, 4H), 1.33-1.44(m, 6H). t5 13C nMR (100.6 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 181.47, 174.74, 173.53, 171.64, 171.50, 171.00, 170.94 , 166.58. (its) РААЙУИСН(О-СНУ(К,5)СН(ОН)-СНООН)-С(О)-Рго-Раб x NOAc. The desired compound was prepared by the method according to example 48 (miii) with 0.038 g (0.069 mmol) of PA--СКЮСН(О-СНо-(К,З)СН(-О-С(СН 53)5-0-СН»-) )-C(O0)-Pho-Par x HOAc from the previous operation (ii) with the yield of the target compound 35 mg (9890).

I6o-M5 t/2 453(M-1)7, 455(Ma1)7

TN NMR (500MHz, 020): 5 7.30-7.82(m, 9H), 5.20-5.38(m, 1H), 3.18-4.60(m, TON), 1, 70-2.38 (m, 4H).

Cs NMR (100.6 MHz, 02O, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: δ 180.26, 174.74, 173.47, 171.80, 171.26, 166.61. yes!

Example 50. Pp-(K or Z)C(-O-C(SNUZ)»-O-СНо-)-С(0)-Age-Par x NOAc and Ry-5 or o kO)C(-O- С(СН3)5-0-СНо-)-С(О)-Age-Rab x NOAc. () РА-(К,5)С(-О-С(СНИи)»-ОО-СНо-)-ФС(О)ОН. The desired compound was prepared by the method of example 48(ih) from 3.51 (20.35 mmol) of c-hydroxytropic acid, prepared according to (Zciigu ei a), Sap. U. Spet. (1991) 69 1904, yielding an intermediate compound of 3.37 g (7490). -

TN NMR (500 MGu, SOSI»z): 5 7.30-7.65 (m, 5H), 4.95 (d, 1H), 4.10 (d, 1H), 1.70 (s, ЗН) , 1.50 (c, ZN). ю (its) Ry-(55,К)С(-О-С(СНУз)2-0О-СНо-)-С(0)-Аге-Раб(7). The intermediate compound was prepared by the method of example C(ii) with 0.25 ((1.12 mmol) RIA-(K,Z)C(-O-C(CH3)»-O-CH-)-C(O)OH from the previous operation (ii) with an output of 0.30 g (53905). "-

TN NMR (500 MGu, SOSIz): 5 7.20-7.90(m, 14Н), 5.22(s, 2Н), 3.70-5.10(m, 7Н), 2.15 -2.75 (m, 2H), 1.40-1.65 (m, 6H). c (ii) RA-(K or 5)С(-О-С(СН3)»-ОО-СН») -C(O0)-Age-Rab x NOAc and RA-(Z or K)C(-O-C(CH3)2-0-CH»-)-C(O)-Age-Par x NOAc. Mixture 0 ,30 psh (0.5 Zmmol) РА-(5,К)С(-0О-С(СН3з3)2-0-СНо-)-С(0)-Age-Rab(7) from the previous operation(s), 0 ,30g (0.47mmol) of ammonium formate. Drops of formic acid and O.ZOg 590 Ra/C in 1Oml of methanol were stirred for 30 minutes at room temperature. The reaction mixture was filtered through brownmillerite and the filtrate was evaporated. Crude product (0.29g) Separate fractions were concentrated to yield 800 mg (3595) of compound 50A with a diastereomer ratio of 99:1. Further fractions were concentrated to yield 80 mg (35905) of compound 50B with a diastereomer ratio of 98:2. BOA

II6-M8 t/2 437(M1)7 "H NMR (400MGu, COzO0): 5 7.28-7.85(m, 9H), 3.70-4.95(m, 7H), 2.10 -2.55(m, 2H), 1.55(s, ЗН), 1.50(s, ЗН).

He») Compound 50B -3z II6-M8 t/2 437(M1)7 "N NMR (400MGu, СО300): 5 7.25-7.80(m, 9Н), 3.70-5.00(m . (SNHON)-C(O)-Age-Rabr x NSI and RI-(Z or K) C(OHX(SNHON)-C(O)-Age-Ra x sl 50 NOI. (i) RA-(K or 5ISONH(SNOH)-C(O)-Age-Par x Nei. 0.060g0.12mmol) RA-(K or what З)С(-О-С(СН 3)5-0О-СНо-)-С(0 )-Age-Par x HOAc (compound 50A from example 50) was dissolved in a mixture of 4 ml of acetic acid and 1 ml of water. The mixture was stirred overnight at room temperature, and then for 2 hours at 907C.

ml of concentrated NSI was added and stirred for 5 minutes at room temperature. Acetic acid and

Acetic acid and NSI were removed under vacuum in the presence of toluene and ethanol, the residue was dissolved in 4 ml of water and dried by sublimation. The crude product (0.29g) was subjected to preparative KRI C, with the obtaining of the target compound with a yield of 9mg (1690) of IS-M5 t/2 395(М-1)7, 397(М1)7

TN NMR (400 MGu, CO300): 5 7.20-7.85 (m, 9H), 3.90-4.70 (m, 5H), 3.30-3.70 (m, 2H), 2.00-2.65(m, 2H). because (its RA-(5 or KYUS(OHX(SNNH)-C(O)-Age-Par x NOSI). The target compound was prepared by the method according to the previous operation (i) with 0.060 (0.12 mmol) RA-(Z or K)C(-O-C(CH3)»-O-CH»o-)-C(O)-Age-Rab x NOAc (compound 50OB from example 50) with an output of 22 mg (40965)

II6-M t/2 397(0M1)7

TN NMR (400MHz, COzO0): 5 7.20-7.85(m, 9H), 3.90-4.75(m, 6H), 3.50-3.60(m, 1H), 2, 10-2.50(m, 2H). 65 Example 52. Pp-(K or C)C(-O-C(CH3)»-O-CH»)-C(O)-Pho-Par x NOAc and Ry-(5 or yuO)C(-O -C(CH3)5-0O-CH»)-C(O)-Pho-Rab x NOAc. () РеА-(5,К)С(-О-С(СНУЗ)»-О-СНо-)-С(0)-Рго-Раб(7). The intermediate compound was prepared by the method of example C(ii) with 0.25 ((1.12 mmol) РЙ-(K,5)С(-ОО-С(СН3з)2-О-СНо-)-С(О)ОН , see example 50(y) with output 01943296).

EAV-M5 t/:2 585(M1)7

TN NMR (400MHz, SOSIsh);: 85 7.20-7.95(m, 14H), 5.25(s, 2H), 5.10-5.20(m, 1H), 4.32-4 ,70(m, ZN), 3.65-3.95(m, 2H), 3.00-3.25(m, 1H), 1.30-2.35(m, 1OH). (i) RA-(K or 5)C(-O-C(CHZ)»-O-CH»-)-C(O0)-Pho-Rab x NOAs and RI-(5 or K)C(-O -C(CH3)»-0-CH»-)-SK(0)-Pho-Par 70 x HOAc. The target compound was prepared by the method according to example 5fFii) with 0.37 (0.6Zmmol)

Ry-(5,Y)C(-0O-C(CH 3)5-0O-CH»-)-C(0)-Pho-Rab(7) from the previous operation (i). Separate fractions were concentrated with a yield of 120 mg of compound 52A with a ratio of diastereomers » 99: 1. Further fractions were concentrated with a yield of 12 mg of compound 52B with a ratio of diastereomers of 98: 2.

Compound 52A

II6-M8 t/2 451(Ma1)7

TN o nMR (400 MHz, СО5О0): 5 7.25-7.80 (m, OH), 4.35-5.05 (m, 4Н), 3.80-3.95 (m, 1Н), 3 ,60-3.65(m, 1H), 3.00-3.10(m, 1H), 2.10-2.20(m, 1H), 1.75-1.90(m, ЗН) , 1.55(s, ZN), 1.45(r, ZN).

Compound 52B

IIS-M5 t/2451(0МА)

TN NMR (400MHz, СО3О0): 5 7.25-7.80(m, 9Н), 4.40-5.10(m, 4Н), 3.30-3.80(m, ЗН), 1, 75-2.20(m, 4H), 1.50-1.55(m, 6H).

Example 53. РА-(K or 5)СХОНХ(SNХНО)-С(О)-Рхо-Рах х НСІІ and RIA-(5 or EE) С(ХОНХ(SNХНХ)-С(О)-Рхо-Rаб x НС () PA-(E or 5)CSONX(CHNOOH)-C(O)-Pho-Ra x NOI. The target compound was prepared by the method of Example 51(i) from 0.069 (0.12 mmol) of РА-(К or 5 )C(-O-C(CH3z)2-O-CH»-)-C(0)-Pho-Par x NOAs (compound 52A from example 52) with a yield of 2 mg (290) He)

And S-M5 t/2 409(M-1)k, 411(MT

TN NMR (400MHz, СО3О0): 5 7.20-7.85(m, 9Н), 4.40-4.60(m, ЗН), 4.05-4.30(m, 1Н), 2, 95-3.90(m, ZN), 1.60-2.20(m, 4H). m (Y) RA-(Z or KUS(OHX(SNNH)-C(O)-Pho-Rab x NOI. The target compound was prepared by the method of example 51(i) from 0.060 g (0.12 mmol) of PH-(Z or K)C(-O-C(CH3)2-0O-CH»-)-C(0)-Pho-Rab x NOAc (compound BOB from example 50) with M yield of mg(190) o

I6-M5 t/2 409(M-1)7, 411(Ma1)7

TN NMR (400MHz, COzO0): 5 7.25-7.85(m, 9H), 4.40-4.65(m, ЗН), 4.05-4.20(m, 1H), 3, 25-3.75 (m, ZN), 7 1.40-2.20 (m, 4H). Gee)

Example 54. RA-(K)CMe(OH)-C(O)-Pho-Rab x NOI. () RI-"KYUSMe(OH)-C(O)-Rho-Rab(7). The intermediate compound was prepared by the method according to the example of Ziii), from 0.204 (1.2 mmol) (K)-(-)-2-hydroxy-2-phenylpropionic acid and 0.50 g (1.1 mmol) H-Pho-Rab(7) х 2НСЙ, see example of Zh(iii) with a yield of 0.13 g (2296).

TN NMR (400MHz, SOSI»z): 5 7.18-7.87(m, 14H), 5.25(s, 2H), 4.37-4.61(m, ЗН), 3.03- 3.19(m, 2H), 1.54-2.17(m, 7H). - c (its RA-(YUSMe(OH)-C(O)-Pho-Rab x HC). The target compound was prepared by the method of example 1(x) with "with 0.134 (0.25 mmol) RA-("K)СMe (ОН)-С(О0)-Rho-Rats(2) from the previous operation (i) with a yield of 94 mg (8996). " EAV-M5 t/: 395(M-1)7

TN NMR (500MHz, 020): 5 7.37-7.91(m, 9H), 4.33-4.61(m, ZN), 3.15-4.01(m, 2H), 1, 72-2.33 (m, 7H). 13C NMR (75.5 MHz, 020, the spectrum is complicated by the presence of rotamers) amidine and carbonyl carbons: 5

F 176.06, 175.49, 174.88, 166.90. - Example 55. RI-(5X)CMe(OH)-C(O)-Pho-Rab x NOI. o () RI--5)SMe(OH)-C(0)-Pho-Rab(7). The intermediate compound was prepared by the method according to the example of Ziii), from 0.204 (1.2 mmol) (K)-(C)-2-hydroxy-2-phenylpropionic acid and 0.501 (1.1 mmol) H-Pho-Rab(7) x 2HCl , see (9) 50 examples of Zh(iii) with a yield of 0.19 g (33905). "m TO NMR (BOOMHCts, SOS): 5 7.20-7.77(m, 14H), 522(s, 2H), 4.53-4.58(m, NN), 4.32-444( m, 2H), 3.13-3.38(m, 2H), 1.53-2.04(m, 7H). (its RI-(3)СMe(OH)-C(0)-Pho-Par x HC. The target compound was prepared by the method of example 1(x) with 0.134 (0.25 mmol) RI-(5)СMe(OH) -C(O)-Rho-Rac(2) from the previous operation (ii) with a yield of 8Omg(82965).

EAV-M5 t/: 395(M-1)7 iF) TN NMR (500 MHz, 020): 5 7.35-7.84(m, 9H), 4.47-4.63(m, ЗН), 3.30-3.70(m, 2H), 1.60-2.29(m, 7H). ime) 130 NMR (75.5 MHz, 020, the spectrum is complicated by the presence of rotamers) amidine and carbonyl carbons: 5 175.58, 175.23, 174.79, 167.07. for Example 56. РНА(3,4-difluoro)-(K,5)CH(OH)-C(O)-Pho-Ra x NOI. () PH(3,4-difluoro)-(K,5)CH(OH)-C(0)-Pho-Rab(7). The intermediate compound was prepared by the method of example C(ii) from 0.20 ((1.0 mmol) (K,5)-3,4-difluoromandelic acid and 0.53 g (1.17 mmol) H-Pho-Rac(2) x 2NOI, see example C5(iii) with a yield of 0.445 g (7690).

I6o-M5 t/2 549(M-1)7, 551(M1)7 bo TN NMR (400MHz, SOSI3);: 5 6.98-7.74(m, 12Н), 5.16-5.21 (m, 2H), 5.06-5.01(m, 1H), 4.22-4.56(m, ЗН),

3.32-3.58(m, 1H), 2.88-3.12(m, 1H), 1.70-2.12(m, 4H). (its) РНА(3,4-difluoro)-(K,5)CH(OH)-C(0)-Pho-HTarch NOSI. The target compound was prepared by the method of Example 1 (mu) with 0.175 ((0.3 mmol) PH(3,4-difluoro)-(K,5)CH(OH)-C(O)-Pho-Rab(7) with of the previous operation (s) with

Output 127m (8896).

IS-M5 t/2 4170MA)" "H NMR (400MGu, СО300): δ 7.11-7.86(m, 7H), 5.37(s, 1H), 4.36-5.00(m , 4H), 3.66-3.78(m, 1H), 1.80-2.31(m, 4H). 13c nMR (1006 MHz, SOZO0, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: δ 174.66, 174.40, 171.96, 171.82, 166.48.

Example 57. RI--SK)CH(OH)-C(O)-(K,5)Ris(4-oxo)-Ra x HOAc. (Y) Bos-(K,5)Ris(4-oxo)-OSH3. A mixture of 1,1 (4,25 mmol) Vos-(K,5)Ris(4-hydroxy)-OSN»z, prepared by the method of SiiMag and a. 9U. Ogd. Spent (1996) 61 2226, 1.8 (8.5 mmol) ROS and 1.0 g of molecular sieve powder (ZA") in 20 ml of dichloromethane were stirred at room temperature for 4 hours. bOml of diethyl ether was added and the mixture was filtered through a short silica gel column with eluent ethyl acetate hexane (1 : 1).Filtrate 72 was evaporated to give 1.01(9295) of intermediate compound.

EAV-M5 t/: 258(M1)7

TN NMR (500MHz, SOSI»z): 5 4.75-5.20(m, 1H), 3.55-4.15(m, 5H), 2.40-2.90(m, 4H) , 1.30-1.65 (m, 9H). (i) H-(K,5)Ris(4-oxo)-OSH3U. 0.48 g (1.87 mmol) of Bos-(K,5)Ris4-oxo)-OSNu from the previous operation (i) was treated with 4 ml of a 5095 solution of trifluoroacetic acid in dichloromethane at room temperature for 30 minutes.

The reaction mixture was evaporated, the residue was dissolved in dichloromethane, washed with aqueous sodium carbonate, dried with potassium carbonate and evaporated, obtaining 0.23 g (78905) of the intermediate compound. "H NMR (500 MGu, SOSIz): 5 3.65-3.80(m, 4H), 3.30-3.40(m, 1H), 2.90-3.00(m, 1H), 2.30-2.70 (m, 4H). C(ii), with 0.221((1.4 mmol) H-(K,5)Ris(4-oxo)-OSH3 from the previous operation (ii), and 0.372g((1.4 mmol) cm

RI-ISN(OTVOM5)-С(ООН, prepared by the method described by Natadia ei ai. in U. At. Spet. Zos. (1989) 111 669, (o) with obtaining 0.288 g (5190) of an intermediate compound.

EAV-M5 t/2 406(M1)7

TN o NMR (B5О0МГЦц, СОСИ3);: 5 7.20-7.50(m, 5Н), 5.25-5.70(m, 2Н), 4.15-4.75(m, 1Н), 3.20-3.80(m, 4H), 2.00-2.90(m, ЗН), 1.30-1.65(m, 1H), 0.85-1.15(m, 9H ), 0.10-0.35 (m, 6Н). (im) RA--KYUSN(OOTVOM5)-C(O)-(K,5)Ris(4-oxo)-OH. A mixture of 0.28 (0.69 mmol) IU

RI-"KYUSN(OTVOM5)-C(O0)-(K,)Ris(4-oxo)-OSN from the previous operation (its) and TOml of a 2M solution of lithium hydroxide in TNE were stirred at room temperature for 1.5 hours. TNE was removed in vacuo, the residue was acidified to pH 2.0 with a 2M KH5BO solution, and extracted with ethyl acetate. The organic layer was washed with water, dried M9504 --

It was evaporated to give 0.24 g (8995) of the intermediate compound. Ge

EAV-M5 t/:2 392(M1)7

TN nMR (400MHz, SOSIz);: 8 7.20-7.55(m, 5H), 5.15-5.75(m, 2H), 4.10-4.30(m, 1H), 3 ,20-3.80(m, 1H), 2.05-3.00(m, 4H), 1.35-1.55(m, 1H), 0.90-1.05(m, 9H) , 0.10-0.25 (m, 6H). "(m). RY-(YUDSN(OTVOM5)-C(O)-(K,5)Ris(4-oxo)-Rab(7). The intermediate compound was prepared by the method of example 40 (iii), with 0.227 (0.58 mmol). RA-(IV)CH(OTVOM)-C(O0)-(B,5)Ris(4-oxo)-OH from the previous operation (mM) 3rd with a yield of 92 mg (24965) in EAV-M5 t/ 2 657(M1)7 i TN NMR (BOOMHC, SOSIz);: 5 6.90-7.90(m, 14Н), 5.10-5.80(m, 4Н), 3.60-4.70 (m, ЗН), 2.10-3.20(m, 4Н), 1.40-1.7О0(m, 1Н), 0.80-1.10(m, 9Н), 0.00-0 , 25 (m, 6H). 45 (m). РАЙУСН(ОТВОМ5)-С(О)-(К,)Ris(4-oxo)-Rab(7). The intermediate compound was prepared by the method according to (22) by the above operation (i), with 0.227 g (0.58 mmol) RA-"YUSN(OTVOM5)-C(O)-(K,B)Ris(4-oxo)-Rab(7) from - previous operation (y) with yield bimg 82965).

EAV-M5 t/2 543(M1)7 - TN o nNMR (B5О0МГЦц, СОСИ3);: 8 6.95-7.90(m, 14Н), 5.00-5.55(m, 4Н), 3 ,95-4,70(m, 2H), 3,20-3,70(m, 2H), layer 2000 1,20-2,80(m, 4H). (E). RA-SUYUSN(OH)-C(O0)-(K,5)Ris(4-oxo)-Rar x NODAs. The target compound was prepared by the method of Example 15(iii) from 0.061 g (0.11 mmol) of PA--"K)CH(OH)-C(O)-(K,5)Ris(4-oxo)-Rab( 7) from the previous operation (mi) with an output of 4bmg (9095).

I6-M5 t/2 407(M-1)7, 409(IMa1)7

TN NMR (400MGu, 020): 5 7.20-7.85(m, 9H), 5.00-5.80(m, 2H), 4.35-4.55(m, 2H), 3, 40-4.05(m, 2H), 1.80-3.10(m, 4H). (F) Example 58. RI-K)CH(OH)-C(0O)--K or 5)Ris(4-methylene)-Tab x NOAs and RIA-K)CH(OH)-C(O)- (5 or co ROS(4-methylene)-Rax NOAc. (Y) Bos-(K,5)Ris(4-methylene)-OSH»z. 2.68 g ((7.5 mmol) methyltriphenylphosphonium bromide was dried for 20 minutes under vacuum and suspended in 20 ml of dry TNE at 0"C. 4.7 ml of a 1.6N solution of butyllithium in hexane was added dropwise and the solution was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -78C and 1.3 g (5, 00mmol) Vos-(K,5)Ris(4-oxo)-OSNH3, see example 57(i), continued moving at -787С

30 minutes, and then another 2 hours at room temperature. Ammonium chloride was added to the mixture, and after separation of the aqueous layer, it was extracted twice with diethyl ether. The combined organic layer was washed and evaporated to give a crude product which was purified by flash chromatography with ethyl acetate hexane (Z0 : 79) as eluent. 0.27 g (9595) of the intermediate compound were obtained.

EAV-M5 t/:2 256(M-1)7

TN NMR (500MHz, SOSI"): 5 4.70-5.10(m, ЗН), 3.95-4.15(m, 1Н), 3.70(s, ЗН), 2.10- 3.10 (m, 5H), 1.35-1.60 (m, 9H). (i) NA(K,5)Ris(4-methylene)-OSNuz. 0.48g (1.8v8mmol) Bos-(K,5)Ris(4-methylene)-OSHz from the previous operation (i) was treated with 5095 bml of a solution of trifluoroacetic acid in dichloromethane at room temperature for 40 minutes.

The reaction mixture was evaporated, the residue was dissolved in dichloromethane, washed with aqueous sodium carbonate, dried with potassium carbonate and evaporated, obtaining 0.27g1(95905) of the intermediate compound.

TO NMR (500MHz, SOS): 85 4.70-4.85(m, 2H), 3.75(m, ЗН), 3.35-3.45(m, МН), 3.15-3, 25(m, 1H), 2.55-2.7O(m, 2H), 2.10-2.30(m, ЗН). (j) РА(СУСН(ОТВОМ5)-С(О0)-(К,)Ris(4-methylene)-ОСНi. The intermediate compound was prepared by the method according to example C(ii), with 0.21 g (1.4 mmol) of H -(K,5)Ris(4-methylene)-OSNuz from the previous operation (ii), and 0.37((1.4 mmol)

RI-ISN(OTVOM5)-С(ООН, prepared by the method described by Natadia ei ai. in U. At. Spet. Zos. (1989) 111 669, with a yield of 0.283 g (5290).

EAV-M5 t/2 404(M1)7

TN NMR (BOOMHC, SOSIz);: 5 7.25-7.55(m, 5BN), 5.15-5.70(m, 2H), 4.20-4.85(m, ЗН), 3 ,65-3.75(m, ЗН), 1.90-3.20(m, 5Н), 0.90-1.10(m, 9Н), 0.10-0.30(m, 6Н) . (m) PH-(YUDSN(OOTVOM5)-C(O)-(K,5)Ris(4-methylene)-SON. The intermediate compound was prepared by the method of example 57(im), with 0.28 ((0, 69 mmol) RIA-""YUSN(OTVOM5)-C(O)-(K,)Ris(4-methylene)-OSNuse from operation (iii) with a yield of 0.24 g (8995).

EAV-M5 t/h Z990(M1)"

TN o NMR (B5О0МГЦц, СОСИ3);: 5 7.15-7.50(m, 5Н), 5.15-5595(m, 2Н), 3.55-5.00(m, ЗН), 1, 75-3.25(m, 5H), 0.85-1.05(m, 9H), 0.10-0.25(m, 6H). (m) RANIUSN(OTVOM5)-C(O0)-(K,5)Ris4-methylene)-Rab(7). The intermediate compound was prepared according to the method of example C(ii), with 0.235 (0.bmmol) RA-IKDSN(OTVOM5)-C(O)-(K,5)Ris(4-methylene)-OH from the previous operation (im ) cm and 0.21140.6bmmol) H-Rac(72) x CARRIERS, with a yield of 124mg(3595). (at)

EAV-M5 t/2 655(M1)7

TN about nNMR (B5О0MGЦc, СОСИ3);: 8 7.10-7.90(m, 14Н), 5.15-5.70(m, 4Н), 4.10-5.05(m, 4Н), 1.75-3.05(m, bH), 0.80-1.10(m, 9H), 0.00-0.25(m, EN). food (m). RNIUSN(OTVOM5)-C(O0)-(K,5)Ris(4-methylene)-Rab(2). The intermediate compound was prepared by the method according to example 57(xi), with 0.08 ((0.12 mmol) РІ-ІІСН(ОТВОМ5)-С(О0)-(К,5)Ris(4-methylene)-Рац(2) from the previous operation about (y) with the output bomg(9196).

Go-M5 t/2 541(Ma1)7

TN about NMR (B5O00MHz, СО53О0): 5 7.15-7.90 (m, 14Н), 5.20-5.80 (m, 4Н), 4.35-4.90 (m, 4Н), 3 ,70-4.15(m, 1H), - 3.20-3.40(m, 1H), 1.10-2.90(m, 4H). (Ce) (mi) RA-A-'USCH(OH)-C(O)-(K or 5)Ris(4-methylene)-Rab x NOAc and RA-(USCH(OH)-C(O)- (5 or YuRis(4-methylene)-Rap x NOAc. A mixture of 0.0351 (0.065 mmol RI-«RIUSN(OTVOM5)-C(O0)-(K,5)Ris(4-methylene)-Rab(7) from the previous operation (mi), 0.50 (7.4 mmol) of ammonium acetate and 0.20 g (3.0 mmol) of imidazole in 1 ml of methanol were stirred overnight at 60°C. The reaction mixture was evaporated and the residue was subjected to preparative KRIS. Separate fractions was concentrated with a yield of 1.8 mg of compound 58B. Further fractions were concentrated with a yield of 7 mg of compound 56BA with a 0 Sh-s ratio of diastereomers 98: 2. t Compound 58A i IS-M5 t/2 405(M-1)7, 407( M1)7

TO NMR (400MHz, 020): 5 7.15-7.80(m, 9H), 5.65-5.70(m, 1), 4.80-5.25(m, 1), 4, 45-4.60(m, 2H), 3.60-4.00(m, 2H), 1.30-3.30(m, 6H). ia Compound 58B - II6-M8 t/2 407(M1)7

CHNO NMR (400 MHz, 050): 5 7.30-7.80(m, 9H), 5.45-5.75(m, 1H), 4.80-5.20(m, 1H), 4, 35-4.70(m, ZN), about 3.75-3.9(m, 1H), 1.70-3.05(m, 6H). (9) 50 Example 59. RA-(3-chloro)-(K,5)CH(OH)-C(O)-Age-Rab x NOAc. «mch () (Kk,5)-3Z-chloromandelic acid. The intermediate compound was prepared by the method of example 15) from 7.03 g (500 mmol) of 3-chlorobenzaldehyde with a yield of 2 g (21905).

I S-M5 t/2 185(M-1)7, 379(2M-1)7,

TN NMR (500 MGu, COzO0): δ 7.28-7.51 (m, 4H), 5.14 (s, 1H). (her) Ri-(3-chloro)-(K,5)CH(OH)-C(0)-Age-Rab(7). The intermediate compound was prepared by the method according to the example

F) C(iii), with 0.149 (0.8 mmol) of (K,5)-3-chloromandelic acid from the previous operation (ii) with a yield of 0.30 g (70905). co TN o nNMR (B5О0МГЦц, СОСИ3);: 8 7.08-7.84(m, 13Н), 5.18-5.24(m, 2Н), 4.86-5.01(m, 2Н) , 4.02-4.66(m, ЗН), 3.57-3.76(m, 1Н), 2.30-2.72(m, 2Н). 60 (its) Ry-(3Z-chloro)-(K,5)CH(OH)-C(OH)-Age-Par x NODAs. The target compound was prepared by the method according to example 43 from 0.10 g (0.19 mmol) of Ry-(3-chloro)-(K,5)CH(OH)-C(O0)-Age-Rac (72) from the previous operation ( iii) with a yield of 50 Mmg (63905).

IS-M5 t/2 399(M-1)7, 401(M1)7

TN NMR (400MHz, 0250): 5 7.10-7.85(m, 8H), 4.82-5.37(m, 2H), 3.96-4.79(m, 4H), 2, 14-2.85 (m, 2H). for 13C nMR (100.6 MHz, 020, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: 5 174.00, 173.17, 172.83, 172.61, 166.59.

Example 60. PA(3-chloro,4-0OH)-(K,5)CH(OH)-C(O0)-Pho-Rab x NOAc (Y) Ry(3-chloro,4-0OH)-(K ,5)CH(OH)-C(O)-Pho-Rac(7) The intermediate compound was prepared by the method according to the example

III) with 0.251 (1.2 mmol) (K,5)-3-chloro-4-hydroxymandelic acid and 0.6151 (1.35 mmol) H-Pho-Rab(2) x 2HCl, see example C5(iii), with a yield of 0.382 g (55905).

I s-m t/2 564(M-1)7

TN nMR (400MHz, СО3О0): 5 6.80-7.85(m, 12Н), 5.16-5.25(m, ЗН), 4.35-4.51(m, ЗН), 3, 45-3.75(m, 1H), 3.07-3.42(m, 1H), 1.72-2.18(m, 4H). 13C nMR (100.6 MHz, CO3O0, the spectrum is complicated by the presence of diastereomers/rotamers) amidine and carbonyl carbons: δ 174.62, 174.27, 173.02, 172.88, 170.41, 165.04. (i) PA(3-chloro,4-OH)-(K,5)CH(OH)-C(0)-Pho-GTar x NOAc. The target compound was prepared by the method of example 43 from 0.10 g (0.177 mmol) of РА(3-chloro,4-OH)-(K,5)CH(OH)-C(O)-Pho-Rab(2) from the previous operations (Her),

3.17 ml (48 mmol) of trifluoroacetic acid and 1.04 ml (8.85 mmol) of thiosanizole with a yield of 57 mg (70905). 12 IS-M5 t/2 431(M)"

TN NMR (400MGu, 020): 5 6.84-7.86(m, 7H), 5.29-5.42(m, 1H), 4.30-4.68(m, ЗН), 3, 05-4.05(ts, 2H), 1.70-2.37(m, 4H).

Example 61.

The target compounds from examples 1 - 60 were tested for the above-described test A, and it was determined that their ICoo values are less than 0.ZCM.

Abbreviation: hell - water

Ae - azetidine-2-carboxylic acid,

Vos is tert-butyloxycarbonyl

Vp - benzyl ch 29 Vy - butyl Ge)

Sp - cyclohexyl ros - dicyclohexylcarbodiimide

OPIREA - diisopropylethylamine

LOBSTER - M,M-dimethylaminopyridine -

OME - dimethylformamide IS o)

EBS - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Eg-ethyl o

EUN - ethanol --

NOAc - acetic acid

NOBZy - M-hydroxysuccinimide і-o

H-bid - 1-amidino-3-aminoethylazetidine

H-Oid(2) - 3-aminoethyl-1-(M-benzyloxycarbonylamidino)dazetidine

H-Nide - 1-amidino-3-aminoethylpyrrolidine "

H-Nid(2) - 3-aminoethyl-1-(M-benzyloxycarbonylamidino)pyrrolidine with 70 H-Ras - 1-amidino-4-aminomethylcyclohexane with H-Rad(2) - 4-aminomethyl-1-(M-benzyloxycarbonylamidino )cyclohexane:z» H-Ris - pipecolinic acid

H-Ride - 1-amidino-3-aminomethylpiperidine

H-Ryd(2) - 3-aminoethyl-1-(M-benzyloxycarbonylamidino)piperidine y and b H-Ray - 1-amidino-3-aminomethylbenzene

H-Rac(2) - 3-aminoethyl-1-(M-benzyloxycarbonylamidino)benzene - ROSS - pyridinium chlorochromate o NRGIS - high performance liquid chromatography

Me - methyl c 70 RA - phenyl -h KRI C - high-performance liquid chromatography with reversed phase zy - succinimide tTvOMm5 - t-butyldimethylsilyl

TV - tetrafluoroborate (M,M,M',M'-tetramethyl-O-(benzotriazol-1-yl)uronium

TNE - tetrahydrofuran

HF) TNR - tetrahydropyranil 7 TM - trimethylsilyl

MUZSIII - water-soluble carbodiimide 7 - benzyl 60 Prefixes n, v, i and t have their usual meanings: normal, iso, secondary and tertiary. Stereochemistry for amino acids is given without a label(5) unless otherwise specified.

Claims (44)

The formula of the invention b5 1. Compound of the formula ke i 1 Kk M u or X (snayuttB 70 v? v o My where r and 4 are independently equal to 0, 1, 2, Z or 4; B - H, 2,3-epoxypropyl, Su alkyl (in which the last group is optional substituted or terminated by one or more hydroxyl groups), a structural fragment of the formula Ia ;Ia va o (c; ki 5 di i : : : 1 ch in which A" is a single bond or C). dalkylene, and KH is H or C. . dalkyle provided that the chain KH-C-C-A" has no more than six of carbon atoms, or, when p is 0, together with 22 is a structural fragment of formula IB and9) . Me) sn, i- Sn; IS) o o "- V! (Se) where KU - N or S. zalkil; b2 - H, vi(Me)z, naphthyl, indolyl, SNK?!B22 or C. dalalkyl (in which the last group is optionally substituted or terminated by one or more hydroxyl groups or fluorine atoms), or Cz dicycloalkyl or phenyl ( in which the last two groups are optionally substituted or terminated by one or more C. alkyl, C. daloxyl, halogen, - with hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, M(H)B2Z, C( 0)0O2273, or, when p "" is equal to 0, together with B! is a structural fragment of the formula IB; " 23 - H, b((Me)z, naphthyl, indolyl, СНЕ2?Б2Э or C. alkyl (in which the last the group is optionally substituted or terminated by one or more hydroxyl groups or fluorine atoms), or C3 dicycloalkyl or phenyl (in which F 45 the last two groups are optionally substituted or terminated by one or more C). alkyl, C. lalkoxy, halogen, hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, MINOV27, C(FOOV 28); - 22, 122, B25 and 29 independently - cyclohexyl or phenyl; about 23 and B?" independently - H, Si dalkil or C(IO)B29; si 227, 28 and K?9 independently - H or Su lalkil; V - N or S. dalkil; "and МУ - C. dalkylene, optionally substituted by C. .alkyl, hydroxy-, methylene or oxo groups; n equals 0, 1, 2, З or 4; and В - structural fragment of the formulas Ма, ИМб or ИМс ; Ма Ф ) name) 60 t dk NM Mn, Still) hny re NM Mn, ; Me s 7 nm mn, o where B5 - H, halogen or S. dalkil; and why X' and X2 independently - a single bond or CH»5; under the condition that when КВ", Б, В - Н, р is equal to 0, У - (СН2)", н is equal to 1 а: о (а) ВЗ - unsubstituted phenyl, and: (ав) (І) В - structural a fragment of the formula Ma, and BZ - H, then d is not equal to 0 or 1; and "- (i) B is a structural fragment of the formula MB, and X! and X? are both CH", then 4 is not equal to 0; and Zo ( c) EZ is unsubstituted cyclohexyl, B is a structural fragment of formula Ma, and В is H, then 4 o is not equal to 0, or its salt is pharmaceutically acceptable. 2. The compound according to claim 1, which differs in that n is equal to 1, when B is a structural fragment of the formula Ма, ИМс « or ИМБ, in which further fragments Х! and X2 - the CH group". from 70 Z. The compound according to claim 1, which differs in that n is equal to 2, when B is a structural fragment of the IMB formula, in which X! - a single connection, and X? - a single connection or a group of SN". ;" 4. A compound according to claims 1 or 2, which differs in that Б is Н, when В is a structural fragment of the formula Ma. 5. The compound according to any of claims 1-4, which differs in that B7-n. 6. A compound according to any of claims 1-5, which differs in that p is equal to 0. Ge") 7. The compound according to any of claims 1-6, which differs in that M is CH», (СНо)», (СНо)з, СНСН(СНУЗ)СН», with СНХС(О)СН» or СНоОС( -СНО)СН». 8. The compound according to claim 7, which differs in that U is СНо, (СНо)» or СНОС(-СНО)СН». (av) 9. The compound according to any of claims 1-8, which differs in that B! - H, methyl, 2,3-dihydroxypropyl. or cl 50 (2,2-dimethyl-1,3-dioxalan-4-yl)umethyl. 10. The compound according to claim 9, which differs in that v/!- nn. "m 11. The compound according to any one of claims 1-10, which differs in that 4 is equal to 0, 1 or 2. 12. The compound according to claim 11, which differs in that 4 is equal to 0. 13. The compound according to any of claims 1-12, which differs in that K2 is optionally substituted S. lalkil. or 29 optionally substituted phenyl. GF) 14. The compound according to claim 13, which differs in that when 22 is an optionally substituted C..alkyl, a possible substituent is hydroxyl. at 15. The compound according to claim 14, which differs in that when the hydroxyl group is attached to a carbon atom, the latter is in the position relative to the carbon atom to which the OB group is attached. 16. The compound according to claim 13, which differs in that in 2 - H, methyl, hydroxymethyl or ethyl. 17. A compound according to any one of claims 1-16, which is characterized by the fact that 3 is C 1 alkyl, naphthyl, indolyl, optionally substituted cyclohexyl or optionally substituted phenyl. 18. The compound according to claim 17, which differs in that KZ is optionally substituted phenyl or optionally 65 substituted cyclohexyl. 19, A compound according to any of claims 1-18, which differs in that У is СНо or СНоС(-СНо)СН», when В! and B? - both H, BZ - unsubstituted phenyl or unsubstituted cyclohexyl, and 4 is equal to 0 or 1. 20. A compound according to any of claims 1-18, which differs in that b2 is methyl, hydroxymethyl or ethyl, when B/- H, 83 is unsubstituted phenyl or unsubstituted cyclohexyl, and 4 is 0 or 1. 21. A compound according to any of claims 1-20, which is characterized by the fact that 3 is substituted by one or more hydroxy-, fluorine, chlorine, methyl, methoxy-, amino-, nitro-, trifluoromethyl-, methylenedioxy-, ethoxy, and propoxy groups , when it is optionally substituted phenyl or optionally substituted cyclohexyl. 22. The compound according to claim 21, which differs in that 3 is substituted by one or more hydroxy-, mono- or difluoro, chlorine, methyl, methoxy or methylenedioxy groups. 23. The compound according to any of claims 1-22, which differs in that U is CH". 24. A compound according to any of claims 1-23, which differs in that B is a structural fragment of formula Ma. 25. The compound according to any one of claims 1-24, which differs in that the carbon atom of the E-amino acid in the fragment 4 Kk DA chech (o) has a 5-configuration. p. 29 26. The compound according to any of claims 1-25, which differs in that when B and in? - both H, and p Ge) is equal to 0.7 - carbon atom in fragment c; and re 5 IS) "c) Hn siv" - 3 (Se) has a K-configuration. 27. The compound according to claim 1, which differs in that it is: Sp-(K,5)CH(OH)-C(O)-Age-Rab; "Sp(Y)CH(OH)-C(O)-Age-Rab; in c RI--BYUSN(OH)-S(O)-Age-Rab; Y Ry(3-Me)-(K,5)CH(OH)-C(O)-Age-Rab; and PH(Z3-OMe)-(K,5)CH(OH)-C(O)-Age-Rab; RA(3,5-diOMe)-(K,5)CH(OH)-C(O)-Age-Rarb; Ry(3-OMe,4-OH)-(K,5)CH(OH)-C(O)-Age-Rab; b RA-"K,5)C(EO(OH)-C(O)-Age-Rab; RA-"K,5)C(EC(OH)-C(O)-Rho-Rab; - RA" -C(OH)-C(O)-Age-Rab; o Ry(3-OMe,4-OH)-(K,5)CH(OH)-C(O)-Pho-Rab; РЙ--ЮСН (OH)-C(O)-Age-Ras; o RI--YUSN(OH)-C(O)-(K,5)Ris(cis-4-Me)-Rab; and RA(3,4- --0-CH»-0-))-(K,5)CH(OH)-C(O)-Age-Rab; Ry(3-OMe)-(K,5)CH(OH)-C(O)-Pho-Rab; PA(3,5-diOMe)-(K,5)CH(OH)-C(O)-Pho-Rab; 5B РИ-«К,5)С(МехоОН)-С(О)-Age-Rarb; RA-(3,5-dimekh,5)C(OH)-C(O)-Age-Rab; (F, RA(3-MH")-(K,5)CH(OH)-C(O)-Age-Rab; ka RA(3-MH")-(K,5)CH(OH)-C (O)-Pho-Rab; Ry(3-MO2")-(K,5)CH(OH)-C(O)-Pho-Rab; 60 RA(3,4---0-CH"-0 -))-(K,5)CH(OH)-C(O)-Pho-Rab; РНА(3,5-difluoro)-(K,5)CH(OH)-C(O0)-Pho-Rab; РЙ--ЮХСН(О-СН»-(К,5)СН(-О-С(СН 3)2-ОО-СН»-))-С(0)-Аге-Раб; Ry-"YUS(Me)HON)-S(O)-Rgo-Rab; RI-(5)C(Me)C(OH)-C(O)-Rho-Rab; 65 Ry-(3,4-difluoro)-(K,5)CH(OH)-C(O0)-Pho-Rab; РІ--ЮЮСН(ОН)-С(О)-(К,5)Ris(4-methylene)-Rab; Ri(3-CI)-(K,5)CH(OH)-C(O)-Age-Rab; РА-(К,5)С(-ОО-СК(СН 3)5-ОО-СН»-)-С(О)-Age-Rarb; RA-(K,5)K(-0O-SK(CH3)5-0O-CH»-)-C(O0)-Pho-Rab; RA-«K,5)С(СНоОНХОН)-С(О)-Аге-Rab; or RA-«К,5)К(СНоОНХОН)-С(О)-Рго-Раб. 28. The compound according to any one of claims 1-27, which differs in that it is used in pharmaceuticals. 29. A compound according to any one of claims 1-27, characterized in that it is used in the treatment of conditions where inhibition of thrombin is required. 70 30. A compound according to any one of claims 1-27, which is characterized in that it is used in the treatment of thrombosis. 31. The compound according to any one of claims 1-27, which is characterized in that it is used as an anticoagulant. 32. A compound according to any one of claims 1-27, which is an active ingredient in the manufacture of a medicament for the treatment of conditions where inhibition of thrombin is required. 33. The compound of claim 32, wherein the condition is thrombosis. 34. The compound according to any one of claims 1-27, which is characterized in that it is an active ingredient in the production of anticoagulants. 35. The compound according to claim 1, which is characterized by the fact that, regardless of the conditions, β3-phenyl is substituted by one or more substituents selected from the group consisting of M(H)K2" and halogen. 36. The compound according to claim 35, which differs in that KZ is phenyl, substituted by M(H)B2" and halogen. 37. The compound according to claim 36, which differs in that KZ is phenyl, substituted by MSH(H)B2" and chlorine. 38. A pharmaceutical composition comprising a compound defined by any one of claims 1-27, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable excipients, diluents or carriers. 39. A method of treating conditions requiring thrombin inhibition, comprising administering to a subject suffering from or susceptible to such conditions a therapeutically effective amount of a compound according to any one of claims 1-27. with 40. The method according to claim 39, characterized in that the condition is thrombosis. d) 41. The method according to claim 39, which is characterized by the fact that the condition is the ability to hypercoagulate in blood or tissues. 42. The method of obtaining the compound defined according to claim 1, in which: a) the interaction of the compound of the formula M is carried out, which is defined in claim 1, with the compound of the formula MI " ; MI in - 5 AH ;" n-m U F (snayutB o My - o where c, U, n and B are defined in claim 1; or b) the interaction of the compound of the formula MII 1 G-zi ; MI and Y X I) in, in 7 snu sna a o I. 1, where) in "o on wo de r, a, VE", B2, VU, 27 and U are defined in claim 1, with the compound of the formula MIIII НМ-(СНо)д-В, МИ! where n and B are defined in claim 1. 43. Compound of the formula KHIM b5 ; ЧИМ ое и АХ nус, св Х -- DV t ia b mi Tk de В" - a structural fragment of the formula Ma, Me or MG , Ma v r'm mno!; Me s (8) in 2 nm Zh iy o'm mno" about KM - (Se) "shi s;" r'm much? Gee! where 0! and 02 - independently H or benzyloxycarbonyl, and p, 4, B", 2, KU, B", Y, p, VU, X! and X7, defined in clause - 1, provided that 0! and 02 are both not N. 44. The compound of the formula (ав) о в ШЧИ ги х М У Сл (sna 2 Z Ф in theo we name) where r and 4 are independently equal to 0, 1. in K'-nH, b2-n, BZ - phenyl (in which the last group is replaced by one or more C dalalkyl, C 1 lalkoxyl, halogen, hydroxy-, cyano-, nitro-, methylenedioxy-, trifluoromethyl groups, MSH(H) B2", С(ФО)ОВ 2); 221 - H, Su dalkil or SIODOV 29; because 228229. regardless of H or Si dalkil; V - N or S. dalkil; M - C. alkylene, optionally substituted by C. alkyl, hydroxy-, methylene or oxo groups; n is equal to 1 and B is a structural fragment of formula Ma; Ma b- na Mn, where B5 - H, halogen or S. dalkil, Also) ' 2 ra 7 nm MN, IM i- , Me yu "v) "- (Se) shi s nm Mn, z de X! and X? regardless - single connection or CH". Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated Ge" microcircuits, 2003, M 11, 11/15/2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - («c) with 50 what F) name) 60 b5