Cyclic peptides, radiopharmaceutical preparation, cyclic peptides, with a radioactive label

 

(57) Abstract:

The invention relates to a new radiopharmaceutical drugs, which are radioactivedecay cyclic compounds containing carbocyclic or heterocyclic ring system and acting as antagonists of glycoprotein complex IIb/IIIa. In addition, the invention relates to a method of use of these radiopharmaceuticals as prospective agents for the diagnosis of arterial or venous thrombosis, as well as new reagents for obtaining data of radiopharmaceuticals and in diagnostic kits containing these reagents. 3 S. and 26 C.p. f-crystals, 7 tab., 2 Il.

The invention relates to a new radiopharmaceutical drugs, representing radioactivedecay cyclic or heterocyclic ring system. In addition, the invention relates to methods of use of these radiopharmaceuticals as creating the image of the compounds for the diagnosis of arterial and venous thrombosis, as well as new reagents for obtaining data of radiopharmaceuticals and in diagnostic kits containing the decree is difficult from the point of view of sensitivity, and specificity. When resolving critical situations, you need to have doctors quick and non-invasive method for the detection of thromboembolic diseases. It is shown that the activation and subsequent platelet aggregation is associated with various pathophysiological conditions including thromboembolic cardiovascular and cerebrovascular disorders, including unstable angina, myocardial infarction, transient ischemic stroke, brain stroke, atherosclerosis, and diabetes. The role of platelets in the development of these diseases due to their ability to form aggregates or blood clots, especially on arterial walls after they have been damaged. In particular, see Fuster et al., JACC, vol. 5, N 6, pp. 175B-183B (1985); Rubenstein et al. , Am. Heart. J., vol. 102, pp. 363-367 (1981); Hamm et al., J. Am. Coll. Cardiol. vol. 10, pp. 998-1006 (1987); and Dsvies et al., Circulation, vol. 73, pp. 418-427 (1986). Was recently identified glycoprotein complex of platelet IIb/IIIa (GPIIb/IIIa), which is a membrane protein that mediates platelet aggregation in the usual way for a known agonist of the receptor of platelets. Cm. Philips et al., Cell, vol.65, pp. 359-362 (1991).

It is believed that the activation and aggregation of platelets are also essential in bolia. In addition, it is known that patients whose blood contact with artificial surfaces, such as prosthetic heart valves made of synthetic materials, have an increased risk of thrombosis, embolism and formation of platelet thrombi. In particular, see Fuster et al., JACC, vol.5, n 6, pp. 175B-183B (1985); Rubenstein et al., Am. Heart. J., vol. 102, pp. 363-367 (1981); Hamm et al. , J. Am. Coll. Cardiol., vol. 10, pp. 998-1006 (1987); and Dsivies et al., Circulation, vol. 73, pp. 418-427 (1986).

Suitable means for non-invasive diagnostics of monitoring patients with this type of possible thromboembolic diseases could be extremely useful, and there have been many attempts to obtain radioactivedecay connection detecting platelets by creating images in non-invasive radionuclide diagnostics. For example, was carried out experimental studies on the use 99mIc-monoclonal antibodies to fibrin for presumptive diagnosis of arterial thrombosis. Cm. Cerqueira et al., Cerculation, vol. 85, pp. 298-304 (1992). The authors reported the possible use of these compounds to create images of newly formed blood clots. In addition, it was reported on the possible use of monoclonal antibodies, the sword is th and venous thrombosis. However, a statistically significant relationship thrombus/blood (the target/background) was achieved only after 4 hours after administration radioactiveman antibodies. Cm. Wu et al. , Clin. Med. J., vol. 105, pp. 533-539 (1992). In addition, recently discussed the use of radioactivedecay 125J131J99mIc and111In monoclonal antibodies AS to the platelets to produce an image of the alleged blood clots. Cm. Cooler et al., A PCT application N 89/11538 (1989). However, the use radioactiveman AS antibodies uncomfortable due to the great ol. mass. Other researchers have used enzymatically inactivated t-PA, radiolabelled iodine123J,125J and131J, to determine the localization of blood clots. Cm. Ordm et al., Cerculation, vol.85, pp. 288-297 (1992). In addition, there are other studies on the radiological definition of thromboembolic diseases. See, for example, Koblik et al., Semin. Nucl. Med., vol. 19, pp. 221-237 (1989).

Identification of the localization of arterial and venous thrombi is essential for accurate diagnosis of thromboembolic diseases and the development of methods appropriate therapy. There is a need for new and improved radioactivedecay connections for non-invasive create images of trouble.my.

The present invention relates to a new radiopharmaceutical drugs, which are radioactivedecay cyclic compounds containing carbocyclic or heterocyclic ring system, and these compounds function as antagonists of glycoprotein complex IIb/IIIa platelet. In addition, the invention relates to methods of use of radiopharmaceuticals as creating the image of the compounds in the diagnosis of arterial and venous thrombosis. The invention also relates to novel reagents for the preparation of these radiopharmaceuticals and diagnostic kits containing these compounds.

Fig. 1A. Shows the normal image obtained using radiopharmaceutical compounds (example 12), administered intravenously (1 µci/kg of body weight) dog in the diagnosis of deep venous thrombosis in experimental models. This model involves the formation of a blood clot in the jugular veins during stasis, and then the blood flow to resume. Compounds injected with renewed blood flow. Shows the image obtained when the enable diagnostic compounds in bestgene, obtained using radiopharmaceutical compounds (example 19), administered intravenously (1 µci/kg of body weight) dog in the diagnosis of deep venous thrombosis in experimental models. This model involves the formation of a blood clot in the jugular veins during stasis, and then the blood flow to resume. Compounds injected with renewed blood flow. Shows the image obtained when the enable diagnostic compounds in the rapidly growing venous thrombi after 15, 60 and 120 min after injection of the compounds.

[1] the Present invention relates to new reagents for producing radiopharmaceuticals formula: (QLndCh; (Q)d Ln-Chand d = 1-3, d' = 2 - 20, Ln- linking group; Ch- chelator of metal and Q is a compound of formula (I)

< / BR>
or a pharmaceutically suitable salt or its inactive form, and R31represents a C6-C14saturated, partially saturated or aromatic carbocyclic ring system, substituted 0-4 R10or R10aand optionally having a connection with the Ln; heterocyclic ring system, optionally substituted 0-4 R10or R10aand optionally having a connection with the L1 and R22independently selected from the following groups: hydrogen, C1-C8-alkyl, substituted 0-2 R11; C2-C8alkenyl, substituted 0-2 R11; C2-C8-quinil, substituted 0-2 R11; C3-C10-cycloalkyl, substituted 0-2 R11; relationship with Ln; aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, and the specified ring system substituted 0-2 R12; =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(=O)N(R13)2, -CHO, -CH2OR13, -OC(= O)R13, -OC(= O)OR13a, -OR13, -OC(=O)N(R13)2, -NR13C(=O)R13, -NR14C(= O)OR13a, -NR13C(=O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a,

-SR13, -S(=O)R13a, -SO2N(R13)2, -N(R13)2, -NHC(=NH)OTHER13, -C(=NH)OTHER13, = NOR13, NO2, -C(= O)NHOR13, -C(= O)NHNR13R13a, -OCH2CO2H, 2-(1-morpholino)ethoxy; R1and R21can be an alternative connected with formation of a 3-7-membered carbocyclic ring, substituted 0-2 R12; when n' = 2, R1or R21can be and is in this way forming a double or triple bond between adjacent carbon atoms; R21and R23independently selected from hydrogen, C1-C4-alkyl, optionally substituted by 1-6 halogen; benzyl; R22and R23can be an alternative connected with formation of a 3-7-membered carbocyclic ring, substituted 0-2 R12; when n = 2, R22or R23can be taken together with R22or R23on adjacent carbon atom with the formation of a direct connection, thus forming a double or triple bond between adjacent carbon atoms; R1and R2where R21- H, can be an alternative connected with education 5-8-membered carbocyclic ring, substituted 0-2 R12; R11choose from one or more of the following compounds: =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(=O)N(R13)2, -CHO, -CH2OR13, -OC(= O)R13, -OC(=O)OR13a, -OR13, -OC(=O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2N(R13)2, -N(R13)2, -NHC(=NH)OTHER13, -C(=NH)OTHER13, =NOR13, NO2, -C(= O)NHOR13, -C(= O)NHNR13R13a, -OCH3
-C6-cyclooctylmethyl,

C2-C6-alkoxyalkyl, C3-C6-cycloalkane, C1-C4the alkyl/alkyl, substituted 1-5 groups independently selected from-NR13R14, -CF3, NO2, -SO2R13aor-S(= O)R13a), aryl, substituted 0-2 R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, and the specified heterocyclic ring substituted 0-2 R12; R12choose from one or more of the following compounds: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C3-C6-cycloalkyl; C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C5-alkoxy, -CO2R13, -C(= O)NHOR13a, -C(=O)NHN(R13)2, =NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(= O)R13, -C(= O)R13, OC(=O)OR13a, -OR13, -(C1-C4-alkyl)-OR13, -N(R13)2, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR13C(=O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2N(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(=O)13a, -SR13, -SO21-C4-haloalkoxy, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4the alkyl/alkyl, substituted-N(R13)2, -CF3, NO2or-S(=O)R13a); R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylcyclohexane, aryl, -(C1-C10-alkyl)-aryl or C3-C10-alkoxyalkyl;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

DM-6591-A

R14- OH, H, C1-C4-alkyl or benzyl;

R2- H or C1-C8-alkyl;

R10and R10aindependently selected from one or more compounds of: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C3-C6-cycloalkyl, C3-C6cycloalkenyl; C7-C(=O)NHN(R13)2, = NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(= O)R13, -C(= O)R13, -OC(= O)OR13a, -OR13, -(C1-C4-alkyl)-OR13, -N(R13)2, -OC(=O)N(R13)2, -NR13C(= O)R13, -NR13C(= O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2N(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(=O)R13a, -SR13, -SO2N(R13)2C2-C6-alkoxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkyl (including-CvFwwhere v = 1-3 and w = 1 to(2v+1)), C1-C4-haloalkoxy, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl,

C1-C4-alkylcarboxylic, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4-alkyl, substituted-N(R13)2, CF3, NO2or-S(=O)R13a);

J - - Ala or L-isomer or D-isomer amino acids, having the structure-N(R3)C(R4)(R5)C(=O)-, and R3- H or C1-C8-alkyl; R4- H or C1-C3-alkyl;

R5choose from compounds: hydrogen; C1-C8-alkyl, substituted 0-2 R11; C2-C8alkenyl, substituted 0-2 R11; C2; aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S or O, with the specified heterocyclic ring substituted 0-2 R12; =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(= O)N(R13)2, -CHO, -CH2OR13, -OC(= O)R13, -OC(=O)OR13a, -OR13, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(=O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2(R13)2, -N(R13)2, -NHC(= NH)OTHER13, -C(= NH)OTHER13, =NOR13, NO2, -C(= O)NHOR13, -C(= O)NHNR13R13a, =NOR13, -B(R34)(R35), -OCH2CO2H, 2-(1-morpholino)ethoxy, -SC(= NH)other13N3, -Si(CH3)3, (C1-C5-alkyl)other16; -(C0-C6alkyl)X;

< / BR>
where q = 0, 1;

< / BR>
-(CH2)mS(O)p'(CH2)2X, where m = 1, 2, and p' = 0-2;

where X is defined below; and

R3and R4can also be taken together with the formation of

< / BR>
n = 0, 1, and X is a

< / BR>
R3and R5can be an alternative together with about what SUP> and R5can be an alternative together with the formation of -(CH2)u- where u = 2-5;

R16choose from connections: aminosidine group; 1-2 amino acids; 1-2 amino acids are substituted aminopterine group;

K is a D-isomer or L-isomer amino acid of the formula-N(R6)CH(R7)C(= O)-, and R6represents H or C1-C8-alkyl; R7choose from connections: -(C1-C7alkyl)X;

< / BR>
each q = 0-2, and the substitution on phenyl is in third or fourth position;

< / BR>
each q = 0-2, and the substitution on the cyclohexyl occurs in the third or fourth position;

< / BR>
-(CH2)mO-(C1-C4-alkyl)-X, where m = 1 or 2;

-(CH2)mS(O)p'-(C1-C4-alkyl)-X, where m = 1 or 2 and p' = 0-2; and X is selected from compounds

< / BR>
-N(R13R13; -C(= NH)(NH2); -SC(= NH)-NH2; -NH-C(= NH)(NHCN); -NH-C(= NCN)(NH2); -NH-C(= N-OR13)(NH2); R6and R7can be an alternative together with education

< / BR>
each q = 1 or 2 and n = 0 or 1 and X represents-NH2or

< / BR>
L - Y- (CH2)vC(=O)-, and Y is NH; N(C1-C3-alkyl), O, or S; and v = 1 or 2;

M - D-from the>R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2, -PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13; R34and R35independently selected from compounds: -OH, -F, -N(R13)2or C1-C8-alkoxy; R34and R35can be an alternative together with the formation of a cyclic ether of the forest, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; bivalent cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; cyclic aminoether boron, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1 reagents, and R31associated with (C(R23R22)nand (C(R21R1)n'on two different atoms specified carbocyclic ring.

[3] In the present invention included specified in [1] reagents, and:

n = 0 and n' = 0;

n = 0 and n' = 1;

n = 0 and n' = 2;

n = 1 and n' = 0;

n = 1 and n' = 1;

n = 1 and n' = 2;

n = 2 and n' = 0;

n = 2 and n' = 1 or

n = 2 and n' = 2.

[4] In the present invention included specified in [1] reagents, and R6represents methyl, ethyl or propyl.

[5] In the present invention included specified in [1] reagents, and R32choose from the compounds: -C(=O)-; -C(=S)-; -S(=O)2-; R1and R22independently selected from the following groups: hydrogen; C1-C8-alkyl, substituted 0-2 R11C2-C8alkenyl, substituted 0-2 R11C2-C8-quinil, substituted 0-2 R11C3-C8-cycloalkyl, substituted 0-2 R11C6-C10-bicycloalkyl, substituted 0-2 R11the connection with Ln; aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S or O, specified heterocyclic ring substituted 0-2 R12; =O, F, Cl, Br, I, -CF3, -OR13, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2N(R13)2, -CH2N(R13)2, -N(R13)2, -NHC(= NH)OTHER13, -C(= NH)OTHER13, NO2; R1and R2can alternatively be connected with the formation of a 5-7-membered carbocyclic ring, substituted 0-2 R12; when n' = 2, R1or R11can alternatively be taken together with R1or R21on adjacent carbon atom with the formation of a direct connection, thus forming a double or triple bond between carbon atoms; R22and R23can alternatively be connected with the formation of a 3-7-membered carbocyclic ring, substituted 0-2 R12; when n = 2, R22or R23can alternatively be taken together with R22or R23on adjacent carbon atom with the formation of a direct connection, thus forming a double or triple bond between adjacent carbon atoms; R1and R2, R21represents H, can alternatively be connected with the formation of a 5-8-membered Carbo, l, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(=O)N(R13)2, -CHO, -CH2OR13, -OC(= O)R13, -OC(=O)OR13a, -OR13, -OC(=O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2N(R13)2, -CH2N(R13)2, -N(R13)2, -NHC(= NH)OTHER13, -C(= NH)OTHER13, = NOR13, NO2; C1-C5-alkyl, C2-C4alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C2-C6-alkoxyalkyl, C1-C4-alkyl (substituted-NR13R14, -CF3, NO2, -SO2R13or-S(=O)R13A), aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S or O, specified heterocyclic ring substituted 0-2 R12;

R3- H or CH3;

R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2de s = 3-5; the relationship with Ln;

R3and R5can alternatively be taken together with the formation of -(CH2)t- (t = 2-4) or-CH2SC(CH3)2-; or

R7choose from: -(C1-C7-alkyl)X;

< / BR>
each q = 0-2, and the substitution on phenyl is in third or fourth position;

< / BR>
each q = 0-2, and the substitution on the cyclohexyl occurs in the third or fourth position;

< / BR>
-(CH2)mO-(C1-C4)-X, where m = 1 or 2; -(CH2)mS-(C1-C4)-alkyl, where m = 1 or 2; and X is chosen from-NH-C(=NH)(NH2), -OTHER13, -C(=NH)(NH2), -SC(NH)-NH2;

R6and R7can be an alternative together with education

< / BR>
where n = 0 or 1 and X represents-NH2or-NH-C(=NH)(NH2);

L - Y - (CH2)vC(=O)-, and Y is NH, N(C1-C3alkyl), O, or S; and v = 1 or 2;

M - D-isomer or L-isomer amino acid formula

< / BR>
and q' = 0-2;

R17represents H, C1-C3-alkyl;

R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2, -PO(OR13R13, -SO2NH-heteroaryl>NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13;

R34and R35independently selected from-OH, -F, -NR13R14or C1-C8-alkoxy;

R34and R35can be an alternative together with the formation of: a cyclic ether boron, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; bivalent cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; cyclic aminoether boron, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms, independently selected from N, S or O.

[6] In the present invention included specified in [1] reagents, and R31selected from the group consisting of

(a) 6-membered saturated, partially saturated or aromatic carbocyclic rings, substituted 0-3 R10or R10aand the optional ima is symbolic carbocyclic ring, substituted 0-3 R10or R10aand optionally having a connection with the Ln; or

(in) 14-membered saturated, partially saturated or aromaticheski fused tricyclic carbocyclic rings, and substituted 0-3 R10or R10aand optionally having a connection with the Ln.

[7] In the present invention included specified in [1] reagents, and R31selected from the group consisting of (a) 6-membered saturated, partially saturated or aromatic carbocyclic ring of formula

< / BR>
with any relationship, forming a carbocyclic ring may be single or double and with the specified carbocyclic ring substituted by 0 to 3 R10and optionally has a connection with Ln;

(b) a 10-membered saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula

< / BR>
with any relationship, forming a carbocyclic ring may be single or double, and said carbocyclic ring is independently substituted by 0-4 R10and optionally has a connection with Ln;

(C) a 9-membered saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula

< / BR>
PI carbocyclic ring is independently substituted by 0-4 R10and optionally has a connection with Ln.

[8] In the present invention are included above in [1] reagents, and R31choose from (a dashed line can mean both single and dual link):

< / BR>
and R31may be independently substituted by 0-3 R10or R10aand optional to have a relationship with Ln;

n = 0 or 1 and n' = 0-2.

[9] In the present invention are included above in [1] reagents, and R1and R22independently chosen from compounds of phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C5-alkoxy, -CO2R13, -C(=O)NHOR13a, -C(=O)NHN(R13)2, =NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(=O)R13-C(=O)R13, -OC(=O)OR13a, -OR13, -(C1-C4-alkyl)-OR13, -N(R13)2, -OC(= O)N(R13)2, -NR13C(= O)R13, -NR13C(= O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(= O)R13a, -SR13, -SO2N(R13)2-haloalkoxy, C1-C4-alkylcarboxylic,

C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4-alkyl (alkyl substituted by-N(R13)2, -CF3, NO2or-S(=O)R13a).

[10] In the present invention are included above in [1] reagents, and R31choose from

< / BR>
and R31may be independently substituted by 0-3 R10or R10aand may optionally have a relationship with Ln;

R32represents-C(=O)-;

n = 0 or 1;

n' = 0-2;

R1and R22independently selected from H, C1-C4-alkyl, phenyl, benzyl, phenyl-(C2-C4)-alkyl, C1-C4-alkoxy, communication with Ln;

R21and R23independently - H or C1-C4-alkyl;

R2represents H or C1-C8-alkyl;

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R13arepresents a C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkyl vasani with a single N, these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R14represents OH, H, C1-C4-alkyl or benzyl;

R10and R10aindependently chosen from compounds of H, C1-C8-alkyl, phenyl, halogen or1-C4-alkoxy;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(=O)-, and R3- H or CH3;

R4- H or C1-C3-alkyl;

R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2CH2SCH3, (CH2)sNH2, -(CH2)sNHC(=NH)(NH2), -(CH2)sOTHER16where s = 3-5; connection c Ln;

or R3and R5can be an alternative together with the formation of -(CH2)t- (t = 2-4) or-CH2SC(CH3)2-; or

R4and R5can be an alternative together with the formation of -(CH2)u- where u = 2-5;

R16choose from compounds aminosidine group;

1-2 amino acids of the Il is P>7)C(=O)-, and R6- H or C1-C8-alkyl; R7represents a

< / BR>
where q = 0 or 1;

-(CH2)rX, where r = 3-6;

< / BR>
-(CH2)mS(CH2)2X, where m = 1 or 2;

-(C3-C7-alkyl)-NH-(C1-C6-alkyl);

< / BR>
-(CH2)m-O-(C1-C4-alkyl)- NH-(C1-C6-alkyl), where m = 1 or 2;

-(CH2)m-S-(C1-C4-alkyl)- NH-(C1-C6-alkyl), where m = 1 or 2; and X represents-NH2or-NHC(=NH)(NH2); or

R6and R7can be an alternative together with education

< / BR>
where n = 0 or 1 and X is-NH2or-NHC(=NH)(NH2);

L - Y- (CH2)vC(=O)-, and Y is NH, O or S and v = 1 or 2;

M - D-isomer or L-isomer amino acid formula

< / BR>
and q' = 0-2;

R17- H; C1-C3-alkyl;

R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2, -PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10 member>
CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13.

[11] In the present invention included the reagents mentioned above in [1], and Q represents a 1,3-substituted compound phenyl of the formula (II)

< / BR>
moreover, given in the formula (II) phenyl ring may be substituted by 0-3 R10and may optionally have a relationship with Ln;

R10independently chosen from compounds of H, C1-C8-alkyl, phenyl, halogen or C1-C4-alkoxy;

R1- H, C1-C4-alkyl, phenyl, benzyl, phenyl-(C1-C4)-alkyl or Association with Ln;

R2- H or methyl;

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylalcohol, aryl, -(C1-C10alkyl)aryl, or C3-C10alkoxyalkyl; and when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2) the formula-N(R3)C(R4)(R5)C(=O)-, and R3- H or CH3;

R4- H or C1-C3-alkyl;

R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2CH2SCH3, (CH2)sNH2, (CH2)sNHC(= NH)(NH2), -(CH2)sOTHER16where s = 3-5, or Association with Ln;

R3and R5can be an alternative together with the formation of-CH2CH2CH2or R4and R5can be an alternative taken with the formation of -(CH2)uwhere u = 2-5;

R16choose from compounds aminosidine group; 1-2 amino acids, or 1-2 amino acids are substituted aminopterine group;

K - L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R6- H or C1-C8-alkyl; R7represents a

< / BR>
where q = 0 or 1;

-(CH2)rX, where r = 3-6;

< / BR>
-(CH2)mS(CH2)2X, where m = 1 or 2;

-(C3-C7-alkyl)-NH-(C1-C6-alkyl)

< / BR>
-(CH2)m-O-(C1-C4-alkyl)-NH- (C1-C62or-NHC(=NH)(NH2), and X is-NH2when r = 4; or

R6and R7can be an alternative together with education

< / BR>
where n = 0, 1;

X IS-NH2or-NHC(=NH)(NH2);

L - Y- (CH2)vC(=O)-, and Y is NH, O, or v and v = 1, 2;

M - D-isomer or L-isomer amino acid formula

< / BR>
and q' = 0-2; R17- H, C1-C3-alkyl; R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3-, -CONHNSO2CF3, -PO(OR13)2, -PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13, -NHSO2NHCOR13a, NHCONHSO2R13a, -SO2NHCONHR13.

[12] In the present invention included the reagents mentioned above in [1], and Q represents a 1,3-substituted compound phenyl of the formula (II)

< / BR>
moreover, the phenyl ring of formula (II) may be substituted by 0-3 R10and R10a1
-C4-alkoxy;

R1- H, C1-C4-alkyl, phenyl, benzyl, or phenyl-(C1-C4)-alkyl;

R2- H or methyl;

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R13a- C1-10-alkyl, C3-C10-cycloalkyl, C4-12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-10-alkoxyalkyl;

R14- OH, H, C1-C4-alkyl or benzyl;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(= O)-, and R3- H or CH3; R4- H; R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2CH2SCH3, (CH2)sNH2, (CH2)sNHC(= NH)(NH2is taken together with the formation of-CH2CH2CH2-;

R16choose from compounds aminopterine group; 1-2 amino acids; 1-2 amino acids are substituted aminopterine group;

K - L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R6- H or C3-C8-alkyl; R7represents a

< / BR>
where q = 0 or 1;

-(CH2)rX, where r = 3-6;

< / BR>
-(CH2)mS(CH2)2X, where m = 1 or 2;

-(C4-C7-alkyl)-NH-(C1-C6-alkyl)

< / BR>
-(CH2)m-O-(C1-C4-alkyl)-NH- (C1-C6-alkyl), where m = 1 or 2;

-(CH2)m-S-(C1-C4-alkyl)-NH- (C1-C6-alkyl), where m = 1 or 2; and

X represents-NH2or-NHC(=NH)(NH2), and X cannot be-NH2when r = 4;

or L is a-YCH2C(=O)-, and Y is NH or O; M is a D-isomer or L-isomer amino acid formula

< / BR>
and q' = 1;

R17- H, C1-C3-alkyl;

R8choose from compounds-CO2H or-SO3R13.

[13] In the present invention are included above in [1] reagents and: phenyl ring of formula (II) has a relationship with Lnand may be further substituted 0-2 R10or R10a1
-C4-alkoxy;

R1- H;

R2- H;

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13groups associated with the same N, the above R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R14- OH, H, C1-C4-alkyl or benzyl;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)CH(R5)C(=O)-, and

R3Is H and R5- H, CH3CH2CH3CH(CH3)2CH(CH3)CH2CH3CH2CH2CH3CH2CH2CH2CH3CH2CH2SCH3CH2CH(CH3)2, (CH2)4NH2, (C3-C5-alkyl)other16; or R3- CH3and R5Is H; or R3and R5can be an alternative together with the formation of-CH2CH2CH
K - L-isomer amino acid of the formula N(CH3)CH(R7)C(=O)-, and R7- -(CH2)3NCH=(NH)(NH2);

L-NHCH2C(=O)-;

M - D-isomer or L-isomer amino acid formula

< / BR>
and q' = 1;

R4- H or CH3;

R17- H;

R8- -CO2H7, -SO3H.

[14] In the present invention are included above in [1] the reagents, and the phenyl ring of formula (II) has a relationship with Ln;

R1and R2independently selected from H and methyl;

J is chosen from D-Val, D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys - Ala, Pro, Phe, NMeGly, D-Nle, D-Phg, D-Ile, D-Phe, D-Tyr, Ala, N- -p-azidobenzoyl-D-Lys, N- p-benzoylbenzoate-D-Lys, N- tryptophanyl-D-Lys, N- o-benzoylbenzoate-D-Lys, N- p-acetylbenzoic-D-Lys, N- dansyl-D-Lys, N- glycyl-D-Lys, N- glycyl-p-benzoylbenzoate-d-Lys, N- p-vinylbenzyl-D-Lys, N- m-benzoylmethyl-D-Lys, N- o-benzoylbenzoate-D-Lys;

K is chosen from NMeArg, Arg;

L is selected from Gly, - Ala, Ala;

M is chosen from Asp; MeAsp; MeAsp; NMeAsp; D-Asp.

[15] In the present invention are included above in [1] reagents, and R31is a phenyl ring and has spasicity, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys - Ala, Pro, Phe, NMeGly, D-Nle, D-Phg, D-Ile, D-Phe, D-Tyr, Ala;

K is chosen from NMeArg;

L is selected from Gly;

M is chosen from Asp; MeAsp; MeAsp; NmeAsp; D-Asp.

[16] In the present invention are included above in [1]-[15] reagents, and Chselected from the group of compounds

< / BR>
< / BR>
< / BR>
moreover, A1- A7independently chosen in each case from the group of compounds NR40R41, S, SH, S(Pg), O, OH, PR42R43, P(O)R42R43P(S)R42R43P(NR44R42R43;

W is a bond, CH, or a spacer elements group, selected from compounds C1-C10-alkyl, substituted 0-3 R52; aryl, substituted 0-3 R52; cycloalkyl, substituted 0-3 R52; heteroseksualci, substituted 0-3 R52; aralkyl, substituted 0-3 R52and alkaryl, substituted 0-3 R52;

Warepresents a C1C10is an alkyl group or a C3-C14-carbocycle;

R40- R44each independently selected from the group of compounds: the relationship with Ln; hydrogen; C1-C10-alkyl, substituted 0-3 R52; aryl, substituted 0-3 R52; cycloalkyl, substituted 0-3 R52; heteroseksualci, substituted 0-3 R52; aralkyl, substituted 0-3 R52; alkaryl, substituted 0-3 R52the e is the electron and moreover, when one of the radicals R42or R43is an electron, the other is also an electron;

additionally, R40and R41can connect with education = C(C1-C3-alkyl)(C1-C3-alkyl);

R52independently chosen in each case from the group of compounds; the relationship with Ln, = O, F, Cl, Br, I, -CF3, -CN, -CO2R53, -C(=O)R53, -C(=O)N(R53)2, -CHO, -CH2OR53, -OC(= O)R53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, -NR53C(=O)R53, NR54C(= O)OR53a, -NR53C(= O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2R53a, -SO3H, -SO2R53a, -SR53, -S(= O)R53a, -SO2N(R53)2, -N(R53)2, -NHC(=NH)OTHER53, -C(= NH)OTHER53, = NOR53, NO2, -C(=O)NHOR53, -C(=O)NHNR53R53a, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C5-alkyl, C2-C4alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C2-C6-alkoxyalkyl, aryl, substituted 0-2 R53, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O;

R53, R53aand R54Neil, C1-C6-alkoxy, halide, nitro, cyano and trifluoromethyl; and

Pg is trialbuy protective group.

[17] In the present invention included the reagents mentioned above in [1]-[15], and Chchoose from compounds

< / BR>
< / BR>
moreover, A1- A7independently chosen in each case from the group of compounds: NR40R41, S, SH, S(Pg), OH;

W is a bond, CH, or a spacer elements group, selected from compounds C1-C3-alkyl, substituted 0-3 R52;

Warepresents a methylene group or a C3-C6-carbocycle;

R40- R44each independently selected from the group of compounds; the relationship with Ln; hydrogen; C1-C10-alkyl, substituted 0-3 R52and an electron, and when one of the radicals R40or R41is an electron, the other is also an electron, and moreover, when one of the radicals R42or R43is an electron, the other is also an electron;

additionally, R40and R41can connect with education = C(C1-C3-alkyl)(C1-C3-alkyl);

R52independently chosen in each case from the group of compounds: the relationship with L53, -OC(=O)OR53a, -OR53, -OC(=O)N(R53)2, -NR53C(=O)R53, -NR54C(= O)OR53a, -NR53C(= O)N(R53)2, -NR54SO2N(R53)2, -NR54SO2R53a, -SO3H, -SO2R53a, -SR53, -S(= O)R53a, -SO2N(R53)2, -N(R53)2, -NHC(=NH)OTHER53, -C(= NH)OTHER53, = NOR53, NO2, -C(=O)NHOR53, -C(=O)NHNR53R53a, -OCH2CO2H, 2-(1-morpholino)ethoxy,

R53, R53aand R54independently chosen in each case from the group of compounds: the relationship with LnC1-C6-alkyl.

[18] In the present invention are included above in [1]-[15] the reagents of the formula (QLn)dChand d = 1 and Chchoose from

< / BR>
moreover, A1and A4- SH or SPg;

A2and A3- NR41;

W is independently selected from the group of compounds CHR52CH2CHR52CH2CH2CHR52and CHR52C=O; and

R41and R52independently selected from hydrogen and communication c Lnand

< / BR>
moreover, A1- NH2or

N=C(C1-C3-alkyl)(C1-C3-alkyl);

W - connection;

A2- OTHER40and R40- heterocycle, substituted R52the being/SUP> represents the relationship with Ln.

[19] In the present invention are included above in [1]-[15] the reagents of the formula (QLn)dChand d = 1 and Chrepresents a

< / BR>
moreover, A1- NH2or N=C(C1-C3-alkyl)(C1-C3-alkyl);

W - connection;

A2- OTHER40and R40- heterocycle, substituted R52and a heterocycle selected from pyridine, thiazole, and R52represents the relationship with Ln.

[20] In the present invention are included above in [1]-[15] reagents and Lnrepresents the relationship between Q and Chor a compound of the formula

M1[Y1(CR55R56)h(Z1)hY2]h'-M2,

and M1- [(CH2)gZ1]g'- (CR55R56)g-;

M2- (CR55R56)g- [Z1(CH2)g]g'-;

g = 0-10;

g' = 0-1;

g = 0-10;

h = 0-10;

h' = 0-10;

n = 0-1;

Y1and Y2in each case independently selected from compounds: bond, O, NR56, C= O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR56, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S;

Z1independently chosen in each case, what we substituted 0-4 R57; heterocyclic ring system, optionally substituted 0-4 R57;

R55and R56independently chosen in each case of compounds: hydrogen; C1-C10-alkyl, substituted 0-5 R57; (C1-C10-alkyl)aryl, and aryl substituted by 0-5 R57;

R57independently chosen in each case from the group of compounds: hydrogen, OH, other58C(= O)R58, OC(= O)R58, OC(=O)OR58C(=O)OR58C(=O)NR58-, CN, SR58, SOR58, SO2R58, NHC(=O)R58, NHC(=O)OTHER58, NHC(=S)OTHER58; or alternatively, being attached to an additional molecule Q, R57independently chosen in each case from the group of compounds O, NR58, C=O, C(=O)O, OC(=O)O, C(=O)N-, C=NR58, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S; and R58independently chosen in each case from the group of compounds: hydrogen; C1-C6-alkyl; benzyl and phenyl.

[21] In the present invention are included above in [1]-[15] reagents and Lnis a compound of the formula

M1[Y1(CR55R56)h(Z1)hY2]h'-M2,

and M1- [(CH2)gZ1]g'- (CR55R56 g' = 0-1;

g = 0-10;

h = 0-10;

h'= 0-10;

h = 0-1;

Y1and Y2in each case independently selected from compounds: bond, O, NR56, C= O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR56, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S; Z1independently chosen in each case of C6-C14saturated, partially saturated or aromatic carbocyclic ring system, substituted 0-4 R57; heterocyclic ring system, optionally substituted 0-4 R57;

R55and R56independently chosen in each case of compounds: hydrogen; C1-C10-alkyl, substituted 0-5 R57; (C1-C10-alkyl)aryl, and aryl substituted by 0-5 R57;

R57independently chosen in each case from the group of compounds: hydrogen, OH, other58C(=O)R58, OC(=O)R58, OC(=O)OR58C(=O)OR58C(=O)NR58, CN, SR58, SOR58, SO2R58, NHC(= O)R58, NHC(=O)OTHER58, NHC(=S)OTHER58; or alternatively, being attached to an additional molecule Q, R57independently chosen in each case from the group of compounds O, NR58, C=O, C(=O)O, OC(=O)O, C(=O)N-, C= NR58, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S, and R57attached to dopolnitelno
-alkyl; benzyl and phenyl.

[22] In the present invention are included above in [1]-[15] reagents and Lnrepresents a

-(CR55R56)g[Y1(CR55R56)hY2]h'- (CR55R56)g-,

moreover, g = 1-10; h = 0-10; h' = 1-10; Y1and Y2in each case independently selected from connections: a connection, a bond, O, NR56, C=O, C(=O)O, OC(=O)O, C(= O)NH-, C=NR56, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S; R55and R56independently chosen in each case of compounds: hydrogen; C1-C10-alkyl, substituted 0-5 R57; (C1-C10-alkyl)aryl, and aryl substituted by 0-5 R57; R57independently chosen in each case from the group of compounds: hydrogen, OH, other58C(= O)R58, OC(= O)R58, OC(=O)OR58C(=O)OR58C(=O)NR58-, CN, SR58, SOR58, SO2R58, NHC(= O)R58, NHC(=O)OTHER58, NHC(=S)OTHER58; or alternatively, being attached to an additional molecule Q, R57independently chosen in each case from the group of compounds O, NR58, C=O, C(=O)O, OC(=O)O, C(=O)N-, C=NR58, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S, and R57attached to an additional molecule Q; and R58nezavisni] In the present invention are included above in [1]-[15] reagents, and Lnrepresents a

-(CR55R56)g[Y1(CR55R56)hY2]h'- (CR55R56)g-,

moreover, g = 1-5; h = 0-5; h' = 1 to 5; Y1and Y2in each case independently selected from compounds: O, NR56, C=O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR56, S, SO, SO2, SO3, NHC(=O) (NH)2C(=O) (NH)2C=S; R55and R56independently chosen in each case of compounds: hydrogen; C1-C10-alkyl, (C1-C10-alkyl)aryl.

[24] In the present invention are included above in [1]-[15] reagents and Lnrepresents a

-(CR55R56)g[Y1(CR55R56)hY2]h'- (CR55R56)g-,

moreover, g = 1-5; h = 0-5; h' = 1 to 5; Y1and Y2in each case independently selected from compounds: O, NR56, C=O, C(=O)O, OC(=O)O, C(=O)NH-, C=NR56, S, NHC(=O) (NH)2C(=O) (NH)2C=S; R55and R56independently chosen in each case hydrogen.

[25] In the present invention are included above in [1] the reagents, which are

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
[26] in Addition, in the present invention includes a set for cooking radiopharmaceuticals richersounds in [23] .

[27] in Addition, in the present invention are included the kit for preparing a radiopharmaceutical preparation, consisting of a certain quantity of a sterile, pharmaceutically suitable reagent, as described in [24] .

[28] in Addition, in the present invention are included the kit for preparing a radiopharmaceutical preparation, consisting of a certain quantity of a sterile, pharmaceutically suitable reagent, as described in [25] .

[29] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [1]-[15], and a radionuclide selected from the group of compounds99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[30] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [16], and a radionuclide selected from the group link99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[31] in Addition, in the present invention included radiopharmaceutical connections99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[32] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [18], and a radionuclide selected from the group of compounds99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[33] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [19], and a radionuclide selected from the group of compounds99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[34] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [20], and a radionuclide selected from the group of compounds99mTc94mTc95Tc111In62Cu 43Sc,45Ti67Ga68Ga97EN,72As,82Rb and201Tl.

[35] in Addition, in the present invention included radiopharmaceutical prni:99mTc111In and62Cu.

[36] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [22], and a radionuclide selected from the group of compounds99mTc111In and62Cu.

[37] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [23], and a radionuclide selected from the group of compounds99mTc111In and62Cu.

[38] in Addition, in the present invention included radiopharmaceutical preparation containing the complex of the reagent described in [24], and a radionuclide selected from the group of compounds:99mTc and111In.

[39] in Addition, in the present invention included radiopharmaceuticals described in [29], which are

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
[40] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) the introduction of the who[29], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[41] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of a radiopharmaceutical preparation, described in [30], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[42] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of radiopharmaceutical described in [31], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[43] in Addition, in the present invention is enabled by means of radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of radiopharmaceutical described in [32], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[44] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of radiopharmaceutical described in [33], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[45] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of radiopharmaceutical described in [34], and (ii) scanning the mammal using a device that detects from the ASEE invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of a radiopharmaceutical preparation, described in [35], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[47] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of a radiopharmaceutical preparation, described in [36], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[48] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of a radiopharmaceutical preparation, described in [37], and (ii) scanning the mammal using a device that detects from the ASEE invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of a radiopharmaceutical preparation, described in [38], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[50] in Addition, in the present invention is enabled to visually identify areas of deposition of platelets in mammals by creating images using radiopharmaceuticals, including (i) introduction to the specified mammal an effective amount of radiopharmaceutical described in [39], and (ii) scanning the mammal using a device that detects the image obtained using the radiopharmaceutical.

[51] moreover, the present invention relates to labeled compounds of formula (I)

< / BR>
or a pharmaceutically suitable salt or its predecessor, and R31represents a C6-C14saturated, partially saturated or aromatic carbocyclic ring system, substituted 0-4 R10or R10a;

R32choose from compounds-C(=O)-; -C(=S)-; -S(=O)2-; -S(=O)-; -P(= Z)(ZRhydrogen: C1-C8-alkyl, substituted 0-2 R11; C2-C8alkenyl, substituted 0-2 R11; C2-C8-quinil, substituted 0-2 R11; C3-C8-cycloalkyl, substituted 0-2 R11; aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, the specified heterocyclic ring, substituted 0-2 R12; =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(=O)N(R13)2, -CHO, -CH2OR13, =OC(=O)R13, -OC(= O)OR13a, -OR13, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2N(R13)2, -N(R13)2, -NHC(=NH)OTHER13, -C(=NH)OTHER13, =NOR13, NO2, -C(=O)NHOR13, -C(=O)NHNR13R13a, -OCH2CO2H, 2-(1-morpholino)ethoxy;

R1and R21can be an alternative connected with formation of a 3-7-membered carbocyclic ring, substituted 0-2 R12; when n' is 2, R1and R21can be an alternative taken together with R1and R21on the neighboring atom perpared;

R22and R23can alternatively be connected with the formation of a 3-7-membered carbocyclic ring, substituted 0-2 R12; when n = 2, R22and R23can be an alternative taken together with R22and R23on adjacent carbon atom with the formation of a direct connection, thus forming a double or triple bond between adjacent carbon atoms;

R1and R2when R21represents H, can alternatively be connected with the formation of a 5-8-membered carbocyclic ring, substituted 0-2 R12;

R11choose from one or more of the following compounds =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(=O)N(R13)2, -CHO, -CH2OR13, -OC(=O)R13, -OC(= O)OR13a, -OR13, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR14C(=O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(= O)R13a, -SO2N(R13)2, -N(R13)2, -NHC(=NH)OTHER13, -C(=NH)OTHER13, =NOR13, NO2, -C(= O)NHOR13, -C(= O)NHNR13R13a, -OCH2CO2H, 2-(1-morpholino)ethoxy; C1-C5-alkyl, C1-C4-UB>-C6-cycloalkane, C1-C4-alkyl (alkyl substituted by 1-5 groups that are independently selected from-NR13R14, -CF3, NO2, -SO2R13aor-S(= O)R13a, aryl, substituted 0-2 R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, the specified heterocyclic ring, substituted 0-2 R12, R12choose from one or more of the following compounds: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C5-alkoxy, -CO2R13, -C(= O)NHOR13a, -C(=O)NHN(R13)2, =NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(= O)R13, -C(=O)R13, -OC(=O)OR13a, -OR13, -(C1-C4-alkyl)-OR13, -N(R13)2, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR13C(=O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2N(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(= O)R13a, -SR13, -SO2N(R13)2C2-C6-alkoxyalkyl, methylenedioxy, atlend the>C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4-alkyl (alkyl, substituted-N(R13)2, -CF3, NO2or-S(= O)R13a);

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R14- OH, H, C1-C4-alkyl or benzyl;

R21and R23independently selected from compounds: hydrogen; C1-C4-alkyl, optionally substituted by 1-6 halogen; benzyl; R2- H or C1-C8-alkyl; R10and R10aindependently selected from one or more of the following compounds: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C32R13, -C(=O)N(R13)2, -C(=O)NHOR13a, -C(=O)NHN(R13)2, = NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(= O)R13, -C(= O)R13, -OC(= O)OR13a, -OR13, -(C1-C4-alkyl)-OR13, -N(R13)2, -OC(=O)N(R13)2, -NR13C(= O)R13, -NR13C(= O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2N(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(=O)R13a, -SR13, -SO2N(R13)2C2-C6-alkoxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkyl (including-CvFwwhere v = 1-3 and w = 1 to (2v+1), C1-C4-haloalkoxy, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4-alkyl (alkyl, substituted-N(R13)2, -CF3, NO2or-S(= O)R13a);

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(=O)-, and R3- H or C1-C8-alkyl; R4- H or C1-C3-alkyl;

R5choose from compounds: hydrogen; C1-C8-alkyl, substituted 0-2 R11; C2SUB>-cycloalkyl, substituted 0-2 R11; aryl, substituted 0-2 R12; a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, and the specified heterocyclic ring, substituted 0-2 R12; = O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C(= O)N(R13)2, -CHO, -CH2OR13, -OC(=O)R13, -OC(=O)OR13a, -OR13, -OC(=O)N(R13)2, -NR13C(= O)R13, -NR14C(= O)OR13a, -NR13C(= O)N(R13)2, -NR14SO2N(R13)2, -NR14SO2R13a, -SO3H, -SO2R13a, -SR13, -S(=O)R13a, -SO2N(R13)2, -N(R13)2, -NHC(= NH)OTHER13, -C(=NH)OTHER13, =NOR13, NO2, -C(=O)NHOR13, -C(=O)NHNR13R13a, = NOR13, -B(R34)(R35), -OCH2CO2H, 2-(1-morpholino)ethoxy; -SC(=NH)other13N3Si(CH3)3, (C1-C5-alkyl)other16; -(C0-C6-alkyl)X;

< / BR>
where q = 0,1;

< / BR>
-(CH2)mS(O)p'(CH2)2X,

where m = 1, 2, and p' = 0-2;

where X is defined below, and

R3and R5can also be taken together with the formation of

< / BR>
where n = 0, 1, and X is a

< / BR>
R3and R52
- where t = 2-4 and p' = 0-2; or

R4and R5can be an alternative together with the formation of -(CH2)u- where u = 2-5;

R16choose from connections: aminosidine group; 1-2 amino acids; 1-2 amino acids are substituted aminosidine group;

K - D-isomer or L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R6- H or C1-C8-alkyl;

R7choose from connections:

-(C1-C7-alkyl)X;

< / BR>
each q = 0-2, and the substitution on phenyl is in third or fourth position;

< / BR>
each q = 0-2, and the substitution on the cyclohexyl occurs in the third or fourth position;

< / BR>
-(CH2)m-O-(C1-C4-alkyl)-X, where m = 1 or 2;

-(CH2)mS(O)p'-(C1-C4-alkyl)-X, where m = 1 or 2 and p' = 0-2; and X is selected from compounds

< / BR>
-N(R13R13; -C(= NH)(NH2); -SC(= NH)-NH2; -NH-C(= NH)(NHCN); -NH-C(= NCN)(NH2); -NH-C(= N-OR13)(NH2); R6and R7can be an alternative together with education

< / BR>
each q = 1 or 2, and n = 0 or 1 and X represents-NH2or

< / BR>
L represents a-Y - (CH2)vC(=O)-, and Y is NH, N(C1-C3-Ala>
-C3-alkyl;

R8choose from compounds

-CO2R13; -SO3R13; -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2, -PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O); -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13;

R34and R35independently selected from compounds-OH, -F, -N(R13)2or C1-C8-alkoxy;

R34and R35can be an alternative together with the formation of a cyclic ether of the forest, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; bivalent cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; cyclic aminoether boron, where said chain or ring steikuniene compound selected from123J,125J,131J, 18F,11C,13N15O,75Br.

[52] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R31associated with (C(R23R22)nand (C(R21R1)n'through two different atoms specified carbocyclic ring.

[53] In the present invention is enabled as described in [51] directly radioactivedecay connection, and

n = 0 and n' = 0;

n = 0 and n' = 1;

n = 0 and n' = 2;

n = 1 and n' = 0;

n = 1 and n' = 1;

n = 1 and n' = 2;

n = 2 and n' = 0;

n = 2 and n' = 1 or

n = 2 and n' = 2,

[54] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R6is methyl, ethyl or propyl.

[55] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R31selected from the group of compounds consisting of

(a) 6-membered saturated, partially saturated or aromatic carbocyclic rings, substituted 0-3 R10or R10a;

(b) 8 to 11-membered saturated, partially saturated or aromatizing saturated, partially saturated or aromaticheski fused tricyclic carbocyclic rings, substituted 0-4 R10or R10a.

[56] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R31selected from the group of compounds consisting of:

(a) 6-membered saturated, partially saturated or aromatic carbocyclic ring of formula

< / BR>
with any relationship, forming a carbocyclic ring may be single or double, and said carbocyclic ring is independently substituted by 0-4 R10;

(b) a 10-membered saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula

< / BR>
with any relationship, forming a carbocyclic ring may be single or double,

and said carbocyclic ring is independently substituted by 0-4 R10or R10a;

(C) a 9-membered saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula

< / BR>
with any relationship, forming a carbocyclic ring may be single or double,

and said carbocyclic ring is independently h is dstvennogo way radioactivedecay connection and R31choose from compounds (dashed line can refer to both single and dual link):

< / BR>
n = 0 or 1 and n' = 0 to 2

[58] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R1and R22independently chosen from compounds of: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C5-alkoxy, -CO2R13, -C(= O)NHOR13a, -C(=O)NHN(R13)2, =NOR13, -B(R34)(R35), C3-C6-cycloalkane, -OC(= O)R13, -C(= O)R13, -OC(=O)OR13a, -OR13, -(C1-C4alkyl)-OR13, -N(R13)2, -OC(= O)N(R13)2, -NR13C(=O)R13, -NR13C(=O)OR13a, -NR13C(=O)N(R13)2, -NR13SO2N(R13)2, -NR13SO2R13a, -SO3H, -SO2R13a, -S(= O)R13a, -SR13, -SO2N(R13)2C2-C6-alkoxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-alkylcarboxylic, C1-C4and the -alkyl (alkyl, substituted-N(R13)2, -CF3, NO2or-S(= O)R13a);

[59] In the present invention is enabled as described in [51] directly radioactivedecay connections, and R31choose from compounds

< / BR>
< / BR>
and R31may be independently substituted by 0-3 R10or R10a;

R32- -C(=O)-,

n = 0 or 1,

n' = 0-2;

R1and R22independently selected from H, C1-C4-alkyl, phenyl, benzyl, phenyl-(C2-C4)alkyl, C1-C4-alkoxy;

R21and R23independently selected from H or C1-C4-alkyl;

R2- H or C1-C8-alkyl;

R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, Ct4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13groups are connected with a single N these R13groups can be an alternative together with the formation of -(CH210aindependently selected from H, C1-C8-alkyl, phenyl, halogen or C1-C4-alkoxy;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(=O)-, and R3- H or CH3;

R4- H or C1-C3-alkyl;

R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2CH2SCH3, (CH2)sNH2, -(CH2)sNHC(=NH)(NH2), -(CH2)sOTHER16where s = 3-5; or

R16choose from connections: aminosidine group; 1-2 amino acids, or 1-2 amino acids are substituted aminosidine group;

R3and R5can be an alternative together with the formation of -(CH2)t- (t = 2-4) or-CH2SC(CH3)2-; or

R4and R5can be an alternative together with the formation of -(CH2)u- where u = 2-5;

K - L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R6- H or C1-C8-alkyl;

R7represents a

< / BR>
where q = 0 or 1;

-(CH2)r-alkyl)

< / BR>
-(CH2)m-O-(C1-C4-alkyl)-NH- (C1-C6-alkyl), where m = 1 or 2;

-(CH2)m-S-(C1-C4-alkyl)-NH- (C1-C6)-alkyl), where m = 1 or 2; and

X represents-NH2or-NHC(=NH)(NH2);

or

R6and R7can be an alternative together with education

< / BR>
where n = 0 or 1; X represents-NH2or-NHC(=NH)(NH2);

L - Y- (CH2)vC(=O)-, and Y is NH, O or S; and v = 1 or 2; M is a D-isomer or L-isomer amino acid formula

< / BR>
and q = 0-2; R17- H, C1-C3-alkyl; R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2,

-PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O); -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13.

[60] In the present invention radioactivedecay 1,3-disubstituted compounds of the phenyl of the formula (II)

< / BR>
moreover, the shown phenyl ring of formula (II) may be further substituted by 0-3 R10;

R10independently selected from H, C1-C8-alkyl, phenyl, halogen or C1-C4-alkoxy; R1- H, C1-C4-alkyl, phenyl, benzyl, or phenyl-(C1-C4)alkyl; R2- H or methyl; R13independently selected from H, C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl; R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl; and when two R13-groups associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5or (CH2)O(CH2)-;

R14- OH, H, C1-C4-alkyl or benzyl;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(=O)-, and R3- H or CH3; R4- H or C1-C3-alkyl; R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C3 CH2CH2SCH3, (CH2)sNH2, -(CH2)sNHC(=NH)(NH2), -(CH2)sOTHER16where s = 3-5; or

R16choose from connections: aminosidine group; 1-2 amino acids, or 1-2 amino acids are substituted aminosidine group;

R3and R5can be an alternative together with the formation of-CH2CH2CH2-; or R4and R5can be an alternative together with the formation of -(CH2)uwhere u = 2-5; K - L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R6- H or C1-C8-alkyl; R7represents a

< / BR>
where q = 0 or 1;

-(CH2)rX, where r = 3-6;

< / BR>
-(CH2)mS(CH2X<where m = 1 or 2, -(C3-C7-alkyl)-NH-(C1-C6-alkyl),

< / BR>
-(CH2)m-O-(C1-C4-alkyl)- NH-(C1-C6-alkyl), where m = 1 or 2;

-(CH2)m-S-(C1-C4-alkyl)- NH-(C1-C6-alkyl), where m = 1 or 2; and

X IS-NH2or-NHC(=NH)(NH2);

where X represents NH2when r = 4; or R6and R7alternative together with education

< / BR>
where n = 0, 1, and X is-NH2or-NHC(=NH)(NH2); L IS-Y - (CH2)vC(=O),B>1
-C3-alkyl; R8choose from compounds-CO2R13, -SO3R13, -SO2OTHER14, -B(R34)(R35), -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2,

-PO(OR13R13, -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O), -SO2NH-heteroaryl (specified heteroaryl is a 5-10-membered and has 1-4 heteroatoms independently selected from N, S or O); -SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13a, -SO2NHCONHR13.

[61] In the present invention is enabled as described in [51] directly radioactivedecay connections, representing radioactivedecay 1,3-disubstituted compounds of the phenyl of the formula (II)

< / BR>
moreover, the phenyl ring of formula (II) may be further substituted by 0-3 R10or R10a;

R10or R10aindependently selected from H, C1-C8-alkyl, phenyl, halogen or C1-C4-alkoxy;

R1represents H, C1-C4-alkyl, phenyl, benzyl, or phenyl-(C1-C4)alkyl;

R2- H or methyl;

C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

R14- OH, H, C1-C4-alkyl or benzyl;

J - - Ala or L-isomer or D-isomer amino acid of the formula N(R3)C(R4)(R5)C(O)-, and R3- H or CH3; R4- H; R5- H, C1-C8-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C1-C6-cycloalkenyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3CH2SCH3CH2CH2SCH3, (CH2)sNH2, (CH2)sNHC(= NH)(NH2), (CH2)sR16where s = 3-5; R3and R5can be an alternative together with the formation of-CH2CH2CH2-;

R16choose from connections: aminosidine group; 1-2 or 1-2 amino acids amino acids, substituted amino is>C8-alkyl; R7represents a

< / BR>
where q = 0 or 1;

-(CH2)rX, where r = 3-6;

< / BR>
-(CH2)mS(CH2)X, where m = 1 or 2

-(C4-C7-alkyl)-NH-(C1-C6-alkyl)

< / BR>
-(CH2)m-O-(C1-C4-alkyl)- NH(C1-C6-alkyl), where m = 1 or 2;

-(CH2)m-S-(C1-C4-alkyl)- NH-(C1-C6-alkyl), where m = 1 or 2; and

X represents-NH2or-NHC(=NH)(NH2);

where X represents NH2when r = 4; or

L - -YCH2C(=O)-, and Y is NH or O; M is a D-isomer or L-isomer amino acid formula

< / BR>
and q = 1; R17- H, C1-C3-alkyl; R8choose from compounds-CO2H or-SO3R13.

[62] In the present invention are included directly radioactivedecay the compounds of formula (II) above, and the phenyl ring of formula (II) may be further substituted 0-2 R10or R10a;

R10or R10aindependently selected from H, C1-C8-alkyl or C1-C4-alkoxy;

R1- H,

R2- H;

R13independently selected from H, C1-C10-alkyl, C3-C10-cialkis;

R13a- C1-C10-alkyl, C3-C10-cycloalkyl, C4-C12-alkylsilanes, aryl, -(C1-C10-alkyl)aryl, or C3-C10-alkoxyalkyl;

when two R13group associated with a single N these R13groups can be an alternative together with the formation of -(CH2)2-5- or -(CH2)O(CH2)-;

R14- OH, H, C1-C4-alkyl or benzyl;

J - - Ala or L-isomer or D-isomer amino acid of the formula-N(R3)C(R4)(R5)C(= O)-, and R3Is H and R5- H, CH3CH2CH3CH(CH3)2CH(CH3)CH2CH3CH2CH2CH3CH2CH2CH2CH3CH2CH2SCH3CH2CH(CH3)2, (CH2)4NH2, (C3-C5-alkyl)other16; or R3- CH3and R5Is H; or R3and R5can be an alternative together with the formation of-CH2CH2CH2-;

R16choose from connections: aminosidine group; 1-2 amino acids, or 1-2 amino acids are substituted aminosidine group;

K - L-isomer amino acid of the formula-N(R6)CH(R7)C(=O)-, and R7represents -(CH2)3NHC(=NH)(NH2) 1; R4- H or CH3;

R17- H;

R8- -CO2H; -SO3H.

[63] In the present invention are included directly radioactivedecay the compounds of formula (II) above, and R1and R2independently selected from H, methyl;

J is chosen from D-Val, D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys - Ala, Pro, Phe, NMeGly, D-Nle, D-Phg, D-Ile, D-Phe, D-Tyr, Ala, N- p-azidobenzoyl-D-Lys, N- p-benzoylbenzoate-D-Lys, N- tryptophanyl-D-Lys, N- o-benzoylbenzoate-D-Lys, N- p-acetylbenzoic-D-Lys, Ndansyl-D-Lys, N- glycyl-D-Lys, N- glycyl-p-benzoylbenzoate-d-Lys, N- p-vinylbenzyl-D-Lys, N- m-benzoylmethyl-D-Lys, N- o-benzoylbenzoate-D-Lys;

K is chosen from NMeArg, Arg;

L is selected from Gly, - Ala, Ala;

M is chosen from Asp; MeAsp; MeAsp; NMeAsp; D-Asp.

[64] In the present invention are included directly radioactivedecay the compounds of formula (II) above, and R1and R2independently selected from H, methyl;

J is chosen from D-Val, D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys - Ala, Pro, Phe, NMeGly, D-Nle, D-Phg, D-Ile, D-Phe, D-Tyr, Ala,

K is chosen from NMeArg;
radioactiveman compound of formula (II), and R1and R2- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-2-aminobutyric acid; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Leu; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Ala; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - Gly; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Pro; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Lys; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - - Ala; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - NMeGly; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1- methyl (isomer 1); R2- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1- methyl (isomer 2); R2- H; J is D-Val; K is NMeArg; L is Gly and M - AL - Gly and M is Asp;

radioactiveman compound of formula (II), and J - D-Met, K - NMeAry, L - Gly, M - Asp, R1- H, R2- H;

radioactiveman compound of formula (II), and J is D-Abu, K - NMe-guanidine-Orn, L - Gly, M - Asp, R1- H, R2- H;

radioactiveman compound of formula (II), and J is D-Abu, K - NMe-Lys, L - Gly, M - Asp, R1- H, R2- H;

radioactiveman compound of formula (II), and R1and R2- H; J - N- p-azidobenzoyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- p-benzoylbenzoate-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- tryptophanyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- o-benzylbutyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- p-acetylbenzoic-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - Ndansyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II) is the Union of the formula (II), and R1and R2- H; J - N- glycyl-p-benzoylbenzoate-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- p-vinylbenzyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- m-benzoylmethyl-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J - N- o-benzoylbenzoate-D-Lysine; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (III)

< / BR>
and R1and R2- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Val; K - D-NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Nle; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Phg; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Phe; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (V)

(V)

and R1and R2- H; J is D-Ile; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (rmula (V), moreover, n=0; R1and R2- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VI)

< / BR>
and R1and R22- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII)

< / BR>
and R1and R2and R10- H; R10a- Cl; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10- H; R10a- I; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10- H; R10a- I; J is D-Abu; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10- H; R10a- Me; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10a- H; R10- Cl; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10a- H; R10- MeO; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10a- H; R10- Me; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VII), and R1, R2and R10- H; R10a- Cl; J is D-Abu; K is NMeArg; L is Gly and M is Asp;

glad and M - Asp;

radioactiveman compound of formula (VII), and R1, R2and R10- H; R10a- Me; J is D-Abu; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Tyr; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Val; K is NMeAmf; L is Gly and M is Asp;

radioactiveman compound of formula (II), and R1and R2- H; J is D-Val; K is NMeArg; L is Gly and M - MeAsp;

radioactiveman compound of formula (II), and R1- H; R2- CH3; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (III), and R1and R2- H; J is D-Val; K is NMeArg; L is Gly and M is Asp;

radioactiveman compound of formula (VIII), and J is D-Val; K is NMeArg; L is Gly and M is Asp;

< / BR>
[66] In the present invention included radioactivedecay compounds described in any of sections [51]-[65], and a radioactive label selected from the group of compounds:18F,11C,123J and125J.

[67] In the present invention included radioactivedecay compounds described in [66], and the radioactive label is a123J.

[68] In the present invention included a radiopharmaceutical composition comprising RA

[69] In the present invention enabled the detection of deposits of platelets in a mammal, which consists in the fact that the specified mammal is administered a radiopharmaceutical composition comprising the compound described in any of sections [51]-[67], and identify the resulting image in this mammal.

[70] In the present invention is included a method for the diagnosis of disease associated with the deposition of platelets in a mammal, which consists in the fact that the specified mammal is administered a radiopharmaceutical composition comprising the compound described in any of sections [51]-[67], and identify the resulting image in this mammal.

As noted above, cyclic compounds claimed under this invention are radioactivedecay.

The concept of "radioactivedecay" means that the cyclic glycoprotein compounds IIb/IIIa platelet contain a radioisotope, which is suitable for administration to a mammal. Such isotopes known to specialists in this field of research, and include, for example, isotopes of Halogens (chlorine, fluorine, bromine and iodine) and metals, including technetium and India. Preferably use the following radioisotope is c, 45Ti67Ga68Ga97EN,72As,82Rb and201Tl. Most preferred are the isotopes123J,111In and99mTc. Radioactivedecay compounds according to this invention can be obtained by conventional procedures, injection of radioactive labels is well known to specialists in this field of research.

Suitable methods of synthesis are described in detail below. As noted above, the cyclic compounds of glycoprotein IIb/IIIa platelet according to the present invention can be tagged with a radioactive label as a direct way (i.e. radioactive label is included in the connection itself) and indirectly (i.e. radioactive label is included in the connection via a chelating agent, which is introduced in the connection).

In addition, the radioactive label can be isotopic or non-isotropic. When radioactive isotope tagging, one group of cyclic compounds, described above, is replaced (exchanged) on the radioisotope. When non-isotropic radioactive tagging, the radioisotope is added to the cyclic connection without replacement (exchange) to any existing group. Thus, used according to the public way, and indirectly, and the label can be isotopic and non-isotropic. Such radioactive labels must be stable as chemical and metabolic point of view in accordance with accepted standards. Moreover, despite the fact that the compounds in accordance with the present invention can be in the state in different ways using different radioisotopes, as is well known to specialists in this field of research, radioactive tagging should be done so that the high binding capacity and specificity of its cyclic compounds glycoprotein GP IIb/IIIa platelet according to the present invention, in relation to the GP IIb/IIIa-receptor substantially not changed. This means that the binding capacity and specificity do not change more than about 3 logarithmic units, preferably more than about 2 logarithmic units, preferably more than 1 logarithmic unit, more preferably more than about 500% and even more preferably more than about 250%, and very preferably, the binding ability and specificity did not change at all.

For radioactivedecay given radioactivedecay compounds where a radioactive label is localized to a carbocyclic ring system R31, R5-Deputy J and R1or R22. Even more preferred compounds are the compounds of formula (II), and the radioactive label is localized to a carbocyclic ring system R31or R5- Deputy J. for preferred and most preferred compounds labeled directly, a preferred label is a label halogen, particularly radioactive iodine. For radioactivedecay compounds obtained indirectly, the preferred radioactive metals are99mTc and111In. Preferred linking groups, Lnand chelators of metals, Chdescribed below.

Discovered that radioactivedecay compounds according to the present invention can be used as radiopharmaceuticals for non-invasive creates an image diagnosis of existing or potential thromboembolic diseases, such as arterial or venous thrombosis, including, for example, unstable angina, myocardial infarction, transient ischemic krovoobrashenie, as well as blood clots and embolism caused by cardiac prostheses, such as artificial heart valves. Radioactiveman connection in accordance with the present invention can be used to detect both newly formed and older clots. In addition, they can be used to diagnose other existing or potential diseases associated with excessive expression of the receptor GPIIb/IIIa, for example in the formation of metastatic cancer cells.

The claimed compounds can be effectively used in low doses to minimize any possible risk of toxicity.

In addition, these compounds are considerably smaller than, for example, with radioactivedecay antibody 7E3, known in the art to reduce the ratio of target/background (M/f) to identify blood clots. Using the stated radioactivedecay compounds shown below in the section on industrial applicability.

In addition, when implementing the present invention discovered that the above radioactivedecay compound suitable for use as inhibitors of glycoprotein IIb/IIIa (GPIIb is described above. As already noted, GPIIb/IIIa mediates the processes of activation and platelet aggregation. Declared in accordance with the present invention radioactivedecay compounds inhibit the activation and aggregation of platelets caused by all known endogenous agonist of platelets.

Described compounds may have asymmetric centers. Unless otherwise stated, in the present invention include all chiral, diastereomeric and racemic forms. In addition, these compounds may be present many geometric isomers of olefins, C=N double bonds and similar structures, as well as in the scope of the present invention includes all stable isomers. It is essential that the claimed compounds contain asimmetricheskii substituted carbon atoms and may be isolated in optically active or racemic form. It is well known how to obtain optically active forms, for example by decomposition of racemic forms or by synthesis, using as starting material an optically active compounds. Describes two different isomers (CIS and TRANS) of the peptide bond, both can be present in the compounds described herein, and all such stable isomeric J, K, L and M declared in accordance with this invention compounds. Except that specified in the preceding sentence, all chiral, diastereomeric, racemic forms and all geometric isomeric forms are included within the scope of the invention unless specifically noted specific stereochemistry or isomeric form of the claimed compounds. D - and L-somery certain amino acids are defined here in accordance with the three-letter code, as shown in the following examples: D-Leu, D-Leu, L-Leu or L-Leu.

When any character (for example, R1-R8, m, n, p, X, Y, and so on) occurs in one formula or its component more than once, its definition in each case depends on the definition in the other. For example, if it is noted that the group is substituted by 0-2 R11then this group may be optional substituted a maximum of two R11and R11in each case, independently are selected from all possible values of R11. In the same way as shown in the example of a group-N(R13)2each of the two R13the N substituents independently chosen from all possible values of R13.

When the connection to the Deputy shows a cross connection between the two atomi and/or variables are allowed only in those cases if such combinations result in the formation of stable compounds.

Under stable connection or "stable structure" is meant a compound which is sufficiently resistant to separation from the reaction mixture and has the required purity and can be included in an effective therapeutic agent.

The term "substituted" used herein means that one or more hydrogen atoms associated with a particular atom is replaced by compound (structure) from a selected group, so that the normal valency of a given atom is not increased, and the substitution leads to the formation of stable compounds. When a Deputy is a ketone (=O), then replaced by 2 hydrogen atoms.

Used herein, the term "alkyl" means having both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "haloalkyl" presupposes the existence of both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted by one or more halogen (for example, -CvFwwhere v=1-3 and w=1 to(2v+1)); "alkoxide bridge; "cycloalkyl" refers to a saturated ring groups, including mono-, bi - or polycyclic ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and substituted; and bicycloalkyl" implies the presence of saturated bicyclic ring groups such as [3.3.0] bicicletta, [4.3.0] bicycleand, [4.4.0] bellocan (decalin), [2.2.2] bicicletta and so on. "Alkenyl" implies the presence of hydrocarbon chains as straight and branched configuration and one or more carbon-carbon bonds, which may be in any stable point, chain, such as this group of compounds include ethynyl, propenyl and similar substances; and "quinil" implies the presence of hydrocarbon chains as straight and branched configuration and one or more triple carbon-carbon bonds, which may be in any stable point in a circuit such as this group of compounds include ethinyl, PROPYNYL and similar substances.

The term "boric acid" used herein denotes a group of formula B(R34)(R35), and R34and R35independently selected from compounds-OH; -F; -NR13R14: cyclic ether boron, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; bivalent cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O; cyclic amido-ether boron, where said chain or ring contains from 2 to 20 carbon atoms, and, optionally, 1-4 heteroatoms independently selected from N, S or O. Such cyclic esters of boron, amides of boron or amido-esters of boron may also be optional substituted by 1-5 groups independently selected from R11.

Esters of boron include protective group of boric acid, including patterns, derived from diols, for example financial and pinacol education piandiong ester of boric acid and pinacoladas boric acid, respectively. Other examples of diols suitable for the formation of esters of boric acid include perferences, ethylene glycol, diethylene glycol, 1-2-ethanediol, 1,3-propandiol, 1,2-propandiol, 1,2-butanediol, 1,4-butanediol, 2,3-butanediol, 2,3-hexanediol, 1,2-hexanediol, catechol, 1,2-diisopropylamino, 5,6-decandiol, 1,2-dicyclohexylmethyl.

The term "halo" or "halogen" ICU, such as chloride, bromide, hydroxide, acetate, such as chloride, bromide, hydroxide, acetate, sulfate and the like.

Used herein, the term "aryl" or "aromatic residue" means phenyl or naphthyl. The term "carbocycle" or "carbocyclic residue" shall mean any stable 3 - or 7-membered monocyclic or bicyclic or 7 - or 14-membered bicyclic or tricyclic or polycyclic (maximum 26-membered) carbon ring, each of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles can serve as (but not limited to the list) cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, substituted or tetrahydronaphthyl (tetralin).

Used herein, the term "heterocycle" or "heterocyclic ring system" means a stable 5 to 7-membered monocyclic or bicyclic 7-10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated or aromatic and which contains carbon atoms and from one to four heteroatoms independently selected from N, O and S, and where the heteroatoms nitrogen and sulfur may be optional oxidized, and at the y, in which any of the above heterocyclic rings is fused with the benzene ring. Heterocyclic ring may be linked with my steam group via any heteroatom or carbon atom with the formation of a stable structure. Listed here heterocyclic ring can be substituted on carbon atom or nitrogen, if the resulting compound is stable. Examples of such heterocycles are benzopyranyl, thiadiazin, tetrazolyl, benzofuranyl, benzothiophene, indole, quinoline, ethenolysis or benzimidazolyl, piperidinyl, 4-piperidin, 2-pyrrolidone, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline, decahydroquinoline, octahydronaphthalene, Asotin, triazine (including 1,2,3-, 1,2,4 - and 1,3,5-triazine), 6H-1,2,5-thiadiazine, 2H, 6H-1,5,2-Dityatin, thiophene, tetrahydrothiophene, tianren, furan, Piran, isobenzofuran, chrome, Xanten, phenoxathiin, 2H-pyrrole, imidazole, pyrazole, thiazole, isothiazol, oxazol (including 1,2,4 - and 1,3,4-oxazol), isoxazol, triazole, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, 3H-indole, indole, 1H-indazole, purine, 4H-hemolysin, isoquinoline, quinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, pteridine, 4aH-carbazole, carbazole, carboline, chroman, pyrrolidin, pyrrolin, imidazolidin, imidazolin, pyrazolidine, pyrazoline, piperazine, indoline, isoindoline, Hinkley or morpholine (see connections do not limit the scope of the invention). In addition, the scope of the claims included fused ring and spiraeoideae containing, for example, the above heterocycles.

Used herein, the term "any group that, when administered to a mammal split with the formation of free hydroxyl, amino or sulfhydryl" means any group associated with the atoms O, N or S, respectively, which is cleaved from the atoms O, N or S, when the compound is administered to a mammal, with the formation of substances with the remaining free hydroxyl, amino or sulfhydryl group, respectively. Examples of groups that, when administered to a mammal are split with the formation of free hydroxyl, amino or sulfhydryl, are (but are not limited to these) C1-C6-alkyl, substituted 0-3 R11; C3-C6-alkoxyalkyl, substituted 0-3 R11; C1-C6-alkylsulphonyl, substituted 0-3 R11; C1-C6-alkoxycarbonyl, substituted 0-3 R11; C1-C6-alkylaminocarbonyl, substituted 0-3 R1112. Examples of groups that, when administered to a mammal, are split with the formation of free hydroxyl, amino or sulfhydryl include hydroxy, amino or sulfhydryl protective group, respectively.

Used herein, the term "aminosidine group" means any group, known to experts in the field of organic synthesis for the protection of amino groups. Such aminosidine group, for example, is given in the book Grune "Protective groups in organic synthesis" published by John Wiley & Sons, New York (1981) and in the book "the Peptides: analysis, synthesis, biology, vol. 3, Academic Press, New York (1981), which is given here as a reference. Can be used and any other protective groups known from the prior art. Examples aminosidine groups are (but are not limited to these) the following connections:

1) atilov, such as formyl, TRIFLUOROACETYL, phthalyl and p-toluenesulfonyl;

2) aromatic carbamates, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethanolamine, and 9-fertilityscore (Fmoc);

3) aliphatic carbamates, such as tertbutyloxycarbonyl (Boc), etoxycarbonyl, diisopropylperoxydicarbonate and allyloxycarbonyl;

6) trialkylsilyl, such as trimethylsilyl; and

7) talasoterapia compounds such as phenylthiocarbamyl and dytiscinae. In addition, under aminosidine groups are understood allowee groups, such as azidobenzoyl, p-benzoylbenzoate, o-benzylbutyl, p-acetylbenzoic, dansyl, glycyl-p-benzoylbenzoate, phenylbenzyl, m-benzoylbenzoate, benzoyl-benzoyl.

Used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the described compounds, and the source connection of the formula (I) is modified by the formation of acidic or basic salts of the compounds of formula (I). Examples of pharmaceutically acceptable salts are (but are not limited to specified mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxilic acids; and the like compounds.

Pharmaceutically acceptable salts of the claimed compounds can be obtained by the reaction of the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in their mesosternum. A list of suitable salts are found in the book Remington's Pharmacentical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, which is indicated here as a reference.

The term "amino acid", as used herein, refers to an organic compound containing both a basic amino group and an acidic carboxyl group. In addition, this concept refers to modified and unusual amino acids, such as, for example, which is given in the book Roberts and Vellaccio (1983) The Peptides, 5: 342-429, shown here as a reference. Modified or unusual amino acids which can be used in carrying out the invention, include (however, the list is not limited to these amino acids to D-amino acids, hydroxylysine, 4-hydroxyproline, ornithine, 2,4-diaminopentane acid, homoarginine, norleucine, N-methylaminomethyl acid, nafcillin, phenylglycine - phenylpropan, tertiary leucine, 4-aminocyclohexanone, N-methyl-norleucine, 3,4-dihydropyran, 4-aminopiperidin-4-carboxyla acid, 6-aminocaproic acid, TRANS-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3 - and 4-(aminomethyl)-benzoic acid, 1-aminocyclohexanecarboxylic acid, 1-aminocyclohexanecarboxylic acid assured, refer to the portion of the amino acid (as defined above), which is part of the peptide.

The term "peptide" as used herein, means connecting line structure, which consists of two or more amino acids (as defined above), connected by a peptide bond. In addition, this term refers to compounds containing both peptide and ones components, for example, pseudopeptide or residues that mimic peptides or other diaminotoluene components. Such compounds containing both peptide and ones components, can also be indicated by the term "peptide analog".

"Pseudopeptide" or "mimic peptide" means a compound that mimics the structure of amino acid residue or peptide, for example, using linking groups other than amide linkages between mimicking peptide and amino acid residue (pseudopeptide communication) and/or substituents nominaciones nature and/or modified amino acid residue.

The concept of "pseudopeptides balance" means an area of pseudopeptide or mimic peptide (defined above), which is part of the peptide.

Panatierre contact carboxyl group of one amino acid and the amino group of another amino acid.

The concept of "pseudopeptide communication" means isothermic the peptide bond, which can be used instead of, or as a substitute for the normal amide bond. Such deputies or amide "is equivalent to" connection formed by combinations of atoms, normally not found in peptides or proteins, and these substituents or links meet the spatial requirements of the amide bond and provide stabilization of the molecule with respect to enzymatic cleavage.

The concept of "Ln", "bind (linker) group" and "linker" are used herein interchangeably, refer to a group of atoms separating Q from metal chelator, Ch.

The concept of "activated Lngroup", "activated Ln", "activated linking group" or "activated linker" are used herein interchangeably, refer to a linking group that has one or more reactive groups capable to react or form a relationship with the chelator or q

The term "Ch", "metal chelator" and "chelator", used herein interchangeably, refer to a chemical that is able to contact or to form complexes with metal nuclide.

31group q

The term "ring, substituted collisuem fragment" refers to a cyclic fragment carrying the replacement group of one or more carbocyclic or heterocyclic rings.

The term "ciclismo fragment modified with linker matches tsiklitiria fragment, which is composed of Lngroup.

The term "cyclic intermediate connection means intermediate compound, which serves as a precursor to the Q group in the above-mentioned compounds.

The term "cyclic intermediate connection, a modified linker" means a cyclic intermediate compound, which is activated Lngroup.

Compounds of the present invention can be obtained by ways well known to a qualified specialist in the field of organic synthesis. Preferred methods are described, but they do not limit the invention.

Use the following abbreviations:

Acm - atsetamidometil;

D-Abu - D-2-aminobutyric acid;

5-Aca - 5-aminocaproate(5-aminohexanoic);

b-Ala, b-Ala or b-Ala - 3-aminopropionic acid;

Boc - tert-butyloxycarbonyl ronil-3-aminomethylbenzoic acid;

Boc-ON - [2-(tert-butyloxycarbonyl)-2-phenylacetonitrile;

Cl2Bzl - dichlorobenzyl;

CBz, Cbz or Z - carbobenzoxy;

DCC - dicyclohexylcarbodiimide;

DIEA - diisopropylethylamine;

Di-NMeOrn - N-aMe-N-gMe-ornithine;

DMAP - 4-dimethylaminopyridine;

HBTU - 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate;

NMeArg, or MeArg - - N-methylarginine;

MeArg - N-methylaminoethanol;

NMeAsp - - N-metilparabena acid;

NMeGly or MeGly - N-methylglycine;

NMe-Mamb - N-methyl-3-aminomethylbenzoic acid;

MMM - N-methylmorpholin;

OcHex - O-cyclohexyl;

OBzl - O-benzyl;

oSu - O-Succinimidyl;

pNP - n-nitrophenyl;

TBTU - 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyleneglutaric;

Teoc - 2-(trimethylsilyl)ethoxycarbonyl;

Tos - tosyl;

Tr - trail.

Use the following three-letter symbols of amino acids: Ala, alanine; Arg, arginine; Asn, asparagine; Asp - aspartic acid; Cys - cysteine; Gln - glutamine; Glu - glutamic acid; Gly is glycine; His - histidine; Ile is isoleucine; Leu - leucine; Lys, lysine; Met, methionine; Nle - norleucine; Phe is phenylalanine; Phg - phenylglycine; Pro - Proline; Ser - serine; Thr - threonine; Trp: tryptophan; Tys - tyrosine; Val - valine.

Connection is ialist in this area. Preferred methods include the following, but are not limited to.

In General, peptides are increasing destruction - amino C-Terminus and linking with the following corresponding protected amino group with the peptide bond, using the methods described. This procedure of removing the protection and binding repeats until then, until it reaches the desired consistency. This binding can be performed as a sequential pairwise combination of amino acids as condensation (connection) fragments (two or more amino acids) or as a combination of both of these processes or by solid-phase peptide synthesis method of Merrifield, J. Am.Chem.Soc., 85, 2149-2154 (1963), the essence of which is summarized here.

Compounds of the present invention can also be synthesized using a special automated pepresentatives equipment. In accordance with the foregoing procedure for the synthesis of peptides are described in Stewart and Young, "Solid phase peptide synthesis", 2nd ed, Pirce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Udenfriend, Eds, "the Peptides: analysis, synthesis, biology", TT 1, 2, 3, 5 and 9, Academic Press, New York, 1980-1987; Bodanzky, "Peptide chemistry: a practical textbook, Springer Verlag, New York (1988) and Bodanzky et al. "Practice with inoculate derivatives, amino acid and peptide, two peptide fragments, or cyclization of the peptide can be carried out using standard methods of binding, such as the azide method, mixed acid-anhydrous method (based on the isobutyl ether of Harborview acid), carbodiimide method (based on dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimides) method, active ester (n-nitroaniline ether, N-hydroxysuccinimidyl ester) method, Woodward reagent K, carbonyldiimidazole method, based on the phosphorus reagents such as BOP-Cl, the method of oxidation-reduction. Some of these methods (especially carbodiimide) can be strengthened by adding 1-hydroxybenzotriazole. These binding assays can be conducted in any solution (liquid phase or solid phase.

Functional groups linked amino acids can be protected during the coupling reaction to prevent the formation of destructive relationships. Protecting agents, which can be used are listed in Greene, "Protecting groups in organic synthesis", John Wiley and Sons, New York (1981) and "the Peptides: Analysis, synthesis, biology, I. 3, Academic Press, New York (1981), the essence of which is here briefly described. -karboksilnuyu. These protecting groups include: 1) alkyl esters such as methyl and tert-butyl,

2) aryl ethers such as benzyl and substituted benzyl,

3) ethers, split with alkaline treatment or processing of a weak oxidant, such as trichlorethylene and finally esters. For solid-phase synthesis of amino acid C-Terminus is attached to an insoluble carrier (usually polystyrene). These insoluble carriers contain a group capable of reacting with carboxyl education connection, resilient in the face of increasing peptide chain and easily split after that. Examples include: the oxime resin (DeGrado and Kaiser (1980) J. Org.Chem., 45, 1295-1300), chlorine - or methyl bromide-resin, hydroxymethyl resin and aminomethyl-resin. Many of these resins with already included commercially desired C-terminal amino acid is quite affordable.

- amino group of each amino acid must be protected. This can be used by any known protecting group. Examples include:

1) atilov - for example, formyl, TRIFLUOROACETYL, phthalyl, p-toluensulfonyl,

2) aromatic carbamates, such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(n-biphenyl)-1-mutilator is l (Boc), etoxycarbonyl, diisopropylperoxydicarbonate and allyloxycarbonyl;

4) cyclic alkyl carbamates, for example, cyclopentanecarbonyl and adamantanecarbonyl;

5) alkyl, such as triphenylmethyl and benzyl,

6) trialkylsilanes, for example, trimethylsilane, and

7) tiradera, for example, phenylthiocarbamyl and dytiscinae.

Preferred - aminoadenosine groups are Boc and Fmoc". Many derivatives of amino acids, suitably protected for peptide synthesis are available.

- Aminoamides group is removed prior to interaction with the next amino acid. Using Boc-group are preferred: triperoxonane acid, pure or in dichloromethane, or HCl in dioxane. The resulting ammonium salt is then neutralized (or before linking or in the process) alkaline solutions such as aqueous buffer solutions or solutions of tertiary amines in dichloromethane or dimethylformamide. Using Fmoc-preferred reagents are piperidine or substituted piperidine in dimethylformamide, however, can be used for any secondary amine or aqueous alkaline solutions. Remove zameshayushaya group in the side chain, must be protected in the process of peptide synthesis using the above-mentioned protecting groups. The specialist will take into account the fact that the selection and use of appropriate protecting groups for the above-mentioned functional groups of the side chains will depend on the amino acids and the availability (presence) of other protecting groups in the peptide. The election of such protecting groups is important for the reason that it should not be removed when removing the protection and binding - amino group.

For example, if selected for Boc protection of the amino group, suitable protecting groups are the following: n-toluensulfonyl (tosyl) ring and the nitro-group to arginine; benzyloxycarbonyl, substituted benzyloxycarbonyl, tosyl or TRIFLUOROACETYL for lysine; benzyl or alkyl esters, such as cyclopentyl for glutamic and aspartic acids; benzyl ethers for serine and threonine; benzyl ethers, substituted benzyl ethers or 2-bromobenzyloxycarbonyl for tyrosine; n-methylbenzyl, n-methoxybenzyl; atsetamidometil, benzyl or tert.butylsulfonyl for cysteine; and the indole ring of tryptophan can be left unsubstituted or secure formal group.

If aminoamide Wiseman for lysine, tributyl ether for serine, threonine and tyrosine and tert-butyl methyl ether for glutamic and aspartic acids. When building and cyclization of the peptide is complete, any protecting groups are removed. Liquid-phase synthesis protecting groups are removed in any way, which depends on the nature itself of the deleted groups. These methods are well known to the specialists.

When using solid-phase peptide synthesis must be removed from the substrate without simultaneously removing the protection of functional groups, so as not to interfere with the cyclization of the peptide. Thus, if the peptide should be subjected to cyclization in solution, the conditions of removal of the protective groups should be chosen in such a way that the free carboxylate group and a free amino group occurred without simultaneous removal of the protecting groups.

For example, the peptide may be removed from the resin by using the so-called "hydrazinolysis" and then attached azide method.

Another suitable method is the synthesis of peptides on akimovoi the resin flowing through intramolecular nucleophilic displacement from the resin, resulting in a synthesized cyclic peptide (Osapay, Profit and Taylor (1990) Tetrah is sustained fashion method of removing the protective groups of the side chains, mainly includes processing anhydride HF containing additives dimethyl sulfide, anisole, thioanisole or n-cresol at 0oC. Cleavage of the protective groups of the peptide can also be completed in other acidic reagents such as a mixture of triftoratsetata and triperoxonane acid.

Rare amino acids used in the present invention, can be synthesized by standard methods described in this area ("the Peptides: analysis, synthesis, biology, T. 5, S. 342-449, Academic Press, New York, 1981). N-alkalmazasa amino acids can be obtained using methods described previously (Cheung et al., 1977, Can. J. Chem. 55, 906; Freidinger et al., 1982, J. Org. Chem. 48, 77, 1982).

Compounds of the present invention can be obtained by the following methods.

The original materials and techniques to produce compounds will be described below, optional.

The procedure of solid-phase peptide synthesis was carried out in 25-ml polypropylene filtration tubes from BioRad Inc. or in 60-ml glass vessels from Peptides International. Akimova resin (substitution level = 0.96 mmol/g) was obtained in accordance with the methodology described: (Degrado and Kaiser (1980) J. Org.Chem., 45, 1295) or purchased from Novabiochem-butyloxycarbonyl (Boc) amino acids and other basic amino acids can be obtained commercially from companies Bachem Inc., Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTech (Luneville, KY), Peminsula Laboratories (Belmont, Ca) or Sigma (St. Louis, MO). 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate (NVTI), TWTI were purchased from Advanced ChemTech. N-Methylmorpholin (MMM) m-cresol, D-2-aminobutyric acid (Abu), trimethylacetylchloride, diisopropylethylamine (DIEA), 3-cyanobenzoic acid and [2-(tert-butyloxycarbonyl)-phenylacetonitrile] (Boc-ON) were purchased from Aldrich Chemical Company. Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl3), methanol (MeOH), pyridine and hydrochloric acid (HCl) were obtained from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), triperoxonane acid (TFA), a complex of ethyl ether, triethylamine, acetone and magnesium sulfate were obtained from EM Scince. Palladium on carbon catalyst (10% Pd) was purchased from Fluka Chemical Company. Absolute ethanol was obtained from Quantum Chemical Corporation. Thin layer chromatography was performed on silicagel 60 F254TCL plates (layer thickness 0.2 mm), which were purchased from EM Separations. TCL visualization was performed using ultracote, injection of iodine, ninhydrin and/or using opryskivatel Sakaguchi. The freezing point was determined using the apparatus Thomas Hoover or Electrothermal 9200 melting point and has not been tested. HPLC-analyses were Pro, Varian 300 or Varian 400 spectrometers. Mass spectrometry ("bombarded by fast atom") (FAB-MS) was performed on a VG Zab-E-mass spectrometer with double focusing using Xenon FAB-gun as an ion source or a Finnigan MAT 8230.

BOC-D-2-aminobutyric acid (BOC-D-Abu) was obtained by modification of the method previously described in the literature (Itoh, Hagiwara, and Kamiya (1975) Tett. Lett., 4393), as shown in the diagram

< / BR>
D-2-aminobutyric acid.

D-2-Aminobutyric acid (1.0 g, to 9.70 mmol) was dissolved in 20 ml of H2O and the solution was added Boc-ON (2,62 g, 10.6 mmol) in 20 ml of acetone. The resulting white precipitate was dissolved by addition of triethylamine (3,37 ml, and 24.2 mmol) before the formation of a pale yellow solution (pH 9, to wet pH paper). At room temperature the solution was stirred overnight under vacuum was distilled acetone. The remaining aqueous phase was extracted three times with ether, acidified to pH 2 with concentrated HCl and then was extracted three times with ethyl acetate.

The collected organic layer was dried over anhydrous magnesium sulfate and subjected to evaporation under reduced pressure, to obtain t-butyloxycarbonyl-D-2-aminobutyric acid, resembling oil (2,05 g, more than quantitative output, contains, H) of 1.73 (m, 1H), 1,90 (m, 1H), 4,29 (m, 1H), of 5.05 (m, 1H).

Synthesis of R31cyclessa explains the synthesis of specific cyclessa, which are intermediate from the group R31to Q. Other sections explain the synthesis of other cyclessa.

Synthesis of derivatives BOC-aminometilbensana acid, BOC-aminophenylarsonic acid and BOC-aminomethylenemalonate acid.

Derivative BOC-aminometilbensana acid used as cyclessa in the synthesis of compounds of the present invention, receive by known methods, for example, described in Tell.Lett., 4393 (1975); Modern Synthetic Reactions, H. O. House (1972); or (Harting et al. J. Am. Chem. Soc., 50: 3370 (1928) and as shown in the diagram

< / BR>
Hydrochloride 3-aminometilbensana acid

3-cyanobenzoic acid (10.0 g, 68 mmol) was dissolved in 200 ml of ethanol under heating on a water bath at 35-50oC. was Added concentrated HCl (6,12 ml, 73 mmol) and the resulting solution was transferred into 500-ml treated with nitrogen round bottom flask containing the catalyst is palladium on coal (1,05 g, 10% Pd/C). The suspension was stirred in an atmosphere of hydrogen for 38 hours, filtered through a glass funnel and thoroughly washed with water. The ethanol was removed under reduced pressure and the remaining aqueous layer, the suspension was transferred to a filter. By vigorously shaking all solids were dissolved and the aqueous layer was then washed twice with ether, one stripped off under reduced pressure, 150 ml and freeze-dried to obtain the above compound (hydrochloride 3-aminometilbensana acid) (8,10 g, 64%) as a beige precipitate.1HNMR (D2O) 4,27 (s, 2H), 7,60 (t, 1H), 7,72 (d, 1H), of 8.06 (d, 2H).

T-butyloxycarbonyl-3-aminomethylbenzoic acid (Boc-Mamb)

The specified connection receive in accordance with the modified standard procedures described in the literature (Itoh, Hagiwara and Kamiya (1975) Tett. , Lett., 4393). 3-Aminomethylbenzoic acid (in the form of cleaners containing hydrochloride salt) (3.0 g, 16.0 mmol) was dissolved in 60 ml of H2O. this solution was added Boc-ON (4,33 g, 17.6 mmol) in 60 ml of acetone, after which triethylamine (5,56 ml, and 39.9 mmol). The solution became yellow and the pH reached 9 (moist pH paper) by the addition of 1.0 ml (7.2 mmol) of triethylamine. The solution was mixed overnight at room temperature, during which time the acetone was distilled under reduced pressure and the remaining aqueous layer was washed three times with ether. The aqueous layer was then acidified to pH 2 2H HCl and then was extracted three times with ethyl acetate. The combined organic layers washed three times with water, dried over basw and the ethyl acetate/hexane and obtained the specified substance twice (2.58 g, 64%) as a white powder tPL123-125oC;1HNMR (CDCl3) to 1.47 (s, 9H), to 4.38 (br s, 2H), 4.95 points (br s, 1H), 7,45 (t, 1H), 7,55 (d, 1H), of 8.06 (d, 2H).

Synthesis of m-butyloxycarbonyl-3-aminophenylarsonic acid T-butyloxycarbonyl-3-aminophenylalanine acid used as intermediate compounds in the synthesis of compounds of the present invention, receive by known methods, for example, described Collman and Groh (1982), J. Am.Chem. Soc., 104; 1391, and as shown in the diagram.

< / BR>
T-butyloxycarbonyl-3-aminophenylalanine acid.

A solution of 3-aminophenylacetic acid (Aldrich, 10 g, 66 mmol), di-tert-BUTYLCARBAMATE (15,8 g, 72 mmol) and DIEA (8.6 g, 66 mmol) in 50 ml of dichloromethane is stirred at room temperature overnight. The reaction mixture is concentrated, the separation between dichloromethane and water, the aqueous layer separated, acidified with 1H HCl to pH 3 and extracted with dichloromethane. The extracts are washed with water, salt solution, dried over anhydrous sodium sulfate and finally dried under reduced pressure. The resulting material was purified by recrystallization from heptane, the result was obtained by the above-mentioned compound (3.7 g, 22%) as white powder, melting point 105oC;1H NMR (CDCl3) to 7.35 (s, 1H), 7,chloride 2-aminomethylpropanol acid

Hydrochloride 2-aminometilbensana acid hydrochloride and 2-aminomethylpropanol acid used as intermediate compounds in the synthesis of the claimed compounds, get known methods, for example, as described by Naito et al. J. Antibiotics, 30: 698 (1977); or Young and Sweet J. Am.Chem. Soc., 80: 800 (1958), and as shown below

< / BR>
d-Lactam 2-aminomethylpropanol acid

This compound is obtained by modification of the method described previously in the literature (Naito et al. 1977) J. Antibiotics, 30: 698). To ice the suspension of 2-indanone (10.8 g, 82 mmole) and azeotropically (9.4 g, 82 mmole) in 115 ml of chloroform was added 25 ml of concentrated sulfuric acid so that the temperature was maintained in the range of 30-40oC. After incubation for 3 h, the reaction mixture was poured onto ice and the aqueous layer was podslushivaet concentrated ammonium hydroxide, chloroform layer was separated, washed with water, brine, dried over anhydrous magnesium sulfate and finally dried in vacuum. The product was purified by sublimation (145oC < 1 mm), and then subjected to recrystallization from benzene to obtain the above compound (5.4 g, 45%) as pale yellow crystals. TPL149-150oC;1NMR (CDCl3) 7,20 (m, 5H), shall comply with the modified method, previously described in the literature ((Naito et al. 1977) J. Antibiotics, 30: 698). A mixture of d-lactam 2-aminomethanesulfonic acid (6.4 g, 44 mmole) and 21 Il 6H HCl was heated under reflux 4 h, the Reaction mixture was treated with activated charcoal (Norit A), was filtered, dried, and distillation residues triturated with acetone. By filtering the received above-mentioned compound (5.5 g, 62%) as colorless crystals. TPL168oC (dec);1H NMR (D6-DMSO) 12,65 (br s, 1H), 8,35 (br s, 3H), 7,50 (m, 1H), 7,35 (m, 3H), of 4.05 (ABq, 2H), 3,80 (s, 2H).

d-Lactam 2-aminometilbensana acid

The specified connection is obtained by modification of the method previously described in the literature (Danishefsky et al. (1975) J.Org. Chem. 40: 796).

A mixture of o-methyl ether Truelove acid (45 g, 33 mol), N-bromosuccinimide (57 g, 21 mol) and Dibenzoyl peroxide (0.64 g) in 175 ml of carbon tetrachloride was heated under reflux for 4 hours. The cooled reaction mixture was filtered, dried under reduced pressure, re-dissolved in 250 ml of methanol was concentrated by adding ammonium hydroxide (74 ml, 1.11 mol). The reaction mixture is then boiled under reflux for 5 hours, concentrated, filtered, the precipitate washed with water, then ether. The resulting product B>150oC;1H NMR (CDCl3) of 7.90 (d, 1H), 7,60 (t, 1H), 7,50 (t, 2H), 7,00 (br s, 1H), 4,50 (s, 2H).

Hydrochloride 2-aminometilbensana acid

This connection get in the way described for hydrochloride 2-aminomethylpropanol acid. Lactam (3.5 g, 26 mmol) was converted into the specified connection (2.4 g, 50%) as colorless crystals.

TPL233oC (dec);1H NMR (D6- DMSO), 13,40 (br s, 1H), 8,35 (br s, 3H), with 8.05 (d, 1H), 7,60 (m, 3H), 4,35 (br s, 2H).

Synthesis of intermediate cyclic compounds

This section discloses the synthesis of certain intermediate cyclic compounds, they perform the role of the predecessor of Q groups in the claimed compounds (QLn)dCn; (Q)d, Ln-Ch. These compounds can be directly in the state of radioisotopes or modified by the accession of the linker group (s) or chelator (chelators).

T-Butyloxycarbonyl-3-aminomethylbenzoic acid (Boc-Mamb) associated with akimovoi resin using a modified method described by DeGrado and Kaiser (1980). J.Org. Chem. 45, 1295, using 1 equivalent of 3-aminometilbensana acid (taking into account the degree of substitution resin, 1 equivalent of HBTU and 3 equivalents of NMM). Boc-Mamb (1 equivalent) can be Evasive 15 - 96 hours-Degree of binding is then determined or picric acid test (Sarin, Rent, Tam and Merrifield (1981), Anal. Biochem, 117, 145-157), or quantitative ninhydrin analysis (Gisin (1972) Anal.Chim. Acta, 58, 248-249). Unreacted oxime group block 0.5 trimethylacetylchloride/0.5 M diisopropylethylamine in DMF for 2 h

Removal of the Boc protecting groups are 25% TFA in DCM for 30 minutes Remaining amino acids or derivatives of amino acids bound at the 2-10-fold excess (associated with the "loading" of the first amino acid and amino acid derivative) of the corresponding amino acids or amino acid derivatives and HBTU in approximately 8 ml of DMF. The resin is then neutralized with 3 equivalents of NMM (in accordance with the number of amino acids) and the duration of the binding is from 1 h to several days. The fullness of the link is controlled by qualitative ninhydrin analysis or test of picric acid in cases where the amino acid interacted with the secondary amine. The absence of binding of the amino acids, if necessary, determined in accordance with the same results.

After the linear peptide was assembled, the N-terminal Boc group was removed by treatment with 25% TFA in DCM for 30 minutes

With the help of the method Osapay and Taylor ((1990) J. Am. Chem. Soc, 112, 6046) suspendirovanie resin in approximately 10 ml/g of DMF, adding 1 equivalent of HOAc (according to the workload of the first amino acids) and stirring at 50-60oC for 60-72 hours Then filtered through a glass funnel, the filtrate DMF evaporated, pererestorani in HOAc or a mixture of acetonitrile : H20(1:1) and was liofilizovane to obtain the protected cyclic product. He is then processed using standard procedures anhydrous HF (Stewart and Joung (1984) "Solid-phase peptide synthesis" 2nd edition, Pierce Chemical Co., 85) containing 1 ml/g of m-cresol or anisole as scavenger at 0oC for 20-60 min to remove the protective groups of the side chains. The crude product can be cleaned back-phase HPLC chromatography using a 2.5 cm preparations Vydac C18 column with a linear gradient of acetonitrile containing 0.1% TFA to obtain pure cyclic product. The following N-a-Boc-protected amino acids can be used for synthesis: Boc-Arg(Tos), Boc-N-a-MeArg(Tos), Boc-Gly, Boc-Asp (OcHex), BOC-3-aminomethyl-H-iodo-benzoic acid, Boc-D-Ile, Boc-NmeAsp (OcHex), Boc-NMe-Mamb, Boc-D-Phg, Boc-D-Asp(OBzl), Boc-L-Asp(OcHex), Boc-aMe-Asp(OcHex), Boc-bMe-Asp(OcHex), Boc-L-Ala, Boc-L-Pro, Boc-D-Nle, Boc-d-Leu, Boc-D-Val, Boc-D-2-aminobutyric acid (Boc-D-Abu), Boc-Phe, Boc-D-Ser(Bzl), Boc-D-Ala, Boc-3-aminomethylbenzoic acid (Boc-Mamb), Boc-D-Lys (2-Clz) is acid, Boc-4-aminomethylbenzoic acid or Boc-NMeGly.

Preferred N-a-Boc-protected amino acids used in the synthesis: Boc-Arg(Tos), Boc-N-a-MeArg(Tos), Boc-Gly, Boc-Asp (OcHex), Boc-D-Deu, Boc-D-Val-Boc-D-2-aminobutyric acid (Boc-D-Abu), Boc-Phe, Boc-D-Ser(Bzl), Boc-D-Ala, The BOC-3-aminomethylbenzoic acid (Boc-Mamb), Boc-D-Lys (2-Clz) Boc-Ala, Boc-D-Pro or Boc-NMeGly.

The synthesis of the claimed compounds illustrated below. The following tables give an idea of the connections that are protected in the present invention.

Cyclic connection - fragment 1 (intermediate 1)

Cyclo-(Gly-NMeArg-Gly-Asp-Mamb); the compound of formula II where J is Gly, K is NMeArg, L = Gly, M - Asp, R1=R2- H

The specified connection receive, using the basic method described below for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained based on the calculation 0,336 mmole, in order to obtain a secure cyclopeptide in the amount of 218 mg, 84%. The peptide (200 mg) in 200 ml of m-cresol were treated with anhydrous HF at 0oC for 1 h the Crude material precipitated with ether, pererestorani in aqueous HOAc, liofilizirovanny and received the connection specified in the form of a pale yellow precipitate (158 mg, greater than quantitative yield, calculated via the acetate salt). Cleanup was completed obremenitve by HPLC with espolea to obtain the TFA salt of the compounds in the form of a fluffy white precipitate (21% - selected, the final output of 16.3%).

Mass spectrum: M+H=533,26.

Cyclic fragment 2

Cyclo-(D-Ala-NMeArg-Gly-Asp-Mamb); the compound of formula II, where J is D-Ala, K is NMeArg, L = Gly, M - Asp, R1=R2- H

The specified connection receive, using the basic method described below for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Found that removing the remainder of Boc-N-MeArg(Tos) is necessary. The peptide was obtained based on the calculation 0,244 mmole in order to get protected cyclopeptide (117 mg; 61%). Peptide (110 mg) and 100 ml of m-cresol were treated with anhydrous HF at 0oC for 1 h the Crude material precipitated with ether, pererestorani in aqueous HOAc, liofilizirovanny and received the connection specified in the form of a pale yellow precipitate. Cleanup was completed obremenitve by HPLC in reverse phase preparative Vydac C18 column (2.5 cm) using a 0.25%/min gradient 2-11% acetonitrile containing 0.1% TFA salt of the compounds in the form of a fluffy white precipitate.

Mass spectrum: M+H=547,33.

Cyclic intermediate compound 3

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb); the compound of formula II, where J is D-Abu, K is NMeArg, L = Gly, M - Asp, R1=R2- H.

The specified connection receive, using the basic method described below on cyclopeptide (51 mg, 63%). Peptide (43 mg) and 50 μl of m-cresol were treated anhydrous HF at 0oC for 30 hours the Crude product is precipitated with ether, pererestorani in aqueous HOAc, liofilizirovanny, to obtain said compound in the form of a pale yellow precipitate (23 mg, 68.7 per cent calculated as the acetate salt). The cleanup was finished obremenitve by HPLC on a preparative Vydac C18 column using a 0.23%/min gradient of 7-14% acetonitrile containing 0.1% triperoxonane acid and then liofilizirovanny to obtain the TFA salt of the compounds in the form of a fluffy white precipitate (31%-allocated); the final yield of 12.4%). Mass spectrum: M+H=561,46.

Cyclic intermediate compound 3a.

Cyclo-(Abu-NMeArg-Gly-Asp-Mamb); the compound of formula II where J - Abu, K is NMeArg, L = Gly, M - Asp, R1- H; R2- H.

The specified connection receive, using the basic method described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (Cyclic intermediate compound 4). DCC/DMAP was used to attach Boc-Mamb to akimovoi resin. TBTU is used as a binding agent. Peptide receive based on 0,596 mmol to get protected cyclopeptide (182 mg, 38.4 per cent). Peptide (176 mg) and 0,176 ml of anisole was treated with anhydrous HF at 0oC for 20 min Crude mater what, 0,4% calculated on the basis of the fluoride salt). The cleanup was finished HPLC chromatography (obremenitve method) on a preparative Vydac C18 column (2.5 cm) with the use of 0.45%/min gradient of 9 to 27% acetonitrile containing 0.1% TFA, and then liofilizirovanny to obtain the TFA salt of the compounds in the form of a fluffy white precipitate (highlighted 1,92%, the final output 0,574%); FAB-MS. Mass spectrum: M+H=561,39.

Cyclic intermediate compound 4.

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb); the compound of formula II, where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1=R2- H.

A 25-ml polypropylene tube fitted with a glass Frit was added Boc-Mamb (0.126 g, 0.5 mmole) and 6 ml of DMF. This was added HBTU (0,194 g, 0.5 mmole), Aksenovo resin (0.52 g, degree of substitution = 0.96 mmol/g) and N-methylmorpholin (0,165 ml, 1.50 mmol). The suspension was stirred at room temperature for 24 hours. Then the resin is thoroughly washed (10-12 volumes): DMF (3X), MeOH (1X), DCM (3X), MeOH (2X) and DCM (3X). Quantitative ninhydrin test was determined level substitution: 0,389 mmol/g of Unreacted axisgroup were blocked as a result of processing of 0.5 M trimethylacetylchloride/0.5 M DIEA in DMF for 2 h

Further was done in the following way: (stage 1). Resin prom is adiya 3). The resin washed with DCM (3X), MeOH (1X), DCM (2X), MeOH (3X) and DMF (3X) (stage 4) Boc-Asp(OcHex) (0,613 g, 1.94 mmol), HBTU (0,753 g, 1,99 mmol), 8 ml of DMF and N-methylmorpholine (0,642 ml of 5.84 mmol) were added to the resin and the reaction was continued for 2.5 h (stage 5). The completion of the binding reaction was monitored by qualitative ninhydrin test. Stages 1-5 were repeated until then, until I got the desired consistency. Linking Boc-D-Val with NMeArg was controlled by the picric acid test.

After the linear peptide was assembled, the N-terminal T-Boc group was removed by treatment with 25% TFA in DMM (30 min). The resin thoroughly washed with DCM (3X), MeOH (2X) and DCM (3X) and then neutralized with 10% DIEA in DCM (2x1 min). The resin thoroughly washed with DCM (3X) and MeOH (3X) and dried. Half of the resin (0,101 mmol) was subjected to a "merging" (cyclically) as a result of processing 6 ml of DMF containing HOAc (5.8 ml, 0,101 mmol) and heating at 50oC for 72 h the Resin was then filtered through a glass filter and thoroughly washed with DMF. DMF-filtrate evaporated in oil, pererestorani in a mixture of acetonitrile: H2O (1:1) liofilizirovanny to obtain the desired cyclopeptide (49 mg, 60%).

Peptide (42 mg) was treated with anhydrous HF at 0oC in the presence of 50 ml of m-cresol as a scavenger) within 30 m is th HOAc and liofilizirovanny to obtain the specified connection in the form of a slightly yellow precipitate (23 mg, 70%, based on the acetate salt). Purification was carried out obremenitve by HPLC in reverse phase preparative Vydac C18 column (2.5 cm) and a 0.23%/min gradient of 7-18% acetonitrile containing 0.1% triperoxonane acid, and received triptorelin the above-mentioned compounds in the form of a fluffy white precipitate (allocated 24%, the final output of 9.4%). FAB-MS: [M+H]=575,45.

Liquid-phase synthesis of cyclic intermediate compound 4

The following abbreviations are used hereinafter for TLC solvent system: chloroform (methanol 95:5=CM;

chloroform/acetic acid 95:5=SA;

chloroform/methanol/acetic acid 95:5=SMA.

BocNMeArg(Tos)-Gly-OBzl - 25 mmol BocNMeArg(Tos) (11,07 g, BacHem), 30 mmol Gly-OBzl tosilata (10,10 g, Bachem), 25 mmol HBTU (O-benzotriazole-N, N,N',N'- tetramethyl-uraniumhexafluoride; 9,48 g, Advanced Chemtech), and 75 mmol DIEA (diisopropylethylamine: Aldrich) were dissolved in 25 ml of CH2Cl2. The reaction proceeded for 1 h, the solvent was distilled under vacuum to a syrup, which was then dissolved in 400 ml of ethyl acetate. The resulting solution was subjected to extraction (portions 150 ml) 2 5% citric acid, 1 water, 2 saturated solution of NaHCO3, 1 a saturated solution of NaCl. The organic layer was dried over MgSO4and the solvent from which the Aquum at least 1 h, the output of 14.7 g (99,5%) TLC Rf(cm)= 0,18, Rf(SA)= 0,10; NMR corresponds to the structure; FABMS M+H+= 590,43 (Theoretically expected 590,26).

NMeArg(Tos)-Gly-OBzl - 14 mmol (BocNMeArg(Tos)-Gly-OBzl (24.5 mmol) was dissolved in 30 ml of TFA, the duration of interaction 5 min, then the solvent is kept at room temperature and a residual pressure of 1 mm.

The resulting syrup was dissolved in 400 ml of ice-cold ethyl acetate and was extracted with 100 ml of ice-cold saturated solution of NaHCO3, the aqueous phase was extracted with twice 200 ml of ethyl acetate, and the mixture of the organic phase was extracted with 25 ml saturated NaCl solution. The solvent was distilled under reduced pressure to obtain a viscous VAT residue, which is triturated with 300 ml of ether. The resulting residue triturated with ether, receiving a hygroscopic substance, which was dried under vacuum: yield 10,33 g (86.2 per cent) TLC Rf(cm)= 0,03, Rf(MCA)= 0,20; NMR corresponds to the structure: FABMS M+H+= 490,21 (Theoretically 490,20).

Boc-D-Val-NMeArg(Tos)-Gly-OBzl - 9,80 mmol, NMeArg(Tos)-Gly-OBzl (4,80 g), 9,82 mmol Boc-D-Val (2,13 g, Bachem) and 10.0 mmol HBTU (3,79 g) was dissolved in 10 ml of methylene chloride. The cone was placed in an ice bath was added 20 mmol DIEA (3,48 ml). The reaction proceeded for 15 min at 0oC and 2 days at room temperature. To reactionfrom NaCl, dried over MgSO4, evaporated under reduced pressure. The resulting oily residue is triturated with 50, then with 30 ml of ether for 30 min with the following indicators: output 4,58 g (69%) TLC Rf(cm)= 0,27 (contains also spot next to the study, which corresponds to the aromatic contamination removed with rubbing the product in the next stage); NMR corresponds to the structure; FABMS M+H+= 689,59 (Theoretically 689,43).

Boc-D-Val-NMeArg(Tos)-Gly - 4,50 g, Boc-D-Val-NMeArg(Tos)-Gly-OBzl (4.44 g), dissolved in 80 ml of methanol was purged with nitrogen (N2) for 10 minutes Then added to 1.30 g of Pd/C catalyst (10% Fluka lof# 273890) and let H2directly above the surface reaction. TLC showed that the reaction ends after about 0.5 hours After 1 h the catalyst was removed by filtration through celiby filter, and the solvent is kept at 40oC under reduced pressure. The resulting precipitate was well washed with 50 ml of distilled ether, filtered and washed with petroleum ether: yield of 3.05 g (78%); TLC Rf(cm)= 0.03; Rf(MCA)= 0,37; NMR corresponds to the structure; FABMS M+H+= 599,45 (Theoretically 599,29).

L-nitrobenzophenone the oxime (Ox) - 50 g of 4-nitrobenzophenone (220 ml, Aldrich) and 30.6 g of hydroxylamine hydrochloride (Aldrich, 440 mmol who stayed under reduced pressure, was dissolved in 500 ml of ether and was extracted (200 ml portions) 5% citric acid (twice) and saturated NaCl solution (1 time), dried over MgSO4was evaporated under reduced pressure, and pulverized with ether to obtain 44,35 g (83%) of the oxime as a mixture of CIS - and TRANS-isomers: TLC Rf(cm)= 0,50; Rf(MCA)= 0,82; NMR corresponds to the structure; FABMS M+H+= 242,07 (Theoretically 242,07).

BocMamb-Ox - 22 mmole BocMamb (5,522 g), 20 mmol nitrobenzophenone of oxime (4,84 g) and 20 mmol DMAP (4-dimethylaminopyridine; Aldrich) was dissolved in 40 ml of CH2Cl2. The flask was placed in a dish with ice and added 21 mmol DCC (dicyclohexylcarbodiimide) to 4.33 g). The reaction was walking on ice 30 min at room temperature over night. The resulting dicyclohexylphosphino was filtered and washed with 40 ml of methylene chloride. The filtrate is evaporated under reduced pressure at room temperature until syrupy residue, which was dissolved in 400 ml of ethyl acetate. This solution was extracted (150 ml each time): twice with 5% citric acid, 1 - water, 2 times with saturated solution of NaHCO3, 1 time with saturated solution of NaCl. The organic layer is dried over MgSO4the solvent is distilled off under reduced pressure. Get the rest of raster is B> = 0,41; Rf(MCA)= 0,66; NMR corresponds to the structure; FABMS M+H+= 476,30 (Theoretically 476,18).

TFA-Mamb-Ox-BocMamb-Ox, 7,4 g (of 15.5 mmol) was dissolved in 30 ml of methylene chloride + 10 ml of TFA (25% TFA). The reaction proceeded at room temperature for 1 h, the solvent evaporated under reduced pressure for 20 min at room temperature, then 15 min at 40oC. the Resulting syrup is triturated with ether (200 ml) and 5oC. After 1 h the resulting crystals were filtered off and well washed with ether: yield 7,22 g (95%); Rf(MCA)= 0,25; NMR corresponds to the structure; FABMS M+H+= 376,22 (Theoretically 376,12).

Boc-Asp(OcHex)-Mamb-Ox - 20 mmol, Boc-Asp(OcHex) (6,308 g Bachem) and 44 mmol DIEA (7,66 mmol) was dissolved in 20 ml of DMF. Added 20 mmol HBTU (7,58 g Aldrich Chtm Tech) and the reaction was 2 min with vigorous shaking. Added TFA-Mamb-Ox (7,13 g, 15 mmol) and continued the reaction overnight at room temperature. The solvent is evaporated under reduced pressure to an oily residue which was then dissolved in 500 ml of ethyl acetate and this solution was extracted with portions of 150 ml: twice with 5% citric acid, 1 times with water, twice with saturated solution of NaHCO3once saturated NaCl solution. The organic layer was dried over MgSO4the solvent drove away under reduced pressure. (cm) = 0,55; NMR corresponds to the structure; FABMS M+H+= 673,45 (Theoretically 673,23).

TFA Asp(OcHex)-Mamb-Ox - 15 mmol of Boc-Asp(OcHex)-Mamb-Ox was dissolved in 50 ml of 35% in CH2Cl2and left for reaction for 90 minutes, the Solvent is kept under reduced pressure at room temperature for 10 minutes and Then at 40oC for 15 minutes To remove traces of TFA was added 25 ml of DMF and the solvent is kept at 50oC. the Remaining syrup is triturated with ether (200 ml), then dried under high vacuum: yield being 9.61 g (93%); Rf(MCA)= 0,45; NMR corresponds to the structure; FABMS M+H+= 573,56 (Theoretically 573,23).

Boc-D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-Mamb-Ox 10 mmol TFA Asp(OcHex)-Mamb-Ox + 10 mmol of Boc-D-Val-NMeArg(Tos)-Gly + 10 mmol HBTU + 30 mmol DIEA were dissolved in 20 ml of DMF. After 4 h the solvent drove away under reduced pressure, and the residue was transferred into a 600 ml ethyl acetate, then was extracted with 300 ml portions of a 5% citric acid, water and saturated NaCl solution. The organic layer was dried over MgSO4, evaporated under reduced pressure, triturated with ether, and dried in vacuo: yield to 9.90 g (86%); Rf(cm)= 0,10; NMR corresponds to the structure; FABMS M+H+= 1153,22 (Theoretically 1153,47).

TFA D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-Mamb-Ox

This compound was obtained from Boc-D-Val-N and the product triturated with ether: yield 9,73 g (98%); Rf(cm)= 0,10; NMR corresponds to the structure; FABMS M+H+= 1053,22 (Theoretically 1053,4).

Cyclo (D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-Mamb)

TFA D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-Mamb-Ox (1.80 g, 1.54 mmol) + 2 mmole DIEA + 2 mmole of acetic acid were dissolved in 200 ml of DMF. The mixture was heated for 2 days (50oC) and then subjected to evaporation under reduced pressure. The remainder pererestorani in 400 ml of a mixture of ethyl acetate/n-butanol (1: 1) and was extracted with portions of 200 ml: 5% citric acid (3); a saturated solution of NaCl. The organic layer was dried over MgSO4and twice triturated with 200 ml of ether: yield 1.07 g (86%); Rf(cm)= 0,10; NMR corresponds to the structure; FABMS M+H+= 811,25 (Theoretically 811,38).

Cyclo (D-Val-NMeArg-Gly-Asp-Mamb) 0.50 g of cyclo (D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-Mamb) was treated with 5 ml of HF at 0oC in the presence of 0.5 ml of anisole for 30 min, the HF was removed under reduced pressure and the obtained peptide was washed with ether, ethyl acetate and again with ether. The precipitate was dissolved in 10% acetic acid and liofilizirovanny: output 0,321 g (82% based on the acetate salt). The product was isolated from the purification efficiency of 40%, using the method described for the product obtained by solid-phase synthesis.

Crystallization of cyclic intermediate saudino, the compounds of the present invention can be isolated by crystallization of the product from organic and aqueous solvents. Zwitter-ion circular intermediate compound 4 was turned into mailovou (methanesulfonate) salt of the cyclic intermediate compound 4 by boiling under reflux and with shaking in isopropanol at the rate of 25 mg/ml and slow addition of a solution of 1.0 molar equivalent methanesulfonic acid (corresponding to water content) dissolved in isopropanol. Heating was off and the solution was cooled to 5oC in an ice bath. After 1 hour of stirring the solution was filtered and the precipitate was washed 3 times with cold isopropanol and dried under vacuum to constant weight.

The following salts of the compounds (cyclic intermediate compound 4) were obtained in this way adding 1.0 equivalent of the appropriate acid:

Cyclic intermediate compound 4 (biphenylmethanol): Twitter-ion + 1.0 equivalent biphenylmethanol acid.

Cyclic intermediate compound 4 (a-naphthalenesulfonate): Twitter-ion + 1.0 equiv. a-naphthalenesulfonate.

Cyclic intermediate compound 4 (b-Naftal the e 4 (Sol benzosulfimide): Twitter-ion + 1.0 equiv. benzosulfimide.

Cyclic intermediate compound 4 (n-toluensulfonate): Twitter-ion + 1.1 equiv. n-toluenesulfonic acid.

The following salts of the compounds (cyclic intermediate compound 4) was obtained by crystallization from aqueous systems.

Cyclic intermediate compound 4 (as sulfate):

10 mg of amorphous cyclic intermediate compound 4 (obtained by lyophilization amphoteric product from a solution of 2 molar equivalents of acetic acid in water) dissolved in 1 ml 1H H2SO4pH to 2.5.

During curing at room temperature, a precipitate may form. It is filtered off on a glass filter and dried under vacuum to constant weight.

Cyclic intermediate compound 4 (methansulfonate (Mesilla)):

100 mg of amorphous DMP 728, dissolved in 1 ml of water + 1,2 molar equivalent methansulfonate (received in the form of a 4M aqueous solution). During curing at room temperature formed a large flat crystal.

Cyclic intermediate compound 4 (in the form of salts benzosulfimide):

100 mg zwitter-ion, dissolved in ml of water + 1.2 equivalent benzosulfimide. When mywaysa a small amount of isopropanol and dried under vacuum to constant weight.

Cyclic intermediate compound 4 (n-toluensulfonate):

100 mg zwitter-ion, dissolved in ml of water + to 1.2 molar equivalent of base. During curing at room temperature, a precipitate may form. He filtered through a glass filter, dried under vacuum until constant weight.

Cyclic intermediate compound 4b

Cyclo-(D-Val-D-NMeArg-Gly-Asp-Mamb); J is D-Val; K - D-NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection is obtained using the basic method described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (i.e. cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. Receive peptide (0,596 mmol) of the calculation to obtain a secure cyclopeptide in the amount of 186 mg, and 38.6%. Peptide (183 mg) and 0,183 ml of anisole was treated with anhydrous HF 0oC for 30 minutes, the Crude product precipitated with ether, dissolved in aqueous acetonitrile. Liofilizirovanny and received the specified compound (145 mg, greater than quantitative yield based on Sol HF). A cleanup HPL chromatography on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 9 to 22.5% acetonitrile containing 0.1% TFA, and then lio; the final yield of 5.3%); FABMS: [M+H] = 575,31.

Cyclic intermediate compound 5.

Cyclo-(D-Leu-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Leu; K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the basic method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was received within 0,115 mmol, from calculation to obtain cyclopeptide in number to 92.4 mg, 98%. Peptide (92,4 mg) and 93 ml of m-cresol were treated with anhydrous HF at 0oC for 20 minutes the Crude product is precipitated with ether, dissolved in aqueous HOAc, liofilizirovanny and received the connection specified in the form of a slightly yellow precipitate (of 45.7 mg, 69% based on the acetate salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 7% to 21% acetonitrile containing 0.1% TFA and then liofilizirovanny product to obtain the TFA-salt of the compounds in the form of a fluffy white precipitate (29% selected, the final yield of 16.5%); FAB-MS: [M+H] = 589,48.

Cyclic intermediate compound 7.

Cyclo-(D-Nle-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Nle; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection receive, using the method described for qi is Ted was calculated from the 0,586 mmol, however, to get protected cyclopeptide (305 mg, 63.3 per cent). Peptide (295 mg) and 0,295 ml of anisole was treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, pererestorani in aqueous acetonitrile and liofilizirovanny, to obtain said compound (207 mg, 95.4 percent based on fluoride salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 5.4 - 18% acetonitrile containing 0.1% TFA, and then liofilizirovanny product to obtain the TFA-salt of the compounds in the form of a fluffy white precipitate (allocated 44%, the final output is 22.9%); FAB-MS: [M+H] = 589,26.

Cyclic intermediate compound 11.

Cyclo-(D-Phg-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J - D-Phg; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection was received on the basis of the method described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained from a calculation 0,611 mmol to get protected cyclopeptide (296 mg, 57,4%). Peptide (286 mg) and 286 ml of anisole was treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, dissolved Yu salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 5.4 - 18% acetonitrile containing 0.1% TFA, and then liofilizirovanny product to obtain the TFA-salt of the compounds in the form of a fluffy white precipitate (highlighted 24,2%, the final yield of 11.9%); FAB-MS: [M+H] = 609,27.

Cyclic intermediate connection 12.

Cyclo-(D-Phe-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Phe; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection is obtained on the basis of the method described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained from a calculation 0,611 mmol order to get protected cyclopeptide in the amount of 140 mg (26.7 percent). Peptide (135 mg) and is 0.135 ml of anisole was treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (108 mg, greater than quantitative yield in the calculation of the fluoride salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 7.2 - 22.5% of acetonitrile containing the precipitate (allocated 35%, the final yield of 8.7%); FAB-MS: [M+H] = 623,28.

Solid-phase synthesis of cyclic intermediate compound 13 f

Cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Lys; K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

This compound was obtained using the basic method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained from a calculation 0,586 mmol to get protected cyclopeptide (349 mg, 58,9%). Peptide (334 mg) and 334 ml of anisole was treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny, to obtain said compound in the form of a pale yellow precipitate (168 mg, 79,1% based on fluoride salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 5.4 - 14.4% of acetonitrile containing 0.1% TFA, and then liofilizirovanny product and received TFA-salt of the compounds in the form of a fluffy white precipitate (highlighted 33,6%, the final yield of 12.1%); FAB-MS: [M+H] = 604,32.

Liquid-phase synthesis of cyclic intermediate compound 13 f

Scheme illustrating the synthesis described below, crassas-Asp(OBzl) (45,80 g, 140 mmol) and HOSu(N-hydroxysuccinimide; 16,10 g, 140 mmol) in 300 ml of n-dioxane with 5-10oC was added DCC (30.20mm g, 140 mmol). The solution was stirred 30 min at 5-10oC, then the precipitate was filtered and washed his dioxane (3 x 50 mm). The collected organic phase was concentrated under reduced pressure to obtain pure oily residue, which has led to obtain a colorless precipitate (42,98 g, 73%) when grinding with diethyl ether (3 x 100 ml), NMR corresponds to the structure; TPL= 98 - 99oC; DCI-MS: [M+NH4] = 438.

Part B-Boc-Asp(OBzl)-Mamb

3-Aminomethylbenzoic acid HCl (Mamb; 13,08 g, 70,0 mmol) was dissolved in 120 ml of DMF and added DIEA (24,32 ml, 140 mmol) at change of pH from 4 to 7.5. The white suspension stirred for 30 min at room temperature before adding a solution of Boc-Asp(OBzl)-OSu (49,40 g, 70,0 mmol) in DMF (50 ml). The mixture was mixed for 24 hours, during which she turned into a Golden brown solution. The solution was added to 5% citric acid (2000 ml) and cooled at 5oC 3 hours the precipitate was filtered, washed with ice water (200 ml) and ice-cold diethyl ether (100 ml), dried under reduced pressure to obtain the specified connection in the form of a colorless precipitate (29,62 g, 92%); TPL= 149-Cl in dioxane (50 ml), was stirred 2 h, the solution was concentrated under reduced pressure to obtain the specified connection in the form of a colorless precipitate (6,80 g; 99%). DCI-MS: [M+NH4] = 374.

Part D-Boc-Lys(Tfa)-NMeArg(Tos)-Gly-OBzl.

NMeArg(Tos)-Gly-OBzl (14,40 g, 29.4 mmol), Boc-Lys(Tfa) (10.0 g, 29.4 mmol) and HBTU (11,37 g, 62,0 mmol) was dissolved in methylene chloride (40 ml). After cooling to 0oC was added DIEA (10,44 g, 62,0 mmol) and the reaction was continued for 20 min at 0oC and 2 days at room temperature. The reaction mixture of pererestorani in ethyl acetate (800 ml), was extracted with 200 ml portions of 0.2 N HCl (1x), saturated solution of NaHCO3(1x), saturated NaCl solution (2x), dried (MgSO4) and was evaporated under reduced pressure to precipitate a yellow color. Purification was carried out by a single chromatography (silica gel; 5: 1 EtOAc : acetonitrile) gave the connection specified in the form of a colorless precipitate (20,34 g, 85%). TPL78 - 85oC; DCI-MS: [M+NH4].

Part E - Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly

A solution of Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly-OBzl (11,0 g, 13.5 mmol) in methanol (200 ml) were placed in the tank of the apparatus for shaking, missed N2within 10 min and was treated with the catalyst 10% palladium on coal" (10% Pd/C, 3.6 g). In the process of shaking the container 7 times subjected to the procedure and discharge spokest of hydrogen was consumed.

The catalyst was separated by filtration through a filter of celite, and the filtrate was concentrated under reduced pressure, obtaining a residue. Rubbing with deregulirovannym diethyl ether (75 ml) to give pure product (9,18 g; 94%) as a colorless precipitate. DCI-MS: [M+H] = 724.

Part F - Boc-D-Lys(Tta)-NMeArg(Tos)-Gly-OSu

Boc-D-Lys(Tta)-NMeArg(Tos)-Gly (8.00 g, 11.0 mmol), HOSu (1,25 g to 10.8 mmol) and DCC (2,22 g to 10.8 mmol) was dissolved in DMF (75 ml) and stirred at room temperature for 2 days. The precipitate was removed by filtration and washed with DMF (2 x 15 ml). The filtrate was concentrated under reduced pressure and the resulting concentrate was dried under reduced pressure at 40oC to obtain a precipitate reddish brown (6.50 g, 72%). TPL= 66 - 69oC; FAB-MS: [M+H] = 821.

Part G - Boc-D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb.

A suspension of Boc-D-Lys(Tfa)-N-MeArg(Tos)-Gly-OSu (cent to 8.85 g to 10.8 mmol) and HCl Asp(OBzl)-Mamb (4,24 g to 10.8 mmol) in 100 ml of a mixture of dioxane: DMF (4:1) was treated DIEA (1.39 g, the 10.8 mmol) for 10 minutes the resulting mixture was stirred for 2 days at room temperature and was concentrated under reduced pressure to a syrup-like state. This residue was dissolved in ethyl acetate (300 ml) and washed with 75 ml portions of 0.2 N HCl (3x), saturated solution of NaHCO3(2x), water (1x) and saturated races> to get amber sediment (9,13 g, 78%). TPL. = 90-93oC; FAB-MS: [M+H]=1062.

Part H - HCl D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb.

Boc-D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb (8,30 g, 7.8 mmol) was partially dissolved in 4N HCl in dioxane (50 ml), stirred at room temperature for 30 min, then evaporated under reduced pressure to obtain a yellow precipitate. Rubbing with warm EtOAc (60 ml) was allowed to receive the product (of 7.65 g, 98%) as a yellow precipitate. FAB-MS: [M+H]=962.

Part I - cyclo-(D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb.

HCl D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb (3.00 g, 3,00 mmole), DIEA (of 0.77 g, 6.0 mmole) and TBTU (0,98 g, 3.0 mmole) was dissolved in DMF (100 ml). The mixture is stirred at room temperature for 22 hours and the pH was raised to 7-8 by addition of DIEA if necessary. The reaction mixture is evaporated under reduced pressure, and the resulting balance pererestorani in 110 ml of a mixture of ethyl acetate and 1-butanol (3,75:1). The organic phase was washed with 50 ml portions of 0.2 N HCl (2x), saturated solution of NaHCO3(1x), water (1x), saturated NaCl solution (1x), dried (MgSO4), was concentrated to a brown oil residue. Rubbing with diethyl ether (100 ml) gave a brown residue, which was purified by chromatography (silica gel, 5:1 EtOAc:EtOH) to obtain nisanka-(D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp-Mamb.

Cyclo-(D-Lys(Tfa)-N-MeArg(Tos)-Gly-Asp(OBzl)-Mamb (0,85 g, 0.9 mmol) was dissolved in TFA (10 ml) and cooled to minus 10oC. Triplicate acid (triftormetilfullerenov 10 ml) was slowly added to the stirred reaction mixture until then, until the temperature began to rise to -5oC. was Added anisole (2 ml) and stirring continued for 3 h at -5oC. If the reaction temperature was lowered to -78oC, was added diethyl ether (200 ml) and the reaction mixture stirred for 1 h white Precipitate was separated by filtration and washed with ice cold ether (50 ml). Sediment pererestorani in a mixture of acetone and water (1:1) (10 ml) and liofilizirovanny to obtain the product (0,63 g; 100%) as a colorless precipitate. FAB-MS: [M+H]=700.

Part K-cyclo-(D-Lys-N-MeArg-Gly-Asp-Mamb).

Cyclo-(D-Lys(Tfa)-N-MeArg-Gly-Asp-Mamb (0,63 g, 0.9 mmol) was dissolved in 1.0 M aqueous piperidine (10 ml) at 0oC and the reaction mixture was allowed to slowly warm to room temperature over 3 hours a Solution liofilizirovanny and received a yellow precipitate. Purification was carried out obremenitve by HPLC on a Vydac C18 column (21 cm) using 0,36%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then lyophilization received the specified connection (0.20 g, 90%) in the form of be is nce description.

Cyclic intermediate compound 13 r

Cyclo-(D-Ile-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Ile; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

This connection will be received, using the method described for cyclo-(D-Val-NMeArd-Gly-Asp-Mamb) (cyclic compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained from a calculation 0,611 mmol, in order to obtain a secure cyclopeptide (349 mg, 69.2 per cent). Peptide (342 mg) and 342 ml of anisole was treated with anhydrous HF at 0oC for 30 minutes the Product is then precipitated with ether, pererestorani in aqueous acetonitrile and liofilizirovanny, to obtain said compound (227 mg, 90% calculated in the calculation of the fluoride salt). Purification was carried out obremenitve by HPLC in reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient to 10.8-19.8% of acetonitrile containing 0.1% TFA, and then liofilizirovanny product to obtain the TFA-salt of the compounds in the form of a white precipitate ($22.5% of the final yield of 12.1%); FAB-MS: [M+H]= 589,34.

Cyclic intermediate compound 17

Cyclo-(D-Met-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Met; K is NMeArg, L = Gly, M - Asp, R1- H, R2- H.

The specified connection get IP the connection Boc-Mamb to the resin. The peptide was obtained from a calculation 0,179 mmol to get protected cyclopeptide (105 mg, 69.7 per cent). Peptide (105 mg) and 0,105 ml of anisole was treated with anhydrous HF at 0oC for 20 minutes the product is precipitated with ether, pererestorani in aqueous acetonitrile and liofilizirovanny to obtain the compound (72 mg, 92.3% of based on fluoride salt). Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient of 14.4-23.4% of acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of the compounds in the form of a white precipitate (highlighted by 13.2%, the final yield of 7.4%); FAB-MS: [M+H]=607,3.

Cyclic intermediate compound 18

Cyclo-(NMeGly-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J - NMeGly; K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the basic method described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained from a calculation 0.43 mmol, in order to obtain a secure cyclopeptide (205 mg, 60%). The peptide (200 mg) and 200 ml of m-cresol were treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, pererestorani in water the salt). The cleanup was finished obremenitve by HPLC in reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 7-22% acetonitrile containing 0.1% TFA, and then the product lyophilizer to get triperoxonane salt of the compound (18) in the form of a white precipitate (dedicated to 14.7%, the final yield of 7.9%); FAB-MS: [M+H]= 547,34.

Cyclic intermediate compound 24

Cyclo-(Pro-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is Pro; K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the basic method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount based on the calculation (0.43 mmol) to obtain a secure cyclopeptide (170 mg, 48,8%). Peptide (164 mg) and 164 ml of m-cresol were treated with anhydrous HF at 0oC for 30 minutes, the Crude product precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the compound (24) in the form of a yellow precipitate (101 mg, 79% in the calculation of the acetate salt). Purification was carried out obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 7-22% acetonitrile containing 0.1% TFA. Then there was the lyophilization lazylaces intermediate compound 25

Cyclo-(D-Pro-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Pro; K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

The method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0.43 mmole of the calculation to obtain secure cyclopeptide (211 mg, 60.8 per cent). The peptide (200 mg) and 200 ml of m-cresol were treated with anhydrous HF at 0oC for 30 minutes the product is precipitated with ether, pererestorani in HOAc, liofilizirovanny to obtain the compound (25) in the form of yellow crystals (145 mg, 93% in the calculation of the acetate salt). Purification was carried out obremenitve by HPLC in reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 7-22% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of the compounds (25) in the form of a white precipitate (highlighted in 6.4% of the final yield of 3.3%); FAB-MS: [M+H]=573,35.

Cyclic intermediate compound 28c

Cyclo-(b-Ala-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J - b-Ala, K is NMeArg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to a mg, 57.5 per cent). Peptide (258 mg) and 258 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (231 mg, greater than quantitative yield based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 5.4-14.4% of acetonitrile,

containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (highlighted 53,2%, the final yield of 32.5%); FAB-MS: [M+H]=547,28.

Cyclic intermediate connection 28f

Cyclo-(D-Tyr-NMeArg-Cly-Asp-Mamb); the compound of formula (II), where J is D-Tyr; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,313 mmol of calculation to obtain secure cyclopeptide (342 mg, greater than quantitative yield). Peptide (331 mg) and 0,330 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, restorany output; based on fluoride salt). Clearance made obremenitve by HPLC in reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (dedicated to 11.3%, the final output 10,8%); FAB-MS: [M+H]=639,54.

Cyclic intermediate compound 29

Cyclo-(Gly-Arg-Cly-Asp-Mamb); the compound of formula (II), where J is Gly; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection was received on the basis of the method described earlier for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of 0,283 mmol and half of it was cyklinowanie in order to get protected cyclopeptide (62 mg, 58%). Peptide 60 mg and 60 ml of m-cresol were treated with anhydrous HF at 0oC 60 minutes the product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny for the specified connection in the form of a yellow precipitate (48 mg, greater than quantitative yield based on the acetate salt). Clearance made obremenitve by HPLC in reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 0 to 9% acetonitrile containing 0.1% TFA, and then liofilizirovanny to get the tick connection 30

Cyclo-(D= Ala-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Ala; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of 0,189 mmol of calculation to obtain secure cyclopeptide (211 mg, greater than quantitative yield). Peptide (195 mg) and 195 ml of m-cresol were treated with anhydrous HF at 0oC 60 minutes the product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (125 mg, 83% based on the acetate salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 2-11% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (allocated 12.5%, the final yield of 13.8%); FAB-MS: [M+H]=533,26.

Cyclic intermediate connection 31

Cyclo-(Ala-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is Ala; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of 0,324 mmol of calculation to get samisen is the product precipitated with ether, was dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (75 mg, 97.4% of based on the acetate salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 2-11% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (dedicated to 15.5%, the final yield of 10.5%); FAB-MS: [M+H]=533,25.

Cyclic intermediate connection 32

Cyclo-(D-Val-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Val; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of rate of 0.193 mmol of calculation to obtain secure cyclopeptide (199 mg, more quantitative yield). Peptide (193 mg) and 193 ml of m-cresol were treated with anhydrous HF at 0oC 1 h the resulting product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny for this compound as a yellow residue (130 mg, 86% based on the acetate salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 2-13% acetonic is the charge allocated 57%, the final output 58,1%); FAB-MS: [M+H]= 561,22.

Cyclic intermediate connection 33

Cyclo-(D-Leu-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Leu; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of 0,202 mmol of calculation to obtain secure cyclopeptide (152 mg, 93%). Peptide (150 mg) and 150 ml of m-cresol were treated with anhydrous HF at 0oC for 1 hour. The resulting product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (78 mg, 66% based on the acetate salt). Cleaning is performed by HPLC-chromatography using reverse phase preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 5-18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (allocated 26%, the final yield of 14.8%); FAB-MS: [M+H]=575,45.

Cyclic intermediate connection 34

Cyclo-(D-Abu-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Abu; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection was obtained using the method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide would be the turn). Peptide (206 mg) and 206 ml of m-cresol were treated with anhydrous HF at 0oC 1 h the resulting product is precipitated with ether, pererestorani in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (153 mg, 99% for the acetate salt). Purification was produced by the method obremenitve high-performance liquid chromatography on a preparative Vydac C18 column (2.5 cm) using a 0.23%/min gradient 2-11% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (allocated 57%, the final output 72,2%); FAB-MS: [M+H]=547,21.

Cyclic intermediate connection 35

Cyclo-(D-Ser-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Ser; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of rate of 0.193 mmol of calculation to obtain secure cyclopeptide (224 mg, more quantitative yield). Peptide (210 mg) and 210 mg of m-cresol were treated with anhydrous HF at 0oC 1 h the resulting product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (145 mg, 89% based on alltounian 0,23%/min gradient 2-13% acetonitrile, containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (highlighted in 22% yield 27%); FAB-MS: [M+H]=549,31.

Cyclic intermediate connection 36

Cyclo-(D-Phe-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Phe; K is Arg; L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The peptide was obtained in the amount of 0,266 mmol of calculation to obtain secure cyclopeptide (202 mg, 90%). Peptide (157 mg) and 157 ml of m-cresol were treated with anhydrous HF at 0oC for 1 hour. The resulting product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (125 mg, > quantitative yield based on the acetate salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient 7-23% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (allocated 35%, the final yield of 29.3%) FAB-MS: [M+H]= 609,25.

Cyclic intermediate connection 37

Cyclo-(Phe-Arg-Gly-Asp-Mamb); the compound of formula (II), where J is Phe; K is Arg; L is Gly; and M is Asp, RoC 1 h the resulting product is precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to obtain the specified connection in the form of a yellow precipitate (214 mg, 98% based on the acetate salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 23% of acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (allocated 32%, the final yield of 31.5%); FAB-MS: [M+H]=609,26.

Cyclic intermediate connection 40

Cyclo-(D-Val-NMeAmf-Gly-Asp-Mamb); the compound of formula (II), where J is D-Val; K is NMeAmf, L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,586 mmol of calculation to obtain secure cyclopeptide (189 mg, 39.9 per cent). Peptide (189 mg) and 189 ml of anisole was treated with anhydrous HF at 0oC Casanova compound (212 mg, > quantitative yield based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient to 10.8-22.5% of acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (dedicated to 8.1%, the final yield of 4.1%); FAB-MS: [M+H]=595,23.

Cyclic intermediate compound 48a.

The specified connection can be synthesized using the methods described by Mosher et al., Tett. Lett. 29: 3183-3186, and in accordance with scheme I (see the end of the description). This method is often used to convert the primary amino group in the guanidine functional group.

Cyclic intermediate 42-45

The synthesis of cyclic intermediates 42-45 shown in scheme II.

Cyclic intermediate compounds 46 and 47

Cyclic intermediate compounds 46 and 47 receive known methods, for example, described Garigipati, Tett. Lett. (1990) 31: 1969-197 and patent Canada N 2008311 shown in scheme III. A group of aspartic acid can be protected (for example, finalley protecting group) to avoid adverse reactions.

Cyclic intermediate with h

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,586 mmol of calculation to obtain secure cyclopeptide (227 mg, 46.9 per cent). Peptide (219 mg) and 219 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (54) as a yellow residue (150 mg, 93,2 based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 7.2-16.2% of acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound (54) in the form of a white precipitate (highlighted 43.6%, and the final yield of 16.5%): FAB-MS: [M+H]=589,32.

Cyclic intermediate 55-58

The synthesis of cyclic intermediates 55-58 shown in scheme IV.

Cyclic intermediate compound 58C trainers

Cyclo-(D-Val-NMeArg-L-Ala-Asp-Mamb); the compound of formula (II), where J is D-Val; K is NMeArg, L - L-Ala; M - Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val the new resin. The peptide was obtained in the amount of 0,611 mmol of calculation to obtain secure cyclopeptide (375 mg, 74,6%). Peptide 360 mg and 0,360 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (220 mg, 83% based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (dedicated to 19.9%, the final yield of 10.6%); FAB-MS: [M+H] = 589,31.

Cyclic intermediate connection 63 and 63a

Cyclo-(D-Val-NMeArg-Gly-a-MeAsp-Mamb); the compound of formula (II), where J is D-Val; K is NMeArg; L is Gly; and M - a-MeAsp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Asp-Mamb). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,794 mmol of calculation to obtain secure cyclopeptide (237 mg, 36.1 per cent). Peptide (237 mg) and 0,237 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in water acedo produced obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile, containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound (54) in the form of a white precipitate, isomer #1 (selected at 8.36%, the final yield of 2.5%); FAB=MS: [M+H] = 589,29; isomer # 2 (highlighted 9,16%, the final yield of 2.7%); FAB=MS: [M+H] = 589,27.

Cyclic intermediate connection 64 and 64a

Cyclo-(D-Val-NMeArg-Gly-B-MeAsp-Mamb); the compound of formula (II), where J is D-Val; K is NMeArg; L is Gly; and M - B-MeAsp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,611 mmol of calculation to obtain secure cyclopeptide (201 mg, 40,0%). The peptide (200 mg) and 0.200 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (162 mg, > quantitative yield based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound (54) as b; AB=MS: [M+H] = 589,45.

Cyclic intermediate connection 64b

Cyclo-(D-Val-NMeArg-Gly-MeAsp-Mamb); the compound of formula (II), where J is D-Val; K is NMeArg; L is Gly; and M - NMeAsp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,611 mmol of calculation to obtain secure cyclopeptide (232 mg, 46.1 per cent). Peptide (225 mg) and 0,225 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (160 mg, 96.4% of based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (highlighted 28,2%, the final yield of 10.9%); FAB-MS: [M+H] = 589,42.

Cyclic intermediate connection 64c

Cyclo-(D-Val-NMeArg-Gly-D-Asp-Mamb); the compound of formula (II), where J is D-Val; K is NMeArg; L is Gly; and M is D-Asp, R1- H, R2- H.

The specified connection is unity Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,611 mmol of calculation to obtain secure cyclopeptide (257 mg, 51.9 percent). Peptide (250 mg) and 0,250 ml of anisole was treated with anhydrous HF at 0oC 30 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (192 mg, > quantitative yield based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 9 to 18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (selected for 44.4%, the final yield of 20.7%); FAB=MS: [M+H] = 575,42.

Cyclic intermediate connection 89e

Cyclo-(D-Abu-di-NMeOrn-Gly-Asp-Mamb); the compound of formula (II), where J is D-Val; K - di-NMeOrn, L is Gly; and M is Asp, R1=R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,498 mmol of calculation to obtain secure cyclopeptide (150 mg, 39.3 per cent). Peptide (150 mg) and 0.150 ml of anisole was treated with anhydrous HF at 0oC 30 is asanoha compound (93 mg, 86% based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 3.6-18% acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (dedicated to 49.3% of the final yield of 14.2%); FAB=MS: [M+H] = 533,34.

Cyclic intermediate connection 89f

Cyclo-(D-Abu-NMeArg-Gly-D-Asp-Mamb); the compound of formula (II), where J is D-Abu; K is NMeArg; L is Gly; and M is D-Asp, R1- H, R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. The peptide was obtained in the amount of 0,596 mmol of calculation to obtain secure cyclopeptide (273 mg, 57.6 per cent). Peptide (263 mg) and to 0.263 ml of anisole was treated with anhydrous HF at 0oC 20 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny to obtain the compound (218 mg, > quantitative yield based on fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient to 10.8-19.8% of acetone sediment (highlighted in 40.4% of the final yield of 21.9%); FAB=MS: [M+H] = 561,37.

Cyclic intermediate connection 89g

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb); the compound of formula (II), where J is D-Abu; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection receive, using the method previously described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound (4). DCC/DMAP method was used to attach Boc-Mamb to akimovoi resin. TBTU was used as a binding agent. The peptide was received within 0,596 mmol, in order to obtain a secure cyclopeptide (241 mg, 50.8 per cent). Peptide (235 mg) and 0,235 ml of anisole processed anhydrous HF at 0oC for 20 minutes the product is precipitated with ether, dissolved in aqueous acetonitrile and liofilizirovanny, to obtain said compound (168 mg, 98.3% in the calculation of the fluoride salt). Clearance made obremenitve by HPLC on a preparative column (Vydac C18 (2.5 cm) using a 0.23%/min gradient of 12.6-21.6% of acetonitrile containing 0.1% TFA, and then the product liofilizirovanny to obtain the TFA-salt of this compound in the form of a white precipitate (highlighted in 2.3% of final output 0,99%); FAB=MS: [M+H] = 561,36.

Cyclic intermediate connection 89h

Cyclo-(D-Ala-p-guanidino-Phe-Gly-Asp-Mamb); the compound of formula (II), where J is D-Ala; K - p-guanidino-Phe, L e TFA-salt, 14.3 mg (USD 114.9 mmol) of formamidine sulfonic acids and 18.7 mg (153,2 mmol) of 4-dimethylaminopyridine in 5 ml of ethanol in a 10-ml round-bottom flask. The mixture was boiled under reflux for 3 h, then further added 14.3 mg of formamidine sulfonic acids and 18.7 mg of 4-dimethyl-aminopyridine. After distillation for 3 h was found (using obremenitve method HPLC), the reaction was terminated by 75%. The ethanol is evaporated under reduced pressure, and the residue was purified on a preparative column (Vydac C18 (2.5 cm) with the use of 0.45%/min gradient of 0 to 18% acetonitrile with addition of 0.1% TFA, lyophilization was possible to distinguish the TFA-salt of the compounds as a white powder (28% allocated; 26,4% - end output); FAB=MS: [M+H] = 581,30.

Cyclic intermediate connection 89i

Cyclo-(D-Abu-(DiNMe, guanidine-Orn)-Gly-Asp-Mamb); the compound of formula (II), where J is D-Abu; K - diNMe, guanidine-Orn, L is Gly; and M - B-MeAsp, R1- H, R2- H.

< / BR>
Dissolved 10,53 mg (16.3 mmole) of cyclo-(D-Abu-diNMeOrn-Gly-Asp-Mamb) (TFA-salt), between 6.08 mg (48,99 mmol) of formamidine sulfonic acids and 8.00 mg (65,57 mmol) of 4-dimethylaminopyridine in 2.5 ml of ethanol in a 10-ml round-bottom flask. The mixture was boiled under reflux for 2 hours and then during the night was stirred at room meeidia, even boiled water for 2 hours, the Ethanol is evaporated under reduced pressure and the residue was purified on a preparative Vydac C18 column (2.5 cm) with the use of 0.45%/min gradient of 3.6-18% acetonitrile with addition of 0.1% TFA. Lyophilization was possible to distinguish the TFA-salt of the compounds as a white precipitate (highlighted 57,2%; final exit - 53,5%); FAB=MS: [M+H] = 575,34.

Cyclic intermediate connection 89j

Cyclo-(D-Abu-(Di-NMeLys-Gly-Asp-Mamb) compound of formula (II), where J is D-Abu; K - di-NMeLys, L is Gly; and M is Asp, R1- H, R2- H.

cyclo-(D-Abu-NMeLys-Gly-Asp-Mamb) compound of formula (II), where J is D-Abu; K - NMeLys, L is Gly; and M is Asp, R1- H, R2- H.

Di-N-methyl derivative of amino acids can be obtained based on the methods described earlier: (Olsen, J. Org. Chem. (1970 35:1912) or, on the other hand, the use of NaH/CH3I. Mono-NMe-lysine amino acid was obtained as a side product during the synthesis of the corresponding di-NMe-derived lysine. These substances were obtained using established rules and techniques of liquid-phase peptide chemistry, as described earlier.

Cyclo-(D-Abu-diNMeLys-Gly-Asp-Mamb) was obtained from 0.31% output, FAB=MS: [M+H] = 547,3.

Cyclo-(D-Abu-NMeLys-Gly-Asp-Mamb) was obtained at 0.25% of the final output, FAB=MS: [M+H] = 533,3.

Cyclic promezhutochnoye received modified conventional liquid-phase chemical method. This approach involves linking operations ether amino acids with aromatic cyclic fragment and dinitrobenzophenone of the oxime as shown in scheme V (n = 1).

Boc-Asp(OcHex)-2-aminomethylenemalonate acid

To a suspension of 2-aminomethylpropanol acid HCl (4.0 g, 20 mmol) in water (20 ml) was added NaHCO3(5.0 g, 60 mmol), then a solution of Boc-Asp(OcHex)-OS4(7.5 g, 18 mmol) in THF (20 ml). The reaction mixture was stirred for 3 hours, filtered, diluted with water, acidified using 1 n HCl, extracted with ethyl acetate. The extracts were washed with water, salt solution, dried over MgSO4and evaporated under reduced pressure. This product is triturated with ether and received the above-mentioned compound (7.0 g, 83%) as a white powder.

1H NMR (D6-DMSO) 12,40 (br s, 1H), 8,30 (br t, 1H), 7,20 (m, 5H) and 4.65 (m, 1H), 4,35 (q, 1H), 4,25 (m, 2H), the 3.65 (s, 2H), 2,70 (dd, 1H), to 2.55 (dd, 1H), 1,70 (m, 4H), of 1.40 (s, 9H), of 1.35 (m, 6H).

4,4'-Dinitrobenzophenone

The specified connection is obtained by modification of the method previously described in the literature: Chapman and Fidler (1936) J. Chem. Soc, 448; Kulin and Leffek (1973) Can. J. Chem. 51: 687). A solution of chromic anhydride (20 mg, 200 mmol) in 125 ml of water was added dropwise over 4 h to a suspension of bis-(4-nitrophenyl)methane (25 g, 97 mmol) in 300 ml of acetic sour is mperature and poured into water. The solid precipitate was separated by filtration, washed with water, 5% solution of bicarbonate of soda, water, dried in air and received a mixture (1:1) bis(4-nitrophenyl)methane and 4,4'-dinitrobenzophenone with1H NMR. This product was oxidized second portion of chromic anhydride (20 g, 200 mmol), and then performed the same procedure to obtain the crude product. Rubbing with 200 ml of benzene, which is boiled for 16 hours under reflux, resulted in the receipt of 4,4'-dinitrobenzophenone (20,8 g, 79%) as a yellow powder. A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) was added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture was heated to boiling under reflux for 2 hours, cooled at room temperature and the formed precipitate was filtered. By recrystallization from ethanol received the specified connection (14.0 g, 70%) as yellow crystals. Tpl.= 194oC;1H NMR (D6-DMSO) 12,25 (s, 1H), 8,35 (d, 2H), to 8.20 (d, 2H), 7,60 (d, 4H).

4,4'-Dinitrobenzophenone the reaction of Boc-Asp(OcHex)-2 - aminomethylenemalonate

It chilled with ice to a solution of Boc-Asp(OcHex)-2 - aminomethanesulfonic acid (3.5 g, 7.6 mmol) and 4,4'-dinitrobenzophenone the oxime (2.2 g; 7.5 mmol) in 50 ml of ethyl acetate and 5 ml of DMF was added DCC (what acetate, washed with saturated sodium bicarbonate solution, water, brine, dried over anhydrous MgSO4, evaporated to the dry state under reduced pressure. The obtained product was purified column chromatography on silica gel (EM Science, 230-400 mesh mesh) using 10: 1 dichloromethane/ethyl acetate to obtain the compound (4.3 g, 78%) as yellow crystals.

1H NMR (D6-DMSO) 8,30 (dd, 5H), 7,80 (d, 2H), 7,65 (d, 2H), to 7.15 (m, 5H) and 4.65 (m, 1H), 4,35 (q, 1H), 4,15 (m, 2H), 3,90 (s, 2H), 2,70 (dd, 1H), 2,50 (dd, 1H), 1,70 (m, 4H), of 1.40 (s, 9H), of 1.35 (m, 6H).

4,4'-Dinitrobenzophenone the reaction of Boc-D-Val-NMeArg(Tos)-Gly - Asp(OcHex)-2-aminomethylenemalonate

To a solution of 4,4-dinitrobenzophenone the reaction of Boc-Asp(OcHex)-2-aminomethylenemalonate (1.5 g, 2 mmol) in 4 ml dichloromethane was added 2 ml triperoxonane acid. The reaction mixture was stirred at room temperature for 1 h, diluted with dichloromethane, evaporated until dry under reduced pressure. The oily residue was concentrated in a strong vacuum to remove traces of excess triperoxonane acid.

To a solution of the crude TFA-salt and Boc-D-Val-NMeArg(Tos)-Gly (1.2 g, 1 mmole) in 5 ml DMF was added TBTU (640 mg, 2 mmole) and DIEA (780 mg, 6 mmol). The reaction mixture was stirred at room temperature during the 2O salt solution, dried over anhydrous magnesium sulfate and evaporated until dry under reduced pressure. The obtained product was washed with ether and received the specified compound (2.3 g, 95%) as a yellow powder. The obtained product was used without further purification.

Cyclo-(D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-2-aminomethylenemalonate acid)

To a solution of 4,4'-dinitrobenzophenone the reaction of Boc-D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-2-aminomethylpyrrolidine (1.2 g, 1 mmol) in 4 ml dichloromethane was added 2 ml triperoxonane acid. The reaction mixture was stirred at room temperature for 3 h, diluted with dichloromethane and dried by evaporation under reduced pressure. The oily residue was concentrated in high vacuum to remove traces of excess triperoxonane acid.

To a solution of the crude TFA salt in 100 ml of DMF was added acetic acid (0,50 ml to 8.7 mmol) and DIEA (1,52 ml to 8.7 mmol). The reaction mixture was stirred at 60oC for 3 days, concentrated in high vacuum, diluted with ethyl acetate and the solution was subjected to crystallization during the night. By filtering the received target compound (563 mg, 68%) as a yellow powder.

1H NMR (D6-DMSO) to 8.70 (d, 1H), 8,40 (br s, 1H), 8,301 H), of 3.45 (m, 2H), 3,05 (m, 2H), 2,80 (s, 3H), 2,80 (m, 1H), 2,60 (dd, 1H), 2,30 (s, 3H), of 1.70 (m, 6H), of 1.30 (m, 9H), of 0.95 (d, 3H), of 0.80 (d, 3H); DCl-(NH3)-MS: [M+H]=825.

Cyclo-(D-Val-NMeArg-Gly-Asp-2-aminomethylenemalonate acid)

A mixture of 352 mg (0.43 mmol) of cyclo-(D-Val-NMeArg(Tos)-Gly-Asp(OcHex)-2-aminomethanesulfonic acid and 352 μl of anisole was treated at 0oC 5 ml HF for 20 minutes, the Excess HF was removed under reduced pressure, the residue triturated with ether, dissolved in (50%) acetonitrile/water and liofilizirovanny to obtain the crude HF-salt cyclopeptide in the form of a white powder.

Purification was carried out obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using 0.8% deg/min 10-38% acetonitrile containing 0.1% triperoxonane acid to obtain the TFA-salt of the compounds (225 mg, 75%) as a white precipitate;

1H NMR (D6-DMSO) to 8.70 (d, 1H), 8,35 (d, 1H), to 8.20 (t, 1H), 8,00 (t, 1H), 7,45 (t, 1H), 7,20 (m, 3H), 7,10 (m, 1H), 7,00 (br s, 1H), 5,10 (dd, 1H), 4,50 (dt, 1H), and 4.40 (m, 2H), 3,85 (dt, 2H), 3,65 (d, 1H), 3,50 (dd, 1H), 3.45 points (d, 1H), 3,10 (m, 2H), 2,90 (s, 3H), of 2.75 (dd, 1H), to 2.55 (dd, 1H), 2,00 (m, 1H), of 1.85 (m, 1H), 1,65 (m, 1H), 1,30 (m, 2H), of 0.95 (d, 3H), of 0.95 (d, 3H), and 0.8 (d, 3H); FAB-MS: [M+H]=589.

Cyclic intermediate connection 91

Cyclo-(D-Val-NMeArg-Gly-Asp-2-aminomethylbenzoic acid)

The specified connection has been the main liquid-phase method described above cyclic intermediate 90 (n=0). Cyclic peptide (192 mg, 0.24 mmole) was subjected to removal of "protection" excess HF in the presence of anisole. Purification was carried out obremenitve by HPLC on a preparative Vydas C18 column (2.5 cm) using 0.8% deg/min 10-38% acetonitrile containing 0.1% triperoxonane acid to obtain the TFA-salt of the compounds (20 mg, 12%) as a white precipitate;

1H NMR (D6-DMSO) is 8.75 (d, 1H), and 8.50 (d, 1H), 7,65 (t, 1H), 7,60 (t, 1H), 7,50 (m, 2H), 7,40 (m, 3H), 7,00 (br s, 4H), of 5.05 (dd, 1H), 4,50 (t, 1H), 4,30 (m, 2H), 4,10 (dd, 1H), 3,70 (m, 2H), 3.15 in (q, 1H), 1,95 (m, 1H), 1,60 (m, 1H), 1,40 (m, 2H), of 1.05 (d, 3H), of 0.95 (d, 3H), of 0.95 (d, 3H); FAB-MS: [M+H]=575.

Cyclic intermediate compound 92

Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethylbenzoic acid)

The specified connection has been the main liquid-phase method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), and as shown schematically in the diagram below. Cyclic peptide (360 mg, 0.44 mmol) was subjected to removal of "protection" excess HF in the presence of anisole. Purification was performed obremenitve by HPLC on a preparative LiChrosher RP-18 column (5 cm) using a gradient of 2.3%/min 22-90% acetonitrile containing 0.1% triperoxonane acid to obtain the TFA-salt of the compounds (150 mg, 50%) as a white precipitate;

1H NMR (D6-DMSO) 12,40 (br s, 1H), of 8.95 (s, 1H), 8,55 (m, 1H), , ,70 (dd, 2H), 2,00 (m, 2H), of 1.75 (m, 1H), 1,35 (m, 2H), of 0.90 (d, 3H), of 0.85 (d, 3H); FAB-MS: [M+H]=575.

Cyclic intermediate connection 87, 88

Cyclo-(D-Val-NMeArg-Gly-Asp-4-aminomethylbenzoic acid); compound of formula (II), where J is D-Val; K is NMeArg; L is Gly; and M is Asp, R1- H, R2- H.

The specified connection was received, using the basic method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). DCC/DMAP method was used to attach Boc-4-aminometilbensana acid to akimovoi resin. The peptide was obtained in the range of 0.43 mmol order to get protected cyclopeptide (212 mg, 60.8 per cent). The peptide (200 mg) and 0.200 ml of m-cresol were treated with anhydrous HF at 0oC for 30 minutes, the Crude product precipitated with ether, dissolved in aqueous HOAc, and liofilizirovanny to the formation of the peptide in the form of a yellow precipitate (152 mg, 97% based on the acetate salt). Purification was performed obremenitve by HPLC on a preparative Vydac C18 column (2.5 cm) using a gradient of 0.23%/min 7-22% acetonitrile containing 0.1% TFA. Two peaks were allocated two isomer #1 (87) (17,1% is selected, the final yield of 9.3%) and # 2 (88) (13.4 per cent is allocated, the final yield of 7.3%); FAB-MS: [M+H]= 575,41 (isomer #1, 87); 575,44 (isomer #2, 88)

R1or R2- substituted fragments

Cyclic intermediate, which is Rahmanov.

The following diagrams, explanations, and examples disclose the receipt of this class of cyclic fragments and the corresponding cyclic intermediates.

t-Butyloxycarbonyl-N-methyl-3-aminomethylbenzoic acid (Boc-NMeMamb)

The specified connection receive in accordance with the standard method, for example, as described Olsen, J. Org. Chem (1970) 35:1912) and as shown schematically below:

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The synthesis of analogues aminometilbensana acid

Cyclic fragments corresponding to the following formula, can be obtained by standard methods, for example, as shown in the following diagram

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When R-CH3CH2CH3CH2CH2CH3CH2CH2CH2CH3CH(CH3)2C(CH3)3CH(CH3)CH2CH3, benzyl, cyclopentyl, cyclohexyl; see scheme 1.

when R = CH3CH2CH2CH2CH3, phenyl, see scheme 2,

when R = CH3, phenyl, see schemes 3 and 4.

3-[1'-(tert-butyloxycarbonyl)amino]ethylbenzene acid (Boc-MeMamb)

This connection receive for the purposes of the present invention in accordance with the above scheme 4.

3-Acetylbenzoic acid (0.50 g, 3 mmol is of 2 h in 10 ml of ethanol. The reaction mixture is concentrated and the product triturated with water, filtered and dried. The oxime is isolated in the form of a white solid (0.51 g, yield 94,4%).

Data1H NMR spectroscopy (CD3OD): 7,45-8,30 (m, 4H), 2,3 (s, 3H). Mass spectrum (CH4-Cl): [M+H-O]=164.

A solution of oxime (0.51 g, 3 mmol) in ethanol containing 10% Pd saturated carbon (1.5 g), concentrated HCl (0.25 ml, 3 mmol), hydronaut when the hydrogen pressure of 30 psi in a Parr autoclave for 5 hours the Catalyst is filtered off, the filtrate is concentrated. The residue is triturated with ether. The amine hydrochloride is isolated in the form of a white solid (0,48 g, yield of 85.7%). Range1H NMR (CD3OD): 7.68 per-8,15 (m, 4H), 4,55 (q, 1H), 1,70 (s, 3H). Mass spectrum: [M+H]=166.

Amine hydrochloride (0.40 g, 2 mmol) dissolved in 15 ml of water. Add a solution of BOC-ON (0.52 g, 2.1 mmol) in 15 ml of acetone, and then triethylamine (0.8 ml, 0.6 mmol). The reaction proceeds for 20 hours, the Reaction mixture is concentrated and separated between ethyl acetate and water. The aqueous layer was acidified to pH 2 using 10% HCl solution. The product is extracted with ethyl acetate. After separation by conventional methods and recrystallization from a mixture of ethyl acetate/hexane receive BOC-MeMamb in the form of a white solid (0,30 g, yield 57%)of 1.40 (s, 9H). Mass spectrum (NH3-Cl): [M+NH4]=283.

3-[1'-(tert. butyloxycarbonyl)amino] ethylbenzylamine acid (BOC-PhMamb)

This connection receive for the purposes of the present invention in accordance with the above scheme 4 by the method similar to the method for producing methyl derivative.

A solution of 3-benzoylbenzene acid (2.00 g, 9 mmol), hydroxylamine hydrochloride (2.00 g, 29 mmol) and pyridine (2.00 ml, 25 mmol) in ethanol is heated under reflux for 12 hours After isolation by conventional methods receive a white solid (2,41 g). This product contains traces of pyridine, but is used in a later stage without additional purification.

The resulting product (without further purification) (2.00 g, 8 mmol) is dissolved in 200 ml of ethanol. Add 10% Pd-C (2.00 g) and concentrated HCl (1.3 ml, 16 mmol). The reaction mixture hydronaut at a pressure of 30 psi for 1 hour. The catalyst is filtered off, the reaction mixture was concentrated. After trituration with ether and drying under vacuum to obtain the amine hydrochloride as a white solid (2,12 g, yield 97%). Data of NMR spectroscopy1H (CD3OD): 7,4-8,15 (m, 10H), of 5.75 (s, 1H). Mass spectrum (CH4-Cl): [M+H-OH]=211.

Amin gidroiassazhnogo. Get to 0.60 g (yield 48%) was recrystallized from a mixture of ethanol/hexane above connection BOC-PhMamb in the form of a white solid. TPL190-192oC. Data NMR spectroscopy1H (CD3OD): 7,2-8,0 (m, 10H), 5,90 (2s, 1H, 2-isomer), of 1.40 (s, 9H). Mass spectrum (NH3-Cl): [M+NH4-C4H8]=289.

Cyclic intermediate compounds 68 and 68a

Cyclo-(D-Val-NMeArg-Gly-Asp-MeMamb); a compound of formula (II), where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1- CH3, R2- H.

Containing MeMamb cyclizes slices are in accordance with scheme 4 (shown earlier). Specified in the title compounds are synthesized by the method of joining MeMamb to the Tripeptide in the solution. After cyclization get protected cyclic peptide. Removing the protectors processing peptide (390 mg) and anisole (0,390 ml) anhydrous HF at 0oC for 30 minutes the Product is precipitated with ether, pererastayut a 10% aqueous solution of acetic acid and lyophilized. Receive a mixture of two isomers (330 mg, yield more than quantitative computed in terms of the salt of acetic acid). Purification and separation of isomers complete obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 7-23% acetonitrile containing 0.1% TFA, gradient of 0.48% of the slots of isomers 1 and 2 respectively. Mass spectrum (FAB), isomer 1: [M+H]=589,31; mass spectrum (FAB), isomer 2: [M+H]=589,31.

Cyclic intermediate compounds 76 and 76a

Cyclo-(D-Val-NMeArg-Gly-Asp-PhMamb); a compound of formula (II), where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1- Ph, R2- H.

Content PhMamb cyclizes slices are in accordance with scheme 4 (described earlier). Specified in the title compound synthesized by the method of joining PhMamb to the Tripeptide in the solution. After cyclization get protected cyclic peptide. Removing the protectors processing peptide (470 mg) and anisole (0,470 ml) anhydrous HF at 0oC for 30 minutes the Product is precipitated with ether, pererastayut a 10% aqueous solution of acetic acid and lyophilized. Receive a mixture of two isomers (310 mg, total yield, with 82.4%). Purification and separation of isomers complete obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 18-36% acetonitrile containing 0.1% TFA, gradient 0,55%/min Fractions collected at Rf= 22 min and Rfto 24.6 min, lyophilized and get salt triperoxonane acid isomers 1 and 2, respectively. Mass spectrum (FAB), isomer 1: [M+H]=651,33; mass spectrum (FAB), isomer 2: [M+H]=651,33.

Cyclic intermediate connection 79

Cyclo-(D-Val-NMeArg-Gly-Asp-title compound get a General methodology, described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (intermediate compound 4). For introduction of the group Boc-NMeArg in retinoid oxime used method of DCC/DMAP. Of the peptide, taken in an amount 0,456 mmol, get protected cyclic peptide (406 mg, yield more quantitative). Peptide (364 mg) and 0,364 ml of anisole is treated with anhydrous hydrogen fluoride at 0oC for 30 minutes the Product is precipitated with ether, pererastayut in aqueous acetonitrile, lyophilized and get listed in the title compound (251 mg, 93.5 per cent, calculated based on the fluoride). Cleanup complete obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 9-18% acetonitrile containing 0.1% TFA, gradient 0,23%/min After separation by lyophilization get salt triperoxonane acid specified in the title compound as a fluffy white solid (yield 34.2%, and the total yield of 29.9%). Mass spectrum (FAB), [M+H]=589,33.

Cyclic fragments containing substituted by the radical R31the aromatic nucleus.

Cyclic fragments, including aromatic nucleus containing substituents, can be obtained using methods that illustrate the following examples and diagrams.

Synthesis of 4,5 and 6-substituted aminomethyl 4,5 and 6-Substituted 3-aminomethylbenzoic acid HCl and 4.5 and 6-substituted derivatives butyloxycarbonyl-3-aminomethylbenzoic acid, used as intermediate compounds for the synthesis claimed in the present invention compounds get by known methods, for example, as described in Felder et. al, Helv. Chim. Acta, 48: 259 (1965); de Diesbach Helv. Chim. Acta, 23: 1232 (1949); Truitt and Creagn J. Org.Chem., 27: 1066 (1962); or (Sekiya et al. Chem. Pharm. Bull., 11: 551 (1963) and as shown schematically below

< / BR>
Synthesis of 4-chloro-3-aminometilbensana acid HCl

Specified in the title compound receive in accordance with the modification previously described in the literature methods (Felder et al. Helv. Chim. Acta, 48: 259). To a solution of 4-chlorbenzoyl acid (15.7 g, 100 mmol) in 150 ml of concentrated sulfuric acid slowly add N-hydroxyethylpiperazine (23.7 g, 150 mmol). The reaction mixture is stirred for 2 days at room temperature, cooled 375 g of ice, stirred for 1 h, the precipitate was separated by filtration and washed with water. The wet precipitate was dissolved in 5% sodium bicarbonate solution, filtered and acidified to pH 1 with concentrated HCl. The precipitate is filtered off, washed with water and after drying in the air get 4-chloro-3-dichlorotetrafiuoroethane acid (26,2 g, 89%) as a white powder.

A suspension of 4-chloro-3-dichlorotetrafiuoroethane acid (26,2 g, 88 mmol) in 45 ml of acetic acid, 150 ml of Koh is Janie and allow to cool to room temperature. The precipitate was separated by filtration, washed with ether and then with a mixture of acetone and ether. After air drying over night get the specified compound (7.6 g, 39%) as white crystals. TPL= 278-279oC. an NMR Spectrum1H (D6- DMSO): 13,40 (br s, 1H), up 8.75 (br s, 3H), to 8.20 (s, 1H), 7,95 (dd, 1H), of 7.70 (d, 1H), 4,20 (br s, 2H).

Tert-butyloxycarbonyl-4-chloro-3-aminomethylbenzoic acid

A suspension of 4-chloro-3-aminometilbensana acid HCl (6.7 g, 30 mmol) and triethylamine (9.3 g, 92 mmol) in 50 ml of H2O added to a solution of Boc-ON (9,2 g, 38 mmol) in 50 ml of tetrahydrofuran, cooled to 0oC. the Reaction mixture was stirred at room temperature overnight, then remove volatile by vacuum concentration. The residue is dissolved in water, washed with ether, acidified to pH 3 1N HCl and extracted with ethyl acetate. The extract is washed with water, evaporated, dried over anhydrous magnesium sulfate overnight and evaporated to a dry residue under reduced pressure. The resulting product is triturated with a mixture of ether and hexane and get listed in the title compound as a white solid (7.4 g, yield 87%). TPL= 159oC (with decomp.).

An NMR spectrum1H (D6- DMSO): 13,20 (br s, 1H), of 7.90 (s, 1H), 7,80 (dd, 1H), 7,60 (br s, H), of 7.55 (d, 1H), 4,20 (b is using a modification of previously described in the literature methods (Felder et al. (1965) Helv, Chim. Acta, 48: 259). To a solution of 6-iodobenzoic acid (24.8 g, 100 mmol) in 150 ml of concentrated sulfuric acid slowly add N-hydroxyethylpiperazine, the reaction mixture was stirred at room temperature for 7 days, cooled 375 g of ice, stirred for 1 h the Precipitate was separated by filtration and washed with water. The wet precipitate was dissolved in 5% sodium bicarbonate solution, filtered and acidified to pH 1 with concentrated HCl. The precipitate was separated by filtration, washed with water, air-dried overnight. Get 3-dichloracetyl-aminomethyl-6-iodobenzoic acid (32,0 g, 82%) as a white powder.

A suspension of 3-dichloroacetylene-6-benzoic acid (32,0 g, 82 mmol) in 51 ml of acetic acid, 170 ml of concentrated HCl and 125 ml of H2O heated under reflux for 3 h, filtered while hot and allowed to cool to room temperature. The precipitate was separated by filtration, washed with ether, then with a mixture of acetone and ether. After air drying overnight get mentioned in the title compound (13,2 g, 51%) as a beige powder. An NMR spectrum1H in D6- DMSO: 13,50 (br s, 1H), and 8.50 (br s, 3H), with 8.05 (d, 1H), a 7.85 (s, 1H), 7,40 (d, 1H), 4,05 (br s, 3H).

Tert-butyloxycarbonyl-3-amino-ethyl-6-iodine is mol) in 32 ml of H2O added to a solution of Boc-ON (8.0 g, 32 mmol) in 23 ml of tetrahydrofuran, cooled to 0oC. the Reaction mixture was stirred at room temperature over night, remove volatile compounds by vacuum concentration. The residue is dissolved in water, washed with ether and acidified to pH 3 1N HCl, extracted with ethyl acetate. The extract is washed with water, evaporated, dried over anhydrous magnesium sulfate and evaporated to a dry residue under reduced pressure. The resulting product is triturated with ether, receive the specified connection (5.7 g, 59%) as a white powder. TPL= 182oC (with decomp.). An NMR spectrum 1H in D6- DMCO: 13,35 (br s, 1H), 7,95 (d, 1H), 7,60 (s, 1H), 7,50 (br, 1H), 7,10 (d, 1H), 4,10 (d, 2H), 1,40 (s, 9H).

Other examples of cyclic compounds containing substituted by the radical R31the aromatic nucleus, obtained according to the General procedure described above for tert-butyloxycarbonyl-3-aminomethyl-6-iodobenzoic acid, are summarized in table I.

4-Bromo - and 6-bromopropane used as intermediate compounds for obtaining claimed in the present invention substances, can be obtained by the method similar to the above method of obtaining tert-butyloxycarbonyl-3-amino-ethyl-6-iodobenzoic kilometerage, can be obtained as described in: Sekiya et al., Chem Pharm Bull., 11: 551 (1963). 5-Nitro and 5-amino derivatives which are suitable as intermediate compounds for the synthesis of substances of the present invention, can be obtained as described in: Felder et al., Helv. Chim. Acta, 48: 259 (1965). Amino derivatives can be converted to 5-iodide, 5-bromo-, 5-chloro - or 5-pteropodidae through salt page, as described in Org. Syn. Coll. Vol. 2: 130 (1943); 2: 299 (1943); 2: 351 (1943) and 3: 185 (1955) (see tab. II).

The synthesis of cyclic intermediates using cyclic fragments containing substituted by the radical R31the aromatic nucleus.

Cyclic intermediate compounds in which the cyclic fragment contains an aromatic nucleus carrying the substituents can be obtained as shown in the following examples.

Cyclic intermediate connection 93

Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethyl-4-chlorbenzene acid)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The protected cyclic peptide (240 mg, 0.28 mmol) is removed by the action of an excess of HF in the presence of anisole as a consuming agent. Cleanup complete obremeniaet HPLC on a preparative column Li triperoxonane acid specified in the title compound (80 mg, 39%) as a fluffy white substance.

An NMR spectrum1H in D6- DMSO: 9,00 (d, 1H), 8,45 (t, 1H), 7,60 (d, 2H), 7,45 (s, 1H), 7,45 (d, 2H), 7,00 (br s, 4H), of 5.15 (dd, 1H), 4,45 (m, 2H), 4,20 (m, 2H), 4,10 (d, 1H), 3,55 (d, 1H), 3,10 (m, 2H), 2,90 (s, 3H), 2,65 (dd, 1H), 2,50 (m, 1H), 2.05 is (m, 2H), 1,50 (m, 1H), 1,30 (m, 2H), of 1.05 (d, 3H), of 0.85 (d, 3H).

Mass spectrum (FAB): [M+H]=609,00.

Cyclic intermediate connection 94

Cyclo-(D-Val-NMeArg-Gly-Asp-iodide-Mamb): compound of formula (VII), where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1=R2- H, R10- H, R10a- I.

Specified in the title compound get the General procedure described for the synthesis of cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (intermediate compound 4). For introduction of the group Boc-iodide-Mamb in retinoid oxime used method of DCC/DMAP. Of the peptide, taken in an amount of 1.05 mmol, get protected cyclic peptide (460 mg, 46,8%). Peptide (438 mg) and 0.5 ml of anisole is treated with anhydrous HF at 0oC for 30 minutes the Product is precipitated with ether, pererastayut in aqueous acetic acid, lyophilized. Get listed in the title compound (340 mg, 95.6% of the calculated per acetic acid salt). Cleanup complete obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 12-22,5% acetonitrile containing 0.1% TFA (gradient 0,23%/min).

After separation of liofol the Dogo substance (yield of 39.7%, the total yield of 16.8%). An NMR spectrum1H in D6- DMSO: 9,05 (d, 1H), 8,55 (d, 1H), 8,55 (t, 1H), of 7.90 (d, 1H), 7,65 (d, 1H), 7,55 (t, 1H), 7,20 (d, 1H), 7,15 (s, 2H), 7,00 (br, s, 4H), of 5.15 (dd, 1H), 4,50 (g, 1H), 4,30 (m, 3H), of 3.95 (dd, 1H), 3,60 (d, 1H), 3,10 (m, 2H), 3.00 and (s, 3H), of 2.75 (dd, 1H), to 2.55 (dd, 1H), 2,10 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), 1,10 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H]=701,37.

Cyclic intermediate connection 95

Cyclo-(D-Val-NMeArg-Gly-Asp-3-amino-ethyl-4-methoxybenzoic acid)

Specified in the title compound get the General procedure described for the synthesis in solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The protected cyclic peptide (600 mg, 0.71 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 7-18% acetonitrile containing triperoxonane acid (gradient of 0.33%/min), and get salt triperoxonane acid specified in the title compound (104 mg, 32%) as a white fluffy solid. An NMR spectrum1H in D6- DMSO: 12,40 (br s, 1H), of 8.25 (d, 1H), to 8.20 (br s, 1H), 8,00 (br s, 2H), a 7.85 (s, 1H), 7,65 (br s, 1H), 7,05 (d, 1H), 7,05 (br s, 4H), 5,00 (dd, 1H), 4,60 (q, 1H), 4,30 (d, 1H), 4,25 (d, 2H), 3,85 (s, 3H), of 3.85 (dd, 1H), 3,70 (dd, 1H), 3,10 (q, 2H), 3.00 and (s, 3H), 2,70 (m, 1H), 2,50 (m, 1H), 2,10 (m, 1H), 1,90 (m, 1H), 1,65 (m, 1H), 1,35 (m, 2H), and 1.00 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H2O+H]=the slot)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). The protected cyclic peptide (210 mg, 0.25 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column LiChrosper RP-18 (5 cm), using 22-90% acetonitrile containing 0.1% triperoxonane acid (gradient of 2.3%/min). Get salt triperoxonane acid specified in the title compound (75 mg, 42%) as a fluffy white solid. An NMR spectrum 1H in D6- DMSO: 12,30 (br s, 1H), cent to 8.85 (d, 1H), 8,55 (d, 1H), 8.30 to (t, 1H), of 7.75 (d, 1H), 7,55 (m, 1H), 7,40 (s, 1H), 7,20 (s, 1H), 7,00 (br s, 4H), 5,20 (dd, 1H), 4,55 (q, 1H), 4,45 (dd, 1H), 4,30 (m, 2H), of 4.05 (dd, 1H), 3,60 (d, 1H), 3,10 (q, 2H), 3.00 and (s, 3H), 2,70 (dd, 1H), 2,50 (m, 1H, in), 2.25 (s, 3H), 2,10 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), 1,10 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H]=589.

Cyclic intermediate connection 97

Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethyl-6-chlorbenzene acid)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), except that the use of oxime 4,4'-dinitrobenzophenone. The protected cyclic peptide (550 mg, of 0.65 mmol) remove excess HF in the presence of anisole as Rel the UYa 10-38% acetonitrile, containing 0.1% triperoxonane acid (gradient of 0.8%/min). Get salt triperoxonane acid specified in the title compound (254 mg, 54%) as a white fluffy solid. An NMR spectrum 1H in D6- DMSO: 12,30 (br s, 1H), 9,05 (d, 1H), 8,45 (m, 2H), 7,50 (t, 1H), 7,35 (d, 1H), 7,30 (m, 2H), 7,10 (s, 1H), 7,05 (br s, 4H), of 5.15 (dd, 1H), 4,45 (dd, 1H), and 4.40 (q, 2H), 4,05 (dt, 2H), 3,55 (dd, 1H), 3.15 in (q, 2H), 3,10 (s, 3H), 2,70 (dd, 1H), 2,50 (m, 1H), 2.05 is (m, 2H), 1,65 (m, 1H), 1,35 (m, 2H), 1,10 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H]=609.

Cyclic intermediate connection 99

Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethyl-6-methoxybenzoic acid)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), except that the use of oxime 4,4'-dinitrobenzophenone. The protected cyclic peptide (256 mg, 0.30 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 0.8%/min). Get salt triperoxonane acid specified in the title compound (137 mg, 63%) as a white fluffy solid. An NMR spectrum 1H in D6- DMSO: to 8.45 (d, 1H), 8,40 (d, 1H), 8.30 to (t, 1H), 7,65 (d, 1H),2H), of 3.00 (s, 3H), 2,70 (dd, 1H), 2,50 (m, 1H), 2.05 is (m, 1H), 1,60 (m, 1H), 1,35 (m, 2H), 1,10 (d, 3H), of 0.95 (d, 3H).

Mass spectrum (FAB), [M+H]=605.

Cyclic intermediate connection 100

Cyclo-(D-Val-NMeArg-Gly-Asp-3-amino-ethyl-6-methylbenzoic acid)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), except that the use of oxime 4,4'-dinitrobenzophenone. The protected cyclic peptide (230 mg, 0.28 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 0.8%/min). Get salt triperoxonane acid specified in the title compound (54 mg, 27%) as a white fluffy solid. An NMR spectrum 1H in d6- DMSO: 12,30 (br s, 1H), 8,80 (d, 1H), 8,40 (d, 1H), 8.30 to (t, 1H), 7,45 (m, 2H), 7,15 (q, 2H), 7,00 (s, 1H), 7,00 (br s, 4H), of 5.15 (dd, 1H), 4,45 (m, 3H), of 4.05 (m, 2H), 3,55 (dd, 1H), 3,10 (q, 2H), 3,05 (s, 2H), 2,70 (dd, 1H), 2,50 (m, 1H), 2,30 (s, 3H), of 2.05 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), of 1.05 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H]=589.

Cyclic intermediate connection 100a

Cyclo-(D-Abu-NMeArg-Gly-Asp-3-amino-ethyl-6-chlorbenzene acid)

Specified in the title compound popolzuyut the reaction of 4,4'-dinitrobenzophenone. The protected cyclic peptide (330 mg, 0.40 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 1.0%/min). Get salt triperoxonane acid specified in the title compound (114 mg, 41%) as a white fluffy solid. An NMR spectrum 1H in D6- DMSO: 9,00 (d, 1H), 8,40 (m, 2H), 7,50 (m, 1H), 7,40 (d, 1H), 7,30 (m, 2H), 7,15 (s, 1H), 7,00 (br s, 4H), of 5.15 (dd, 1H) and 4.65 (q, 1H), 4,50 (dd, 1H), and 4.40 (q, 1H), of 4.05 (dd, 1H), 3,95 (dd, 1H), 3,65 (dd, 1H), 3,10 (q, 2H), 3,05 (s, 3H), of 2.75 (dd, 1H), 2,50 (m, 1H), 1,95 (m, 1H), about 1.75 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), of 0.95 (t, 3H).

Mass spectrum (FAB), [M+H]=595,4.

Cyclic intermediate connection 89d

Cyclo-(D-Abu-NMeArg-Gly-Asp-iodine-Mamb); the compound of formula (VII), where J is D-Abu, K is NMeArg, L = Gly, M - Asp, R1=R2- H, R10- H, R10a- I.

Specified in the title compound get the General procedure described for the synthesis of cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). For introduction of the group Boc-iodide-Mamb in retinoid oxime used method of DCC/DMAP. Of the peptide, taken in an amount of 3.53 mmol, get protected cyclic peptide (4,07 g, the output of the above quantitative). Peptide (4,07 Aut in an aqueous solution of acetic acid and was isolated by lyophilization specified in the title compound (2,97 g, the output of the above quantitative, calculated on the acetate salt). Cleanup complete obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 16,2-or 22.5% acetonitrile containing 0.1% TFA (gradient of 0.16%/min). After lyophilization get salt triperoxonane acid specified in the title compound as a fluffy white solid (yield 28.7% of the total output 30,2%). Mass spectrum (FAB), [M+H]=687,33.

Cyclic intermediate connection 100b

Cyclo-(D-Abu-NMeArg-Gly-Asp-3-aminomethyl-6-iodobenzoic acid)

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), except that the use of oxime 4,4'-dinitrobenzophenone. The protected cyclic peptide (350 g, 0.38 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 1.0%/min). Get salt triperoxonane acid specified in the title compound (150 mg, 49%) as a fluffy white substance. An NMR spectrum1H in D6-DMSO: 8,90 (d, 1H), 8,40 (m, 2H), of 7.70 (d, 1H), 7,50 (m, 1H), 7,30 (m, 1H), 7,05 (s, 1H), 7,00 (d, 1H), 7,00 (bs, s, 4H), of 1.40 (m, 2H), of 0.95 (t, 3H);

Mass spectrum (FAB), [M+H] = 687,3.

Cyclic intermediate compound 100c

Cyclo-(D-Abu-NMeArg-Gly-Asp-3-aminomethyl-6-methylbenzoic acid); compound of formula (VII), where J is D-Abu, K is NMeArg, L = Gly, M - Asp, R10- Me.

Specified in the title compound get the General method of synthesis in the solution described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), except that the use of oxime 4,4'-dinitrobenzophenone. The protected cyclic peptide (130 mg, 0.16 mmol) remove excess HF in the presence of anisole as a consuming agent. Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 1.0%/min). Get salt triperoxonane acid specified in the title compound (31 mg, 28%) as a white fluffy solid. An NMR spectrum 1H in D6-DMSO: an 8.70 (d, 1H), 8,40 (d, 1H), 8.30 to (t, 1H), 7,50 (m, 1H), 7,45 (m, 1H), 7,15 (q, 2H), 7,05 (s, 1H), 7,00 (br, s, 4H), of 5.15 (dd, 1H) and 4.65 (q, 1H), 4,45 (m, 2H), 4.00 points (m, 2H), 3,65 (dd, 1H), 3,10 (q, 2H), 3,05 (s, 3H), of 2.75 (dd, 1H), 2,50 (m, 1H), 2,30 (s, 3H), 2,00 (m, 1H), about 1.75 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), of 0.95 (t, 3H);

Mass spectrum (FAB), [M+H] = 575,4.

Solid-phase synthesis of cyclic intermediate compound 101

Cyclo-(D-Val-NMeArg-Gly-Asp-aminomethyl-4-iodobenzene mb). For introduction of the group Boc-iodide-Mamb in retinoid oxime used method of DCC/DMAP. Of the peptide, taken in an amount of 1.05 mmol, get protected cyclic peptide (460 mg, 46,8%). Peptide (438 mg) and anisole treated with anhydrous HF at 0oC for 30 minutes the Product is precipitated with ether, pererastayut in aqueous acetic acid and was isolated by lyophilization specified in the title compound (340 mg, 95.6% of that calculated for acetic acid salt). Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using the 12.6-22.5% of acetonitrile containing 0.1% triperoxonane acid (gradient 0,23%/min), and then lyophilization get salt triperoxonane acid specified in the title compound as a white fluffy solid (yield of 39.7%, the total yield of 16.6%). An NMR spectrum1H in D6- DMSO: 9,05 (d, 1H), 8,55 (d, 1H), 8,55 (t, 1H), of 7.90 (d, 1H), 7,65 (d, 1H), 7,55 (t, 1H), 7,20 (d, 1H), 7,15 (s, 2H), 7,00 (br, s, 4H), of 5.15 (dd, 1H), 4,50 (q, 1H), 4,30 (m, 3H), of 3.95 (dd, 1H), 3,60 (d, 1H), 3,10 (m, 2H), 3.00 and (s, 3H), of 2.75 (dd, 1H), to 2.55 (dd, 1H), 2,10 (m, 2H), 1,60 (m, 1H), 1,35 (m, 2H), 1,10 (d, 3H), of 0.90 (d, 3H);

Mass spectrum (FAB), [M+H] = 701,37.

The synthesis of cyclic intermediate compound 102 in solution

Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethyl-6-iodobenzoic acid)

Specified in the title compound get under 3-aminomethyl-6-iodobenzoic acid HCl (4.9 g, 16 mmol) in H2O (16 ml) is added HaHCO3(3,9 g, 47 mmol), and then a solution of Boc-Asp(OcHex)-OSu (5.9 g, 14 mmol) in THF. The reaction mixture was stirred at room temperature overnight, filtered, diluted with H2O, acidified with 1N HCl and extracted with ethyl acetate. The extract is washed with water, evaporated, dried over anhydrous magnesium sulfate and finally dried in vacuum. The resulting product is triturated with ether, receive specified in the title compound (6.7 g, 82%) as a white powder. Range1H NMR in D6- DMSO: to 8.45 (br t, 1H), of 7.90 (d, 1H), 7,60 (s, 1H), 7,15 (m, 2H) and 4.65 (m, 1H), 4,35 (m, 1H), 4,25 (d, 2H), 2,70 (m, 1H), to 2.55 (m, 1H), 1,70 (m, 4H), of 1.40 (s, 9H), of 1.35 (m, 1H).

2. 4,4'-dinitrobenzophenone

Specified in the title compound receive in accordance with the modification previously described in the literature methods (Chapman and Fielder (1936), J. Chem. Soc, 448, Kulin and Leffek (1973), Can. J. Chem, 51: 867). A solution of chromic anhydride (20 g, 200 mmol) in 125 ml of H2O for 4 h was added dropwise to a suspension of bis-(4-nitrophenyl)methane (25 g, 97 mmol) in 300 ml of acetic acid, heated under reflux. After that, the reaction mixture is heated under reflux for 1 h, cooled to room temperature and poured into water. The precipitate was separated by filtration, washed with water, 5% solution biker is (according to NMR data1H). This product oxidizes the second portion of chromic anhydride (20 g, 200 mmol), followed by similar methods produce the reaction product, triturated with 200 ml of benzene. After heating for 16 h under reflux get 4,4'-dinitrobenzophenone (20,8 g, 79%) as a yellow powder.

A solution of hydroxylamine hydrochloride (10.2 g, 147 mmol) are added to a suspension of 4,4'-dinitrobenzophenone (19 g, 70 mmol) in 100 ml of ethanol. The reaction mixture is heated under reflux for 2 h, cooled to room temperature, separating the solid product by filtration. After recrystallization from ethanol specified in the title compound (14.0 g, 70%) as pale yellow crystals.

Tpl.= 194oC NMR Spectrum of 1H in D6- DMSO:d 12,25 (s, 1H), 8,35 (d, 2H), to 8.20 (d, 2H), 7,60 (d, 4H).

4,4'-Dinitrobenzophenone Boc-Asp(OcHex)-3-aminomethyl-6 - iodobenzoic

It chilled with ice to a solution of Boc-Asp(OcHex)-3-aminomethyl-6 - iodobenzoic acid (3,3 g of 5.75 mmol) and 4,4'-dinitrobenzophenone (1.7 g, 5.9 mmol) in 32 ml of ethyl acetate added DCC (1.2 g, 5.8 mmol). The reaction mixture was stirred at room temperature for 3 hours, filtered, diluted with ethyl acetate, washed with a saturated solution of bicarbonate is obtained the product was then purified on a column of silica gel (EM Science, 230-400 mesh mesh.), using a mixture of 10:1 dichloromethane and ethyl acetate. Get listed in the title compound (1.8 g, 36%) as pale yellow crystals.

An NMR spectrum1H in D6- DMSO:d 8,40 (dd, 5H), of 7.90 (m, 5H), was 7.45 (s, 1H), 7,20 (m, 2H) and 4.65 (m, 1H), 4,35 (m, 1H), 4,20 (m, 2H), 2,75 (dd, 1H), 2,50 (dd, 1H), 1,70 (m, 4H), of 1.40 (s, 9H), of 1.35 (m, 6H).

4. Boc-D-Val-NmeArg(Tos) (11,07 g, 25 mmol) and Gly-OBzl tosilata (10,10 g, 30 mmol) in 25 ml dichloromethane added HBTU (9,48 g, 25 mmol) and DIEA (RS 9.69 g, 75 mmol).

The reaction mixture was stirred at room temperature for 1 h, concentrated in vacuo, diluted with ethyl acetate, washed with 5% citric acid solution, saturated sodium bicarbonate solution, evaporated, dried over anhydrous magnesium sulfate and finally dried under reduced pressure. The obtained oily product is triturated with petroleum ether. Receive Boc-NmeArg(Tos)-Gly-OBzl (14,7 g, 100%); mass spectrum (FAB): [M+H] = 590,43. This product is used without further purification.

A solution of Boc-NmeArg(Tos)-Gly-OBzl (14.5 g, 24.6 mmol) in 30 ml triperoxonane acid is stirred at room temperature for 5 min, dried under reduced pressure. The obtained oily product was diluted with cold ethyl acetate, washed with cold saturated sodium bicarbonate solution, is but dried in vacuum, the obtained oily product was washed, evaporated and finally dried in vacuum, the obtained oily product is triturated with ether. The hard part is filtered off, washed with ether and dried in a vacuum desiccator. Get NmeArg(Tos)-Gly-OBzl (10.3 g, 86%); mass spectrum (FAB): [M+H] = 490,21. This product is used without further purification.

To a solution of NmeArg(Tos)-Gly-OBzl (4,80 g, 9.8 mmol) and Boc-D-Val (2,13 g, 9.8 mmol) in 10 ml of dichloromethane, cooled at the base with ice, add HBTU (3,79 g, 10.0 mmol) and DIEA (2.58 g, 20.0 mmol). The reaction mixture was stirred at room temperature for 48 h, diluted with ethyl acetate, washed with 5% citric acid, evaporated, dried over anhydrous magnesium sulfate and finally dried under reduced pressure. The obtained oily product is triturated with ether, after which they receive Boc-D-Val, NmeArg(Tos)-Gly-OBzl (4,58 g, 68%); mass spectrum (FAB): [M+H] = 689,59. This product is used without further purification.

A solution of Boc-D-Val-NmeArg(Tos)-Gly-OBzl (4,50 g, 6,53 mmol) and purge with nitrogen, add 1,30 g 10% Pd/c and passed into the reactor hydrogen. After 1 h, the catalyst was filtered through a layer of celite, remove the solvent under reduced pressure. The obtained solid is triturated with ether, filtered and (d, 2H), 7,30 (d, 2H), 7,00 (d, 1H), 6,85 (br d, 1H), 6,60 (br s, 1H), 5,00 (dd, 1H), 5,00 (dd, 1H), 4,15 (t, 1H), 3,70 (m, 2H), 3,05 (m, 2H), 2,90 (s, 3H), of 2.35 (s, 3H), 1,90 (m, 2H), 1.55V (m, 2H), 1,35 (s, 9H), 1,25 (m, 2H), 1,80 (br t, 6H).

mass spectrum (FAB): [M+H] = 599,45.

5. 4,4'-Dinitrobenzophenone Boc-D-Val-NmeArg(Tos)-Gly-(OcHex)-3-aminomethyl-6-iodobenzoic

To a solution of 4,4'-dinitrobenzophenone Boc-Asp(OcHex)-3-aminomethyl-6-iodobenzoate (0.5 g, 0.59 mmol) in 1 ml dichloromethane added 0.5 ml of triperoxonane acid. The reaction mixture was stirred at room temperature for 90 min, diluted with dichlormethane and finally dried under reduced pressure. Oily residue was concentrated in high vacuum to remove traces of excess triperoxonane acid.

To a solution of the salts triperoxonane acid and Boc-D-Val-NmeArg(Tos)-Gly (0.52 g, or 0.57 mmol) in 3.8 ml of DMF is added TBTU (0.28 g, 0.87 mmol) and DIEA (0.33 g, 2.58 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under high vacuum, diluted with ethyl acetate, washed with 5% citric acid, H2O, evaporated, dried over anhydrous magnesium sulfate and finally finally dried under reduced pressure. The resulting product is triturated with ether, after which get mentioned in the title compound (0,48 g, 61%) in veetil-6 - iodobenzoic acid

To a solution of 4,4'-dinitrobenzophenone Bos-(D-Val-NmeArg(Tos)-Gly-Asp(OcHex)-3-aminomethyl-6-iodobenzoic acid (0,48 g, 0.36 mmol) in 1 ml dichloromethane added 0.5 ml of triperoxonane acid. The reaction mixture was stirred at room temperature for 45 min, diluted with dichloromethane and finally dried under reduced pressure. Oily residue was concentrated in high vacuum to remove traces of excess triperoxonane acid.

To a solution of the crude salt triperoxonane acid in 38 ml of DMF is added acetic acid (0.09 g, 1.57 mmol) and DIEA (0.26 g, 1,49 mmol). The reaction mixture was stirred at 60oC for 3 days, concentrated under high vacuum, diluted with ethyl acetate, washed with 5% citric acid, evaporated, dried over anhydrous magnesium sulfate and finally finally dried under reduced pressure. This product is purified column chromatography on silica gel (FM Seince, 230-400 mesh mesh. ) using chloroform and isopropanol, taken in the ratio of 10:1. Get listed in the title compound (0,13 g, 38%) as a powder.

An NMR spectrum 1H (D6- DMSO):d of 8.95 (d, 1H), and 8.50 (t, 1H), 8,45 (d, 2H), of 7.70 (d, 1H), 7,60 (d, 2H), 7,30 (d, 3H), 7,05 (d, 1H), 7,00 (s, 1H), 6,80 (br s, 1H), 6,60 (br s, 1H), 5,10 (dd, 1H) and 4.65 (m, 1H), 4,45 (m, 1H), of 4.35 (m, 1H), 4.00 points (m, 1H), 3 the Tr (FAB(GLYC):[M+H] = 937.

7. Cyclo-(D-Val-NMeArg-Gly-Asp-3-aminomethyl-6-iodobenzoic acid)

Removing the protection of cyclic peptide (490 mg, 0.52 mmol) carry excess HF in the presence of anisole as acceptor. Cleaning is performed by the method obremenitve HPLC on a preparative column (Vydac C18 (2.5 cm) using 10-38% acetonitrile containing 0.1% triperoxonane acid (gradient of 0.8% min). Get salt triperoxonane acid specified in the title compound (194 mg, 46%) as a fluffy white solid;

An NMR spectrum 1H (D6- DMSO):d 12,30 (br s, H), of 9.00 (d, 1H), 8,40 (m, 2H), of 7.70 (d, 1H), 7,50 (m, 1H), 7,30 (m, 1H), 7,05 (d, 1H), 7,00 (s, 1H), 7,00 (br s, 4H), of 5.15 (dd, 1H), and 4.40 (d, 1H), and 4.40 (q, 2H), 4.00 points (m, 2H), 3,55 (dd, 1H), 3.15 in (q, 2H), 3,10 (s, 3H), 2,70 (dd, 1H), 2,50 (m, 1H), 2.05 is (m, 2H), 1,65 (m, 1H), 1,35 (m, 2H) and 1.15 (d, 3H), of 0.90 (d, 3H); mass spectrum (FAB):[M+H] = 701.

Table A shows the data mass spectroscopy (FAB) for some cyclic intermediates.

Other fragments containing the substituents in the aromatic nucleus, can be synthesized as shown in schemes and comments to the schemes. The fragment above formula, where Z=NH2can be obtained, at least two different ways. For example, using as starting compound 4-acetamidobenzoic acid (Aldrich Chemi is the initial 3-amino-ethyl-4-acetamidobenzoic acid (Felder, Pitre and Fumagall: (1964), Helv. Chim. Acta, 48, 259-274). As a result of hydrolysis of the two amide groups receive 3-aminomethyl-4-aminobenzoic acid.

< / BR>
Otherwise, using as starting compound 3-cyano-4-nitrotoluene, oxidation with chromium trioxide and subsequent recovery receive 3-aminomethyl-4-aminobenzoic acid.

< / BR>
a] CrO3b] H2- catalysis

The fragment above formula, where Y=CH2NH2can be obtained from 3,5-dicentral, by oxidation of the methyl group with chromium trioxide and subsequent recovery.

< / BR>
a] CrO3b] H2- catalysis

The fragment above formula, where Z=CH2NH2can be obtained from 3-cyano-4-methylbenzoic acid (K and K Rare and Fine Chemicals). Bromirovanii N-bromosuccinimide can be obtained 4-bromomethyl-3-cyanobenzoic acid. The reaction of nucleophilic substitution bromomethyl group amide anion yields a protected amine. As the amide anion in the reaction can be used phthalimide potassium (Gabriel Synthesis) and anion trifurcated (Usui (1991), Nippon Called Kaishi, 206-212) used in this example. The restoration of the nitrile group allows to obtain secondary aminomethyl groups groups with an aqueous solution of piperidine leads to the formation of the above segment.

< / BR>
This fragment can also be obtained from 4-bromobenzoic acid, as shown in the diagram

< / BR>
a] H2SO4, HOCH2NHCOCHCl2b] H+, boc-ON,

c] CuCN, DMF d] H2-catalyst

These substituted in the aromatic nucleus cyclic fragments can be used for the synthesis of cyclic intermediates.

Cyclic intermediate connection 113

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(4-NH2)

< / BR>
This compound can be obtained by the method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb), by the substitution of the cyclic fragment, containing the substituents in the aromatic nucleus at Z=NH2.

Cyclic intermediate 114, 115 and 116

< / BR>
x1- 2-propyl, ethyl or p-hydroxyphenylethyl;

x2- H.

The compound Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-CH2NHX2), Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-CH2NHX2) and cyclo(D-Tyr-NMeArg-Gly-Asp-Mamb(5-CH2NHX2can be obtained by the above method using substituted in the aromatic nucleus fragment with Y-CH2NH2.

Cyclic intermediate 117, 118 and 119

< / BR>
x1- 2-propyl, ethyl or p-hydroxyphenylethyl;

x2- H.

mb(4-CH2NHX2) obtained by the above method using substituted in the aromatic nucleus fragments with Z=CH2NH2.

Other cyclic fragments containing substituent R31< / BR>
Instead Mamb as forming a loop fragment R31in the cyclic peptides of the present invention can be used balances aminoalkylation acid or tetrahydronaphthyl acid.

Typical examples of derivatives aminoalkylation acid and aminoethylethanolamine acid used in the synthesis of cyclic peptides of the present invention below. The synthesis of these derivatives illustrates a diagram 7.

8-Amino-5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride (8).

To obtain specified in the connection name used modification of the conventional techniques previously described in the literature (Earnest, I, Kalvoda, J. Rihs, G., Mutter, M., Tett. Lett., vol. 31, No. 28, pp. 4011-4014, 1990).

As shown in scheme 7, 4-phenylalanyl acid (1) was transferred into ethyl ether (2), which is then acelerou acetylchloride in the presence of aluminum chloride, and receive the ethyl ester of 4-acetylphenylalanine acid (3). This broadcast omelet, and receive a 4-acetylphenyl is then converted into 1-tetralin-7-carboxylic acid (6) by cyclization of the Friedel-Crafts using aluminum chloride, with a fairly high output.

At this point, the tetralone is divided into two portions, and one of them turned into the oxime (7), using sodium acetate and hydroxylamine hydrochloride. The oxime restore the action of hydrogen, and receive a racemic mixture of 8-amino-5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride (8), which is used as an intermediate compound for the introduction of a cyclic peptide.

Part A. a Solution of 4-phenylalkanoic acid (50.0 g, 0.3 mol) in ethanol (140 ml) with addition of concentrated sulfuric acid (0,53 ml) is stirred under reflux for 5 hours, the Cooled solution is poured into ice water and extracted with ethyl acetate. The combined organic layers washed, vymalivayut and dried over anhydrous magnesium sulfate, finally finally dried under reduced pressure. Get the ethyl ester of 4-phenylalkanoic acid (56,07 g, 0.29 mol, 97%) as a yellow liquid.

An NMR spectrum1H (CDCl3):d to 7.3, and 7.1 (m, 5H), 4,1 (q, 2H, J = 7,1 Hz), and 2.7 (t, 2H, J = 7,7 Hz), 2,3 (t, 2H, J = 7.5 Hz), of 1.95 (quintet, 2H, J = 7.5 Hz), 1,25 (t, 3H, J = 7,1 Hz).

Part B. To a solution containing aluminum chloride (153 g, 1.15 mol) and acetylchloride (a 38.5 ml, 42.5 g, 0.54 mol) in dichloromethane (1500 ml), was added dropwise a solution of ethyl EF temperature for 15 minutes The solution was poured into cold concentrated hydrochloric acid (2000 ml) and then extracted with dichloromethane. The combined organic layers are subjected to the reverse washing, evaporated, dried over anhydrous magnesium sulfate and finally finally dried under reduced pressure. Get the ethyl ester of 4-acetylphenylalanine acid (53,23 g, 0.23 mol, 88%) as a dark yellow liquid.

An NMR spectrum1H (CDCl3):d to 7.9 (d, 2H, J = 8.1 Hz), 7,25 (d, 2H, J = 8,4 Hz), 4,1 (q, 2H, J = 7,1 Hz) of 2.75 (t, 2H, J = 7,6 Hz), and 2.6 (s, 3H), 2,35 (t, 2H, J = 7,6 Hz), 2.0 (quintet, 2H, J = 7.5 Hz), 1,25 (t, 3H, J = 7,1 Hz).

Part C. To a solution of ethyl ester of 4-acetylphenylalanine acid (50.0 g, 0.21 mol) in ethanol (1250 ml) was added dropwise a solution of sodium hydroxide (50.0 g) in water (1250 ml). All stirred under reflux for 4 hours. The solution is concentrated to half volume and then acidified with 1H HCl until pH = 1. The precipitate is collected and washed with water. Receive a 4-acetylphenylalanine acid (53,76 g, 0.26 mol, 99%) as a white solid. TPL= 50 - 52oC.

An NMR spectrum1H (CDCl3):d to 7.9 (d, 2H, J = 8.1 Hz), 7,25 (d, 2H, J = 9.1 Hz), a 2.75 (t, 2H, J = 7,7 Hz), and 2.26 (s, 3H), 2,4 (t, 2H, J = 7,3 Hz), 2.0 (quintet, 2H, J = 7,4 Hz).

Part D. To a solution of hydrochloride sodium (330 ml, Limassol acid (16.0 g, 0,078 mol) in the form of solids, maintaining the temperature between 60 - 70oC. All stirred at 55oC for 20 hours, the Cooled solution is quenched by precapitalism solution of sodium bisulfite (25%, 330 ml). Then the mixture is transferred into a glass and carefully acidified by adding concentrated hydrochloric acid. The obtained solid is collected, washed with water and dried, then triturated sequentially with chlorobutanol and hexane. Receive a 4-carboxyphenylazo acid (15,31 g 0,074 mol, 95%) as a white solid, TPL= 190-195oC.

An NMR spectrum1H DMCO:d 12,55 (bs, 1H), and 8.1 (s, 1H), a 7.85 (d, 2H, J = 8.1 Hz), and 7.3 (d, 2H, J = 8.1 Hz), and 2.7 (t, 2H, J = 7.5 Hz), 2,2 (t, 2H, J = 7,4 Hz), and 1.8 (quintet, 2H, J = 7.5 Hz).

Part E. a Mixture of 4-carboxyphenylazo acid (the 10.40 g, 0.05 mol), aluminum chloride (33,34 g, 0.25 mol) and sodium chloride (2,90 g, 0.05 mol) is heated with continuous stirring to 190oC for 30 minutes once the mixture is cooled to 60oC, carefully add cold hydrochloric acid (1H, 250 ml). The mixture is extracted with dichloromethane. The combined organic layers are subjected to the reverse washing with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate and finally be dried pcislot (9,59 g, 0.05 mol, 100%) as a brown solid.

TPL= 210 - 215oC. an NMR Spectrum1H DMCO:d and 8.4 (s, 1H) and 8.1 (d, 2H, J = 8.0 Hz), and 7.5 (d, 2H, J = 7.9 Hz), 3,0 (t, 2H, J = 6.0 Hz), to 2.65 (t, 2H, J = 6.6 Hz), 2.1 (quintet, 2H, J = 6.3 Hz).

Part F. a Solution containing 1-tetralone-7-carboxylic acid (1.0 g, 0,0053 mol), sodium acetate (1,93 g 0,024 mol) and hydroxylamine hydrochloride (1,11 g to 0.016 mol) in a mixture of methanol water (1:1,15 ml), stirred under reflux for 4 hours the Mixture is cooled and then add additional water (50 ml). The solid is collected, washed with water and dried, then triturated with hexane. Get 1-tetradeoxy-7-carboxylic acid (0,78 g, 0,0035 mol, 72%) as a white solid.

TPL205 - 215oC. an NMR Spectrum1H in DMSO:d 11,3 (s, 2H), and 8.4 (s, 1H), and 7.8 (d, 1H, J = 7,7 Hz), and 7.3 (d, 1H, J = 7,7 Hz), 2.8 (t, 2H, J = 5,9 Hz), and 2.7 (d, 2H, J = 6.6 Hz), 1,9 - 1,7 (m, 2H).

Part G. a Mixture of 1-tetralonoxime-7-carboxylic acid (0.75 g, 0,0037 mol) in methanol (25 ml) with concentrated hydrochloric acid (0.54 ml, 0.20 g, 0,0056 mol) and the catalyst is palladium supported on carbon (0.10 g, 5% Pd/C), shaken for 20 h at ambient temperature in an atmosphere of hydrogen (60 psi). The reaction mixture was filtered through Celite@and washed metanexus and ethyl acetate in the ratio of 1:1. Get a racemic mixture of 8-amino-5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride (0,255 g, 0.001 mol, 27%) as a white solid.

TPL= 289 - 291oC. an NMR Spectrum1H in DMSO:d 8,55 (bs, 3H), and 8.2 to 8.1 (m, 1H), 7,85 one - 7.8 (m, 1H), 7,35 - 7,25 (m, 1H), and 4.5 (m, 1H), 2,9 - 2,8 (m, 2H), 2,1 to 1.9 (m, 3H), 1.85 to 1,7 (m, 1H).

N-Boc-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (12)

As shown in figure 7, the remaining tetralone then transferred to the methyl ester (9). Using the methodology described Gregory, G. B. and Johnson, A. L., JOC, 1990, 55, 1479, methyl ester tetralone (9) first turn in cyanhydrin treatment trimethylsilylcyanation and iodide of zinc, and then carry out in situ dehydration with phosphorus oxychloride in pyridine, and get methyl-8-cyano-5,6-dihydro-2-aftout (11). This aftout divided into two parts. One part of the restore the action of hydrogen injected N-BOC-protection, amyraut and get N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (12), an intermediate compound that is intended for the introduction of cyclic peptides.

Part A. a Mixture of 1-tetralone-7-carboxylic acid (7.0 g, 0,037 mol) in methanol (13,6 ml, 10.8 g, 0.30 mol) with a catalytic amount of hydrochloric acid (of 0.07 ml, 0.12 g, 0,0012 mol) is stirred under reflux for 5 hours of OHL is Lois put the backwash and evaporated, dried over anhydrous magnesium sulfate and finally dried under reduced pressure. The obtained solid is triturated with hexane. Get methyl ether 1-tetralone-7-carboxylic acid (3,61 g, 0.018 mol, 49%) as a yellow solid.

TPL= 170 - 172oC. an NMR Spectrum 1H (CDCl3):d to 8.7 (s, 1H), 8,15 (d, 1H, J = 8.1 Hz), 7,35 (d, 1H, J = 8.1 Hz), of 3.95 (s, 3H), 3,05 (d, 2H, J = 6,1 Hz), and 2.7 (t, 2H, J = 6.4 Hz), of 2.15 (quintet, 2H, J = 6.2 Hz).

Part B. a Solution of methyl ester 1-tetralone-7-carboxylic acid (3.50 g, is 0.017 mol), trimethylsilylacetamide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene (20 ml) was stirred at ambient temperature for 15 hours Then added successively dropwise, pyridine (20 ml) and phosphorus oxychloride (4.0 ml, 6,55 g, 0,0425 mol). The reaction mixture is stirred under reflux for 1 h, and then completely remove the volatiles under reduced pressure. The residue is combined with chloroform, washed with water, dried over anhydrous magnesium sulfate and finally dried under reduced pressure. Get methyl-8-cyano-5,6-dihydro-2-aftout (1.70 g, 0,008 mol, 47%) as a yellow solid.

TPL= 73 - 75oC. an NMR Spectrum1H (CDCl3):d of 8.0 to 7.9 (m, 1H), and 7.3 to 7.2 (m, 1H), 6,95 (t, 0038 mol) in methanol (25 ml) with concentrated hydrochloric acid high (0.56 ml) and the catalyst is palladium, printed on carbon (0.40 g, 5% Pd/C) is shaken for 20 h at room temperature in a nitrogen atmosphere (60 psi). The reaction mixture was filtered through Celite and washed with methanol. The filtrate is completely dried under reduced pressure, the residue triturated with hexane. Get a racemic mixture of methyl-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0,80 g, 0,0037 mol, 97%) as a white solid.

TPL= 170 - 179oC. an NMR Spectrum1H in DMSO:d for 8.2 (m, 4H), from 7.9 to 7.7 (m, 6H), 7,5 to 7.2 (m, 4H), from 3.9 to 3.8 (m, 7H), 3,3 - 3,2 (m, 10H), of 2.0 to 1.6 (m, 8H).

Part D. To a solution of methyl-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0,78 g, 0,0036 mol) and triethylamine (0,55 ml, 0.40 g, 0,004 mol) in aqueous tetrahydrofuran (50%, 75 ml) is added parts, in the form of solids, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile. Everything is stirred at room temperature for 3 hours the Solution is concentrated to half volume and extracted with diethyl ether. Then the aqueous layer was acidified to pH to 1.0 with hydrochloric acid (1H) and extracted with ethyl acetate. The combined organic layers dried over anhydrous magnesium sulfate and evaporated until dry under reduced pressure. The residue is purified chromatography using hexane and ethyl acetate in sootnesti.

TPL= 72 - 80oC. an NMR Spectrum1H (in DMSO):d 13,8 (s, 1H), 7,8 - of 7.65 (m, 3H), of 7.6 to 7.5 (m, 3H), 7,25 - 7,20 (m, 1H), 7,15 - 7,05 (m, 1H), from 3.9 to 3.8 (m, 1H), 3,2 - 2,8 (m, 4H), 1,8 - 1,6 (m, 3H), and 1.4 (s, 6H).

Part E. To a solution of methyl N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.50 g, 0,0016 mol) in ethanol (12.5 ml) was added dropwise a solution of sodium hydroxide (0.50 g) in water (12.5 ml). All stirred under reflux for 4 hours, the Reaction mixture was concentrated to half volume and then acidified to pH 1 with hydrochloric acid (1H). The residue is purified chromatographically using a gradient of hexane:ethyl acetate (1:1), ethyl acetate, ethyl acetate: methanol (9:1). Get a racemic mixture specified in the title compound, N-(BOC)-2-amino-ethyl-5,6,7,8-tetrahydro-2-naphthoic acid (0,19 g, 0,00062 mol, 39%) as a white solid.

TPL= 172 - 176oC. an NMR Spectrum1H (in DMSO):d of 7.8 (s, 1H), 7,65 (d, 1H, J = 8.1 Hz), to 7.15 (d, 1H, J = 8.1 Hz), 7,1 - a 7.0 (m, 1H), 3,2 - 3,1 (m, 2H), 3,0 - 2,7 (m, 4H), 1,8 - 1,6 (m, 4H), and 1.4 (s, 9H).

N-(BOC)-8-aminomethyl-2-naphthoic acid (14)

The remaining aftout (11) is treated with 2,3-sodium dichloro-5,6,-dicyano-1,4-benzoquinone (DDQ) in dioxane to obtain a condensed bicyclic system - methyl-8-cyano-2-naphthoate (13). Then methyl group restore the action of hydrogen and methyl ipirou acid (14) - intermediate compound for the synthesis of cyclic peptide.

Part A. a Solution of methyl 8-cyano-5,6-dihydro-2-naphthoate (1.0 g, 0,0047 mol) and 2,3-sodium dichloro-5,6-dicyano-1,4-benzoquinone (1.07 g, 0,0047 mol) in dioxane (50 ml) was stirred at 120oC for 16 h, the Reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers dried over anhydrous magnesium sulfate and evaporated to a dry residue under reduced pressure. The dry residue is purified chromatographically using ethyl acetate.

Obtain methyl 8-cyano-2-aftout (0,72 g, 0,0034 mol, 73%) as a reddish brown solid.

TPL= 178 - 182oC. an NMR Spectrum1H (CDCl3):d of 8.95 (s, 1H), from 8.3 to 8.2 (m, 1H), 8,15 - 8,10 (m, 1H), 8.0 to to 7.95 (m, 2H), 7,7 - to 7.6 (m, 1H), 4,05 (s, 1H).

Part B. a Mixture of methyl 8-cyano-2-naphthoate (1.0 g, 0,0047 mol) in methanol (35 ml) with concentrated hydrochloric acid (0,69 ml) and the catalyst is palladium supported on carbon (0.20 g, 5% Pd/C), shaken for 6 h at room temperature in hydrogen atmosphere (50 lb/inch). The reaction mixture was filtered through Celite@and washed with methanol. The filtrate is evaporated to a dry residue under reduced pressure, the solid residue is triturated with hexane. Get me - of 7.70 (m, 2H), 4,6 (s, 2H), 3,95 (m, 3H).

Part C. To a solution of methyl-8-aminomethyl-2-naphthoate (0.75 g, 0,0035 mol) in dry tetrahydrofuran, cooled to 0oC, add a solution of lithium hydroxide (0.5 M, of 5.83 ml). Everything is stirred at room temperature for 20 hours, Add the following aliquot of lithium hydroxide, and everything is stirred for further 20 hours solid product is Filtered off, the filtrate is evaporated to dryness.

Solids triturated with diethyl ether.

Get 8-aminomethyl-2-naphthoic acid (0,67 g, 0,0033 mol, 95%) as a white solid.

TPL= 223 - 225oC. an NMR Spectrum1H (in DMSO):d to 8.6 (s, 1H), 8,1 - 7,9 (m, 1H), 7,8 - in 7.7 (m, 4H), 7,55 - 7,5 (m, 1H), 7,45 - 7,35 (m, 2H), 4.2V (s, 2H).

Part D. To a solution of 8-aminomethyl-2-naphthoic acid (0.50 g, 0,00025 mol) and triethylamine (0,038 ml 0,028 g, 0,000275 mol) in aqueous tetrahydrofuran (50%, 5 ml), add parts, in the form of solids, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0,068 g, 0,000275 mol). Everything is stirred at room temperature for 5 hours the Solution is concentrated to half volume and extracted with diethyl ether. Then the aqueous layer was acidified to pH 1 with hydrochloric acid (1H) and extracted with ethyl acetate. The combined organic layers visos the OE in the title compound, N-(BOC)-8-aminomethyl-2-naphthoic acid (0,050 g, 0,00017 mol) as a white solid.

TPL= 190 - 191oC. an NMR Spectrum1H (in DMSO):d 13,11 (s, 1H), and 8.8 (s, 1H), 8.0 a (q, 2H, J = 7.9 Hz), and 7.9 (d, 1H, J = 8,1 Hz), and 7.5 (t, 1H, J = 7.5 Hz), 7,65 - of 7.55 (m, 2H), and 4.6 (d, 2H, J = 5.5 Hz), and 1.4 (s, 9H).

Cyclic intermediate compound 89a and 89b

Cyclo-(D-Val-NMeArg-Gly-Asp-aminomethylenemalonate acid), a compound of formula (VII), where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1=R2- H.

Specified in the title compound get the General procedure described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). To join Boc-aminotetralin-carboxylic acid to a reaction using the method of DCC/DMAP. Of the peptide used in the amount of 0,164 mmol, get protected cyclic peptide (69 mg, 49,3%). Peptide (69 mg) in the presence 0,069 ml of anisole is treated with anhydrous hydrogen fluoride at 0oC for 30 minutes the product is precipitated with ether, pererastayut in aqueous acetonitrile and allocate the lyophilization specified in the title compound (59,7 mg, the output of the above quantitative, calculated on the fluoride salt).

Cleaning is performed by the method obremeniaet HPLC on a preparative column (Vydac C18 (2.5 cm) using 16,2 - 27% acetone is shown in the title compound as a white fluffy solid, 2 isomer, isomer #1 (the output of 12.5%, the total yield of 6.2%), mass spectrum (FAB): [M+H] = 615,34; isomer #2 (output of 18.6%, the total yield of 9.3%, mass spectrum (FAB): [M+H] = 615,35.

Cyclic intermediate compound 89c

Cyclo-(D-Val-NMeArg-Gly-Asp-aminomethylation acid), a compound of formula (IX), where J is D-Val, K is NMeArg, L = Gly, M - Asp, R1- H, R2- H.

Specified in the title compound get the General procedure described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) (cyclic intermediate compound 4). To join Boc-aminomethylating acid to the oxime used method of DCC/DMAP. Of the peptide used in the amount of 0,737 mmol, get protected cyclic peptide (463 mg, 73.1 per cent). Peptide (463 mg) in the presence of 0,463 ml of anisole is treated with anhydrous hydrogen fluoride at 0oC for 20 minutes the resulting product is precipitated with ether, pererastayut in aqueous acetonitrile and allocate the lyophilization specified in the title compound (349 mg, the output of the above quantitative, calculated on the fluoride salt).

Cleaning is carried out by the method of reversed-phase HPLC on a preparative column (Vydac C18 (2.5 cm) using a 4.5 - 22.5% of acetonitrile containing 0.1% TFA, gradient of 0.45%/min and then lyophilized, resulting in a gain of salt triperoxonane acid is, the ACC-spectrum (FAB): [M+H] = 625,32.

The synthesis of cyclic intermediates, modified by the introduction of "bundles".

Cyclic intermediate compounds which are modified by doing "bundles" can be obtained either by joining pre-protected link to the movie cycle with the subsequent inclusion of this fragment in the cyclic system, or the introduction of "bundles" in the cyclic intermediate connection.

Fragments of the cycle, modified by the introduction of "bundles"

Fragments of the cycle, modified by the introduction of the "ligaments", can be synthesized either attach link to part of a cycle containing substituents in the aromatic nucleus, as described above, either the pre-accession protected link in the process of synthesis of the fragment.

For example, the above-described cyclic fragments containing the substituents in the aromatic nucleus, where X=NH2can interact with Succinimidyl "bundle", RCOOSu (R= -(CH2)5-NH2or CH2-C6H5-p-NH2), resulting in a "bundle" is attached in position X via an amide group.

< / BR>
a] Boc-ON, b] RCOOSu

Substituted in the aromatic nucleus fragments of cyclic p the lubricant consists of four etileno units, the separated ether groups, and contains Z is replaced by the amino group on one end and useplease group, such as tosylate, on the other.

Thus can be obtained "link", attached in position X through the ether group.

Cyclic fragments containing the substituents in the aromatic nucleus, where Z is NH2can interact with (Z-NH(CH2)5CO)2O with the formation of "bundles", attached in position Z through amide group.

< / BR>
"Bundles" can be attached to a portion of a loop containing the substituents in the aromatic nucleus at Z=OH. To attach a link to the aromatic ring, you must use the "bundle" containing useplease group capable of interacting with the phenolate-ion.

Such otsepleniya group include halide, arylsulfonate (i.e. tozilaty), alkylsulfate (mesylates). For example, the use of alkyl chain containing tonilou group on one end and a protected amino group on the other. The literature provides several examples of alkylation of the phenyl group in the presence of a carboxyl group (for example, Brakmann, Kluge and Muxfeldt (1957), Ber. Deutsh. Chem. Ges., 90, 2302).

< / BR>
Fragments of the cycle, UB>COOS

with the formation of "bundles", attached in position Z through amidomethyl group.

< / BR>
The preceding examples illustrate the use of "bundles" containing terminal protected amino group. "Bundles" containing end carboxyl or ester group may also be of interest. Some of these "bundles" can be attached to the cyclic fragments described above. For example, according to the following scheme, 3-aminomethyl-4-hydroxybenzoic acid, protected tert-Boc group, interacts with benzylchloride and the substrate, resulting entered short "connection", ending with essential group.

< / BR>
"Linkage" can be attached to a portion of a loop containing the substituents in the aromatic nucleus, Y=NH2. As shown in scheme 8, a mild alkaline hydrolysis of the methyl ester 3-aminomethyl-5-aminobenzoate protected tert-Boc group with subsequent interaction with benzoylacrylate (Lancaster Synthesis, Inc.) in the presence of a catalyst, acetic acid and yields a product join Michael. Even if the movie cycle, modified by the introduction of "bundles", contains unprotected secondary amino group, it can be directly COI is eat benzylchloride and soft grounds.

The bundle can also be introduced during synthesis of cyclic fragment. An example is the synthesis of cyclic fragment, a modified "a bunch of" 5-Aca-Mamb.

Synthesis Of Boc-Mamb (Z-5-Aca).

This synthesis is shown in scheme 9.

Part A. Methyl-3-nitro-5-hydroxymethylbenzene

To a solution of monomethyl-3-nitroisophthalate add 2.0 M RMS (boron complex of methyl sulfide) in THF (880 ml of 1.76 mol), dropwise over 1 h the resulting solution was heated under reflux for 12 h and then slowly add MeOH (750 ml) to quench the reaction. After concentrating receives a yellow solid, which is recrystallized from toluene (297,5 g, 80%).

An NMR spectrum1H (CDCl3): 8,71 - to 8.70 (m, 1H), to 8.41 - to 8.40 (m, 1H), 8,31 - 8,30 (m, 1H), a 4.86 (s, 1H), 3.96 points (s, 3H), 2,47 (s, 1H). Tpl.76,5 - 77,5oC. Mass spectrum (DCl): [M+H]=212.

Part B. 3-carbomethoxy-5-nitrobenzenesulfonate

Methyl 3-nitro-5-hydroxymethylbenzene (296,0 g to 1.40 mol) and proton acceptor (360,8 g, 1,68 mol) is dissolved in ethylene dichloride (150 ml). Anhydride, triftoratsetata (292,3 g, 1,68 mol) dissolved in ethylene dichloride (800 ml), added dropwise to the suspension for 90 min and stirred the mixture for 18 h under nitrogen atmosphere. The reality is, asystem solution of NaHCO3H2O and saturated NaCl solution.

The organic layer is dried (MgSO4) and concentrate under reduced pressure. The obtained yellow solid is recrystallized from toluene and get listed in the title compound as a tan solid (366,8 g, 91%).

An NMR spectrum1H in CDCl3: 8,84 cent to 8.85 (m, 1H), 8,45 - 8,46 (m, 1H), 8,40 - 8,39 (m, 1H), to 5.35 (s, 2H), 3,98 (s, 3H), 3,10 (s, 3H). Tpl.96 - 97oC. Mass spectrum (DCl): [M+NH4]=307.

Part C. Methyl-3-azidomethyl-5-nitrobenzoate

3 Carbomethoxy-5-nitrobenzenesulfonate (300,0 g, 1.04 mol) and sodium azide (81,0 g, 1.25 mol) are suspended in DMF (1700 ml) and stirred at room temperature for 5 hours, the Reaction mixture was diluted with ethyl acetate (2000 ml), washed with portions of 1000 ml, H2O (2 times) and saturated NaCl solution (1 time), dried (MgSO4) and then concentrated under reduced pressure. Received amber syrup was dried in vacuum at 40oC and get listed in the title compound as a tan solid (226,5 g, 92%).

An NMR spectrum1H (CDCl3): at 8.60 (s, 1H), compared to 8.26 (s, 1H), to 8.20 (s, 1H), to 4.52 (s, 2H), 3,88 (s, 3H). Tpl.44 - 46oC.

Part d is facility (22,14 g, 140 mmol) in warm methanol is placed in vstryahivaya the Parr reactor and rinsed with nitrogen for 15 minutes Add the catalyst is palladium supported on carbon (10% Pd/C, 4.0 g), and spend 7 times blowing ustraivayuschee reactor with hydrogen in a circular diagram - pressure supply - discharge pressure, then relieve pressure and shaken for 18 h, during this time absorbed the desired amount of hydrogen. The catalyst was removed by filtration through a layer of Calite, after concentration of the filtrate under reduced pressure to obtain a reddish brown oil. Triturated with distilled EtOAc (g ml), then cooled for 12 h at -5oC and get a reddish-brown solid, which was collected by filtration, washed with EtOAc (g ml) and dried under vacuum (25,82 g, 80%).

An NMR spectrum1H (CD3OD): 8,25 - of 8.33 (m, 1H), 8.07 - a of 8.06 (m, 1H), 7,86 - 7,80 (m, 5H), 7,49 - 7,42 (m, 6H), the 4.29 (s, 2H), of 3.97 (s, 3H).

Part E. Methyl-3-amino-5-(tert-butoxycarbonylamino)-methylbenzoate

Spend interaction in a solution of MeOH (350 ml) of methyl 3-amino-5-aminomethylbenzoic (19.32 g, 39,0 mmol), TFA (7,89 g, 78,0 mmol) and di-tert-BUTYLCARBAMATE (8,51 g, 39,0 mol) for 24 h at room temperature. After concentrating receive a colorless solid washes the CT (of 9.21 g, 84%) as a colourless solid.

An NMR spectrum1H (CD3OD): 7,26 - 7,25 (m, 2H), 6,86 - 6,85 (m, 1H), 4.16 the (s, 2H), 3,88 (s, 3H), of 1.48 (s, 9H). Tpl.57 - 65oC. Mass spectrum (ESI): [M+H)=281.

Part F. Boc-Mamb(Z-5-Aca)-OMa

N-CBZ-e-aminocaproic acid (to 7.77 g of 29.3 mmol) and TEA (2,97 g, 23,3 mol) is dissolved in anhydrous THF (250 ml) and cooled to -20oC. is Added dropwise isobutylbarbituric (of 4.00 g of 29.3 mmol) and conducting the reaction for 5 min at -20oC. Methyl-3-amino-5-(tert-butoxycarbonylamino)methylbenzoate (8,20 g of 29.3 mmol) dissolved in anhydrous THF (50 ml), cooled to -20oC and added dropwise to the reaction mixture. The reaction mixture is allowed to slowly warm to room temperature and stirred for further 2 days. Solids are removed by filtration, the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in EtOAc (125 ml) and washed with portions of 50 ml of 0.2 H HCl, a saturated solution of NaHCO3and saturated NaCl solution. The organic layer is dried (MgSO4) and concentrate under reduced pressure. The obtained product is purified chromatographically (silica gel, hexane: EtOac, 1:2) and recrystallized from CCl4get listed in the title compound (of 10.09 g, 65%) as a colourless firmly the 3,17 - of 3.12 (m, 2H), 2,34 - of 2.28 (m, 2Y), 1,72 - of 1.66 (m, 2H), 1,48 - of 1.53 (m, 2H), USD 1.43 (s, 9H), 1,36 is 1.34 (m, 2H). Tpl.52 - 54oC.

Mass spectrum (ESI): [M+H]=528.

Part G. of Boc-Mamb(Z-5-Aca)

Boc-Mamb(Z-5-Aca)-OMe (22,58 g, 43,0 mmol) dissolved in a mixture 1:1 1N NaOH and MeOH (500 ml) and stirred at room temperature for 18 hours, the Reaction mixture was separated between EtOAc (300 ml) and H2O (200 ml) and separate the layers. The pH of the aqueous layer is reduced to 4.5 and the obtained oily residue is extracted with EtOAc (g ml). The organic extract was dried (MgSO4), after concentrating receives a yellow solid. The solid is triturated with distilled CCl4(G ml) and obtain the target product (14,47 g, 64%) as a colourless solid. An NMR spectrum1H (CD3OD): 8,04 (s, 2H), 7,71 - 7,66 (m, 2H), 7,30 - of 7.23 (m, 5H), 5,02 (s, 2H), 4,24 (s, 2H), 3,32 (s, 3H), 3,11 (t, J = 6,8 Hz, 2H), 2,34 (t, J = 6,8 Hz, 2H), 1,74 - of 1.35 (m, 15H). Tpl.168 - 169oC. Mass spectrum (DCl):[M+NH4)=531.

Figure 10 shows how can be synthesized fragment of the loop containing the "glue" that are attached through the opposite amide functional group. The restoration of the nitrogroup monomethyl-3-nitroisophthalate (Fluka) using palladium supported on carbon, allows to obtain monomethyl-3-aminoisophthalate, catilina allows to obtain the corresponding amide. The protective group of the diamine must be stable under the hydrogenation. The diagram shows the use of theos(2-trimethylsilylethynyl)groups, but can be used and other well-known experts in this field such groups. The restoration of the nitrile group using palladium supported on carbon, allows to obtain a cyclic fragment, a modified "bundle" (see diagram 10).

Link attached in the Y position of the aromatic ring cyclic fragment through the ether group can be obtained using as a starting compound 3-hydroxy-5-aminobenzoic acid. For translation amine 3-hydroxy-5-cyanobenzoic acid can be used in the reaction, proposed Sandmeyer. "Bunch" introduced by alkylation. The restoration of the nitrile group using a catalyst is palladium supported on carbon, allows you to get the aminomethyl group. Protection of the amino group, tert-Boc-group using di-tert-BUTYLCARBAMATE, allows to obtain a cyclic fragments containing the same package, ready for use in solid-phase synthesis. This is shown in scheme 11.

Link ending in a carboxylic acid group, can be polucheniya. The reaction of methyl-3-aminomethyl-5-aminobenzoate protected tert-Boc-group with succinic anhydride, gives a "bunch" of carboxylic acids. Activation of the carboxylic acid and condensation with benzoylhydrazone (Lancaster Synthesis, Inc.) allows to obtain the substituted hydrazide. This hydrazide is used to protect carboxylic acid during the synthesis. Hydrolysis of methyl ester yields a cyclic fragment, a modified "a bunch" in a form ready for solid-phase synthesis. After completion of the synthesis, cleavage of Cbz protective group from the hydrazide opens the way for the synthesis of azide and attach azide to the complexing agents (Hofmann, Magee and Lindenmann (1950) J. Amer. Chem. Soc., 72, 2814). This is shown in figure 12.

Link can also introduced in the process of synthesis of other cyclic fragments. For example, "connection", modifying heterocyclic fragment of a cyclic system can be obtained from 4-amino-6-carbethoxy-1-hydroxyethylpyrrolidine (Boger (1994), J. Amer, Chem. Soc, 116, 82 - 92). The alcohol can be converted into amine in three stages.

First interaction with toluensulfonyl chloride and base allows you to get toilet, which upon treatment with sodium azide gives azide. The restoration of the azide using catalyst-p which allows selective protection aminomethyl group, using di-tert-BUTYLCARBAMATE. Joining a secure link, such as Z-5-Aca, the remaining amino groups can be carried out using a mixed anhydride or symmetrical anhydride. Finally, hydrolysis of the ethyl ester allows you to get the heterocyclic fragment of a cyclic system, a modified "bundle", which is used in solid-phase synthesis. This is shown in figure 13.

Link

The synthesis of link-based tetraethyleneglycol discussed above, is shown in scheme 14. As the parent compound using 1-amino-11-azido-3,6,9-trioxadecyl (Bertozzi and Bednarski (1990), J. Org.Chem, 56, 4326-4329). Recovery azide by using a catalyst of palladium supported on carbon, leads to the amine, which protects Cbz group (designated as Z in figure 14, below). The alcohol is transformed into toilet action toluensulfonate and grounds.

< / BR>
Another type of "bundles" that include etilenglikolevye balances shown in the following diagram. This "linkage" has at one end a group of carboxylic acids which may be attached to the fragment cyclo containing functional amino group. The synthesis begins with the above-described introduction of Cbz-protection in amerosport. About causehe tetraethyleneglycol "tail". As a result of hydrolysis of the ethyl ester receive the same package, ready for insertion into the circular portion. This is shown in scheme 15:

< / BR>
The following fragments of a cyclic structure, modified by the introduction of "bundles" that can be used in the synthesis of intermediate cyclic compounds, modified by the introduction of "bundles".

Cyclic compound 1, modified by the introduction of "bundles" cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca))

Synthesis indicated in the title of the connections shown in the diagram below 16.

60 ml - flask for reaction of peptide added to the resin - oxime (1,61 g, degree of substitution = of 0.62 mmol/g). After a single wetting DMF (30 ml), the resin swells. In the reaction flask is added Boc-Mamb(Z-5-Aca) (513 mg, 1.0 mmol), HBTU (379 mg, 1.0 mmol) and DIEA (of 0.52 ml, 3 mmol). The suspension is stirred at room temperature for 96 hours. The resin is thoroughly washed with 30 ml, DMF (3 times), MeOH (1 times), DCM (3 times), MeOH (2 times) and DCM (3 times). The substitution level, a specific test with picric acid, is 0,381 mmol/g

Then carry out the following stages. Stage 1 - the resin is washed with 30 ml, DMF (3 times), MeOH (1 times), DCM (3 times), MeOH (2 times) and DCM (3 times).

Stage 2 - resin soaked 30 ml of 50% TFA in which Ino washed with DCM (3 times), MeOH (1 times), DCM (2 times), MeOH (3 times) and DMF (3 times). Stage 4 - add to the resin Boc-Asp(OBz1) (0,982 g, 3.04 from mmol), HBTU (1,153 g, 3.04 from mmol), DIEA (1,59 ml, 9,14 mmol) and DMF (14 ml) and conducting the reaction for 22 hours. Stage 5 - Completion of the reaction, the merger control test with picric acid. Stage 1-5 repeat until until you reach the desired result.

Once assembled linear peptide, remove the N-terminal t-Boc group by washing with 50% TFA in DCM, and then the processing of 30 ml of 50% TFA in DCM for 30 minutes the Resin is then washed thoroughly with DCM (3 times), MeOH (2 times), DCM (3 times) and then neutralized with 30 ml 10 DIEA in DCM (2 times for 1 min). The resin was washed with DCM (3 times) and MeOH (3 times) and after drying in a vacuum get 1,965 g of a brown resin. Resin cyclist suspendirovanie in DMF (20 ml), content HOAc (35 μl, 0,609 mmol) and heated at 50oC for 72 h, the Resin is filtered through a funnel with a glass filter and washed thoroughly with 10 ml of DMF (3 times). DMF - filtrate is evaporated and the resulting oil pererastayut in a mixture of acetonitrile and H2O (1:1, 20 ml), after separation by lyophilization get protected cyclic peptide (342 mg). Cleaning is performed by the method of "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm) with isocrates under in order to obtain purified protected peptide (127 mg).

The protected peptide (120 mg, 0.11 mmol) is removed by the action of TFA (1 ml) and anhydride triftormetilfullerenov acid (1 ml) in the presence of anisole (0.2 ml) for 3 h at - 10oC. the Peptide precipitated by the addition of ether and cooled to - 35oC for 1.5 hour. The peptide is collected by filtration, washed with ether and dried. The obtained solid is dissolved in a mixture of 1:1 acetone and H2O (12 ml) and the pH adjusted to 4-6 treatment ion exchange resins Rad AGI-x8 acetate. The resin is filtered and washed with water. The filtrate lyophilized and get chromatographic pure peptide (75 mg, total yield of 13.5%); mass spectrum (FAB): [M+H]=703,3951.

Cyclic compound 2, modified by the introduction of "bundles" Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-Aca))

Specified in the title compound get the General procedure described for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca)). Of the peptide used in the amount of 1.35 mmol, get the crude protected cyclic peptide (1,05 g, 73%). Removing the protection peptide (500 mg) carry out the action of TFA (4 ml) and anhydride triftormetilfullerenov acid (4 ml) in the presence of anisole (0.8 ml) for 3 h at -10oC. the Peptide precipitated with ether and cooled to - 35oC for 1.5 hour. The peptide is separated by filtration, washed with ether avodat method obremeniaet HPLC on a preparative column (Vydac C18 (2.1 cm), using 9-18% acetonitrile containing 0.1% TFA (gradient of 0.36%/min), and then lyophilization. Get salt triperoxonane acid specified in the title compounds as a colorless fluffy solid (218 mg, yield 69%, the total yield 37%); mass spectrum (FAB):[M+H]=689,3735.

Modified by the introduction of "bundles" of cyclic compounds 3-8

< / BR>
R IS -(CH2)5-NH2or CH2-C6H5-p-NH2< / BR>
x1- 2-propyl, ethyl or n-hydroxyphenylethyl.

The compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(4-NHCOR), cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(4-NHCOR) and cyclo(D-Tyr-NMeArg-Gly-Asp-Mamb(4-NHCOR) can be obtained by the method described above.

"Bundles" can be introduced during synthesis of cyclic intermediates.

Modified by the introduction of "bundles" of cyclic compounds 9, 10 and 11

< / BR>
x - CH2CH2CH2CH2CH2CH2CH2CH2CH2,

Cyclo(O-2-amino-ethyl-D-Tyr)-NMeArg-Gly-Asp-Mamb),

Cyclo(O-3-aminopropyl-D-Tyr)-NMeArg-Gly-Asp-Mamb),

Cyclo(O-4-aminobutyl-D-Tyr)-NMeArg-Gly-Asp-Mamb):

These compounds can be obtained according to the method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb) using a modified introduction link D-Tyr. O-substituted D-Tyr may be the floor is POI in the presence of a base.

Link can also be attached already ready to cyclic intermediate connection.

Modified by the introduction of "bundles" cyclic connection 12 cyclo-(D-Lys(5-Aca)-NMeArg-Gly-Asp-Mamb).

The synthesis of this compound is shown in scheme 17.

Spend the interaction in solution of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) (100 mg, 0.12 mmol), Boc-5-aminocaproic acid hydroxysuccinimide ester (47 mg, 0.144 mol) and Et3N (50 ml, 0.36 mmol) in DMF (1.50 ml) at room temperature for 60 min Course of the reaction control "normalizes" TLC (90:8:2, CHCl3:MeOH:HOAc), using the ninhydrin test and Sakaguehi. DMF is removed under reduced pressure. The crude product is treated with TFA (3 ml) at room temperature for 45 min to remove the tert-Boc-protective groups. TFA is removed under reduced pressure and purify the conjugate method "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 6% acetonitrile containing 0.1% TFA, over 20 minutes, then 6-36% acetonitrile containing 0.1% TFA with a gradient of 3.0%/min After separation by lyophilization get salt triperoxonane acid specified in the title compounds as a colorless fluffy solid (80 mg, 70%).

Modified by the introduction of "bundles" cyclines)-propionate (Bolton-Hunter rcagent; of 0.022 g, 0.08 mmol) and DIEA (0,02 ml, 0.10 mmol) in dioxane (5 ml) was added to a solution of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) (0,026 g, 0.04 mmol) in phosphate buffer with pH 9 (5 ml) and conducting the reaction under stirring for 2 days. The solution lyophilized, and the resulting white solid purified by the method of "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 9-18% acetonitrile containing 0.1% TFA (gradient of 0.36%/min), and obtain the target product (0,018 g, 60%) as a colourless solid. Tpl.= 146 = 155oC.

Mass spectrum (ESI):[M] = 751.

Modified by the introduction of "bundles" cyclic connection 14 cyclo((N-E-Tyr-D-Lys)-NMeArg-Gly-Asp-Mamb)

< / BR>
This compound can be obtained by the reaction of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) with Boc-Tyr-OSu in a solvent such as DMF, in the presence of a base, such as triethylamine, followed by removal of the protection.

Modified by the introduction of "bundles" cyclic connection 15 cyclo-(N-E-(4-aminophenylacetic)D-Lys)-NMeArg-Gly-Asp-Mamb)

< / BR>
The specified connection can be obtained by the reaction of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) with Succinimidyl-fmoc-4-aminophenylacetate in a solvent such as DMF, in the presence of a base such as triethylamine with subsequent removal of the protection.

Modificirovana the>/BR>The specified connection can be obtained by the reaction of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) with Succinimidyl-4-amino-2-hydroxybenzoate in a solvent such as DMF or TNF in the presence of a base such as triethylamine.

Several modified by the introduction of "bundles" of cyclic compounds can be obtained by the use of bifunctional cross-linking agents used for modification of proteins. These reagents contain two electrophilic groups, such as active air or isocyanate, divided by the spatial grouping. Such reagents can be homobifunctional, if the two reactive groups are identical or heterobifunctional. Spatial grouping may be aliphatic or aromatic and may contain additional functional groups for modification of the liquid conjugates or for the separation circuit. The following examples will illustrate the use of some of the produced cross-linking agents using as the parent compound cyclic intermediate compounds obtained using 4-aminomethyl-Mamb structural units.

In accordance with the first example of a cyclic compound is treated with an excess of DSS (disuccinic is via reactions such cross-linking reagents. Excess cross-linking reagent minimizes the formation of dimers. The pH value 7-9 allows the amino group to interact with sufficient speed, but does not undergo significant hydrolysis of the second reactive group and prevents interaction with guanidino group of arginine. Active ether group at the end of the link is quite stable, which makes it possible to carry out purification by HPLC or evaporative chromatography. After cleaning, modified by the introduction of "bundles" cyclic compound may interact with the complexing agents containing nucleophilic groups such as amino group or Tolna group. This is shown in figure 18.

Heterobifunctional reagents typically used for very selective activation of peptides and proteins. In the following example, SMPB (succinimide 4-(n-maleinimide)butyrate, Pierce Chemical Co.) use to modify amidofunctional cyclic compounds and preparation for interaction with diastereomer complexing agents. Treatment of cyclic compounds SPMB in a weak alkaline medium leads to the formation modified by the introduction of link connections, where "link" is at stake is the promotional ability with respect to the amino group, and dimerization minimum. After cleaning maleinimide group can connect with diastereomer complexing agents. This is shown in figure 19.

"Bundles" containing internal functional groups, can be obtained using the reagents shown in scheme 20, EGS (ethylene glycol bis-(succinimidylester), Sigma Chemical Co. is bisacrylamide-ether, which primarily reacts with the amine. Dimethyl 3,3'-dithio-bis-propionamide (DTBP, also called reagent Wang and Richards; Pierce Chemical Co.) also mainly interacts with amines. The disulfide unlinked thiols. Meares and cjmp. showed (Int. J. Cancer: Supplement 2, 1988, 99-102) that conjugates the antibody-chelate labelled 111In attached dyslipidaemia "bundle", characterized by a more rapid decrease in radioactivity (in mice) than conjugates; which do not contain able to split link. The third example in figure 20 shows the use BSOCOES (bis[2-(succinyldicholine)ethyl]sulfon, Pierce Chemical Co), homobifunctional cross-linking agent, which contains an internal sulfonic group. With the addition of this reagent to an amine is formed fragment of carbamino acid.

Scheme 21 Illustra compounds. These reagents interact with amines with the formation of urea and timesaving groups, respectively. These reagents are used in excess in order to reduce the formation of dimers.

Isocyanate and thioisocyanate group at the end of the link is stable enough for cleaning product.

The complexing agents

The present invention also provides new reagents required for the synthesis of radioactive pharmaceuticals. These reagents consist of complexing agents, Chattached through a linking group, Lnto the cyclic intermediate connection Q. These reagents can be obtained in several ways, either by the addition of complexing agents to the modified by the introduction of "bundles" cyclic intermediate connection or joining of complexing agents, carrying a bridging group to the cyclic intermediate connection. Mainly complexing agents attached to the cyclic intermediate connection, modified by the introduction of "bundles".

A variety of complexing agents can be used in this invention, provided that they form a stable Ally, the coordination compound with the complexing agents is a complex metal chelate. Examples of metal complexes-gelatt can be found in a recent review (S. Jurisson et al., Chem.Rev., 1993, 93, 1137-1156, shown here as a reference.

The complexing agents can be added to the "links" in a variety of ways, known to specialists in this field. In General, the reactive group link can interact with the complexing agents or, alternatively, the reactive group of the complexing agents can interact with the "bundle". Suitable reactive groups include activated esters, isothiocyanates, alkyl - and oringally, amines, thiols, hydrazines, maleinimide, etc., Some modified by the introduction of "bundles" of cyclic compounds containing reactive group described in the examples below.

Typical complexing agents: Diethylenetriamine-pentaoxa acid (DTPA) Ethylenediamine-tetraoxane acid (EDTA), 1,4,7,10-tetraazacyclododecane-N, N', N", N"'-tetraoxane acid (DOTA), 1,4,7,10-tetraazacyclododecane-N, N', N"-trioxane acid, hydroxybenzylidene-diamine dioxyna acid, N,N'-bis(pyridoxyl-5-phosphate)Ethylenediamine, N,N'-diacetate, 3,6,ucsusa acid, 1,4,8,11-tetraacetic-tetradecane-N, N', N", N"'-tetraoxane acid, 2,3-bis(S-benzoyl) mercaptobenzotriazole acid and the following complexing agents.

Other complexing agents may include connecting the metal fragments derived from proteins that bind metal, such for example, as rich in sulfhydryl groups of proteins in the cytoplasm contained in vertebrates, invertebrates and fungi

Synthesis of complexing agents

Synthesis of 4,5-bis((S-benzoyl)mercaptoacetate) pentanol acid (mapt)

The complexing agents receive, as described in: Fritzberg et al., Appl. Radiat. Isot. 1991, 42, 525-530.

Synthesis of (S-benzoyl)mercaptoacetyltriglycine-Goldengorin (MAG3)

The complexing agents receive, as described in: Brandau W, et al., Appl. Radiat. Isot. 1988, 39, 121-129.

Synthesis Succinimidyl 6-Boc-hydrazinopyridazine-3-carboxylate (SHNH)

The complexing agents receive, as described in: Schwartz et al., 1990, European Patent Application 90301949.5.

Synthesis of ester of N-[4-(carboxy)benzyl]-N,N'- bis[(2-triphenylmethyl)ethyl] glycinamide N-hydroxysuccinimide

Synthesis specified in the title compounds are illustrated below in scheme 22

Part A. S-triphenylmethyl-2-aminoethanethiol

Renola (182 g, 0.7 mol) and stirred at room temperature for 1 hour. Then TFA is removed under reduced pressure at 45oC and the resulting dark orange oil was dissolved in EtOAc (700 ml). Solution in EtOAc washed with cold 2N NaOH (g ml), H2O (g ml), saturated sodium bicarbonate solution (350 ml) and saturated NaCl solution (350 ml). The combined wash water is re-extracted with EtOAc (350 ml). The combined organic layers dried (MgSO4and after concentrating receives a yellow solid. After trituration with ether (500 ml) to obtain the target product (97,2 g, 43%) as a colourless solid. Tpl.= 90-92oC (D. Brenner et. al., J. Inorg. Chem. 1984, 23, 3793-3797, Tpl.= 93-94oC).

Concentration of the ether extract to a volume of 100 ml with subsequent cooling allows additional gain of 40.9 g of the product with Tpl.= 89-91oC, the total yield is 62%.

Part B. N-2-bromacetyl-S-triphenylmethyl-2-aminoethanethiol

A solution of S-triphenylmethyl-2-aminoethanethiol (48 g, 0.15 mol) and Et3N (20,9 ml, 0.15 mol) in DOM (180 ml) is added slowly with stirring to a solution of bromoacetamide (to 13.9 ml, 0.15 mol) in DCM (100 ml) at -20oC. Then the reaction mixture is allowed to warm to room is and saturated NaCl solution. The organic solution is dried (MgSO4). After concentration get oily product, which is recrystallized from a mixture of DSM-hexane and receive a colourless solid Tpl.= 137-139,5oC (J. A. Wolff, Ph.D.Thesis, Massachusetts Institute of Technology, February 1992, Tpl.= 130-135oC.

Part C - N,N'-bis[(2-triphenylmethyl)ethyl]glycinamide

A solution of N-2-bromacetyl-S-triphenylmethyl-2-aminoethanethiol (35.2 g, 0.08 mol), S-triphenylmethyl-2-aminoethanethiol (25,5 g, 0.08 mol) and Et3N (of 16.7 ml, 0.12 mol) in DCM (375 ml) incubated at room temperature for 24 hours. Then the solution is washed in portions of 200 ml, water (1 time), a saturated solution of NaHCO3(2 times), water (1x), saturated NaCl solution (1 time), dried (MgSO4and after concentrating obtain a viscous oil, which was dissolved in a mixture of DCM : EtOH (70:30, 150 ml) and cooled in a bath with ice. The resulting solid is removed by filtration. The filtrate is concentrated to a state viscous oil. This oil is purified chromatographically on silica gel (200-400 mesh, 60 A) using as mobile phase a mixture of DCM:EtOAc in the ratio of 70:30, and get the target product (34.4 g, 63%) as a colorless amorphous foamy solid.

Part F - N-[4-carbomethoxy)benzyl]-N,N-bis-[(2-triphenylmethyl)ethyl] glycinamide

A solution of methyl N, N'-bis[(2-triphenylmethyl)ethyl]glycinamide (16,27 g 0,024 mol) and methyl-4-(methanesulfonyl) benzoate (4,88 g, 0.02 mol) in ethylene dichloride (200 ml) is heated under reflux for 28 hours. The reaction mixture is washed with portions of 200 ml, saturated solution of NaHCO3and H2O, dried (MgSO4) after preconcentration get a light brown oil (30 g). This oil is purified by chromatography on silica gel (200-400 mesh, 60 A), using as podvigla. An NMR spectrum1H (CDCl3): of 7.90 (d, 2H, J=6.5 Hz), 7,49 - to 7.18 (m, 32H), 3,91 (s, 3H), 3,47 (s, 2H), 3,01 (q, 2H, J = 6.2 Hz), is 2.88 (s, 2H), 2,43 (t, 2H, J = 6.2 Hz), 2,39 - of 2.27 (m, 4H),

Part F - N-[(carboxy)benzyl]-N,N'-bis[(2-triphenylmethyl)ethyl]glycinamide

A mixture of N-[4-(carbomethoxy)benzyl] -N, N'-bis-[(2-triphenylmethyl)ethyl] glycinamide (6.0 g, 7,26 mmol) in dioxane (65 ml) and 1H NaOH (65 ml) was stirred at room temperature for 24 h the Mixture was acidified with 2.5 M citric acid (100 ml) and the resulting rubbery precipitate is extracted with EtOAc (400 ml). Solution in EtOAc washed with H20(G ml) and saturated NaCl solution (100 ml), dried (MgSO4and after concentrating obtain the target product (5,90 g 100%) as a colourless, amorphous foamy solid.

An NMR spectrum1H (CDCl3): of 7.96, (d, 2H, J = 8.1 Hz), 7,40 - 7,16 (m, 32H), 3,71 (s, 3H), 3,49 (s, 2H), 3.00 and (q, 2H, J = 5.4 Hz), 2.91 in (s, 2H), 2,44 (t, 2H, J = 5.4 Hz), 2,38 - of 2.30 (m, 4H).

Part G - Ether-N-[4-(carboxy)benzyl] -N, N'-bis- [(2-triphenylmethyl)ethyl]glycinamide N-hydroxysuccinimide

A solution of N-[4-(carboxy)benzyl]-N,N'-bis[(2-triphenylmethyl)ethyl]glycinamide (450 mg, 0.55 mmol) and N-hydroxysuccinimide (76 mg, 6 mmol) in DCM (7 ml) is treated with a solution WSCDHCl (122 mg, 0.66 mmol) in DCM (7 ml) and stirred at room temperature for 22 h Rea is l), 0,1 H NaOH (35 ml), H2O (g ml) and saturated NaCl solution (35 ml), dried (Na2SO4), and after concentrating obtain the target product (469 mg, 93%) as a colourless solid.

Synthesis of N - [2-(benzylthio)propionyl] glycylglycyl-g-aminobutyric acid (Bz-Me-MAG2-gaba)

Specified in the title compound receive in accordance with the scheme 23 of N-(2-mercaptopropionyl)-glycine (1), which is manufactured by Aldrich company. Protection Tilney group in compound 1 is achieved by interaction with benzoyl chloride under alkaline conditions with the formation of compound 2. The carboxyl group can be activated by formation of its operations ether (3), which interacts with glycyl-g-aminobutyric acid in 90% methanol solution with the formation of benzoyl-substituted Me-MaG2-gaba (4). Spectral data (IR, NMR and mass spectroscopy (FAB) is fully consistent with the proposed scheme 23.

Stage 1: N-[2-(benzylthio)propionyl]glycine (2).

Sodium hydroxide (4.5 g, 0,109 mol) and N-(2-mercaptopropionyl)glycine (8,20 g, 0.05 mol) is dissolved in a mixture of water (40 ml) and toluene (30 ml). The temperature is reduced to 5-15oC, using a bath of ice. Add dropwise a benzoyl chloride (4.6 ml, 0,051 mol) in toluelene temperature 2 hour. The organic layer was separated, washed with water (2x20 ml) and discarded. The aqueous fractions are combined and acidified to pH of 1.5, using conc, HCl, forming a white precipitate is separated by filtration, washed with water and a small amount of ethanol, dried in vacuum. The output is of 13.0 g (97%). Elemental analysis: calculated (found) for C12H13NO4S: C, 53,90 (53,89); H, 4,90 (4,81); N, 5,24 (5,22). IR-spectrum (KBr tablet with cm-1): 3375 (s, nN-n, 3200-2500 (br, no-n); 1745 (vs, tiefer nc=o); 1663, 1625 (vs, amide and carboxyl nc=o). An NMR spectrum1H in d6-DMCO (d, M. D.): to 1.47 (d, 3H, CH3, J = 7,0 Hz); 3,79 (d, 2H, CH2, J = 5,9 Hz); however, 4.40 (q, 1H, CH, J = 7,0 Hz); 7,53 (m, 2H, =CH); of 7.69 (m, 1H, =CH); of 7.90 (dd, 2H, =CH, J=7,0 Hz), 8,59 (t, 1H, NH, J = 5.8 Hz); and 12.6 (bs, 1H, COOH). Mass spectrum (DCl): m/z=268 ([M+H]+).

Stage 2: N-[2-benzylthio)propionyl]glycine

Succinimide ether (3). To a suspension of N-hydroxysuccinimide (5,80 g, 0.05 mol) and N-[2-benzylthio)propionyl]glycine (13,35 mg, 0.05 mol) in dry THF (400 ml) was added DCC (12.0 mg, 0,052 mol) in the same solvent (1000 ml THF) at 5-10oC. the Mixture was stirred at 5-10oC for 2 h and then at room temperature for 2 days. To the reaction mixture add 2-3 ml of acetic acid and then stirred for further 2 hours. The precipitate is filtered off, the AI get a white solid, which is collected, washed with diethyl ether and dried in air. The output is 14.5 g (80%). Elemental analysis, calculated (found): C16H16N2O6S: C, 52,72 (52,70); H, 4,43 (4,21); N, 7,69 (7,69). IR-spectrum (KBr tablet with cm-1); 3290 (s, nN-H), 1820 (m, succinimide, nc-o); 1785 (m, ether nwith=o); 1735 (vs, thioether, nwith=o), 1600 (vs, amide, nwith=o). An NMR spectrum1H (CDCl3(d) in M. D.): 1,57 (d, 3H, CH3, J = 7,0 Hz); and 2.79 (s, 4H, CH2); to 4.33 (q, 1H, CH3, J = 7,0 Hz), 4,39 (m, 2H, CH2); 7,00 (t, 1H, NH, J = 5.8 Hz); 7,44 (m, 2H, = CH), to 7.59 (m, 1H, =CH); to 7.93 (dd, 2H, =CH, J = 7,0 Hz). Mass spectrum (DCT): m/z=365 ([M+H]+).

Stage 3: Synthesis of N - [2-(benzylthio)propionyl]-glycylglycyl-g - aminobutyric acid (Bz-Me-MAG2-gaba, 4). N - [2-(benzylthio)propionyl]glycine-succinimide ether (1,82 g, 5 mmol) and glycyl-g-aminobutyric acid (0,80 g, 5 mmol) is suspended in a mixture of methanol (150 ml) and water (30 ml). The mixture is heated under reflux for 5 hours, during this time, the cloudy mixture turned into a clear solution. Then the solution is cooled to room temperature and left under stirring overnight. Evaporation under reduced pressure allows to obtain a white solid, which is purified by washing with water and drying in vacuum. The output is 1.85 g (93%) of the spectrum (KBr tablet with, cm-1); 3380, 3320 (s, nN-H), 3100-2500 (br, nO-H); 1725 (vs, thioether, nwith=o), 1680, 1640, 1624 (vs, amide. Nwith=o). An NMR spectrum 1H (d6-DMSO) (d in M. D.): for 1.49 (d, 3H, CH3, J = 7,0 Hz); 1,62 (qin, 2H, CH2, J = 7,1 Hz); of 2.21 (t, 2H, CH2COOH, J = 7.5 Hz), 3,05 (qart, 2H, NH-CH2, J = 7,0 Hz); to 3.67 (d, 2H, NHCH2, J = 5.7 Hz); 3.75 to (d, 2H, NH-CH2, J = 7,0 Hz), 4,42 (q, 1H, CH, J = 7,0 Hz); EUR 7.57 (m, 2H, =CH); of 7.70 (m, 1H, =CH); 7,80 (t, 1H, NH, J = 3.0 Hz); of 7.90 (dd, 2H, =CH, J = 7,0 Hz); 8,14 (t, 1H, NH, J = 5,70 Hz); to 8.57 (t, 1H, NH, J = 5,90 Hz), to 12.0 (bs, 1H, COOH). Mass spectrum (DCl): m/z=410 ([M+H]+).

Synthesis of N - [2-(benzylthio)propionyl]glycylglycylglycine(Bz-Me-MAG3)

Specified in the title compound receive according to the method described above for Bz-Me-MAG2-gaba, replacing glycylglycine on glycyl-g-aminobutyric acid. The yield is 83%. Elemental analysis, calculated (found) for C16H19N3O6S: C, 50,39 (50,59); H, 5,02 (5,78); N, 11,02 (10,70). IR-spectrum (KBr tablet with cm-1): 3380, 3300 (s, nN-H), 3100-2500 (br, nO-H); 1738 (vs, thioether, nwith=o), 1680, 1660 (vs, amide, nwith=o). An NMR spectrum1H (d6-DMCO) (d in M. D.): to 1.48 (d, 3H, CH3, J = 7,0 Hz); of 3.78 (m, 4H, CH2); of 3.85 (d, 2H, CH2, J = 6,00 Hz); to 4.41 (m, 1H, CH); 7,52 (m, 2H, =CH); of 7.70 (m, 1H, =CH); of 7.90 (m, 2H, =CH), 8,15 (t, 1H, NH, J = 3,00 Hz), 8,51 (t, 1H, NH, J = 3,00 Hz), 8,80 (t, 1H, NH, J=3,00 Hz). Mass spectrum (ESI): m/z=381,9 ([M+H]+).

Sentences Bz-Me-MAG2-ACA consists of several stages (scheme 24). Compound 1 can be easily translated into the corresponding chloride 2, which interacts with 4-transmediterranean acid with the formation of compound 3. Connection security 3 using hydrazine in ethanol and subsequent merger of HCl leads to the formation of compound 4. The interaction of the compounds with 4 Bz-Me-MAG-Succ in methanol in the presence of Et3N gives Bz-Me-MAG2-ACA - connection 5.

Stage 1: phthaloylglycine. Phthaloylglycine (40 g) is suspended in chloroform (400 ml) and then added thionyl chloride (60 ml). The mixture is heated under reflux for 2 h, during which time the mixture becomes homogeneous transparent solution. The solvent and excess thionyl chloride are removed under reduced pressure, and get a whitish solid, which is dried in vacuum and used without further purification. An NMR spectrum1H corresponds to the expected structure.

Stage 2: 4-TRANS-[(phthaloylglycine)aminomethyl] cyclohexanecarbonyl acid

In DMF (150 ml) suspended 4-TRANS-aminomethylenemalonate acid (a 7.85 g, 509 mmol) and K2CO3(5 g, 50 mmol). To the suspension is added by phthaloylglycine and then filtered in hot condition. The solvent is removed under reduced pressure and get oily product. After adding diethyl ether (50 ml) white precipitate is formed. The solid is filtered off, washed with diethyl ether and dried in air. The output is 10,32 g (60%). An NMR spectrum1H (d6-DMSO) (d memorial plaques on tetramethylsilane): 0,87-2,00 (m, 9H, CH2and CH and cyclohexane ring): 2,10 (m, 1H, CHCOOH): 2,92 (t, 2H, CH2, J = 4.6 Hz); 4,19 (s, 2H, CH2); a 7.85 (m, 4H, -CH=); 8,21 (t, 1H, NH, J = 4,1 Hz).

Stage 3. Glycyl-4-TRANS-(aminomethyl)cyclohexanecarbonyl acid hydrochloride (Gly-ACAHCl).

To a suspension of 4-TRANS-[(phthaloylglycine)aminomethyl)cyclohexanecarboxylic acid (10,32 g, 30 mmol) in ethanol (300 ml) was added 85% hydrazine hydrate (100 ml). The mixture is heated under reflux for 12 h, during which time a white precipitate is formed. After removal of solvent the residue is added 2N HCl (200 ml). The mixture is heated to 60-70oC for 20 min, the precipitate is filtered off and discarded. The filtrate is concentrated to 1/3 the original volume. The mixture is cooled in a bath with ice for 2 hours the Precipitate was separated by filtration, washed with a small amount of water and ethanol and dried in vacuum. Out - of 3.45 g (45%).

An NMR spectrum2); to 2.35 (m, 1H, - CHCOOH); 3.15 in (d, 2H, CH2, J = 4,9 Hz), of 3.84 (s, 2H, CH2).

Stage 4: N-[2-(benzylthio)propionyl]glycylglycyl-4-amino - methylcyclohexane carboxylic acid (Bz-Me-MAG2The ACA). Gly-ACAHCl (1.25 g, 5 mmol). Et3N (1.0 g, 10 mmol) and Bz-Me MAG-SuCC (1,82 g, 5 mmol) is suspended in a mixture of methanol (200 ml) and acetonitrile (100 ml). The mixture is heated under reflux in the evening until the morning. The solvent is removed under reduced pressure and get the white solid residue, to which is added 6H HCl (10 ml). The solid product is separated by filtration, washed with water and a small amount of ethanol, dried in vacuum. Output - 1.35 g (58%). Elemental analysis, calculated (found) for C22C29N3O6S: C 57,00 (58,41), H, OF 6.31 (6,70); N, 9,06 (9,72). IR-spectrum (KBr tablet with cm-1); 3600-2000 (br, OH---N) 3270 (s, nN-H), 1720, 1656, 1625 and 1565 (vs, nc=o): 1738 (vs, thioether, nwith=o), 1680, 1660 (vs, amide, nwith=o). Mass spectrum (FAB): m/z=464 (M+1). An NMR spectrum1H (d6-DMSO) (d expressed in the memorial plaques on tetramethylsilane): 0,81-1,90 (m, 9H, CH2and CH cyclohexane ring): to 1.48 (d, 3H, CH3, J = 5,2 Hz); 2,10 (t, 1H, CHCOOH, J = 9,00 Hz); 2.91 in (t, 2H, CH2, J = 4.6 Hz); 3,68 (d, 2H, CH2and 4.2 Hz); 3.75 to (d, 2H, =CH2, J = 4,1 Hz); was 4.42 (q, 1H, CH, J = 5,2 Hz), 7,50 (t, 2H, -CH, J = 5.8 Hz), 7,71 (t, 2H=, J = 5.4 Hz), to $ 7.91 (d, 1H, -C]benzoic acid (Bz-MABA)

To a solution of S-benzoylthiourea (8.69 g, 40 mmol), freshly prepared by the reaction of S-benzoylthiourea acid with excess thionyl chloride in chloroform, in dry THF (300 ml) was added 4,4-diaminobenzoic acid (totaling 3.04 g, 20 mmol), the solution becomes brown. The solution is heated under reflux in the evening until the morning, during which time precipitate is formed. The mixture is cooled, the solid is separated by filtration, washed with THF, ethanol and diethyl ether and dried in vacuum. Get a light grey solid. Output - 5.8 g (54%). Elemental analysis, calculated (found for C25H20N2O6S2: C 59,04 (58,82); H 3,96 (4,04); N the 5.51 (s, 46). IR-spectrum (tablet with KBrcm-1): 3600-2000 (br, OH---N), 3340 (s, nN-H), 1690, 1670, 1655, 1610, and 1595 (s or m, nC=o. Mass spectrum (FAB):m/z= 509 (M+1). An NMR spectrum1H (COCl3(d) expressed in the memorial plaques on tetramethylsilane): 4,12 and to 4.14 (s, 4H, CH2); 7,50-8,30 (m, 13H, aromatic protons); 9,85 and of 9.89 (s, 2H, NH); 12,99 (bs, 1H, COOH).

S-triphenylmethyl-L-cysteine ethyl ester (2). To a solution of L-cysteine ethyl ester hydrochloride (18.6 g, 0.1 mmol) in 200 ml triperoxonane acid add triphenylmethanol (52 g, 0.2 mol). The obtained dark brown solution stirred Aut ethanol (100 ml). 1M solution ethylate sodium is added to the ethanol solution and stirred for 90 min, during which time the solution becomes cloudy. The mixture is filtered, the filtrate was concentrated in vacuo and get an oily residue. After chromatography on a column using a mixture of ethyl acetate and hexane (1:3) and ethyl acetate to obtain the target product (containing some amount of ethyl acetate, which is difficult to remove), which is kept under vacuum.

N-bromoacetyl-S-triphenylmethyl-L-cysteine ethyl ester (3): a Solution of S-triphenylmethyl-L-cysteine ethyl ester (18 g, 46 mmol) and triethylamine (6.4 ml, 46 mmol) in dry THF (250 ml) under nitrogen atmosphere cooled to 0oC. is Added dropwise a solution of bromoacetamide (9.28 are g, 46 mmol) in dry (60 ml), at this time, the solution becomes cloudy. The reaction mixture was stirred at 0oC for 1 h and then at room temperature for 1 h, the Reaction mixture was filtered, and the filtrate was concentrated in vacuo, resulting in a receive oil. This oil fractionary between methylene chloride and water (60 ml), the organic layer washed with 5% HCl, NaHCO3, dried (magnesium sulfate), filtered and, after removal of volatile obtain the target product (69%).

2-(S-triphenylethylene)acylaminoacyl-replica rolex, to 1.98 mmol) and triethylamine (0.4 ml, 2.9 mmol) in methylene chloride (10 ml) add S-triphenylmethyl-2-aminoethanethiol (0.64 g, 2.0 mmol). The reaction mixture was stirred at room temperature for seven days. Add water (10 ml). The organic layer was washed with NaHCO3(2x10 ml), water (2x10 ml) and salt solution (10 ml), dried (magnesium sulfate) and after concentration in vacuo get foamy product. After chromatographic purification using a mixture of ethyl acetate : hexane (3:1) to obtain the target product with a yield of 22%. Mass spectrum: (M+H)=751. Calculated 751,3.

Synthesis of complexing agents containing one carboxylic acid group capable of attaching to "bundle", is shown in scheme 26. The synthesis starts from the N-alkylation of Cys (Acm)OMa dimethylacetal group bromoacetaldehyde. The secondary amino group of the alkylated product protects from participation in further transformations of the Teoc group. Can also be used other protective groups, which are stable in alkaline and acid medium and removed in the presence of sulfur. Teoc group is introduced by the action of 2-(trimethylsilyl)ethyl n-nitrophenyl carbonate. So, acetal hydrolyzing in a slightly acidic environment, aldehyde recovery miniroot S-triphenylmethyl-2-aminor hydrolyzing an aqueous solution of alkali, resulting in getting carboxylic acid, ready to interact with the reactive group of the cyclic compound, modified by the introduction of "bundles".

The complexing agents containing one additional amino group capable of interaction with a cyclic compound, modified by the introduction of "bundles" can be obtained according to the method shown in scheme 27. Acm - protected thioglycolate acid may be added to N-tert-butoxycarbonylamino using standard methods of joining peptide synthesis. Protective Boc group can be removed by trifluoroacetic acid and the resulting amine can react with Boc-Cys(Acm)-OH. The removal of the Boc protective group leads to the production of S-substituted complexing agents in a form suitable for reaction with the reactive group of the cyclic compound, modified by the introduction of "bundles".

The object of the present invention are reagents of the formula (QLn)dChfor injection of radioactive labels, which consist of more than one cyclic intermediate compounds modified by the introduction of "bundles" that are attached to the complex is Klionsky connection connected to "bundle", which is also attached to the complexing agents.

An example of a reagent containing two cyclic intermediate compounds which are modified by the introduction of "bundles" and attached to the complexing agents below (scheme 28 and 29). Other typical examples are shown in the following diagrams. According to this scheme, the two amino groups modified with the introduction of "bundles" of intermediate compounds interact with two activated ester groups, resulting in a compound of this invention of the formula (QLn)2Ch.

Protection mercaptopropyl, Pgshown above, as well as other Pg group stated herein, can be any protection mercaptopropyl capable chipped off under the action of radioactive isotopes of metals. Such protective groups are well known in the art. Examples of suitable protective groups are described in U.S. patents NN 4897255, 4965392 and 4980147 listed here as references.

Catalysts that can be used in the synthesis of these reagents are described in: Chervu et al., U.S. patent N 4883862; Bergstein et al., U.S. patent N 5279811. The synthesis of other suitable complexing agents shown in the following the La of this type. In the diagram 30 shows the synthesis of N2S2ligand containing two groups of carboxylic acid, which can be attached to the desired connection. The synthesis begins with the alkylation reaction of two amino DL-2,3-diaminoethane acid (Sigma Chemical Co.) s-triphenylmethyl-2-bromoethanol. Here it is necessary to protect secondary amino groups, in order to avoid autocompensation when you activate groups of carboxylic acids. This is carried out by standard methods, protection of the amino group; z is a group selected so that she could be removed in an acidic environment (HBr/HOAC or triperoxonane acid/triftormetilfullerenov acid) simultaneously with trailvoy protection mercaptopropyl.

The synthesis of other compounds of N2S2containing two groups of carboxylic acid, is shown in scheme 31. Alkylation of the Ethylenediamine-N,N'-dipropionate acid (American Tokyo kasei) S-triphenylmethyl-2-bromoethanol network is ready for pairing connection N2S2. The amino group is tertiary and do not require additional protection.

Scheme 32 illustrates the synthesis of N2S2ligand containing two additional amino group to attach the desired cyclic compound, vkluchaya the mining between benzylamine and glyoxal leads to the formation of N,N'-dibenziletilendiaminom. Alkylation of the two amino groups of N-(3-bromopropyl)phthalimide results in a fully protected tetraamine. Benzyl protection of two secondary amino groups can be removed by catalytic regeneration, then three free amino groups can be proaccelerin S-triphenylmethyl-bromoethanol with the formation of fully protected ligand. Selective removal of the protection of the primary amino groups can be carried out with hydrazine.

Reagents containing two specified groups and one complexing agents that are attached to a common "bond", can be synthesized in accordance with the methodology shown in scheme 33. The reaction benzylamine with N-(3-bromopropyl)phthalimide leads to the formation of N,N-bis(3-phthalimidopropyl)benzylamine (Niitsu and Samejima (1986), Chem. Pharm. Bull, 34, 1032 - 1038). Treatment with hydrazine removes phthalimide protective group, N, N-bis(3-aminopropyl)benzylamine can then react with succinic anhydride to form decollate, which can then be transferred to the activated bis(ether)by the action of DCC and N-hydroxysuccinimide. This activated bis(ether) may then interact with modified by the introduction of "bundles" cyclic connection. Hydrogenation removes the benzyl of seducta.

More than two connections Q and more than one complexing agents, can be connected together using a star-shaped or dendritic link. Dendrites are constructed by adding razvetvlyayushchikh segments to the functional core, forming a product that contains two times more functional groups than the original kernel. Adding razvetvlyayushchikh fragments can be carried out several times and leads to the formation of bulk polyfunctional molecules. One example is the PAMAM (polyamidoamine) - dendrite (Aldrich Chemical Co.), in which the functional core is Ethylenediamine. Scheme 34 illustrates a General method of obtaining radioactive pharmaceutical product on the basis of PAMAM-dendrite that contain the specified cyclic compounds and complexing agents in the ratio of 2: 1. According to this scheme, when n = 1 the original dendrite will contain two specified cyclic compounds and one complexing agents, and the next generation of dendrites, when n = 2, will contain four specified cyclic compounds and two complexing agents. The ratio and the total number of specified cyclic compounds and complexing agents will be controlled by the stoichiometry of the reaction.

The synthesis of compounds containing radioactive tag

Containing radioactive label cyclic compounds of glycoprotein IIb/IIIa platelet, which is the subject of the present invention, can be obtained using standard methods known in the art, using radioactive isotopes of Halogens (such as chlorine, fluorine, bromine and iodine), technetium, and India, and others. The predominant radioactive isotopes include123I125I131I99mTc andIIIIn.

In cyclic compounds of glycoprotein IIb/IIIa platelet radioactive label can be entered either directly (that is, the binding of a radioactive label directly connect the e included in the connection). Direct introduction of a radioactive label, as known in the art, the introduction of the label can be isotopic or non-isotropic. If you carry out isotopic label introduction, one of the groups that already exist in cyclic connection, replace (swap) on a radioactive isotope. If you carry out non-isotropic introduction of the label, a radioactive isotope is added to the cyclic compounds without replacement (exchange) already existing group.

In General labeled compounds prepared as in methods that include the introduction of labels in the final stages of synthesis. This helps improve the radiochemical yield and to reduce the time of work with radioactive material. When working with short-lived isotopes significant factor is the time required for operations of synthesis and purification. Methods of synthesis of radioactive pharmaceutical preparations are described in: Tubis and Wolf, Eds., "Radiopharmacy", Wiley-Interscience, New York (1976); Wolf, Christman, Fowler, Lanbrecht, "Synthesis of Radiopharmaceuticals and Labeled Compounds, vol. 1, p. 345 - 381 (1973), listed here as references.

To obtain containing radioactive labeled compounds of the present invention in the case where a radioactive label is halogen, can be used a variety of me in aromatic compounds are the reaction of substitution of iodine radicals, page, borough, Stanno, Silom, Tallo groups and exchange reactions of Halogens. The most common for non-isotropic injection of radioactive label in aromatic compounds of this type, as described in the present invention are the reaction itterative and electrophilic substitution of aromatic compounds.

These methods and additional methods are described in: Merkushev, Syntesis, 923 (1988) and Seevers et al., Chem. Rev., 82: 575 (1982), cited here as reference.

For example, labeled with radioactive isotopes derived 4,5 and 6-halo-tert-butyloxycarbonyl-3-aminometilbensana acid can be obtained using the above General procedure for the synthesis of not containing radioactive labeled compounds. For such injection of radioactive labels is important that the half-decay time of the selected isotope was much more than a practical implementation of the synthesis. Known source materials include 2,3 and 4-iodo (123I125I131I) benzoic acid.

Labeled with radioactive iodine derivatives Mamb can also be obtained from analine by the reaction of Sandmeyer, as described in Ellis et al. Aust J. Chem 26: 907 (1973).

In addition, such compounds can be obtained by introducing the radioactive and the example, using trialkylsilyl reactive groups, as described in: Wilson et al. J. Org.Chem., 51: 483 (1986) and Wilbur et al. J. Label. Compound. Radiopharm., 19: 1171 (1982), the use of trialkylsilyl reagents described in: Chumpradit et al. J. Med. Chem. , 34: 877 (1991) and Chumpradit et al. J. Med.Chem., 32: 1431 (1989). The use of derivatives of boric acid described in: Kabalka et al. J. Label. Compound. Radiopharm. , 19: 795 (1982) and Koch et al. Chem. Rer., 124:2091 (1991). Transformations in the course of the synthesis is shown in scheme 36.

Although the above methods can be used to produce radiolabelled compounds of the present invention, to improve the radiochemical yield, reduction in hours of work with radioactive materials and produce the short-lived labeled halogen compounds, it is preferable to carry out the introduction of isotope labels halogen in the final stages of the synthesis of cyclic compounds. The following are methods of introducing a radioactive label in the final stages of synthesis.

Not containing the label iodo-compounds are a convenient starting compounds which can be converted into labeled derivatives of any of the two-stage reactions above. Suitable functional groups for the introduction of Mamb-containing CEC shall ntes and the use of such starting compounds described above.

The least complicated way to radioiodine cyclic compounds of the present invention by isotope exchange at the final stage of the synthesis is the replacement of radioactive iodine stable iodine atoms already present in the molecule, this can often be done by heating the compounds with radioactive iodine in a suitable solvent, as described in Ellis et al., Aust. J. Chem. , 26: 907 (1973). For aromatic iodides very small amounts and low concentrations are used radioactive iodide lead to very moderate specific activity. The sequence of operations shown in scheme 37.

Radioactive label can be entered in cyclic compounds at the last stage of their synthesis of anilines by reaction of Sandmeyer, as described in Ellis et al. Aust J. Chem 26: 907 (1973). This approach allows to obtain labeled cyclic compounds with high specific activity. To resolve the difficulties in the synthesis of cyclic compound is to use the nitrogroup, as a source for obtaining substituted aniline.

Otherwise, the cyclic compounds can be introduced radioactive label by reactions not containing the label bromo - and iodine-derivative razlichnymi et al, J. Org. Chem., 51: 4833 (1986) and Wilbur et al., J. Label. Compound. Radiopharm., 19: 1171 (1982), using trialkylsilyl reagents, as described in: Chumpradit et al., J. Med. Chem, 34: 877 (1991) and Chumpradit et al., J. Med. Chem., 32: 1431 (1989), as well as using derivatives of boric acid, as described in: Kabalka et al. , J. Label. Compound. Radiopharm., 18: 795 (1982) and Koch et al., Chem. Ber., 124: 2091 (1991).

A similar approach when carried out isotopic incorporation of radioactive label halogen in the final stages of the synthesis involves the conversion of substituted Mamb-group derived in cyclic compound, which already includes trialkylsilyl, trialkyltin or group of boric acid. Synthesis of some Mamb-derivatives was described in the previous sections. Synthetic transformation on the cyclic compounds shown in scheme 38.

Labeled vodoprovodnie can be easily obtained nestopia of amino-, hydroxy-, methoxy-substituted cyclic compounds, as described in Arora et al. , J. med. Chem., 30: 918 (1987). Reactions of electrophilic aromatic substitution is facilitated in the presence of such electron-donor substituents. The sequence of operations of the synthesis shown in the circuits 39 and 40.

Another option is the introduction of a radioactive halogen is that methylsiloxane Cilicia free radical halogenation. Benzylamine can be gently replaced by radioactive iodine by the reaction of nucleophilic substitution. The sequence of operations shown in scheme 41.

Although the examples illustrate the obtaining mainly labeled iodine compounds, the above methods can be used for injection of radioactive isotopes of any halogen.

18F - Derivatives of these cyclic compounds can be obtained by coupling with cyclic compounds18F - substituted phenyl intermediates.18F-substituted cyclic compound can be obtained, as shown in figure 42 (R. H. March et al., J. Med. Chem., 1993, 36, 3707-3720). Reaction of n-trimethylammoniumchloride with [18F] CsF in aqueous DMF at 120oC for 10 min (water [18F] KF/kryptofix/ACN can also be used to obtain a18F-phenyl compounds from the corresponding ammonium - or nitro-derivatives) followed by treatment with a mixture of LAH/THF/pentane and 57% aqueous solution HI leads to the formation of n18F-benzylidene.

< / BR>
To obtain containing radioactive labeled compounds of the present invention, in the case where a radioactive label is metal, and technetium or indium, about the invention of the formula (QLn)dChand (Q)d'Ln-Ch. The typical technique of injection of technetium and indium as a radioactive label is given, for example, Cerqueira et al., Circulation, vol. 85, N. 1, pp. 298-304 (1992), Pak et al., J. Nucl. Med., Vol. 30, n 5, p. 793, 36th Ann. The Meet. Soc. Nucl. Med. (1989), Epps et al., J. Nucl. Med., Vol. 30, n 5, p. 794, 36th Ann. The Meet. Soc. Nucl. Med. (1989), Pak et al., J. Nucl. Med. Vol. 30, n 5, p. 794, 36 th Ann. The Meet. Soc. Nucl. Med. (1989), and Dean et al., J. Nucl. Med., vol. 30, n 5, p. 794, 36th Ann. The Meet. Soc. Nucl. Med. (1989), which are listed here only as a reference. In addition, special techniques below in the examples.

Another suitable method of introducing a radioactive label in the cyclic compound of the present invention includes the synthesis of99mTc-containing (as a label) of the complexing agents and its interaction with either cyclic intermediate connection or modified with the introduction of "bundles" cyclic connection. This method involves the introduction of the label to the final complex formation.

As shown, for example, in the diagram below, 4,5-bis(S-benzoyl)mercaptohexadecanoic acid (1) interacts with99mTcO4in reducing conditions with the formation of (2). Then the compound (2) is transferred to the activated ester (3) containing tetrafluorophenyl is m, such as (5) or (6) with the formation of radiolabelled compounds (4). Other suitable complexing agents with technetium - 2,3-bis(S-benzoyl)mercaptobenzotriazole acid (7). Purification by HPLC complex99mTc can be carried out at each stage. This method is shown in scheme 43.

Examples.

Section A. Reagents for the introduction of a radioactive label

Example 1.

The compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb (5-ACA))-N- [4-(carboxy)benzyl]-N,N-bis[(2-triphenylmethyl)ethyl]-glycinamide

A solution of N-[4-(carboxy)benzyl]-N,N'-bis[(2-triphenylmethyl) ethyl]-glycinamide-N-hydroxysuccinimide ether (0,017 mmol), cyclo-(D-Val-NMeArg-Gly-Asp-Mamb (5-ACA)) (13.9 mg, 0.015 mol) and Et3N (of 6.25 μl, 0.045 mmol) in DMF (350 μl) was stirred at room temperature for 14 hours the Progress of the reaction is controlled "normal-phase" TLC (CHCl3:MeOH:HOAc, 90:8:2) using ninhydrin and Sakaguchi test. DMF is removed under reduced pressure. The clear connection method "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 18-36% acetonitrile containing 0.1% TFA (gradient of 1.0%/min), after lyophilization get salt triperoxonane acid specified in the title compounds as a colorless fluffy solid (11 mg, 53%).


A solution of N-[4-(carboxy)benzyl]-N,N'-bis[(2-triphenylmethyl) ethyl]-glycinamide-N-hydroxysuccinimide ester (30 mg, 0,033 mol), cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) (23,8 mg 0,029 mmol) and Et3N (12 μl, 0,087 mmol) in DMF (0,60 ml) was stirred at room temperature for 63 hours. The progress of the reaction is controlled "normal-phase" TLC (CHCl3: MeOH:HOAc, 90:8:2) using ninhydrin and Sakaguchi test. DMF is removed under reduced pressure. The clear connection method "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 18-36% acetonitrile containing 0.1% TFA (gradient of 0.9%/min), after lyophilization get salt triperoxonane acid specified in the title compound as a fluffy colorless solid (24 mg, 60%). Mass spectrum (ESI):[M] = 1397,3.

Example 3.

Cyclo-(D-Val-NMeArg-Asp-Mamb(N-hydrazino-nicotinyl-5-Aca)) TFA salt

Part A. Synthesis of cyclo-(D-Val-NMeArg-Gly-Asp-Mamb (N-boc - hydrazino-nicotinyl-5-Aca)) TFA salt

To a solution of cyclo(D-Val-NMeArg-Gly-Asp-Mamb(N-boc - hydrazino-nicotinyl-5-Aca) (10 mg, to 0.011 mmol), Succinimidyl boc-hydrazinonicotinamide (4.6 mg, 0,0132 mmol) in DMF (0.3 ml) is added triethylamine (0,0061 ml 0,044 mmol) and stirred the reaction mixture under nitrogen atmosphere at room temperature for 24 hours the Solvent is removed in vacuum, and the rest of Rastishka part of the product make obscenites" HPLC on a preparative column (Vydac C18 (2.1 cm), using the 6.3-72% aqueous acetonitrile containing 0.1% TFA (gradient of 2.0%/min). After lyophilization salt triperoxonane acid specified in the title compound as a fluffy substance. Mass spectrum: [M+H] = 938,4849 calculated 938,4848.

Part B. Removing protection and the synthesis of the compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(N-hydrazinonicotinamide-5-Aca)) TFA salt

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(N-boc-hydrazinonicotinamide-5-Aca)) TFA salt dissolved in a mixture (98:2) TFA and anisole (2 ml) and stirred the reaction mixture for 15 minutes the Solvent is removed in vacuum and the residue is dissolved in aqueous solution of acetonitrile. After lyophilization get white solid. Cleanup complete "obscenites" HPLC on a preparative column (Vydac C18 (2.1 cm), using 6,3-72% aqueous acetonitrile containing 0.1% TFA (gradient of 2.0%/min). After lyophilization get salt triperoxonane acid specified in the title compound as a fluffy solid. Mass spectrum: [M+H] = 838,4849 calculated 838,4324.

Example 4.

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(N-hydrazinonicotinamide-5-Aca)) TFA salt

Part A. Synthesis of cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(N-boc-hydrazino-nicotinyl-5-Aca)) TFA salt

To a solution of cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-Aca) (10 mg, 0,0019 mmol), Succinimidyl boc-hydrazinonicotinamide (4,55 mg, 0,0131 mmol who matney temperature for 24 hours. The solvent is removed in vacuum, the residue is dissolved in aqueous solution of acetonitrile. After separation by lyophilization overnight get whitish solid. Purification of the product is completed "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 6,3-72% aqueous acetonitrile containing 0.1% TFA (gradient of 2.0%/min). After lyophilization get salt triperoxonane acid specified in the title compound as a fluffy solid. Mass spectrum: [M+H] = 924,4699 calculated 924,4692.

Part B. Removing protection and the connection is cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(N-hydrazino-nicotinyl-5-Aca)) TFA salt

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(N-hydrazinonicotinamide-5-Aca) TFA salt: cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(N-boc-hydrazinonicotinamide-5-Aca) TFA salt dissolved in a mixture (98:2) TFA and anisole (2 ml) and stirred the reaction mixture for 15 minutes the Solvent is removed in vacuum, the residue is dissolved in aqueous solution of acetonitrile. After lyophilization get white solid. Cleanup complete "obremeniaet" HPLC on a preparative column (Vydac C18 (2.1 cm), using 6,3-85,5% aqueous acetonitrile containing 0.1% TFA (gradient 2,07%/min), after lyophilization get salt triperoxonane acid specified in the title compound in the form of posistor inel-D-Lys)-NMeArg-Gly-Asp-Mamb) TFA salt

Part A. Synthesis of the compound cyclo-((N-E-boc-hydrazinonicotinamide-D-Lys)-NMeArg-Gly-Asp-Mamb) TFA salt

To a solution of cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb 2TFA (4,2 mg of 0.005 mmol), Succinimidyl boc-hydrazinonicotinamide (2.1 mg, 0,006 mmol) in DMF (0.15 ml) is added triethylamine (0.003 ml, 0.02 mmol) and the reaction mixture stirred at room temperature under nitrogen atmosphere for 48 hours the Solvent is removed in vacuum, the residue is dissolved in aqueous solution of acetonitrile. After drying over night get whitish solid. Cleanup complete "obremeniaet" HPLC on a preparative column (Vydac C18, using 6,3-85,5% aqueous acetonitrile containing 0.1% TFA (gradient of 1.7%/min). After lyophilization get salt triperoxonane acid specified in the title compound as a fluffy solid. Mass spectrum: [M+H] = 839,4157 calculated 839,4164.

Part B. Removing protection and obtaining compounds cyclo-(N-E-hydrazinonicotinamide-D-Lys)-NMeArg-Gly-Asp-Mamb) TFA salt

Cyclo-(N-E-hydrazinonicotinamide-D-Lys)-NMeArg-Gly-Asp-Mamb) TFA salt: cyclo-((N-E-boc-hydrazinonicotinamide-D-Lys)-NMeArg-Gly-Asp-Mamb) TFA salt (3 mg) dissolved in a mixture (98:2) TFA and anisole (2 ml) and stirred the reaction mixture for 15 minutes the Solvent is removed in vacuo and the residue pererastayut in an aqueous solution of acetonitrile, paratively column (Vydac C18, using the 6.3 - 72% aqueous acetonitrile containing 0.1% TFA (gradient of 2.0%/min). After lyophilization get salt triperoxonane acid specified in the title compound as a fluffy solid. Mass spectrum: [M+H] = 739,3629 calculated 739,3640.

Example 6

The compound cyclo-([DTPA-D-Lys]-NMeArg-Gly-Asp-Mamb)

To a solution of 250 mg (2 mmol) of cyclo(D-Lys-NMeArg-Gly-Asp-Mamb) in 208 ml of 0.1 M borate (pH 9,88) at room temperature, added with continuous stirring DTPA-anhydride (743 mg, 10 mmol). The reaction mixture is stirred for 2 hours. The crude mixture of products obtained after removal of the solvent, purified preparative HPLC (Vydac column C18, gradient 0 to 50% ACN containing 0.1% TFA over 60 min, flow rate 20 ml/min). There are two main components. Component A - cyclo([DTPA-D-Lys]-NMeArg-Gly-Asp-Mamb). Mass spectrum: 979,1 (M+H)+.

Example 7.

Cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb)]2-DTPA

Component B obtained as described in example 6 synthesis, is a [cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb)]2-DTPA. Mass spectrum: 1565,4 (M+).

Section B. the Connection of radiolabelled

Direct introduction of the label

Example 8.

Cyclo-((125I)D-Tyr-NMeArg-Gly-Asp-Mamb)

In patibility bubble dobovlyaemogo compound cyclo-(D-Tyr-NMeArg-Gly-Asp-Mamb), dissolved in 75 μl of 0.1% aqueous TFA and 50 μg of chloramine-T dissolved in 50 μl of H2O. After reaction for 1 min add 50 μg of sodium metabisulfite dissolved in H2O. the resulting product was then purified preparative HPLC (column Bond-Rx C18, flow rate 1 ml/min, gradient from 100% A to 100% B in 30 min; solvent A = 0.1% of TFA in H2O, solvent B = 40% ethanol in A. the Product is characterized by a retention time equal to 30 minutes

Example 9.

[(125I)N-3-(4-hydroxyphenyl)propionyl] -cyclo- (D-Lys-NMeArg-Gly-Asp-Mamb)

In patibility bubble add 11.4 MCI (25 μl) of an aqueous solution of Na125I, 100 μl of 0.5 M phosphate buffer (pH 7.5), and 4.5 μl 1H HCl 50 mg modified by the introduction of "bundles" of cyclic compounds [N-3(4-hydroxyphenyl)propionyl]-cyclo (D-Tyr-NMeArg-Gly-Asp-Mamb), dissolved in 50 μl of H2O. After 1 min after start of the reaction, add 50 μg of sodium metabisulfite dissolved in H2O. the Product was then purified preparative HPLC (conditions described in example 10). The product is characterized by a retention time equal to 32 minutes Indirect introduction of the label.

Example 10.

99mTcO (MAMA)-cyclo-(D-Val-NMeArg-Gly-Asp-Mamb-(5-Aca))

Part A. unprotect

Remove tritill reagent and 0.1 ml triperoxonane acid (TFA). When dissolving a solid substance is formed yellow solution.

Part C. Synthesis99mTc-glucoheptonate

In the bubble GlucoscanRinject 1.0 ml of Milli-Q-H2O.

Take 0.2 ml of this solution into a clean vial of 10 cm3and add ~ 20 MCI99mTcO4. The reaction proceeds at room temperature 20 minutes

Part C. Synthesis99mTcO (MAMA)-cyclo- (D-Val-NMeArg-Gly-Asp-Mamb-(5-Aca))

The reagent solution from part A, with remote protective group, add 0.2 ml of 5N NaOH and 0.4 ml of 0.2 M phosphate buffer (pH 6). Measure the pH and, if necessary, adjusted to 6.

This solution is immediately added to a vial99mTc-glucoheptonate, closed and heated at 100oC 15 minutes After cooling ~ 2 min and 20 µl of this solution is analyzed by HPLC using method 1 (see table 1).

Example 11

99mTcO (MAMA)-cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb)

Part A. unprotect

Remove triteleia protective group reagent described in example 2: clean bubble displacement of 10 cm3add the reagent and 0.1 ml triperoxonane acid (TFA). When dissolving a solid substance is formed yellow solution.

Part B. Synthesis99mTcO (MAMA)-cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb)

It races seraut pH, and if necessary, adjusted to 6. This solution is immediately added to the vesicle solution99mTc-glucoheptonate, obtained as described in example 11, part B, closed and heated at 100oC 15 minutes After cooling ~ 2 min and 20 µl of this solution is analyzed by HPLC according to method 1 (see table 1).

Example 12

99mTc (tricin)2-cyclo- (D-Val-NMeArg-Gly-Asp-Mamb(hydrazino-nicotinyl-5-ACA))

To a solution of 70 mg of Tricine(N-[Tris(hydroxymethyl)methyl]glycine) in 1.0 ml of water, add 0.05 ml of 1.0 N NaOH to raise the pH to 7.0, then the 0.1-1.0 ml99mTcO4in physiological solution 10-100 MCI, 10 μg of the reagent, the receipt of which is described in example 3, dissolved in 100 μl of 0.1 N HCl, and 100 µg SnCl22H2O, dissolved in 0.1 H HCl. The reaction proceeds at room temperature for 45 minutes the resulting product analyzed by HPLC according to method 1 and method TIX according to method 2 (see table 1).

Example 13.

99mTc (EDDA)-cyclo-(D-Val-NMeArg-Gly-Asp-Mamb (hydrazino-nicotinyl-5-Aca))

To a solution of 10 mg Ethylenediamine-N,N'-luxusni acid (EDDA) in 1.0 ml of water, add 0.05 ml of NaOH to create the pH to 7.0, then the 0.1-1.0 ml99mTcO4in the form of salt (10-100 MCI) and then 50 mg of the reagent described in example 3, dissolved in 100 μl of 0.1 N HCl, and 100 the obtained product is analyzed by HPLC, using method 1, and method TIX using method 2 (see table 1).

Example 14.

99mTc (tricin)2-cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb (hydrazino-nicotinyl-5-Aca))

To a solution of 70 mg of Tricine(N- [Tris(hydroxymethyl)methyl]glycine) in 1.0 ml of water, add 0.05 ml of 1.0 N NaOH to raise the pH to 7.0, then the 0.1-1.0 ml99mTcO4in physiological solution (10-100 MCI), and then 10 mg of the reagent, the method which described in example 4, dissolved in 100 μl of 0.1 N HCl, and 100 µg SnCl22H2O, dissolved in 0.1 N HCl. The reaction proceeds at room temperature for 45 minutes the resulting product is analyzed by HPLC using method 1, and method TIX using method 2 (see table 1).

Example 15

99mTc (tricin)2-cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb (hydrazino-nicotinyl-5-Aca))

To a solution of 70 mg of Tricine(N- [Tris(hydroxymethyl)methyl]glycine) in 1.0 ml of water, add 0.05 ml of 1.0 N NaOH to raise the pH to 7.0, then the 0.1-1.0 ml99mTcO4in physiological solution (10-100 MCI) and then 10 mg of the reagent, the receipt of which is described in example 5, dissolved in 10 μl of 0.1 N NaOH, and 100 µg SnCl22H2O, dissolved in 0.1 N HCl. The reaction proceeds at room temperature for 45 minutes the resulting product analyzed method]-NMeArg-Gly-Asp-Mamb)

50 Μl ofIIIIn Cl3(~100 cubic mdugm/ml of 0.05 M HCl), obtained from Du Pont-NTN Products, Billerica, MA, mixed with an equal volume of freshly prepared 1.0 M solution of ammonium acetate. After about 5 minutes add 0.1-1 mg of the reagent described in example 6, dissolved in 0.25 ml of water. The reaction proceeds at room temperature for 30 minutes the Product is analyzed by HPLC according to method 3.

Example 17.

IIIIn-DTPA-[cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb)]2< / BR>
To 0.5 ml of the reagent solution described in example 7, in water (0.9 mg/1 ml) addIIIIn Cl3(~3 mKt) in 0.5 ml of 1N solution of NH4The OAC. The mixture was kept at room temperature for 30 min, and then analyzed by HPLC using method 3 (see table 2).

Section C. Labeled99mTc reagents, obtained by the introduction of the label through the coordination compound

Labeled99mTc reagents described in these examples synthesized using the method of introducing the label to complexation. This method includes the following stages: (1) coordination99mTc with complexing agents; (2) activation of the uncoordinated carboxyl group of the obtained complex formation of its tetraterpenes (TFP) ester; (3) the interaction of TFP-essential coenam through the formation of amide linkages.

Example 18

Cyclo-([(99mTcO(mapt)]-DLys]-NMeArg-Gly-Asp-Mamb)

Part A. the Formation of coordination compounds.

In a clean bottle with a capacity of 10 cm3place of 0.35 ml Bz-mapt (3.0 mg/ml in 1H NaOH), 0.10 ml SnCl22H2O (10 mg/ml in 1H HCl) and 200 MCI99mTcO4in physiological solution. The vial was closed and placed in a water bath (100oC). After cooling for ~2 min 10 ál of solution analyzed by HPLC according to method 1.

Part C. Activation

To the solution obtained in part A, add 0.3 ml of 0.5 M solution of sodium phosphate with a pH of 6.0, 0.3 ml of 2,3,5,6 - tetrafluorophenol (100 mg/ml in 90% acetonitrile), 0.3 ml of 1-(3 - dimethylamino-propyl)-3-ethylcarbodiimide (100 mg/ml in 90% acetonitrile) and ~0.1 ml 1H HCl. If necessary, the pH is brought to 6. The vial was closed and heated at 40oC 25 minutes After cooling for ~2 min and 20 μl of the solution is analyzed by HPLC using method 1.

Part C. the Pairing

of 1.0 - 2.5 mg of the intermediate cyclic compound cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) and add a solution, the receipt of which is described in part B. the pH of the solution was adjusted to 9 by the action of 1H NaOH. The reaction mixture is heated at 40oC within 30 minutes After klipler 19.

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb([99mTcO(mapt)]-5Aca))

1,0 - 2,5 mg modified by the introduction of "bundles" cyclic compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca)) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) and add a solution, the receipt of which is described in example 18 part B. Using 1H NaOH to bring the pH to 9. The reaction is carried out at 40oC for 30 minutes After cooling (~2 min), 25 μl of the solution is analyzed by HPLC using method 1 (see table 3).

Example 20

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb([99mTcO(mapt)]-5Aca))

1,0 - 2,5 mg modified by the introduction of "bundles" cyclic compound cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-Aca)) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) add a solution, the receipt of which is described in example 18 part B. Using 1H NaOH to bring the pH to 9. The reaction is carried out at 40oC for 30 minutes After cooling (~2 min), 25 μl of the solution is analyzed by HPLC using method 1 (see table 3).

Example 21

Cyclo-([(99mTcO(mapt)]--5-Aca)D-Lys]-NMeArg - Gly-Asp-Mamb)

1,0 - 2,5 mg modified by the introduction of "bundles" cyclic compound cyclo-((5-Aca)D-Lys-NMeArg-Gly-Asp-Mamb) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) and add a solution, the receipt of which is described in example 18 part B. Using 1H NaOH, adjusted p by HPLC, using method 1 (see table 3).

Example 22.

Cyclo-([(99mTcO(MeMAG2gaba)]--D-Lys-NMeArg-Gly-Asp-Mamb)

Part A. the Formation of coordination compounds

In desyatikilometrovy bubble add 100 to 250 MCI99mTcO4-in 1.0 ml of physiological solution, 1.0 ml of a solution of Bz-MeMAG2gaba (1 mg/ml in 0.5 M phosphate buffer with pH 12), and then to 0.15 - 0.20 ml of a solution of SnCl22H2O (15 mg/3ml in 1H HCl). The pH was adjusted to ~11, and then the mixture is heated at 100oC for 30 minutes the Solution is analyzed by HPLC using method 1.

Part B. Activation

To the solution obtained by the method described in part A, add 0.2 ml of 0.1 H HCl, 0.5 ml of a solution of tetraterpene (100 mg/ml in 90% CH3CN), then 0.5 ml of solution (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide chloride (100 mg/ml in 90% CH3CN).

The pH was adjusted to 6.0, and then the mixture is heated at 50oC for 30 minutes

Part C. the Pairing

of 1.0 - 2.5 mg of the intermediate cyclic compound cyclo-(D-Lys-NMeArg-Asp-Mamb) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) and added to the solution, the receipt of which is described in part B. Using 1H NaOH, pH adjusted to 9. The reaction mixture is heated at 40oC for 30 is.

Example 23

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb([99mTcO(MeMAG2gaba)] --5-Aca))

1,0 - 2,5 mg modified by the introduction of "bundles" cyclic compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca)) dissolved in 0.3 ml of 0.5 M phosphate buffer (pH 9) and add a solution, the receipt of which is described in example 22 part B. Using 1H NaOH, pH adjusted to 9. The reaction mixture is heated at 40oC 30 minutes After cooling (~2 min), 25 μl of the solution is analyzed by HPLC using method 1 (see table 3).

Example 24

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb([99mTcO(MeMAG2gaba)] --5-Aca))

1,0 - 2,5 mg modified by the introduction of "bundles" cyclic compound cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-Aca)) dissolved in 0.3 ml of 0.5 M phosphate buffer with a pH of 9 and add a solution, the receipt of which is described in example 22 part B. Using 1H NaOH, the pH is brought to 9. The reaction mixture is heated at 40oC for 30 minutes After cooling (~2 min), 25 μl of the solution is analyzed by HPLC using method 1 (see table 3).

Example 25

Cyclo-([[99mTcO(MAG2)]--D-Lys]-NMeArg-Gly-Asp-Mamb)

This connection receive according to the method described in example 22, using as the complexing agents Bz-MAG3(see table 3).

Example Noy in example 22, using as complexing agents Bz-Me-MAG3(see table 3).

Example 27

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb([99mTcO(MeMAG2ACA)]--5-Aca))

Specified in the title compound get through the procedure described in example 22, using in part A as the complexing agents Bz-Me-MAG2-ACa, and in part C as modified by the introduction of "bundles" cyclic compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca)) (see table 3).

Example 28.

Cyclo-([99mTcO(MABA)]--D-Lys]-NMeArg-Gly-Asp-Mamb)

Part A. the Formation of coordination compounds

In desyatikilometrovy bubble add 50 to 300 MCI99mTcO4-in 0.5 ml of physiological solution, and then 0.5 ml of a solution of Bz-MABA (1 mg/ml in 0.5 M phosphate buffer with pH 12), and then 0.15 ml of a solution of Na2S2O4(5 mg/ml in 0.5 M phosphate buffer with a pH of 11.5). Using 1H NaOH, pH adjusted to 10 to 12, and heat the mixture for 30 min at 100oC, then analyzed by HPLC according to method 1.

Part B. Activation

To the solution, the receipt of which is described in part A, add 0.2 ml 1H HCl, 0.5 ml of TFP (50 mg/0.5 ml in 90% CH3CN) and 0.5 ml DCI (50 mg in 0.5 90% CH3CN). If necessary, pH was adjusted to 6 and the mixture is heated at 45 - 50oC teeenie described in part B, add 2 to 3 mg of the intermediate cyclic compound cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb), dissolved in 0.5 ml of 0.5 M phosphate buffer pH 9, and pH adjusted to 9.5 - 10. The solution is heated at 50oC for 30 min, then analyzed by HPLC according to method 1 (see table 3).

Example 29.

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb([99mTcO(MABA]--5-Aca))

Specified in the title compound get through the procedure described in example 28, using in part C modified by the introduction of "bundles" cyclic compound cyclo-(D-Val-NMeArg-Gly-Asp-Mamb(5-Aca)) instead of the intermediate cyclic compound cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb).

Example 30

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb([99mTcO(MABA]--5-Aca))

Specified in the title compound get through the procedure described in example 28, using in part C modified by the introduction of "bundles" cyclic compound cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb(5-Aca)) instead of the intermediate cyclic compound cyclo-(D-Lys-NMeArg-Asp-Mamb).

Example 31

Cyclo-([[99mTcO(MA-MAMA)]--D-Lys]-NMeArg-Gly-Asp-Mamb)

Part A. unprotect

Triteleia group of complexing agents MAMAMA removed by dissolving 6 mg in 1 ml anhydrous triperoxonane acid (TFA). The obtained yellow solution was kept at room Lucie removed under reduced pressure, and get a white residue.

Part B. Hydrolysis of ethyl ether.

The white precipitate obtained as described in part A of the method, add 0.5 ml 5H NaOH and 1 ml THF. The mixture is heated on a water bath (100oC) 5 min, during this time a large part of the THF evaporated. To the reaction mixture add 3 ml of 0.5 M phosphate buffer with a pH of 11.5. The pH was adjusted to 10-12 and add dithionite sodium (15-30 mg). The mixture is filtered and bring the total volume to 6 ml of 0.5 M phosphate buffer with a pH of 11.5.

Part C. the Formation of coordination compounds

In desyatikilometrovy bubble put 50-150 MCI99mTcO4-in 0.5 ml of physiological solution, and then 0.5 ml of a solution of the ligand obtained by the method described in part B. Using 1H NaOH, the pH was adjusted to 10-12, then the mixture is heated at 100oC for 30 min and analyzed by HPLC according to method 1.

Part D. activating

To the solution obtained by the method described in part C, add 0.2 ml 1H HCl, 0.5 ml of TFP (50 mg/0.5 ml 90% CH3CN). If necessary, the pH is brought to 6, and heated the mixture at 45-50oC for 30 min, then analyzed by HPLC according to method 1.

Part E. Mate

To the solution, extracting the-Asp-Mamb), dissolved in 0.5 ml of 0.5 M phosphate buffer with a pH of 9, and bring the pH to 9.5 - 10. After heating at 50oC for 30 min the solution is analyzed by HPLC according to method 1.

Example 32.

Cyclo-(D-Val-NMeArg-Gly-Asp-Mamb([99mTcO(MAMABA]--5-Aca))

Specified in the title compound get through the procedure described in example 31, using in part E modified by the introduction of a binding compound cyclo-(D-Lys-NMeArg-Gly-Asp-Mamb).

Methods of analysis

HPLC, method 1

Column: Vydac C18, 250 mm x 4.6 mm, 300 A

Solvent A: 10 mm sodium phosphate, pH 6

Solvent B: 100% acetonitrile

Gradient:

0%B TO 30%B 75%B

O' 15' 25'

Flow rate: 1.0 ml/min

Detection: sample NaI.

TLC, method 2

Strip ITLC-SG, 1 cm x 7.5 cm, eluent a mixture of acetone and water, 1:1.

HPLC, method 2

Column: Vydac C18, 250 mm x 4 mm, a size of 300 pairs A

Solvent A: 10 mm sodium phosphate, pH 6,0

Solvent B: 75% acetonitrile in solvent A

Gradient:

5%B 5%B 100%B

O' 5' 40'

Flow rate: 1.0 ml/min

Detection: sample NaS.

The usefulness

Containing radioactive label compounds of the present invention can be useful in image quality is stable angina, myocardial infarction, transient ischemic attack, sudden attack, atherosclerosis, diabetes, thrombophlebitis, pulmonary embolism or cardiac protezioni devices, such as a heart valve, as well as for the diagnosis of such existing or potential violations. The patient may be any type of mammal, but preferably people. Containing radioactive label compounds can be used alone or in the form of a radiopharmaceutical composition with acceptable carriers and/or in combination with other diagnostic or therapeutic means. Suitable radiopharmaceutical media, and that their use is well known in the art and can be found for example in: Remington''s Pharmaceutical Sciences, Gennaro, A. R., ed, Mack Publishing Company, Easton, PA (1985), and The United States Pharmacopia - The National Formulary, 22nd Revision, Mack Printing Company, Easton, PA (1990) - the generally accepted guidelines for the pharmaceutical industry. Can also be used other additives known in the art for stabilizing composition including anti-oxidation agents, such as sodium bisulfite, sodium sulfite, ascorbic acid, gentisic acid or citric acid (or their salts), as well as atlantium is which they are used, also described in Remington's Pharmaceutical Sciences and The United States Pharmacopia - The National Formulary, cited above.

The present invention also contains a radiopharmaceutical kits containing the labeled compounds of the present invention. Such kits can contain the labeled compound in the sterile liofilizovannyh form and may contain a sterile tank with a radiopharmaceutical acceptable dilution liquid. Suitable diluting fluid described in Remington's Pharmaceutical Sciences and The United States Pharmacopia - The National Formulary, cited above. Such kits may include a sterile container with the composition of the compounds of the present invention containing radioactive label. Such sets, if necessary, may include other conventional components such sets, such as one or more carriers, one or more additional vials for mixing. The kit may also include instructions (inserts or labels) characterizing the amount of labelled compound and the carrier, the conditions of mixing of the components and the method of introduction. Sterilization of tanks and other materials included in the kit, and lyophilization (also known as freeze drying) labeled compounds of the present invention can the>For implementing the method of the present invention labeled with radioactive isotopes compounds may be usually administered intravenously or in the form of pills, although they can also be entered in any medium, provided the contact of these compounds with platelets. Suitable quantities for injection can be easily installed by professionals using the invention. Input dose, of course, vary depending on such factors as the connection type, age, health and weight of the patient, and the symptoms present in a patient, the amount of radioactive label, the rate of excretion of radiolabelled compounds from the blood.

A suitable dose for administration labeled with radioactive isotopes materials is given, for example, the guide Physicians Desk Refevence (PDR) for Nuclear Medicine, published Medical Exonomics Company, well known in the art. Discussion of some of the above factors is given in Eckelman et al., J. Nucl. Med., Vol. 209. pp. 350-357 (1979). As usual recommended dose of radiolabelled compounds of the present invention can vary from about 1 to about 40 MCI.

After radiolabelled compound introduced is zobrazenie, such as a gamma camera or a computer tomography device, which will be revealed thromboembolic disorder. Such systems produce images of well-known and described, for example, Macovski, A., Medical Imaging Systems, Information and Systems Science Series, Kailath, T., ed., Prentice-Hall, Inc., Englewood Cliffs, NJ (1983). Preferred are single photon emission computed tomography (SPECT) and positron emission tomography (PET). In particular, the image acquisition may be performed by scanning the entire patient or a separate area of the patient, in which a suspected blood clot, using radioscintigraphy system, and a detection signal of the radioactive isotope. The detected signal is then converted by the system into an image of a blood clot. The resulting image should be read by an experienced technician, such as a medical specialist in the field of nuclear medicine. The above process is called here a snapshot of the patient. In General, obtaining a snapshot of the patient is carried out for from about 1 minute to about 48 hours after administration of radiolabelled compounds of the present invention. The exact time of image acquisition will depend on factors such as lane which can be installed by a specialist in this area. Mainly, the image acquisition is carried out for from about 1 minute to about 4 hours after drug administration.

The advantages of using radioactive labeled compounds of the present invention, which possess the property-specific localization and high affinity to blood clots that can detect the presence of thrombus and/or to diagnose thromboembolic disorders in the patient, will be obvious to the person skilled in the art, met with the present invention.

Model - arteriovenous anastomosis. Adult mongrel dogs of different gender (9-13 kg) were anesthetized with pentobarbital sodium (35 mg/kg, I.V.) and ventilated by outside air through the tracheal tube (12 times/min, 25 ml/kg). To determine the blood pressure of the left carotid artery kanyoro polyethylene catheter (PE-240) filled with physiological salt solution, and connected to a Statham pressure transducer (P23ID; Oxnard, CA). Mean arterial blood pressure is determined by the attenuation of the pulsed signal. Heart rate control using cardiotachometer (Biotach, Grass Quincy, MA) connected to the second lead electrocardiogram from Concilium treated with silicone (Sigmacote, Sigma Chemical Co., St. Louis, Mo) filled with saline tubing (PE-200), and combined with the 5 cm section treated with silicone tubing (PE-240) for education in vitro arterial-venous shunts (A-V). The open state of the bypass control using the Doppler system flow control (model VF-1, Crystac Biotech Ine, Hopkinton, MA) and the sample number passing fluid (2-2,3 mm, Titronies Med. Inst., Iowa City, IA), located in close proximity to the shunt. All parameters are continuously recorded by a multichannel recorder (model 7D Grass), the speed of the paper feed of 10 mm/min or 25 mm/sec.

After the 15-minute post-surgical stabilization period form obtenerse clot the introduction of a thrombogenic surface (silk thread in a 4-0 plexus, length 5 cm, hicon Inc., Somervillie, NJ) in one shunt other shunt is used for control. The study was conducted for two consecutive 1 h periods introduced by infusion over 5 minutes investigational agent, starting 5 min before the introduction of the thrombogenic surface. At the end of each one-hour period bypass silk carefully removed, weighed and define count % incorporation. The weight of the thrombus is calculated by subtracting the weight of the silk prior to the introduction of the sum to the first shunt every 30 min to determine blood clearance, full of collagen-induced aggregation of platelets, thrombin-induced platelet degranulation (release of platelet ATP), prothrombin time and platelet count. Bleeding time is also determined every 30 min by a standard method.

The model of deep vein thrombosis (on dogs). This model includes the triad of phenomena (hypercoagulable state, a period of stasis, a slight change in the environment), essential for the formation of venous enriched fibrin actively growing thrombus. The method consists in the following. Adult mongrel dogs of both sexes (9 - 13 kg) narcoticyou pentobarbital sodium (35 mg/kg, I.V.) and ventilated by outside air through the tracheal tube (12 times/min, 25 ml/kg). To determine the blood pressure of the right femoral artery kanyoro filled with saline polyethylene catheter and connected to a Statham pressure transducer (P23ID, Oxnard, Ca). Mean arterial blood pressure is determined by the attenuation of the pulsed signal. Heart rate control using cardiotachometer (Biotach, Grass Quin-su, MA) connected to the second lead electrocardiogram from limb. The right femoral artery is with silk suture. Microterminal placed on a vessel that is used for indirect measurement of venous flow. In order to cause a 15-minute period of stasis, use the catheter balloon to embolectomy, at this time there is a hypercoagulable state caused by using 5U of thrombin (American Diagnosticia, Grttnwich CT), introduced in the blocked segment. After 15 min the restore blood flow by removing the cylinder. The agent is administered within the first 5 min after the restoration of stream and control the speed of incorporation, using gamma scintillanet. The results for the samples in examples 12 and 19 shown in Fig.1.

Example 33 (see tab. 4).

Analysis of aggregated platelets. Dog blood is collected in 10 ml citrate Vacutainer tubes. The blood is centrifuged for 15 min at HD at room temperature. Separate the platelet-rich plasma (PRP). The remaining blood is centrifuged 15 min at HD at room temperature and separated depleted platelet plasma (PPP). Samples will be analyzed by aggregometer (PAP-4 Platelet Affregation Profiler), using PPP as a standard (100% transmittance). In each microprobe for analysis add 200 μl of PRP and transmission set to 0%. To each tube add 20 ál of various asset is time). The results are expressed as % inhibition induced by activators of aggregated platelets. To determine the IC50the compounds added in various concentrations to activate platelets.

Analysis of the binding of platelet fibrinogen

Binding125I-fibrinogen and platelets is carried out, as described in: Btnnett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-24122, with some modifications described below. To clear fractions of platelets plasma (h-PRP) is injected into a column Separate. An aliquot of the platelet (5108cells) together with 1 mm of calcium chloride added to the activation of purified gel-chromatographic platelets (h-GPP).

Activation of purified gel-chromatographic platelets is done using ADP, collagen, arachidonate, adrenaline and/or thrombin in the presence of ligand,125I-fibrinogen.125I-fibrinogen attached to the activated platelets, separated from unbound forms by centrifugation and then measure the gamma counter. To assess IC50the compounds added in various concentrations to activate platelets.

New cyclic compounds of glycoprotein IIb/IIIa of the present invention may also have Tambol the AMI fibrinogenesis blood clots, and this can be useful in the treatment of thrombosis, as can be seen from the data on the activity of these compounds in the following tests. The predominant cyclic compounds of the present invention for destruction (lysis) of blood clots are compounds characterized by the value of the IC50(this is the molar concentration of cyclic compounds, can cause a 50% destruction of clots) less than about 1 mm, more preferably the value of the IC50less than about 0.1 mm, even more preferably the value of the IC50less than about 0.01 mm, more preferably the value of the IC50less than about 0.001 mm and most preferred is the value of the IC50about 0,0005 mm.

The estimation of the IC50can be carried out using standard methods of analysis thrombolyse, as described below. Another class of preferred thrombolytic compounds of the present invention may include such compounds, which are characterized by the Kd< 100 nm, predominantly < 10 nm, and most preferably 0.1 to 1.0 nm.

Analysis of thrombolite. Venous blood obtained from human donors, were not taking medications and aspirin for at least two weeks for delivery croley platelet-rich plasma (PRP).

To the PRP then add 110-3M activator - ADP, adrenaline, collagen, arachidonate, serotonin or thrombin, or their mixture, PRP and incubated for 30 min Centrifuged PRP 12 min (HD) at room temperature. Pour the supernatant, and platelets remaining in the test tube, suspended in United platelet plasmer (PPP), which serves as the source of plasminogen. The suspension is then analyzed using the counter Coutler Counter (Coutler Electronics, Inc., Hialeah, FL) to determine the number of platelets in the initial time zero point. After determining the origin type of the investigated compounds in different concentrations. The samples examined in different times and count the number of platelets, using a Coulter counter Counter. In order to determine the percentage of lysis, the number of platelets, defined in the time after administration of the compounds, subtract the number of platelets in the zero point, and the obtained value is divided by the number of platelets in the zero point. Multiplying the result by 100 to get the percentage of lysis of clots caused by addition of the compounds.

To estimate the IC50the compounds added in various concentrations, and n is tion, quoted in this document are provided only as a reference.

From the preceding description specialists will be understood various modifications of the invention, in addition to what is shown and described here. Such modifications are assumed to be the entire volume of the claims.

1. The cyclic peptides of the formula:

(QLn)dCh,

where d = 1 to 2; Ln- linking group;

Chthe metal chelator;

Q - compound of formula (I)

< / BR>
or its pharmaceutically acceptable salt or inactive form,

where J is D - Val, D - Lys, containing a link with Lnand D - Abu, when J represents different than D - Lys containing the relationship with Lnshown phenyl ring may have an optional link with Ln-Chin position *, Ln- NHC(O) - (CH2)h- Y2- M2or C(O) - (CH2)h- Y2- M2; M2absent or selected from phenylene-CH2, cyclohexyl-CH2-, (CH2)2and (CH2)3; h = 0, 1, 2, 3, or 5, Y2absent or represents NHC(O),

Chselected from

< / BR>
where A1- NH2N = C(C1- C3alkyl)(C1- C3alkyl), N(-Ln)(CH2CO2H), S, SH and>(CH2CO2H) or N(CH2CO2H)2;

A4- N - Ln, S, SH, S(Pg);

W is absent or selected from (CH2)2CH2C(O) CH(CH3)C(O), C(O)CH2CH2CH - Lnor

< / BR>
Pg - thiol protective group which can be replaced when interacting with the radionuclide.

2. Cyclic peptide under item 1, where d = 1 - 2, Ln- linking group, Ch- chelator of metal and Q is a compound of formula (Ia)

or its pharmaceutically acceptable salt, or an inactive form,

where J is D - Lys containing the relationship with Ln, Ln- C(O) - (CH2)n- Y2- M2M2absent or selected from phenylene-CH2or (CH2)2, h = 0, 1, 2, 3, or 5, Y2absent or represents NHC(O), Chselected from

< / BR>
where A1- NH2N = C(C1- C3alkyl)(C1- C3alkyl), N(-Ln)(CH2CO2H), S, SH, S(Pg);

A2- N, NH, NH-pyridyl-Lnor N(CH2CO2H);

A3- N, NH, NH-LnN(-Ln)(CH2CO2H) or N(CH2CO2H)2;

A4- N-Ln, S, SH, S(Pg);

W is absent or selected from (CH2)2CH2C(O) CH(CH3)C(O), C(O)CH2CH2CH - Lnand
tx2">

3. Cyclic peptide under item 2, where d = 1, Ln- linking group, Ch- chelator of metal and Q is a compound of formula (Ia), where J is D - Lys - Ln- Ch, Ln- C(O) - (CH2)h- Y2- M2M2absent or selected from phenylene-CH2or (CH2)2, h = 0, 1, 2, 3, or 5, Y2absent or represents NHC(O); Ch-

< / BR>
where A1- NH2N = C(C1- C3alkyl)(C1- C3alkyl), N(-Ln)(CH2CO2H), S, SH, S(Pg);

A2- N, NH, NH-pyridyl-Lnor N(CH2CO2H);

A3- N, NH, N-Lnor N(CH2CO2H)2;

A4- N-Ln, S, SH, S(Pg);

W is absent or selected from (CH2)2CH2C(O) CH(CH3)C(O), C(O)CH2CH2CH - Lnand

< / BR>
Pg - thiol protective group which can be replaced when interacting with the radionuclide.

4. Cyclic peptide under item 3, where Ln- C(O), Chrepresents a

< / BR>
A1- NH2or N = C(C1- C3alkyl)(C1- C3alkyl), A2- NH-pyridyl-Lnand W is absent.

5. Cyclic peptide under item 3, where Ln- C(O) - CH2Chrepresents a

< / BR>
A1- N(-LnR> W - (CH2)2.

6. Cyclic peptide under item 3, where J is D - Lys containing the relationship with Ln, Ln- C(O)-phenylene-CH2- Chrepresents a

< / BR>
A1- S, SH, S(Pg);

A2- N or NH;

A3- N - Ln;

A4- S, SH, S(Pg);

W - (CH2)2or C(O)CH2;

Pg thiol protective group which can be replaced when interacting with the radionuclide.

7. Cyclic peptide under item 3, where Ln- C(O) - (CH2)h, h = 1 or 3, Chrepresents a

< / BR>
where A1- S, SH, S(Pg);

A2- N or NH;

A3- N or NH;

A4- N - Ln;

W - (CH2)2CH2C(O) and CH(CH3)C(O);

Pg - thiol protective group which can be replaced when interacting with the radionuclide.

8. Cyclic peptide under item 3, where Ln- C(O) - (CH2)2Chrepresents a

< / BR>
where A1- S, SH, S(Pg);

A2- N or NH;

A3- N or NH;

A4- S, SH, S(Pg);

W is absent or is selected from CH2C(O), C(O)CH2and CH2CH - Ln,

Pg - thiol protective group which can be replaced when interacting with the radionuclide.

9. Cyclizes is - or NH;

A3- N or NH;

A4- S, SH, S(Pg);

W is absent or is selected from CH2C(O), C(O)CH2and

< / BR>
Pg - thiol protective group which can be replaced when interacting with the radionuclide.

10. Cyclic peptide under item 2, where d = 2, Ln- linking group, Ch- chelator of metal and Q is a compound of formula (Ia), Ln- C(O) - CH2Chrepresents a

< / BR>
where A1- N(-Ln)(CH2CO2H);

A2- N(CH2CO2H);

A3- N(-Ln)(CH2CO2H)2;

W - (CH2)2.

11. Cyclic peptide under item 1, where d = 1, Ln- linking group, Ch- chelator of metal and Q is a compound of formula (Ib)

< / BR>
where J is D - Val or D - Abu;

Ln- NHC(O) - (CH2)5- NHC(O) - M2;

M2absent or selected from phenylene-CH2, cyclohexyl-CH2-, (CH2)2and (CH2)3;

Ch-

< / BR>
A1- NH2N = C(C1- C3alkyl)(C1- C3alkyl), S, SH, S(Pg);

A2- N, NH, NH-pyridyl-Ln;

A3- N, NH or N - Ln;

A4- N, NH, N - Ln, S, SH, S(Pg);

W is absent or selected from (CH2)2CH2C(O) is on when interacting with the radionuclide.

12. Cyclic peptide according to p. 11, where J is D - Val or D - Abu, Ln- NHC(O) - (CH2)5- NHC(O), Ch-

< / BR>
where A1- NH2or N = C(C1- C3alkyl)(C1- C3alkyl);

A2- NH-pyridyl-Ln;

W is absent.

13. Cyclic peptide according to p. 12, where J is D-Val.

14. Cyclic peptide according to p. 12, where J is D-Abu.

15. Cyclic peptide according to p. 11, where J is D-Val or D-Abu, Ln- NHC(O) - (CH2)5- NHC(O) - M2M2selected from phenylene-CH2, cyclohexyl-CH2-, (CH2)2and (CH2)3Chrepresents a

< / BR>
where A1- S, SH, S(Pg);

A2- N or NH;

A3- N, NH or N-Ln;

A4- N, NH, N-Ln, S, SH, S(Pg);

W - (CH2)2CH2C(O) CH(CH3)C(O), C(O)CH2or CH2CH-Ln;

Pg - thiol protective group which can be replaced when interacting with the radionuclide.

16. Cyclic peptide according to p. 11, where J is D-Val or D-Abu, Ln- NHC(O) - (CH2)5- NHC(O) - phenylene-CH2Chrepresents a

< / BR>
where A1- S, SH, S(Pg);

A2- N or NH;

A3- N-Ln;

A4- S, SH, S(Pg);

W - (CH2)2C(O)CH2;

Pg - thio the ski peptide on p. 11, where J is D-Val or D-Abu, Ln- NHC(O) - (CH2)5- NHC(O) - M2M2- cyclohexyl-CH2or (CH2)3Chrepresents a

< / BR>
A1- S, SH, S(Pg);

A2- N or NH;

A3- N, NH;

A4- N-Ln;

W - CH2C(O) or CH(CH3)C(O);

Pg - thiol protective group which can be replaced when interacting with the radionuclide.

18. Cyclic peptide according to p. 11, where J is D-Val or D-Abu, Ln- NHC(O) - (CH2)5- NHC(O) - M2M2- phenylene-CH2, cyclohexyl-CH2-, (CH2)2or (CH2)3Chrepresents a

< / BR>
where A1- S, SH, S(Pg);

A2- N or NH;

A3- N or NH;

A4- S, SH, S(Pg);

W - CH2C(O), C(O)CH2or CH2CH-Ln;

Pg - thiol protective group which can be replaced when interacting with the radionuclide.

19. Cyclic peptide under item 1, selected from

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
20. Radiopharmaceutical preparation, which is a complex connection on one of the PP.1 - 19 and a radionuclide selected from the group99mTc99mTcO and111In.

21. Radiopharmaceutical drug on p. 20, containing the>BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
22. Cyclic peptide having a radioactive label, entered directly, formula (II)

< / BR>
or its pharmaceutically acceptable salt or inactive form,

where R1and R2is hydrogen;

J - D-isomer amino acid of structure-N(R3)C(R4) (R5)C(=O)-, where R3- H, R4- H, R5- C1-C8alkyl, unsubstituted or substituted R11, R11selected from one or more-NHC(= O)R13and aryl, unsubstituted or substituted R12, R12represents-OH, R13(hydroxyphenyl)-C1-C10alkyl,

K - L-isomer amino acid of structure-N(R6)CH(R7)C(= O)-, where R6- C1-C4alkyl, R7- (C1-C7alkyl)X, X -

< / BR>
where R13- H;

L-NHCH2C(=O)-;

M - L-isomer amino acid of structure

< / BR>
where q' = 1 - 2;

R4- H;

R17- H;

R8- -CO2H;

where tag is a125I or 123I and it is bound to the aryl group represented in formula I.

23. Cyclic peptide having a radioactive label, p. 22, where R>6is methyl, ethyl or propyl.

24. Cyclic peptide, which is SUP> - H, R4- H, R5- C1-C8alkyl, unsubstituted or substituted R11, R11selected from one or more: -NHC(= O)R13and aryl, unsubstituted or substituted R12, R12- -OH, K - NeArg, L - Gly, M - Asp.

25. Cyclic peptide having a radioactive label, p. 22, selected from

< / BR>
< / BR>
26. Cyclic peptide having a radioactive label, one from PP.22 - 25, which is used to determine the deposition of platelets in mammals.

27. Cyclic peptide having a radioactive label, one from PP.22 - 25, which is used for diagnosing diseases associated with the deposition of platelets.

28. Radiopharmaceutical preparation according to one of paragraphs.20 - 21, which is used to determine the deposition of platelets in mammals.

29. Radiopharmaceutical preparation according to one of paragraphs.20 - 21, which is used for diagnosing diseases associated with the deposition of platelets.

Priority points:

30.03.93 on PP.22 - 27;

28.03.94 on PP.1 - 21, 28 and 29.

 

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