Peptide derivatives, their stereoisomers, or a physiologically acceptable salt with antithrombotic, anticoagulant or anti-inflammatory activity, the method of production thereof, pharmaceutical composition, method of suppressing thrombin, a method of suppressing kininogens, the use of compounds as a source in the synthesis of the thrombin inhibitor

 

(57) Abstract:

The peptide derivative of General formula I AND1- AND2- NH -(CH)n- D, where a1a structural fragment of formula IIA-d, k = 0-3, m = 1, 2; q = 0, 1, 2 or 3; R1- H1-4alkyl, R11OOC-alkyl (other designations, see item 1 f-crystals of the invention). The compounds of formula I are effective inhibitors of serine proteases, especially thrombin, and kininogens, such as kallikrein. 10 C. and 28 C.p. f-crystals, 2 PL.

The invention relates to new competitive inhibitors of trypsin-like serine proteases, especially thrombin, and kininogens, such as kallikrein, their synthesis, pharmaceutical forms containing these compounds as active ingredients, and to the use of these compounds as thrombin inhibitors and anticoagulants, as well as anti-inflammatory drugs. The invention relates also to a new use of compounds as starting products in the synthesis of inhibitors of the serine protease. Additionally, the invention relates to new fragments in the structure of the inhibitors of the serine protease.

Coagulation of blood is a key process involved in hemostasis (i.e., preventing blood loss from the damages the Oia is the result of a complex series of enzymatic reactions, where one of the final stages is turning proferment of prothrombin to the active enzyme thrombin.

Thrombin plays a Central role in coagulation. Thrombin activates platelets, converts fibrinogen into fibrin monomers, which spontaneously polymerize into filaments, and activates factor XIII, which in turn knits polymer to insoluble fibrin. Fibrin also activates factor V and factor VIII in a reaction with positive feedback. Thus, it is expected that thrombin inhibitors are effective anticoagulants by inhibiting platelets, inhibiting the formation and stabilization of thrombin. It is expected that by suppressing mechanism of positive feedback inhibition by them is in the early stages in the chain of events leading to koagulirovannogo and thrombosis.

Kininogenase belong to the serine-proteases that act on kininogen with the formation of kinins (bradykinin, kallidin and Met-Lys-bradykinin). The most important kininogenase are kallickrein plasma kallickrein tissues and tryptase of mastocytes.

Kinini (bradykinin, kallidin), as a rule, participate in the inflammatory process. For example, the process of active inflammation bind xsdt contains all of the protein system of the circulating blood. Originating from plasma kininogen inevitably react with different kallikreins continuous formation of kinins as long as you continue the active process of exudation of plasma. The exudation of plasma occurs regardless of the mechanism involved in inflammation, whether it is allergies, infection or other factors (Persson and others , edited by Thorax, 1992, 47, 993-1000). Thus, the exudation of plasma is a symptom of many diseases, including: asthma, rhinitis, rhinitis, and inflammatory bowel disease. In particular, when Allergy is the selection of tryptase mastocytes (Salomonsson, etc., Ann. Rev. Pespir. Dis., 1992, 146, 1535-1542) contribute to the formation of kinins and other pathogenic factors in asthma, rhinitis and bowel disease.

From a biological point of view kinini belong to highly active substances acting on the smooth muscles, secretory activity, neurogenic activity and action, capable of influencing inflammatory processes, including activation of phospholipase A2and increases vascular permeability. The latter effect is potentially induces a continuous cycle with the participation of kinins with the formation of an increasing number of kinins, etc.

TKA is built kallickrein preferably forms a bradykinin from high-molecular kininogen.

The first reports about the thrombin inhibitors based on amino acid sequence near the site of cleavage for A chain of fibrinogen are working Blomback and others (J. Clin. Lab. Invest. 24, suppl. 107, 59 (1969), in which it is assumed that the sequence Phe-Val-Arg (P9-P2-P1, hereinafter referred to as P3-P2-P1 sequence) is the best inhibitor.

In U.S. patent 4,346,078 (S. Bajusz and others) as an inhibitor of thrombin revealed H-DPhe-Pro-Agm, i.e. dipeptidyl derived from aminoalkyl guanidine in the P1-position.

Thrombin inhibitors based on peptide derivatives with cyclic aminoalkyl guanidine, e.g., 3-aminomethyl-1-aminopiperidine in the P1-position are disclosed in EP-A2-0,468,231.

In EP-A2-0,185,390 (S. Bajusz and others) have shown that replacement of agmatine arginine aldehyde leads to thrombin inhibitor with a much higher efficiency.

Earlier there were reports about the inhibitors of kallikrein, based on amino acid sequence near the site of cleavage of the Arg-Ser.

In the works of Kettner and Shaw (Biochemistry 1978, 17, 4778-4784 and Meth. Enzym. 1981, 80, 826-842) reported chloromethylketone arginine formulas H-DPro-Phe-Arg-CH2Cl and H-DPhe-Phe-Arg-CH2Cl as inhibitors of kallikrein Pak about the inhibitors of plasma kallikrein, are given in the work Farred and others (Ann. N. Y. Acad. Sci. 1981, 370, 765-784).

Inhibitors of serine proteases based on electrophilic ketones, and not on the aldehydes in the P1-position are disclosed in the following patent publications.

In EP-A2-0,195,212 disclosed peptidyl - ketoesters and amides, in EP-A1-0,362,002 revealed foraminotomy and in EP-A2-0,364,344 disclosed,- trichloroethane with different properties of peptidase inhibitors.

Inhibitors of trypsin-like serine proteases, such as thrombin and kallikrein, based on C-terminal derivatives of arginine with Bronevoy acid, and isothiuronium analogues of these derivatives are disclosed in EP-A2-0,293,881.

In patent WO 92/04371 disclosed inhibitors kininogenase, e.g., inhibitors of kallikrein based on derivatives of arginine.

In the patent EP-A1-0,530,167 disclosed - alkoxycarbonyl arginine as inhibitor of thrombin.

The present invention is to create a new and effective inhibitors of trypsin-like serine protease, especially anticoagulant and anti-inflammatory compounds with competitive inhibitory activity against their enzymes, i.e., causing reversible inhibition. More to what had been forecast thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial infarction and cerebral thrombosis, state total sverkayuschie and States local sverkayuschie, for example, after plastic surgery on the blood vessels and coronary bypass operations and other situations in which, as I believe, plays its role thrombin, for example, in Alzheimer's disease, as well as for inhibition of kininogens in the treatment of inflammatory disorders, such as asthma, rhinitis, urticaria, inflammatory bowel disease and arthritis. Another objective of the invention is to obtain inhibitors of thrombin, which is characterized by the oral bioavailability and selective inhibition of thrombin compared with other serine-proteases. Another object of the invention is to obtain inhibitors kininogens, which can be administered orally, rectally, topically, for example, by application to the skin or by inhalation.

Connection

In accordance with the invention it was found that the compounds of General formula 1, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors of serine proteases, especially thrombin and kininogens, for example, kallikrein:

< / BR>
where k is an integer 0, 1, 2, 3 or 4;

m is an integer 1, 2, 3 or 4;

q is an integer 0, 1, 2 or 3;

R1represents H, alkyl group with 1 to 4 carbon atoms, or R11-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p is an integer 0, 1 or 2 and R17is methyl, phenyl, OH, COOR12, CONHR12where R12- H or an alkyl group with 1 to 4 carbon atoms and R11- H or an alkyl group with 1 to 6 carbon atoms, or

R1is Ph (4-COOR12)-CH2- where R12accept above values, or

R1is R13-NH-CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms, and where R13Is H, an alkyl group with 1 to 4 carbon atoms or-CH2-COOR12where R12accept above values, or R1is R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with/SUP>SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12accepts the above meanings and R14is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1represents-CO-OR15where R15accept above values, or

R1represents-CO-(CH2)p-COOR12where R12takes values above, p is an integer 0, 1 or 2, or

R1represents-CH2PO(OR16)2, -CH2SO3H or-CH2-(5-(1H)-tetrazolyl), where R16independently in each case represents H, methyl or ethyl;

R2represents H, alkyl group with 1 to 4 carbon atoms, or R21OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and where R21- H or an alkyl group with 1 to 4 carbon atoms;

R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms, or

R3is cyclopentyloxy, tsiklogeksilnogo or phenyl groups which are unsubstituted or substituted alkyl group with 1 to 4 atoms alcalina group 1 4 carbon atoms and k = 0, 1, or

R3is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or TRANS-calinowo group and k = 0, 1, or

R3is 4-pyridyl, 3-pyrrolidyl or 4-indolyl, which is unsubstituted or substituted by a group OR31where R31accept above values, and k = 0, 1, or

R3is Si(Me)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents H, alkyl group with 1 to 4 carbon atoms, cylcohexane or phenyl group;

A2represents a structural fragment of formula IIIa, IIIb and IIIc

< / BR>
where p = 0, 1, or 2;

m = 1, 2, 3 or 4;

Y represents a methylene group or

Y represents an ethylene group, and educated in the 5-membered cycle unsubstituted or substituted by one or two fluorine atoms, a hydroxy-group or oxopropoxy in the 4-position, or unsaturated, or

Y represents-CH2-O-, -CH2-S-, -CH2SO with heteroatomic functionality at the 4-position, or

Y is n-propylene group, and educated in the 6-membered cycle unsubstituted or substituted in 5-position by one fluorine atom, hydroxyprop is ogenyi or may contain in the 4-position of the alkyl group with 1 to 4 carbon atoms, or

Y represents-CH2-O-CH2-, -CH2-S-CH2-, -CH2-SO-CH2- or

Y represents-CH2-CH2-CH2-CH2-;

R3accept above values;

R5represents H or alkyl group with 1 to 4 carbon atoms or

R5represents-CH2p-COOR51where p = 0, 1 or 2 and R51- H or an alkyl group with 1 to 4 carbon atoms;

n = 0, 1, 2, 3 or 4;

B represents a structural fragment of formula IVa, IBb, IVc, or IVd:

< / BR>
where r = 0 or 1;

X1is CH2, NH or is absent;

X2is CH2, NH or C=NH;

X3represents NH, C=NH, N-C(NH)-NH2CH-C(NH)-NH2CH-NH-C(NH)-NH2or CH-CH2-C(NH)-NH2;

X4is CH2or NH;

The recommended combinations of X1X2X3X4and r are:

X1X2and X4group CH2X3group CH-C(NH)-NH2and r = 0, 1, or

X1X2and X4group CH2X3group N-C(NH)-NH2and r = 0, 1, or

X1and X3group NH, X2- group C=NH, X4group CH2and r = 0, 1, or

X1and X4group CH2X2 - group C=NH and r = 0, 1, or

X1X2and X4group CH2X3group CH-NH-C(NH)-NH2and r = 0, 1, or

X1no, X2and X4group CH2X3group CH-C(NH)-NH2and r = 0 or

X1no, X2and X4group CH2X3group N-C(NH)-NH2and r = 0.

It is especially recommended combinations of X1X2X3X4and r are:

X1X2and X4group CH2X3group CH-C(NH)-NH2and r = 1;

X1X2and X4group CH2X3group N-C(NH)-NH2and r = 0 or 1;

X1no, X2and X4group CH2X3group N-C(NH)-NH2and r = 0;

X1and X3group NH, X2- group C=NH, X4group CH2and r = 1;

X5represents C(NH)-NH2or NH-C(NH)-NH2;

R6- H or an alkyl group with 1 to 4 carbon atoms;

X6represents CH or n

The recommended compounds of formula I include compounds having the S-configuration amino acid A2and of these compounds, especially preferred are also compounds with R-configuration amino acids (A1.

In the context of the to a straight or branched group. An alkyl group with 1 to 4 carbon atoms can be represented by stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, second-bootrom and tert-bootrom.

In the context of the present invention, the term "alkyl group with 1 to 6 carbon atoms", unless otherwise specified, refers to a straight or branched group. An alkyl group with 1 to 6 carbon atoms can be represented by stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, second-bootrom, tert-bootrom, n-Pentium, isopentyl, tretention, neopentyl, n-hexyl or isohexyl. When reference is made to the unsaturation, in this case we are talking about the carbon-carbon double bond.

The wavy line on the carbon atom in the carbonyl group in formula IIa, IIb, IIc, IId, IIe, IIIa, IIIb, IIIc, the nitrogen atom in formula IIIa, IIIb, IIIc and V of the carbon atom in the cyclic system in formulas IVa, IVb, IVc, IVd means the position of the link in the snippet.

The list of possible applications of abbreviations is given at the end of this description.

According to the present invention discovered that the compounds of formula Ia, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors of thrombin:

A1c or IId, preferably IIa or IIb;

where k = 0, 1, 2, 3 or 4, preferably 0, 1;

q = 0, 1, 2 or 3, preferably 1;

R1represents H, alkyl group with 1 to 4 carbon atoms, R1IOOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p = 0, 1, or 2, R17is methyl, phenyl, OH, COOR12, CONHR12where R12- H or an alkyl group with 1 to 4 carbon atoms and R11- H or an alkyl group with 1 to 6 carbon atoms, or

R1is Ph(4-COOR12)-CH2- where R12accept above values, or

R1is R13-NH-CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R13represents H, alkyl group with 1 to 4 carbon atoms or-CH2-COOR12where R12accept above values, or

R1is R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R1 2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12accepts the above meanings and R14is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1represents-CO-OR15where R15accept above values, or

R1represents-CO-(CH2)p-COOR12where R12takes values above, p is 0, 1 or 2, or

R1represents-CH2PO(OR16)2, -CH2SO3H or-CH2-(5-(1H)-tetrazolyl), where R16independently in each case represents H, methyl or ethyl.

Preferably R1is R11-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms, and R11- H.

R2represents H, alkyl group with 1 to 4 carbon atoms, or R21OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms, and R21- H or an alkyl group with 1 to 4 carbon atoms;

R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms, or

R3is cyclopentyloxy, tsiklogeksilnogo and the/SUP> is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or TRANS-calinowo group and k = 0, 1, or

R3is Si(Me)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents an alkyl group with 1 to 4 carbon atoms, cylcohexane or phenyl group, preferably tsiklogeksilnogo or phenyl group;

A2represents a structural fragment of formula IIIa, IIIb or IIIc, preferably IIIa,

where p = 0, 1, or 2;

m = 1, 2, 3 or 4, preferably 2, 3;

Y represents a methylene group or

Y represents an ethylene group, and educated in the 5-membered cycle unsubstituted or substituted by one or two fluorine atoms, a hydroxy-group or oxopropoxy in the 4-position, or may be saturated or unsaturated, or

Y represents-CH2-O-, -CH2-S-, -CH2SO with heteroatomic functionality at the 4-position, or

Y is n-propylene group, and educated in the 6-membered cycle unsubstituted or substituted in 5-position by one fluorine atom, hydroxy-group or exography, substituted by two fluorine atoms in one of the 4 - or 5-positions, can be nonsystematically-CH2-O-CH2-, -CH2-S-CH2-, -CH2-SO-CH2- or

Y represents-CH2-CH2-CH2-CH2-;

R3represents an alkyl group with 1 to 4 carbon atoms or

R3represents a group Si(Me)3;

R5represents H or alkyl group with 1 to 4 carbon atoms, preferably H or methyl, or

R5represents -(CH2)p-COOR51where p = 0, 1 or 2 and R51- H or an alkyl group with 1 to 4 carbon atoms, preferably p = 0, and R51- H;

n = 0, 1, 2, 3 or 4, preferably 1, 2, 3;

B represents a structural fragment of formula IVa, IBb, IVc or IVd, preferably IVa or IVb;

where X1X2X3X4X5and X6take the above values;

r = 0 or 1;

R6- H or an alkyl group with 1 to 4 carbon atoms, preferably H;

the recommended combinations of X1X2X3X4and r are:

X1X2and X4group CH2X3group CH-C(NH)-NH2and r = 0 or 1, or

X1X2and X4group CH2X3group N-C(NH)-NH2and r = 0 or 1, or

X1and X3group NH, X2- group C=NH, X4group CH2and R>
X1group CH2X2and X4group NH, X3- group C=NH and r = 0, 1, or

X1X2and X4group CH2X3group CH-NH-C(NH)-NH2and r = 0, 1, or

X1no, X2and X4group CH2X3group CH-C(NH)-NH2and r = 0, 1, or

X1no, X2and X4group CH2X3group N-C(NH)-NH2and r = 0;

it is especially recommended combinations of X1X2X3X4and r are:

X1no, X2and X4group CH2X3group N-C(NH)-NH2and r = 0 or

X1X2and X4group CH2X3group CH-C(NH)-NH2and r = 1, or

X1X2and X4group CH2X3group N-C(NH)-NH2and r = 0, 1, or

X1and X3group NH, X2- group C=NH, X4group CH2r = 1;

X5represents C(NH)-NH2or NH-C(NH)-NH2; preferably C(NH)NH2;

X6represents CH or n

According to a recommended embodiment of the invention relates to compounds of formula Ia,

where

A1represents a structural fragment of formula IIa, where

k = 0 or 1;

R1is /BR>R2represents H;

R3is tsiklogeksilnogo group;

A2represents a structural fragment of formula IIIa, where

Y represents a methylene group, ethylene group or a n-propylene group, an educated and 6-membered cycle unsubstituted or substituted in the 4-position of the alkyl group with 1 to 4 carbon atoms, preferably Y represents a methylene, ethylene;

R5represents H;

B represents a structural fragment of formula IVa, where

X1no, X2and X4group CH2X3group N-C(NH)-NH2r = 0, n = 1 or 2;

X1and X3group NH, X2- group C=NH, X4group CH2, r = 1, n = 2, or

X1X2and X4group CH2X3group CH-C(NH)-NH2, r = 1, n = 1, or

X1X2and X4group CH2X3group N-C(NH)-NH2r = 0 or 1, n = 1 or 2, or

more preferable compounds where B represents a structural fragment of formula IVb, where

X5represents C(NH)-NH2, R6- H, n = 1.

The recommended compounds of the invention include compounds of formula:

HOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-(R)Cgl-Pro-Pab

H-(R)Cha-Aze-Pab

HOOC-CH2-(R)Cha-Aze-Pab

HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Aze-Pab

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Aze-Pab/a

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Aze-Pab/b

HOOC-CH2-CH2-(R)Cha-Aze-Pab

HOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab

H-(R)Cha-Pro-Pab

HOOC-CH2-(R)Cha-Pro-Pab

HOOC-CH2-(Me)(R)Cha-Pro-Pab

HOOC-CH2-CH2-(R)Cha-Pro-Pab

HOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pro-Pab/a

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pro-Pab/b

HOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab

EtOOC-CH2-CH2-CH2-(R)Cha-Pro-Pab

Ph(4-COOH)-SO2-(R)Cha-Pro-Pab

H-(R)Cha-Pic-Pab

HOOC-CH2-(R)Cha-Pic-Pab

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pic-Pab/a

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pic-Pab/b

HOOC-CH2-CH2-(R)Cha-Pic-Pab

HOOC-CO-(R)Cha-Pic-Pab

HOOC-CH2-CO-(R)Cha-Pic-Pab

Me-OOC-CH2-CO-(R)Cha-Pic-Pab

H2N-CO-CH2-(R)Cha-Pic-Pab

Boc-(R)Cha-Pic-Pab

Ac-(R)Cha-Pic-Pab

Me-SO2-(R)Cha-Pic-Pab

H-(R)Cha-(R,S)betaPic-Pab

HOOC-CH2-CH2-(R)Cha-(R,S)betaPic-Pab

HOOC-CH2-(R)Cha-Val-Pab

HOOC-CH2-CH2-(R)Cha-Val-Pab

H-(R)Hoc-Aze-Pab

HOOC-CH2-CH2-(R)Hoc-Aze-Pab

HOOC-CH2-(R,S)CH(COOH)-(R)Hoc-Pro-Pab

HOOC-CH2-(R)Hoc-Pic-Pab

(HOOC-CH2)2-(R)Hoc-Pic-Pab

HOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab

HOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab
HOOC-CH2-(R)Cgl-Aze-Pac

H-(R)Cha-Pro-Pac

H-(R)Cgl-Ile-Pab

H-(R)Cgl-Aze-Pab

HOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab

MeOOC-CH2-(R)Cgl-Aze-Pab

EtOOC-CH2-(R)Cgl-Aze-Pab

nBuOOC-CH2-(R)Cgl-Aze-Pab

nHexOOC-CH2-(R)Cgl-Aze-Pab

H-(R)Cgl-Pro-Races

HOOC-CH2-(R)Cha-Pro-Pac

HOOC-CH2-CH2-(R)Cgl-Pro-Races

HOOC-CH2-CH2-(R)Cha-Aze-Pac

HOOC-CH2-(R)Cha-Aze-Pig

HOOC-CH2-(R)Cha-Pro-Pig

HOOC-CH2-CH2-(R)Cha-Pro-Pig

(HOOC-CH2)2-(R)Cgl-Pro-Pig

HOOC-CH2-CH2(HOOC-CH2)-(R)Cha-Pro-Pig

HOOC-CH2-(R)Cgl-Aze-(R,S)Itp

HOOC-CH2-(R)Cha-Aze-(R,S)Itp

H-(R)Cha-Pic-(R,S)Itp

HOOC-CH2-(R)Cha-Pic-(R,S)Itp

H-(R)Cgl-Pro-(R,S)Hig

HOOC-CH2-(R)Cgl-Pro-(R,S)Hig

H-(R)Cha-Pro-(R,S)Hig

H-(R)Cgl-Aze-Rig

HOOC-CH2-(R)Cgl-Aze-Rig

HOOC-CH2-(R)Cha-Pro-Rig

HOOC-CH2-CH2-(R)Cha-Aze-Rig

HOOC-CH2-(R)Cha-Pro-(S)Itp

H-(R)Cha-Pro-(R,S)Nig

H-(R)Cha-Pro-Mig

H-(R)Cha-Pro-Dig

H-(R)Cha-Aze-Dig

B present especially recommended for compounds of formula Ia include the following compounds:

HOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-CH2-(R)Cha-Aze-Pab

HOOC-CH2-(R)Cha-Pro-Pab

HOOC-CH2-CH2-(R)Cha-Pro-Pab

HOOC-CH2-(R)Cha-Pic-Pab

HOOC-CH2-(R)Cgl-Pro-Pig

EtOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-(R)Cha-Pro-Pac
Zomer on the carbon atom, marked "R / S". Stereoisomer can be identified for each connection by reference to the following experimental part. The designation "R, S" refers to a mixture of stereoisomers.

In accordance with the invention it was found that the compounds of General formula Ib, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors kininogens:

A1---A2---NH---(CH2)n---B (Ib)

where A1represents a structural fragment of formula IIa, IIb or IIe, preferably IIa or IIb, where

k=0, 1, 2, 3 or 4, preferably 0, 1;

q = 0, 1, 2 or 3, preferably 1;

R1represents H, alkyl group with 1 to 4 carbon atoms, or R11-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p is 0, 1 or 2 and R17is methyl, phenyl, OH, COOR12, CONHR12where R12- H or an alkyl group with 1 to 4 carbon atoms, and R11- H or an alkyl group with 1 to 6 carbon atoms, or

R1is Ph (4-COOR12)-CH2- where R12- H or an alkyl group with 1 to 4 atoms possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R13Is H, an alkyl group with 1 to 4 carbon atoms or-CH2-COOR12where R12accept above values, or

R1is R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R12accept above values, or

R1is R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12accepts the above meanings and R14is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1represents-CO-OR15where R15accept above values, or

R1represents-CO-(CH2)p-COOR12where R12takes values above and p = 0, 1, or 2, or

R1represents-CH2PO(OR16)2, -CH2SO3H or-CH2-(5-(1H)-tetrazolyl), where R16independently in each case represents H, methyl or ethyl;

R2represents H, alkyl group with 1 to 4 carbon atoms, or R21
R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms, or

R3is cyclopentyloxy, tsiklogeksilnogo or phenyl groups which are unsubstituted or substituted alkyl group with 1 to 4 carbon atoms, or

R3represents a phenyl group substituted by a group OR21where R21- H or an alkyl group with 1 to 4 carbon atoms and k = 0, 1, or

R3is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or transdiciplinary group and k = 0, 1, or

R3is 4-pyridyl, 3-pyrrolidyl or 3-indolyl, which is unsubstituted or substituted by a group OR31where R31takes values above and k = 0, 1, or

R3is Si(Me)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents H, alkyl group with 1 to 4 carbon atoms, tsiklogeksilnogo or phenyl group, preferably H;

A2represents a structural fragment of formula IIIb or IIIc, preferably IIIb, where

p = 0, 1, or 2;

m = 1, 2, 3 or 4, preferably 2, 3;

R3adopts the formula IVa, IBb, IVc or IVd, preferably IVa or IVb, where

X1X2X3X4take the above values;

R6- H or an alkyl group with 1 to 4 carbon atoms, preferably H or methyl;

r = 0 or 1;

the recommended combinations of X1X2X3and X4include:

X1X2and X4group CH2X3group CH-C(NH)-NH2and r = 0 or 1, or

X1X2and X4group CH2X3group N-C(NH)-NH2and r = 0 or 1, or

X1and X3group NH, X2- group C=NH, X4group CH2and r = 0 or 1, or

X1and X4group CH2X2- group C=NH, X3group NH and r = 0 or 1, or

X1group CH2X2and X4group NH, X3- group C=NH and r = 1, or

X1X2and X4group CH2X3group CH-NH-C(NH)-NH2and r = 0 or 1, or

X1no, X2and X4group CH2X3group CH-C(NH)-NH2and r = 0, or

X1no, X2and X4group CH2X3group N-C(NH)-NH2and r = 0;

especially recommended combinations of X1X2X3and X4include:

X1X2the and CH2X3group N-C(NH)-NH2and r = 1;

X5represents C(NH)-NH2or NH-C(NH)-NH2preferably C(NH)-NH2;

X6represents CH or n

Featured compounds of the invention include compounds of formula:

H-(R)Pro-Phe-Pab

HOOC-CH2-(R)Pro-Phe-Pab

H-(R)Phe-Phe-Pab

HOOC-CO-(R)Phe-Phe-Pab

HOOC-CH2-(R)Phe-Phe-Pab

H-(R)Cha-Phe-Pab

HOOC-CH2-(R)Cha-Phe-Pab

H-(R)Phe-Cha-Pab

HOOC-CH2-(R)Phe-Cha-Pab

H-(R)Cha-Cha-Pab

HOOC-CH2-(R)Cha-Cha-Pab

Also discovered that the compounds of General formula V, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors of serine proteases, especially thrombin, and kininogens, such as kallikrein, after oral or parenteral administration:

A1- A2- NH - (CH2)n- B - D (V)

where A1represents a structural fragment of formula IIa, IIb, IIc, IId or IIe:

< / BR>
where k = 0, 1, 2, 3 or 4;

m = 1, 2, 3 or 4;

q = 0, 1, 2 or 3;

R1is R11OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and possible substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p Yes or benzyl group, and R11Is H, an alkyl group with 1 to 6 carbon atoms or benzyl group, or

R1is Ph(4-COOR12)-CH2- where R12accept above values, or

R1is R13-NH-CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R13Is H, an alkyl group with 1 to 4 carbon atoms or-CH2-COOR12where R12accept above values, or

R1is R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R12accept above values, or

R1is R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12accepts the above meanings and R14is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1represents-CO-OR15where R15accept above values, or

R1represents-CO-(CH221
OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and where R21Is H, an alkyl group with 1 to 4 carbon atoms or benzyl group;

R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms, or

R3is cyclopentyloxy, tsiklogeksilnogo or phenyl groups which are unsubstituted or substituted alkyl group with 1 to 4 carbon atoms, or

R3represents a phenyl group substituted by a group OR31where R31- H or an alkyl group with 1 to 4 carbon atoms and k = 0, 1, or

R3is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or TRANS-calinowo group and k = 0, 1, or

R3is 4-pyridyl, 3-pyrrolidinyl or 3-indolyl, which is unsubstituted or substituted by a group OR31where R31takes values above and k = 0, 1, or

R3is Si(Me)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents H, alkyl group with 1 to 4 carbon atoms, tsiklogeksilnogo or phenyl predstavljaet benzyloxycarbonyloxy group.

Benzyloxycarbonyl group (Z or (Z)2) attached to the nitrogen atoms amidino or guanidinopropionic present in B.

Recommended especially recommended combinations are the same as above for formula I.

In addition, it was found that the compounds of General formula Va, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors of thrombin after oral or parenteral administration:

A1- A2- NH - (CH2)n- B - D (Va)

where A1represents a structural fragment of formula IIa, IIb, IIc or IId, preferably IIa or IIb, where

k = 0, 1, 2, 3 or 4, preferably 0, 1;

q = 0, 1, 2 or 3, preferably 1;

R1is R11OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and possible substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p is 0, 1 or 2 and R17group COOR12, CONHR12where R12Is H, an alkyl group with 1 to 4 carbon atoms or benzyl group, and R11Is H, an alkyl group with 1 to 6 carbon atoms or benzyl group, or

R1is Ph (4-COOR13
Is H, an alkyl group with 1 to 4 carbon atoms or-CH2-COOR12where R12accept above values, or

R1is R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R12accept above values, or

R1is R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12accepts the above meanings and R14is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1represents-CO-OR15where R15accept above values, or

R1represents-CO-(CH2)p-COOR12where R12accept above values, or

preferably R1is R11OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and R11accepts the above znacheniya has 1 - 4 carbon atoms, and R21Is H, an alkyl group with 1 to 4 carbon atoms or benzyl group;

R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms, or

R3is cyclopentyloxy, tsiklogeksilnogo or phenyl groups which are unsubstituted or substituted alkyl group with 1 to 4 carbon atoms, or

R3is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or TRANS-calinowo group and k = 0, 1, or

R3is Si(Me)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents an alkyl group with 1 to 4 carbon atoms, tsiklogeksilnogo or phenyl group, preferably tsiklogeksilnogo or phenyl group;

A2, B and n take the values given above for formula Ia;

D - group Z or (Z)2;

Z represents benzyloxycarbonyl group.

Featured digital indicators, groups, and combinations and particularly preferred combinations are the same as given above for formula Ia, however, R11Is H, an alkyl group with 1 to 6 carbon atoms which-CH2-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cgl-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Cgl-Pro-Pab(Z)

(BnOOC-CH2)2-(R)Cgl-Pro-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cgl-Pic-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/a

BnOOC-CH2-(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/b

BnOOC-CH2-CH2-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-(Me)(R)Cha-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab(Z)

Ph(4-COOH)-SO2-(R)Cha-Pro-Pab(Z)

Boc-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-CH2-(R)Cha-Pic-Pab(Z)

EtOOC-CO-(R) Cha-Pic-Pab(Z)

MeOOC-CH2-CO-(R)Cha-Pic-Pab(Z)

H2N-CO-CH2-(R)Cha-Pic-Pab(Z)

Ac-(R)Cha-Pic-Pab(Z)

Me-SO2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cha-Val-Pab(Z)

BnOOC-CH2-CH2-(R)Cha-(R,S)Val-Pab(Z)

BnOOC-CH2-CH2-(R)Hoc-Aze-Pab(Z)

BnOOC-CH2-(R,S)CH(COOB-(R)Hoc-Pro-Pab(Z)

BnOOC-CH2-(R)Hoc-Pic-Pdb(Z)

(BnOOC-CH2)2-(R)Hoc-Pic-Pab(Z)

BnOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Tic-Pro-Pab(Z)

BnOOC-CH2-CH2>/BR>MeOOC-CH2-(R)Cgl-Aze-Pab(Z)

EtOOC-CH2-(R)Cgl-Aze-Pab(Z)

nBuOOC-CH2-(R)Cgl-Aze-Pab(Z)

nHexOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pac(Z)

BnOOC-CH2-CH2-(R)Cgl-Pro-Pac(Z)

BnOOC-CH2-CH2-(R)Cha-Aze-Pac(Z)

BnOOC-CH2-(R)Cha-Aze-Pig(Z)

BnOOC-CH2-(R)Cha-Pro-Pig(Z)

BnOOC-CH2-CH2-(R)Cha-Pro-Pig(Z)

(BnOOC-CH2)2-(R)Cgl-Pro-Pig(Z)

BnOOC-CH2-CH2(BnOOC-CH2)-(R)Cha-Pro-Pig(Z)

BnOOC-CH2-(R)Cha-Pic-(R,S)Itp(Z)

BnOOC-CH2-(R)Cgl-Pro-(R,S)Hig(Z)

BnOOC-CH2-(R)Cgl-Aze-Rig(Z)

BnOOC-CH2-(R)Cha-Pro-Rig(Z)

BnOOC-CH2-CH2-(R)Cha-Aze-Rig(Z)

Especially recommended for the following connections:

BnOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cgl-Pro-Pig(Z)2< / BR>
EtOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pac(Z)

BnOOC-CH2-(R)Cha-Pro-Pig(Z)

Also discovered that the compounds of General formula Vb, as such or in the form of physiologically acceptable salts, and including stereoisomers, are effective inhibitors of kallikrein after oral or parenteral administration:

A1-A2-NH-(CH2)N-B-D (Vb)

where A1represents a structural fragment of formula IIa, IIb or IIe, predpochtite is R11OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p = 0, 1 or 2 and R17group COOR12, CONHR12where R12- H or an alkyl group with 1-4 carbon atoms, and R11Is H, an alkyl group with 1-6 carbon atoms or benzyl group, or

R1is Ph(4-COOR12)-CH2- where R12accept above values, or

R1is R13-NH-CO-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and where R13Is H, an alkyl group with 1 to 4 carbon atoms or-CH2COOR12where R12accept above values, or R1is R12OOC-CH2OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1 to 4 carbon atoms and

where R12accept above values, or

R1is R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12received the t-CO-R15where R15is an alkyl group with 1 to 4 carbon atoms, or

R1is-CO-R15where R15accept above values, or

R1represents-CO-(CH2)p-COOR12where R12accept above values, and p = 0, 1, or 2, or

R2represents H, alkyl group with 1 to 4 carbon atoms, or R21OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and R21Is H, an alkyl group with 1 to 4 carbon atoms or benzyl group;

R3represents an alkyl group with 1 to 4 carbon atoms, and an alkyl group unsubstituted or substituted by one or more fluorine atoms or

R3is cyclopentyloxy, tsiklogeksilnogo or phenyl groups which are unsubstituted or substituted alkyl group with 1 to 4 carbon atoms, or

R3represents a phenyl group substituted by a group OR31where R31- H or an alkyl group with 1 to 4 carbon atoms and k = 0, 1, or

R3is 1-naftalina or 2-naftalina group and k = 0, 1, or

R3is CIS - or TRANS-calinowo group and k = 0, 1, or

R3is 4-pyridyl, 3-pyrrolidyl or 3-indolyl, which is unsubstituted or substituted the e)3or CH(R32)2where R32- tsiklogeksilnogo or phenyl group;

R4represents H, alkyl group with 1 to 4 carbon atoms, tsiklogeksilnogo or phenyl group, preferably H;

A2, B and n take the values given above for formula Ib;

D represents Z or (Z)2.

Featured digital values, groups, and combinations and particularly preferred combinations are the same as given above for formula Ib, however, R11Is H, an alkyl group with 1 to 6 carbon atoms or benzyl group.

Recommended connection Vb include:

Boc-(R)Pro-Phe-Pab(Z)

BnOOC-CH2-(R)Pro-Phe-Pab(Z)

Boc-(R)Phe-Phe-Pab(Z)

MeOOC-CO-(R)Phe-Phe-Pab(Z)

BnOOC-CH2-(R)Phe-Phe-Pab(Z)

In still another embodiment of the invention relates to a new use of compounds of the formula:

< / BR>
as the initial product in the synthesis of a peptide inhibitor of serine protease, in particular, in the synthesis of peptide inhibitors of thrombin inhibitors or cinogens. The connection can be used, as such or with amidinopropane mono - or disubstituted on the nitrogen atom protecting group, for example, benzyloxycarbonyl. Protection amidinopropane exercise known primestyle in this description of the "H-Pab". Previously the connection disclosed in Biochem. Pharm. so 23, pp. 2247-2256.

However, the structural fragment of the formula:

< / BR>
has not been previously specified as a structural element of pharmaceutically active compounds, in particular peptide compounds. The fragment gives the connection properties of the inhibitor of serine protease, in particular, thrombin inhibitor or inhibitor kininogens.

In still another embodiment of the invention relates to previously unknown use of the compounds of formula:

< / BR>
as the initial product in the synthesis of a peptide inhibitor of thrombin. The amino group in the specified connection can be mono - or dissemina on the nitrogen atoms of such a protective group, as benzyloxycarbonyl. Protection amidinopropane known methods used to protect amidinopropane. The name of this connection - "1-amidino-4-aminoheterocycles" or in this description of H-Pac". Previously, the compound disclosed in patent DE 2748295.

However, the structural fragment of the formula:

< / BR>
not previously been mentioned as a structural element, representing a value of a thrombin inhibitor.

In still another aspect, the invention relates to a new compound of the formula:

< / BR>
and nasty thrombin inhibitor or inhibitor kininogenase. The nitrogen atoms in amidinopropane compounds may be mono - or tizamidine such protecting group, as benzyloxycarbonyl. Protection amidinopropane carried out by known methods used to protect amidinopropane. The name of this connection - "4-amino-ethyl-1-amidinopropane" or in this description of the "H-Rig".

However, the structural fragment of the formula:

< / BR>
not previously been mentioned as a structural element of pharmaceutically active compounds, in particular peptide compounds. The fragment gives the connection properties of the inhibitor of serine protease, in particular, thrombin inhibitor or inhibitor kininogens.

In still another embodiment of the invention relates to a new compound of the formula:

< / BR>
and to its use as a raw product in the synthesis of an inhibitor of serine proteases, especially thrombin inhibitor or inhibitor kininogenase. The nitrogen atoms in amidinopropane compounds may be mono - or tizamidine such protecting group, as benzyloxycarbonyl. Protection amidinopropane carried out by known methods of protection amidinopropane. The name of this connection - "1,3-diaza-2-amino-1-aminoheterocycles" or in this description of the "H-Itp".

Takitaki active compounds, in particular peptide compounds. The fragment gives the connection properties of the inhibitor of serine protease, in particular, thrombin inhibitor or inhibitor kininogens.

In still another embodiment of the invention relates to new compounds of the formula

< / BR>
where n = 1 or 2

s = 0 or 1,

and to the use of these compounds as starting products in the synthesis of inhibitors of serine proteases, especially thrombin inhibitors or inhibitors kininogens. The nitrogen atoms in amidinopropane compounds can be mono - or tizamidine such protecting group, as benzyloxycarbonyl. Protection amidinopropane carried out by known methods of protection amidinopropane. These compounds have the following names:

1-amidino-3-aminomethylpyrrolidine or "H-Nig" for n = 1 and s = 1,

1-amidino-3-aminomethylpyrrolidine or "H-Hig" when n = 2 and s = 1,

3-aminomethyl-1-imigination or "H-Mig" for n = 1 and s = 0,

3-amino-ethyl-1-imigination or "H-Dig" for n = 2 and S = 0.

However, the structural fragment of the formula:

< / BR>
not previously been mentioned as a structural element of pharmaceutically active compounds, especially peptide compounds. The fragment gives the connection properties of an inhibitor of serine proteases, in cast to new compounds, in which the nitrogen atoms of amidinopropane mono - or di-protected benzyloxycarbonyloxy group. Examples of such compounds include:

4-aminomethyl-1-(N-benzyloxycarbonylamino)benzene (H-Pab (Z)),

4-aminomethyl-1-(N,N'-di(benzyloxycarbonyl)amidino)benzene (H-Pab (Z)2)

4-aminomethyl-1-(N-benzyloxycarbonylamino)cyclohexane (H-Pac (Z)),

4-aminomethyl-1-(N, N'-di(benzyloxycarbonyl)amidino)cyclohexane (H-Pac (Z)2)

4-amino-ethyl-1-(N-benzyloxycarbonylamino)piperidine (H-Rig (Z)),

4-amino-ethyl-1-(N, N'-di(benzyloxycarbonyl)amidino)piperidine (H-Rig (Z)2)

(3RS)-1-(N-benzyloxycarbonylamino)-3-aminomethylpyrrolidine (H-Hig (Z)),

(3RS)-1-(N, N'-di(benzyloxycarbonyl)amidino)-3-aminomethylpyrrolidine (H-Hig (Z)2)

(3RS)-1-(N-benzyloxycarbonyl)amidino)-3-aminomethylpyrrolidine (H-Hig (Z)),

(3RS)-1-(N, N'-di(benzyloxycarbonyl)amidino)-3-aminomethylpyrrolidine (H-Hig (Z)2)

3-aminomethyl-1-(N-benzyloxycarbonylamino)azetidin (H-Mig (Z)),

3-aminomethyl-1-(N, N'-di(benzyloxycarbonyl)amidino)azetidin (H-Mig (Z)2)

3-amino-ethyl-1-(N-benzyloxycarbonylamino)azetidin (H-Dig (Z)),

3-amino-ethyl-1-(N,N'-di(benzyloxycarbonyl)amidino)azetidin (H-Dig (Z)2).

These connections use the Application in medicine and pharmacy

In the invention displayed medicines and methods of treatment of humans and animals in those States that require the inhibition of thrombin and physiological disorders, in particular inflammatory diseases.

It is expected that inhibit thrombin compounds of the invention are useful for the treatment and prevention of human and animal thrombosis and sverhkategorijnost in the blood and tissues. Moreover, it is expected that the compounds will find use in situations when there is excessive formation of thrombin without signs of sverhkategorijnost, as for example, in Alzheimer's disease and pancreatitis. Painful condition in which these compounds are potentially applicable for the treatment and/or prevention include: venous thrombosis, pulmonary embolism, arterial thrombosis, for example, in myocardial infarction, unstable angina, attack as a result of thrombosis and peripheral arterial thrombosis, General embolism usually from the atrium during arterial fibrillation or from the left ventricle after transmural myocardial infarction. Moreover, it is expected that the compounds will find use in the prevention of atherosclerotic diseases such as coronary arterial diseases will have a synergistic antithrombotic effect in their application with any antithrombotic agent with a different mechanism of action, for example, with such an antiplatelet agent, as acetylsalicylic acid. These compounds are expected to be useful in the treatment in combination with thrombolytics thrombotic diseases, such as myocardial infarction. In addition, it is expected that the compounds will find use for the prevention of re-occlusion after thrombosis, percutaneous transposons plastic operations on vessels (PTCA) and coronary bypass operations. It is also expected that the compounds will find use for the prevention of rethrombosis after microsurgery and surgery on the blood vessels in General. It is also expected that the use of compounds for the treatment and prevention of diffuse intravascular coagulation caused by bacteria, multiple trauma, intoxication and other reasons. In addition, it is expected that the compounds will be applicable for anticoagulant treatment when blood is in contact with foreign surfaces in the body, such as vascular implants, vascular grafts, vascular catheters, mechanical and biological prostheses or any other medical device. It is also expected the possibility of using the compounds for anticoagulant treatment in cases when the blood contacts the receiving apparatus of the heart-lung or kidney.

Another expected use of anticoagulant compounds of the invention consists in rinsing catheters and medical devices used in the body of patients in vivo, and as anticoagulants for the preservation of blood plasma and other blood derivatives in vitro.

Anti-inflammatory compounds of the invention are expected to find application, in particular for the treatment and prevention of human and animal inflammatory diseases, such as asthma, rhinitis, pancreatitis, urticaria, inflammatory bowel disease and arthritis. The effective amount inhibits kininogenase compounds can be used as pure compounds or as mixtures thereof with physiologically acceptable carriers and diluents, or in combination with other therapeutic agents.

The ability of compounds to inhibit the activity of kallikrein determine analysis by known methods using chromogenic substrates. Anti-inflammatory effect of the compounds of the present invention may be investigated, for example, by inhibition them caused by allergens exudative inflammation in the respiratory mucosa or the mucosa of the intestine.

Lek is receiving on the skin, through the nose, through the trachea, through the bronchi, parenterally or by inhalation. Connections are introduced in the form of dosage forms containing the active ingredient in the form of a free base or as a pharmaceutically acceptable non-toxic salts formed by the pressure of an organic or inorganic acid, e.g. : hydrochloride, hydrobromide, sulfate, hydrosulfate, nitrate, lactate, acetate, citrate, benzoate, succinate, tartrate, triptoreline and so on, in a pharmaceutically acceptable dosage form. Depending on the type of disease and the patient to be treated and the route of administration of drugs can be administered in various doses.

Dosage forms can be solid, semisolid and liquid prepared by known techniques. Usually the amount of active component is 0.1-99 wt.% on the drug, more specifically, 0.1 to 50 wt.% the drug is intended for parenteral administration, and 0.2-75 wt.% the drug is acceptable for oral administration.

Acceptable daily dose of the compounds of the invention for the treatment amount of 0.001-100 mg/kg body weight by oral administration and 0.001-50 mg/kg body weight at parenteral administration.

Getting

Even odegbami, including the accession protected on the N-end of the dipeptide or amino acids, if used N-terminal amino acid with the subsequent addition by known methods of the second amino acid, to the compound of the formula:

H2N --- (CH2)n--- X

where n = 0, 1, 2, 3 or 4, X is a group B or B-D, where B takes the values specified for formula I, and D takes the values specified for formula V, and the nitrogen atoms in guanidino or amidinopropane unprotected or mono - or tizamidine aminosidine group, for example: benzyloxycarbonyl, tert-butyloxycarbonyl or p-toluensulfonyl band or X - band, portable B, with the subsequent removal of the protective groups or the release of N-terminal nitrogen and then alkylation of the N-terminal nitrogen and optionally releasing known methods. If desired, can be obtained physiologically acceptable salts, and in those cases, when the reaction is a mixture of stereoisomers, their possible share standard chromatographic methods or recrystallization emitting optionally, a single stereoisomer.

Compounds of formulas I or V can be obtained in one of the following disclosed in more detail way is based on the values of A1and A2for formulas I and V and is obtained by the standard method of connection of peptides, compounds of the formula:

< / BR>
using standard methods of attaching peptides illustrated by the following reaction scheme:

< / BR>
In the above formulas, n takes on the values specified for formula I, W1N-terminal aminosidine group, for example: tert-butyloxycarbonyl and benzyloxycarbonyl and Q1group-C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NHW2or-NH-C(NW2)-NH-W2where W2- aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl, or Q1group-CN, -CO-NH2or-CS-NH2, which is then transferred to amidinopropane (for example, with the formation of Q1= -C(NH)-NH2) known in the art methods, or Q1group NH2or NH-W2where W2accept above values, and the amino group is then transferred to guanidinium (with the formation of Q1= -NH-C(NH)-NH2after removal W2group when Q1group-NH-W2(W2in this case must be orthogonal to W1) known in the art methods.

End with the dust. Remove the protective group(s) (when Q1group-C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2or conduct selective release with removal W1group (e.g., when Q1group-C(NW2)-NHW2, -C(NH)-NH-W2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2(W2the group in this case must be orthogonal to W1group), followed by alkylation by known methods of the N-terminal nitrogen and optionally releasing known methods.

Method Ib

The method consists in joining protected at N-end amino acid selected based on the value of A2for formulas I or V and obtained by standard methods, the compounds of formula:

< / BR>
using standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n, W1and Q1take the above values, with the subsequent removal W1group releasing and attaching the N-terminal amino acid in protected form, thereby protecting the peptide described in Method Ia. Then according to the way Ia continue synthesis sobrannogo based on the values of A1and A2for formulas I or V and synthesized by the standard method of connecting peptides, with the compound of the formula:

< / BR>
using the standard method of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I, W1N-terminal aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl and Q1group-C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(W2)-NH-W2where W2- aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl, or Q1group-CN, -CO-NH2or-CS-NH2, which is then transferred to amidinopropane (education, for example, Q1IS-C(NH)-NH2) known in the art methods, or Q1group NH2or NH-W2where W2accept above values, and the amino group is transferred to guanidinium (with the formation of Q1= -NH-C(NH)-NH2after removal W2group releasing, when Q1group-NH-W2(in this case, W2-the group must be orthogonal to W1-group) known in the art methods.

1-group. Remove the protective group(s) (when Q1group-C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2), or selectively remove the release W1group (e.g., when Q1group-C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2) (W2the group in this case must be orthogonal to W1group), followed by alkylation by known methods of the N-terminal nitrogen and optionally releasing known methods.

The way IIb

The method consists of the reaction of protected N-end amino acids selected based on the value of A2for formulas I or V and obtained by standard methods, with a compound of the formula:

< / BR>
application of standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n, W1and Q1take the above values, with the subsequent removal W1group releasing and attaching the N-terminal protected amino acid and the obtained protected peptide described in method IIa. The final synthesis of peptides Anie of the dipeptide, selected on the basis of the values of A1and A2for formulas I or V and obtained by the standard method of connection of the peptides with the compound of the formula:

< / BR>
using standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I, r = 0, 1 if X1X2and X4group CH2or r = 0, when X2and X4group CH2and X2no, W1N-terminal aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl and Q2group-C(NH)-NH2, -C(NW2)-NH-W2or-C(NH)-NH-W2where W2-aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl, or Q2= W2and the amino group after removal W2- group release (in this case, W2- the group must be orthogonal to W1group) is transferred then to guanidinium use by known methods unprotected, N-protected or N,N'-desasosiego reagent guanidine (with the formation of Q2= -C(NH)-NH2, -C(NW2)-NH-W2or-C(NH)-NH-W2).

End connections can be obtained by any of the following Spa -C(NH)-NH2, -C(NW2)-NH-W2or-C(NH)-NH-W2or selectively removed by releasing W1group (e.g. when Q2group-C(NW2)-NH-W2, -C(NH)-NH-W2in this case, W2-the group must be orthogonal to W1group), followed by alkylation of the known methods of the N-terminal nitrogen and optionally a release by known methods.

The way IIIb

The method consists of the reaction of protected N-end amino acids, selected on the basis of the values of A2for formulas I or V and obtained by standard methods, with a compound of the formula:

< / BR>
using standard methods of connection peptides illustrated in the following reaction equation:

< / BR>
where n, r, X1X2and X4, W1and Q2take the above values, with the subsequent removal W1group releasing and attaching the N-terminal amino acid in protected form with education in the protected dipeptide, characterized in method IIIa. Then according to the method of method IIIa continue the final synthesis of peptides.

How IVa

The method consists in the reaction are protected at the N end of the dipeptide, selected on the basis of the values of A1and >BR>
using standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I, W1N-terminal aminosidine group, for example: tert-butyloxycarbonyl or benzyloxycarbonyl and W3- H or aminosidine group, for example: arylsulfonyl, benzyloxycarbonyl or tertbutyloxycarbonyl. End connections can be obtained by any of the following methods. Remove the protective group(s) or selectively remove W1-group release (in this case, W1-the group must be orthogonal to W3group), followed by alkylation of the N-terminal nitrogen and optionally a release.

The way IVb

The method consists in the reaction of protected N-end amino acids selected from the values of A2for formulas I or V and obtained by standard methods, with a compound of the formula:

< / BR>
using standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n, W1and W3take the above values, with the subsequent removal W1-group release (W1-the group must be orthogonal to W3-gruppevaresuiten in the way of IVa. Then according to the method of method IVa continue the final synthesis of peptides.

The following description is intended to illustrate aspects of the invention.

Experimental part

General experimental techniques

Mass spectra were recorded on a triple quadrupole mass spectrometer Finnigan MAT TSQ 700, equipped with electrocapillary surface of section.

1H NMR and13C NMR determination is performed on a spectrometer BRUKER AC-P 300 and BRUKER AM 500, the first of which operates at 1H frequency 500,14 MHz and13C frequency 125,76 MHz, and the second with1H and13C frequency, respectively, in 300,13 MHz and 75,46.

Samples weighing 10 - 50 mg dissolved in 0.6 ml of one of the following solvent: CDCl3(isotopic purity > 99.8 per cent), CD3OD (isotopic purity > 99.95 per cent), D2O (isotopic purity > of 99.98%) or DMSO-d6(isotopic purity > 99.8 per cent), All solvents manufactured by Others. Glaser AG, Basel.

Values1H and13C chemical shifts in CDCl3and CD3OD are given relative to tetramethylsilane as an external standard.1H chemical shifts in D2O are given relative to the sodium salt of 3-(trimethylsilyl)-d4-propanoic acid is an external standard. Calibration external standard may in some cases lead to small differences in chemical shifts compared with the calibration by internal standard, however, the difference in1H chemical shifts of less than 0.02 ppm million, and in13C chemical shifts of less than 0.1 part/million

1H NMR spectrum of peptide sequences containing Proline or "polynomially" residue frequencies characterized by the presence of resonance of the two series. This phenomenon corresponds to the existence of two contributing in the range of conformers relative rotation amide bond, while Proline is an N-part of the amide bond. The conformers identified as having CIS - and TRANS-configuration. In the compounds of the invention sequence (R)Cha-Aze-, (R)Cha-Pro - (R)Cha-Pic - often lead to CIS-TRANS equilibrium with a predominance of one of the conformers (> 90%). In these cases, are only 1H chemical shifts of the main conformer. And only in those cases when the signals smaller rotamer clearly distinguishable, their lead in the NMR documentation. The same criterion holds for NH signals in CDCl3when NMR documentation are only clearly resolvable signals. This means that the number of protons that are listed for some">

Thin-layer chromatography carried out on selling glass or aluminum plates coated with silica gel 60F254firm Merck. Visual analysis is performed by the combination of UV irradiation and subsequent spraying a solution prepared by mixing 372 ml of EtOH (95%), of 13.8 ml of concentrated H2SO4and 4.2 ml of concentrated acetic acid and 10.2 ml of p-methoxybenzaldehyde or phosphomolybdenum reagent (5 - 10 wt.% in EtOH (95%) and heating.

Column chromatography is performed on silica gel 60 (40-63 mm, 230-400 mesh mesh) company Merck under the pressure of the air.

Liquid chromatography high-resolution reversed-phase (abbreviated Examples OPGH) is performed on the device a waters M-590, equipped with three columns with reversed phases Kromasil 100, C8 (Eka-Nobel) different sizes: analytical (4.6 mm x 250 mm), prepreparation (1" (25.4 mm) x 250 mm) and preparative (2" (50.8 mm) x 500 mm) with detection at 226 nm.

Drying by freezing is performed with the use of the instrument of Leybold-Heraus models Lajovic GT 2.

Getting original products

Boc-(R)Pgl-OH

Retrieved from H-(R)Pgl-OH according to the method specified to obtain Boc-(R)Cha-OH (see below).

Boc-(R)Cha-OH

To p is 5 h at room temperature. After evaporation of THF, add 150 ml of water. The aqueous alkaline phase is washed twice EtOAc, then acidified with 2 M KHSO4and extracted with EtOAc (3 x 150 ml). The combined organic phase washed with water, brine and dried (Na2SO4). Evaporation of the solvent receive 30,9 g (90,5%) of the title compound as a white solid.

Boc-(R)Hop-OH

Obtained by the method described for Boc-(R)Cha-OH, on the basis of H-(R)Hop-OH.

1H-NMR (300 MHz, CDCl3) : 1,45 (s, 9H), 2 (m, 1H), 2,22 (m, 1H), 2,75 (sh.t, 2H), 4,36 (sh.s, 1H), of 5.05 (sh.s, 1H), 7,15-7,33 (m, 5H).

4-(tert-Butyloxycarbonyl)pyridine

To a solution of 10,81 g (100 mmol) 4-aminomethylpyridine in 100 ml of THF over 20 minutes, add in 10oC a solution of 24 g (110 mmol) (Boc)2O in 70 ml of THF. The solution is allowed to warm to room temperature and stirred for 4 hours (during the reaction, a precipitate, and the suspension becomes red color). The solvent is removed, the residue is dissolved in EtOAc and filtered through silica gel. Evaporation of the solvent to obtain the title compound as a red oil, which slowly crystallizes. The crude product is used without further purification.

1H-NMR (300 MHz, CDCl3) : 1,45 (s, 9H), 4,32 (d, 2H), of 5.05 (sh.s, (NH)), 7,2 (d, 2H), 8,55 (target 49,15 g (251 mmol) of 4-cyanobenzaldehyde in 200 ml of DMF added at room temperature a solution on 20, 23 g (0,31 mole) of sodium azide in 50 ml of water. Proceeds exothermic reaction, and after 1.5 h the reaction mixture was diluted with 200 ml of toluene (Note! In order to avoid separation of potentially explosive azide before the addition of water to the reaction mixture, it is recommended to add toluene and 500 ml of water. The aqueous phase is extracted with additional toluene (2 x 50 ml). The combined organic extracts washed with water (2 x 50 ml) and brine, dried (MgSO4) and filtered. The solution is used as such in the next stage.

1H-NMR (300 MHz, CDCl3) : 4,4 (s, 2H), and 7.4 (d, 2H), 7.7 (d, 2H).

(II) 4-Amidinotransferase

In a mixture of 250 ml of absolute ethanol and the solution from stage (I) (approximately 200 ml) pronunciat when -5oC to saturation of hydrogen chloride. Maintaining 24 h in 8oC and evaporation of the greater part of the solvent, followed by precipitation by addition of anhydrous ether to obtain white crystals, which are filtered off and dissolved in 1.8 liters of alcoholic ammonia. After 48 h the greater part of the solvent is removed and after adding 200 ml of 3.75 M NaOH solution is deposited in the form of colorless crystals of 4-amidinopropane. The crystals are filtered and at this point, the output 4-amidinotransferase of 22.5 g (51%).

Hydrochlori is).

4-Amidinopropane

1H-NMR (500 MHz, CDCl3) : a 4.3 (s, 2H), 5,7 (sh.s, 3H), and 7.3 (d, 2H), and 7.6 (d, 2H).

13C-NMR (125 MHz, CDCl3) : carbon amidinopropane: 165,5.

(III) 4-(Benzyloxycarbonylamino)benzylated

The crystals from step (II) is dissolved in 500 ml of methylene chloride, the resulting solution was dried (K2CO3) and after filtering add 27 ml (194 mmole) of triethylamine. To stir the solution slowly added to 25 ml of benzylchloride with cooling of the reaction mixture in the bath with ice. After 30 minutes, add 2 ml of benzylchloride and stirring is continued for 30 minutes. After adding water to the aqueous phase by addition of 2 M HCl establish a pH of 7. The organic phase is dried (MgSO4) and the solvent is removed in vacuum. Finally from a mixture of ether-methylene chloride-hexane isolated in the form of colorless crystals of 4-(benzyloxycarbonylamino)benzilate.

1H-NMR (500 MHz, CDCl3) : 4,4 (s, 2H), 5,3 (s, 2H), 6,3-7 (Sch.s, 1H), 7.3 to 7.4 (m, 5H), 7.5 (d, 2H), 7,9 (d, 2H), 9.3 to 9.6 " W.s, 1H).

13C-NMR (125 MHz, CDCl3) : 167,5 (C amidinopropane).

(IV) 4-aminomethyl-1-(benzyloxycarbonylamino)benzene (H-Pab (Z)).

To a solution of 4-(benzyloxycarbonylamino)benserazida from stage (III) 160 m is s) of triphenylphosphine, and before removing the solvent in vacuum, the solution is stored at 4 o'clock The residue is dissolved in methylene chloride and extracted with 2 M HCl. The aqueous phase is washed with methylene chloride and ether and then alkalinized 3.75 M solution of sodium hydroxide. The extraction of methylene chloride, followed by drying (K2CO3) and removal of solvent in vacuo receive a 20 g (total yield on the original cyanobenzeneboronic 28%) of a yellow oil that solidified upon standing.

1H-NMR (500 MHz, CDCl3) : 1,2-2,2 (sh.s, 2H), and 3.8 (s, 2H), and 5.2 (s, 2H), 7,2-to 7.35 (m, 5H), and 7.4 (d, 2H), and 7.8 (d, 2H), 9.1 to 9.6 " W.s, 1H).

13C-NMR (125 MHz, CDCl3) : 164,6 and 168,17 (carbon amidinopropane and carbonyl).

H-Pig (Z)2< / BR>
(1) 4-(tert-Butyloxycarbonyl)piperidine

To a solution of 17.7 g of 4-tert-butyloxycarbonyl in 125 ml of MeOH is added 2 g of 5% Rh-Al2O3and the mixture hydronaut about the day when 0,34 MPa.1H-NMR spectrum indicates partial hydrogenation. Therefore, the catalyst is filtered off, the solvent is removed in vacuum, the residue is dissolved in 100 ml of acetic acid and after adding 2 g of 5% Rh-Al2O3the mixture hydronaut 4 days when 0,34 MPa. The catalyst is filtered off and most of the acetic acid removed in vacuo. After adding to the residue 50 ml of water the mixture is alkalinized provide 25 ml water and dried (MgSO4). Evaporation of the solvent receive and 17.2 g of a brownish oil, which was dissolved in 50 ml of diethyl ether. The addition of 200 ml of pentane get a precipitate, filtering which gives 7,7 g of brown powder. Evaporation of the mother liquor get 7 grams of white oil. The brown powder was dissolved in 100 ml EtOAc and the organic phase is washed with 1 M KHSO4(1 x 50 ml + 1 x 25 ml). The combined acidic phase is alkalinized with 2 M NaOH and extracted with EtOAc (1 x 200 ml + 1 x 75 ml). The combined organic phase is dried and after evaporation receive in the form of a white powder of 5.2 g of the title compound.

The processing of the above-mentioned white oil obtained from the mother liquor, in the same way will receive an additional 3.4 g of product. The overall yield of 40%.

1H-NMR (500 MHz, CDCl3, mixture of two rotamers, 3:1) : (main rotamer) 1,11 (DK, 2H), of 1.44 (s, 9H), 1,49-1,6 (m, 1H), 1,63-1,7 (m, 2H), 2,58 (dt, 2H), 2,93-3,03 (m, 2H), of 3.07 (m, 2H), 4.75 in (sh.s, 1H (NH)).

Allow the signals generated less retamero appear at : 1,21 (DK) and at 1.91 (dt).

(II) Boc-Pig (Z)2< / BR>
To a solution of 2 g (was 9.33 mmole) of 4-tert-butyloxycarbonyl)piperidine in 60 ml of CH3CN add 3,34 g (was 9.33 mmole) N,N'-(dibenzalacetone)methylisoleucine and the mixture is stirred for 22 h at 604). Evaporation of the solvent and subsequent column chromatography using as eluent a mixture of petroleum ether-EtOAc (1:1) get 2,43 g (50%) of the target product.

1H-NMR (500 MHz, CDCl3) : to 1.19 to 1.31 (m, 2H), USD 1.43 (s, 9H), 1,63-1,8 (m, 3H), 2,66 was 3.05 (m, 4H), 3,7-4,5 (sh.s, 2H) and 4.65 (sh.t, 1H (NH)), 5,13 (s, 4H), of 7.2 to 7.4 (m, 10H), 10,5 (sh.s, 1H (NH)).

Separate signals, in particular for piperidinol cycle selectively broadened due process of intramolecular exchange. This is especially noticeable for the 2 - and 6-CH2groups piperidino cycle, providing a broad peak in the range of 3.7-4.5 hours/million

(III) H-Pig (Z)2< / BR>
A solution of 163 mg (0.31 in mmole) Boc-Pig (Z)2in 5 ml of EtOAc saturated with HCl (g), stirred for 3 hours and 20 minutes at room temperature. The solvent is evaporated and the residue is dissolved in 30 ml of CH2Cl2. The organic phase is washed with 5 ml of 2 M NaOH, 5 ml water, 5 ml of brine and dried (MgSO4). Evaporation of the solvent receive 100 mg (76%) of the title compound.

1H-NMR (500 MHz, CDCl3) : of 1.18 to 1.37 (m, 2H), 1,46-to 1.63 (m, 1H), 1,68 of-1.83 (m, 2H), 2.57 m (d, 2H), 2,86-3,03 (m, 2H), 3,7-4,5 (sh.s, 2H), 5,13 (s, 4H), of 7.2 to 7.4 (m, 10H).

Separate signals, in particular for piperidinol cycle selectively broad due process vnotch in the range of 3.7 to 4.5 ppm million

4-Aminomethyl-1-(N-benzyloxycarbonylamino)cyclohexane (H-Pac(Z) 2HCl)

(I) N-N/-4-(Benzyloxycarbonyl)lidinopril/tert - BUTYLCARBAMATE

To a cooled with ice to a solution of 1.81 g (6.4 mmole) 4-(benzyloxycarbonyl)amidinopropane and 1 ml (7.1 mmole) of triethylamine in 25 ml methylene chloride was added with stirring 1,466 g (6.7 mmole) of (Boc)2O. After 20 minutes add the additional number of methylene chloride and the mixture is washed with 5% acetic acid and 10% sodium carbonate solution. Drying (magnesium sulfate) and removal of solvent in vacuum to get a residue that can be crystallized from a mixture of methylene chloride-hexane. Yield 1.66 g (68%).

(II) N-/N-4-Lidinopril)-tert-BUTYLCARBAMATE

A mixture of 1.6 g (4.2 mmole) N-/4-(benzyloxycarbonyl)lidinopril/tert-BUTYLCARBAMATE, 5 ml of acetic acid and 160 mg of 10% palladium on coal in 50 ml of ethanol is stirred for 2 hours under hydrogen atmosphere. The catalyst was removed by filtration through cellit and removal of solvent in vacuo receive acetate the title compound in quantitative yield.

(III) N-/4-Amidinothiourea)-tert-BUTYLCARBAMATE

Acetate N-/4-lidinopril/tert-BUTYLCARBAMATE (17 mmol) hydronaut in 100 ml of methanol hydronaut out in vacuum. The residue is dissolved in water and the solution is alkalinized with sodium hydroxide. Subsequent extraction methylene chloride, drying the combined organic phases (potassium carbonate) and removal of solvent in vacuo obtain 3.8 g (87%) of the title compound.

(I) N-/N-4-(Benzyloxycarbonyl)amidinothiourea/ tert-BUTYLCARBAMATE

To stir at 0oC solution 2,04 g (8 mmol) N-/4-amdinocillin/carbamate, 1.23 ml (8.8 mmole) of triethylamine and 197 mg DMAP in 40 ml of methylene chloride add 1.25 ml (8.8 mmole) of benzylchloride. After 10 minutes the reaction mixture is diluted with methylene chloride and extracted with water, dilute acetic acid, and sodium hydrogen carbonate solution. The organic phase is applied on a column of silica and subsequent elution methylene chloride containing increasing amounts of ethyl acetate, get 2,49 g (80%) of the title compound.

(V) 4-Aminomethyl-1-(N-benzyloxycarbonylamino)cyclohexane (H-Pac (Z) 2HCl).

Through a solution of 2 g (5.1 mmole) N-/4-(benzyloxycarbonyl)- amidinothiourea/tert-BUTYLCARBAMATE in 40 ml of ethyl acetate miss hydrogen chloride. After 10 minutes add the methanol and after the removal of the vacuum, some o-methyl 1-(N-benzyloxycarbonylamino)piperidine (H-Pig (Z) HCl)

(I) 4-(N-tert-Butyloxycarbonyl)-1-(N - benzyloxycarbonylamino)piperidin (Boc-Pig (Z))

In 25 ml of ethanol is mixed with 7.8 g (of 36.4 mmole) of 4-(N-tert-butyloxycarbonyl)of piperidine and 8,98 g (40 mmol) of N-benzyloxycarbonyl-S-methylisothiazoline. The mixture is heated for six hours at 60 - 70oC and leave for two days at room temperature. The solvent is evaporated and the residue dissolved in CH2Cl2. The organic layer is washed twice with 0.3 M KHSO4and once with brine. The combined organic layer is dried (Na2SO4), filtered and evaporated. Purification of the crude product column chromatography using as eluent a stepwise gradient of CH2Cl2/MeOH (100/0, 97/3, 95/5, 90/10) get 5,22 g (37%) of the title compound.

(II) H-Pig (Z) HCl (4-aminomethyl-1-(N - benzyloxycarbonylamino)piperidine

In 100 ml of ethyl acetate saturated with HCl (g), is dissolved with 5.22 g (13.5 mmole) of Boc-Pig (Z). The mixture is left for one hour and then evaporated. The residue is dissolved in water and washed with a mixture of diethyl ether with ethyl acetate. Freeze-drying the aqueous layer receive 4 g (91%) of the title compound.

1H-NMR (D2O, 300 MHz) : is 1.4-1.6 (m, 2H), 2.05 is (sh.d, 2H), 2,19 (m, 1H), of 3.07 (d, 2H), 3,34 (sh.t, 2H), 4,08 (sh.d, 2H), 5,4 (s, 2H), 7,

(I) 1-Benzyloxycarbonylamino-4-hydroxyethylpiperazine

A mixture of 6.2 g (0,028 mole) of 4-hydroxyethylpiperazine and 3.6 g (0,028 mole) N-benzyloxycarbonyl-S-methylisothiazoline in 50 ml of acetonitrile is boiled for about a day. Evaporation and column chromatography on silica gel with elution by ethyl acetate to obtain 3.5 g (41%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 1,1-of 1.85 (m, 7H), 2,83 (sh.t, 2H), 4,7 (sh.t, 2H), 4,18 (sh.d, 2H), 5,12 (s, 2H), 6,9-7,2 (m, 2H), 7,2-7,5 (m, 5H).

(II)-1-Benzyloxycarbonylamino-4-methylacetanilide

To a cooled with ice to a solution of 3.5 g (0,0115 mole) 1-benzyloxycarbonylamino-4-hydroxyethylpiperazine and 1.15 g (0,0115 mole) of triethylamine in 40 ml of methylene chloride and 10 ml of tetrahydrofuran are added dropwise 1.3 g (0,0115 mole) of methylchloride. The reaction mixture is stirred for 1 h, the Mixture is transferred into water and the organic layer separated. The aqueous layer was extracted with methylene chloride, the combined organic layers are dried (Na2SO4) and evaporated. Products used in the next stage without additional purification. Yield 4.4 g (100%).

1H-NMR (500 MHz, CDCl3) : 1,15-1,3 (m, 2H), 1,65-1,8 (m, 5H), 2,84 (sh. t, 2H), 3,01 (s, 3H), 4.2V (sh.d, 2H), 4,27 (t, 2H), 5,12 (s, 2H), and 7.1-7.5 (m, 7H).

(III) 4-Azidomethyl-1 benzyloxycarbonyl is on in 100 ml of dimethylformamide added 4.5 g (0,069 mole) of sodium azide and the mixture is heated for 2.5 h at 100oC. the mixture is Then transferred into water and extracted three times with ethyl acetate. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. The residue is subjected to column chromatography on silica gel using as eluent a mixture of ethylacetate (1:1). Yield 3 g (79%).

1H-NMR (500 MHz, CDCl3) : 1,2 (DK, 2H), 1.5 and 1.8 (m, 5H), 2,85 (dt, 2H), 3,35 (t, 2H), 4,22 (sm, 2H), 5,13 (s, 2H), 6,9-7,2 (W., 2H), 7,2 was 7.45 (m, 5H).

(IV) 4-amino-ethyl-1-benzyloxycarbonylamino (H-Rig (Z))

To 30 ml of water is added 0.4 g of 10% Pd-C. In 30 ml of water, dissolve 1 g (0,031 mole) sodium borohydride and the solution is carefully added to a cooled ice mist Pd-C in water. In 80 ml of tetrahydrofuran dissolve 2.9 g (8.8 mmole) of 4-azidomethyl-1-benzyloxycarbonylamino and the resulting solution was added dropwise to a cooled ice above water mist. After stirring 4 h at room temperature the mixture is again cooled with ice, then add 30 ml of 2 M HCl. The mixture is filtered through cellit and cellit rinsed with additional water. The tetrahydrofuran is evaporated and the aqueous phase washed with ethyl acetate. After alkalizing water phase 2 M NaOH her thrice extracted with methylene chloride. United organizeschedule cleanup.

1H-NMR (500 MHz, CDCl3) : 1,1-1,5 (m, 6H), 1,55-1,65 (m, 1H), 1,73 (sh. d, 2H), 2,72 (W., 2H), 2,81 (dt, 2H), 4.2V (sh.d, 2H), 5,12 (s, 2H), 6,9-7,2 (W., 2H), 7,2-7,5 (m, 2H).

(3RS)-1-(N-Benzyloxycarbonylamino)-3-aminomethylpyrrolidine (H-(R, S)Nig(Z))

(1) (3RS)-3-Hydroxyethylpyrrolidine

(3RS)-1-Benzyl-3-hydroxyethylpyrrolidine (16.4 g, 0,0857 mol) (H-R,S) Hig (Z) (1), see above) is mixed with 1.6 g of Pd-C (10%), 5 ml of water and 50 ml of ethanol and the mixture hydronaut at 0.26 MPa for about a day. After filtration through hyflo and solvent evaporation1H-NMR indicates incomplete reaction. Continuing the hydrogenation at 0.26 MPa in the presence of 1.6 g of Pd-C (10%) ml of water and 150 ethanol for three days complete recovery. By filtration through hyflo and evaporation of the solvent with a quantitative yield obtain the title compound.

(II) (3RS)-1-(N-Benzyloxycarbonylamino)-3 - hydroxyethylpyrrolidine

In toluene dissolved 1.01 g (0,01 mol) of (3RS)-3-hydroxyethylpyrrolidine and to 2.29 g (to 0.011 mole) N-benzyloxycarbonyl-O-methylisoleucine (Amin is not very soluble in toluene) and the mixture is heated 3 hours at 60oC, followed by stirring for about a day at room temperature. After evaporation of the mixture1H-NMR indicates incomplete reaction. Therefore, the mixture is dissolved in 15 ml Aceto the ducks. The solvent is evaporated and the residue dissolved in CH2Cl2, washed with water once, dried (Na2SO4) and evaporated. Purification of the crude product column chromatography using as eluent CH2Cl2-MeOH (95:5) to obtain 0.7 g (25%) of the product.

MC: m/z 278 (M++ 1).

(III) (3RS)-1-(N-Benzyloxycarbonylamino)-3 - methyloxazolidine

In 15 ml of a mixture of diethyl ether-CH2Cl2(1:1) dissolve 0.7 g (2,53 mmole) (3RS)-1-(N-benzyloxycarbonylamino)-3-hydroxyethylpyrrolidine and 0.7 ml (of 5.05 mmole) of triethylamine and the mixture cooled to 0oC. and Then slowly added 0.25 ml (3,29 mmole) of methanesulfonamide in 3 ml diethyl ether and the reaction mixture is stirred for three hours at 0oC. the Solvent is evaporated, the residue is dissolved in ethyl acetate and extracted with 0.3 M solution of KHSO4. The aqueous layer was washed once CH2Cl2. The water layer is neutralized 10 M NaOH solution and extracted twice CH2Cl2. The combined organic layer is dried (Na2SO4), filtered and after evaporation obtain 0.45 g (50%) of the title compound.

(IV) (3RS)-1-(N-Benzyloxycarbonylamino)-3 - azidopyridine

In 10 ml of dimethylformamide is dissolved 0.45 g (1,27 grebaut four FAA at 60oC, followed by stirring for about a day at room temperature. After addition of water the mixture is extracted twice with a mixture of toluene-ethyl acetate (2:1). The combined organic layer is dried (Na2SO4), filtered and evaporated. Purification of the crude product column chromatography using as eluent CH2Cl2-MeOH (95: 5) receive 0,262 g (68%) of product.

MC: m/z 303 (M++ 1).

(V) (3RS)-1-(N-Benzyloxycarbonylamino)-3 - aminomethylpyrrolidine (H-(R, S) Nig (Z))

Mix 32 mg of Pd-C (10%) and 2.6 ml of H2O and carefully pass a stream of nitrogen. Add 98 mg NaBH42.6 ml of H2O, followed by slow addition of 262 mg (of 0.87 mmole) (3RS)-1-(N-benzyloxycarbonylamino)-3-methyloxazolidine in 7 ml of MeOH. After keeping for one hour, to the mixture add 5 ml of 1 M HCl and filtered through hyflo. The organic solvent is evaporated under reduced pressure, the remaining aqueous layer was once washed with ethyl acetate, alkalinized with NaOH solution and repeatedly extracted with CH2Cl2. The combined organic layer is dried (Na2SO4), filtered and after evaporation obtain 130 mg (54%) of product.

MC: m/z 277 (M++ 1).

(3RS)-1-(N-Benzyloxycarbonylamino)-3-amide in 160 ml of diethyl ether in an argon atmosphere is slowly added to 25.2 g (0,1063 mole) (3RS)-1-benzyl-2-oxo-4-ethoxycarbonylpyrimidine. After stirring for approximately twenty-four hours the mixture is boiled for one hour. The reaction mixture is cooled to room temperature, add 0.2 g of Na2SO410H2O, followed by slow addition of order 6 ml of water, 18 ml of 3.75 M NaOH and 6 ml of water. From the suspension to remove the excess water by addition of Na2SO4-cellite, filtered and after evaporation of the gain of 20.3 g of the product.

1H-NMR (CDCl3, 300 MHz) : 1,64-to 1.77 (m, 1H), 1.93 and-2,07 (m, 1H), 2,27-2,4 (m, 2H), of 2.51 (DD, 1H), 2,62 (DD, 1H), 2,82 (m, 1H), 3,52 (DD, 1H) and 3.59 (s, 2H), to 3.67 (DD, 1H), 7,15 to 7.4 (m, 5H).

(II) (3RS)-1-Benzyl-3-chloromethylpyridine

To the boiling solution of 15.3 g (0.08 mmole) (3RS)-1-benzyl-3 - hydroxyethylpyrrolidine in 220 ml of CHCl3slowly added thionyl chloride in 60 ml of CHCl3and continue boiling for one hour. After evaporation of the mixture, the residue is dissolved in water. The aqueous layer was washed with ethyl acetate and alkalinized 0.2 M NaOH solution. The aqueous layer was extracted three times with ethyl acetate, the combined organic layer is dried (Na2SO4), filtered and after evaporation with a quantitative yield of a product (16,8 g).

1H-NMR (CDCl3, 300 MHz) : 1.55V (m, 1H), 2.05 is (m, 1H), of 2.38 (DD, 1H), 2,48-of 2.64 (m, 3H; ibid of 2.58 (t, 2H)), 2,73 (DD, 1H), 3,51 (d, 2H), and 3.6 (s, 2H), 7,2-7,4 (m, 5H).

(III) (3RS)-1-Berolina and 5,88 g (0.12 moles) of sodium cyanide. The mixture is stirred for two days at 60oC and one week at room temperature. After adding water, the mixture extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and after evaporation of the gain of 14.7 g (92%) of product.

1H-NMR (CDCl3, 500 MHz) : 1.55V (m, 1H), 2,13 (m, 1H), 2,35 (DD, 1H), 2,42 (t, 2H), 2,44 at 2.59 (m, 2H), 2,65 (m, 1H), 2,73 (DD, 1H), 3,61 (s, 2H), 7,2-7,4 (m, 5H).

(IV) (3RS)-1-Benzyl-3-aminomethylpyrrolidine

To a suspension 2,94 g sociallyengaged in 74 ml of diethyl ether is slowly added in an argon atmosphere of 14.7 g (0,0734 mole) (3RS)-1-benzyl-3-cyanoethylidene dissolved in 220 ml of diethyl ether. After stirring the mixture for about a day, add 6 ml of water, 18 ml of 3.75 M NaOH and 6 ml of water. The suspension is dried in the presence of Na2SO4-cellica to remove excess water, filtered with suction and, after evaporation receive 14,84 g (99%) of product.

1H-NMR (CDCl3, 300 MHz) : 1,41 (m, 1H), 1,51 (K, 2H), 1,9-2,1 (m, 2H, there is 2.05 (DD, 1H)), to 2.18 (m, 1H), 2,43 (m, 1H), 2,55 is 2.75 (m, 3H), 2,8 (apparent t, 1H), to 3.58 (apparent d, 2H), 7,15 to 7.4 (m, 5H).

(V) (3RS)-1-Benzyl-3-(N-tert-butyloxycarbonyl)- pyrrolidin

To the mixture 14,84 g (0,0726 mole) (3RS)-1-benzyl-3-aminomethylpyrrolidine, to 72.6 ml of 1 M solution the Solution is concentrated and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. Purification of the crude product column chromatography using as eluent a stepwise gradient of CH2Cl2-MeOH (95/5, 80/10) get 14,69 g (80%) of product.

1H-NMR (CDCl3, 300 MHz) : 1,25-of 1.65 (m, 12H; there's also a 1.4 (s, 9H)), 1,9-of 2.25 (m, 3H), 2,46 (m, 1H), to 2.67 (m, 1H), 2,8 (apparent t, 1H), 3,09 (m, 2H) and 3.59 (s, 2H), 4,6 (sh.s, NH), 7,15-to 7.35 (m, 5H).

(VI) (3RS)-3-(N-tert-Butyloxycarbonyl)pyrrolidin

(3RS)-1-benzyl-3-(N-tert-butyloxycarbonyl)aminoethyl)- pyrrolidine (3.1 g, of 0.01 mole) hydronaut when 0,28 MPa in the presence of 0.6 g of the catalyst of Pearlman, MD (Pd(OH)2) in 40 ml of ethanol for about a day. After removal of catalyst by filtration through cellit and evaporation of solvent1H-NMR showed incomplete reaction. So once again, add 0.6 g of the catalyst of Pearlman, MD in 40 ml of ethanol (95%) and the mixture is kept for about a day under the pressure of the H2in 0,28 MPa. Filtering through cellit and evaporation of the solvent with a quantitative yield of a product (2,18 g).

MC: m/z 214 (M+)

(VII) (3RS)-1-(N-Benzyloxycarbonylamino)-3-aminomethylpyrrolidine (H-(R, S)Hig (Z))

In 30 ml of toluene is dissolved 2,18 g (0,0102 mole) (3RS)-3-(N-tert-bout the live eight hours at 60-70oC, followed by stirring for one day at room temperature. After adding 0.3 M solution of KHSO4the aqueous layer was washed with a mixture of toluene with ethyl acetate and leave for 2 days, during which the removal of Boc-group. The acid aqueous phase is alkalinized and extracted four times CH2Cl2. The combined organic layer is dried (Na2SO4and after evaporation receive 2 g (51%) of the title compound.

1H-NMR (CDCl3, 330 K, 300 MHz) : 1,45-1,7 (m, 3H), 2,07 (m, 1H), and 2.26 (m, 1H), 2,74 (t, 2H), 3 (apparent t, 1H), (3,33 (seeming to, 1H), 3.45 points to 3.8 (m, 2H), 5,12 (s, 2H), 6,72 (sh.s, 2NH), 7,15 was 7.45 (m, 5H).

(4RS)-1,3-diaza-2-tosylimines-4-aminoheterocycles (H-(R,S)Itp(TS))

(I) (4RS)-1,3-diaza-2-tosylimines-4-carboxylicacid

Obtained by the method described in Journal of Org. Chem. page 46, 1971.

(II) (4RS)-1,3-diaza-2-tosylimines-4-hydroxymethylcellulose

To a cooled suspension (bath temperature with ice) of 9.9 g (33 mmole) of (4RS)-1,3-diaza-2-tosylimines-4-carboxylicacid in 330 ml of dry THF carefully added 12.9 g (345 mmol) of LiAlH4and the reaction mixture is stirred for about a day at room temperature. The reaction mixture is treated according to the recommendations of Fisher and Fisera, e.g., adding to the mixture of 12.9 g which are square-7 g (75%) of the target product.

MC: m/z 284 (M++ 1).

(III) (4RS)-1,3-diaza-2-tosylimines-4-methyloxybenzylidene

To a cooled suspension (bath temperature with ice) 7 g (24.7 mmole) of (4RS)-1,3-diaza-2-tosylimines-4-hydroxymethylcytosine 6.9 ml (49,4 mmole) of triethylamine and 125 ml of CH2Cl2gently added to 2.9 ml (37.1 mmole) Ms-Cl. After 1 h 15 min, water is added, the organic layer separated, dried (Na2SO4), filtered and after evaporation of the quantitative outputs receive the title compound.

MC: m/z 362 (M++ 1).

(IV) (4RS)-1,3-diaza-2-tosylimines-4-cyanomethylene

In 75 ml of DMSO dissolved 8,9 g (24.7 mmole) of (4RS)-1,3-diaza-2-tosylimines-4-methyloxazolidine and 1.3 g (to 27.2 mmole) NaCN. After stirring for 60 hours at 60oC add NaCN in the amount of 0.31 g (6 mmol) and the solution stirred for three hours at 65oC. After adding 150 ml of water from the solution drop crystals. By filtering and drying the crystals gain of 5.4 g (75%) of the target product.

MC: m/z 293 (M++ 1).

(4RS)-1,3-diaza-2-tosylimines-4-aminoheterocycles (H-(R,S)Itp(Ts))

To a cooled suspension (bath temperature with ice) 2.4 g (8.2 mmole) of (4RS)-1,3-diaza-2-tosylimines-4-cyanomethylene in 90 ml of THF carefully add 935 m is t and CH2Cl2. Filtration of the mixture and removal of solvent in vacuo obtain 2.2 g (80%) of the target product.

1H-NMR (500 MHz, MeOD) : 1,52-1,71 (m, 3H), 1,88 is 1.96 (m, 1H), is 2.37 (s, 3H), 2,64-by 2.73 (m, 2H), 3,2-3,4 (m, 2H, partially obscured by solvent signals), 3,44-of 3.53 (m, 1H), 7,28 (d, 1H), 7,71 (d, 2H).

(4S)-1,3-diaza-2-tosylimines-4-aminoheterocycles (H-(S)Itp(Ts))

Obtained on the basis of optically pure 2,4-diaminoalkanes acid according to the method described for obtaining H-(R,S)Itp(Ts).

1H-NMR (300,13 MHz, CDCl3) : 0,97-1,15 (sh.s, 1H), 1,48 was 1.69 (m, 3H), 1,84-of 1.95 (m, 1H), is 2.37 (s, 3H), 2,68-2,82 (m, 1H), 2,86 are 2.98 (m, 1H), 3,22-3,44 (m, 2H), 3.45 points-to 3.58 (m, 1H), 7,19 (d, 2H), 7,19 (d, 2H), 7,72 (d, 2H).

13C-NMR (300,13 MHz, CDCl3) : 154,5 (C guanidinium).

H-Aze-OEt HCl

Retrieved from H-Aze-OH according to the method of synthesis of H-Pic-OEt HCl (see below).

H-Aze-OMe HCl

Obtained according to the method described in: D. Seebach and others, Liebigs Ann. Chem., page 687, 1990.

H-Pab (Z) HCl

Obtained by adding 1 g molar equivalent of 5 M HCl in isopropanol to a solution of crude H-Pab (Z) in EtOH (about 1 g/10 ml) and immediate precipitation from a solution of H-Pab (Z) HCl. After filtration of the precipitate is washed 2 times with cold EtOH and dried in a receive with a quantitative yield of the title compound.

H-Pic-OEt HCl

In 100 ml ADO clear solution is formed. The solution is cooled in a bath with ice, and thereto within 15 minutes added dropwise 17 ml of thionyl chloride. Bath removed and the mixture is boiled for 2.5 hours After evaporation of the solvent are obtained from a quantitative yield of product in the form of its hydrochloride.

1H-NMR (300 MHz, D2O) : to 1.33 (t, 3H), 1,8-2,1 (m, 5H), of 2.3-2.5 (m, 1H), 3,1-3,3 (m, 1H), of 3.5-3.7 (m, 1H), 4,14 (DD, 1H), of 4.44 (K, 2H).

H-(R,S)bears-OMe HCl

To a cooled in a bath of ice a mixture of 2 g (15,5 mmole) nicotinebuy acid and 8 ml of methanol add chloride thionyl (2.76 g, 23,2 mmole), after which the mixture is stirred for 20 hours at room temperature. The solvent is evaporated, the residue is dissolved in a small amount of methanol and after addition of diethyl ether precipitated H-(R,S)bears-OMe HCl in the form of white crystals. Crystals to 2.57 g (92%) is separated by filtration.

Boc-(R)Cgl-OH

To a solution of 32.6 g (of 0.13 mmole) Boc-(R)-Pgl-OH in 300 ml of methanol is added 5 g of Rh-Al2O3and the mixture hydronaut 3 days with a 5.2-2.8 MPa. After filtration and evaporation of the solvent NMR showed the presence of about 25% methyl ester of the title compound. The crude product is dissolved in 500 ml of THF and 300 ml of water and to the solution was added 20 g of LiOH. The mixture is stirred for about a day and THF evaporated. The remaining aqueous phase is acidified with KHSOB>4and after evaporation of the gain of 28.3 g (83%) of the target product.

1H-NMR (300 MHz, CDCl3) : 0,9-1,7 (m, 20H), 4-4,2 (m, 1H), and 5.2 (d, 1H).

Boc-(R)Cgl-OSu

To a cooled with ice to a solution 2,01 g (7,81 mmole) Boc-(R)Cgl-OH and 1.83 g (15.6 mmole) of GSE in 25 ml of CH3CN add 1,69 g (8.2 mmole) DCC and the reaction mixture left to warm to room temperature. After stirring for 3 days the precipitate filtered DCM and the solvent is evaporated. The residue is dissolved in EtOAc and the organic phase is washed with H2O, KHSO4, NaHCO3, brine and dried (Na2SO4). Evaporation of the solvent with a quantitative yield obtain the title compound.

Boc-(R)Cha-OSu

Boc-(R)Cha-OH (1 EQ. ), GSE (1.1 EQ.) and DCC or CMA-CBI (1.1 EQ.) dissolved in acetonitrile (approximately 2.5 ml/mole acid) and all was stirred at room temperature for about a day. Formed during the reaction the precipitate was filtered off, the solvent evaporated and the product dried in vacuum. (In the case of applying CMA-CBI in the reaction obtained after evaporation of CH3CN the residue is dissolved in EtOAc, the organic phase is washed with water and dried). Evaporation of the solvent to obtain the title compound.

1H-NMR (500 MHz, CDCl32 rotamer in the ratio of approx. 1:1)er).

Boc-(R)Hoc-OH

To a solution of 3.2 g (11,46 mmole) Boc-(R)Hop-OH (see above) in methanol (75 ml) is added 0.5 g of rhodium on activated alumina (Ph-Al2O3) and the mixture is stirred for 18 hours under the hydrogen pressure of 0.41 MPa. The catalyst was removed by filtration through hyflo and evaporation with almost quantitative yield receive the product.

1H-NMR (500 MHz, CDCl3) : 0,9 (m, 2H), only 1.08 and 1.33 (m, 6H), USD 1.43 (s, 9H), 1,6-of 1.74 (m, 6H), 1,88 (sh.s, 1H), 4,27 (sh.s, 1H).

Boc-(R)Hoc-OSu

Obtained from Boc-(R)Hoc-OH according to the method of obtaining Boc-(R)Cha-OSu

Boc-(R)Pro(3-(S)Ph)-OH

Obtained according to the method described in: J. Y. L. Chung and others, Journal of Organic Chemistry, No. 1, pp. 270-275, 1990.

Boc-(R)Cgl-Aze-OH

(1) Boc-(R)Cgl-Aze-OMe

To stir the mixture 3,86 g (15 mmol) Boc-(R)Cgl-OH, and 2.27 g (15 mmol) of H-Aze-OMe HCl and 2.75 g (22.5 mmole) of DMAP in 40 ml of CH3CN add in 5oC and 3.16 g (of 16.5 mmole) of EDC and the reaction mixture was stirred 48 h at room temperature. The solvent is evaporated and the residue is dissolved in 150 ml EtOAc and 20 ml of H2O. the Separated organic layer was washed with 0.5 M KHSO4(2 x 20 ml), a saturated solution of NaHCO3(2 x 10 ml), 10 ml of H2O, and 10 ml of brine and dried (MgSO4). Evaporation of the solvent receive 4,91 g (92%) of the title compounds used in the next stage without more,18-2,27 (m, 1H), 2,5-2,62 (m, 1H), and 3.72 (s, 3H), 3,94-4,06 (m, 1H), 4,07-to 4.15 (m, 1H), 4,39-4,47 (m, 1H), and 4.68 (DD, J = 9,1 J = 5,1, 1H), 5,09 (d, J = 9,2, 1H).

Resolvable peaks smaller rotamer: of 2.27 to 2.35 (m, 1H), of 3.77 (s, 3H), 3,8-a 3.87 (m, 1H), 3,88-3,95 (m, 1H), 4.92 in (d, J = 9,2, 1H), total of 5.21 (DD, J = 9,1, J = 5,1 H).

(II) Boc-(R)Cgl-Aze-OH

Hydrolysis of Boc-(R)Cgl-Aze-OMe carried out by the method of hydrolysis of Boc-(R)Cha-Pic-OEl (see below). The product is crystallized from a mixture of EtOH-acetone-water (1:1: 3,95). Yield 80%.

1H-NMR (500 MHz, CDCl3) : 0,85-1,3 (m, 5H), and 1.4 (s, 9H), of 1.5-1.9 (m, 6H), 1,95-2,2 (m, 2H), 3,92 (m, 1H), 4.09 to (m, 1H), 4,35 (m, 1H), 4.95 points (m, 1H), 5,16 (sh.d, 1H).

Boc-(R)Cgl-Pic-OH

(I) Boc-(R)Cgl-Pic-OMe

To a solution of Boc-(R)Cgl-Pic-OH (2,086 g, 8.1 mmole) and triethylamine (1.13 ml, 8.1 mmole) in toluene (25 ml) and DMF (5 ml) add pivaloate (1 ml, 8.1 mmole). Then, when the bath temperature with ice add the mixture of H-Pic-OMe HCl (1,46 g, 8.1 mmole) and triethylamine (1.13 ml, 8.1 mmole) in DMF (20 ml). The reaction mixture was left to slowly warm to room temperature and after 24 h, diluted with water and extracted with toluene. After washing with 0.3 M KHSO410% OF N2CO3and brine evaporation of the solvent in vacuo get 2,52 g (81%) of colorless oil, which was used without further purification.

1H-NMR (500 MHz, CDCl32 rotamer in the ratio of 5:1) : 0,8-1,8 (m, 25H), of 2.25 (d, 1H), 2,75 (t, 1H, mens-OH

Obtained by the method of hydrolysis of Boc-(R)Cha-Pic-OEl (see below) using the product of the above stage (1). The product crystallized from diisopropyl ether and hexane.

1H-NMR (500 MHz, CDCl32 rotamer in the ratio of 5:1) : 0,8-1,8 (m, 25H), 2,3 (d, 1H), and 2.8 (t, 1H, lower rotamer), and 3.3 (t, 1H), 3,9 (d, 1H), 4,4 (t, 1H, lower rotamer), 4,5-4,6 (m, 1H), 5,1 (s, 1H, lower rotamer), 5,3 (d, 1H), 5,4 (d, 1H).

Boc-(R)Cgl-Pro-OH

To the mixture 3,59 g (31,24 mmole) of L-Proline, 20 ml of water and 1.18 g (29,7 mmole) of sodium hydroxide added 2.8 g (7,8 mmole) Boc-(R)Cgl-Pro-OSu in 10 ml of DMF. Due to poor solubility add another 30 ml of DMF and the reaction mixture is stirred for three days. After evaporation of the solvent, water is added. The aqueous phase is washed with ethyl acetate, acidified with 0.3 M KHSO4and extracted three times with ethyl acetate. The organic phase is washed once with water and once with brine, dried (Na2SO4), filtered and after evaporation obtain 2.3 g (83%) of product.

1H-NMR (300 MHz, CDCl3) : 0,89-2,17 (m, 23H), is 2.37 (m, 1H), 3,55 (K, 1H), 3,9 (sh.s, 1H), 4,28 (t, 1H), to 4.52 (sh.s, 1H), 5,22 (sh.s, 1H (NH)).

Boc-(R)Cha-Aze-OH

Obtained by the reaction of Boc-(R)Cha-OH with H-Aze-OEt HCl (see below) according to the method of obtaining Boc-(R)Cha-Prc-OH.

Boc-(R)Cha-Pro-OH

750 ml of 0.87 M solution of sodium hydroxide dissolved H-(S)Pro-OH (680 memisevic 20 h at room temperature, the mixture is then acidified (2M KHSO4) and extracted three times with ethyl acetate. The organic layers are combined and washed three times with water and once with brine. After drying over sodium sulfate and evaporation of the solvent syrupy oil is dissolved in diethyl ether, the solvent evaporated and finally drying the product in vacuo get with almost quantitative yield Boc-(R)Cha-Pro-OH as a white powder.

1H-NMR (500 MHz, CDCl3, mixture of two rotamers, 9:1) : 0,8-1,05 (m, 2H), of 1.05 to 1.55 (m, 15H; ibid 1,5 (sh.s, 9H)), of 1.55 to 1.8 (m, 5H), 1,8-of 2.15 (m, 3H), 2,47 (m, 1H), 3,48 (m, 1H), with 3.89 (m, 1H), 4,55 (m, 2H), is 5.06 (m, 1H).

Resolved signals smaller rotamer appear when 2,27 (m) to 3.58 (m), 4,33 (m), 5 (m).

Boc-(Me)(R)Cha-Pro-OSu

(I) Boc-(Me)(R)Cha-Pro-OH

Obtained by the reaction of Boc-(Me)(R)Cha-OSu and H-Pro-OH according to the aforementioned technique to obtain Boc-(R)Cha-Pro-OH.

(II) Boc-(Me)(R)Cha-Pro-OSu

Obtained on the basis of Boc-(R)Cha-Pro-OH according to the method described for the synthesis of Boc-(Me)(R)Cha-OSu.

Boc-(R)Cha-Pic-OH

(Ia) Boc-(R)Cha-Pic-OEt

In 150 ml of CH2Cl2dissolve 6.3 g (is 0.023 mole) Boc-(R)Cha-OH. The solution is cooled in a bath with ice, then add 6.3 g (0,047 mole) of N-hydroxybenzotriazole and 11.2 g (0,0265 mole) of TMA-CBI. After 15 min bath with ice is removed and the reaction mixture is stirred for 4 h at room those whom bauleni 4.1 g (0,021 mol) H-Pic-OEt HCl by addition of N-metamorphosen establish a pH of about 9. After 15 min bath with ice is removed and the reaction mixture is stirred for 3 days. The solvent is evaporated, the residue is dissolved in ethyl acetate and washed with diluted aqueous KHSO4(aq. ), NaHCO3(aq.) and water. The organic layer is dried (Na2SO4and after evaporation of the solvent gain of 7.7 g (89%) of Boc-(R)Cha-Pic-OEt, which is used without further purification.

1H-NMR (500 MHz, CDCl3, two rotamer in the ratio 3:1) : 0,7-1 (m, 2H), 1,1-1,9 (m, 29H; ibid of 1.28 (t, 3H)), 1,45 (sh.s, 9H), 2,01 (sh.d, 1H, main rotamer), 2,31 (sh.d, 1H), 2,88 (sh.t, 1H, lower rotamer), 3,33 (sh.t, 1H, main rotamer), 3,8 (sh.d, 1H, main rotamer), 4,15-4,3 (m, 2H), 4,5-4,7 (m, 2H, lower rotamer), 4,77 (sh.we, 1H, main rotamer), 4,9 (sh. d, 1H, lower rotamer), 5,28 (sh.d, 1H, main rotamer), 5,33 (sh.d, 1H, main rotamer).

(Ib) Boc-(R)Cha-Pic-OMe

To stir a mixture of 875 mg (3,22 mmole) Boc-(R)Cha-OH and 450 µl (3,23 mmole) of triethylamine in 10 ml of toluene and 2 ml of DMF add 400 ál (3,23 mmole) of pivaloate. After 45 minutes, to the resulting suspension add a mixture of 596 mg (3.32 mmole) of the hydrochloride of methyl-(S)-papakosta and 463 μl (3,32 mole) of triethylamine in 5 ml of DMF. After 2 h, add 1000 μl (0.72 mmole) of triethylamine and stirring is continued for another 18 hours After adding to the reaction mixture of water and toluene of ovaries in vacuum gain of 1.16 g of the title compound.

(II) Boc-(R)Cha-Pic-OH

Boc-(R)Cha-Pic-OEt (5.6 g, of 0.014 mole) is mixed with 100 ml of THF, 100 ml of water and 7 g of LiOH and the mixture is stirred for about a day at room temperature. THF is evaporated, the aqueous solution acidified with KHSO4(aq.) and extracted three times with ethyl acetate. The combined organic phase was washed with water, dried (Na2SO4and after evaporation obtain 4.9 g (94%) Boc - (R)Cha-Pic-OH, which is used without further purification. The connection can be crystallized from a mixture of diisopropyl ether-hexane.

Methyl ether, formed by the above method (Ib) can be obtained using methods described in section (II) for ethyl ether.

1H-NMR (500 MHz, CDCl32 rotamer in the ratio of 3.5:1) : 0,8-1,1 (m, 2H), 1,1-2,1 (m, 27H; there was 1.43 (s, 9H, main rotamer), of 1.46 (s, 9H, lower rotamer)), 2,33 (sh.s, 1H), 2,8 (sh.t, lower rotamer), 3,33 (sh.t, 1H, lower rotamer), 3,85 (sh.d, 1H, main rotamer), 4,57 (sh.d, 1H, lower rotamer), and 4.68 (m, 1H, lower rotamer), and 4.68 (m, 1H, lower rotamer), 4,77 (sh.to, 1H, main rotamer), 5,03 (sh.s, 1H, lower rotamer), 5,33 (sh. d, 1H, main rotamer), 5.56mm (m, 1H, main rotamer).

Boc-(R)Cha-(R,S)bears-OH

(I) Boc-(R)Cha-(R,S)bears-OMe

To a solution of 2 g (7.3 mmole) Boc-(R)Cha-OH and 0.81 ml (7.3 mmole) of 4-N-metalmorph is)bears-OMe HCl and of 1.62 ml (to 14.6 mmole) of 4-N-methylmorpholine and the reaction mixture is stirred for 24 hours The solvent is evaporated and the residue is dissolved in toluene and a small amount of diethyl ether. After washing with 0.3 M KHSO4and KHCO solution3and drying over Na2SO4the solvent is removed in vacuum. Displacement chromatography using as eluent a mixture of hexane-ethyl acetate (7:3) to obtain 2.4 g (83%) of the target product.

(II) Boc-(R)Cha-(R,S)bears-OH

In 35 ml of THF is dissolved at room temperature of 2.35 g (5.9 mmole) Boc-(R)Cha-(R, S)bears-OMe and to the solution was added 2.1 g LiOH in 35 ml of water. After stirring 5 h THF removed in vacuo. The aqueous phase is acidified with 2 M KHSO4and extracted with ethyl acetate, dried over Na2SO4and after evaporation receive 2 g (89%) of product.

Boc-(R)Cha-Val-OH

(I) Boc-(R)Cha-Val-OMe

To a stirred mixture of 6.75 g (25 mmol) Boc-(R)Cha-OH and 3.5 ml (25 mmol) of triethylamine in 50 ml of DMF added at room temperature of 3.1 ml (25 mmol) of pivaloate. After stirring 3 hours type of 4.16 g (25 mmol) of the hydrochloride of the methyl ester of valine in 50 ml of DMF and 3 ml of triethylamine. After stirring for about a day, add a few crystals of DMAP and the reaction mixture is heated 5 minutes at 50oC. the Solvent is removed in vacuo and to the residue is added ether and toluene. Prom is get me the rest, which is subjected to column chromatography using as eluent a mixture of toluene-ethyl acetate. The yield of the title compound of 6.99 g (73%).

(II) Boc-(R)Cha-Val-OH

The mixture 8,73 g (23 mmole) Boc-(R)Cha-Val-OMe and 5.6 g (230 mmol) of lithium hydroxide in 75 ml of THF and 75 ml of water is stirred for 4 hours. THF is removed in vacuo, the remaining solution was diluted with water and extracted with ether. Acidification 2M KHSO4and extraction with ethyl acetate followed by drying (MgSO4) and removal of solvent in vacuo get 8,15 g (96%) of the title compound.

Boc-(R)Hoc-Aze-OH

(I) Boc-(R)Hoc-Aze-OEt

In 15 ml of CH2Cl2at room temperature, dissolve 1 g (3.5 mmole) Boc-(R)Hoc-OH and 0.95 g (7 mmol) of the peso. The solution is cooled in a bath of ice and to it add of 0.77 g (4 mmole) of EDC. Bath ice is removed and the reaction mixture is stirred for 3 h at room temperature. The solvent is evaporated and the residue is dissolved in 20 ml of DMF. Type of 0.58 g (3.5 mmole) H-(R)Aze-OH and adding N-methylmorpholine establish a pH of about 9. Then the reaction mixture is stirred for one day. After distribution of the reaction mixture between water and toluene, the organic phase is separated, washed with 0.3 M KHSO4diluted solution KHCO3, brine, dried over Na2th product.

(II) Boc-(R)Hoc-Aze-OH

In 10 ml of THF was dissolved at room temperature 0.65 g (1.6 mmole) Boc-(R)Hoc-Aze-OEt and to the solution add 0,59 g LiOH in 10 ml of water. After stirring 24 h, add 2 M KHSO4and the THF removed in vacuo. The aqueous phase is acidified with an additional amount of KHSO4, then extracted with ethyl acetate, dried over Na2SO4and after evaporation obtain 0.5 g (85%) of the title compound.

Boc-(R)Hoc-Pro-OH

Obtained from Boc-(R)HOc-OSu according to the method of obtaining Boc-(R)Cha-Pro-OH.

1H-NMR (500 MHz, CDCl3) : from 0.8 to 0.94 (m, 2H), of 1.05 to 1.36 (m, 7H), 1,36 is 1.48 (W.s, 9H), 1,48-of 1.78 (m, 7H), 1,98 with 2.14 (m, 2H), 2,34 (m, 1H), 3,48 (m, 1H), 3,85 (m, 1H), 4,43 (m, 1H), to 4.52 (sh.d, 1H), 5,26 (sh.d, 1H); signals smaller rotamer appear when : 1,92, 2,25, 4,2 and 4.93.

Boc-(R)Hoc-Pic-OH

(I) Boc-(R)Hoc-Pic-OMe

Obtained by the reaction of Boc-(R)Hoc-OH with H-Pic-OMe HCl according to the method described for the synthesis of Boc-(R)Cha-Pic-OEt (see above).

(II) Boc-(R)Hoc-Pic-OH

Obtained from Boc-(R)Hoc-Pic-OMe according to the method described for the synthesis of Boc-(R)Cha-Pic-OH (see above).

1H-NMR (500 MHz, CDCl3) : of 0.82 to 0.97 (m, 2H), 1,1-of 1.36 (m, 7H), 1,36-1,5 (sh. s, 9H), 1,5-1,82 (m, 11H), 2,35 (sh.d, 1H), 3,28 (sh.t, 1H), 4,63 (m, 1H), 5,33 (sh.s, 1H), 5,44 (sh.d, 1H); signals smaller rotamer appear when : 1,88, 2,8, 4,25, 4,55 and equal to 4.97.

Boc-(R)Pro-Phe-OH

(I) Boc-(R)Pro-Phe-OMe

To a solution of 2 g (9,29 mmole) Boc-(R) - Pro-OH and 0.94 Mas stirred for 30 minutes at room temperature. After cooling the mixture to 0oC add a mixture of 2 g (9,29 mmole) of H-Phe-OMe and 0.94 g of triethylamine in 40 ml of DMF and the reaction mixture is stirred for about a day at room temperature. The reaction mixture is diluted with toluene, the organic phase is washed with 0.3 M KHSO4(3 x 50 ml), 50 ml of water and dried (Na2SO4).

Evaporation of the solvent with a quantitative yield receive the title compound which is used in the next stage without additional purification.

(II) Boc-(R)-Pro-Phe-OH

A mixture of 4 g (10.6 mmole) Boc-(R)Pro-Phe-OMe and 8,93 g (21.3 mmole) of LiOH H2O in 140 ml of aqueous THF (1:1) intensively stirred for about a day at room temperature. THF is evaporated, the aqueous phase is acidified with 1 M KHSO4and extracted with EtOAc (3 x 75 ml). The combined organic phase washed with water and dried (Na2SO4). Filtration and evaporation of solvent gives a residue cleaning which by crystallization from diisopropyl ether get 2,329 g (60%) of the title compound as a white crystalline substance.

Boc-(R)Pro(3-(S)Ph)-Pro-OH

(I) Boc-(R)Pro(3-(S)Ph)-Pro-OBn

To a mixture of 1.61 g of Boc-(R)Pro(3-(S)Ph)-OH, of 1.65 g of H-Pro-OBn HCl and 0.75 g of the peso in 11 ml of DMF added at room temperature 0,84 ml MMOs and 2,92 g CMA-CBI and the reaction mixture was stirred M KHSO4(2 x 100 ml), 1 M NaOH (3 x 100 ml), water (3 x 100 ml) and dried (MgSO4). Evaporation of the solvent receive oil (2,53 g), treatment of which column chromatography using as eluent CH2Cl2-MeOH (97:3) receive 2,11 g (88%) of the title compound.

(II) Boc-(R)Pro(3-(S)Ph)-Pro-OH

In 70 ml of EtOH was dissolved 0,94 g of Boc-(R)Pro(3-(S)Ph)-Pro-OH hydronaut in the presence of 0.42 g of 5% Pd-C for 3.5 hours. Filtration of the catalyst and evaporation of the solvent are obtained from a quantitative yield of the title compound.

Boc-(R)Tic-Pro-OH

Obtained by the method described in patent EP-0,479,489-A2 (P. D. Gesellchen, R. T. Shuman).

BnOOC-CH2-NH-CO-CH2-Br

To a solution of p-TS-OH H-Gly-OBn (5 mmol) and triethylamine (5 mmol) in 10 ml of CH2Cl2add a solution of 2-bromoxynil acid (5 mmol) in 10 ml of CH2Cl2and dicyclohexylcarbodiimide (5 mmol). The mixture is stirred for about a day at room temperature and filtered. The organic phase is washed twice with 0.2 M KHSO4, 0.2 M NaOH, brine and dried. Evaporation and column chromatography (CH2Cl2-MeOH, 95:5) with a quantitative yield get the target connection.

1H-NMR (300 MHz, CDCl3) : the 3.89 (s, 2H), 4,05-4,11 (d, 2H), 5,19 (s, 2H), 7,06 (sh.s, 1H), 7.3 to 7.4 (m, 5H).

Boc Boc-(R)Phe-Phe-OH

(I) Boc-(R)Phe-Phe-OMe

In 30 ml of acetonitrile is dissolved Boc-(R)Phe-OH (18,8 mmole; production company Bachem Feinchemikalien AG), Phe-OMe (20,7 mmole) and 4-dimethylaminopyridine (37,7 mmole). It is cooled to the temperature of ice water solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mmole). The cooling bath removed and the reaction mixture is stirred for about a day. The solvent is removed under reduced pressure and the residue is dissolved in 50 ml of ethyl acetate. By washing the organic phase with aliquot of 50 ml of 0.5 M potassium hydrosulfate, 1 M sodium bicarbonate and finally with water followed by evaporation of solvent to obtain 7.5 g of Boc-(R)Phe-Phe-OMe (94%), which is used in the next stage without additional purification.

(II) Boc-(R)Phe-Phe-OH

To a solution of Boc-(R)Phe-Phe-OMe (to 16.4 mmole) in 40 ml of tetrahydrofuran are rapidly added a solution of lithium hydroxide (32,8 mmole) in 20 ml of water. The reaction mixture is stirred for 3.5 h, after which the solvent is removed under reduced pressure. The residue is dissolved in 50 ml ethyl acetate and washed with 50 ml of 0.5 M potassium sulfate and then 50 ml of water. Removal of solvent receive 8 g (Quant. ) Boc-(R)Phe-Phe-OH in the form of an amorphous substance.1H-NMR (200 MHz, d-CHCl3): of 7.4 and 6.7 (m, 10H), 5,7-4,2 (m, 6H), of 1.34 (s, 9H).

HO-CH2
2)Ph - SO2-OCH2-COOBn

In 25 ml of CH2Cl2and 25 ml of diethyl ether are dissolved 1.66 g (10 mmol) of benzylglycine. The mixture is cooled to 0oC and added to 2.8 ml (10 mmol) of triethylamine. Maintaining the temperature at 0oC, in small portions during 15 minutes add 2,44 g (11 mmol) of o-nitrobenzenesulfonamide. After stirring the suspension for 50 minutes at 50oC add 20 ml of water and 30 ml of CH2Cl2. The phases are separated, the organic phase is washed with 20 ml of 1 M HCl and 20 ml of water, dried (Na2SO4), filtered and evaporation in vacuo get to 3.34 g of residue, which was subjected to column chromatography using as eluent a mixture of heptane-EtOAc (2:1) and obtain 1.18 g (34%) of the title compound.

1H-NMR (300 MHz, CDCl3) : to 4.92 (s, 2H), 5,17 (s, 2H), 7,83 (m, 5H), 7,76 (m, 3H), 8,16 (DD, 1H).

Benzyl-2-(para-nitrobenzenesulfonate)acetate (4-NO2)Ph - SO2-OCH2-COOBn

Obtained by the method used for the synthesis of benzyl-2-(o-nitrobenzenesulfonate)acetate and above. The target compound was obtained after evaporation of the solvent in the crystalline form and is sufficiently pure for use without further purification (yield 64%).

1H-NMR (300 MHz) of methylglucose and 4.04 ml (50 mmol) of pyridine in CH2Cl2(total of 62.5 ml) at 0oC for 25 minutes added dropwise to 10.09 ml (60 mmol) of anhydride triftormetilfullerenov acid in CH2Cl2and then stirred for 1 h at 0oC. After washing with 0.3 M KHSO4, a saturated solution of Na2CO3drying (Na2SO4and filtering, evaporation of the solvent in vacuo get 9,94 g (90%) of the title compound.

TfO-CH2-COOEt

From ethylglycol according to the method described for the synthesis of TfO-CH2-COOMe.

TfO-CH2-COO-n-Bu

From butylglycol according to the method described for the synthesis of TfO-CH2-COOMe.

TfO-CH2-COOBn

Obtained on the basis of HO-CH2COOBn according to the method of obtaining TfO-CH2-COOMe.

TfO-CH2-COO-n-Hex

(I) HO-CH2-COO-n-Hex

To glycolic acid (215 mg, 2,82 mmole) in 12.8 ml of CH3CN add 719 mg (3,39 mmole) of 1-hexylidene and 429 mg (2,82 mmole) of DBU. After stirring for about a day and boiling 6 h the solvent is evaporated, add ethyl acetate and 1 M KHSO4and the phases are separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporation in vacuo get 333 mg (74%) of product.

(II) TfO-CH2COO-n-Hex

Derived from HO-CH2
(I) 3-Aminomethyl-1-benzhydrylamine obtained according to the literary source, see: A. G. Anderson Jr., R. Lok, J. Org. Chem., 37, 3953, 1972.

(II) 3-(N-tert-Butyloxycarbonyl)-1-benzhydrylamine

To a solution of 3.5 g (13.9 mmole) 3-aminomethyl-1-benzhydrylidene in 45 ml of THF added a solution of 0.56 g (13.9 mmole) of NaOH in 45 ml of water. After cooling the reaction mixture to 0oC there was added 3.03 g (13.9 mmole) of di-tert-BUTYLCARBAMATE. The cooling bath is removed after a few minutes, and the mixture is stirred for about a day at room temperature. THF is evaporated and the residue extracted with diethyl ether (3 x 45 ml). The combined organic layer was washed with brine, dried over Na2SO4and filtered. Evaporation of the solvent to obtain 4.6 g (94%) of the title compound.

(III) 3-(N-tert-butyloxycarbonyl)azetidin

In 170 ml of MeOH is dissolved 3.4 g (9.6 mmole) of 3-(N-tert-butyloxycarbonyl)-1-benzhydrylpiperazine and hydronaut about the day at 5 MPa in the presence of 0.3 g of Pd(OH)2. The catalyst is filtered off and the solvent evaporated. Purification of the crude product column chromatography using as eluent mixtures of MeOH-CH2Cl2(1:9), then MeOH (saturated with NH3(g)) -CH2Cl2

6.5 ml of toluene is mixed with 0.9 g (4.8 mmole) of 3-(N-tert-butyloxycarbonyl)azetidine and 1.3 g (6.3 mmole) of N-benzyloxycarbonyl-O-methylisoleucine and all are heated for 72 h at 70oC and then leave for another 72 h at room temperature. Evaporation and subsequent column chromatography using as eluent EtOAc, then MeOH (saturated with NH3(g)) -CH2Cl2(1:9) gain of 0.67 g (38%) of the title compound as a white powder.

(V) 3-aminomethyl-1-(N-benzyloxycarbonylamino) azetidin (H-Mig (Z))

In 10 ml of EtOAc saturated with HCl (g), dissolved 0,67 g (of 1.85 mmole) of Boc-Mig (Z), stirred for 10 min at room temperature, then added dropwise 10 ml of saturated aq. solution of KOH. The layers are separated and the aqueous phase is extracted with EtOAc (3 x 8 ml). The organic layers are combined, washed with brine, dried (Na2SO4) and evaporation gain of 0.43 g (89%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 2,55-to 2.65 (m, 1H), 2,84 (d, 2H), 3,66 (DD, 2H), a 4.03 (DD, 2H), 5,07 (s, 2H), 7,2-7,4 (m, 5H).

MC: m/z 263 (M++ 1).

3-amino-ethyl-1-(N-benzyloxycarbonylamino)azetidin (H-Dig (Z))

(1) 3-(carboxylic acid)-1-benzhydrylamine obtained from published source, see Anderson Jr., R. Lok, J. Org. Chem., 37, 3953, 1972.

(III) 3-methanesulfonamido-1-benzhydrylamine

To a solution 6,62 g (26,1 mmole) of 3-hydroxymethyl-1-benzhydrylidene in 50 ml dry pyridine is added at 0oC 4.5 g (39.2 mmole) of methanesulfonamide. The reaction mixture is stirred for 1 h and then left overnight in the refrigerator. The reaction mixture is transferred into a mixture of ice water, the precipitate was separated, washed with water and after drying in a vacuum gain of 7.75 g (89,5%) of the title compound.

(IV) 3-cyanomethyl-1-benzhydrylamine

To a solution of 7.75 g (23.4 mmole) 3-methanesulfonamido-1-benzhydrylidene in 50 ml of DMF add a solution 3,44 g (70 mmol) of NaCN in 10 ml of water. The mixture is heated for 20 h at 65oC, cooled and transferred into a mixture of ice water. The precipitate was separated, washed with water and after drying in a vacuum get 5.7 g (93%) of the title compound.

(V) 3-amino-ethyl-1-benzhydrylamine

To a suspension of 2.9 g (76 mmol) of LiAlH4in 80 ml of su is e boiling the reaction mixture for 4 h, the excess hydride hydrolyzing careful addition of cooling NH4Cl (aq.). A jelly-like mixture is filtered and the filter cake washed several times with THF. The solvent is evaporated, the residue is dissolved in diethyl ether, washed with brine and dried over Na2SO4. Evaporation of the solvent receive 5 g (87%) of the title compound.

(IV) 3-(N-tert-butyloxycarbonyl)-1 - benzhydrylamine

The target compound is obtained with a yield of 6.5 g (95%) of 3-amino-ethyl-1-benzhydrylidene by the method of preparation of 3-(N-tert-butyloxycarbonyl)-1-benzhydryl of azetidine.

(VII) 3-(N-tert-butyloxycarbonyl)azetidin

The target compound is obtained with a yield of 1.2 g (70%) of 3-(N-tert-butyloxycarbonyl)-1-benzhydrylidene by the method of preparation of 3-(N-tert-butyloxycarbonyl)azetidine.

(VIII) 3-(N-tert-butyloxycarbonyl)-1- (N-benzyloxycarbonylamino)azetidin (Boc-Dig (Z))

The target compound is obtained with a yield 0.09 g (34%) of 3-(N-tert-butyloxycarbonyl)azetidine by the method of preparation of 3-(N-tert-butyloxycarbonyl)-1- (N-benzyloxycarbonylamino)azetidine.

(IX) 3-amino-ethyl-1-(N-benzyloxycarbonylamino) azetidin (H-Dig (Z))

In 10 ml of EtOAc saturated with HCl (g), dissolved 0,589 g (1,56 Molen.), the layers are separated and the aqueous phase is extracted with EtOAc (3 x 8 ml). The organic layers are combined, washed with brine, dried over Na2SO4and evaporation receive 0,415 g (96%) of the title compound.

1H-NMR (500 MHz, CDCl3) : 1,6 (dt, 2H), 1,52-of 2.54 (m, 3H), 3,53 (sh.s, 2H), 4 (Sch.t, 2H), 5 (s, 2H), 7,17-7,31 (m, 5H).

Example 1

HOOC-CH2-(R)Cgl-Aze-Pab

(1) Boc-(R)Cgl-Aze-Pab (Z)

To a stirred mixture of 3.4 g (10 mmol) Boc-(R)Cgl-Aze-OH (see: getting parent compounds) and to 5.13 g (42 mmole) of DMAP in 120 ml of CH3CN add 3,18 g H-Pab (Z) HCl (see: getting the initial connection). After stirring 2 hours at room temperature the mixture is cooled to -8oC and then add a 2.01 g (10.5 mmol) of EDC. The reaction mixture was left to warm to room temperature and stirring is continued for another 47 hours. The solvent is evaporated and the residue is dissolved in 200 ml EtOAc. The organic phase is washed with 50 ml of water, 0.5 M KHSO4(1 x 50 ml + 2 x 25 ml), NaHCO3(2 x 25 ml saturated solution), 50 ml of water and dried. Evaporation of solvent gives a total of 5.21 g (86%) of the title compound.

1H-NMR (500 MHz, CDCl3) : 0,8-1,9 (m, 20H; it as a 1.3 (s, 9H)), 2,35 of 2.6 (m, 2H), 3,74 (sh.t, 1H), 4,1 (m, 1H), 4,25-4,4 (m, 2H), 4,45-4,6 (m, 1H, rotamer), 4,75-5 (m, 1H, rotamer), 5,08 (sh.d, 2H), further 5.15 (s, 2H), 7,15-to 7.35 (m, 5H), 7,41 (the HCl in 195 ml of EtOAc add 4,69 g (7,743 mmole) Boc-(R)Cgl-Aze-Pab (Z) together with 40 ml of EtOAc. The reaction mixture was left to warm to room temperature and stirred for 30 minutes To a transparent solution was added 140 ml of Et2O with the formation of a precipitate. The reaction mixture was left for another 1 hour and 40 minutes at room temperature. The precipitate is filtered off, quickly washed with 150 ml of Et2O and dried in vacuum. Then the precipitate is dissolved in 50 ml of water and alkalinized 15 ml of 2M NaOH. The alkaline phase is washed with CH2Cl2(1 x 100 ml + 1 x 50 ml). The combined organic phase is washed with 20 ml water, 20 ml of brine and dried (MgSO4). Evaporation of the solvent receive 3,44 g (88%) of the title compound.

1H-NMR (500 MHz, CDCl3) : 0,8-2 (m, 11H), of 2.51 (m, 1H), to 2.67 (m, 1H), of 3.07 (d, 1H), 4,11 (m, 1H), 4,18 (m, 1H), 4,43 (DD, 1H), 4.53-in (DD, 1H), 4,91 (m, 1H), 5,22 (s, 2H), 7,2-7,4 (m, 7H), was 7.45 (d, 2H), 8,51 (d, 2H).

(III) BnOOC-CH2-(R)Cgl-Aze-Pab (Z)

A mixture of 1.13 g (2.2 mmole) H-(R)Cgl-Aze-Pab (Z), 0.9 g (2.6 mmole) benzyl-2-(o-nitrobenzenesulfonate)acetate ((2-NO2)-Ph-SO2-OCH2-COOBn, see: getting the initial connection), 0,99 g (5.6 mmole) K2CO3and 113 ml of CH3CN heated 3 h at an oil bath at 60oC. After evaporation of the solvent added EtOAc and the mixture is washed with water. The organic phase is extracted with 1M KHSO4and the resulting aqueous phase washed with EtOAc. the at (Na2SO4), filtered and evaporation in vacuo get 1,17 g of residue, which is twice subjected to column chromatography using as eluent for the first time CH2Cl2-MeOH (saturated with NH3) (95:5) and the second time diethyl ether-MeOH (saturated with NH3) (9:1) to obtain the 0,526 g (36%) of the title compound.

Alkylation is also carried out using benzyl-2-(p-nitrobenzenesulfonate)acetate ((4-NO2)Ph-SO2-OCH2-COOBn, see: getting parent compounds) and using the above techniques, resulting in a gain of the title compound with a yield of 52%.

1H-NMR (300 MHz, CDCl3) : 0,85-of 2.15 (m, 11H), 2,48 (m, 1H), 2.63 in (m, 1H), 2,88 (d, 1H), 3,24 (d, 1H), 3.27 to (d, 1H), 3,95 (m, 1H), of 4.05 (m, 1H), of 4.44 (m, 1H), 4,55 (m, 1H), 4,91 (m, 1H), 5,07 (s, 2H), with 5.22 (s, 2H), of 7.2 to 7.4 (m, 10H), was 7.45 (d, 2H), 7,79 (d, 2H), 8,42 (m, 1H).

(IVa) HOOC-CH2-(R)Cgl-Aze-Pab 2 HCl

In 5 ml of methanol was dissolved 20 mg (0,031 mmole) of BnOOC-CH2-(R)Cgl-Aze-Pab (Z). Add a few drops of chloroform and 5% Pd-C and the mixture hydronaut 1 h at atmospheric pressure. After filtration and evaporation of the lyophilization product of water get 11 mg (72%) of the title compound.

1H-NMR (500 MHz, D2O) : 1-2 (m, 11H), 2,1 (m, 1H), 2,44 (m, 1H), 2,82 (m, 1H), 3,9 (c, 2H), 4.09 to (d, 1H), 4.4 to 4.5 (m, 2H), 4,66 (which of arbonyl).

(IV) HOOC-CH2-(R)Cgl-Aze-Pab

In EtOH (99%) dissolved BnOOC-CH2-(R)Cgl-Aze-Pab (Z) and hydronaut at atmospheric pressure in the presence of 5% Pd-C. Filtration of the catalyst through cellit and evaporation of the solvent receive a 97% yield of the title compound.

1H-NMR (500 MHz, CD3OD, mixture of two rotamers) main rotamer : 1-1,12 (m, 1H), 1,13-of 1.34 (m, 4H), of 1.55 to 1.7 (m, 3H), 1,73-of 1.85 (m, 2H), 1,94-2,02 (sh. d, 1H), 2,32-to 2.42 (m, 1H), 2,54-of 2.64 (m, 1H), 2.95 and-3,1 (AB-system plus d, 3H), 4,18-4,25 (sh.for, 1H), 4,28-4,32 (sh.for, 1H), 4,43-4,6 (AB-system, 2H), 4,8-is 4.85 (DD, 1H), of 7.48-rate of 7.54 (d, 2H), 7,66-7,71 (d, 2H). Soluble signals smaller rotamer appear when : 0,95 (m), 1; 43 (m), 2,24 (m) 2,84 (d), of 3.96 (m), a 4.03 (m), EUR 7.57 (sh.D.), 7,78 (sh.D.).

13C-NMR (125 MHz, CD3OD) : 168, 173, 176,3 and 179 (carbon amidinopropane and carbonyl).

Example 2

HOOC-CH2-CH2-(R)Cgl-Aze-Pab 2HCl

(I) H-(R)Cgl-Aze-Pab (Z)

Obtained by the method described in Example 1 (II) treatment of the hydrochloride of the base to obtain the free base.

(II) BnOOC-CH2-CH2-(R)Cgl-Aze-Pab (Z)

In 2 ml of isopropanol was dissolved 0,19 g (range 0.38 mmole) H-(R)Cgl-Aze-Pab (Z) and 70 ml (0.43 mmole) of benzoylacrylate and the mixture is left for 6 days. Column chromatography using as eluent CH2Cl2- THF (8:2) to obtain 0.12 g (48%) of the title soybeans is 3 (m, 1H), 4,37 (DD, 1H), 4,6 (DD, 1H), equal to 4.97 (DD, 1H), 5,09 (DD, 1H), 5,22 (s, 2H), 7,25 to 7.4 (m, 10H), 7,47 (d, 2H), 7,83 (d, 2H), 8,61 (sh.t, 1H).

(III) HOOC-CH2-CH2-(R)Cgl-Aze-Pab 2HCl

In 10 ml of ethanol was dissolved 0.1 g (0.15 mmole) of BnOOC-CH2-CH2-(R)Cgl-Aze-Pab (Z) and hydronaut 1 h at atmospheric pressure in the presence of 5% Pd-C. the Solution is filtered, evaporated and the crude product purified using OFGH with the use of CH3CN - 0.1 M NH4OAc (1:4). The resulting product is dried by freezing, is treated with excess conc. HCl and after repeated freeze-drying obtain 31 mg of the dihydrochloride.

1H-NMR (300 MHz, D2O) : 0,8-2,1 (m, 11H), of 2.38 (m, 1H), 2,7-2,9 (m, 3H), 3,2-3,4 (m, 2H), 3,98 (d, 1H), 4,35-4,55 (m, 2H), 4,6 (s, 2H), 5,04 (DD, 1H), to 7.59 (d, 2H), 7,83 (d, 2H).

13C-NMR (75 MHz, D2O) : of 167.2, 167,6, 172,3 and 175,5 (carbon amidinopropane and carbonyl).

Example 3

HOOC-CH2-(R)Cgl-Pro-Pab 2HCl

(1) Boc-(R)Cgl-Pro-Pab (Z)

In 30 ml of acetonitrile is mixed with 2.3 g (of 6.49 mmole) Boc-(R)Cgl-Pro-OH (see: getting the initial connection), 2.38 (19,47 mmol) DMAP and 1.84 g (of 6.49 mmole) H-Pab (Z) (see: getting the initial connection). The mixture is cooled to -15oC and to it was added 1.31 g (for 6.81 mmole) of EDC. The mixture is left to warm to room temperature and then stirred for about a day. After evaporation the residue of restore the positive phase is washed twice with 0.3 m solution of KHSO4twice with a solution of NaHCO3and once with brine, dried (Na2SO4), filtered and evaporated. Purification of the crude product column chromatography on silica gel using ethyl acetate as eluent get 1,77 g (44%) of product.

1H-NMR (500 MHz, CDCl3) : 0,9-1,49 (m, 14H), of 1.5-2.1 (m, 9H), 2,37 (sh. s, 1H), 3,53 (K, 1H), 3,94 (sh.s, 1H), was 4.02 (m, 1H), 4,43 (sh.s, 2H) and 4.65 (d, 1H), 5,09 (sh.s, 1H), and 5.2 (s, 2H), 7,18 to 7.4 (m, 5H), was 7.45 (d, 2H), 7.62mm (sh.s, 1H), 7,81 (m, 2H).

H-(R)Cgl-Pro-Pab (Z)

In 75 ml of saturated HCl in ethyl acetate was dissolved 1.45 g (2,34 mmole) Boc-(R)Cgl-Pro-Pab (Z) and the mixture is left for 10 minutes at room temperature. Evaporation of the solvent receive the dihydrochloride of the product.

1H-NMR (300 MHz, D2O) : 1-1,45 (m, 5H), 1,58-2,2 (m, 9H), of 2.3-2.5 (m, 1H), 3.75 to a 3.9 (m, 2H), 4.25 in (d, 2H), 4,5-of 4.66 (m, 3H), 5,49 (s, 2H), 7,45 to 7.7 (m, 7H), 7,87 (d, 2H).

Amin obtained by dissolving the dihydrochloride in 0.1 M NaOH solution and three times with extraction of the aqueous phase with ethyl acetate. The organic phase is washed once with brine, dried (Na2SO4), filtered and after evaporation obtain 1.19 g (97%) of the title compound.

(III) BnOOC-CH2-(R)Cgl-Pro-Pab (Z)

In 4 ml of dichloromethane is mixed 0.34 g (0.65 mmole) H-(R)Cgl-Pro-Pab (Z), 0,215 g (0.65 mmole) of BnOOC-CH2-OTf (see: getting the source soedinenii at room temperature. The reaction mixture was diluted with CH2Cl2and the organic layer washed once with water and brine, dried (Na2SO4), filtered and evaporated. Purification of the crude product column chromatography using a stepwise gradient of CH2Cl2-MeOH (97: 3, then 95:5) receive 299 mg of a mixture of two products (according to TLC). This mixture is optionally purified column chromatography using a stepwise gradient of ethyl acetate: toluene(9:1, 93:7, 95:5, 100:0) and obtain 46 mg (9%) (BnOOC-CH2)2-(R)Cgl-Pro-Pab (Z), which eluted from the column first and followed allerban 133 mg (31%) target BnOOC-CH2-(R)Cgl-Pro-Pab (Z).

1H-NMR (300 MHz, CDCl3) : BnOOC-CH2-(R)Cgl-Pro)Pab (Z): 0,9-1,3 (m, 5H), 1,4-2,1 (m, 9H), 2.3 to 2.4 (m, 1H), 3,05 (d, 1H), 3,2-3,37 (AB-system with center at 3,29, 2H), 3,5-3,6 (m, 2H), 4,29-4,57 (ABX-system with center at 4,43, 2H), to 4.62 (d, 1H), 4,91 (apparent singlet, 2H), 5,19 (s, 2H), 6.75 in (sh.s, NH), and 7.1-7.5 (m, 12H), of 8.7 to 8.8 (m, 2H, + NH), 9,45 (sh.s, NH).

1H-NMR (300 MHz, CDCl3) : (BnOOC-CH2)2-(R)Cgl-Pro-Pab (Z): of 0.68 to 0.9 (m, 2H), 1-1,3 (m, 3H), 1,43 (sh.d, 1H), 1,55-2 (m, 7H), 2.05 is (sh.d, 1H), 2.3 to 2.4 (m, 1H), 3.15 in (d, 1H), 3.25 to of 3.48 (m, 2H), 3,55-3,79 (AB-system with center at 3,67, 4H), to 4.38-4,58 (ABX-system with center at 4,48, 2H), and 4.68 (d, 1H), 4,82-to 4.98 (AB-system with center at 4,91, 4H), 5,19 (s, 2H), 6,66 (sh. s, NH), and 7.1-7.5 (m, 17H), of 7.75 (d, 2H), 7,8 (t, NH), 9,P CLASS="ptx2">

(IV) HOOC-CH2-(R)Cgl-Pro-Pab 2HCl

Mix of 0.133 g (0.2 mmole) of BnOOC-CH2-(R)Cgl-Pro-Pab (Z) with 0.06 g of 5% Pd-C, 1 ml of 1 M HCl solution and 10 ml ethanol and the mixture hydronaut 1 hour in an atmosphere of H2. After filtration through hyflo and evaporation of the solvent double freezing of water yield 93 mg (90%) receive the product.

1H-NMR (300 MHz, D2O) : 1-1,45 (m, 5H), of 1.5-2.1 (m, 9H), 2,2-2,4 (m, 1H), 3,55-of 3.85 (m, 4H; it 3,79 (s, 2H)), to 4.23 (d, 1H), 4,33-of 4.57 (m, 3H), 7,44 (d, 2H), 7,69 (d, 2H).

13H-NMR (75 MHz, D2O) : 166,9, 167,2, 169,1, 174,5 (the carbon amidinopropane and carbonyl).

Example 4

HOOC-CH2-CH2-(R)Cgl-Pro-Pab 2HCl

(1) BnOOC-CH2-CH2-(R)Cgl-Pro-Pab (Z)

In 3 ml of ethanol is dissolved 0,406 g (0,762 mmole) H-(R)Cgl-Pro-Pab (Z). (see Example 3) and to the solution was added 132 μl (0,861 mmole) of benzoylacrylate. After stirring the reaction mixture at room temperature the mixture is evaporated and purification of the crude product column chromatography using as eluent a stepwise gradient of CH2Cl2-MeOH (95:5 and 90:1) with output 0,399 mg (75%) receive the product.

1H-NMR (300 MHz, CDCl3) : 0,8-1 (m, 1H), 1-1,3 (m, 4H), 1,35-2,2 (m, 9H), 3,4-3,6 (m, 2H), 4.26 deaths-to 4.52 (ABX-system with center at 4,4, 2H), with 4.64 (DD, 1H), of 5.05 (s, 2H), and 5.2 (s, 2H), 7,2-7,38 (m, 10H), the 7.43 (d, 2H), 7,78 (d, 2H).

13SUB>2-(R)Cgl-Pro-Pab 2HCl

BnOOC-CH2-CH2-(R)Cgl-Pro-Pab (Z) (0,261 g, 0,383 mmole) is mixed with 0.075 g of 5% Pd-C, 1 ml of 1 M HCl solution and 10 ml ethanol and the mixture hydronaut two hours at atmospheric pressure. After filtration through hyflo and evaporation of the solvent double freezing of water get 0,196 g (96%) of product.

1H-NMR (300 MHz, D2O) : 1,17-1,4 (m, 5H), 1,6-to 1.82 (m, 5H), 1,92-2,2 (m, 4H), 2,32-2,48 (m, 1H), of 2.81 (t, 2H), 3,11-3,36 (ABX2system center at 3,24, 2H), 3,63 to-3.9 (m, 2H), 4.25 in (d, 1H), 4,42-4,63 (m, 3H), 7,54 (d, 2H), 7,78 (d, 2H).

13C-NMR (75 MHz, D2) : 167, 167,3 174,6 and 174,7 (carbon amidinopropane and carbonyl).

Example 5

(HOOC-CH2)2-(R)Cgl-Pro-Pab 2HCl

(BnOOC-CH2)2-(R)Cgl-Pro-Pab (Z) (46 mg, 0,056 mmole; see Example 3) is mixed with 25 mg of 5% Pd-C, 0.7 ml of 1 M HCl solution and 7 ml of ethanol and the mixture hydronaut one hour at atmospheric pressure. The catalyst was removed by filtration through hyflo and the solvent evaporated. The final product in amounts of 25 mg (77%) received double freeze-drying from water.

1H-NMR (300 MHz, D2O) : 1-1,4 (m, 5H), 1,45-2,2 (m, 9H), 2,25-of 2.45 (m, 1H), 3,53-a-3.84 (m, 2H), 3,84-4,22 (AB-system with center at a 4.03, 4H), 4.26 deaths (d, 1H), 4,35-4,6 (m, 3H), 7,53 (d, 2H), to 7.77 (d, 2H).

13C-NMR (75 MHz, D2) : 167,1, 167,3, 170,6 and of 174.5 (carbon Aydinoglu is 875 g (2,37 mmole) Boc-(R)Cgl-Pic-OH (see topic: retrieving parent compounds), 1.22 g (becomes 9.97 mmole) DMAP and 0,706 g (2,49 mmole H-Pab (Z) (see: getting parent compounds) in a mixture of 30 ml of acetonitrile and 1 ml DMF was added when -18oC 0,478 g (2,49 mmole) of EDC. The reaction mixture is left for two hours to warm to room temperature and stirring is continued for 48 C. After removal of the solvent in vacuo the residue is dissolved in 50 ml of ethyl acetate. The solution was washed with 15 ml of water, 0.3 M KHSO4(3 x 15 ml), a solution of Na2CO3(2 x 15 ml) and water. Removal of solvent receive the remainder, which is subjected to column chromatography using as eluent a mixture of ethyl acetate-heptane (9:1). Yield 0.96 g (64%).

(II) H-(R)Cgl-Pic-Pab (Z)

Through a solution of 0.56 g (0,88 mmole) Boc-(R)Cgl-Pic-Pab (Z) in 25 ml of ethyl acetate propulsive hydrogen chloride. Two minutes from the solution deposited crystals. The solvent is removed in vacuo and to the residue are added 50 ml of ethyl acetate. Washing with 2 M sodium hydroxide solution (2 x 15 ml) and extraction of the aqueous phase 25 ml of ethyl acetate followed by drying (sodium sulfate) of the combined extracts and removal of solvent in vacuo get 0,448 g (95%) of the target product.

(III) H-(R)Cgl-Pic-Pab 2HCl

A solution of 98 mg (0,18 mmole) H-Cgl-Dic-Pab (Z) VI add 0.3 ml of 1 M hydrochloric acid. The ethanol is removed under vacuum and freeze-drying the residue receive 70 mg (81%) of target compound.

1H-NMR (300 MHz, CD3OD) : 1 - to 1.56 (m, 1H), 1.56 to was 1.94 (m, 9H), 1.56 to was 1.94 (m, 9H), 2,32 (sh.d, 1H), 3,32 is - 3.45 (m, 1H), 3,9 (W, d, 1H), 4,35 (d, 1H), and 4.5 (s, 2H), 5,1 - 5,2 (m, 1H), 7,55 (d, 2H), 7,76 (d, 2H).

13C-NMR (75 MHz, D2O) : of 167.2, 170,5 and 173,4 (carbon amidinopropane and carbonyl).

Example 7

HOOC-CH2-(R,S)CH(COOH)-(R)Cgl-Pic-Pab 2HCl

(I) BnOOC-CH2-(R,S)CH(COOBn)-(R)Cgl-Pic-Pab (Z)

A mixture of 350 mg (0,66 mmole) H-(R)Cgl-Pic-Pab (Z) (see Example 6) and 233 mg of dibenzylamine in 2.5 ml of ethanol, incubated for 4 days at room temperature. The ethanol is removed in vacuo and the residue is subjected to column chromatography using as eluent a mixture of ethyl acetate-heptane (9:1) receiving and 0.108 mg of the target product.

(II) HOOC-CH2-(R,S)CH(COOH)-(R)Cgl-Pic-Pab 2HCl

A solution of 105 mg (0,13 mmole) of BnOOC-CH2-(R,S)CH(COOBn)-(R)Cgl-Pic-Pab (Z) in 5 ml of 95% ethanol and 1 ml of water hydronaut 5 hours in the presence of 5% Pd-C. After adding 0.3 ml of 1 M hydrochloric acid, the mixture is filtered and the solvent is removed in vacuum. The residue is dissolved in water and freeze-drying obtain 54 mg (73%) of target compound.

1H-NMR (300 MHz, CD3OD, mixture of two diastereomers, 5:4) : 1,1 - 1,6 (m, 7H), 1,6 - 2,04 (m, 9H), 2,23 - to 2.42 (m, 1H) 2H), the 7.7 and 8.1 (m, 2H).

13C-NMR (75 MHz, D2O) : 167,1, 168,95, 169,6, and 173,1 (carbon amidinopropane and carbonyl).

MS: m/z 516 (M++ 1).

Example 8

H-(R)Cha-Aze-Pab 2HCl

(I) Boc-(R)Cha-Aze-Pab (Z)

To stir the mixture to 0.72 g (2,03 mmole) Boc-(R)Cha-Aze-OH (see: getting the initial connection), 1.04 g (8,53 mmole) DMAP and 604 mg (2.13 mmole) H-Pab (Z) (see: getting parent compounds) in 20 ml of acetonitrile is added at -18oC 604 mg (2.13 mmole) of EDC. The reaction mixture is left overnight to warm at room temperature and the solvent then removed in vacuum. The residue is dissolved in 40 ml ethyl acetate and the organic phase is successively washed with 10 ml of water, 0.3 M KHSO4(3 x 10 ml), Na2CO3NaCl (aq. , 2 x 10 ml) and finally with 10 ml of brine. Drying (Na2SO4) and removal of solvent in vacuo get the remainder, which is subjected to column chromatography using as eluent a mixture of ethyl acetate-methanol (9:1) and receiving 645 mg (51%) of the title compound.

(II) H-(R)Cha-Aze-Pab (Z)

Through a solution of 640 mg (equivalent to 1.03 mmole) Boc-(R)Cha-Aze-Pab (Z) in 25 ml of ethyl acetate propulsive hydrogen chloride. After two minutes, TLC analysis indicates complete reaction. To remove excess hydrogen chloride Ave is followed by extraction of the aqueous phase 15 ml of ethyl acetate. The combined organic extracts washed with water, dried (Na2CO3) and removal of solvent in vacuo receive 513 mg (96%) H-(R)Cha-Aze-Pab (Z).

(III) H-(R)Cha-Aze-Pab 2HCl

A solution of 76 mg (0.15 mmole) H-(R)Cha-Aze-Pab (Z) in 5 ml of 95% ethanol and 1 ml of water hydronaut 4 hours at atmospheric pressure in the presence of 5% Pd-C. Removing the catalyst by filtration, the addition of 0.4 ml of 1 M hydrochloric acid and evaporation of the solvent in vacuo get a residue, which was dissolved in 2 ml of water. Drying by freezing give 57 mg (85%) of the target product.

1H-NMR (500 MHz, D2O a mixture of 2 rotamers, 1:1) : 1,02 - 1,2 (m, 2H), 1,22 - of 1.92 (m, 11H), 2,4 - 2,5 (m, 1H), 2,8 - 2,9 (m, 1H), 4,25 (sh.t, 1H), 4,4 (DK, 1H), 4.53-in (DK, 1H) and 4.65 (s, 2H), of 5.05 - 5,1 (m, 1H), 7,65 (d, 2H), 7,88 (d, 2H).

Chemical shifts for soluble signals smaller rotamer : 0,57 (m) of 0.85 (m), 2,95 (m) 4,06 (DK), 4,17 (DK), 4,63 (C) 5,33 (m), 7.7 (d), to 7.93 (d).

13C-NMR (125 MHz, D2O) : of 167.2, 170,4 and to 172.8 (carbon amidinopropane and carbonyl).

Example 9

HOOC-CH2-(R)Cha-Aze-Pab 2HCl

(I) BnOOC-CH2-(R)Cha-Aze-Pab (Z)

To a mixture of 0.27 g (0,52 mmole) H-(R)Cha-Aze-Pab (Z) (see Example 8) and 0,158 g (1,14 mmole) K2CO35.2 ml of acetonitrile add 0,119 g (0,52 mmole) of benzylbromide and heated 1 h at an oil bath at 60oC. After removal of the p/SUB>SO4). Evaporation in vacuo get 0,344 g of residue, which was subjected to column chromatography using as an eluent of ethyl acetate, and at other times use a mixture of ethyl acetate-tetrahydrofuran-NH3-saturated methanol (60:5:2). Received 0,163 g of the target product.

1H-NMR (300 MHz, CDCl3) : 0,7 - 1 (m, 2H), 1,05 - of 2.05 (m, 11H), 2,35 is 2.55 (m, 1H), 2,55 is 2.75 (m, 1H), 3,15 - of 3.32 (m, 3H), 3.95 to of 4.05 (t, 2H), 4.4 and 4.5 m (ABX-system, 2H), 4,8 - of 4.95 (m, 1H), of 5.05 (s, 2H), and 5.2 (s, 2H), 7,2 - 7,5 (m, 12H), 7,7 - a 7.85 (d, 2H), 8,3 - to 8.45 (t, 1H).

13C-NMR (75 MHz, CDCl3) : 164,5, 167,8, 170,7, 171,9 and 175,9 (carbon amidinopropane and carbonyl).

(II) HOOC-CH2-(R)Cha-Aze-Pab 2HCl

The solution 0,163 g (0,243 mmole) of BnOOC-CH2-(R)Cha-Aze-Pab (Z) in 5.5 ml of ethanol (99.5% pure) and 0.7 ml of hydrochloric acid (1 ad) hydronaut 4 h in the presence of 0.17 g of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent followed by dissolving in water and freeze-drying obtain 107 mg (85%) of the title compound.

1H-NMR (500 MHz, CD3OD, mixture of two rotamers) main rotamer : 0,95 - of 1.95 (m, 13H), 2.3 to 2.4 (m, 1H), 2,6 - of 2.75 (m, 1H), 3,5 - of 3.75 (m, 2H), 4,05 - to 4.15 (m, 1H), 4,15 - to 4.23 (m, 1H), 4,36 - 4,43 (m, 1H), 4,43 to 4.5 (m, 1H), 4,58 with 4.65 (m, 1H), a 4.83 - 4,88 (m, 1H), of 7.5 to 7.6 (m, 2H), 7,73 - of 7.82 (m, 2H).

Resolved signals smaller rotamer appear when: is demography and carbonyl).

Example 10

HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Aze-Pab 2HCl

(I) BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Aze-Pab (Z)

A mixture of 230 mg (0,443 mmole) H-(R)Cha-Aze-Pab (Z) (see Example 8) and 144 mg (0,487 mmole) of dibenzylamine 1.5 ml of 95% ethanol is stirred for 5 days at room temperature. After removal of the ethanol in vacuo, the residue is subjected to column chromatography using as eluent a mixture of ethyl acetate-methanol (95:5) and obtain 54 mg (15%) of the target product.

(II) HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Aze-Pab

A solution of 49 mg (0.06 mmole) of BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Aze-Pab (Z) in 5 ml of 95% ethanol and 1 ml of water hydronaut 4.5 hours in the presence of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo get a residue, which was dissolved in 2 ml of water and 0.2 ml of 1 M hydrochloric acid. Freeze-drying obtain 32 mg (93%) of the target audiences.

1H-NMR spectrum of the title compound is characterized by two series of strongly overlapping signals due to the presence of two diastereomers. In addition, resolvable resonances smaller rotamer, approximately 15%, also appear in the spectrum.

1H-NMR (300 MHz, D2O) : 1,03 - 2 (m, 13H), 2,32 of $ 2.53 (m, 1H), 2,72 - 2,96 (m, 1H), 3,06 of 3.28 (m, 2H), 4,1 - 4,55 (m, 4H), 4,62 (sh. s, 2H), 5 - 5,1 (m, 1H), 7,55 - to 7.68 (m).

13H-NMR (75 MHz, D2O) : of 167.2, 169, 171, 172,3 and 174,1 (carbon amidinopropane and carbonyl).

Example 11

HOOC-CH2-(R or S)CH(COOH)-Cha-Aze-Pab/a 2HCl

(I) BnOOC-CH2-(R or S)CH(COOBn)-(R)Cha-Aze-Pab (Z)/a

A mixture of 2 g (3,8491 mmole) H-(R)Cha-Aze-Pab (Z) (see Example 8) and of 1.37 g of dibenzylamine in 10 ml of 95% ethanol is stirred for 4 days at room temperature. After removal of the ethanol in vacuo, the residue is subjected to column chromatography using as eluent a mixture of ethyl acetate-methanol (98: 2) and receiving 1,024 g (32%) BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Aze-Pab (Z). Two diastereoisomer share OFGH using as eluent CH3CN-0.1 M NH4OAc (65:35). This diastereoisomer eluted in the first column. After removal of the acetonitrile in vacuo the aqueous phase is shaken out three times with ethyl acetate. The organic phase is washed once with water, dried (Na2SO4), filtered and evaporation in vacuo get 0,352 g of the title compound in the form of a pure stereoisomer.

(II) HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Aze-Pab/a 2 HCl

A solution of 350 mg (0.43 mmole) of BnOOC-CH2-(R or S)CH(COOBn)-(R)Cha-Aze-Pab (Z)/a (diastereoisomer with the above stage (I)) in 15 ml of 95% ethanol and 3 ml of water hydronaut 4.5 hours in the presence of 5% Pd-C. Removing the catalyst by filtration the freeze-Drying obtain 214 mg (74%) of product in the form of a pure stereoisomer.

1H-NMR (300 MHz, MeOD, mixture of two rotamers) : 0,85 - of 1.93 (m, 13H), 2,25 - of 2.38 (m, 1H), 2,6 - of 2.75 (m, 1H), 2,88 (DD, 2H), 3,92 (t, 1H), 4,15 - of 4.25 (m, 2H), 4,3 - 4,43 (m, 2H), 4,56 (AB-system, 2H), 4,76 - a 4.86 (m, 1H, partially covered with the signal of solvent), to 7.59 (d, 2H), 7,78 (d, 2H).

Allow the signals generated less retamero appear at: 0,7, 2,95, 3,82, 4, 5,08 and 7,83.

13C-NMR (75 MHz, D2O) 166,9, 168, 8mm, 171,7, 172,3 and 173,8 (carbon amidinopropane and carbonyl).

Example 12

HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Aze-Pab/b 2HCl

(I) BnOOC-CH2-(R or S)CH(COOBn)-(R)Cha-Aze-Pab (Z)/b

The title compound was synthesized according to the method described in Example 11 to obtain BnOOC-CH2-(R, S)CH(COOBn)-(R)Cha-Aze-Pab (Z). This diastereoisomer comes with speakers after the first diastereoisomer. Output 0,537,

(II) HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Aze-Pab/b 2 HCl

A solution of 530 mg (0.65 mmole) of BnOOC-CH2-(R or S)CH(COOBn)-(R)Cha-Aze-Pab (Z)/b in 15 ml of 95% ethanol and 3 ml of water hydronaut 5 h in the presence of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo get a residue, which was dissolved in 6 ml of water and 1 ml of 1 M hydrochloric acid. Drying by freezing gives 280 mg (78%) of the target product.

1H-NMR (300 MHz, MeOD, mixture of two rotamers) : 0,86 - 1,9 (m, 13H), 2,3 - 2,42 (m, 1H), 2,6 - of 2.75 (m, 1H), 2,75 - to 2.85 (m,La) EUR 7.57 (d, 2H), of 7.75 (d, 2H). Allow the signals generated less retamero appear at : 0,78, 2,92, 3,82, are 5.36 and 7.8.

13C-NMR (75 MHz, D2O) : 166,8, 169, 172, 172,4 and 175,2 (carbon amidinopropane and carbonyl).

Example 13

HOOC-CH2-CH2-(R)Cha-Aze-Pab 2HCl

(I) (BnOOC-CH2-CH2-(R)Cha-Aze-Pab (Z)

A mixture of 182 mg (0.35 mmole) H-(R)Cha-Aze-Pab (Z) (see Example 8) and 62.5 mg (0,385 mmole) of benzoylacrylate 1.5 ml of 95% ethanol is stirred for 4 days at room temperature. The solvent is removed in vacuum and the residue is subjected to column chromatography using as eluent a mixture of ethyl acetate-methanol (9:1) and obtain 200 mg (84%) of the title compound.

(II) HOOC-CH2-CH2-(R)Cha-Aze-Pab 2HCl

A solution of 195 mg (0,29 mmole) of BnOOC-CH2-CH2-(R)Cha-Aze-Pab (Z) in 10 ml of 95% ethanol and 2 ml of water hydronaut 4 h in the presence of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo get a residue, which was dissolved in 2 ml of water and 0.4 ml of 1 M hydrochloric acid. Drying by freezing gives 130 mg (86%) of the target product.

1H-NMR (500 MHz, CD3OD) : 0,98 - of 1.27 (m, 1H), 1,3 - 1,9 (m, 11H), and 2.27 to 2.35 (m, 1H), 2,65 - to 2.74 (m, 1H), 2,77 (t, 2H), 3,32 (t, 2H), 4,1 (t, 1H), 4,17 - of 4.25 (m, 1H), 4,4 - of 4.49 (m, 1H), 4,55 (AB, 2H), a 4.83 - 4,9 (m, 1H), 7,58 (d, 2H), to 7.77 (d, 2H).

132-NH-CO-CH2-(R)Cha-Aze-Pab 2HCl

(I) BnOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab (Z)

The mixture 0,212 g (0,408 mmole) H-(R)Cha-Aze-Pab (Z) (see Example 8), 0.124 g (0,89 mmole) K2CO3and 0,128 g (0,449 mmole) of BnOOC-CH2-NH-CO-CH2-Br (see: getting parent compounds) in 6 ml of acetonitrile is stirred for two hours at 50oC. After evaporation of the solvent the residue is dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, the combined organic layer is dried (Na2SO4), filtered and evaporated. Purification of the product column chromatography using a stepwise gradient of ethyl acetate: tetrahydrofuran(85:15, 4:1, 7:3) get 0,19 g (64%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,75 - 2,1 (m, 13H), 2,43 (m, 1H), 2,56 (d, 1H), and 2.79 (m, 1H), 3 - 3,15 (m, 2H; it was 3.05 (d, 1H)), 3,89 - 4,18 (m, 5H), 4,8 - to 4.98 (m, 2H), further 5.15 (s, 2H), by 5.18 (s, 2H), 7,2 - 7,47 (m, 12H), 7,72 (m, 11H), 7,86 (d, 2H), 8,14 (sh. s, NH), 8,31 (DD, NH), 9,42 (sh. S. NH).

13C-NMR (75 MHz, CDCl3) : 164,5, 168,7, 169,22, 169,83, 171,7, 175,5 (the carbon amidinopropane and carbonyl).

(II) HOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab 2HCl

Mix 0,19 g (of 0.26 mmole) of BnOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab (Z) with 0.075 g of 5% Pd-C, 1.5 ml 1 n HCl solution, 3 ml of water and 17 ml of ethanol and hydronaut four hours at atmospheric pressure. Filtered avego connection.

1H-NMR (D2O, 300 MHz, two rotamer, 4:1) : 0,88 - 1,88 (m, 13H), 2,25 - to 2.42 (m, 1H), 2,3 - 2,89 (m, 1H), 3,94 (s, 2H), 3,89 (apparent doublet, 2H), 4.16 the (t, 1H), 4,28 (K, 1H), to 4.41 (K, 1H), 4,56 (s, 2H), to 4.98 (DD, 1H), 7,53 (d, 2H), to 7.77 (d, 2H). Resolved signals smaller rotamer appear when : 0,5 (sh. K) 0,77 (sh. K) to 5.21 (DD), 7,56 (d) and 7,81 (d).

13C-NMR (D2O, 75 MHz) : 166,8, 166,9, 168,6, 172,3 and 173,4 (hydrocarbons CARBONYLS and amidinopropane). Resolved signals smaller rotamer appear when : 166,8, 169,6 and 172.

Example 15

H-(R)Cha-Pro-Pab 2HCl

(I) Boc-(R)Cha-Pro-Pab (Z)

To stir at room temperature the mixture is 0.135 ml (1.1 mmole) of triethylamine and 405 mg (1.1 mmole) Boc-(R)Cha-Pro-OH (see: getting parent compounds) in 5 ml of DMF type is 0.135 ml (1.1 mmole). After 3 h added 340 mg (1.1 mmole) H-Pab (Z) (see: getting parent compounds) in 5 ml of DMF and stirring is continued for about a day. The reaction mixture was diluted with water and extracted with a mixture of ethyl acetate-toluene (1:1). The organic phase is dried (MgSO4) and removal of solvent in vacuo get the remainder, which is subjected to column chromatography using ethyl acetate as eluent. The output of 309 mg (49%).

(II) H-(R)Cha-Pro-Pab (Z)

Through a solution of 1.246 g (2 mmole) Boc-(R)Cha-Pro-Pab

(Z) in 20 ml of ethyl acetate about the sodium carbonate, the organic phase is separated and dried (K2CO3). The drying agent is washed methylene chloride and evaporation of the solvent from the combined organic phase gain of 1.11 g (100%) of the title compound.

(III) H-(R)Cha-Pro-Pab 2HCl

A solution of 100 mg (0,19 mmole) H-(R)Cha-Pro-Pab (Z) in 15 ml of ethanol hydronaut 1.5 h in the presence of 38 mg of 10% Pd-C. by Diluting the reaction mixture with water and removing the catalyst by filtration followed by removal of the ethanol under vacuum and freeze-drying receive in the form of a colorless powder of the title compound. The peptide is converted into the dihydrochloride by dissolving in hydrochloric acid and freeze-drying. Yield the title compound 90 mg (100%).

1H-NMR (300 MHz, D2O) : 1 - 2 (m, 13H), 2 to 2.3 (m, 3H), of 2.3 - 2.5 (m, 1H), up 3.6 - 3.7 (m, 1H), 3,8 - 3,9 (m, 1H), a 4.3 to 4.5 (t, 1H), 4,5 - 4,6 (m, 3H), 7,4 - 7,6 (m, 3H), of 7.6 to 7.9 (m, 2H).

13C-NMR (75 MHz, D2O) : of 167.2, 170, 174,9 (carbon amidinopropane and carbonyl).

Example 16

HOOC-CH2-(R)Cha-Pro-Pab 2HCl

(I) BnOOC-CH2-(R)Cha-Pro-Pab (Z)

A mixture of 268 mg (0.5 mmole) H-(R)Cha-Pro-Pab (Z) (see example 15), 90 μl (0.55 mmole) of benzylbromide and 181 mg (1.3 mmole) K2CO3in 2 ml of acetonitrile is treated with 2.5 hours by ultrasound at 40oC. the Mixture is filtered through hyflo and removal of solvent in which zitat and obtain 194 mg (57%) of the title compound.

HOOC-CH2-(R)Cha-Pro-Pab 2 HCl

A solution of 194 mg (0,28 mmole) of BnOOC-CH2-(R)Cha-Pro-Pab (Z) in 10 ml of ethanol hydronaut 3 h in the presence of 77 mg of 10% Pd on charcoal. The reaction mixture was diluted with water and the catalyst removed by filtration. Evaporation of the ethanol under vacuum, followed by drying by freezing get white residue. Add hydrochloric acid and freeze-drying the resulting solution obtain 115 mg (68%) of the target product.

1H-NMR (330 MHz, D2O) : 1 - 1,2 (m, 2H), 1.2 to 1.5 (m, 3H), 1.5 to 2 (m, 8H), 2 to 2.3 (m, 3H), of 2.3 - 2.5 (m, 1H), 3,6 - 3,8 (m, 1H), 3,8 - 4 (m, 3H), 4,4 - 4,7 (m, 4H), 7.5 to 7.7 (d, 2H), 7,7 - of 7.9 (d, 2H).

13C-NMR (75 MHz, D2O) : 167,2, 168,2, 169,3, 174,6 (the carbon amidinopropane and carbonyl).

Example 17

HOOC-CH2-(Me)(R)Cha-Pro-Pab

(I) Boc-(Me)(R)Cha-Pro-Pab (Z)

To a solution of 0.8 g (1,67 mmole) Boc-(Me)(R)Cha-Pro-OSu (see: getting parent compounds) in 3 ml DMF add a solution 0,562 g (of 1.85 mmole) H-Pab (Z) (see: getting parent compounds) in 3 ml DMF. The addition of N-methylmorpholine in the obtained solution set pH 8 to 9, and the solution was stirred for 2 days at room temperature. The solution was poured into water and the resulting mixture extracted with ethyl acetate (3 x 25 ml). The organic solution was washed with 1 m solution of KHSO4that g (60%) of the title compound as a yellowish-white powder.

(II) Me-(R)Cha-Pro-Pab (Z)

A solution of 0.6 g (0,92 mmole) Boc-(Me)(R)Cha-Pro-Pab (Z) in 50 ml of EtOH saturated with HCl at 0oC and then stored in the refrigerator for about a day. The resulting solution is evaporated to dryness, the residue is dissolved in a solution of Na2CO3and extracted with ethyl acetate (3 x 25 ml). The extract was washed with brine and after evaporation obtain 0.4 g (79%) of target compound as a white fluffy powder.

1H-NMR (CDCl3300 MHz) : 0,8 - 1 (m, 2H), 1.1 to 1.4 (m, 5H), 1,4 - of 1.55 (m, 1H), 1,6 - 1,9 (m, 10H), 1,9 - 2,05 (m, 2H), 2.05 is - 2,2 (m, 2H), 2,19 (s, 3H), 2,4 - 2,5 (m, 1H), or 3.28 (DD, 1H), 3,41 (K, 1H), 3,62 (m, 1H), 4,42 (m, 2H), br4.61 (d, 1H), and 5.2 (s, 2H), 7,2 was 7.45 (m, 7H), 7,72 (t, 1H), 7,79 (d, 2H).

(III) BnOOC-CH2-(Me)(R)Cha-Pro-Pab (Z)

A mixture of 0.4 g (0.73 mmole) Me-(R)Cha-Pro-Pab (Z), 0.17 g BnOOC-CH2Br and 0.2 g (2 EQ. ) K2CO3(crushed in a mortar) in 15 ml of CH3CN stirred for about a day at room temperature. The resulting mixture is evaporated, add ethyl acetate and the mixture washed with water and brine, dried (Na2SO4) and evaporated. The crude product subjected to column chromatography (CH2Cl2-MeOH, 10:1) to give 0.39 g (77%) of light yellow, very viscous oil.

HOOC-CH2-(Me)(R)Cha-Pro-Pab

To a solution of 0.39 g (of 0.56 mmole) of BnOOC-CH2-(Me)(R)Cha-Pro-Pab (Z) in 30 ml of EtOH added 0.1 g of 10% Pd-C and the mixture hydronaut shaped product is obtained 0.25 g (95%) of target compound in the form of white crystalline powder.

1H-NMR (300 MHz, CD3OD) : 0,85 - 1,1 (m, 2H), 1.1 to 1.4 (m, 6H), 1,5 - of 1.85 (m, 9H), 1.9 to 2.05 is (m, 3H), 2.05 is - of 2.15 (m, 1H), 2,15 - 2,3 (m, 1H), 2.57 m (s, 3H), 3,32 (d, 1H), 3,55 of 3.75 (m, 2H), 3.95 to a 4.1 (m, 2H), 4,35 to 4.5 (m, 3H), at 7.55 (d, 2H), 7,72 (d, 2H).

13C-NMR (75 MHz, CD3OD) : 168,4, 171,5, 174,7, 175,1 (the carbon amidinopropane and carbonyl).

Example 18

HOOC-CH2-CH2-(R)Cha-Pro-Pab 2HCl

(I) BnOOC-CH2-CH2-(R)Cha-Pro-Pab (Z)

A mixture of 149 mg (0,28 mmole) H-(R)Cha-Pro-Pab (Z) (see Example 15) and 66 mg (0.4 mmole) of benzoylacrylate in 1.5 ml of ethanol, incubated for 36 h at room temperature. The solvent is removed in vacuum and the residue is subjected to column chromatography using as an eluent of ethyl acetate and obtain 124 mg (64%) of the target product.

(II) HOOC-CH2-CH2-(R)Cha-Pro-Pab 2HCl

A solution of 124 mg (of 0.18 mmole) of BnOOC-CH2-CH2-(R)Cha-Pro-Pab (Z) in 10 ml of ethanol hydronaut 1 h in the presence of 55 mg of 10% Pd-C. the Catalyst is removed by filtration and the solvent evaporated in vacuum. The residue is dissolved in hydrochloric acid and freeze-drying the resulting solution obtain 87 mg (79%) of the title compound.

1H-NMR (300 MHz, D2O) : 1 - 2 (m, 13H), 2 - 2,2 (m, 3H), 2,2 - 2,4 (m, 1H), 2,7 - 2,8 (t, 2H), 3,2 - 3,3 (m, 1H), 3,3 - 3,4 (m, 1H), of 3.5 - 3.7 (m, 1H), of 3.7 - 3.9 (m, 1H), 4,3 - 4,6 (m, 4H), 7,4 - 7,6 (m, 2H), 7,7 - 7,8 (m, 2H).

Example 19

HOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab 2HCl

(I) BnOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab (Z)

To a solution of 274 mg (0.5 mmole) (Me)-(R)Cha-Pro-Pab (Z) (see Example 17) in 5 ml EtOH (99%) type of 97.3 mg (0.6 mmole) of benzoylacrylate and the reaction mixture was stirred at room temperature. After 72 h contribute an additional amount (16.2 mg, 0.1 mmole) of benzoylacrylate and stirring is continued for 24 hours the Solvent is evaporated, the residue is subjected to column chromatography (CH2Cl2-MeOH (NH3-saturated), 95:5) and obtain 198 mg (56%) of the title compound.

1H-NMR (500 MHz, CDCl3) : 0,8 - 2 (several m, 16H), and 2.14 (s, 3H), 2,24 is 2.33 (m, 2H), 2,38 is 2.46 (m, 1H), to 2.67 (t, 2H), 3,32 - 3,4 (m, 2H), 3,71 (m, 1H), 4,36 - of 4.44 (m, 2H), 4,58 (m, 1H), 5,03 (apparent s, 2H), and 5.2 (s, 2H), 7,25 - 7,37 (m, 10H), the 7.43 (d, 2H), to 7.64 (t, 1H) (NH)), 7,81 (d, 2H).

13C-NMR (125 MHz, CDCl3) : 164,7, 167,9, 171,7, 172,3 and 172,6 (carbon amidinopropane and carbonyl).

(II) HOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab 2HCl

To a solution of 198 mg (or 0.27 mmole) of BnOOC-CH2-CH2-(Me)(R)Cha-Pro-Pab (Z) in 10 ml of EtOH and 1 ml of 1 M HCl add 60 mg of 5% Pd-C (containing 50 wt.% water) and the mixture hydronaut 4 h at atmospheric pressure. The catalyst is filtered off and the solvent evaporated. The remaining oil is dissolved in water and freeze-drying with quantitative vyhoda the 1,93 - of 2.08 (m, 2H), 2,09 - of 2.26 (m, 3H), 2,48 (m, 1H), 2.95 and (m, 2H), 3,03 (s, 3H), 3,6 (seemingly sh. s, 2H), 3,82 (m, 1H), 3,98 (m, 1H), 4.53-in (m, 1H), br4.61 (sh.s, 2H), with 4.64 (m, 1H), 7,63 (d, 2H), of 7.97 (d, 2H).

13C-NMR (75 MHz, D2O) : of 167.2, 167,8, of 174.5 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

Example 20

HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pro-Pab/a 2HCl

(I) BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pro-Pab (Z)

A mixture of 0.5 g (0,94 mmole H-(R)Cha-Pro-Pab (Z) (see Example 15) and 0.28 g (0,94 mmole) of dibenzylamine in 20 ml of ethanol, incubated 5 days at room temperature. Evaporation of the solvent and subsequent column chromatography using as eluent CH2Cl2-MeOH obtain 0.15 g (19%) diastereomeric mixture.

1H-NMR (500 MHz, CDCl3) : 0,7 - 2,1 (m, 17H), 2.3 to 2.4 (m, 1H), of 2.5 - 2.8 (m, 2H), 3,2 - 3,7 (m, 4H), to 4.46 (d, 1H) and 4.65 (sh. d, 1H), 4,81 (d, 1H), 4,9 - 5,1 (m, 3H), and 5.2 (s, 2H), and 7.1 to 7.4 (m, 2H), and 7.4 - 7.5 (m, 2H), 7,6 - 7,8 (m, 3H).

(II) HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pro-Pab/a 2HCl

A mixture of 0.15 g (0,18 mmole) of BnOOC-CH2-(R, S)CH(COOBn)-(R)Cha-Pro-Pab (Z) dissolved in 5 ml of ethanol and hydronaut 1 h in the presence of 5% Pd-C at atmospheric pressure with the formation of HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Pro-Pab. A mixture of two diastereomers share OFGH using as eluent CH3CN-0.1 M NH4OAc (15: 85) with subsequent freeze-drying of the Nes two rotamers) main rotamer : 1 - 2 (m, 15H), of 2.15 (m, 2H), 2,44 (m, 1H), 3 (Sch.d, 1H), 3,05 (sh.d, 1H), 3,69 (m, 1H), 3,84 (m, 1H), 3,97 (sh. s, 1H), 4,5 - 4,7 (m, 3H), a 7.62 (d, 2H), 7,87 (d, 2H).

13C-NMR (75 MHz, D2O) : of 167.2, 168,3, 173,8, 174,6 and 178,2 (carbon amidinopropane and carbonyl).

Example 21

HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pro-Pab/b 2HCl

The title compound is obtained according to the method described in Example 20 synthesis HOOC-CH2-(R, S)CH(COOH)-(R)Cha-Pro-Pab. This diastereoisomer eluted from the column after the first diastereoisomer. Yield 19 mg (18%).

1H-NMR (500 MHz, D2O, mixture of two rotamers) main rotamer : 1 - 2 (m, 14H), 2,15 was 2.25 (m, 3H), 2,44 (m, 1H), 3,11 (sh.d, 1H), 3,19 (sh.d, 1H), 3,71 (m, 1H), 3,92 (m, 1H), 4,03 (sh.s, 1H), 4,5 - 4,7 (m, 3H), 7,56 (d, 2H), to 7.84 (d, 2H).

Allow the signals generated less retamero appear at : 7,66 (d) and to $ 7.91 (d).

13C-NMR (75 MHz, D2O) : 167,3, 168,5 and 174,7 (carbon amidinopropane and carbonyl. Two carbon probably overlap).

Example 22

HOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab 2HCl

(I) BnOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab (Z)

In 6 ml of acetonitrile is mixed 0,246 g (0,46 mmole) H-(R)Cha-Pro-Pab (Z) (see Example 15), 0.14 g (a 1.01 mmole) K2CO3and 0,145 g (0,506 mmole) of BnOOC-CH2-NH-CO-CH2-Br (see: getting the initial connection). The mixture is stirred for 2 h 30 minutes at LOI extracted again with ethyl acetate. The combined organic layer is dried (Na2SO4), and evaporation receive oil. Purification of the crude product column chromatography using a stepwise gradient of CH2Cl2-MeOH(97:3, 95:5, 92,5:7,5) get 0,277 g (67%) of the title compound.

13C-NMR (75 MHz, CDCl3) : 25, 26, 26,2, 26,4, 26,7, 32,4, 34,2, 34,4, 40,8, 42,9, 46,7, 50,5, 58,4, 60,2, 67, 67,2, 127,5, 127,8, 128,2, 128,4, 128,5, 128,6, 134,1, 135,2, 137, 142,6, 164,7, 168,9, 169,3, 170,4, 172,2, 175.

(II) HOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab 2HCl

BnOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab (Z) (0,089 g, 0.12 mmole) is mixed with 30 mg of 5% Pd-C and dissolved in 10 ml of acetic acid. The mixture is then hydronaut half hour at atmospheric pressure. Removing the catalyst by filtration through hyflo and freeze-drying of 1 ml of 1 N. hydrochloric acid get 0,058 g (82%) of the target product.

1H-NMR (300 MHz, D2O) : 0,9 - 2,2 (m, 16H), 2,25 - 2,47 (m, 1H), 3,55 - 3,7 (m, 1H), 3.7 to 4.1 (m, 5H), 4,42 (t, 1H), 4,48 - 4,6 (m, 3H), 7,51 (d, 2H), to 7.77 (d, 2H).

13C-NMR (75 MHz, D2O) : 166,8, 167,1, 168,2, 173,6 and 174,6 (carbon amidinopropane and carbonyl).

Example 23

EtOOC-CH2-CH2-CH2-(R)Cha-Pro-Pab HOAc

(I) EtOOC-CH=CH-CH2-(R)Cha-Pro-Pab (Z)

A mixture of 275 mg (0,51 mmole) H-(R)Cha-Pro-Pab (Z) (see Example 15), K2CO3(141 mg, of 1.02 mmole) and BrCH2CH=CHCOOEt (108 which 5 ml of EtOAc and 2 ml of water. The organic layer is separated, dried (Na2SO4and after concentrating receive 387 mg oil, cleaning which column chromatography using as eluent EtOAc-heptane (1:4) to obtain 252 mg (77%) of the title compound.

1H-NMR (500 MHz, CDCl3) : from 0.8 to 1.05 (m, 2H), 1,1 - of 1.45 (m, 3H) and 1.3 (t, 3H), of 1.5 - 1.9 (m, 8H), 1,95 - 2,05 (m, 1H), from 2.1 to 2.15 (m, 1H), 2,45 is 2.55 (m, 1H), 3 and 3.15 (two d, 2H), 3,35 is - 3.45 (m, 2H), 3,55 - the 3.65 (m, 1H), 4,15 (K, 2H), 4,6 - 4,7 (m, 2H), and 5.2 (s, 2H), to 5.85 (d, 1H), 6.75 in (dt, 1H), 5,3 - 5,4 (m, 4H), was 7.45 (d, 2H), a 7.85 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 165,7, 171,2 and 175,7 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

(II) EtOOC-CH2-CH2-CH2-(R)Cha-Pro-Pab HOAc

A solution of 250 mg (range 0.38 mmole) EtOOCCH=CHCH2-(R)Cha-Pro-Pab (Z) in ethanol hydronaut 2 h in the presence of 5% Pd-C. Removing the catalyst by filtration and evaporation of solvent in vacuo followed by purification OFGH using as eluent CH3CN-0.1 M NH4OAc will receive 70 g (36%) of the target product.

1H-NMR (500 MHz, CD3OD) : 0,9 - 1,05 (m, 2H), 1,15 - of 1.55 (m, 5H), 1,25 (t, 3H), 1,6 - of 1.85 (m, 7H), 1,95 of 2.6 (m, 8H), 3,55 - the 3.65 (m, 2H), and 3.8 (m, 1H), 4,1 (, 2H), 4,45 (m and d, 2H), 4,55 (d, 1H), 7,55 and 7.75 (two d, 4H).

13C-NMR (75 MHz, CD3OD) : 168,3, 173,2, 174,6 and 174,9 (carbon amidinopropane and carbonyl).

2SO4). Removal of solvent in vacuo followed by purification of the residue column chromatography using as eluents mixtures of ethyl acetate-methanol (9:1) and then methylene chloride-methanol (3:1) to obtain 82 mg (39%) of the target product.

(II) Ph(4-COOH)-SO2-(R)Cha-Pro-Pab HCl

Ph(4-COOH)-SO2-(R)Cha-Pro-Pab (Z) (80 mg, of 0.11 mmole) hydronaut in EtOH over 5% Pd-C. the Catalyst is filtered off, the solvent USAREUR, the crude product is purified OFGH using as eluent CH3CN-0.1 M NH4OAc (1:4) and then converted into the dihydrochloride freeze-drying of HCl to obtain 21 mg (29%) of the target product.

1H-NMR (300 MHz, CD3OD, mixture of two rotamers) : 0,45 - to 1.82 (m, 13H), of 1.9 - 2.3 (m, 4H), 2.95 and - 4,16 (several m, total 3H), 4,35 - and 4.68 (m, 3H), 7,54 (d, 2H), 7,74 (d, 1H), and 7.8 (d, 1H), 7,9 - 8 (m, 2H), 8,05 is 8.22 (m, 2H).

13C-NMR (75 MHz, CD3OD) : 168,4, 173,4, 173,9 and 174,2 (carbon amidinopropane and carbonyl).

MS: m/z 564 (M++ 1)

Example 25

H-(R)Cha-Pic-Pab 2HC,2 mmole) of DMAP and of 5.26 g (to 18.6 mmole) H-Pab (Z) (see topic: retrieving parent compounds) in 200 ml DMF added at -15oC 3.57 g (to 18.6 mmole) of EDC and the mixture is left to warm up for about a day before the 20oC. After removal of the solvent in vacuo, add toluene and water. The organic phase is washed with water, 1 M KHSO410% of Na2CO3and brine. Drying (MgSO4) and evaporation of the solvent in vacuo get 13,63 g of residue, which was subjected to column chromatography on silica gel using as eluent a mixture of ethyl acetate-toluene (2:1) and obtain 9.5 g (79%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,7 - 1 (m, 2H), 1 - 2,2 (m, 25H), of 2.3 - 2.5 (m, 1H), 2,9 - 3,1 (m, 1H), and 3.8 (d, 1H), 4,3 (DD, 1H), 4,4 - 4,6 (m, 2H), 5,1 (s, 2H), 5,1 - 5,3 (m, 2H), 7,2 - 7,3 (m, 5H), 7,35 (d, 2H), and 7.4 - 7.5 (m, 1H), of 7.75 (d, 1H).

13C-NMR (75 MHz, CDCl3) : 156,8, 164,6, 168,2, 170 and 173,4 (carbon amidinopropane and carbonyl).

(II) H-(R)Cha-Pic-Pab (Z)

Through a solution of 9.5 g (14.7 mmole) Boc-(R)Cha-Pic-Pab (Z) in 100 ml of ethyl acetate at room temperature propulsive before saturation of hydrogen chloride. After 10 minutes add 10% solution of Na2CO3separated the organic phase is dried (K2CO3) and removal of solvent in vacuo get with a quantitative yield of the title compound.

(II) H-(R)Cha-Pic-Pab 2HCl

In a mixture of 5 ml ethanol and 0.45 ml of 1 M hydrochloric acid dissolve 55 mg (0.1 mmole) H-(R)Cha-Pic-Pab (Z) and hydronaut 1.5 h in the presence of 13 mg of Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo get the remainder, which is subjected to column chromatography using as eluent 0.1 M NH4OAc-CH3CN. Then the purified peptide is converted into its dihydrochloride by dissolving in hydrochloric acid with subsequent freeze-drying. Yield the title compound 17 mg (35%).

1H-NMR (300 MHz, D2O a mixture of 2 rotamers, 1:1) : 1 - 2 (m, 18H), 2,33 (d, 1H), 3,4 - 3,5 (m, 1H), 3,8 - 3,9 (m, 1H), 4,4 - 4,8 (m, 3H), 5,15 - 5,25 (m, 1H), 7,5 - 7,7 (m, 2H), 7,8 - 8 (m, 2H).

Resolved signals smaller rotamer appear when : 0,5 - 0,7 (m) and 3 - 3,1 (m).

13C-NMR (75 MHz, D2O) 167,3, 171,6 and 173,6 (carbon amidinopropane and carbonyl).

Resolved signals smaller rotamer appear when: 170,6 and 172,4.

Example 26

HOOC-CH2-(R)Cha-Pic-Pab 2HCl

(I) BnOOC-CH2-(R)Cha-Pic-Pab (Z)

The mixture 742 mg (1,35 mmole) H-(R)Cha-Pic-Pab (Z) (see Example 25), 230 ml (1,45 mmole) of benzylbromide and 558 mg (4 mmole) K2CO3in 4 ml of acetonitrile is treated with 40 min is 720 mg (77%) of the target product.

1H-NMR (500 MHz, CDCl3) : 0,8 - 1 (m, 2H), 1,1 - 1,9 (m, 16H), 2.1 to 2.4 (W. with 1 or 2H), 2,4 (d, 2H), 3 (m, 1H), 3,25 (d, 1H), 3.45 points (d, 1H), 3,55 - the 3.65 (m, 1H), 3,7 (m, 1H), 4,35 (DD, 1H), 5,55 (DD, 1H), 4,8 (two d, 2H), and 5.2 (s, 2H), 5,3 (m, 1H), 7,2 - 7,4 (m, 12H), and 7.8 (d, 2H).

13C-NMR (125 MHz, CDCl3) : 164,5, 167,9, 170,5, 173,4 and 175,5 (carbon amidinopropane and carbonyl).

(II) HOOC-CH2-(R)Cha-Pic-Pab 2HCl

A solution of 509 mg (0.73 mmole) of BnOOC-CH2-(R)Cha-Pic-Pab (Z) in 25 ml of ethanol hydronaut 4 h in the presence of 259 mg of 10% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo get a residue, which was dissolved in distilled water. Add hydrochloric acid and subsequent freeze-drying obtain 281 mg (79%) of the title compound.

1H-NMR (500 MHz, D2O, mixture of rotamers, 4:1) main rotamer : 1 - 2 (m, 18H), 2,25 - 2,4 (m, 1H), 3,4 - 3,5 (m, 1H), 3,8 - 3,95 (m, 3H), 4,55 - 4,65 (two d, 2H), 5,15 (m, 1H), 7,55 to 7.75 (m, 2H), 7,8 - 8 (m, 2H).

13C-NMR (125 MHz, D2O) : 167,3, 169,9, 170,3 and 173.5 metric (carbon guanidinium and carbonyl).

Resolved signals smaller rotamer appear when : 169,2 and 172.

Example 27

HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pic-Pab/a 2HCl

(I) BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pic-Pab (Z)

A mixture of 592 mg (1.1 mmole) H-(R)Cha-Pic-Pab (Z) (see Example 15) and 332 mg (1.1 mmole) debenzylation column chromatography using as eluent a mixture of methanol-methylene chloride and obtain 275 mg (30%) diastereomeric mixture.

(II) HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pic-Pab/a 2HCl

A solution of 275 mg BnOOC-CH2-(R, S) CH(COOBn)-(R)Cha-Pic-Pab (Z) in 20 ml of 95% ethanol hydronaut 18 hours in the presence of 75 mg of 10% Pd-C. the Mixture is filtered through hyflo and the solvent is removed in vacuum. The addition of water, followed by drying by freezing obtain 166 mg of HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Pic-Pab. A mixture of two diastereomers share OFGH with the use of CH3CN-0.1 M NH4OAc (1:4) with subsequent freeze-drying of HCl. This diastereoisomer eluted from the column first. Exit 9 mg.

1H-NMR (300 MHz, D2O, mixture of rotamers) : 1 - 2 (m, 18H), 2,25 - 2,4 (m, 1H), 3 - 3,2 (m, 2H), 3,4 (t, 1H), and 3.8 (d, 1H), of 4.05 (t, 1H), 4,5 - 4,7 (m, 3H), and 5.2 (s, 1H), 7,55 (d, 2H), 7,9 (d, 2H).

Resolved signals smaller rotamer appear when : 4 (t) and 7.7 (d).

Example 28

HOOC-CH2-(R or S)CH(COOH)-(R)Cha-Pic-Pab/b 2HCl

The title compound is obtained according to the method described in Example 27 for the synthesis of HOOC-CH2-(R, S)CH(COOH)-(R)Cha-Pic-Pab. This diastereoisomer eluted from the column after the first diastereoisomer.

1H-NMR (500 MHz, D2O, mixture of rotamers) : 1 - 2 (m, 18H), 2,25 - 2,4 (m, 1H), 3 - 3,2 (m, 2H), 3,5 (t, 1H), 3,85 (d, 1H), 4,15 (s, 1H), 4,5 - 4,7 (m, 3H), of 5.15 (s, 1H), 7,55 (d, 2H), and 7.8 (d, 2H).

Resolved signals smaller rotamer appear when : 4,35 (C),(Z)

The mixture 851 mg (1,55 mmole) H-(R)Cha-Pic-Pab (Z) (see Example 25) and 269 mg (1,71 mmole) of benzoylacrylate in 5 ml of ethanol incubated for 40 h at room temperature. The solvent is removed in vacuum, the residue is subjected to column chromatography using as eluent a mixture of methylene chloride-methanol and receive 812 mg (74%) of the target product.

1H-NMR (500 MHz, CDCl3) : 0,8 - 1 (m, 2H), 1,1 - 1,9 (m, 16H), of 2.3 - 2.5 (m, 3H), 2,6 - 2,8 (m, 2H), 3 (m, 1H), 3,5 (m, 1H), up 3.6 - 3.7 (m, 1H), 4,3 (DD, 1H), 4,6 (DD, 1H), 4.95 points - of 5.05 (two d, 2H), and 5.2 (s, 2H), 5,3 (m, 1H), 6,5 - 6,9 (sh. s, 1H), 7, and 7.1 (m, 1H), 7,2 - 7,5 (m, 12H), 7,75 - a 7.85 (d, 2H), and 9.3 and 9.7 (sh. s, 1H).

(II) HOOC-CH2-CH2(R)Cha-Pic-Pab 2HCl

A solution of 780 mg (1.1 mmole) of BnOOC-CH2-CH2(R)Cha-Pic-Pab (Z) in 25 ml of ethanol hydronaut 4 h in the presence of 306 mg of Pd-C (15%). The catalyst was removed by filtration and the solvent evaporated in vacuum. The residue is dissolved in hydrochloric acid and freeze-drying the resulting solution obtain 481 mg (78%) of the title compound.

1H-NMR (500 MHz, D2O) : 0,95 - 1,1 (m, 2H), 1,15 - 1,9 (m, 16H), about 2.2 - 2.3 (m, 1H), 2,7 - 2,8 (t, 2H), 3,2 - 3,3 (m, 3H), 3,4 - 3,5 (m, 1H), 3.75 to of 3.85 (m, 1H), 4,4 - 4,6 (m, 3H), of 5.15 (m, 1H), 7.5 to about 7.6 (m, 2H), 7,8 - 7,9 (m, 2H), 8,6 - to 8.7 (m, 1H).

13C-NMR (125 MHz, CD3OD) : 170,6, 175,9, 179,5 and 183,5 (carbon amidinopropane and carbonyl).

Example 30

HOOC-CO-(R)Cha-P3 in 10 ml of CH3CN added at room temperature, 0.12 g of acrocallosal. After 2 hours contribute additional amounts (0.07 g, 0.5 mmole) heterocalixarenes and the mixture is stirred for about a day at room temperature. The solvent is removed in vacuum, the residue is dissolved in CH2Cl2and washed with water. Evaporation and column chromatography (toluene-ethyl acetate (1:2), then CH2Cl2-methanol) 0.21 g (42%) of the target product.

(II) HOOC-CO-(R)Cha-Pic-Pab (Z)

To a solution of 0.21 g (0,32 mmole) EtOOC-CO(R)Cha-Pic-Pab (Z) in 3 ml THF added a solution of 0.17 g (4.2 mmole) of LiOH in 3 ml of water. The mixture is stirred for about a day at room temperature and then transferred into a mixture of ethyl acetate with water. The phases are separated and the organic phase is washed with a solution of KHCO3. The aqueous phase is acidified with 0.5 M HCl (pH 1), extracted with CH2Cl2, dried over Na2SO4, evaporated and receive 80 mg of the target product.

(III) HOOC-CO(R)Cha-Pic-Pab HOAc

HOOC-CO(R)Cha-Pic-Pab (Z) hydronaut in EtOH in the presence of 5% Pd-C. the Catalyst is filtered off and the solvent evaporated. Purification of the residue OFGH get the title compound.

1H-NMR (500 MHz, DMSO-d6) : 0,8 - 1 (m, 2H), 1,1-of 1.75 (m, 15H), 1,86-of 1.94 (m, 1H), 2,13-2,2 (m, 1H), 3.75 to-3,81 (m, 1H), 4,32, of 4.44 (AB, 2H), 4,71-of 4.77 (m, 1H), 4,98-5,02 runirvana signal solvent.

MS: m/z 486 (M++ 1).

Example 31

HOOC-CH2-CO(R)Cha-Pic-Pab

(I) MeOOC-CH2-(R)Cha-Pic-Pab (Z)

To a solution of 0.39 g (0.72 mmole) H-(R)Cha-Pic-Pab (Z) (see Example 25) and 0.9 g (0.8 mmole) of monomethylamine in 40 ml of CH2Cl2added 0.16 g (0.8 mmole) DCC and the solution stirred at room temperature for about a day. Sediment DCM is filtered off, the filtrate is washed with 0.3 M KHSO4and KHCO solution3and dried (Na2SO4). Evaporation of the solvent and subsequent column chromatography using as eluent a mixture of toluene-ethyl acetate (1: 3) to obtain 0.27 g (58%) of the target product.

(II) MeOOC-CH2-CO-(R)Cha-Pic-Pab

In 10 ml of ethanol is dissolved 90 mg (about 0.14 mmole) MeOOC-CH2-CO-(R)Cha-Pic-Pab (Z) and hydronaut 5 hours in the presence of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent receive 50 mg (70%) of the title compound.

1H-NMR (300 MHz, CD3OD) : 0,85-1,1 (m, 2H), 1,1-1,9 (m, 16H), 2,35 at 2.45 (m, 1H), 3,2-3,4 (m, 3H), and 3.7 (s, 3H), 3.95 to of 4.05 (m, 1H), 4,4-4,55 (m, 3H), 5,15-5,25 (m, 1H), 7,4-of 7.55 (m, 2H), 7,7-a 7.85 (m, 2H).

13C-NMR (75 MHz, CD3OD) : 168,2, 168,7, 170, 172,4, 174,6 (the carbon amidinopropane and carbonyl).

MC: m/z 514 (M++ 1).

(III) HOOC-CH2-CO-(R)Cha-Pic-Pab

To a solution of 0.14 g (a 0.27 mmole) MeOOC-CH2-CO-(R)remote control and the methanol removed in vacuo. The aqueous phase is then dried by freezing. Soluble substances extracted from the insoluble inorganic salts absolute ethanol. Remaining after evaporation of ethanol, the solid is suspended in water and filtered allocate 70 mg (52%) of the title compound.

1H-NMR (300 MHz, DMSO-d6) : 0,8 - 1 (m, 2H), 1-1,9 (m, 16H), 2,15-2,3 (m, 1H), 2,58, 2,86 (AB, 2H), 3,8-3,95 (m, 1H), 4,2-4,5 (m, 2H), 4,7-is 4.85 (m, 1H), 4.95 points-of 5.05 (m, 1H), and 7.4 (d, 2H), to 7.77 (d, 2H), and 8.2 to 8.3 (m, 1H), of 9.3 and 9.4 (m, 1H), 9,9 (broad s, 3H). The signal of one of the protons (3,21) partially shielded by the signal of the solvent.

13C-NMR (75 MHz, DMSO-d6) : is 165.8, 168, 8mm, 169,9, 172,2 and 172,4 (carbon amidinopropane and carbonyl).

MC: m/z 500 (M++ 1).

Example 32

MeOOC-CH2-CO-(R)Cha-Pic-Pab

Cm. the above Example 31 (II)

Example 33

H2N-CO-CH2(R)Cha-Pic-Pab

(1) H2N-CO-CH2(R)Cha-Pic-Pab (Z)

Attempted alkylation of 455 mg (0,83 mol) H-(R)Cha-Pic-Pab (Z) (see Example 25), 80 mg (0,86 mmole) of chloracetamide in 3 ml of acetonitrile in the presence of 395 mg (2.86 mmole) of potassium carbonate processing at 40oC ultrasound, as it turned out, leading to an extremely slow reaction. Even the addition of 230 mg (2.6 mmole) of lithium bromide, apparently, does not increase the reaction rate. However, the addition of the iodide Litka the addition of water, extraction with a mixture of ethyl acetate-toluene, drying the organic phase (MgSO4) and removal of solvent in vacuo gives a residue, which was subjected to column chromatography using as eluent a mixture of MeOH-CH2Cl2and obtain 118 mg (24%) of the target product.

(II) H2N-CO-CH2-(R)Cha-Pic-Pab 2HCl

A solution of 118 mg (0.2 mmole) of H2N-CO-CH2-(R)Cha-Pic-Pab (Z) in 10 ml of 95% ethanol hydronaut 2 h in the presence of 143 mg of 10% Pd-C. the Mixture is diluted with distilled water and hydrochloric acid and filtered through hyflo. Drying by freezing give 26 mg (24%) of the target product.

1H-NMR (300 MHz, CD3OD) : 0,9-1,1 (m, 2H), 1,1-1,9 (m, 16H), 2,3 (d, 1H), 3,4 (t, 1H), 3,6 (AB-system, 2H), and 3.8 (d, 2H), 4,35 (t, 1H), and 4.5 (s, 2H), and 5.2 (s, 1H), 7,55 (d, 2H), and 7.8 (d, 2H).

Example 34

Boc-(R)Cha-Pic-Pab

A solution of 10 mg (0,0,15 mole) Boc-(R)Cha-Pic-Pab (Z) (see Example 25) in 5 ml of ethanol hydronaut 4 h in the presence of 38 mg of 10% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo, followed by dissolving the residue in water and freeze-drying gain of 7.6 mg (95%) of product.

1H-NMR (300 MHz, CD3OD): 0,9-1,1 (m, 2H), 1,1-1,9 (m, 16H), 2,4 (d, 1H), 3,25 (t, 1H), 4 (d, 1H), 4,5 (AB-system, 2H), 4,5-4,6 (m, 1H), 5.25 in (s, 1H), 7,45 (d, 2H), of 7.75 (d, 2H).

Example 35

Ac-(R)Cha-Pic>in 10 ml of CH3CN at room temperature is added 0.06 g (0.8 mmole) of acetylchloride. After stirring for 30 minutes at room temperature the solvent is removed in vacuum. The residue is dissolved in CH2Cl2and washed with water. Evaporation and column chromatography using a stepwise gradient of CH2Cl2MeOH(99,9:0,1, 99,8:0,2, 99,6:0,4, 99,2:0,8 and 98.4: 1,6) obtain 0.24 g (60%) of product.

(II) Ac-(R)Cha-Pic-Pab HCl

Ac-(R)Cha-Pic-Pab (Z) hydronaut over 5% Pd-C at atmospheric pressure. After filtration of the catalyst and evaporation of the solvent the crude product is purified OFGH using as eluent CH3CN-0.1 M NH4OAc (35:65). Removal of solvent and excess NH4OAc with subsequent freeze-drying of 1 M HCl receive the title compound.

1H-NMR (300 MHz, CD3OD) : 0,85-1,1 (m, 1H) and 1.15-2 (m, 19H), 2,35-2,47 (m, 1H), 3,2-to 3.33 (m, 1H), 3.95 to of 4.05 (m, 1H), 4,46-4,57 (ABX, 2H) 5,16 with 5.22 (m, 1H), 7,51 (d, 2H), 7,76 (d, 2H), 8,23 (m, 1H). The signal of one of the protons is fully shielded by the signal of the solvent.

13C-NMR (75 MHz, CD3OD) : 168,3, 172,5, 173,8, 175,1 (the carbon amidinopropane and carbonyl).

MC: m/z 456 (M++ 1).

Example 36

Me-SO2-(R)Cha-Pic-Pab HCl

(I) Me-SO2-(R)Cha-Pic-Pab (Z)

A solution of 48 mg (0,42 mmole) methanol is)Cha-Pic-Pab (Z) (see Example 25) and 0.11 ml (0,763 mmole) of triethylamine in 5 ml of methylene chloride. The reaction mixture overnight to warm to room temperature. By washing with water, followed by drying (Na2SO4) and evaporation of the solvent in vacuo get the remainder, which is subjected to column chromatography using as eluent a mixture of ethyl acetate-methanol (95:5), and obtain 159 mg (67%) of product.

(II) Me-SO2-(R)Cha-Pic-Pab HCl

A solution of 150 mg (0.24 mmole) Me-SO2-(R)Cha-Pic-Pab (Z) in 5 ml of 95% ethanol and 1 ml of water hydronaut 4 h in the presence of 5% Pd-C. Removing the catalyst by filtration, the addition of 0.2 ml of 1 M hydrochloric acid and evaporation of the solvent in vacuo get a residue, which was dissolved in 2 ml of water, and freeze-drying obtain 116 mg (86%) of the target product.

1H-NMR (500 MHz, CD3OD) : 0,9-1,1 (m, 2H), 1,15-of 1.85 (m, 15H), 1,9 (sh. d, 1H), 2,3 (sh. d, 1H), 2,85 (s, 3H), at 3.35 (dt, 1H), 3,9 (sh. d, 1H), 4,45 (AB-system, 2H), 4,5-4,55 (m, 1H), 5,13 (DD, 1H), 7.5 (d, 2H), of 7.75 (d, 2H).

13C-NMR (125 MHz, D2O) : 166,8, 173 and 174,6 (carbon amidinopropane and carbonyl).

Example 37

H-(R)Cha-(R,S)bears-Pab 2HCl

(I) BOC-(R)Cha-(R,S)bears-Pab (Z)

To stir at -18oC to a solution of 1 g (2.6 mmole) BOC-(R)Cha-(R, S)bears-OH (see: getting ishaa add the EDC. The reaction mixture is left overnight to warm to room temperature and then the solvent is removed in vacuum. The residue is dissolved in CH2Cl2, the organic layer is successively washed with 0.3 M KHSO4, KHCO solution3and brine. Drying (Na2SO4) and removal of solvent receive the remainder, which is subjected to pressure chromatography using a mixture of heptane-ethyl acetate 4% of methanol as eluent, and obtain 0.74 g (44%) of the target product.

(II) H-(R)Cha-(R,S)bears-Pab (Z)

In a saturated HCl (g) dissolved in ethyl acetate of 0.68 g (1.05 mmole) BOC-(R)Cha-(R, S)bears-Pab (Z) and the solution stirred for 1 h at room temperature. After adding water, the mixture is alkalinized K2CO3. The aqueous phase is extracted with ethyl acetate and the organic phase is washed with water and dried (Na2SO4). Evaporation obtain 0.5 g (87%) of the target product.

(III) H-(R)Cha-(R,S)bears-Pab 2HCl

In 7 ml of ethanol is dissolved 65 mg (0,19 mmole) H-(R)Cha-(R,S)bears-Pab (Z) and hydronaut 4 hours in the presence of 5% Pd-C. Removing the catalyst by filtration, evaporation of the solvent and freeze-drying of 1 M HCl and water obtain 41 mg (71%) of the target product.

1H-NMR (300 MHz, D2O, diastereoisomer of (4:5) and rotamer is R>
HOOC-CH2-CH2-(R)Cha-(R, S)bears-Pab 2HCl

(I) BnOOC-CH2-CH2-(R)Cha-(R, S)bears-Pab (Z)

In ml of ethanol is dissolved 0.21 g (range 0.38 mmole) H-(R)Cha-(R,S)-bears-Pab (Z) (see Example 37), add to 0.68 g (at 0.42 mmole) of benzoylacrylate and the solution is stirred for 5 days. Evaporation and column chromatography with CH2Cl2-MeOH (95:5) as eluent get to 0.19 g (70%) of the target product.

(II) HOOC-CH2-CH2-(R)Cha-(R, S)bears-Pab 2HCl

In 10 ml of ethanol was dissolved 170 mg (0.24 mmole) of BnOOC-CH2CH2-(R)Cha-(R, S)bears-Pab (Z) and hydronaut 4 hours in the presence of 5% Pd-C. Removing the catalyst by filtration, evaporation of the solvent and freeze-drying of 1 M HCl and water obtain 103 mg (77%) of the target product.

1H-NMR (300 MHz, D2O, mixture of 2 diastereomers (4:5) and rotamer) : 0,92-2,03 (m, H), of 2.51-2,78 (m, 1H), 3,21-to 3.52 (m, 1H), 3,88-4,01 (m, 1H), 4,07-4,3 (m, 2H), 4,4-4,71 (m, 2H), to 7.59 (d, 2H), 7,86 (d, 2H).

13C-NMR (300,13 MHz, D2O, mixture of 2 diastereomers (4:5) and rotamer) : 167, 168, 168,1, 175,9, 176, 176,3, 176,4 and 178,2 (carbon amidinopropane and carbonyl).

Example 39

HOOC-CH2-(R)Cha-Val-Pab 2HCl

(I) Boc-(R)Cha-Val-Pab (Z)

To the mixture is 3.41 g (8.2 mmole) Boc-(R)Cha-Val-OH (see: getting the initial connection), 2,61 g (9.2 mmole) H-Pab (Z) (see: getting parent compounds) and the to room temperature and treated with dilution water followed by extraction with toluene, ether and ethyl acetate. Subsequent drying (MgSO4) the combined organic extracts removal of solvent in vacuum and column chromatography with CH2Cl2-MeOH as eluent get 2,77 g (47%) of the target product.

(II) H-(R)Cha-Val-Pab (Z)

Through a solution 2,77 g (4.4 mmole) Boc-(R)Cha-Val-Pab (Z) in 75 ml of ethyl acetate propulsive hydrogen chloride. After 15 minutes, add a solution of sodium carbonate to pH 10 and the aqueous phase extracted with ethyl acetate. The dried (potassium carbonate) and removal of solvent in vacuo obtain 1.8 g (77%) H-(R)Cha-Val-Pab (Z).

(III) BnOOC-CH2-(R)Cha-Val-Pab (Z)

A mixture of 326 mg (0,61 mmole) H-(R)Cha-Val-Pab (Z), 105 ml (0.67 mmole) of benzylbromide and 252 mg (1,83 mmole) of potassium carbonate in 2 ml of acetonitrile, 2.5 hours, treated with ultrasound at 40oC. To dissolve the product add a further quantity of acetonitrile, the mixture is then filtered and the solvent is removed in vacuum. The residue is purified column chromatography using as eluent a mixture of methanol-methylene chloride. Crystallization of the product from the extract up to 124 mg (30%) of colorless crystals.

(IV) HOOC-CH2-(R)Cha-Val-Pab 2HCl

BnOOC-CH2-(R)Cha-Val-Pab (Z) (124 mg, 0,128 mmole) in 20 ml of ethanol hydronaut 2 hours when the ez hyflo and the filter cake washed with diluted hydrochloric acid. The combined filtrates in vacuo to remove organic solvents. Freeze-drying the remaining solution obtain 55 mg (50%) of target compound.

1H-NMR (500 MHz, D2O) : 0,75-1,4 (m, 12H), of 1.5-1.9 (m, 7H), 2-2,15 (Sch. s, 1H), 3,45 (AB-system, 2H), 4,1 (m, 2H), and 4.5 (m, 2H), 7.5 (m, 2H), and 7.7 (s, 2H), 8,9 (s, 1H).

Example 40

HOOC-CH2-CH2-(R)Cha-Val-Pab 2HCl

(I) H-(R)Cha-(R, S) Val-Pab (Z)

The title compound is obtained by joining Boc-(R)Cha-Val-OH to H-Pab (Z) by the method of connection of pivaloyl described for Boc-(R)Cha-Pic-OMe (see, obtaining the parent compounds). There is a complete epimerization of valine with the formation of Boc-(R)Cha-(R, S) Val-Pab (Z). The removal of the Boc protective group according to the method described for Boc-(R)Cha=Val-Pab (Z) (see Example 39), get the title compound.

(II) BnOOC-CH2-CH2-(R)Cha-(R, S) Val-Pab (Z)

The solution 1,007 g (1.9 mmole) H-(R)Cha-Val-Pab (Z) and 308 mg (1.9 mmole) of benzoylacrylate in 3 ml of ethanol is kept for about a day when the 40oC. the Solvent is removed in vacuo and purification of the residue column chromatography using as eluent a mixture of methanol-methylene chloride (10:90) receive 1,086 g (82%) of the title compound.

(III) HOOC-CH2-CH2-(R)Cha-Val-Pab (Z) 2HCl

BnOOC-CH2-CH2-(R)Cha-(R, S) Val-Pab (Z) (1,086 g, 1,6 what trovanjem through celite and evaporation of the THF under vacuum, with subsequent freeze-drying, the remaining solution get the rest, approximately 300 mg of which are subjected to AFGH using as eluent 25% acetonitrile in 0.1 M ammonialyase buffer. There are two main fractions, of which the second contains the title compound. In the form of a dihydrochloride allocated 67 mg of the title compound.

1H-NMR (500 MHz, D2O) : 1-1,5 (m, 12H), 1,2-1,4 (m, 7H), of 1.65 to 1.9 (m, 7H), 2,15 was 2.25 (m, 1H), 2,85 (t, 2H), 3,15-3,2 (m, 1H), 3,3-to 3.34 (m, 1H), 4,15-4,2 (m, 1H), 4,25 (d, 1H), 4,55 with 4.65 (AB-system, 2H), 7.5 (d, 2H), the 7.85 (d, 2H).

13C-NMR (75 MHz, D2O) : 167, 169,8, 173,96 and 174,04 (carbon amidinopropane and carbonyl).

Example 41

H-(R) Hoc-Aze-Pab 2HCl

(I) Boc-(R)Hoc-Aze-Pab (Z)

Obtained by the method described for the synthesis of Boc - (R) Cha-Pic-Pab (Z) (see Example 25) by replacing Boc-(R)Cha-Pic-OH for Boc-(R)Hoc-Aze-OH (see: getting the initial connection). The crude product subjected to column chromatography (toluene-EtOAc, 1:6) to give 0.32 g (37%) of the target product.

(II) H-(R)Hoc-Aze-Pab (Z)

The title compound with a yield of 0.23 g (88%) obtained by treating Boc-(R)Hoc-Aze-Pab (Z) by the method described in Example 25 to obtain Boc-(R)Cha-Pic-Pab (Z).

(III) H-(R)Hoc-Aze-Pab 2HCl

In 3 ml of ethanol was dissolved 20 mg (0,037 mmole) H-(R)Hoc-Aze-Pab (Z) and hydronaut 4 hours at atmospheric pressure in the presence of 5% Pd-C. Removing the catalyst by filtration, ispremium MHz, D2O, Mixture of two rotamers, 3:1) : main rotamer: 0,9-2,1 (m, 15H), 2,4-2,6 (m, H), 2,7-3 (m, 1H), 4,1-4,3 (m, 1H), 4,35-4,56 (m, 1H) and 4.65 (s, 2H), 5-5,11 (m, 1H), 7.62mm (d, 2H), 7,9 (d, 2H). The signal of one of the fully shielded protons H-O-D - signal.

Example 42

HOOC-CH2-CH2-(R)Hoc-Aze-Pab 2 TFUK

(I) BnOOC-CH2-CH2-(R)Hoc-Aze-Pab (Z)

To a solution of 0.2 g (0.37 mmole) h-(R)Hoc-Aze-Pab (Z) (see Example 41) in 2 ml of 95% ethanol is added at room temperature 0,067 g (0,41 mmole) of benzoylacrylate and the reaction mixture is left for 5 days at the same temperature. The solvent is removed in vacuo and purification of the residue column chromatography (CH2Cl2-MeOH, 96:4) to obtain 0.16 g (62%) of the target product.

(II) HOOC-CH2-CH2-(R)Hoc-Aze-Pab 2 TFUK

In 10 ml of ethanol was dissolved 160 mg (0,23 mmole) of BnOOC-CH2-CH2-(R)Hoc-AZe-Pab (Z) and hydronaut 3 hours at atmospheric pressure in the presence of 5% Pd on charcoal. Removing the catalyst by filtration, evaporation of the solvents, freeze-drying from water and TFUK obtain 120 mg (87%) of the target product.

1H-NMR (300,13 MHz, D2O, 2 rotamer, 3:1) main rotamer : 0,9-1,9 (m, 13H), 1,94-of 2.16 (m, 2H), 2,38 is 2.55 (m, 1H), 2,7-of 2.97 (m, 3H), 3,2-3,44 (m, 2H), 4.16 the (m, 1H), 4,35-4,58 (m, 2H) and 4.65 (s, 2H), 5-5,12 (m, 1H), 7,63 (d, 2H), 7,87 (d, 2H).

13SUB>2-(R, S)CH(COOH)-(R)Hoc-Pro-Pab 2HCl

(I) Boc-(R)Hoc-Pro-Pab (Z)

Obtained from Boc-(R)Hoc-Pro-OH (see: getting parent compounds) according to the method described in Example 25 for the synthesis of Boc-(R)Cha-Pic-Pab(Z). Column chromatography using ethyl acetate as eluent get 0,886 g (58%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,7-of 0.95 (m, 2H), 0,95-2,1 (m, 27H (it is 1.2 (s, 9H)), of 2.1-2.4 (m, 1H), 3,3 (m, 1H), 3,6-3,95 (m, 1H), 4-4,2 (m, 1H), 4,2 is 4.45 (m, 2H), 4,45-4,6 (d, 1H), 5,15 (seemingly sh.S., 2H), 5,2-5,3 (d, 1H), and 7.1 to 7.4 (m, 7H), the 7.65 (m, 1H), 7,7-of 7.9 (d, 2H), and 9.4 (sh.s, 1H).

13C-NMR (75 MHz, CDCl3) : 156,3, 164,6, 168,1, 171,4, and 172,4 (carbon amidinopropane and carbonyl).

(II) H-(R)Hoc-Pro-Pab (Z)

To 0,82 g (1,266 mmole) Boc-(R)Hoc-Pro-Pab (Z) is added at 0oC 40 ml of ethyl acetate saturated with hydrogen chloride, and the temperature is left to rise to room temperature. After 1.5 hours the reaction is not completed yet, so through the reaction mixture for 5 minutes propulsive hydrogen chloride. The solvent is evaporated, add ethyl acetate and saturated sodium carbonate solution and the phases are separated. The organic phase is washed with brine, dried (Na2SO4) and evaporation of the solvent in vacuo receive the title compound with an almost quantitative yield.

1H-NMR (300 MHz, CDCl35 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 164,5, 167,8, 171,4 and 175,3 (carbon amidinopropane and carbonyl).

(III) BnOOC-CH2-(R, S)CH(COOBn)-(R)Hoc-Pro-Pab (Z)

To 0.15 g (0.5 mmole) of benzoylacrylate in 1.5 ml EtOH add 0,273 g (0,498 mmole) H-(R)Hoc-Pro-Pab (Z) and the mixture is stirred for 10 days at room temperature. The solvent is removed in vacuum, the residue is subjected to column chromatography using as an eluent of ethyl acetate and get 0,103 g (25%) BnOOC-CH2-(R, S)CH(COOBn)-(R)Hoc-Pro-Pab (Z).

1H-NMR (300 MHz, CDCl3) : 0,75-of 2.05 (m, 18H), 2,3 at 2.45 (m, 1H), 2,45-2,8 (m, 3H), 3.15 and is-3.45 (m, 3H), 3,5-of 3.65 (m, 1H), a 4.3 to 4.5 (m, 2H), 4,55-4,7 (m, 1H), 4,8 (s, 1H), 4,9-5,1 (m, 3H), and 5.2 (s, 2H), 7,1-7,2 (m, 1H), of 7.2 to 7.4 (m, 13H), 7,4 was 7.45 (d, 2H), 7,6-7,8 (m, 3H).

(IV) HOOC-CH2-(R, S)CH(COOH)-(R)Hoc-Pro-Pab 2HCl

A solution of 103 mg (0,122 mmole) of BnOOC-CH2-(R, S)CH(COOBn)-(R)Hoc-Pro-Pab (Z) in 43 ml of 99.5% ethanol and 0.3 ml of chloroform hydronaut 2 h in the presence of 111 mg of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent followed by dissolving in water and freeze-drying discovered the incompleteness of hydrogenation. The hydrogenation continued for 5 hours in the presence of ethanol, 1 N. HCl and 5% Pd-C.

Removing the catalyst by filtration and evaporation of the solvent followed by dissolving in water and freeze-drying receive for the,6-1,8 (m, 5H), 1,9-of 2.15 (m, 5H), of 2.25 to 2.35 (m, 1H), 2,9-3,2 (m, 2H), 3,5-of 3.65 (m, 1H), 3,7-3,9 (2 m, total 1H), 4,15-4,4 (2 m, total 1H), 4,4-4,6 (m, 4H), 7.5 to about 7.6 (m, 2H), 7,7-a 7.85 (m, 2H).

13C-NMR (75 MHz, CDCl3) : 167,9, 168,2, 172,8, 173,6, 174,3 and of 174.4 (carbon amidinopropane and carbonyl. The signals from the two diastereomers partially overlap).

Example 44

HOOC-CH2-(R)Hoc-Pic-Pab 2HCl

(I) Boc-(R)Hoc-Pic-Pab (Z)

Obtained from Boc-(R)Hoc-Pic-OH (see: getting parent compounds) and H-Pab (Z) (see: getting parent compounds) according to the method described for the synthesis of Boc-(R)Cha-Pic-Pab (Z) (see Example 25). Column chromatography using as an eluent of ethyl acetate to obtain 1.3 g (78%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,75 - 0,95 (m, 2H), 0,95 - 2 (m, 31H (as a 1.3 (s, 9H)), 2,4 - 2,5 (m, 1H), 3 - 3,1 (m, 1H), and 3.8 (m, 1H), 4,2 is 4.45 (m, 2H), 4,45 - 4,55 (m, 2H), 5,15 (seemingly sh. s, 3H), 5.25 - in to 5.3 (m, 1H), 7 (Sch. s, 1H), 7,15 - 7.5 (m, 7H), 7,7 - a 7.85 (d, 2H), 9,45 (sh. s, 1H).

13C-NMR (75 MHz, CDCl3) : of 156.6, 164,7, 168,1, 170 and 173 (carbon amidinopropane and carbonyl).

(II) H-(R)Hoc-Pic-Pab (Z)

To 1.3 g (a 1.96 mmole) Boc-(R)Hoc-Pic-Pab (Z) is added at 0oC 100 ml of saturated hydrogen chloride ethyl acetate. The temperature is left to rise to room temperature. After 40 minutes, the solvent is evaporated, add ethyl acetate and saturated RA is arenium of the solvent in vacuo get 0,85 g (77,5%) of the target product.

1H-NMR (300 MHz, CDCl3) : 0,75 - 0,95 (m, 2H), 1,05 - 2,3 (m, 25H), 3 - 3,15 (m, 1H), 3,6 - of 3.75 (m, 2H), 4,25 - 4,4 (m, 2H), 5,15 (seemingly sh.with. 3H), 7,05 to 7.2 (d, 2H), 7,2 - 7,35 (m, 4H), 7,35 to 7.4 (d, 1H), 7,6 - 7,8 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 164,5, 167,9, 170,8 and 175,7 (carbon amidinopropane and carbonyl).

(III) BnOOC-CH2-(R)Hoc-Pic-Pab (Z)

To a mixture of 0.4 g (0,712 mmole) H-(R)Hoc-Pic-Pab (Z) and 0.217 g (of 1.57 mmole) K2CO3in 7 ml of acetonitrile add 0,171 g (0,748 mmole) of benzylbromide and the mixture is heated 1 hour on an oil bath at 60oC. After removal of solvent added ethyl acetate and water. The phases are separated, the organic phase is washed with brine and dried (Na2SO4). Evaporation in vacuo get 0,626 g of residue, which was subjected to column chromatography using ethyl acetate as eluent and getting 2 products. First eluruumis with column connection is (BnOOC-CH2)2-(R)Hoc-Pic-Pab (Z) (0.28 g), with the second column eluted the title compound (0.27 g).

BnOOC-CH2(R)Hoc-Pic-Pab (Z)

1H-NMR (300 MHz, CDCl3) : 0,7 - of 0.95 (m, 2H), 1 is 1.75 (m, 18H), of 2.3 - 2.5 (m, 1 or 2H), 2,9 - 3,05 (m, 1H), 3,2 - 3,3 (m, 1H), 3,35 - 3,5 (m, 2H), up 3.6 - 3.7 (m, 1H), 4,35, 4,55 (ABX-system, 2H), and 4.75 (s, 2H) 5,15 (apparent s, 3H), 5.25 - in to 5.3 (m, 1H)and 7.1 was 7.45 (m, 12H), of 7.7 to 7.8 (d, 2H).

13C-NMR (75 MHz, CDCl3thief 259 mg (0,365 mmole) of BnOOC-CH2-(R)Hoc-Pic-Pab (Z) in 7.8 ml of ethanol and 1.2 ml of 1 N. hydrochloric acid hydronaut 4 h in the presence of 280 mg of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent followed by dissolving in water and freeze-drying obtain 170 mg (83%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,4 - of 1.85 (m, 20H), 1.85 to 2,2 (m, 1H), 2,9 - 3,2 (m, 1H), 3,4 - 3,9 (m, 3H), 3,05 - 4,3 (m, 2H), 4,3 - of 5.05 (m, 2H), and 7.1 to 7.4 (m, 2H), and 7.4 to 7.7 (m, 2H).

13C-NMR (75 MHz, CDCl3) : 167,8, 168,6, 169,6 and 172,3 (carbon amidinopropane and carbonyl).

Example 45

(HOOC-CH2)2-(R)Hoc-Pic-Pab 2HCl

(1) (BnOOC-CH2)2-(R)Hoc-Pic-Pab (Z)

The title compound is obtained by alkylation of H-(R)Hoc-Pic-Pab (Z) by the method of Example 44.

1H-NMR (300 MHz, CDCl3) : 0,7 - of 0.95 (m-H), 0,95 - of 1.95 (m, 18H), 2,35 - 2,5 (m, 1H), 2,9 - 3,05 (m, 1H), 3,5 - of 3.85 (m, 6H), 4,35 - 4,55 (m, 2H), 4,9 (2 s, 4H), and 5.2 (s, 2H), 5.25 to 5.35 (m, 1H), 7,1 was 7.45 (m, 16H), 7.5 to the 7.65 (m, 1H), 7,7 - a 7.85 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 164,7, 167,9, 170,5, 172 and 172,4 (carbon amidinopropane and carbonyl).

(II) (HOOC-CH2)2-(R)Hoc-Pic-Pab 2HCl

A solution of 153 mg (0,178 mmole) (BnOOC-CH2)2-(R)Hoc-Pic-Pab (Z) in 4.5 ml of ethanol (99.5% pure) and 0.5 ml of 1 N. hydrochloric acid hydronaut 3.5 h in the presence of 150 mg of 5% Pd-C. Removing the catalyst by filtration and Ilaria (HOOC-CH2)2-(R)Hoc-Pic-Pab. The resulting crude product (80% purity) were OFGH with the use of CH3CN-0.1 M NH4OAc (1:4) as eluent. Removal of solvent and excess NH4OAc with subsequent freeze-drying of 1 M HCl receive the title compound.

1H-NMR (500 MHz, D2O, mixture of two rotamers) main rotamer : 0,95 - of 2.15 (m, 20H), of 2.25 to 2.35 (m, 1H), 3,45 - 3,55 (m, 1H), 3.95 to of 4.25 (m, 5H), 4.6 to the 4.65 (m, 2H), 4.92 in - 5,01 (m, 1H), 5,15 - 5,2 (m, 1H), 7,58 - 7,63 (d, 2H), 7,84 - 7,89 (d, 2H).

Allow the signals generated less retamero appear at : 0,7 - 0,85 (m), 2,35 is - 3.45 (m), of 3.05 - 3.15 in (m), 4,47 - 4,55 (m), 4,55 - 4,6 (m) and 4.65 - 4,7 (m), 7,63 - to 7.67 (d), 7,89 - 7,95 (d).

13C-NMR (75 MHz, D2O) : 168,2, 169,7, 170,2 and 172,71 (carbon amidinopropane and carbonyl).

Example 46

(HOOC-CH2-(R)Pro(3-(S)Ph-Pro-Pab 2HCl

(1) (Boc-(R)Pro(3-(S)Ph)-Pro-Pab (Z)

To a solution of 570 mg (1.5 mmole) of (Boc-(R)Pro(3-(S)Ph)-Pro-OH (see: getting the initial connection), 425 mg (1.5 mmole) H-Pab (Z) (see: getting parent compounds) and 733 mg (6 mmol) of DMAP in 25 ml of CH3CN-DMF (1.5 to 1) add 310 mg (of 1.62 mmole) of EDC and the mixture is stirred for 23 h at room temperature. After removal of the greater part of the solvent to the residue are added 50 ml of water. The aqueous phase is extracted with EtOAc (1 x 75 ml 2 x 50 ml). United orgasam (MgSO4). Filtration and evaporation of the solvent receive 670 ml of oil, which is purified column chromatography using ethyl acetate as eluent, and receive 529 mg (55%) of the title compound.

1H-NMR (300 MHz, CDCl3) : of 1.26 (s, 9H), 1,53 - of 1.88 (m, 3H), 2.1 to 2,31 (m, 3H), 2,52 (K, 1H), to 3.58 - of 3.77 (m, 4H), or 4.31 (d, 1H), 4,35 and 4,47 (ABX-system, 2H) and 4.65 (DD, 1H), 5,19 (s, 2H), 7,1 - 7,37 (m, 10H), 7,42 (d, 2H), 7,81 (d, 2H), 8 (t, 1H (NH)).

13C-NMR (75 MHz, CDCl3) : 154, 6mm, 164,6, 168,1, RUB 171.1 and is 171.3 (carbon amidinopropane and carbonyl).

(II) H-(R)Pro(3-(S)Ph-Pro-Pab-(Z)

In 15 ml EtOAc-HCl (g saturated) is dissolved at room temperature 529 mg (0,81 mmole) Boc-(R)Pro(3-(S)Ph)-Pro-Pab (Z) and stirred for 3 hours. The solvent is evaporated and the residue is dissolved in 70 ml of CH2Cl2. The organic phase is washed with 10 ml of 2 M NaOH, 10 ml water, 10 ml of brine and dried (MgSO4). Filtration and evaporation of solvent to obtain 403 mg (90%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 1,44 - of 1.57 (m, 1H), 1,62 is 1.86 (m, 2H), 1,96 to 2.35 (m, 3H), 2,45 (K, 1H), 3,05 - to 3.35 (m, 4H), 3,83 (sh. d, 1H), 4,25 is 4.45 (m, 2H), 4.53-in (m, 1H), 5,19 (s, 2H), 7,16 - 7,37 (m, 10H), 7,42 (d, 2H), 7,66 (t, 1H, (NH)), to 7.77 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 164,4, 167,9, RUB 171.1 and 173 (carbon amidinopropane and carbonyl).

(III) BnOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab (Z)

A mixture of 200 mg (ewout 1 hour and 30 minutes at 50oC. the Solvent is evaporated and the residue is dissolved in 70 ml of EtOAc. The organic phase is washed with 10 ml water and dried (MgSO4).

Filtration and evaporation of solvent to obtain 260 mg of oil. Purification of the crude product column chromatography using a stepwise gradient of CH2Cl2-MeOH(NH3-saturated) (95:5, then 9:1) obtain 182 mg (72%) of the title compound as a white solid.

1H-NMR (300 MHz, CDCl3) : 1,43 - to 1.82 (m, 1H), 1,96 and 2.13 (m, 1H), 2,13 - 2,22 (m, 1H), 2.26 and is 2.43 (m, 2H), 3,02 - 3,14 (m, 2H), 3,24 - 3,51 (m, 4H), 3,83 (d, 1H), 4,29 - 4,46 (ABX-system with center at 4.37, 2H), 4,58 (DD, 1H), equal to 4.97 - 5,1 (AB-system with center at 5,03, 2H), 5,19 (s, 2H), 7,16 - 7,38 (m, 15H), the 7.43 (d, 2H), 7,5 - 7,8 (m, 3H, one NH-group).

13C-NMR (75 MHz, CDCl3) : 164,5, 167,9, 171,15, 171,2 and 172,7 (carbon amidinopropane and carbonyl).

(IV) HOOC-CH2-(R)Pro(3-(S) Ph)-Pro-Pab 2HCl

BnOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab (Z) (0.18 g, 0.26 per mmole) is mixed with 0.075 g of 5% Pd-C, 1 ml of 1 n HCl solution, 1 ml of water and 10 ml ethanol and the mixture hydronaut one hour at atmospheric pressure. Filtration of the catalyst through hyflo, evaporation of the solvent followed two freeze-drying from water getting 129 mg of crude product. The crude product is purified OFGH using a stepwise gradient of 0.1 M is ucaut 70 mg (50%) of the pure product.

1H-NMR (300 MHz, D2O) : 1,42 - 1,6 (m, 1H), 1,65 of - 1.83 (m, 1H), 1,83 - to 1.98 (m, 1H), 2,03 - 2,2 (m, 2H), 2.63 in (t, 2H), 3,28 - 3,4 (m, 1H), 3,55 - of 3.78 (m, 2H), 3,81 - 3,96 (AB-system with center at 3,88, 2H), 4,06 - 4,19 (m, 1H), 4,37 - br4.61 (AB - system with center at 4,49, 2H), 4,48 (DD, 1H), 4,7 (d, 1H), 7,35 - 7,98 (m, 7H), 7,74 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 167,02, of 167.2, 169,3 and of 174.4 (carbon amidinopropane and carbonyl).

Example 47

HOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab 2HCl

(1) BnOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab (Z)

To a solution of 190 mg (0,34 mmole) H-(R)Pro(3-(S)Ph)-Pro-Pab (Z) (see Example 46) in 7 ml EtOH (99%) are added 114 mg (0.7 mmole) of benzoylacrylate and the reaction mixture was stirred 24 h at room temperature. Evaporation of the solvent and subsequent column chromatography using a stepwise gradient of CH2Cl2-MeOH(NH3-feast upon. ) (95:5, then 9:1) obtain 202 mg (83%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 1,5 - 1,71 (m, 2H), 1,74 to 1.9 (m, 1H), 1,9 - 2,05 (m, 1H), 2,2 - of 2.64 (m, 5H), 2,69 - 2,82 (m, 2H), 2,84 - 2,96 (m, 1H), 3,18 - of 3.48 (m, 4H), 4,28 - of 4.44 (m, 2H), br4.61 (m, 1H), 4,48 - 5,08 (AB-system with center at 5,03, 2H), 5,19 (s, 2H), 7,15 - 7,37 (m, 15H), 7,44 (d, 2H), 7,75 - a 7.85 (m, 3H, one NH-group).

13C-NMR (75 MHz, CDCl3) : 164,6, 168, 171,2, 172,5 and 172,9 (carbon amidinopropane and carbonyl).

(II) HOOC-CH2-CH2-(R)Pro(3-(S) Ph)-Pro-Pab and 10 ml of ethanol and the mixture hydronaut one hour at atmospheric pressure. Filtration of the catalyst through hyflo, evaporation of the solvent followed two freeze-drying from water getting 125 mg (79%) of the title compound.

H-NMR (300 MHz, D2O) : the 1.44 (m, 1H), 1,65 - 1,9 (m, 2H), 2-2,2 (m, 2H), 2,62 (K, 2H), and 2.83 (t, 2H), 3.27 to 3,4 (m, 1H), 3,4 - 3,8 (m, 4H), 4-4,15 (m, 1H), 4,35-4,6 (m, 3H), and 4.68 (d, 1H), 7,38-to 7.6 (m, 7H), to 7.77 (d, 2H).

13C-NMR (75 MHz, CDCl3) : to 166.2, 167,1, 174,1 and 174,2 (carbon amidinopropane and carbonyl).

Example 48

HOOC-CH2-CH2-(R)Tic-Pro-Pab 2HCl

(I) Boc-(R)Tic-Pro-Pab (Z)

Obtained by the method described for the synthesis of Boc-(R)Cha-Pic-Pab (Z) (see Example 25), using Boc-(R)Tic-Pro-OH (see: getting parent compounds) instead of Boc-(R)Cha-Pic-OH. Column chromatography using as eluents mixture of heptane-EtOAc (4:1) and then EtOAc get 425 mg (37%) of the title compound.

1H-NMR (500 MHz, CDCl3) : of 1.35 (s, 9H), 1,95-2,15 (m, 3H), 2,4 (m, 1H), 2,8 (m, 1H), 3,3 (m, 1H), 3,55 (m, 2H), 4,25-4,4 (two m, 2H), 4,55-4,7 (two m, 2H), 7,15-7.5 (m, 10H), a 7.85 (d, 2H).

13C-NMR (75 MHz, CDCl3) : 164,6, which is 171,5 and 171.6 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

(II) H-(R)Tic-Pro-Pab (Z)

Boc-(R)Tic-Pro-Pab (Z) (379 mg, of 0.59 mmole) was dissolved in EtOAc saturated with HCl (g) and stirred at room temperature. Cl3) : 1,65-2,15 (two m, 7H), of 2.45 (m, 1H), 2,75 (m, 1H), 2,9 (m, 1H), 3 (m, 1H), 3,25 (m, 1H), 3,55 (m, 1H), 3,85 (m, 1H), 4,35-4,55 (m, 2H), 4.75 in (d, 1H), 4,9 (s, 1H), 5.25 in (s, 2H), 6,8-7,45 (several m, 8H), 7.5 and a 7.85 (two d, 4H).

13C-NMR (75 MHz, CDCl3) : 164,5, and is 171.3 172,7 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

(III) BnOOC-CH2-CH2-(R)Tic-Pro-Pab (Z)

A mixture of H-(R)Tic-Pro-Pab (Z) (140 mg, 0.26 per mmole) and 63 mg (0,39 mmole) of benzoylacrylate in EtOH (1.3 ml) incubated 48 h at 20oC. Evaporation of the solvent and column chromatography using as eluents 50% EtOAc in heptane and then with 10% MeOH in EtOAc receive in the form of a white solid substance 133 mg (73%) of the target product.

1H-NMR (500 MHz, CDCl3) : 1,75-2 (two m, 4H), of 2.25 (m, 1H), 1,4-of 1.65 (m, 3H), 2,7-2,95 (two m, 4H), 3,05-3,2 (m, 2H), 3,9 (m, 1H), 4,45 (m, 2H) and 4.65 (m, 1H), 5,1 (two d, 2H, in), 5.25 (s, 2H), 6,85 -7,45 (several m, 12H), to 7.5 and 7.9 (two d, 4H).

13C-NMR (75 MHz, CDCl3) : which is 171,5, 171,9 and 172,1 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

(IV) HOOC-CH2-CH2-(R)Tic-Pro-Pab 2HCl

BnOOC-CH2-CH2-(R)Tic-Pro-Pab (Z) (125 mg, 0,17 mmole) hydronaut over 5% Pd-C using EtOH-HCl as solvent. Filtration of the catalyst and freeze-drying obtain 73 mg (77%) of the title compound.

13C-NMR (75 MHz, D2O) : 166,9, 167,1 and 174,3 (carbon amidinopropane and carbonyl. Two peaks probably overlap).

Example 49

HOOC-CH2-CH2-(R)Cgl-Aze-Pig - 2HCl

(I) Boc-(R)Cgl-Aze-Pig (Z)2< / BR>
To the mixture 0,623 g (1,83 mmole) Boc-(R)Cgl-Aze-OH (see: getting the initial connection), 0,816 g (1,92 mmole) H-Pig(Z)2(see: getting parent compounds) and 0,89 g (7.3 mmole) DMAP in 10 ml of dichloromethane add 0,368 g (1,92 mmole) of EDC and the mixture is stirred for about a day. After diluting the mixture was washed with 0.3 M KHSO4and brine. The organic layer (Na2SO4) filtered and evaporation obtain 1.4 g of crude product. Cleaning column chromatography using ethyl acetate as eluent obtain 0.3 g (22%) of pure product.

(II) H-(R)Cgl-Aze-Pig (Z)2< / BR>
Boc-(R)Cgl-Aze-Pig (Z)2(0.3 g, 0.4 mmole) is mixed with 10 ml of dichloromethane and 2.5 ml triperoxonane acid and the mixture is stirred for an hour and a half. After dissolution of the solvent the residue is dissolved in dichloromethane and washed twice with 0.2 M NaOH solution. The combined aqueous layer was again washed with dichloromethane. The combined organic layer is dried (Na2SO4), filtered and after evaporation obtain 0.24 g (93%) goal 3H), and 3.2 (t, 2H), 4,05 - to 4.28 (m, 4H), a 4.86 (DD, 1H), 5,16 (s, 4H), 7,2 - 7,42 (m, 10H), 7,98 (sh. s, NH).

(III) BnOOC-CH2-CH2-(R)Cgl-Aze-Pig (Z)2< / BR>
To a solution of 0,231 g (of 0.36 mmole) of the product of stage (II) in 2 ml ethanol add 61 μl (0.4 mmole) of benzoylacrylate and the reaction mixture is stirred for five days at room temperature. Evaporation of the mixture and purification of the crude product column chromatography using a stepwise gradient of CH2Cl2-MeOH (95:5, 90:10) as eluent get 0,218 g (75%) of pure product.

1H-NMR (300 MHz, CDCl3, 335 K) : 0,93 (sh. for, 1H), 1,02-of 1.85 (m, 14H), 1,94 (sh. d, 1H), 2,33-2,5 (m, 3H), 2,58-2,77 (m, 2H), 2,79-to 3.02 (m, 4H), 3,17 (t, 2H), 4-4,25 (m, 4H), a 4.86 (DD, 1H), 5,11 (s, 2H), 5,12 (s, 4H), of 7.2 to 7.4 (m, 15H), 8,03 (sh. s, NH), 10,35 (sh. s, NH).

(IV) HOOC-CH2-CH2-(R)Cgl-Aze-Pig 2HCl

BnOOC-CH2-CH2-(R)Cgl-Aze-Pig(Z)2(0,218 g of 0.27 mmole) is mixed with 0.1 g of 5% Pd-C, 1 ml of 1 M HCl solution, 1 ml of water and 10 ml ethanol and the mixture hydronaut one hour at atmospheric pressure. Filtration of the catalyst through hyflo, evaporation of the solvent followed two freeze-drying from water getting 134 mg (95%) of the title compound.

1H-NMR (300 MHz, D2O) : 1-1,4 (m, 7H), 1,55-2,05 (m, 9H), 2,22-of 2.34 (m, 1H), 2,61-to 2.74 (m, 1H), 2,88 (t, 2H), is 3.08 (sh. t, 2H), 3,19 (d, 2H), 3,34 (m, 2H), 3,83 (sh. d, 2H), 3,95 (d, 1H), 4,29-4,4 is).

Example 50

HOOC-CH2-(R)Cgl-Pro-Pig 2HCl

(I) Boc-(R)Cgl-Pro-Pig (Z)2< / BR>
To a mixture of 1 g (2,96 mmole) Boc-(R)Cgl-Pro-OH (see: getting the initial connection), 1.197 g (2,82 mmole) H-Pig(Z)2(see: getting parent compounds) and 1.38 g (11.28 mmole) DMAP in acetonitrile added at -15oC 0,568 g (2,96 mmole) of EDC. The mixture is left overnight to warm to room temperature. After evaporation of the solvent in vacuo, add methylene chloride and 1 M KHSO4. The phases are separated, the organic phase is washed with a saturated solution of NaHCO3, water and brine, dried (Na2SO4) and evaporation of the solvent receive at 2,033 g of residue, which was subjected to column chromatography using ethyl acetate as eluent. Chromatography selected two products: 720 mg (34%) of the title compounds eluting from the first column, followed by elution 775 mg (44%) of Boc-(R)Cgl-Pro-Pig (Z) formed by loss of one Z protective group.

1H-NMR (300 MHz, CDCl3) : 0,85 - 2,1 (m, 19H), 2,3 at 2.45 (m, 1H), 2,8-3,2 (m, 4H), 3,45-3,55 (m, 1H), 3,55 - the 3.65 (m, less rotameter), 3,8 - 3,93 (m, 1H), 3,97 of 4.1 (m, 1H), to 4.52-to 4.62 (d, 1H), 5,1 (apparent s, 5H), 7,12-7,41 (m, 10H).

Separate signals especially piperidino cycle selectively broader due process venturino the th peak in the range of 3.5 to 4.5 part/million

13C-NMR (75 MHz, CDCl3) : 155, 2mm, 156, 3mm, 171 and 172,1 (carbon piperidinium and carbonyl).

(II) H-(R)Cgl-Pro-Pig (Z)2< / BR>
In 35 ml TFUC-CH2Cl2(1:4) dissolve 720 mg (0,946 mmole) Boc-(R)Cgl-Pro-Pig (Z)2and stirred for 30 minutes. The solvent is removed in vacuum, and then add ethyl acetate and 2 M NaOH. The organic layer was washed with water and brine, dried (Na2SO4) and evaporation of the solvent in vacuum with a quantitative yield obtain the title compound.

1H-NMR (300 MHz, CDCl3) : 0,8-of 2.15 (m, 19H), 2,22 - 2,4 (m, 1H), 2,75 are 2.98 (m, 2H), 2,98 - 3,18 (m, 2H), 3,18-to 3.35 (m, 1H), 3,35-3,5 (K, 1H), of 3.5-3.7 (m, 1H), to 4.52-4,58 (d, 1H), 5,1 (s, 1H), and 7.1-7.5 (m, 10H).

Separate signals, in particular piperidino cycle, selectively broader due process of intramolecular exchange. This is especially evident for the 2 - and 6-CH2groups piperidino cycle, providing a broad peak in the range of 3.5 to 4.5 ppm million

13C-NMR (75 MHz, CDCl3) : 154,96, 171,31, 174,82 (carbon amidinopropane and carbonyl).

(III) BnOOC-CH2-(R)Cgl-Pro-Pig (Z)2< / BR>
To a mixture of 0.64 g (0,999 mmole) H-(R)Cgl-Pro-Pig (Z)2and mean HDI of 0.531 g (2,996 mmole) K2CO36.4 ml of acetonitrile add 0,298 g (0,999 mmole) of BnOOC-CH2-OTf ( see: getting parent compounds) and nagriamel receive 729 mg of the residue, which is subjected to column chromatography using ethyl acetate as eluent. The result is two products: 120 mg (BnOOC-CH2)2-(R)Cgl-Pro-Pig (Z)2, eluruumideta in the first column, and 142 mg (18%) of the title compound.

1H-NMR (300 MHz, CDCl3) : 0,94-of 2.27 (m, 19H), 2,28 is 2.43 (m, 1H), 2,8-2,98 (m, 2H), 2,98-of 3.06 (m, 1H), a 3.06-3.15 in (d, 1H), 3.15 and is 3.25 (m, 1H), 3,3-3,5 (m, 4H), 4,5-br4.61 (d, 1H), 5,1 (s, 6H), a 7.1 to 7.6 (m, 15H), 10,52 (sh. s, 1H).

Separate signals, in particular piperidino cycle, selectively broadened due process of intramolecular exchange. This is especially evident for the 2 - and 6-CH2groups piperidino cycle, providing a broad peak in the range of 3.5-4.6 HR/million

(IV) HOOC-CH2-(R)Cgl-Pro-Pig 2HCl

BnOOC-CH2-(R)Cgl-Pro-Pig (Z)2(142 mg, 0,176 mmole) hydronaut in the presence of from 0.88 ml of 1 M hydrochloric acid, 10 ml of ethanol (99.5% pure) and 180 mg of 5% Pd-C for 2 hours Removing the catalyst by filtration through hyflo and militarily filter with subsequent evaporation of the solvent in vacuo and freeze-drying obtain 95 mg of HOOC-CH2-(R)Cgl-Pro-Pig 2HCl. The resulting crude product (79% purity) clean OFGH with the use of CH3CN-0.1 M NH4OAc (15:85) as eluent. Removal of solvent and excess NH4OAc, freeze-drying, prevrashaet the title compound.

1H-NMR (500 MHz, D2O) : 1.1 to about 1.35 (m, 6N), 1,63 with 2.14 (m, 13H), and 2.26-of 2.36 (m, 1H), 3,01 is 3.23 (m, 4H), 3,49-3,62 (K, 2H), 3,62-of 3.77 (m, 2H), of 3.77-3,88 (apparent d, 2H), 4,18-4,32 (d, 1H), 4,37 to 4.5 (m, 1H).

Example 51

H-(R)Cha-Aze-Pig - 2HCl

(I) Boc-(R)Cha-Aze-Pig (Z)2< / BR>
To a well stirred mixture of 86 mg (0,243 mmole) Boc-(R)Cha-Aze-OH (see: getting parent compounds), 100 mg (0,236 mmole) H-Pig (Z)2(see: getting parent compounds) and 115 mg (0,944 mmole) DMAR in 5 ml of CH3CN add 50 mg (of 0.26 mmole) of EDC and the reaction mixture was stirred 20 h at room temperature. The solvent is evaporated, the residue is dissolved in 70 ml of EtOAc, the organic phase is washed with 1M KHSO4(3 x 5 ml), 5 ml of KHCO3, water (3 x 5 ml), 5 ml of brine and dried (MgSO4). Filtration and evaporation of solvent to obtain 141 mg of oil. Purification of the crude product column chromatography (36 g SiO2) using a stepwise gradient of CH2Cl2-MeOH (97:3, then 95:5) to obtain 43 mg (24%) of the title compound.

(II) H-(R)Cha-Aze-Pig (Z)2< / BR>
Through a mixture of 43 mg (0,0565 mmole) Boc-(R)Cha-Aze-Pig(Z)2and 10 ml of ethyl acetate 5 minutes propulsive hydrogen chloride. After evaporation of the solvent in vacuum, add ethyl acetate and 0.1 M NaOH solution. The phases are separated, the organic phase is washed with water and supplies chromatography using as eluent 10% NH3-saturated methanol in ethyl acetate, and obtain 28 mg of the target product.

1H-NMR (300 MHz, CDCl3) : 0,75-of 1.85 (m, 18H), 2,55 of $ 2.53 (m, 1H), 2,62-2,78 (m, 1H), 2.8 to 3 (m, 2H), 3-3,28 (m, 2H), 3,28-3,37 (m, 1H), 3,97-4,18 (m, 2H), 4,8-4,9 (m, 1H), 5,1 (s, 4H), 7,2 was 7.45 (m, 9H), 8,05-of 8.15 (m, 1H).

Separate signals, in particular piperidino cycle, selectively broadened due process of intramolecular exchange. This is particularly noticeable in the case of 2 - and 6-CH2groups piperidino cycle, providing a broad peak in the range of 3.7-4.5 hours/million

(III) H-(R)Cgl-Aze-Pig 2HCl

A solution of 28 mg (0,042 mmole) H-(R)Cgl-Aze-Pig (Z)2in 2 ml of ethanol (99.5% pure) and 0.13 ml of 1 N. hydrochloric acid hydronaut 4 h in the presence of 35 mg of 5% Pd-C. Removing the catalyst by filtration and evaporation of the solvent in vacuo, followed by dissolving in water, freeze-drying receive 12 mg (60%) H-(R)Cgl-Aze-Pig dihydrochloride.

1H-NMR (500 MHz, 300 K, CD3OD) : 0,75-2,1 (m, 18H), of 2.2 to 2.35 (m, 1H), 2,62 is 2.75 (m, 1H), 3-3,12 (t, 2H), 3,12 is 3.23 (d, 2H), 3,85-of 3.95 (d, 2H), 3.95 to 4 (DD, 1H), 4,15-to 4.23 (m, 1H) 4,35 was 4.42 (m, 1H), 4.72 in-4,78 (m, 1H).

Separate signals, in particular piperidino cycle, selectively broadened due process of intramolecular exchange. This is particularly noticeable in the case of 2 - and 6-CH2groups piperidino cycle, providing a broad peak in inela).

Example 52

HOOC-CH2-(R)Cgl-Aze-Pac 2HCl

(1) Boc-(R)Cgl-Aze-Pac (Z)

To a solution of 0.47 g (1.4 mmole) Boc-(R)Cgl-Aze-OH (see: getting the initial connection), 0.4 g (1.4 mmole) H-Pac (Z) (see: getting parent compounds) and 0.67 g (5.5 mmole) of DMAP in 5 ml of acetonitrile is added at 0oC 0.27 g EDC and the mixture is stirred for about a day at room temperature, then diluted with ethyl acetate. The solution was washed with KHSO4(aq. ) and NaHCO3(aq.), dried (Na2SO4), filtered and evaporated. Column chromatography using ethyl acetate and then a mixture of ethyl acetate-methanol (98: 2) to obtain 0.25 g (30%) of the title compounds as a mixture of 1,4-CIS - and TRANS-isomers relative to the Pac-fragment molecules.

1H-NMR (500 MHz, CDCl3) : 0,8-2 (m, 29H; it was 1.45 (s, 9H)), 2,15 and was 2.34 (m, 1H, isomers), a 2.45 to 2.7 (m, 2H), 3-3,4 (m, 2H), 3,85 (m, 1H), 4,14 (m, 1H), 4,33 (m, 1H), around 4.85 (m, 1H), to 4.98 (m, 1H), 5,04 (s, 2H), 7,25 was 7.45 (m, 5H), 7,8-7,9 (m, 1H), 9,2-9,5 (m, 1H).

(II) H-(R)Cgl-Aze-Pac(Z) HCl

In 100 ml of ethyl acetate to dissolve 0.25 g (0,41 mmole) Boc-(R)Cgl-Aze-Pac(Z) and cooled in a bath of ice. Through the solution for 5 min propulsive HCl (g) and the solvent evaporated.

1H-NMR (300 MHz, MeOD) : 0,8-2 (m, 22H), of 2.05 to 2.35 (m, 1H), 2,4-by 2.55 (m, 1H), 2,6-of 2.75 (m, 1H), 3 (d, 1H), 3.05, and 3,37 (multiplets, and 0.6 H 0.4 H, respectively, isomers), 3,15-3,3 (m, the mole) of H-(R)Cgl-Aze-Pac(Z) HCl, 0.11 g (0.37 mmole) of benzoyltrifluoroacetone and 0.14 g (1 mmol) of K2CO3in 5 ml of acetonitrile is stirred for three days at room temperature. The crude product subjected to column chromatography with elution with a mixture of EtOAc-CH2Cl2-MeOH (95:20:5). Yield 70 mg (32%).

1H-NMR (500 MHz, CDCl3) : 0,85-2,3 (m, 20H), 2,48 (m, 1H), 2.63 in (m, 1H), 2,87 (m, 1H), 3,05-of 3.25 (m, 1H), of 3.25 to 3.35 (m, 2H), 3,38 (DD, 1H), 3,95 (m, 1H), 4,08 (m, 1H), 4,88 (m, 1H), 5,1-5,2 (m, 4H), 5,9-6,3 (m, 1H), of 7.25-7.5 (m, 10H), 8-8,08 (broad triplet, 1H, isomers).

(III) HOOC-CH2-(R)Cgl-Aze-Pac(Z) 2HCl

To a solution of 70 mg (0.11 mmole) of BnOOC-CH2-(R)Cgl-Aze-Pac(Z) in 5 ml of ethanol is added 5% Pd-C and 0.1 ml conc. HCl and the mixture hydronaut 1 h at atmospheric pressure. After filtration and evaporation the product was then purified preparative OFGH with 0.1 M NH4OAc-CH3CN as eluent. After replacing the hydrochloride salt and freeze-drying the title compound are obtained in the form of a mixture of 1,4-CIS and TRANS-isomers (45:55) relative to the RAS-fragment molecules. Yield 40 mg (74%).

1H-NMR (500 MHz, D2O) : 1,1-2,1 (m, 20H), 2,32 (m, 1H), 2,52 (m, 1H), 2.63 in (m, 1H), 2,72 (m, 1H), 3,1-3,3 (m, 1H), 3,4 (m, 1H), 3,8-3,95 (m, 2H), Android 4.04 (d, 1H), 4,39 (m, 1H), is 4.93 (m, 1H).

13C-NMR (125 MHz, D2O) : 167,7, 172, 174,9 and 175,2 (carbon amidinopropane and carbonyl),

Example 53

H-(R)Cha-P is the doctrine of the parent compounds), 0.4 g (1.1 mmole) Boc-(R)Cha-Pro-OH (see: getting parent compounds) and 0.55 g DMAP in 7 ml of acetonitrile add 211 mg (1.1 mmole) of EDC. The reaction mixture was stirred 1 h at 0oC and 2 h at room temperature. After removal of solvent in vacuo, the residue diluted with ethyl acetate and water. The organic phase is washed with acetic acid, water and sodium hydrogen carbonate solution and dried (MgSO4). Removal of solvent in vacuum to get the residue, which is purified column chromatography using as an eluent of ethyl acetate, and obtain 196 mg (27%) of the title compound.

H-(R)Cha-Pro-Pac (Z)

Through a solution of 196 mg of Boc-(R)Cha-Pro-Pac (Z) in 25 ml of ethyl acetate propulsive hydrogen chloride. After 10 minutes the reaction mixture is diluted with methylene chloride and then add a solution of sodium hydroxide. The aqueous phase is repeatedly extracted with methylene chloride, the combined organic phases are dried (K2CO3) and removal of solvent in vacuo obtain 86 mg (52%) of the title compound.

(III) H-(R)Cha-Pro-Pac 2HCl

The title compound is obtained by hydrogenation of H-(R)Cha-Pro-Pac(Z) in ethanol in the presence of 10% Pd-C.

1H-NMR (300 MHz, D2O, a mixture of 1,4-CIS and TRANS-isomers in the Pac fragment ASS="ptx2">

Example 54

H-(R)Cgl-Ile-Pab 2HCl

(I) Boc-(R)Cgl-Ile-Pab (Z)

To stir at +5oC mixture of 1.33 g (3.6 mmole) Boc-(R)Cgl-Ile-OH (see: getting the initial connection), 1.12 g (3.9 mmole) H-Pab (Z) (see: getting parent compounds) and 1.76 g (14.4 mmole) of DMAP in 50 ml of CH3CN-DMF (1:1) add 0.75 g (3.9 mmole) of EDC. The reaction mixture was left to warm to room temperature and incubated for 60 hours After evaporation of CH3CN the residue is transferred in 100 ml of water is formed yellow precipitate). The mixture is extracted with EtOAc (2 x 50 ml), the combined organic phase was washed with a saturated solution of NaHCO3(2 x 30 ml), 0.2 M HCl (2 x 50 ml), 50 ml of brine and dried (MgSO4). Evaporation and subsequent column chromatography using CH2Cl2-THF (85:15) as eluent obtain 510 mg (24%) of the title compound.

(II) H-(R)Cgl-Ile-Pab (Z)

In 14 ml of CH2Cl2-TFOC (2,5:1) dissolve 530 mg of Boc-(R)Cgl-Ile-Pab (Z) and stirred for 2 h at room temperature. Evaporation of the solvent and subsequent column chromatography using CH2Cl2-MeOH(NH3-saturated.) (95:5) as eluent get the title compound.

(III) H-(R)Cgl-Ile-Pab 2HCl

H-(R)Cgl-Ile-Pab (Z) (75 mg, 0.15 mmole) hydronaut 6 h at atmospheric pressure over 10% of RLA and 20 ml of EtOH, followed by filtration through cellit, evaporation of the solvent and freeze-drying from water getting in the form of a white powder 50 mg (89%) of the title compound.

1H-NMR (500 MHz, MeOD) : of 0.9 (t, 3H), were 0.94 (d, 3H), 1,1-2 (m, 14H), 3,83 (W, s, 1H), 4.26 deaths (d, 1H), 4,5 (m, 2H), EUR 7.57 (W, d, 2H), 7,78 (W, d, 2H).

Example 55

H-(R)Cgl-Aze-Pab

The hydrogenation of 257 mg (5.08 mmole) H-(R)Cgl-Aze-Pab (Z) (see Example 1 (11)) 6 h at atmospheric pressure over 5% Pd-C in 6 ml of aqueous ethanol, followed by filtration of the catalyst, evaporation of the solvent and freeze-drying from water receive 200 mg (89%) of the title compound.

1H-NMR (500 MHz, D2O) : 1-2 (m, 11H), of 2.25 (m, 1H), and 2.7 (m, 1H), 3,3 (m, 1H, in), 3.75 (m, 1H), 4,3 (m, 1H), 4,45 (m, 1H), 4,55 (m, 2H), 7,6 (m, 2H), to 7.77 (m, 2H).

MC: m/z 372 (M++1).

Example 56

HOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab HOAc

(I) BnOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab (Z)

To a cooled to -10oC to a solution of 0.25 g (of 0.47 mmole) H-(R)Cha-Pro-Pab (Z) (see example 15) in 5 ml of CH2Cl2slowly added a solution of 150 mg (0.48 mmole) TfOCH2COOBn (see: getting parent compounds) in 3 ml of CH2Cl2. After adding 200 mg (1,45 mmole) of potassium carbonate the mixture is stirred for 20 h at room temperature. The mixture is then diluted with CH2Cl2, washed with water and dried (MgSO4). Evaporation of the solvent followed to what about the connection.

(II) HOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab HOAc

BnOOC-(R, S)CH(Me)-(R)Cha-Pro-Pab (Z) (150 mg, 0.2 mmole) hydronaut 4 h at atmospheric pressure on 50 mg of 5% Pd-C in 20 ml of EtOH. Filtration of the catalyst, evaporation of the solvent and subsequent purification OFGH with the use of CH3CN-0.1 M NH4OAc (1:4) as eluent obtain 35 mg (37%) of the title compound.

1H-NMR (500 MHz, MeOD) : 1 (m, 1H), 1,2-a 1.45 (m, 5H), 1,5 (m, 1H), of 1.6-1.8 (m, 6H), 1,9-2,1 (m, 6H), of 2.25 (m, 1H), 3,25 (m, 1H), 3,5 (m, 1H), 3,85 (m, 1H), 4,15 (m, 1H), 4,35-4,6 (m, 3H), 4,9 (m, partially shielded HO line, 6H), at 7.55 (d, 2H), of 7.75 (d, 2H).

Example 57

MeOOC-CH2-(R)Cgl-Aze-Pab 2HCl

(I) MeOOC-CH2-(R)Cgl-Aze-Pab (Z)

The solution 0,186 g (0,841 mmole) TfO-CH2-COOMe (see: getting parent compounds) in CH2Cl2slowly added at room temperature to a mixture 0,425 g (0,841 mmole) H-(R)Cgl-Aze-Pab (Z) (see example 1), 0,894 g (5,04 mmole) K2CO3in CH2Cl2(a total of 4.3 ml) and stirred for about a day. After making additional amount of CH2Cl2the mixture is washed with water and brine, dried, filtered and evaporation of the solvent in vacuo get the remainder, which is three times subjected to column chromatography on silica gel using as eluents following mixtures: first CH2Cl2 is the result 0,324 g (67%) of the title compound.

(II) MeOOC-CH2-(R)Cgl-Aze-Pab 2HCl

MeOOC-CH2-(R)Cgl-Aze-Pab (Z) (220 mg, of 0.38 mmole) hydronaut in the presence of 1.14 ml of 1 N. HCl, 6,5 ml MeOH and 300 mg of Pd-C for 2 hours Removing the catalyst by filtration on celite and misopristol filter with subsequent evaporation of the solvent in vacuo and double freeze-drying obtain 178 mg (91%) of the title compound.

1H-NMR (500 MHz, D2O) : 1,12-1,4 (m, 5H), 1,68-of 1.81 (m, 2H), 1,81-1,9 (m, 3H), 1,97-2,1 (m, 1H), 2,29-2,4 (m, 1H), 2,68-2,8 (m, 1H), 3,86 (s, 3H), 4,1 (s, 2H), 4.1 and 4.5 (d, 1H), 4,36 was 4.42 (t, 2H), 4,59 (s, 2H), 4,99-5,04 (s, 1H), 7,65-7.7 (d, 2H), 7,8-a 7.85 (d, 2H).

13C-NMR (75 MHz, MeOD) : 146,78, 167,68, 168,15, 172,29 (the carbon amidinopropane and carbonyl).

Example 58

EtOOC-CH2-(R)Cgl-Aze-Pab 2HCl

(I) EtOOC-CH2-(R)Cgl-Aze-Pab (Z)

TfO-CH2-COOEt (0,208 g, 0,876 mmole) (see: getting parent compounds) dissolved in CH2Cl2and slowly added to cooled in a bath with ice mixture 0,443 mg (0,876 mmole) H-(R)Cgl-Aze-Pab (Z) (see example 1) and 0,931 mg (5,26 mmole) K2CO3in CH2Cl2(total 4 ml). After 2 h bath is removed and stirring is continued for 2 h Pori room temperature. After making additional amount of CH2Cl2the mixture is washed with water and brine, dried, filtered and evaporation of the solvent the mixture and diethyl ether-methanol(NH3-saturated.) (95:5). The result 0,387 g (75%) of the title compound.

(II) EtOOC-CH2-(R)Cgl-Aze-Pab 2HCl

EtOOC-CH2-(R)Cgl-Aze-Pab (Z) (395 mg, 0,668 mmole) hydronaut 5 h in the presence of 12 ml EtOH and 390 mg of 5% Pd-C. Removing the catalyst by filtration through cellit and militarily filter with subsequent evaporation of the solvent in vacuo and twice with subsequent evaporation of the solvent in vacuo and double freeze-drying obtain 281 mg (88%) EtOOC-CH2-(R)Cgl-Aze-Pab. After adding 1 N. HCl and three freeze-drying obtain 288 mg (81%) of the title compound.

1H-NMR (500 MHz, D2O) : of 1.05 to 1.48 (m, 8H), 1,6-2,05 (m, 6H), 2,15 is 2.33 (m, 1H), 2,58-and 2.79 (m, 1H), 3,89-4 (m, 3H), 4,2-to 4.33 (m, 3H), 4,33-of 4.44 (m, 1H), of 4.44-of 4.66 (m, 2H), 4,91 (m, 1H partially shielded H-O-D signal)), 7,54-7,63 (d, 2H), 7,72-to 7.84 (d, 2H).

Example 59

n-BuOOC-CH2-(R)Cgl-Aze-Pab HOAc

(I) n-BuOOC-CH2-(R)Cgl-Aze-Pab (Z)

Obtained by the method described for the synthesis of n-HexOOC-CH2-(R)Cgl-Aze-Pab (Z) (see example 60 (1)), using Tf-O-CH2-Coo-n-Bu as the alkylating agent. The crude product is purified twice column chromatography using as eluent first CH2Cl2-MeOH (95:1) and then a mixture of CH2Cl2-isopropyl alcohol (90:7). Received 324 mg (47%) supravaginal in example 57 (II). The crude product is purified OFGH using as eluent CH3CN in 0.05 M NH4OAc and 0.05 M HOAc. Obtained 100 mg (53%) of the title compound.

1H-NMR (300 MHz, MeOD) : 0,85-2,1 (m, 18H), 2,15-is 2.37 (m, 1H), 2,58-2,8 (m, 1H), 3.7 to 5 (m, 10H), 4,88-5 (partially shielded H-O-D signal)), 7,46-the 7.65 (d, 2H), 7,71-7,88 (d, 2H).

13C-NMR (75 MHz, MeOD) : 146,8, 168,12, 168,2, 172,2 (the carbon amidinopropane and carbonyl).

Example 60

n-HexOOC-CH2-(R)Cgl-Aze-Pab 2HCl

(I) n-HexOOC-CH2-(R)Cgl-Aze-Pab (Z)

TfO-CH2-COO-n-Hex (0,402 g 1,375 mmole) (see: getting parent compounds) dissolved in CH2Cl2and slowly added to a cooled to a temperature below -10oC mixture 0,695 g (1,375 mmole) H-(R)Cgl-Aze-Pab (Z) (see example 1) and 1,463 g (of 8.25 mmole) K2CO3in CH2Cl2(total 4 ml). After 1 h bath with dry ice is removed and stirring is continued for 45 minutes at room temperature. After making additional amount of CH2Cl2the mixture is washed with water and brine, dried, filtered and evaporation of the solvent in vacuo get 0.828 g of residue which is subjected to a double column chromatography using initially as eluent a mixture of diethyl ether-MeOH(NH3-saturated) (95:5) and then CH2Cl2-MeOH(NH
Hydrogenation of 400 mg (0,617 mmole) n-HexOOC-CH2-(R)Cgl-Aze-Pab (Z) in the presence of 12 ml of THF and 400 mg of Pd-C for 1.5 h does not fully release. The hydrogenation is completed within 4 h in the presence of 1.7 ml 1 N. HCl, 12 MeOH and 340 mg of Pd-C. Removing the catalyst by filtration through cellit and militarily filter with subsequent evaporation of the solvent in vacuo and double freeze-drying receive 287 mg (79%) of the title compound.

1H-NMR (300 MHz, MeOD) : 0,8-to 2.13 (m, 22H), 2,13-2,31 (m, 1H), 2,61-of 2.81 (m, 1H), 3,93-to 4.15 (m, 3H), 4,15-4,37 (m, 3H), 4,37-4,7 (m, 3H), 4,88-5 (m, 1H, partially shielded H-O-D signal)), 7,52-of 7.69 (d, 2H), 7,75 was 7.9 (d, 2H).

13C-NMR (75 MHz, MeOD) : 146,84, 167,67, 167,84, 172,17 (the carbon amidinopropane and carbonyl).

Example 61

H-(R)Cgl-Pro-Pac 2HCl

(I) Boc-(R)Cgl-Pro-Pac (Z)

To stir at 0oC the solution of 708 mg (1,95 mmole) Boc-(R)Cgl-Pro-OH (see: getting the initial connection), H-Pac(Z) 2HCl (see: getting parent compounds) and 1,078 g (8.8 mmole) of DMAP 12.5 ml of acetonitrile add 377 mg (of 1.87 mmole) of EDC. The reaction mixture is left overnight to warm to room temperature. The solvent is removed in vacuo and the residue purified first column chromatography using 10% methanol in methylene chloride as eluent and then AFGH. Will) Boc-(R)Cgl-Pro-Pac (Z) in 50 ml of ethyl acetate propulsive hydrogen chloride. After 15 minutes add 10% sodium carbonate solution, the organic phase separated and dried (K2CO3). Evaporation of the solvent give 71 mg (61%) of the target product.

(III) H-(R)Cgl-Pro-Pac 2HCl

A mixture of 71 mg (about 0.14 mmole) H-(R)Cgl-Pro-Pac (Z) and taken a small spatula 10% Pd-C in 10 ml of ethanol hydronaut 2 h at room temperature and atmospheric pressure. The catalyst was removed by filtration and the solvent evaporated in vacuum. The residue is dissolved in 50 ml of water and 0.6 g of 1 M hydrochloric acid. Freeze-drying obtain 38 mg (58%) of the title compound.

MS: m/z 392 (M + 1).

Example 62

HOOC-CH2-(R)Chal-Pro-Pac HOAc

(I) BnOOC-CH2-(R)Cha-Pro-Pac (Z)

A mixture of 84 mg (0.15 mmole) H-(R)Cha-Pro-Pac (Z) (see Example 53 (II)), one spatula of potassium carbonate and 47 mg Tf-OCH2COOBn (see: getting parent compounds) in 3 ml of methylene chloride is stirred for about a day at room temperature. The reaction mixture is filtered and removal of solvent in vacuo get the remainder, which is subjected to column chromatography using as eluent a mixture of ethyl acetate-methylene chloride-methanol (95:20:5). Selected 29 mg of the target product.

(II) HOOC-CH2-(R)Cgl-Pro-Pac HOAc

A mixture of 29 mg BnOOC-CH2-(R)Cgl-Pro-Pac (Z) and 37 mg of 10% of the RA with the subsequent removal of solvent and purification by the use of AFGH get the target connection.

MS: m/z 464 (M + 1).

Example 63

HOOC-CH2-CH2-(R)Cgl-Pro-Pac

(I) BnOOC-CH2-CH2-(R)Cgl-Pro-Pac (Z)

A solution of 0.35 g (of 0.64 mmole) H-(R)Cgl-Pro-Pac (Z) (see example 61 (11)), 124 mg (from 0.76 mmole) of benzoylacrylate and 280 μl (2 mmole) of triethylamine in 1 ml of ethanol incubated for 3 days at room temperature. Removal of solvent followed by purification using OFGH obtain 18 mg (4%) of the title compound.

(II) HOOC-CH2-CH2-(R)Cgl-Pro-Pac

A mixture of 18 mg of BnOOC-CH2-CH2-(R)Cgl-Pro-Pac (Z) and small spacelike 10% Pd-C hydronaut 2 h at room temperature and atmospheric pressure in EtOH. Filtration followed by removal of solvent in vacuo, dissolved in water and freeze-drying receive 7 mg (78%) of the title compound.

MS: m/z 464 (M + 1).

Example 64

HOOC-CH2-CH2-(R)Cha-Aze-Pac

(I) Boc-(R)Cha-Aze-Pac (Z)

A solution of 0.4 g (1,38 mmole) H-Pac (Z) (see: getting the parent compounds, the synthesis of H-Pac (Z) 2HCl), 0.5 g (1,41 mmole) Boc-(R)Cha-Aze-OH (see: getting parent compounds) and 0.67 g (5.5 mmole) of DMAP in 20 ml of acetonitrile is mixed at 0oC with a solution of 0.26 g (1.4 mmole) of EDC in 15 ml of acetonitrile. The reaction mixture is kept for about a day at room temperature and then the solvent by UAT and the combined organic phases are washed with a solution of sodium hydrosulphate, the sodium carbonate solution, brine and then dried (sodium sulfate). Evaporation of the solvent gain of 0.54 g (63%) of the title compound.

(II) H-(R)Cha-Aze-Pac (Z)

In a solution of 0.54 g (0.9 mmole) Boc-(R)Cha-Aze-Pac (Z) in ethyl acetate propulsive hydrogen chloride. The solution is stored overnight in the refrigerator, then the solvent is removed in vacuum and the residue is dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate, water, brine and dried (sodium sulfate). Removal of solvent obtain 0.35 g (77%) of the target product.

(III) BnOOC-CH2-CH2-(R)Cha-Aze-Pac (Z)

A solution of 180 mg (0,33 mmole) H-(R)Cha-Aze-Pac (Z) and 53 mg (0,33 mmole) of benzoylacrylate in ethanol incubated for 60 h at room temperature. The solvent is removed in vacuum and the residue is dissolved in ethyl acetate. The solution is washed with a solution of potassium hydrosulfate, sodium hydrogen carbonate solution and brine. Drying (sodium sulfate) and removal of solvent in vacuum to get the residue, which is purified column chromatography using as eluent 10% methanol in methylene chloride and receiving 150 mg (66%) of the title compound.

(IV) HOOC-CH2-CH2-(R)Cha-Aze-Pac 2HCl

A mixture of 115 mg BnOOC-CH2-CH2-(R)Cha-Aze-Pac (Z) and 67 mg of 10% Pd-C in 10 ml of athanassiades in vacuum and dissolve the residue in water and 1.5 ml of 1 M hydrochloric acid to obtain a solution, drying by freezing which give 30 mg (33%) of the title compound.

MS: m/z 464 (M + 1).

Example 65

HOOC-CH2-(R)Cha-Aze-Pig 2HCl

(I) Boc-(R)Cha-Aze-Pig (Z)

To the mixture 0,473 g (1,236 mmole) Boc-(R)Cha-Aze-OH (see: getting the initial connection), 0,404 g (1,236 mmole) H-Pig (Z) HCl (see: getting parent compounds) and 0,604 g (4,94 mmole) DMAP 13.5 ml of DMF was added when the temperature is below -15oC 0,249 g (1,298 mmole) of EDC. The mixture is left overnight to warm to room temperature. After evaporation of the solvent in vacuo, add EtOAc and 2 M KHSO4. The phases are separated and the organic phase is washed with a saturated solution of NaHCO3and brine. By repeating the procedure of extraction, drying (Na2SO4), filtration and evaporation of the solvent receive 0,612 g of residue, which was subjected to column chromatography using as eluent a mixture of EtOAc-MeOH (9:1). The result 407 mg (53%) of the title compound.

(II) H-(R)Cha-Aze-Pig (Z)

24.4 ml TFUC-CH2Cl2(1:4) dissolve 0.4 g (0,638 mmole) Boc-(R)Cha-Aze-Pig (Z), stirred for 30 minutes in a bath of ice and 30 minutes at room temperature. After removal of solvent in vacuo, add EtOAc and a saturated solution of Na2CO3. The phases are separated and organicheskoi 336 mg (100%) of the title compound.

(III) BnOOC-CH2-(R)Cha-Aze-Pig (Z)

It is heated to 60oC in the oil bath of the mixture 0,296 g (0,562 mmole) H-(R)Cha-Aze-Pig (Z) and 0,171 g (1,236 mmole) K2CO3in 6 ml of CH3CN slowly added 89 ml (0,562 mmole) of BnOOC-CH2Br. After 1 hour 45 minutes the solvent is evaporated, add EtOAc, the mixture was washed with water, dried (Na2SO4), filtered and evaporation of the solvent in vacuo get 346 mg of residue, which was subjected to column chromatography using a mixture of CH2Cl2-THF-MeOH (8:2:1) as eluent. The result is 297 mg (78%) of the title compound.

(IV) HOOC-CH2-(R)Cha-Aze-Pig 2HCl

BnOOC-CH2-(R)Cha-Aze-Pig (Z) (243 mg, of 0.36 mmole) hydronaut in the presence of 1.7 ml 1 N. HCl, 10 ml EtOH (99.5% pure) and 300 mg of Pd-C for 2 hours Removing the catalyst by filtration on celite and misopristol filter with subsequent evaporation of the solvent in vacuo and double freeze-drying obtain 186 mg (88%) of the title compound.

1H-NMR (500 MHz, D2O) : 0,6-1,9 (m, 18H), 2,1-of 2.27 (m, 1H), 2,62 was 2.76 (m, 1H), 2,82-3,2 (m, 4H), 3.46 in-3,61 (m, 1H), 3,61-3,81 (m, 2H), 3,81-4 (m, 2H), 4-4,24 (m, 3H), 4,24-4,4 (m, 1H).

Example 66

HOOC-CH2-(R)Cha-Pro-Pig 2HCl

(I) Boc-(R)Cha-Pro-Pig (Z)

To the mixture 0,3495 g (0.95 mmole) Boc-(R)Cha-Pro-OH (see: getting the initial connection), 0,464 g (3,8 mmol g (1 mmol) of EDC and the mixture is stirred for about a day at room temperature. The mixture is evaporated and the residue is dissolved in ethyl acetate. The organic phase is twice washed with 0.3 M KHSO4and again with brine. The organic layer is dried (Na2SO4), filtered and evaporated. Purification of the crude product using a stepwise gradient of CH2Cl2-MeOH(100:0, 97:3: 95:5, 90:10) as eluent obtain 307 mg of the title compound.

(II) H-(R)Cha-Pro-Pig (Z)

In 30 ml of saturated HCl in ethyl acetate was dissolved 0,306 g (0,408 mmole) Boc-(R)Cha-Pro-Pig (Z) and the mixture is left for half an hour. The solvent is evaporated and the residue dissolved in CH2Cl2. The organic layer is washed twice with 0.2 M NaOH. The combined aqueous layer was extracted with CH2Cl2and the combined organic layer is dried (Na2SO4), filtered and after evaporation obtain 257 mg (99%) of the title compound.

(III) BnOOC-CH2-(R)Cha-Pro-Pig (Z)

The mixture 0,256 g (0,473 mmole) H-(R)Cha-Pro-Pig (Z), 0,144 g (1,04 mmole) K2CO3and 82 μl (0,521 mmole) of benzylbromide in 6 ml of acetonitrile is stirred for two hours at 60oC. the Solvent is evaporated, the residue dissolved in CH2Cl2, washed with water and brine, dried (Na2SO4), filtered and the solvent evaporated. Purification of the crude product column chromatography using as e is th cleaning is performed on chromatotron (Harrison research, model T) using 2 mm plates with silicon dioxide and a mixture of CH2Cl2(95:5) and receiving 0,158 g (48%) of pure product.

(IV) HOOC-CH2-(R)Cha-Pro-Pig 2HCl

BnOOC-CH2-(R)Cha-Pro-Pig (Z) (0,158 g, 0,227 mmole) is mixed with 0.075 g of Pd-C (5%), 1 ml of 1 n HCl solution and 10 ml ethanol and the mixture hydronaut one hour at atmospheric pressure. Filtration of the catalyst through cellit and evaporation of the solvent followed two freeze-drying from water getting 119 mg (87%) of the target product.

1H-NMR (D2O, 300 MHz) : 0,95-of 1.44 (m, 7H), of 1.52 (m, 1H), 1,6-2,2 (m, 13H), 2,39 (m, 1H), 3,07-of 3.32 (m, 4H), 3,68 (m, 1H), of 3.77-was 4.02 (m, 5H; it 3,98 (s, 2H), of 4.44-4,58 (m, 2H).

13C-NMR (D2O, 75 MHz) : 156,5, 168,3, 169,6, 174,5 (the carbon of the carbonyl and guanidinium).

Example 67

HOOC-CH2-CH2-(R)Cha-Pro-Pig 2HCl

(I) BnOOC-CH2-CH2-(R)Cha-Pro-Pig (Z)

To a solution of 0,297 g (0.55 mmole) H-(R)Cha-Pro-Pig (Z) (see Example 66 (II)) in 2 ml ethanol add 90 µl (0,59 mmole) of benzoylacrylate and the reaction mixture was stirred for four days at room temperature. The solvent is evaporated and the crude product chromatografic on chromatotron (Harrison research, model T) using 2 mm plates with silicon dioxide and a stepped gradient of CH2Cl2-MeOH (95:5, 9Pig 2HCl

BnOOC-CH2-CH2-(R)Cha-Pro-Pig (Z) (0,238 g, 0,227 mmole) is mixed with 0.12 g of Pd-C (5%), 1.2 ml of 1 n HCl solution and 15 ml of ethanol and the mixture hydronaut one hour at atmospheric pressure. Filtration of the catalyst through cellit, evaporation of the solvent followed a two-drying from water getting 178 mg (95%) of the title compound.

1H-NMR (D2O, 300 MHz ) : 0,82-of 1.45 (m, 8H), 1,45-of 2.15 (m, 13H), to 2.29 (m, 1H), and 2.83 (t, 3H), 2,9-3,4 (m, 6H), 3,57 (sh. for, 1H), 3,67-a 3.87 (m, 3H), 4,25-4,43 (m, 2H).

13C-NMR (D2O, 75 MHz) 156, 3mm, 168,2, 174,3, 174,6 (the carbonyl carbon and guanidinium).

MS: m/z 479 (M + 1).

Example 68

(HOOC-CH2)2-(R)Cgl-Pro-Pig 2HCl

(BnOOC-CH2)2-(R)Cgl-Pro-Pig (Z)2(120 mg, 0,126 mmole) (see example 50 (III)) hydronaut in the presence of 0.75 ml of 1 N. HCl, 7 ml of EtOH (99.5% pure) and 150 mg of Pd-C for 4 hours Removing the catalyst by filtration on celite and misopristol filter and evaporation of the solvent in vacuum with subsequent freeze-drying obtain 66 mg (90%) of the title compound.

1H-NMR (500 MHz, D2O) : of 1.05 to 1.38 (m, 7H), 1,53-of 1.64 (d, 1H), 1,64 with 2.14 (m, 11H), 2,27-2,39 (m, 1H), 3,03 of 3.28 (m, 4H), to 3.58 to 3.7 (m, 1H), of 3.7-3.8 (m, 1H), 3,8-3,9 (d, 2H), 4,08-4,22 (m, 2H), 4,22 is 4.35 (m, 1H), of 4.38 to 4.5 (m, 1H).

13C-NMR (75 MHz, D2O) : 156,28, 166,73, 170,14, 174,01 (the carbon amidinopropane and carbonyl2)-(R)Cha-Pro-Pig (Z)

To a chilled (bath temperature with ice) mixture of 100 mg (about 0.14 mmole) of BnOOC-CH2-CH2-(R)Cha-Pro-Pig (Z) (see example 67 (I)) and 80 mg (0,21 mmole) of potassium carbonate in 4 ml of CH2Cl2carefully add the solution of 64 mg (0,21 mmole) TfO-CH2-COOBn in 1 ml of CH2Cl2. The reaction mixture is left for 30 minutes at 0oC, then leave for 2 hours to warm to room temperature and then boiled for 30 minutes and finally left overnight at room temperature. Evaporation of the solvent and subsequent column chromatography using CH2Cl2-MeOH (97:3) to obtain 65 mg (54%) of the title compound.

(II) HOOC-CH2-CH2-(HOOC-CH2)-(R)Cha-Pro-Pig 2HCl

In 10 ml of EtOH - 1 M HCl (9:1) dissolving 65 mg (0.08 mmole) of BnOOC-CH2-CH2-(BnOOC-CH2)-(R)Cha-Pro-Pig (Z) and hydronaut 3 h at atmospheric pressure over 10% Pd-C. Filtration of the catalyst, evaporation of the solvent, followed by drying by freezing of water get 40 mg (97%) of the title compound as a white powder.

13C-NMR (125 MHz, MeOD) : 157,5, of 167.2, 169,1 and 174,1 (carbon amidinopropane and carbonyl).

Example 70

HOOC-CH2-(R)Cgl-Aze-(R,S)Itp 2HCl

(I) Boc-(R)Cgl-Aze-(R,S)Itp (TS)

In 6 ml of CH3CN was dissolved 400 mg (1,17 mmole) Boc-(R)Cgl-Aze-OH and 286 mg (2,34 mmole) DMAP and cooled to -5oC. Add 236 mg (1,23 mmole) of EDC and the mixture was stirred for about a day at room temperature. After removal of CH3CN the residue is dissolved in MeOH-EtOAc-H2O. the Separated organic layer was washed with K2CO3(feast upon. ), 2 M KHSO4, brine and dried (Na2SO4). Evaporation of the solvent receive 688 mg (85%) of a white solid.

MS: m/z 620 (M++ 1).

(II) H-(R)Cgl-Aze-(R,S)Itp (TS)

In 50 ml of CH2Cl2dissolved 500 mg (0.8 mmole) Boc-(R)Cgl-Aze-(R,S)Itp (TS) and through the solution for approximately 4 min propulsive HCl (g). After 45 min the solvent is evaporated, the product dissolved in EtOAc-MeOH-H2O and acid solution is alkalinized with 2 M NaOH (aq.) to pH 8-9. The organic layer is separated and dried (Na2SO4). Evaporation of the solvent to obtain 425 mg (100%) of the title compound as a white solid.

MS: m/z 520 (M++ 1).

(III) BnOOC-CH2-(R)Cgl-Aze-(R,S)Itp (TS)

A mixture of 400 mg (0.77 mmole) H-(R)Cgl-Aze-(R,S)Itp(TS), 325 mg (0,92 mmole) benzyl-2-(p-nitrobenzenesulfonate)acetate (see: getting parent compounds) and 235 mg (1.7 mmole) K2CO3stirred in 5 ml of CH3CN at 45oC. After several hours the conversion is only 25%, so the rate is. actionnow the mixture is stirred for 48 h (initial connection: product 25:63) and then treated. After evaporation of the solvent to the residue add EtOAc-H2O. the Phases are separated, the aqueous phase is twice washed with EtOAc and the combined organic phase is washed then K2CO3(feast upon.), 2 M KHSO4, water and dried (Na2SO4). The result after back extraction of acid KHSO4about 340 mg of product, cleaning which OFGH obtain 34 mg (7%) of the title compound.

MS: m/z 668 (M++ 1).

(IV) HOOC-CH2-(R)Cgl-Aze-(R,S)Itp 2HCl

In 5 ml of THF was dissolved 34 mg (0.05 mmole) of BnOOC-CH2-(R)Cgl-Aze-(R,S)Itp (TS) and the reaction flask cooled with dry ice evaporated to 40 ml of NH3(g). Adding 11a appears dark blue color. The reaction mixture was stirred 5 min and then neutralized with 50 μl of HOAc. Cooling with dry ice, stopped and the mixture is left for evaporation of NH3(W). To the residue water is added and HOAc to pH 7. Freeze-drying and preparative OFGH get several factions that are analyzed by the method of the Belarusian library Association-MS. Two fractions containing the target compound obtained in an amount of 3 mg (10%) after freeze-drying with 2.2 equiv. 1 M HCl.

MS: m/z 424 (M++ 1).

Cha-Aze-(R,S)Itp(TS) (see topic: retrieving parent compounds), 155 mg (0,52 mmole) H-(R, S)Itp(TS) (see: getting the initial connection), 122 mg (1 mmol) and the solution cooled to 5oC. Add 115 mg (0.6 mmole) of EDC x HCI and the resulting mixture is stirred for about a day at room temperature. Then pay an additional amount (0.5 EQ.) H-(R,S)Itp(TS) and the EDC and the reaction mixture is stirred for another night, and then treated according to the method specified for the allocation of Boc-(R)Cgl-Aze-(R, S)Itp(TS) (see example 70). The result is 260 mg of crude product. Purification via OFGH receive 180 mg (57%) of the title compound.

MS: m/z 634 (M++ 1).

(II) H-(R)Cha-Aze-(R,S)Itp(TS)

In 20 ml of CH2Cl2dissolved 180 mg (0,28 mmole) Boc-(R)Cha-Aze-(R, S)Itp(TS) and a solution of approx. 4 min propulsive HCl (g). After 45 min the solvent is evaporated, the product dissolved in CH2Cl2and washed with 2 M NaOH to pH 8. The phases are separated, the organic phase is dried (Na2SO4and after evaporation obtain 163 mg (approx. 100%) of product.

MS: m/z 534 (M++ 1).

(III) BnOOC-CH2-(R)Cha-Aze-(R,S)Itp(TS)

A mixture of 80 mg (0.15 mmole) H-(R)Cha-Aze-(R,S)Itp(TS), 45 mg (0,33 mmole) K2CO3and Br-CH2-COOBn (39 mg, 0.17-mmole) in 1.5 ml of CH2CN stirred for 2.5 h at 60oC. Posim citric acid solution and dried (Na2SO4). Evaporation of the solvent to obtain 171 mg of the crude product, treatment of which with AFGH obtain 53 mg (52%) of the title compound.

MS: m/z 681 (M++ 1).

(IV) HOOC-CH2-(R)Cha-Aze-(R,S)Itp

BnOOC-CH2-(R)Cha-Aze-(R, S)Itp(TS) is treated according to the method of allocation of BnOOC-CH2-(R)Cgl-Aze-(R, S)Itp(TS) (see example 70 (IV)). As a result, the quality of the product is obtained mixture, which is cleaned by AFGH and receive 12 mg of a mixture (1:1) uppercase connection with its remedial form, giving m/z mass 439.

MS: m/z 438 (M++ 1).

Example 72

H-(R)Cha-Pic-(R,S)Itp 2HCl

(I) Boc-(R)Cha-Pic-(R,S)Itp(TS)

In 40 ml of acetonitrile is dissolved at room temperature, 2.1 g (5.5 mmole) Boc-(R)Cha-Pic-OH (see: getting parent compounds), 1 g (8.2 mmole) of DMAP and 1.7 g (5.8 mmole) H-(R,S)Itp(TS) (see: getting the initial connection). After several minutes of mixing, add 1.1 g (5.8 mmole) of EDC and the stirring is continued for 60 hours. The solvent is removed in vacuum, the residue is dissolved in CH2Cl2, washed with water, 0.3 M KHSO4and KHCO3(aq. ) and dried (Na2SO4). Evaporation of the solvent and filtration through silica gel get 2,43 g (67%) of the target product.

MS: m/z 661 (M++ 1).

3(g) and then add Na. After 5 min the reaction is stopped by adding acetic acid, then NH3and the THF evaporated. The residue is dried by freezing of water and after OFGH (CH3CN - 0.1 M NH4OAc, 6:4) receive 0,93 g (51%) of the target product.

MS: m/z 507 (M++ 1).

(III) H-(R)Cha-Pic-(R,S)Itp 2HCl

In ethyl acetate saturated with HCl (g), is dissolved at room temperature, 50 mg (0,099 mmole) Boc-(R)Cha-Pic-(R,S)Itp. After stirring 2 h, the solvent is removed in vacuum. Three freeze-drying of the residue from water obtain 35 mg (74%) of the target product.

MS: m/z 407 (M++ 1).

Example 73

HOOC-CH2-(R)Cha-Pic-(R,S)Itp 2HCl

(I) Boc-(R)Cha-Pic-(R,S)Itp(Z)

In 10 ml of CH2Cl2and 10 ml of 0.5 M NaOH is dissolved at room temperature 0.84 g (of 1.66 mmole) Boc-(R)Cha-Pic-(R,S)Itp (see example 72) and to the solution are added dropwise to 0.29 ml (average of 1.82 mmole) of Z-Cl. After stirring 3 h, the phases are separated, the organic phase is washed with water and dried over Na2SO4. Evaporation and column chromatography (ethyl acetate-heptane, 9:1) to obtain 0.5 g (47%) of the target product.

MS: m/z 641 (M++ 1).

(II) H-(R)Cha-Pic-(R,S)Itp(Z)

In a saturated HCl in ethyl acetate was dissolved at room temperature, 0.5 g (0,78 mmole) Boc-(R)Cha-Pic-(R,S)Itp(Z).

/SUB>Cl2and the organic phase is washed with water. The combined organic phase is dried over Na2SO4. Evaporation of the solvent to obtain 0.3 g (71%) of the target product.

MC: m/z 541 (M++ 1).

(III) BnOOC-CH2-(R)Cha-Pic-(R,S)Itp (Z)

In 25 ml of acetonitrile is transferred to 0.29 g (0.5 mmole) H-(R)Cha-Pic-(R, S)Itp(Z) and 0.15 g (1 mmol) of K2CO3and after adding 154 mg (0.6 mmole) of benzylbromide the mixture is stirred for 4 h at 50oC. Evaporation and OFGH (acetonitrile-0.1 M NH4OAc, 70:30) get about 200 mg of the target product.

(IV) HOOC-CH2-(R)Cha-Pic-(R,S)Itp 2HCl

To a solution of 200 mg BnOOC-CH2-(R)Cha-Pic-(R,S)Itp (Z) a small spoon, add 10% Pd on coal and the mixture hydronaut 4 hours Filtering through hyflo, evaporation of solvent, followed by drying by freezing of water get 53 mg of the target product.

1H-NMR (300,13 MHz, D2O) : 1-2,35 (overlapping m, 22H), 3,28-3,51 (m, 5H), 3,51-of 2.64 (m, 1H), 3.75 to a 4.03 (m, 3H), 5,03-5,14 (sh. s, 1H), Signal one of the protons partially shielded H-O-D-signal.

MS: m/z 465 (M++ 1).

Example 74

H-(R)Cgl-Pro-(R,S)Hig 2HCl

(I) Boc-(R)Cgl-Pro-(R,S)Hig(Z)

To a mixture of 1 g (2,95 mmole) Boc-(R)Cgl-Pro-OH (see: getting the initial connection), 1.44 g (11.8 mmole) of DMAP and 1.12 g (3.25 mmole) H-(R, S)Hig(Z) (see rastimer day at room temperature. After evaporation of the solvent the residue is dissolved in ethyl acetate. Two washing of the organic layer 0.3 M solution of KHSO4organic layer is allocated oil. An ethyl acetate layer is dried (Na2SO4) and filtered. The oil and the aqueous layer was extracted with CH2Cl2. The organic layer is dried (Na2SO4), filtered and unite previously received an ethyl acetate phase. Evaporation and purification of the crude product on chromatotron (Harrison research, model T) using 2 mm plates with silicon dioxide and a stepped gradient of CH2Cl2-MeOH(97: 3, 95:5, 90:10) as eluent obtain 1.1 g (59%) of the title compound.

(II) H-(R)Cgl-Pro-(R,S)Hig 2HCl

In 50 ml of ethyl acetate saturated with HCl, dissolved 81 mg (0,13 mmole) Boc-(R)Cgl-Pro-(R, S)Hig(Z). The mixture is left for one hour, evaporated and the residue is dissolved in 10 ml of ethanol. Add 40 mg of Pd-C (5%), 1 ml of water and 0.5 ml of 1 M HCl solution and the mixture hydronaut about days at atmospheric pressure. Filtration of the catalyst through cellit and evaporation of the solvent followed three freeze-drying from water with a yield of 75% get the title compound.

1H-NMR (D2O, 300 MHz) : 0,95-of 1.35 (m, 5H), 1,5-of 2.45 (m, 15H), to 3.02 (sh. t, 1H), 3,1-3,8 (m, 7H), 4,13 (d, 1H), to 4.38 (sh. The example 75

HOOC-CH2-(R)Cgl-Pro-(R,S)Hig 2HCl

(I) H-(R)Cgl-Pro-(R,S)Hig(Z)

In 100 ml of ethyl acetate saturated with HCl, dissolve 1 g (1.6 mmole) Boc-(R)Cgl-Pro-(R, S)Hig(Z) (see example 72 (I)), and the mixture is left for one hour. The mixture is then evaporated and the residue dissolved in CH2Cl2. The organic layer is washed twice with 0.2 M NaOH solution, dried (Na2SO4), filtered and after evaporation receive 0,825 g (98%) of the title compound.

(II) BnOOC-CH2-(R)Cgl-Pro-(R,S)Hig(Z)

In 12 ml of THF is mixed 0,442 g (0,839 mmole) H-(R)Cgl-Pro-(R,S)Hig(Z), 0,256 g (of 1.85 mmole) K2CO3and 145 μl (0,521 mmole) of benzylbromide and the mixture is stirred for one hour at 40oC and about a day at room temperature. After evaporation of the solvent the residue is dissolved in CH2Cl2and washed with water and brine. The organic layer is dried (Na2-SO4), filtered and evaporated. The crude product is purified on chromatotron (Harrison research, model T) using 2 mm plates with silicon dioxide and a stepped gradient of CH2Cl2-MeOH(97:3, 95:5, 90:10) as eluent and receiving 0,165 g (29%) of the title compound).

(III) HOOC-CH2-(R)Cgl-Pro-(R,S)Hig 2HCl

The mixture 0,165 g (0.25 mmole) of BnOOC-CH2-(R)Cgl-Pro-(R,S)Hig(Z), 0.05 g of Pd-C (5%), 0.7 ml of 1M HCl solution and 10 ml ethanol hydronaut four cha is th double freeze-drying from water get 0.1 g (75%) of the target product.

1H-NMR (D2O, 300 MHz) : of 1.05 to 1.45 (m, 5H), 1,55-2,5 (m, 15H), is 3.08 (sh. t, 1H), 3,2-of 5.05 (m, 9H), 4,3 (d, 1H), of 4.44 (m, 1H).

13C-NMR (D2O, 75 MHz) : 154,9, 167,2, 169,4, 174,1 (the carbon of the carbonyl and guanidinium).

Example 76

H-(R)Cha-Pro-(R,S)Hig 2HCl

(I) Boc-(R)Cha-Pro-(R,S)Hig(Z)

To 0,72 g (1,95 mmole) Boc-(R)Cha-Pro-OH (see: getting the initial connection), 0.95 g (of 7.8 mmole) of DMAP, 0.74 g (2,14 mmole, 82% purity) H-(R, S)Hig(Z) (see: getting parent compounds) in 10 ml of CH2Cl2add 0,486 g (of 2.54 mmole) of EDC and the mixture is stirred for 3 days at room temperature. After dilution of the mixture of CH2Cl2it is washed with water, twice with 0.3 M KHSO4and brine. The organic layer is dried (Na2SO4), filtered, evaporated and the crude product is purified column chromatography using CH2Cl2-MeOH (95:5) to obtain 0.45 g (33%) of the target product.

(II) H-(R)Cha-Pro-(R,S)Hig 2HCl

In 20 ml of ethyl acetate saturated with HCl, dissolve 50 mg (0,078 mmole) Boc-(R)Cha-Pro-(R, S)Hig(Z). The mixture is left for one hour, evaporated and the residue is dissolved in 10 ml of ethanol. Add 20 mg of Pd-C (5%) and 0.3 ml of 1 M HCl solution and the mixture hydronaut two hours at atmospheric pressure. Filtration of the catalyst through cellit and evaporation of the solvent followed a two-drying 6 (m, 6H), 1,6-2,5 (m, 16H), to 3.09 (t, 1H), and 3.31 (t, 1H), 3,37-3,74 (m, 4H), 3,81 (m, 1H), 4,35-4,47 (m, 2H).

13C-NMR (D2O, 75 MHz) : 154,9, 169,8, of 174.5 (the carbonyl carbon and guanidinium).

Example 77

H-(R)Cgl-Aze-Rig 2HCl

(I) Boc-(R)Cgl-Aze-Rig(Z)

To a solution of 0.5 g (1.6 mmole) H-Rig(Z) (see: getting the initial connection), 0,59 g (1.6 mmole) Boc-(R)Cha-Aze-OH (see: getting parent compounds) and 0.84 g (6.9 mmole) of dimethylaminopyridine in 30 ml of acetonitrile and 5 ml of dimethylformamide added 0.33 g (1.7 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. The reaction mixture is stirred for 3 days, then evaporated between an aqueous solution of potassium hydrosulfate and methylene chloride. The layer of methylene chloride was washed with aqueous sodium bicarbonate solution and water, dried (Na2SO4) and evaporated. Filtration of the crude product with suction through a layer of silica gel with a mixture of methylene chloride-methanol (9: 1) obtained after evaporation 0,78 g (76%) of target compound.

1H-NMR (300 MHz, CDCl3) : 0,8-1,9 (m, 27H), 2,4-2,6 (m, 2H), 2,78 (sh. t, 2H), 3,15-3,4 (m, 2H), 3,8 (sh. t, 1H), 4-4,4 (m, 4H), 4,76 (sh. t, 1H), equal to 4.97 (sh. d, 1H), to 5.08 (s, 2H), and 7.1 to 7.4 (m, 7H), 7,74 (W., 1H).

(II) H-(R)Cgl-Aze-Rig(Z) 2HCl

The flask containing 0,76 g (1.2 mmole) Boc-(R)Cgl-Aze-Rig(Z) in 50 ml of ethyl acetate, cooled in a bath of ice. Samples of the of hydrochloride.

1H-NMR (300 MHz, MeOD) : 1,1-2 (m, 18H), of 2.23 (m, 1H), 2,68 (m, 1H), 3.15 and is-3.45 (m, 4H), 3.72 points III. d, 1H), 3.9 to 4 (Sch. d, 1H), 4,27 (m, 1H), 4,39 (m, 1H), 4,78 (m, 1H), 5,3 (s, 2H), 7.3 to 7.5 (m, 5H).

(III) H-(R)Cgl-Aze-Rig 2HCl

A solution of 20 mg of H-(R)Cgl-Aze-Rig(Z) and a small amount of 5% Pd-C hydronaut in the flask 1 h at atmospheric pressure. The mixture is filtered through cellit and evaporated. The lyophilization of the residue by adding a few drops of conc. receive 8 mg (52%) of the target product.

1H-NMR (300 MHz, D2O) : 1,1-2 (m, 18H), is 2.37 (m, 1H), 2,75 (m, 1H), is 3.08 (sh. t, 2H), 3,39 (sh. t, 2H), 3.8 to 4 (m, 3H), 4,35 to 4.5 (m, 2H), 4,9 (m, 1H).

13C-NMR (75.5 MHz, D2O) : 172,2, 169,4, 156, 4mm (carbon guanidinium and carbonyl).

Example 78

HOOC-CH2-(R)Cgl-Aze-Rig 2HCl

(I) BnOOC-CH2-(R)Cgl-Aze-Rig(Z)

A mixture of 0.2 g (0,33 mmole) H-(R)Cgl-Aze-Rig(Z) (see example 77), of 0.13 g of potassium carbonate, 80 mg of sodium iodide, 10 ml of tetrahydrofuran and 10 ml of acetonitrile is heated for 10 h at 60oC. the Solvent is evaporated and the crude product subjected to column chromatography using as eluent a mixture of methylene chloride-methanol (92:8). The output of 0.13 (58%).

1H-NMR (300 MHz, CDCl3) : 0,9-2,1 (m, 18H), a 2.45 (m, 1H), 2,61 (m, 1H), 2,81 (m, 2H), 2,88 (d, 1H), 3,2-3,5 (m, 4H), of 3.94 (m, 1H), 4-4,25 (m, 3H), around 4.85 (m, 1H), 5,12 (s, 2H), 5,14 (s, 2H), 6,9-7,2 (W., 2H), 7,2-7,5 (m, 10H), to 7.95 (m, 1H).

(II) HOOC-CH2-(R)Cg Is 5% Pd-C hydronaut 1 h at atmospheric pressure. The mixture is filtered through cellit and evaporated. The lyophilization of the residue in water to obtain 91 mg (98%) of the target product.

1H-NMR (500 MHz, D2O) : 1,1-1,9 (m, 17H), 2 (m, 1H), to 2.29 (m, 1H), and 2.7 (m, 1H), 3,1 (m, 2H), 3,34 (t, 2H), 3,83 (sh. d, 2H), with 3.89 (DD, 2H), 4 (d, 1H), 4,35 (m, 2H), 4,87 (m, 1H).

13C-NMR (for 125.8 MHz, D2O) : 171,8, 169,6, 167,7, 156,3 (carbon guanidino group and carbonyl).

Example 79

HOOC-CH2-(R)Cha-Pro-Rig(Z)

(I) Boc-(R)Cha-Pro-Rig(Z)

To a solution of 0.25 g (of 0.82 mmole) of 4-amino-ethyl-1-benzyloxycarbonylamino (H-Rig(Z)) (see: getting the initial connection), 0.32 g (of 0.82 mmole) Boc-(R)Cha-Pro-OH (see: getting parent compounds) and dimethylaminopyridine (0.4 g, 3.3 mmole) in 10 ml of acetonitrile and 2 ml of dimethylformamide add the hydrochloride of N-(dimethylaminopropyl)-N'-ethylcarbodiimide (0,165 g 0,86 mmole). The reaction mixture is stirred for 3 days, then evaporated and partitioned between aqueous solution of the potassium hydrosulfate and methylene chloride. The layer of methylene chloride was washed with aqueous sodium bicarbonate solution and water, dried (Na2SO4) and evaporated. The NMR spectrum of the crude product was satisfactory and the product containing a certain amount of dimethylformamide used in the next stage without additional purification.

(II) H-(R)Cha-Pro-Rig(Z)

The flask containing the crude Boc-(R)Cha-Pro-Rig(Z) in 100 ml of ethyl acetate, cooled in a bath of ice. Through the solution for 5 min propulsive dry HCl to remove excess HCl, the solution is evaporated. The residue is dissolved in water and to remove remaining from the previous stage of the dimethylformamide solution was extracted twice with ethyl acetate. The aqueous phase is alkalinized NaHCO3and twice extracted with methylene chloride. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. The output of the two stages of 0.37 g (81%).

1H-NMR (300 MHz, CDCl3) : 0,8-2,4 (m, 24H), 2,82 (sh. t, 2H), 3,26 (m, 2H), 3,42 (sh.K. 1H), and 3.7 (m, 2H), 4,19 (m, 2H), 4,49 (sh. d, 1H), 5,11 (s, 2H), and 6.9-7.5 (m, 8H).

(III) BnOOC-CH2-(R)Cha-Pro-Rig(Z)

A mixture of 0.18 g (0,32 mmole) H-(R)Cha-Pro-Rig(Z), an excess of potassium carbonate and 10 ml of acetonitrile is heated for 2 hours at 60oC. the Solvent is evaporated and the crude product chromatografic on a column of silica gel using as eluent a mixture of methylene chloride-methanol (95:5). Yield 0.2 g (88%).

1H-NMR (300 MHz, CDCl3) : 0,8-2,1 (m, 23H), is 2.37 (m, 1H), 3,1-3,5 (m, 7H), 4-4,2 (m, 2H), 4,54 (m, 1H), 5,1 (m, 4H), of 6.9-7.5 (m, 13H).

(IV) HOOC-CH2-(R)Cha-Pro-Rig 2HCl

A mixture of 0.15 g (0,21 IMO the second pressure. The mixture is filtered through cellit and evaporated. The lyophilization of the residue in water get 95% of mg (64%) of the target product.

1H-NMR (500 MHz, MeOD) : 0,85-2,1 (m, 23H), 2,3 (m, 1H), 3,1 (m, 2H), 3,25 (m, 1H), 3,35 (m, 1H), 3,54 (m, 1H), 3,85-4 (m, 3H), a 4.03 (d, 1H), to 4.41 (m, 1H), and 4.5 (m, 1H).

13C-NMR (for 125.8 MHz, D2O) : 174, 168,9, 168,1, 157,5 (the carbon guanidinium and carbonyl).

Example 80

HOOC-CH2-CH2-(R)Cha-Aze-Rig 2HCl

(I) Boc-(R)Cha-Aze-Rig(Z)

To a solution of 0.25 g (of 0.82 mmole) of 4-amino-ethyl-1-benzyloxycarbonylamino (H-Rig(Z)) (see: getting the initial connection), 0.31 g (0,86 mmole) Boc-(R)Cha-Aze-OH (see: getting the initial connection), 0.4 g (3.3 mmole) of dimethylaminopyridine in 10 ml of acetonitrile and 2 ml of dimethylformamide added 0.17 g (0,86 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. The reaction mixture is stirred for 3 days, then evaporated and partitioned between aqueous solution of the potassium hydrosulfate and methylene chloride. The layer of methylene chloride was washed with aqueous sodium bicarbonate solution and water, dried (Na2SO4) and evaporated. The crude product containing some amount of dimethylformamide, is used in the next stage without additional purification.

1H-NMR (500 MHz, CDCl3) : 0,85 (m, 1H), 0,97 (m, 7 (m, 1H), 5,09 (s, 2H), and 7.1 to 7.4 (m, 7H), the 7.65 (m, 1H).

(II) H-(R)Cha-Aze-Rig(Z)

The flask containing the crude Boc-(R)Cha-Aze-Rig(Z) in 100 ml of ethyl acetate, cooled in a bath of ice. Through the solution for 5 min propulsive dry HCl to remove excess HCl, the solution is evaporated. The residue is dissolved in water and to remove remaining from the previous stage of dimethylformamide extracted twice with ethyl acetate. The aqueous phase is alkalinized NaHCO3(aq.) and twice extracted with methylene chloride. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. The output of the two stages of 0.31 g (70%).

1H-NMR (300 MHz, CDCl3) : 0,8-1,9 (m, 20H), 2,48 (m, 1H), 2,73 (m, 1H), 2,85 (sh. t, 2H), 3,25 (m, 1H), 3,35 (m, 2H), 4,05 (K, 1H), 4,1-of 4.25 (m, 3H), a 4.86 (m, 1H), 5,12 (s, 2H), 6,9-7,2 (m, 2H), 7,2 was 7.45 (m, 5H), to 7.93 (m, 1H).

(III) BnOOC-CH2-CH2-(R)Cha-Aze-Rig(Z)

A solution of 0.31 g (0.57 mmole) H-(R)Cha-Aze-Rig(Z) and 93 mg (0.57 mmole) of benzoylacrylate in 5 ml of ethanol is left for one week at room temperature. The solution is evaporated and the residue chromatographic on a column of silica gel using as eluent a mixture of methylene chloride-methanol (94:6). Yield 0.2 g (49%).

1H-NMR (500 MHz, CDCl3) : 0,8-1 (m, 2H), 1,1-1,8 (m, 18H), 2,48 (m, 1H), 2,54 (sh. t, 2H), 2,68 (m, 2H), 2,81 (sh. t, 2H), 2,87 (m, 1H), 3,2 (m, 1H), 3,25 (m, 1H), and 3.31 (m, 1H), 4.04 the (K, 1H), 4,1 to 4, the unity obtained and purified from 0.2 g (of 0.28 mmole) of BnOOC-CH2-CH2-(R)Cha-Aze-Rig(Z) using the procedure described in example 80. Output dihydrochloride 30 mg (19%).

1H-NMR (500 MHz, CDCl3) : 1-1,9 (m, 20H), 2,33 (m, 1H), and 2.7 (m, 1H), and 2.83 (m, 2H), 3,1 (m, 2H), 3,3-3,4 (m, 4H), 3,85 (sh. d, 2H), 3,92 (m, rotamer), 4,14 (t, 1H), 4,17 (m, rotamer), or 4.31 (m, 1H), 4,46 (m, 1H), 4,89 (m, 1H), 5,18 (m, rotamer).

13C-NMR (for 125.8 MHz, D2O) : 175,4, 171,8, 168,8, 156,3 (the carbon guanidinium and carbonyl).

Example 81

HOOC-CH2-(R)Cha-Pro-(S)Itp 2HCl

(I) Boc-(R)Cha-Pro-(S)Itp(TS)

In 12 ml of acetonitrile was dissolved at room temperature 0.87 g (a 2.36 mmole) Boc-(R)Cha-Pro-OH (see: getting the initial connection), 0,78 g (4,72 mmole) DMAP and 0.7 g (a 2.36 mmole) H-(S)Itp(TS) (see: getting the initial connection). After stirring for 20 minutes add 0,59 g (of 3.07 mmole) of EDC. After 18 hours the solvent is removed in vacuum, the residue is dissolved in CH2Cl2, washed with water, 10% citric acid solution, KHCO3(aq. water and dried over Na2SO4. Evaporation gives 1,74 g (>100%, purity 60%) of the desired product, which is used in the next stage without additional purification.

The Belarusian library Association-MS: m/z 647 (M++ 1).

(II) H-(R)Cha-Pro-(S)Itp(TS)

The removal of the Boc protective group according to the method described for Boc-(R)Cha-Pic-(R, S)Itp(Z) (see example 72 (II)), p(S)Itp(TS)

In 15 ml of acetonitrile carry 0.75 g (1,37 mmole) H-(R)Cha-Pro-(S)Itp(TS) and 0.38 g (2,74 mmole) K2CO3. After addition of 0.39 g (1.65 mmole) of benzylbromide the mixture is stirred for 2 h at 50oC. Evaporation of the solvent and subsequent column chromatography using as eluent a mixture of ethyl acetate-methanol (95:5) receive about 530 mg of the target product.

The Belarusian library Association-MS: m/z 695 (M++ 1).

(IV) HOOC-CH2-(R)Cha-Pro-(S)Itp 2HCl

In 15 ml of THF is dissolved 0,53 g (0,76 mmole) of BnOOC-CH2-(R)Cha-Pro-(S)Itp(TS). In the reaction flask condense NH3(g) and add Na. After 30 min the reaction is stopped by adding acetic acid, then NH3and the THF evaporated. The residue is dried by freezing of water and purification of the crude product using OFGH (acetonitrile-0.1 M HOAc) are obtained after freeze-drying from aqueous HCl 0.25 g (61%) of the target product.

1H-NMR (500,13 MHz, D2O) : 0,9-2,09 (overlapping m, 20H), 2,22 to 2.35 (m, 1H), 3,2-to 3.36 (m, 4H), 3,44-3,62 (overlapping m, 2H), of 3.7-3.8 (m, 1H), a 3.87-to 3.99 (m, 2H), 4,33-4,48 (overlapping m, 2H).

13C-NMR (500,13 MHz, D2O) : 154,3, 168,1, 169 and 174,2 (the carbonyl carbon and guanidinium).

Example 82

H-(R)Cha-Pro-(R,S)Nig 2HCl

(I) Boc-(R)Cha-Pro-(R,S)Nig(Z)

In 2 ml of CH2Cl2mix 174 mg (is. topic: retrieving parent compounds) and after adding 117 mg (0,61 mmole) of EDC mixture is stirred for four days. The mixture was diluted with CH2Cl2and washed with water, twice with 0.3 m solution of KHSO4and brine. The organic layer is dried (Na2SO4), filtered, evaporated and the crude product is purified twice column chromatography using for the first time as eluent CH2Cl2-MeOH (95:5) and the second time - CH2Cl2-MeOH (97:3) to give 0.104 g g (35%) of the title compound.

MS: m/z 627 (M++ 1).

(II) H-(R)Cha-Pro-(R,S)Nig 2HCl

In 15 ml of ethyl acetate saturated with HCl, dissolve 10 mg (0.016 mmole) Boc-(R)Cha-Pro-(R, S)Nig(Z) and the mixture is left for half an hour. The mixture is evaporated, the residue is dissolved in 6 ml of ethanol, add 8 mg of 5% Pd-C and 0.1 ml of 1 M HCl solution and the mixture hydronaut half hour at atmospheric pressure. After filtration through hyflo and evaporation of the solvent receive 4 mg of the title compound.

1H-NMR (300 MHz, D2O) : 0,9 is 1.58 (m, 6H), 1,58 at 2.45 (m, 13H), to 2.65 (m, 1H), 3,19 (m, 1H), 3,34 (d, 1H), 3,4-of 3.73 (m, 4H), 3,82 (m, 1H), 3,34 figure-4.49 (m, 2H).

13C-NMR (75 MHz, D2O : 155, 1mm, 169,9 and 174,8 (the carbonyl carbon and guanidinium).

Example 83

H-(R)Pro-Phe-Pab 2HCl

(I) Boc-(R)Pro-Phe-Pab(Z)

To a mixture of 1.2 g (3,31 mmole) is based temperature 0,98 g (3,35 mmole) H-Pab(Z) (see topic: retrieving parent compounds) dissolved in 1 ml DMF. After stirring 2 h, the reaction mixture was cooled to -18oC add 0.66 g (3,48 mmole) of EDC portions and the reaction mixture is left for about a day at room temperature. The solvent is evaporated, the residue is dissolved in 100 ml EtOAc and washed with 30 ml of water, 0.3 M KHSO4(3 x 30 ml), 30 ml of Na2CO330 ml of water and dried. Evaporation of the solvent and subsequent column chromatography using as eluent CH2Cl2-MeOH (95: 5) receive 0,691 g (38%) of the title compound.

(I) H-(R)Pro-Phe-Pab(Z)

In 30 ml of ethyl acetate is dissolved 0,673 g of Boc-(R)Pro-Phe-Pab(Z) and the solution saturated with HCl (g) for a few minutes (from a solution of saliva). The solvent and excess HCl is evaporated, to the residue add 60 ml of EtOAc and the organic phase is washed with 2 M NaOH (2 x 20 ml). The washing water is extracted with EtOAc, the extract attach to another EtOAc phase, the combined organic phase washed with water, dried and after evaporation obtain 560 mg (98%) of the target product.

1H-NMR (500 MHz, CDCl3) : 1,5-of 1.74 (m, 3H), 1,98-2,05 (m, 1H), 2,78-to 2.85 (m, 1H), 2,9-2,96 (m, 1H), 3-3,2 (ABX-system with center at 3,1, 2H), 3,62 (DD, 1H), 4,3-4,45 (ABX-system with center at 4.37, 2H), 4,58 (K, 1H), 5,22 (s, 2H), of 6.96 (sh. t, 1H), and 7.1 to 7.4 (m, 10H), 7,46 (t, 2H is hydronaut 5 hours over 5% Pd-C at atmospheric pressure. Filtration of the catalyst and the addition of 1 ml of 1 M HCl followed by evaporation and freeze-drying from water with the release of 88% receive the title compound.

1H-NMR (500 MHz, CD3OD) : 1,51-to 1.59 (m, 1H), 1,69-1,8 (m, 1H), 1,87-of 1.97 (m, 1H), 2,19-to 2.29 (m, 1H), 2,9 (DD, 1H), 3,2-to 3.33 (m, 3H, partially screened by the solvent peak), 4,27 (m, 1H), 4,43-of 4.54 (AB-system with center at 4,48, 2H), 4.75 V-to 4.81 (m, 1H), to 4.87 (s, 2H), a 7.2 to 7.3 (m, 5H), was 7.45 (d, 2H), of 7.75 (d, 2H).

13C-NMR (125 MHz, D2O) : 166,7, USD 170.1 and 173,4 (carbon amidinopropane and carbonyl).

Example 84

HOOC-CH2-(R)Pro-Phe-Pab 2HCl

(I) BnOOC-CH2-(R)Pro-Phe-Pab(Z)

To a suspension of 244 mg (0,463 mmole) H-(R)Pro-Phe-Pab(Z) (see example 83) and 159,9 mg (1,157 mmole) K2CO3in 8 ml of DMF-CH3CN (5:3) add to 127.2 mg (0,555 mmole) of benzylbromide in 2 ml of DMF and the mixture is stirred for 1.5 h at 60oC and about a day at room temperature. The solvent is evaporated, the residue is dissolved in 50 ml of EtOAc, washed with water (2 x 20 ml) and dried (Na2SO4). Evaporation of the solvent and subsequent column chromatography using CH2Cl2-MeOH (9: 1) as eluent obtain 176 mg (56%) of the title compound.

1H-NMR (300 MHz, CDCl3) : of 1.45 to 1.8 (m, 3H), of 2.06 (m, 1H), 2,54 (m, 1H), 2,92 of 3.28 (m, 6H), 4,3-4,5 (ABX-system with center at 4,4, 2H),Pro-Phe-Pab 2HCl

In 12 ml of EtOH-water (5: 1) was dissolved 170 mg (0,252 mmole) of BnOOC-CH2-(R)Pro-Phe-Pab(Z) and hydronaut 4.5 hours over 5% Pd-C at atmospheric pressure. The catalyst is filtered off, the solvent evaporated and the dried residue freezing of HCl in water.) get the title compound.

1H-NMR (500 MHz, CD3OD) : of 1.62 (m, 1H), equal to 1.82 (m, 1H), 2,08 (m, 1H), of 2.38 (m, 1H), 2,9 (DD, 1H), of 3.25 to 3.35 (m, 2H, partially screened by the solvent peak), and 3.8 (m, 1H), 4,08-4,19 (AB-system with center at 4,19, 2H), 4,39 (m, 1H), 4,45-4,58 (AB-system with center at 4.5, 2H), and 4.8 (m, 1H), a 7.2 to 7.35 (m, 5H), was 7.45 (d, 2H), of 7.75 (d, 2H).

13C-NMR (125 MHz, D2O) : 166,8, 169,1, 169, 5mm and 173,2 (carbon amidinopropane and carbonyl).

Example 85

H-(R)Phe-Phe-Pab

(I) Boc-(R)Phe-Phe-Pab(Z)

In 50 ml of acetonitrile is dissolved Boc-(R)Phe-Phe-OH (to 16.4 mmole) (see: getting the initial connection), Pab(Z)-HCl (18 mmol) and 4-dimethylaminopyridine (24,6 mmole). After cooling the solution to a temperature of cold water add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (21.3 mmole). The cooling bath removed and the reaction mixture is stirred for about a day. The solvent is then removed under reduced pressure, the residue is dissolved in 50 ml of ethyl acetate and the resulting solution was washed with 50 ml of water. Usageprice of the two-phase mixture of Boc-(R)Phe-Phe-Pab(Z) otfit 1
H-NMR (200 MHz, d-CHCl3and d4-CH3OH) : 8,35-7 (m, 18H), 4,63 (t, 1H), from 4.3 to 4.1 (m, 1H), 3,4-2,7 (m, 6H) and 1.3 (s, 9H).

(II) H-(R)Phe-Phe-Pab(Z)

To a suspension of Boc-(R)Phe-Phe-Pab(Z) (10.3 mmole) added 31 ml of 3.3 M HCl in ethyl acetate. The suspension is stirred for 4 h, after which the hydrochloride H-(R)Phe-Phe-Pab(Z) is filtered and washed with several portions of ethyl acetate. Salt dissolved in a mixture of 50 ml of methylene chloride, 50 ml of 1 M potassium carbonate solution and approx. 5 ml of ethanol. The organic layer is separated and removal of solvent under reduced pressure to obtain 5 g (84%) H-(R)Phe-Phe-Pab(Z).

1H-NMR (200 MHz, d6-DMSO) : 9,1 (s, 2H), 8,59 (m, 1H), 8,1 (m, 1H), 7,9 (d, 2H), 7,4-7 (m, 17H), 5,09 (s, 2H), 4,58 (m, 1H), or 4.31 (m, 2H), 3,1-to 2.7 (m, 4H).

(III) In 10 ml of tetrahydrofuran and 1 ml of water is dissolved H-(R)Phe-Phe-Pab(Z). Add palladium on coal (42 mg) and the mixture hydronaut 2 days in a shaking Parra under hydrogen pressure of 45 psi (3.2 kg/cm2). After hydrogenolysis mixture is diluted with methanol and the catalyst is filtered off. Evaporation of the solvent to obtain crude H-(R)Phe-Phe-Pab, which is purified by chromatography on neutral alumina (70-230 mesh) by elution with a mixture of methylene chloride-methanol-ammonium hydroxide (80:20:2). Yield the title compound 76 mg (41%).

1H-NMR (200 MHz, d6-Phe-Phe-Pab(Z)

In 10 ml of tetrahydrofuran is dissolved H-(R)Phe-Phe-Pab(Z) (0,87 mmole) (see example 85 (II). The solution is cooled in a bath of ice and added triethylamine (1,73 mmole) and then methyloxirane (0.95 mmole). The cooling bath is removed and the reaction mixture was stirred 18 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase is separated and removal of solvent under reduced pressure to obtain 0.45 g (78%) MeOOC-CO-(R)Phe-Phe-Pab(Z), which is used in the next stage without additional purification. TSP-MS: found m/z 664 (calculated for MH+(C37H38N5O7) 664).

(II) HOOC-CO-(R)Phe-Phe-Pab(Z)

In 4 ml of tetrahydrofuran and 2 ml of water is dissolved MeOOC-CO-(R)Phe-Phe-Pab(Z) (of 0.68 mmol), the solution was added lithium hydroxide (2.6 mmole) and the reaction mixture was stirred 1.5 h at room temperature. At the end of the hydrolysis reaction mixture is diluted with 25 ml of water and acidified by the addition of 0.5 ml of acetic acid. The precipitate is filtered off and washed with several portions of water and drying in vacuum for 24 h at 45oC obtain 0.4 g of crude HOOC-CO-(R)Phe-Phe-Pab(Z) form a suspension of the crude product in 10 ml of ethanol and 1 ml of water, which is brought to boiling, and filtering the insoluble capital soy), to 8.41 (d, 1H), 7,89 (d, 2H), 7,4-6,9 (m, 17H), a 5.1 (s, 2H), 4,54 (m, 2H), 4,34 (m, 2H), 3,2 to 2.6 (m, 4H).

(III) HOOC-CO-(R)Phe-Phe-Pab

In 20 ml of tetrahydrofuran and 5 ml of water to form a suspension HOOC-CO-(R)Phe-Phe-Pab (0.2 mmole), to which is added palladium on coal (52 mg) and the mixture hydronaut 2 days in a shaking Parra under hydrogen pressure of 45 psi (3.2 kg/cm2). After hydrogenolysis mixture is diluted with 40 ml of methanol and the catalyst is filtered off. Evaporation of the solvent receive 50 mg (49%) of the title compound.

1H-NMR (200 MHz, d6-DMSO) : 9,2 (C) 8,78 (d), or 8.6 (m), to $ 7.91 (m), 7,79 (d, 2H), 7,35 to 6.8 (m, 12H), 4,6-4 (m, 4H), 3-2,6 (m, 4H).

Example 87

HOOC-CH2-(R)Phe-Phe-Pab

(I) BnOOC-CH2-(R)Phe-Phe-Pab(Z)

In 10 ml of acetonitrile to form a suspension of H-(R)Phe-Phe-Pab(Z) (0,87 mmole) (see example 85 (II)) and potassium carbonate (2.6 mmole). To the mixture add identitatea (0.95 mmole), the solution is heated to 30oC and stirred at this temperature for 2 days. After alkylation, the solvent is removed and the residue is dissolved in 10 ml of ethyl acetate. The solution is quickly washed with 10 ml of water, and the separated organic phase is precipitated title compound. BnOOC-CH2-(R)Phe-Phe-Pab(Z) is filtered off and after drying for 24 h under vacuum at 45oC obtain 177 mg (28%) BnOOC-CH2-(R)Phe-Phe-Pab(Z).

(II) HOOC-CH2-(R)Phe-Phe-Pab

In 30 ml of tetrahydrofuran and 3 ml of water to form a suspension BnOOC-CH2-(R)Phe-Phe-Pab(Z), which is added palladium on coal (41 mg) and the mixture hydronaut 2 days in apparatus for shaking Parra under hydrogen pressure of 45 psi (3.2 kg/cm2). After hydrogenolysis mixture is diluted with 40 ml of water and the catalyst is filtered off. Evaporation of the solvent to obtain 95 mg (59%) of the title compound. TSP-MS: found m/z 502 (calculated for MH+(C28H32N5O4) 502).

Example 88

H-(R)Cha-Pro-Mig

(I) Boc-(R)Cha-Pro-Mig(Z)

To stir the mixture 0,344 g (0,93 mmole) Boc-(R)Cha-Pro-OH (see: getting the initial connection), 0,245 g (0,93 mmole) H-Mig(Z) (see: getting parent compounds) and 0,227 g (of 1.86 mmole) in 10 ml of CH2CN added at -10oC 0,232 g (of 1.86 mmole) of EDC. The reaction mixture was left to warm to room temperature and incubated for 5 days. After evaporation of CH3CN the residue is dissolved in EtOAc and washed with water, NaHCO3(aq.) and brine. The organic layer is dried over Na2SO4and evaporated. Purification of the crude product column chromatography using a stepwise gradient of EtOAc-MeOH (95:5 to 90:10) to obtain 0.34 g (60%) of the title compound.

(II) H-(R)Cha-Pro-M is th temperature. Then added dropwise 10 ml of a saturated solution of KOH (aq.). The layers are separated and the aqueous phase is extracted with EtOAc (3 x 8 ml). The organic layers are combined, washed with brine, dried over Na2SO4and after evaporation receive 0,286 g (100%) of the title compound.

(III) H-(R)Cha-Pro-Mig

In 3 ml of MeOH is dissolved 0.05 g (0,132 mmole) H-(R)Cha-Pro-Mig(Z) and hydronaut about days at atmospheric pressure over 10% Pd-C. the Solution is filtered through cellit and evaporation of the solvent to obtain 0.04 g (80%) of the title compound.

1H-NMR (500 MHz, MeOD) : 0,92-1,02 (m, 2H), 1.18 to about 1.47 (m, 6H), 1,66-of 1.73 (m, 4H), 1.85 to 2,04 (m, 4H), 2,17-2,22 (m, 1H), 2.95 and are 2.98 (m, 1H), 3,12-and 3.16 (m, 1H), 3,47-3,55 (m, 2H), 3,62-3,66 (m, 1H), 3.75 to of 3.78 (m, 1H), 3,85-to 3.89 (m, 1H), 4,05-4,12 (m, 3H), 4,34-4,37 (m, 1H).

Signals smaller rotamer appear when: 3,4, 3,7, 4,13-4,16, 4,3.

MS: m/z 379 (M++ 1).

Example 89

H-(R)Cha-Pro-Dig

(I) Boc-(R)Cha-Pro-Dig(Z)

To stir at -10oC a mixture of 0.28 g (0,76 mmole) Boc-(R)Cha-Pro-OH (see: getting the initial connection), 0.21 g (0,76 mmole) H-Dig(Z) (see: getting parent compounds) and 0,186 g (1.52 mmole) of DMAP in 8 ml of CH3CN add 0,189 g (0.99 mmole) of EDC. The mixture is left to warm to room temperature and incubated for 4 days. After evaporation of CH3CN the residue is dissolved in EtOAc and washed the second product column chromatography using as eluent a linear gradient of EtOAc-MeOH (95:5 to 90:10) to obtain 0.21 g (44%) of the title compound.

(II) H-(R)Cha-Pro-Dig(Z)

In 8 ml of EtOAc saturated with HCl (g), dissolved 0.21 g (0,33 mmole) Boc-(R)Cha-Pro-Dig(Z) and stirred for 10 min at room temperature. Then added dropwise a saturated solution of KOH (aq.). The layers are separated and the aqueous phase is extracted with EtOAc (3 x 8 ml). The organic layers are combined, washed with brine, dried over Na2SO4and after evaporation receive 0,146 g (83%) of the title compound.

(III) H-(R)Cha-Pro-Dig

In 3 ml of MeOH is dissolved 0,046 mmole H-(R)Cha-Pro-Dig(Z) and hydronaut about days at atmospheric pressure over 10% Pd-C. the solution is filtered through cellit and evaporation of the solvent to obtain 0.04 g (100%) of the title compound.

1H-NMR (500 MHz, MeOD) : 0,9-1,04 (m, 2H), 1,1-of 1.47 (m, 6H), 1,66-of 1.74 (m, 4H), 1,78-2,05 (m, 4H), 2,13-of 2.21 (m, 1H), 2,74-and 2.83 (m, 1H), 2,94-2,99 (m, 1H), 3,15 to be 3.29 (m, 1H), 3,44 is 3.57 (m, 2H), 3,65-a 3.87 (m, 3H), 4,07-of 4.25 (m, 3H), 4,35-4,39 (m, 2H).

Signals smaller rotamer appear when : 4,29-4,32.

MS: m/z 393 (M++ 1).

Example 90

H-(R)Cha-Aze-Dig

(I) Boc-(R)Cha-Aze-Dig(Z)

The title compound with a yield 0,253 g (54%) was obtained from Boc-(R)Cha-Aze-OH and H-Dig(Z) (see: getting parent compounds) according to the method described for the synthesis of Boc-(R)Cha-Pro-Dig(Z).

(II) H-(R)Cha-Aze-Dig(Z).

The title compound with a yield of 0.21 g (100%) was obtained from Boc-(R)Cha-Aze-Dig(Z) PA-Aze-Dig(Z) and hydronaut about days at atmospheric pressure over 10% Pd-C. The solution is filtered through cellit and evaporation of the solvent receive 0,042 g (95%) of the title compound.

1H-NMR (500 MHz, MeOD) : 0,91-1,02 (m, 2H), of 1.18 to 1.48 (m, 6H), 1,66 to 1.9 (m, 8H), 2,15-2,17 (m, 1H), 2,66 of 2.68 (m, 1H), 2,8-of 2.83 (m, m, 1H), 3,14-3,29 (m, 1H), 3,39-3,44 (m, 1H), 3.72 points to 3.8 (m, 2H), 4,01-Android 4.04 (m, 1H), 4,14-to 4.23 (m, 2H), 4,48 figure-4.49 (m, 1H), 4,6-with 4.64 (m, 1H).

Signals smaller rotamer appear when: 2,25, 2,6, 4,3, 4,67.

MS: m/z 379 (M++ 1).

Examples of pharmaceutical preparations

Compounds according to the invention can be included in the solid dosage forms intended for oral administration, for example: simple tablets, coated tablets or tablets for the modified discharge, liquid or solid-semisolid dosage forms for rectal administration, liofilizirovannogo substances or liquids in the form of emulsions or suspensions for parenteral injection, liquid, solid and semi-solid dosage forms for application topically.

Compounds according to the invention can be incorporated in pressurised aerosols or dry powders in an inhaler for inhalation through the mouth or nose.

Example P1

Tablets for oral

Tablets (1000 pieces) is obtained from the following components:

Actively the>Magnesium stearate - 6

The active ingredient and the lactose are mixed with an aqueous solution of polyvinylpyrrolidone. The mixture is dried and after grinding receive granules. Then mixed with microcrystalline cellulose and magnesium stearate. The mixture is pressed in teletrauma car and get 1000 tablets each containing 100 mg of the active component.

Example P2

The solution for parenteral administration

The solution is obtained from the following components:

Active connection - 5

Sodium chloride for injection - 6

The sodium hydroxide to establish a pH of 5 to 7

Water for injection to volume in a 1,000 ml

The active ingredient and the sodium chloride is dissolved in water. The addition of 2 M NaOH establish a pH of 3-9 and mortar fill sterile ampoules.

Example P3

Tablets for oral intake, g:

Active connection - 150

Natroalunite - 20

Paraffin - 120

Microcrystalline cellulose - 20

Hydroxypropylcellulose - 5

Nutritionalvalue - 3

Components 1-4 are mixed with each other and to them add the aqueous solution of the component 5. The mixture is dried, pulverized and mixed with the component 6. The mixture is then pressed into teletrauma machine.

Note realimage for inhalation (mass diameter < 4 μm).

Sprayed powder (100 mg) is filled with powder mnogorazovyj inhaler (Turbuhaler). Nebulizer supply metering device that supplies a dose of 1 mg.

Biology

Determination of clotting time, thrombin (TSA)

Human thrombin (T 6769, Sigma Whom. Co.) in buffer solution (pH of 7.4, 100 μl) and inhibitor solution (100 μl) is incubated for one min Then add the original normal with the addition of citrate human plasma (100 μl) and automatic device (KC 10, Amelung) measure the clotting time.

Build a curve based clotting time in seconds from the concentration of inhibitor and interpolation define IR50UGT.

IR50UGT is the concentration of inhibitor at which there is a doubling of the clotting time, thrombin from human blood plasma.

Define the time of the partial activated thromboplastin (VCAT)

VCAT determine the source of the normal with the addition of citrate plasma human blood using reagent PTT 5 for the auto manufacturing company Stage. To add plasma inhibitor (10 μl of inhibitor solution to 90 μl of plasma) and VCAT determined by using a coagulation analyzer To the Dah concentration of inhibitor in plasma and interpolation define IR50VCAT.

IR50VCAT is defined as the concentration of inhibitor in the plasma, in which there is a doubling time of partial activated thromboplastin.

Determination of clotting time, thrombin ex vivo

Inhibition of thrombin after oral administration of the compounds examined on in the minds of rats, which two days before experiments embed catheter for sampling of blood from the carotid artery. On the day of the experience of the blood samples taken at a certain time in plastic tubes containing 1 part of a solution of sodium citrate (0,13 mol/l) and 9 parts of blood. To obtain depleted platelet plasma tubes centrifuged. The plasma is used to determine clotting time, thrombin by the following method.

The blood plasma of rats with the addition of citrate (100 μl) diluted with saline solution (0.9%, 100 ml) and plasma coagulation initiated by the addition of human thrombin (T 6769, Sigma Whom. Co.) in buffer solution (pH of 7.4, 100 μl). The clotting time is measured by an automatic analyzer (COP 10, Amelung, Germany).

Determination of the inhibition constants (Kandfor plasma kallikrein

The determination of Kandcarry out the method using Chromogen the exact enzymatic activity after incubation of plasma kallikrein person with different concentrations of the test compounds is determined at three concentrations of the substrate and is measured by the change in optical absorption at 405 nm and 37oC.

Plasma kallickrein person (E. C. 3.4.21.34, Chromogenix AB, Mölndal, Sweden) in an amount of 250 μl of 0.4 nkat/ml in buffer (0.05 mol/l Tris-HCl, pH 7,4, added to 0.15 mol/l NaCl) with bovine serum albumin (5 g/l, cat. N 810033, ISI Biochemicals Ltd., High Wycombe, Bucks, UK) incubated for 300 sec with 80 μl solution of the test compound in a solution of NaCl (0.15 mol/l) containing 10 g/l bovine albumin. At this stage also add 10 ál of water. Then add 40 ál of substrate kallikrein (S-2302, Chromogenix AB, at a concentration of 1.25, 2 and 4 mmol/l in water) together with 20 μl of water and record the change of absorption.

The value of Kanddefine curves Dixon, i.e. graphs of the concentration of the inhibitor relative to 1/(A/min), on which data for different concentrations to form straight lines, intersecting at X= -Kand.

Reduction

Ac - acetyl

aq. water

Aze - azetidin-2-carboxylic acid

bears - piperidine-3-carboxylic acid

Boc - tert-butyloxycarbonyl

Boc-Dig(Z) - 3-(N-tert-butyloxycarbonyl)-1-(N - benzyloxycarbonylamino)azetidin

Boc-Mig(Z) - 3-(N-tert-butyloxycarbonyl)-1-(N - benzyloxycarbonylamino)azetidin

Boc-Pig(Z) - 4-(N-tert-butylaniline)-1-(N,N'- dibenzylethylenediamine)piperidine

the brine - saturated aqueous NaCl solution

Bn - benzyl

Bu - butyl

Cgl - cyclohexylglycine

Cha--cyclohexylamine

CMA-CBI - 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide - method-p-toluensulfonate

DBU is 1,8-diazabicyclo/5.4.0/undec-7-ene

DCC - dicyclohexylcarbodiimide

DCU - disclosable

DMAP - N,N-dimethylaminopyridine

DMF - dimethylformamide

DMSO - dimethyl sulfoxide

The EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Et - ethyl

EtOAc - ethyl acetate

EtOH - ethanol

Gly is glycine

h = hours

HCl - muriatic (hydrochloric) acid

Hex - hexyl

HOAc is acetic acid

GOBT - N-hydroxybenzotriazole

Hop - homophenylalanine

Hoc homecollection

Sit - N-hydroxysuccinimide

H - Dig(Z) - 3-amino-ethyl-1-(N-benzyloxycarbonylamino)-azetidin

H - Dig - 3-amino-ethyl-1-imigination

H-(R, S)Hig(Z)-(3RS)-1-(N-benzyloxycarbonylamino)-3 - aminomethylpyrrolidine

H-(R,S)Hig-(3RS)-1-amidino-3-aminomethylpyrrolidine

n-Hig-1-amidino-3-aminomethylpyrrolidine

H-(R,S)Itp(TS)-(4RS) - 1,3-diaza-2-tosylimines-4-aminoheterocycles

H-(R,S)Itp-(4RS)-1,3-diaza-2-imino-4-aminoheterocycles

H-(S)Itp(TS)-(4S)-1,3-diaza-2-tosylimines-4-am is clohexane

H-Mig-(Z)-3-aminomethyl-1-(N-benzyloxycarbonylamino)-azetidin

H-Mig-3-aminomethyl-1-imigination

H-(R, S)Nig(Z)-(3RS)-1-(N-benzyloxycarbonylamino)-3 - aminomethylpyrrolidine

H-(R,S)Nig-(3RS)-1-amidino-3-aminomethylpyrrolidine

H-Nig-1-amidino-3-aminomethylpyrrolidine

H-Pab-1-amidino-4-aminomethylbenzoic

H-Pab(Z)-4-aminomethyl-1-(N-benzyloxycarbonylamino)-benzene

H-Pac-1-amidino-4-aminoheterocycles

H-Pac(Z)-4-aminomethyl-1-(N-benzyloxycarbonylamino)-cyclohexane

H-Pig-4-aminomethyl-1-amidinopropane

H-Pig(Z)-4-aminomethyl-1-(N-benzyloxycarbonylamino)-piperidine; H-Pig(Z)2-4-aminomethyl-1-(N, N'-dibenzylethylenediamine) piperidine; H-Rig(Z)-4-amino-ethyl-1-(N-benzyloxycarbonylamino)-piperidine

H-Rig-4-amino-ethyl-1-N-amidinopropane

Me - methyl

MeOH - methanol

Ms - mesyl

NMM is N-methylmorpholine

MPa - R

Pd-C is palladium on coal

Pgl - phenylglycine

Phe - phenylalanine

Pic - pipecolinate acid

Pro - Proline

OFGH - reversed-phase liquid chromatography high resolution

Tf - trifloromethyl

TFUC - triperoxonane acid

THF - tetrahydrofuran

Tic-1-carboxy-1,2,3,4-tetrahydroisoquinoline

Ts - totally, secondary, tertiary. The stereochemistry of amino acids, unless otherwise specified, a priori (S).

Abbreviations (continued. Wavy lines of nitrogen atoms in the following structural formulas indicate the position of communication in the fragment).

< / BR>
Example 91

H-(R)Cha-Pro-(R,S)Nap 2HCl

(I) 1-Benzyl-3-hydroxymethyl-5-oxo-3-pyrrolidin

To a mixture of methyl 1-benzyl-5-oxo-3-pyrrolidin-carboxylate (2.0 g, 8,574 mmole) in dry THF (5 ml) under nitrogen atmosphere was added lithium borohydride (0,176 g, 9,00 mmol) in dry THF (10 ml). The reaction mixture is boiled under reflux for 3 hours and added an additional amount of THF (10 ml)). Added water (10 ml) and the mixture is boiled away. The water layer was cooled in an ice bath and added NaOH (2 M, 15 ml), followed by extraction with methylene chloride. The organic layer was washed with brine and boiled away. Output: 1,62 g (92%).

1H-NMR (300 MHz, CDCl3): 2,15-2,55 (multiplet, 3H), 3.00 and-of 3.60 (m, 4H), 4,25-4,50 (m, 2H), 7,10-7,40 (m, 5H).

(II) 1-Benzyl-3-CH2OMs-5-oxo-3-pyrrolidin

To a mixture of 1-benzyl-3-hydroxymethyl-5-oxo-3-pyrrolidine (1,61 g 7,863 mmole) and triethylamine (1,64 ml 11,795 mmole) in methylene chloride (20 ml) at 4oC added methanesulfonyl chloride (0,64 ml, 8,256 mmole). The reaction mixture(1 M, 2 x 10 ml), then washed with water and with brine, dried (Na2SO4and boiled away. Output: 2,11 g (95%).

1H-NMR (300 MHz, CDCl3): 2,20-2,30 (multiplet, 1H), 2,55 is 3.15 (m, 6H), 3,35 is-3.45 (m, 1H), 4,00-4,20 (m, 2H), 4,40 (singlet, 2H), 7,15-7,40 (m, 5H).

(III) 1-Benzyl-3-cyanomethyl-5-oxo-3-pyrrolidin

1-Benzyl-3-CH2OMs-5-oxo-3-pyrrolidin (5,25 g, 18,53 mmole) was dissolved in DMSO (93 ml) and added sodium cyanide (2,27 g, 46,32 mmole). The reaction mixture was stirred at 80oC for 1 hour. Added sodium cyanide (0.45 g, 9,18 mmole) and the mixture was stirred at 80oC for 1 hour. Added 500 ml of water and the reaction mixture is boiled away. To the water layer was added methylene chloride and after separation the organic layer was washed with water, dried (Na2SO4and boiled away. Output: 3,49 g (88%).

1H-NMR (300 MHz, CDCl3): 2,10-2,75 (multiplet, 5H), 2,90 was 3.05 (m, 1H), 3,35-to 3.50 (m, 1H), 4,25-4,50 (m, 2H), 7,05-to 7.35 (m, 5H).

(IV) 1-Benzyl-3-amino-ethyl-5-oxo-3-pyrrolidin

To a mixture of 1-benzyl-3-cyanomethyl-5-oxo-3-pyrrolidine (0,254 g 1,185 mmole) and anhydrous cobalt chloride (0,308 g, is 2.37 mmole) in methanol (34 ml) at 4oC was added sodium borohydride (0,448 g, 11,85 mmole) in parts. Added HCl (2 M, 7,11 ml, 14,22 mmole) and the mixture was stirred for 30 minutes. A mixture of n the organic layer was washed with brine, dried (Na2SO4and boiled away. Output: 0,205 g (80%).

1H-NMR (300 MHz, CDCl3): 1,35-to 1.60 (multiplet, 3H), 1,95-2,95 (m, 5H), 3,20 is-3.45 (m, 1H), 4,25-4,50 (m, 2H), 7,05-to 7.35 (m, 5H).

(V) Boc-NH-CH2-CH2-4-pyrrolidinyl-1-benzyl-2-he

To a mixture of 1-benzyl-3-amino-ethyl-5-oxo-3-pyrrolidine (0,199 g, 0,912 mmole) and NaOH (2 M, and 0.46 ml, 0,912 mmole) in water (1.2 ml) and THF (1.2 ml) at 4oC added (Boc)2O (0,239 g 1,094 mmole). The reaction mixture was stirred at 4oC for 30 minutes, followed by 5 hours at room temperature. The mixture is boiled away and the residue was diluted with water (20 ml) and was Proektirovanie with ethyl acetate (3 x 10 ml). The combined organic layer was washed with brine, dried (Na2SO4and boiled away. The crude product was purified flash chromatography (EtOAc:MeOH 95:5). Yield : 0.16 g (55%).

1H-NMR (300 MHz, CDCl3): 1,15-to 1.60 (multiplet, 11H), 2,00-2,60 (m, 3H), of 2,75 3,15 (m, 3H), 3.25 to 3.40 in (m, 1H), 4,25 is 4.45 (m, 2H), 7,10-to 7.35 (m, 5H).

(VI) Boc-NH-CH2-CH2-4-pyrrolidinyl-2-he

Boc-NH-CH2-CH2-4-pyrrolidinyl-1-benzyl-2-he (0.16 g, 0,502 mmole) in dry THF (2 ml) was cooled to - 80oC. was Added ammonia (15-20 ml), then added sodium (0,115 g, 5 mmol) in three portions and the reaction mixture was stirred for 1.5 hours. Added was cirulli with ethyl acetate (3 x 20 ml). The combined organic layer was washed with brine, dried (Na2SO4and boiled away. Yield: 97 mg (85%).

1H-NMR (300 MHz, CDCl3): 1,25-1,70 (multiplet, 11H), 1,90-2,05 (m, 1H), 2,30-of 2.50 (m, 2H), 2,90 is 3.15 (m, 3H), 3,40-to 3.50 (m, 1H), 4,80 (bs, NH), 6.75 in (bs, NH).

(VII) Boc-NH-CH2-CH2-4-pyrrolidinyl-2-tion

A mixture of Boc-NH-CH2-CH2-4-pyrrolidinyl-2-it (0,289 g, 1,264 mmole) and the reagent Lawesson (Lawesson) (0,256 g, 0,632 mmole) in dry THF (12 ml) was stirred for 1 hour. Added a spoonful of silica gel and the mixture is boiled away. The residue was purified flash chromatography (suirable THF and CH2Cl2:MeOH 9:1). Output: 0.187 g (77%).

1H-NMR (300 MHz, CDCl3): 1,25-1,75 (multiplet, 11H), 2,45-2,70 (m, 2H), 2.95 and is 3.40 (m, 4H), 3,65-of 3.85 (m, 1H), 4,70 (bs, NH), 8,80 (bs, NH).

(VIII) Boc-(R)Cha-Pro-NH-CH2-CH2-4-pyrrolidinyl-2-tion

As described in example 1 (i) from Boc-NH-CH2-CH2-4-pyrrolidinyl-2-thione (strength of 0.159 g, 0,651 mmole) and Boc-(R)Cha-Pro-OH (0.24 g, 0,651 mmole) (see preparation of starting materials). Output: 0:273 g (85%).

1H-NMR (300 MHz, CDCl3): 0,75-2,10 (m, 26H), 2,30-to 2.65 (m, 3H), 2.95 and-3,50 (m, 5H), 3,70-3,95 (m, 2H), 4,20 with 4.65 (m, 2H), of 5.05-of 5.15 (m, 1H), 7,15 (bs, NH), 7,95 (bs, NH).

(IX) Boc-(R)Cha-Pro-NH-CH2-CH2-(5-(methylsulphonyl)- 3,4-dihydro-2H-3-pyrrolyl x HI

A mixture of Boc-(R)Cha-Pro-NH-CH2-CHNoi temperature for 6 hours. The precipitated product was filtered. Output: 0,243 g (73%).

1H-NMR (300 MHz, CDCl3): 0,70 was 2.25 (m, 29H), 2,60-to 3.50 (m, 8H), 3,60-3,90 (m, 2H), 4,05-4,55 (m, 3H), 5,00-a 5.25 (m, 1H).

(X) Boc-(R)Cha-Pro-(R,S)Nap HI

A mixture of Boc-(R)Cha-Pro-NH-CH2-CH2-(5-(methylsulphonyl)- 3,4-dihydro-2H-3-pyrrolyl x HI (0.24 g, 0,376 mmole) and THF saturated with ammonia (25 ml) was stirred at room temperature overnight. The reaction mixture is boiled away. Output: 0,237 g (100%).

Mass spectrometry by fast atom bombardment: m/z = 478 (M++ 1)

(XI) H-(R)Cha-Pro-(R,S)Nap 2HCl

A mixture of Boc-(R)Cha-Pro-(R, S)Nap x HI (0,229 g, 0,378 mmole) and triperoxonane acid (1.5 ml) in methylene chloride (1.5 ml) was mixed at room temperature for 2 hours. The reaction mixture is boiled away and the crude product was purified RPLC (25% CH3CN/75% 0.1 M NH4OAc). Yield: 68 mg (40%).

Mass spectrometry by fast atom bombardment: m/z = 378 (M++ 1)

Example 92

HOOC-CH2-OOC-CH2-(R)Cgl-Aze-Pab 2HCl

(I) HOOC-CH2-(R)Cgl-Aze-Pab(Z)

A mixture of BnOOC-CH2-(R)Cgl-Aze-Pab(Z) (0.5 g, from 0.76 mmole) (see example 1 (iii), lithium hydroxide (0.765 ml (2M), 1.5 mmole) and water (few drops) in methanol was mixed at room temperature for 30 minutes. Added HCl (2 M, 0.765 ml) and the mixture is boiled away. Neojidanni: 0,90-1,95 (multiplet, 11H), 2,20-2,70 (m, 2H), 3.25 to of 3.85 (m, 3H), 3.95 to 4,55 (m, 4H), 4.75 V-5.25 (m, 3H), 7,25-of 7.90 (m, 9H).

(II) BnOOC-CH2-OOC-CH2-(R)Cgl-Aze-Pab(Z)

Benzyl bromoacetate (0,0924 g, 0,403 mmole) was added to HOOC-CH2-(R)Cgl-Aze-Pab(Z) (0,189 g, 0,336 mmole) in dry DMF (1 ml) at 0oC. the Reaction mixture was mixed at room temperature for 24 hours. Added toluene (5 ml) and the mixture was washed with water (4 x 2.5 ml), and dried (Na2SO4and boiled away. The crude product (0.18 g) was purified flash chromatography (ethyl acetate/methanol), after which was followed by RPLC (60% CH3CN/40% 0.1 M NH4OAc). Yield: 82 mg (34%).

Mass spectrometry by fast atom bombardment: m/z = 712 (M++ 1)

(III) HOOC-CH2-OOC-CH2-(R)Cgl-Aze-Pab 2HCl

BnOOC-CH2-OOC-CH2-(R)Cgl-Aze-Pab(Z) (0,070 g, 0,098 mmole) was dissolved in THF (10 ml) and water (5 ml). Added HCl (1 M, 0.4 ml) and the mixture was hydrogencarbon over 50% Pd/C at atmospheric pressure for 4.5 hours. The solution was filtered, boiled away and the crude product was purified RPLC (10% CH3CN/90% 0.1 M HOAc pH of 2.8). The resulting product was dried by freezing, was treated with excess HCl (1 M) and again dried by freezing. Yield: 21 mg (38%).

Mass spectrometry by fast atom bombardment: m/z = 488 (M++ 1).

1. The peptide of prosvent formula IIa, IIb, IIc, IId or IIe

< / BR>
where k = 0, 1, or 2;

m = 1 or 2;

q = 0, 1, 2 or 3;

R1represents H, alkyl group with 1-4 carbon atoms, or R11OOC-alkyl-, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to the carbonyl and alpha-Deputy group represented by R17-(CH2)p- where p = 0, 1 or 2 and R17is methyl, HE COOR12where R12Is h or an alkyl group with 1-4 carbon atoms or benzyl group, R11Is H, an alkyl group with 1-6 carbon atoms or benzyl group,

or R1- R13-NH-CO-alkyl-, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1-4 carbon atoms and where R13Is h, an alkyl group with 1-4 carbon atoms or CH2COOR12where R12adopt these values,

or R1- R12OOC-CH2-OOC-alkyl, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1-4 carbon atoms and where R12adopt these values,

or R1- R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(2-COOR12)-SO2- where R12is the 5
is an alkyl group with 1-4 carbon atoms,

or R1- CO-OR15where R15adopt these values,

or R1- -CO-(CH2)p-COOR12where R12adopt these values and p = 0, 1, or 2;

R2represents H, alkyl group with 1-4 carbon atoms, or R21OOC-alkyl, where the alkyl group has 1-4 carbon atoms and where R21Is h, an alkyl group with 1-4 carbon atoms or benzyl group;

R3represents an alkyl group with 1-4 carbon atoms,

or R3is cyclopentyloxy, tsiklogeksilnogo or phenyl group which is unsubstituted or substituted alkyl group with 1-4 carbon atoms,

or R3represents a phenyl group substituted by a group OR31where R31Is h or an alkyl group with 1-4 carbon atoms and k = 0, 1;

or R3- 4-pyridyl, 3-pyrrolidyl or 3-indolyl, which is unsubstituted or substituted or SIG31group, where R31adopt these values and k = 0, 1;

R4represents H, alkyl group with 1-4 carbon atoms, tsiklogeksilnogo or phenyl group;

A2a structural fragment of formula IIIa, IIIb or IIIc:

< / BR>
where p = 0, 1, or 2;

m = 1, 2, or 3,

Y represents is Eden or substituted by one or two fluorine atoms, hydroxy-group or oxopropoxy in 4th position or may be saturated or unsaturated,

or Y is n-propylene group, and educated in the 6-membered cycle can be unsubstituted or substituted in the 5-th position of one atom of fluorine, hydroxy-group or exography, or contain two atoms of fluorine in the 4-th or 5-th position, or be unsaturated in the 4th and 5th position, or may contain in the 4th position of the alkyl group with 1-4 carbon atoms,

or R3takes the specified values;

R5is H, alkyl group with 1-4 carbon atoms

or R5- -(CH2)p-COOR51where p = 0, 1 or 2 and R51Is h or an alkyl group with 1-4 carbon atoms;

n = 0, 1, 2, 3, or 4

In a structural fragment of formula IVa, IVb, IVc or IVd

< / BR>
where r = 0 or 1;

X1- CH2, NH or is absent;

X2- CH2, NH or C=NH;

X3- NH, C=NH, N-C(NH)-NH2or CH-C(NH)-NH2;

X4- CH2or NH;

X5- C(NH)-NH2;

X6Is CH or N;

R6- H or an alkyl group with 1-4 carbon atoms;

D is the group Z, or (Z)2or N, where Z is benzyloxycarbonyl group that communicates with the nitrogen atoms amidino or guanidino, prisutstvuyuthie General formula I under item 1

A1----A2----NH-(CH2)n----B---D,

where A1a structural fragment of formula IIa, IIb, IIc, IId or IIe

< / BR>
k = 0, 1, or 2;

m = 1 or 2 ;

q = 0, 1, 2 or 3;

R1- R11OOC-alkyl-, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to the carbonyl group, and alpha-Deputy group represented by R17-(CH2)p- where p = 0, 1 or 2 and R17group COOR12where R12Is h, an alkyl group with 1-4 carbon atoms or benzyl group, R11Is H, an alkyl group with 1-6 carbon atoms or benzyl group,

or R1- R13-NH-CO-alkyl-, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to Carbonado alkyl group with 1-4 carbon atoms and where R13Is h, an alkyl group with 1-4 carbon atoms or-CH2-COOR12where R12adopt these values,

or R1- R12OOC-CH2-OOC-alkyl-, where the alkyl group has 1-4 carbon atoms and is possibly substituted in the alpha position to the carbonyl alkyl group with 1-4 carbon atoms and where R12adopt these values,

or R1- R14SO2-, Ph(4-COOR12)-SO2-, Ph(3-COOR12)-SO2-, Ph(Lerida,

or R1- CO-R15where R15is an alkyl group with 1-4 carbon atoms,

or R1- CO-OR15where R15adopt these values,

or R1- -CO-(CH2)p- COOR12where R12adopt these values and p = 0, 1, or 2,

or R2represents H, or alkyl group with 1-4 carbon atoms, or R21OOC-alkyl-, where the alkyl group has 1-4 carbon atoms and where R21Is h, an alkyl group with 1-4 carbon atoms or benzyl group;

R3represents an alkyl group with 1-4 carbon atoms,

or R3is cyclopentyloxy, tsiklogeksilnogo or phenyl group which is unsubstituted or substituted alkyl group with 1-4 carbon atoms,

or R3represents a phenyl group substituted by a group OR31,

where R31- H or an alkyl group with 1-4 carbon atoms and K = 0, 1,

or R3- 4-pyridyl, 3-pyrrolidyl or 3-indolyl, which is unsubstituted or substituted by a group OR31where R31adopt these values and k = 0, 1;

R4represents H, alkyl group with 1-4 carbon atoms, tsiklogeksilnogo or phenyl group;

A2a structural fragment of formula IIIa, IIIb or IIIc


or Y is n-propylene group, and educated in the 6-membered cycle unsubstituted or substituted in the 5-th position of one atom of fluorine, hydroxy-group or oxopropoxy or may contain in the 4th or 5th position of two atoms of fluorine, or be unsaturated in the 4th or 5th position, or may contain in the 4th position of the alkyl group with 1-4 carbon atoms;

R3takes the specified values;

R5represents H or alkyl group with 1-4 carbon atoms,

or R5- -(CH2)p-COOR51where p = 0, 1 or 2 and R51Is h or an alkyl group with 1-4 carbon atoms,

n = 0, 1, 2, 3 or 4;

In a structural fragment of formula IVa, IVb, IVc or IVd

< / BR>
where r = 0 or 1;

X1- CH2, NH or is absent;

X2- CH2, NH or C = NH;

X3- NH, C = NH, N-C(NH)-NH2CH-C(NH)-NH2;

X4- CH2or NH;

X5- C(NH)-NH2;

X6Is CH or N;

R6- H or an alkyl group with 1-4 carbon atoms, D is a group Z or (Z)2Z - benzyloxycarbonyl group, spezialmassagen or connection in the form of physiologically acceptable salts.

3. Connection under item 1 or 2, wherein A1a structural fragment of formula IIa or IIb.

4. Connection on one or more of the preceding paragraphs.1 to 3, wherein R1- R11OOC-alkyl-, where the alkyl group has 1-4 carbon atoms and R11- H.

5. Connection on one or more of the preceding paragraphs.1 to 4, wherein A2a structural fragment of formula IIIa.

6. Connection on one or more of the preceding paragraphs.1 to 4, wherein A2a structural fragment of formula IIIb.

7. Connection on one or more of the preceding paragraphs.1 - 6, characterized In that a structural fragment of formula IVa, where X1X2and X4group CH2X3group CH-C(NH)-NH2, r = 1 and n = 1.

8. Connection on one or more of the preceding paragraphs.1 - 6, characterized In that a structural fragment of formula IVa, where X1X2and X4group CH2X3group N - C(NH) -NH2r = 0 or 1 and n = 1 or 2.

9. Connection on one or more of the preceding paragraphs.1 - 6, characterized In that a structural fragment of formula IVb, where X5- group C(NH)-NH2, R6- H and n = 1.

10. With the s IVa, where X1and X3group NH, X2- group C=NH, X4group CH2, r = 1 and n = 2.

11. Connection on one or more of the preceding paragraphs.1 - 6, characterized In that a structural element of the formula IVa, where X1no, X2and X4group CH2X3group N-C(NH)-NH2r = 0 and n = 1 or 2.

12. Connection under item 1 or 2, characterized in that n = 1 or 2, A1a structural fragment of formula IIa, where k = 0 or 1, R1- R11OOC-alkyl, where the alkyl group has 1-4 carbon atoms, R2- H, R3is tsiklogeksilnogo group, A2a structural fragment of formula IIIa, where Y represents methylene group, ethylene group or a n-propylene group, formed by the 6-membered cycle unsubstituted or substituted in the 4-position of the alkyl group with 1-4 carbon atoms, R5- H, - a structural fragment of formula IVa, where X1X2and X4group CH2X3- group SN-C(NH) - NH2or N-C(NH)-NH2r = 0 or 1, or X1and X3group NH, X2the group = NH, X4group CH2, r = 1, or X1no, X2and X4group CH2X3group N-C(NH)-NH2r = 0.

13. Connection under item 1 or 2,where the alkyl group has 1-4 carbon atoms, R2- N, R3is tsiklogeksilnogo group, A2a structural fragment of formula IIIa, where Y represents methylene group, ethylene group or a n-propylene group, and educated in the 6-membered cycle unsubstituted or substituted in the 4-position of the alkyl group with 1-4 carbon atoms, R5- N, - a structural fragment of formula IVB, where X5- C(NH)-NH2and R6- H.

14. Connection on p. 1, wherein is selected from

HOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-(R)Cgl-Pro-Pab

HOOC-CH2-CH2-(R)Cgl-Pro-Pab

(HOOC-CH2)2-(R)Cgl-Pro-Pab

H-(R)Cgl-Pic-Pab

HOOC-CH2-(R,S)CH(COOH)-(R)Cgl-Pic-Pab

H-(R)Cha-Aze-Pab

HOOC-CH2-(R)Cha-Aze-Pab

HOOC-CH2-(R,S)CH(COOH)-(R)Cha-Aze-Pab

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Aze-Pab/a

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Aze-Pab/b

HOOC-CH2-CH2-(R)Cha-Aze-Pab

HOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab

H-(R)Cha-Pro-Pab

HOOC-CH2-(R)Cha-Pro-Pab

HOOC-CH2-(Me) (R)Cha-Pro-Pab

HOOC-CH2-CH2-(R)Cha-Pro-Pab

HOOC-CH2-CH2-(Me) (R)Cha-Pro-Pab

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pro-Pab/a

HOOC-CH2-(RorS)CH(COOH)-(R)Cha-Pro-Pab/b

HOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab

EtOOC-CH2-CH2-CH2-(R)Cha-Pro-Pab

Ph(4-COOH)-SORorS)CH(COOH)-(R)Cha-Pic-Pab/b

HOOC-CH2-CH2-(R)Cha-Pic-Pab

HOOC-CO-(R)Cha-Pic-Pab

HOOC-CH2-CO-(R)Cha-Pic-Pab

Me-OOC-CH2-CO-(R)Cha-Pic-Pab

H2N-CO-CH2-(R)Cha-Pic-Pab

Boc-(R)Cha-Pic-Pab

Ac-(R)Cha-Pic-Pab

Me-SO2-(R)Cha-Pic-Pab

H-(R)Cha-(R,S)betaPic-Pab

HOOC-CH2-CH2-(R)Cha-(R,S)betaPic-Pab

HOOC-CH2-(R)Cha-Val-Pab

HOOC-CH2-CH2-(R)Cha-Val-Pab

H-(R)Hoc-Aze-Pab

HOOC-CH2-CH2-(R)Hoc-Aze-Pab

HOOC-CH2-(R,S)CH(COOH)-(R)Hoc-Pro-Pab

HOOC-CH2-(R)Hoc-Pic-Pab

(HOOC-CH2)2-(R)Hoc-Pic-Pab

HOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab

HOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab

HOOC-CH2-CH2-(R)Tic-Pro-Pab

HOOC-CH2-CH2-(R)Cgl-Aze-Pig

HOOC-CH2-(R)Cgl-Pro-Pig

H-(R)Cha-Aze-Pig

HOOC-CH2-(R)Cgl-Aze-Pac

H-(R)Cha-Pro-Pac

H-(R)Cgl-Ile-Pab

H-(R)Cgl-Aze-Pab

HOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab

MeOOC-CH2-(R)Cgl-Aze-Pab

EtOOC-CH2-(R)Cgl-Aze-Pab

nBuOOC-CH2-(R)Cgl-Aze-Pab

nHexOOC-CH2-(R)Cgl-Aze-Pab

H-(R)Cgl-Pro-Pac

HOOC-CH2-(R)Cha-Pro-Pac

HOOC-CH2-CH2-(R)Cgl-Pro-Pac

HOOC-CH2-CH2-(R)Cha-Aze-Pac

HOOC-CH2-(R)Cha-Aze-Pig

HOOC-CH2-(R)Cha-Pro-Pig

HOOC-CH2-CH2-(R)Cha-Pro-Pig

(HOOC-CH2)2-(R)Cgl-Pro-Pig

HOOC-CH2-CH2(HOOC-CH2)-(R)Cha-Pro-Pig

HOOC-CH2-(R)Cgl-Aze-(R,S)Itp

HOOC-CH2-(R H-(R)Cha-Pro-(R,S)Hig

H-(R)Cgl-Aze-Rig

HOOC-CH2-(R)Cgl-Aze-Rig

HOOC-CH2-(R)Cha-Pro-Rig

HOOC-CH2-CH2-(R)Cha-Aze-Rig

HOOC-CH2-(R)Cha-Pro-(S)Itp

H-(R)Cha-Pro-(R,S)Nig

H-(R)Cha-Pro-Mig

H-(R)Cha-Pro-Dig

H-(R)Cha-Aze-Dig

either as such or as a stereoisomer, or a physiologically acceptable salt.

15. Connection on p. 14, wherein selected from

HOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-CH2-(R)Cha-Aze-Pab

HOOC-CH2-(R)Cha-Pro-Pab

HOOC-CH2-CH2-(R)Cha-Pro-Pab

HOOC-CH2-(R)Cha-Pic-Pab

HOOC-CH2-(R)Cgl-Pro-Pig

EtOOC-CH2-(R)Cgl-Aze-Pab

HOOC-CH2-(R)Cha-Pro-Pac

HOOC-CH2-(R)Cha-Pro-Pig

either as such or in the form of a stereoisomer, or a physiologically acceptable salt.

16. Connection on p. 2, wherein selected from

BnOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cgl-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Cgl-Pro-Pab(Z)

(BnOOC-CH2)2-(R)Cgl-Pro-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cgl-Pic-Pab(Z)

BnOOC-CH2-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/a

BnOOC-CH2-(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/b

BnOOC-CH2-CH2-(R)Cha-Aze-Pab(Z)

BnOOC-CH2-NH-CO-CH2-(R)Cha-Aze-Pab(Z)

BnOOC-CHB>-(Me)(R)Cha-Pro-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-NH-CO-CH2-(R)Cha-Pro-Pab(Z)

Ph(4-COOH)-SO2-(R)Cha-Pro-Pab(Z)

Boc-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-CH2-(R)Cha-Pic-Pab(Z)

EtOOC-CO-(R)Cha-Pic-Pab(Z)

MeOOC-CH2-CO-(R)Cha-Pic-Pab(Z)

H2N-CO-CH2-(R)Cha-Pic-Pab(Z)

Ac-(R)Cha-Pic-Pab(Z)

Me-SO2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cha-Val-Pab(Z)

BnOOC-CH2-CH2-(R)Cha-(R,S)Val-Pab(Z)

BnOOC-CH2-CH2-(R)Hoc-Aze-Pab(Z)

BnOOC-CH2-(R,S)CH(COOBn)-(R)Hoc-Pro-Pab(Z)

BnOOC-CH2-(R)Hoc-Pic-Pab(Z)

(BnOOC-CH2)2-(R)Hoc-Pic-Pab(Z)

BnOOC-CH2-(R)Pro(3-(S)Ph)-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Pro(3-(S)Ph)-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Tic-Pro-Pab(Z)

BnOOC-CH2-CH2-(R)Cgl-Aze-Pig(Z)2< / BR>
BnOOC-CH2-(R)Cgl-Pro-Pig(Z)2< / BR>
BnOOC-CH2-(R)Cgl-Aze-Pac(Z)

BnOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab(Z)

MeOOC-CH2-(R)Cgl-Aze-Pab(Z)

EtOOC-CH2-(R)Cgl-Aze-Pab(Z)

nBuOOC-CH2-(R)Cgl-Aze-Pab(Z)

nHexOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pac(Z)

BnOOC-CH2-CH2-(R)Cgl-Pro-Pac(Z)

BnOOC-CH2-CH2-(R)Cha-Aze-Pac(Z)

BnOOC-CH2-(R)Cha-Aze-Pig(Z)

BnOOC-CH2-(R)Cha-Pro-Pig(Z)

BnOOC-CH2-CH2-(R)Cha-Pro-Pig(Z)

(BnOOC-CH2)2-(R)Cgl-Pro-Pig(Z)

B/BR>BnOOC-CH2-(R)Cgl-Aze-Rig(Z)

BnOOC-CH2-(R)Cha-Pro-Rig(Z)

BnOOC-CH2-CH2-(R)Cha-Aze-Rig(Z)

either as such or in the form of a stereoisomer, or a physiologically acceptable salt.

17. Connection on p. 16, wherein selected from

BnOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pab(Z)

BnOOC-CH2-(R)Cha-Pic-Pab(Z)

BnOOC-CH2-(R)Cgl-Pro-Pig(Z)2< / BR>
EtOOC-CH2-(R)Cgl-Aze-Pab(Z)

BnOOC-CH2-(R)Cha-Pro-Pac(Z)

BnOOC-CH2-(R)Cha-Pro-Pac(Z)

either as such or in the form of a stereoisomer, or a physiologically acceptable salt.

18. Connection on p. 1, wherein is selected from

H-(R)Pro-Phe-Pab

HOOC-CH2-(R)Pro-Phe-Pab

H-(R)Phe-Phe-Pab

HOOC-CH2-(R)Phe-Phe-Pab

HOOC-CO-(R)Phe-Phe-Pab

either as such or in the form of a stereoisomer, or a physiologically acceptable salt.

19. Connection on p. 2, wherein selected from

Boc-(R)Pro-Phe-Pab(Z)

BnOOC-CH2-(R)Pro-Phe-Pab(Z)

Boc-(R)Phe-Phe-Pab(Z)

MeOOC-CO-(R)Phe-Phe-Pab(Z)

BnOOC-CH2-(R)Phe-Phe-Pab(Z)

either as such or as a stereoisomer, or a physiologically acceptable salt.

20. The method of obtaining connection PP.1 - 19 involves attaching protected at N-end amino acids, dipeptides, using standard methods, for connection

H2N-(CH2)n-X

where n= 0, 1, 2, 3;

X - or-D, where takes the values specified for formula I, and D takes the values specified for formula V, as such, either with guanidine or amidinopropane, the nitrogen atoms which are either mono or tizamidine aminosidine group representing benzyloxycarbonyl, tert-butyloxycarbonyl, n-toluensulfonyl group, or X is a group, turning in, followed by removing the protective group or groups or releasing the N-terminal nitrogen with subsequent alkylation of the N-terminal nitrogen and, if necessary, the release by known methods, education physiologically acceptable salt and in those cases, when the reaction is a mixture of stereoisomers, mixture may share standard chromatographic or precrystallization methods allocation if desired, a single stereoisomer.

21. The method according to p. 20 for connection according to any one of paragraphs.1 to 19, characterized in that it includes:

a) (Method Ia) accession protected at the N-end of the dipeptide, selected on the basis of the values of A1and A2in formula I, the use of the n takes on the values, specified for formula I;

W4N-terminal aminosidine group, for example tert-butyloxycarbonyl, benzyloxycarbonyl;

Q1represents a group-C(NH)-NH2, -C(NW2)-NHW2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2where W2- aminosidine group, for example tert-butyloxycarbonyl, benzyloxycarbonyl,

or Q1group-CN, -CO-NH2or-CS-NH2, which is then transferred to amidinopropane,

or Q1group NH2or NH-W2where W2takes the specified values, and the amino group is then transferred to guanidinium (with the formation of Q1= -NH-C(NH)-NH2after unprotect W2group when Q1group-NH-W2(in this case, W2- the group must be orthogonal to W1-group) known in the art methods or

b) (Method Ib) accession protected at N-end amino acids, selected on the basis of the values of A2for formula I and received the standard method of attaching peptides illustrated in the following reaction equation:

< / BR>
where n, W1and Q1accept these values,

with the subsequent removal W
or (C) (Method IIa) accession protected at the N-end of the dipeptide, selected on the basis of the values of A1and A2for formula I, using the standard method of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I;

W1N - terminal aminosidine group, for example tert-butyloxycarbonyl or benzyloxycarbonyl;

Q1group-C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2where W2- aminosidine group, for example tert-butyloxycarbonyl or benzyloxycarbonyl,

or Q1group-CN, -CO-NH2or-CS-NH2, which is then transferred to amidinopropane,

or Q1group NH2or NH-W2where W2takes the specified values, and the amino group is then transferred to guanidinium (with the formation of Q1= NH-C(NH)-NH2after unprotect W2group when Q1group-NH-W2(in this case, W2-the group must be orthogonal to W1-group) known in the art methods,

or (d) (JV the mules I, the use of standard methods of attaching peptides illustrated in the following reaction equation:

< / BR>
where n, W1and Q1accept these values,

with the subsequent removal of the protection W1-group and coupling with N-terminal protected amino acid with the formation of the protected peptide described in method IIa,

or (e) (Method IIIa) accession protected at the N-end of the dipeptide, selected on the basis of the values of A1and A2for formula I, by applying the standard method of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I;

r = 0 or 1, when X1X2and X4group CH2or r = 0, when X2and X4group CH2and X1no;

W1N-terminal aminosidine group, for example tert-butyloxycarbonyl or benzyloxycarbonyl;

Q2group-C(NH)-NH2, -C(NW2)-NH-W2or-C(NH)-NH-W2where W2- aminosidine group, for example tert-butyloxycarbonyl or benzyloxycarbonyl, or Q2= W2while the amino group after removing the protective W2group (in this case, W2-the group must be orthog-tizamidine agents grandravine well-known specialist methods,

or (f) (Method IIIb) accession protected at N-end amino acids, selected on the basis of the values of A2in formula I, the use of standard methods for attaching peptides illustrated in the following reaction equation:

< / BR>
where n, r, X1X2X4, W1and Q2accept these values,

with the subsequent removal of the protective W1-group and coupling with N-terminal amino acid in protected form with the formation of the protected peptide described in method IIIa,

or (g) (Method IVa) accession protected at the N-end of the dipeptide, selected on the basis of the values of A1and A2for formula I, by applying the standard method of attaching peptides illustrated in the following reaction equation:

< / BR>
where n takes on the values specified for formula I;

W1N - terminal aminosidine group, for example tert-butyloxycarbonyl or benzyloxycarbonyl;

W3- N or aminosidine group, for example arylsulfonyl, benzyloxycarbonyl or tert-butyloxycarbonyl,

or (h) (Method IVb) accession protected at N-end amino acids, selected on the basis of the values of A2for the formula I, the standard is>
accept these values,

with the subsequent removal of the protective W1-group and coupling with N-terminal amino acid in protected form with the formation of the protected peptide described in method IVa, the target compound can be obtained by any of the following ways, depending on the nature of the used Q1or Q2group: remove a protective group(s) (when Q1= -C(NH)-NH2, -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2or selectively remove a protective W1group (for example, when Q1or Q2= -C(NW2)-NH-W2, -C(NH)-NH-W2, -NH-C(NH)-NH-W2, -N(W2)-C(NH)-NH-W2or-NH-C(NW2)-NH-W2(in this case, W2-the group must be orthogonal to W1group)), followed by alkylation of the N-terminal nitrogen and, optionally, a release.

22. The compound according to any one of paragraphs.1 - 5 or 7 - 17 with antithrombotic or anticoagulant activity.

23. The compound according to any one of paragraphs.1 to 4, 6 to 10 or 18, 19, possessing anti-inflammatory activity.

24. Pharmaceutical composition having inhibitory trypsin-like serine-prot is ascoltami pharmaceutical carriers, characterized in that the peptide is derived, it contains the connection PP.1 - 19 in an effective amount.

25. The pharmaceutical composition according to p. 24, with anticoagulation or antithrombotic activity, containing an effective amount of a compound according to any one of paragraphs.1 - 5 or 7 - 17 in combination with one or more pharmaceutical carriers.

26. The pharmaceutical composition according to p. 24, possessing anti-inflammatory activity, containing an effective amount of a compound according to any one of paragraphs.1 to 4, 6 to 10 or 18, 19 in combination with one or more pharmaceutical carriers.

27. The compound according to any one of paragraphs.1 to 5 or 7 to 17 as an active ingredient for the preparation of pharmaceutical compositions intended for the suppression of thrombin in human or animal.

28. The compound according to any one of paragraphs.1 to 4, 6 to 10 or 18, 19 as an active ingredient for the preparation of pharmaceutical compositions intended to suppress kininogens in the body of man or animal.

29. The method of suppressing thrombin in the body in need of such suppression of the human or animal, comprising the introduction into the body effects in the body in need of such suppression of a person or animal, consisting in the introduction in the body effective to suppress the amount of the compound according to any one of paragraphs.1 to 4, 6 to 10 or 18, 19.

31. The connection formulas

< / BR>
as such, or in which the nitrogen atoms of amidinopropane mono - or tizamidine protecting group, or as a salt.

32. Connection on p. 31 as a starting compound in the synthesis of inhibitor serine protease.

33. The connection formulas

< / BR>
as such, or in which the nitrogen atoms of amidinopropane mono - or tizamidine protecting group, or as a salt.

34. Connection on p. 33 as starting compounds in the synthesis of an inhibitor of a serine protease.

35. The connection formulas

< / BR>
where n = 1 or 2;

s = 0 or 1,

as such, or in which the nitrogen atoms of amidinopropane mono - or tizamidine protecting group, or as a salt.

36. Connection on p. 35 as a starting compound in the synthesis of inhibitor serine protease.

37. Amidinopropane selected from the group consisting of 4-aminomethyl-1-(N-benzyloxycarbonyl-amidino)benzene, 4-amino-methyl-1-(N-benzyloxycarbonyl-amidino)cyclohexane, 4-amino-ethyl-1-benzyloxycarbonylamino-piperidine, (3RS)-1-(N-benzyloxycarbonylamino)-3-aminomethylphenol is seidina, 3-amino-ethyl-1-(N-benzyloxycarbonylamino)azetidine, as such, in the form of a salt or protected benzyloxycarbonyloxy group on the other nitrogen.

38. The use of the compounds of formula

< / BR>
as such, or in which the nitrogen atoms of amidinopropane mono - or tizamidine protecting group, or in the form of salts as starting compounds in the synthesis of an inhibitor of thrombin, and in particular a peptide inhibitor of thrombin.

 

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