Cyclic peptides or their pharmaceutically acceptable salts, pharmaceutical composition

 

(57) Abstract:

Purpose: in medicine as compounds having antithrombotic activity. The essence of this invention are cyclic peptides of General formula I given in the text of the description, or their pharmaceutically acceptable salts, where R1is hydrogen, (C1-C4) alkyl, phenyl, benzyl; R2is hydrogen, lower alkyl; R10is hydrogen, halogen; n=1, n'=0; j=D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-cyclohexyl Gly, D-Gly, D-Norvaline, D - 2 - aminobutyric acid, D-2-aminopentanoic acid Gly, N-R-azidobenzoyl-D-Lys, N-R-benzoylmethyl-D-Lys, Np-azidobenzoyl-D-Lys, N-dansyl-D-Lys, Nt-butoxycarbonyl glycyl-D-Lys, N-glycyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N-R-vinylbenzyl-D-Lys, N-m-benzoylmethyl-D-Lys or N-o-benzoylbenzoate-D-Lys; K = NMeArg , NN-Dima-N-guanidine Orn, NMeLys or NN-MeLys, L=Gly, M=Asp, MeAsp or NMeAsp and pharmaceutical composition having the ability to inhibit the action of platelets containing quality is The present invention relates to new cyclic peptides, containing aminomethylbenzoic acid and used as antagonists of the platelet glycoprotein complex IIb/IIIa and to pharmaceutical compositions containing these cyclic peptides.

Activation of platelets and, as a result, their aggregation and secretion of their factors associated with various pathophysiological conditions including cardiovascular and cerebralischemia thromboembolic complications, such as thromboembolic complications associated with unstable angina, myocardial infarction, transient ischemic stroke, palsy, atherosclerosis, and diabetes. The role of platelets in these processes is determined by their ability to form aggregates or blood clots, especially on the walls of arteries after injury.

It is known that platelets play an important role in maintaining homeostasis and in the pathogenesis of arterial thrombosis. It has been shown that activation of platelets increases with coronary thrombolyse, which can lead to delayed reperfusion and reocclusion. Clinical studies using aspirin, ticlopidine and monoclonal antibodies to platelet glycoprotein IIb/IIIa allowed to obtain biochemical, decastella, when transient disorders of cerebral circulation, cerebral ischemia and stroke.

Platelets are activated by a large variety of substances with affinity to the receptor, which leads to a change in platelet shape, secretion of granular components and aggregation. Platelet aggregation contributes to the formation of a clot due to the concentration of activated factor of the blood coagulation system in one place. Identified several endogenous substances with affinity to receptors, including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin and collagen. Because the processes of activation and aggregation of platelets involved several endogenous substances with affinity to the receptor inhibitor that is effective against all of these substances, should be a more effective protivotrevozhny agent than currently known protivotromboznoe drugs, each of which is specific only to a certain substance having affinity to the receptors.

Modern protivotromboznoe drugs are effective only against one type of such substances; examples included the dignity of A2synthetase or receptor antagonists, anti thromboxane A2; and hirudin, anti thrombin.

Recently was discovered common to all known substances having affinity to receptors, mechanism of action, in which the key role is played by the platelet glycoprotein complex IIb/IIIa (GPIIb/IIIa), which is a membrane protein mediating platelet aggregation. One of the recent reviews of research GPIIb/IIIa was made Phillips et al. (1991) Cell 65: 359-362. Creating antagonists for GPIIb/IIIa represents a new, promising approach to the problem protivotromboznoe therapy. Recent studies conducted in humans with the use of monoclonal antibodies to GPIIb/IIIa shows that the antagonist GPIIb/IIIa should be an effective antithrombotic agent.

Currently, there is a need in specific for GPIIb/IIIa protivotromboznoe the agent capable of inhibiting the activation and aggregation of platelets in response to exposure to any substance having affinity to the receptors. Such an agent should be more effective protivotrevozhnym therapeutic tool than currently known inhibitors of the platelet to the>

GPIIb/IIIa does not bind soluble proteins on non-activated platelets, but it is known that in the case of activated platelet GPIIb/IIIa binds four soluble adhesive protein, namely fibrinogen, factor a background of Villebranda, fibronectin and vitronectin. The binding of fibrinogen and factor a background of Villebranda GPIIb/IIIa causes platelet aggregation. The binding of fibrinogen partially mediated by a recognition sequence Arg-Gly-Asp (RGD), which is common to the adhesive proteins associated GPIIb/IIIa.

It has been described several RGD-containing peptides and related compounds that block the binding of fibrinogen and prevent the formation of blood clots. Cm. for example, Cadroy et al. (1989). J. Clin. Invest. 84: 939 - 944; Klein et al. U.S. patent 4952562, publ. 8/28/90; European patent application EP 0319506 A; European patent application EP 0422938 A1; European patent application EP 0422937 A1; European patent application EP 0341915 A2; PCT patent application WO 89/07609; PCT patent application WO 90/02751; PCT patent application WO 91/04247; and European patent application EP 0343085 A1.

In the present invention, we used a constraining rigid conformation of amino acids (isomers aminometilbensana acid) as templates for.

Detailed description of the invention

The present invention relates to cyclic peptides of formula (I):

< / BR>
or their pharmaceutically acceptable salts, where

R1is H, (C1-C4)alkyl, phenyl, benzyl;

R2represents H or nits.alkyl;

R10represents H, halogen;

n 1;

n'-0;

J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, D-2-aminopentanoic acid Gly, Ne-R-azidobenzoyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N-p-azidobenzoyl-D-Lys, N-dansyl-D-Lys, N-t-butoxycarbonylmethyl-D-Lys, N-glycyl-D-Lys, N-p - benzoylbenzoate-D-Lys, N-p-vinylbenzyl-D-Lys, N-m-benzoylmethyl-D-Lys or N-o-benzoylbenzoate-D-Lys;

K is NMeArg, NNdi Me Nguanidino, NMeLys or NN-MeLys;

L is Gly;

M is selected from Asp-MeAsp or NMeAsp.

Preferred compounds of the present invention are:

The compound of formula (I), where:

R10 represents H, halogen;

J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro, b-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, D-2-aminopentanoic Gly, Ne-R-azidobenzoyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N-p-azidobenzoyl-D-Lys, N-dansyl-D-Lys, N-t-butoxycarbonylmethyl-D-Lys, N-glycyl-D-Lys, N-p - benzoylbenzoate-D-Lys, N-p-vinylbenzyl-D-Lys, N-m - benzoylmethyl-D-Lys or N-o-benzoylbenzoate-D-Lys;

K is NMeArg, NNdi Me-N-guanidinium,MeLys or NeN-MeLys;

L is Gly;

M is selected from Asp-MeAsp or NMeAsp.

The compound of formula (I), where:

R1is H, (C1-C4)alkyl, phenyl, benzyl;

R2represents H or methyl;

R10represents H, halogen;

J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro, b-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, Ne-p-azidobenzoyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N- p-azidobenzoyl-UP>-p-benzoylbenzoate-D-Lys, N-p-vinylbenzyl-D-Lys, N-m-benzoylmethyl-D-Lys or N-o-benzoylbenzoate-D-Lys;

K is NMeArg;

L is Gly; and

M is selected from Asp, b-MeAsp or NMeAsp.

The compound of formula (I), where:

R1and R2independently selected from H or methyl;

R10represents H;

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

It is a NMeArg;

L is Gly;

M is selected from Asp, b-MeAsp or NMeAsp.

As well as cyclic peptides, which are selected from the group of compounds in which R1, R2and R10are H; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-2-aminobutyric acid; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Leu; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Ala; K is NMeArg; L predstavljaet D-Pro; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1represents methyl (isomer 1), R2and R10are H; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1represents methyl (isomer 2), R2and R10are H; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1represents phenyl (isomer 1), R2and R10are H; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Met; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-2 - aminobutyric acid; K NdNadi Me-Ndguanidinium; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-2 - aminobutyric acid; K NNdi Me Lys; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10
the compounds of formula (I), where R1, R2and R10are H; J is N-p-benzoylbenzoate-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-tryptophanyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-o-benzylbutyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-R-acetylbenzoic-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-dansyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-glycyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-R-benzoylbenzoate-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-p-vinylbenzyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-m-antistable N-o-benzoylbenzoate-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Nle; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Gly; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Phe; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Ile; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-Cl; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-I; J is D-Val; K is NMeArg; L is Cly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-I; J is D-2-aminobutyric acid; K is NMeArg; L I is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10rmula (I), where R1and R2represent H; R10is 6-Cl; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 6-methoxy; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 6-Me; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-Cl; J is D-2-aminobutyric acid; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-I; J is D-2-aminobutyric acid; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1and R2represent H; R10is 4-Me; J is D-2-aminobutyric acid; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Tyr; K is NMeArg; L is Gly; and M is Asp;

soedinenie Gly; M is Asp;

the compounds of formula (I), where R1and R10represent H; R2is CH3; J is D-Val; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Gly; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is N-t-butoxycarbonylmethyl-D-Lys; K is NMeArg; L is Gly; and M is Asp;

the compounds of formula (I), where R1, R2and R10are H; J is D-Ser; K is NMeArg; L is Gly; and M is Asp.

Cyclic peptides of formula (I), where

R1is H, (C1-C4)alkyl, phenyl;

R2represents H or methyl;

R10represents H, halogen;

J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, D-2-aminopentanoic Gly, NeN-p-azidobenzoyl-D-Lys;

K represents the Ndi Me-N-guanidino, N-MeLys; L D-Pro, D-Ser or D-Lys.

In the present invention it was found that the above compounds may be used as inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa). As mentioned above, GPIIb/IIIa is the mediator of the activation and aggregation of platelets.

Compounds according to the present invention inhibit the activation and aggregation of platelets caused by any known endogenous substances with affinity to receptors of platelets.

The present invention also provides methods of therapeutic treatment of diseases associated with the activation and aggregation of platelets, including cardiovascular and cerebralischemia thromboembolic complications, such as thromboembolic complications associated with unstable angina, myocardial infarction, transient ischemic stroke, palsy, atherosclerosis, and diabetes, by introducing a recipient in need of such treatment, a pharmaceutically effective amount of the compounds of the above formula (I).

It is known that in metastatic tumor cells the level of expression of GPIIb/IIIa is increased. Compounds according to the present invention can also use the Kie centers. Unless otherwise noted, the present invention covers all chiral, diastereomeric and racemic forms. It is known that there are two different isomers (CIS and TRANS) relative to the peptide bond; both of these isomers can occur in the case of the described compounds, and all such stable isomers are also included in the scope of the present invention. Unless specifically stated otherwise, it uses the L-isomer amino acids. D - and L-isomers of specific amino acids are indicated in this description using the standard three-letter abbreviations adopted for this amino acid, e.g. d-Leu, D-Leu, l-Leu or L-Leu.

If any variable, that is able to take on different values, the symbol (for example, R1-R8, m, n, p, Q, W, X, Y, Z and so on) occurs in any fragment or in any formula more than once, its value in each of his positions does not depend on its values in any of his positions. Combinations of substituents and/or variables of the characters are considered valid only if such combinations result in stable connection.

In the context of the present description, the term "alkyl" ("alkyl" encompasses saturated carbon atoms; the term "alkoxy" embraces alkyl group with the specified number of carbon atoms connected via mastic oxygen atom; the term "cycloalkenyl" ("cycloalkyl") covers a saturated cyclic group, such as cyclopropyl, cyclobutyl, cyclopentamine, cycloheptyl and cyclooctyl. The term "alkanniny" ("Alchemilla") covers the hydrocarbon chain as branched and unbranched structure containing one or more double carbon-carbon bonds, which may take any stable position along the chain, such as Attila, protanilla and similar groups; the term "alkynylaryl" ("Alchemilla") covers the hydrocarbon chain as branched and unbranched structure containing one or more triple carbon - carbon bonds, which may take any stable position along the chain, such as etinilnoy, proponila and similar groups. The term "halogen" in the context of the present description refers to fluorine atoms, chlorine, bromine and iodine; the term "counterion" is used to denote a small negatively charged particles, for example, chloride, bromide, hydroxide, acetate, sulfate and similar.

Under "ostoich the full-time, so it can be selected with the desired degree of purity from a reaction mixture, and turned into an efficacious therapeutic agent.

The term "pharmaceutically acceptable salts and prodrugs" refers to derivatives of the disclosed compounds, which are obtained by the translation of these compounds in acidic or basic salts, or by modifying functional groups present in these compounds so that these modifications under normal procedures or in vivo has developed in the parent connection. Examples include, but are not limited to, the following variants: salts of basic residues of organic or inorganic acids, such as amines, salts of acidic residues alkaline or organic acids such as carboxylic acids; esters of carboxylates; acetate, formiate and benzoate derivatives of alcohols and amines; and similar.

Pharmaceutically acceptable salts of the compounds of the present invention can be obtained by the reaction of these compounds in the form of free acids or bases with stoichiometric amounts of the corresponding bases or acid in water or in an organic solvent, or mixtures thereof; as a rule, are preferred environment, containing no water is on s Pharmaceutical Sciences, 17th ed. Mack Publishing Company, Easton, PA, 1985, p.1418.

The term "amino acid" in the context of the present description means an organic compound containing a primary amino group and an acidic carboxyl group. This term also includes modified and unusual amino acids.

The term "amino acid residue" in the framework of the present description means that part of the amino acids (the term is defined above), which is present in the peptide or pseudopeptide. The term "peptide" in the context of the present description means a linear connection, consisting of two or more amino acids (definition see Above), linked together by peptide or pseudopeptide links.

Compounds of the present invention can be obtained in a number of ways, well known to experts in the field of organic synthesis. The preferred methods described below include, but are not limited to.

In the description uses the following abbreviations:

D-Abu, D-2-aminobutyric acid

b-Ala or bAla 3-aminopropionic acid

Boc t-butoxycarbonyl

Boc-Mamb t-butoxycarbonyl-C-aminomethylbenzoic acid

Boc-ON 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile

DCC dicial-1-yl)-1,1,3,3-tetramethyleneglutaric

NMeArg, or MeArg a-N-methylarginine

NMeGly or MeGly N-methylglycine

NMM N-methylmorpholine

OcHex O-cyclohexyl

OBzl O-benzyl

Tos toil

In the description uses the following standard three-letter abbreviations of amino acids:

Ala alanine

Arg arginine

Asn asparagine

Asp aspartic acid

Cys cysteine

Gln glutamine

Glu glutamic acid

Gly glycine

His histidine

Ile isoleucine

Leu is leucine

Lys lysine

Met methionine

Phe phenylalanine

Pro Proline

Ser serine

Thr threonine

Trp tryptophan

Tyr tyrosine

Val valine.

Synthesis of peptides

Compounds of the present invention can be synthesized by standard synthetic methods known to experts in this field of technology. Typically, the capacity of the peptide chain is carried out, removing the protection from a-amino C-terminal residue and adding the following appropriately protected amino acid of the peptide bond, using the literature methods. These operations remove the protection (deprotection) and attach repeat until, until you get the desired consistency. Connection can be made is or several amino acids), or a combination of both methods, or solid-phase peptide synthesis according to the method, first described by Merrifield, J. Am. Chem. Soc. 85, 2149-2154 (1963).

Compounds of the present invention can also be synthesized using automated equipment for the synthesis of peptides, described by Stewart and Young, "Solid Phase Peptide Synthesis", 2nd ed. Pierce Chemical Co. Rockford, IL (1984); Gross, Meienhofer, Udenfriend, Eds. "The Peptides: Analysis, Synthesis, Biology", vol. l, 2, 3, 5 and 9, Academic Press, New York, (1980-1987); Bodanszky, "Peptide Chemistry: A Practical Textbook", Springer - Verlag, New York (1988); and Bodanszky et al. "The Practice of Peptide Synthesis" Springer-Verlag, New York (1984).

The connection between two amino acid derivatives, amino acid and peptide, two peptide fragments or cyclization of the peptide can be carried out using standard techniques of doubling, such as the azide method, mixed anhydride carbolic acid (isobutylphenyl), carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide) method, the method using an active complex ester (p-nitroaniline ether, ether N-hydroxysuccinimide), the method using Woodward reagent K, carbonyldiimidazole method, the method using phosphate reagents, for example, BOP-Cl, or oxidation-osteosinteza. These reactions doubling or can be in solution (liquid phase), or in the solid phase.

To avoid the formation of undesirable connection, while reactions of doubling the functional groups of the constituent amino acids must be protected. Protective groups which can be used are listed in the following sources: Greene, "Protective Groups in Organic Synthesis", John Wiley Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", vol.3, Academic Press, New York (1981).

a-carboxyl group terminal residue is usually protects, receiving ester group which can be hydrolyzed to carbolic acid. These protective groups include: 1) alkalemia esters, such as methyl and tert-butyl, 2) akrilovye esters, such as benzyl and substituted benzyl, or 3) esters that can be cleaved by alkaline hydrolysis under mild conditions or recovery under mild conditions, such as trichlorethylene or phenylalanyl esters. In the case of synthesis in the solid phase C-terminal amino acid attached to an insoluble carrier (usually polystyrene). These insoluble carriers contain a group reactive with a carboxyl group with bond formation, which is stable under the reaction conditions of the extension of the peptide chain, 1295-1300), chlorine - or brometalia resin, hydroxymethylene resin and aminomethyl resin. Many of these resins are produced on an industrial scale, and in such a form that already contain the desired C-terminal amino acid.

Each amino acid a-amino group must be protected. This can be used any known in the art of protective groups. Examples are: 1) acyl types such as formyl, trifluoracetyl, Tallina and p-toluensulfonyl; 2) aromatic urethane groups, such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-metalelectronica and 9-formationsecurity (Fmoc); 3) aliphatic urethane groups, such as tert. -butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylperoxydicarbonate, allyloxy - carbonyl; 4) cycloalkylcarbonyl groups, such as cyclopentanecarbonyl and adamantanecarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl groups, such as trimethylsilyl; and 7) talasoterapia groups, such as phenylthiocarbamyl and diseaseclinical. Preferred protective groups for a protected amine to conduct peptide synthesis.

The protective group is removed from the a-amino group before attaching the next amino acid. When using the Boc group removal are implementing or using triperoxonane acid, taken in its pure form or in the form of a solution in dichloromethane, or with a solution of HCl in dioxane. The obtained ammonium salt is then neutralized by alkaline solutions such as aqueous buffer solutions or tertiary amines in dichloromethane or dimethylformamide, before doubling or in situ. When using the Fmoc group is used piperidine or substituted piperidine in dimethylformamide, but can be used also any secondary amines or aqueous solutions of bases. Deprotection carried out at a temperature from 0oC to room.

Any amino acids containing functional group in the side chain, upon receipt of the peptides must be protected using any of the above groups. Specialist in the art will understand that the selection and use of appropriate protective groups for these functionalities in the side chains depends on the amino acids and the presence of the peptide other protective groups. An important requirement for the choice of such protective groups is that they should not tapletop, suitable are the following protective groups: p-toluensulfonyl (tselnye) residues and the nitro-group to arginine; benzyloxycarbonyl, substituted benzyloxycarbonyl and Casilina group for lysine; benzyl complex or alkalemia esters, such as cyclopentyloxy for glutamic and aspartic acids; simple benzyl ethers for serine and threonine; a simple benzyl ethers, substituted simple benzyl ester or 2-bromobenzyloxycarbonyl group to tyrosine; n-methylaniline, p-methoxyaniline, acetamidomethyl, benzyl or tert. butylsulfonyl group for cysteine; and, finally, indole to tryptophan can be left unprotected, or protected formyl group.

When choosing for Fmoc protection of the a-amino group usually are suitable protective groups on the basis of tert.-butyl. For example, Boc can be used for lysine, simple tert.-butyl ether for serine, threonine and tyrosine, and complex tert.-butyl ether for glutamic and aspartic acids.

At the end of the building and cyclization of the peptide, all the protective groups are removed. Liquid-phase synthesis method of removal is determined which groups were selected as Sami peptide must be removed from the resin without simultaneous removal of the protective groups with those functional groups, which could interfere with the cyclization process. Thus, if the peptide intend to cyclicality in the solution, the conditions of removal of protection should be chosen in such a way to get free a-carboxyl group and a free a-amino group without removing the remaining protective groups. On the other hand, the peptide can be removed from the surface of the resin hydrazinolysis, and then cycletour azide method. Another very convenient method involves the synthesis of pantodon on oximes resin with subsequent intramolecular nucleophilic displacement from the resin, resulting cyclic peptide (Osapay, Profit and Taylor (1990), Tetrahedron Letters 43, 6121-6124). When using oximes resin, typically used protection scheme based on the Boc. Hereinafter, the preferred method of removal of the protective groups of the side chains usually involves the manipulation of anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole or p-cresol at 0oC. removing the protective groups of the peptide can also be accomplished using an acid reagent, for example, mixtures triftormetilfullerenov and triperoxonane acids.

Used in the present invention unusual amino acids can is, Synthesis, Biology", vol.5, pp.342-349, Academic Press, New York (1981)). N-alkylaminocarbonyl you can get previously described methods (Cheung E1 A1. (1977) Can. J. Chem. 55, 906; Preidinger et al. (1982) J. Org. Chem. 48, 77).

Compounds of the present invention can be obtained by methods which are described in detail below.

Typical materials and techniques that can be used to obtain compounds of the present invention, also described below.

Manual solid-phase peptide synthesis was performed in polypropylene tubes for filtering a volume of 25 ml, purchased from BioRad Inc. Oximo resin (degree of substitution 0.96 mmol/g) were prepared according to published methods (DeGrado and Kaiser (1980) J. Org. Chem. 45, 1295). All chemical reagents and solvents (mark "jet") used in the form in which they were received from the suppliers without further purification. Tert. -butoxycarbonyl (Boc) amino acids and other basic amino acids can be purchased from Bachem Inc. Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTech (Louisville, KY), Peninsula Laboratories (Belmont, CA.) or Sigma (St. Louis, MO). 2-(IH - benzotriazol-1-yl)-1,1,3,3-tetramethylhexadecane (HBTU) were purchased from Advanced CheroTech. N-methylmorpholine (NMM), m-cresol, D-2 - aminobutyric acid (Abu), trimethylacetylchloride, Diisopropylamine from Aldrich Chemical Company. Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl3), methanol (MeOH), pyridine and hydrochloric acid (HCl) were purchased from Baker. Acetonitrile, dichloromethane (DHM), acetic acid (AcOH), triperoxonane acid (TFOC), diethyl ether, triethylamine, acetone and magnesium sulfate were purchased from EM Science. The catalyst is palladium on coal (10% palladium) was purchased from Fluka Chemical Company. Absolute ethanol was obtained from Quantum Chemical Corporation. Thin-layer chromatography was carried out on plates for TLC coated with silica gel 60 F254(layer thickness 0.2 mm), purchased from EM Separations. Visualization of the TLC chromatogram was carried out using UV radiation and/or spraying the composition on the basis of ninhydrin. The melting point was determined with the help of the device Thomas Hoover to determine melting temperatures and other method not corrected. All ghud-analyses conducted or on the instrument Hewlett Packard 1090, Rainin, or on the device DuPont 8800. NMR spectra were taken on the spectrometer General Electric QE-300 300 MHz. Mass spectrometry with fast atom bombardment (MS-Belarusian library Association) was performed on the mass spectrometer VG Zab-E with double focusing, using as an ion source gun Xenon FAB.

Synthesis of 2, 3 and 4-Re-aminotetraline derivatives of benzoic centermedical in the synthesis of the compounds of the present invention, receive, using the standard techniques described, for example, Tett. Lett, 4393 (1975); in "Modern Synthetic Reactions", N. 0. House (1972); or (Harting et al. J. Am. Chem. Soc. 50: 3370 (1928), in accordance with the following schema.

< / BR>
3 aminomethylbenzoic acid HCl

3-cyanobenzoic acid (10.0 g, 68 mmol) was dissolved in 200 ml of ethanol under heating on a water bath with a temperature of 35-50oC. Add concentrated HCl (6,12 ml, 201 mmol), and transfer the resulting solution in a nitrogen-filled round-bottom flask 500 ml, containing the catalyst is palladium on coal (1,05 g, 10% Pd/C). The suspension is stirred in an atmosphere of hydrogen for 38 h, filtered, washed thoroughly with water. Under reduced pressure to remove ethanol and the remaining aqueous layer containing the solid white color, dilute with water to 250 ml Add diethyl ether (250 ml), and transfer the suspension into a separating funnel. By vigorously shaking all the solid is dissolved; then the aqueous layer was washed twice with ether, evaporated under reduced pressure to a volume of 150 ml, and lyophilized, obtaining the target compound (3 - aminomethylbenzoic HCl) (8,1 g, 64% ), in the form of a solid beige color.1H-NMR (D2O): 4,27 (s, 2H), 7,60 (t, 1H), 7,72 (d, 1H), of 8.06 (d, 2H).

Tert-butoxycarbonyl-N-methyl-3-aminomethylbenzoic acid (Boc-Mamb)

The target connection receive in accordance with standard techniques, for example what antinoi acid

Intermediates that meet the following General formula can be obtained using standard synthetic methods, for example, shown in the following reaction schemes

< / BR>
For R CH3CH2CH3CH2CH2CH3CH2CH2CH2CH3CH(CH3)2C(CH3)3CH(CH3)CH2CH3, benzyl, cyclopentyl, cyclohexyl see diagram 1.

For R CH3CH2CH2CH2CH3, phenyl see diagram 2.

For R CH3, phenyl see schemes 3 and 4.

Tert-butoxycarbonyl-D-2-aminobutyric acid

The target connection receive, altering previously described in the literature method (Itoh, Hagiwara and Kamiya (1975) Tett. Lett. 4393), according to the scheme below

< / BR>
D-2-aminobutyric acid

D-2-aminobutyric acid (1.0 g, to 9.70 mmol) was dissolved in 20 ml of water and add a solution of Boc-ON (2,62 g, 10.6 mmol) in 20 ml of acetone. The resulting white precipitate is dissolved by adding triethylamine (3,37 ml, and 24.2 mmol), yielding the solution is pale yellow (pH 9, moist indicator paper). This mixed solution is kept at room temperature until morning, and then at reduced pressure to remove acetone. The remaining aqueous layer three times actionee organic layers dried over anhydrous magnesium sulfate and evaporated under reduced pressure, getting tert.-butoxycarbonyl-D-2 - aminobutyric acid oil (2,05 g, yield exceeded quantitative, contains solvent), which is further used without additional purification.1H-NMR (CDCI3): and 0.98 (t, 3H), 1,45 (s, N), at 1.73 (m, 1H), 1,90 (m, 1H), 4,29 (m, 1H), of 5.05 (m, 1H).

The synthesis of cyclic peptides

Tert-butoxycarbonyl-C-aminomethylbenzoic acid (Boc-Mamb) chemically fixed on oximes the resin using a modified method of DeGrado and Kaiser (1980) J. Org. Chem. 45,1295, using 1 equivalent of 3-aminometilbensana acid (calculated on the degree of substitution resin), 1 equivalent of HBTU and 3 equivalent of NMM. On the other hand, the BOC-Mamb (1 equivalent) can be mounted on oximes the resin using 1 equivalent of DCC and OMAR in the environment of methylene chloride. The reaction time is from 15 to 96 hours Then determine the degree of substitution, using a test with picric acid (Sarin, Kent, Tain and Merrifield, (1981) Anal. Biochem. 117, 145-157), or quantitative ninhydrin analysis (Gisin (1972) Anal. Clum. Acta 58, 248-249). Unreacted Aksinya group block, using a mixture of 0.5 M trimethylacetylchloride/0.5 M diisopropylethylamine in DMF for 2 hours removing the protective group BOC carried out using 25% TFUK in dichloromethane, time of hydrolysis 30 minutes the Rest of iminocyclitol the first derived amino acids or amino acids) corresponding to amino acids or derivatives of amino acids and HBTU in approximately 8 ml of DMF. Then the resin is neutralized in situ with three equivalents of NMM (based on the used amount of amino acids); the synthesis time is from 1 hour before the time remaining until the morning. The completeness of the reaction determine the qualitative ninhydrin analysis or test with picric acid in cases where the amino acid is associated with a secondary amino group. Based on these results, if necessary, re-connection of amino acids.

After assembling the linear peptide N-terminal Boc-group is removed, processing 25% TFUK in dichloromethane for 30 minutes and Then the resin is neutralized, making it 10% DIEA in dichloromethane. Cyclization with simultaneous cleavage of the peptide from the resin is performed by the method Osapay and Taylor (1990) J. Am, Chem. Soc. 112, 6046), suspending the resin in about 10 ml (1 g resin) DMF, adding one equivalent of HOAc (based on the loading of the first amino acids), and stirring at 50oC for 60-72 hours After filtration the filtrate (solution in DMF) evaporated, the residue is dissolved in HOAc or in a mixture of acetonitrile-water composition 1: 1, and lyophilized, receiving protected cyclic product. For removal of the protective groups of the side chains of this product is treated according to standard procedures anhydrous fatal, at a temperature of 0oC for 20-60 minutes the crude product can be purified by the method jhud with reversed phases using preparative 2,5 cm column of Vydac C18 with a linear gradient of acetonitrile containing 0.1% TFUK, obtaining pure cyklinowanie material. For syntheses by the described method can be used the following amino acids, -amino group of which is protected Boc-group: Boc-Atg(Tos), Boc-N - a-MeArg(Tos), Boc-Gly, Boc - Asp(OcHex), Boc-D-Leu, Boc-D-Val, BOC-D-2-aminobutyric acid (Boc-D-Abu), Boc-Phe, Boc-D-Ser(Bzl), Boc-D-Ala, Boc-C-aminomethylbenzoic acid (Boc-Mamb), Boc-D-Lys(2-ClZ), Boc - b-Ala, Boc-D-Pro, Boc - NMeGly.

The synthesis of compounds of the present invention is illustrated further by means of examples. In table. 1-6 presents representative compounds of the present invention.

Example 1

Cyclo- (Gly-NMeArg-Gly-Asp-Mamb); J Gly, NMeArg, L Gly, M Asp, R1R2H

(Identification sequence N 1)

The target connection receive, using the General method described below for cyclo- (D-Val-NMeArg-Gly-Asp-Mamb). Get 0,336 mmol linear peptide cyclist in the protected cyclic peptide (218 mg, 84%). 200 mg of the peptide and 200 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. Not the e in the form of a solid pale yellow color (158 mg, output exceeds the quantitative calculation was made for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 2 to 11% at a speed of 0,23%/min, and lyophilization obtained after chromatography of the product. Get the target product in the form of triptoreline (fluffy solid white color output when cleaning up 21% of the total yield of 16.3%). Mass spectrum: M+H 533,26.

Example 2

Cyclo-(D-Ala-NMeArg-Gly-Asp-Mamb);J is D-Ala, NMeArg, L Gly, M Asp, R1R2H

The target connection receive, using the General method described below for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). It was found that it is necessary to re-joining the rest of Boc-N-MeArg(Tos). Get 0,244 mmol linear peptide cyclist in the protected cyclic peptide (117 mg, 61%). This peptide (110 mg) and 110 ml of m-cresol treated at 0oC for 1 h, anhydrous hydrogen fluoride. The crude material periostat from the ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target compound as a pale yellow solid. Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetone the project product. Get the target compound as a fluffy solid white color (in the form of triptoreline). Mass spectrum: M+H 547,23.

Example 3

Cyclo-(D-Abu-NMeArg-Gly-Asp-Mamb);J is D-Abu, NMeArg, L Gly, M Asp, R1R2H

The target connection receive, using the General method described below in example 4. Get 0,101 mmol linear peptide cyclist in the protected cyclic peptide (51 mg, 63%). This peptide (43 mg) and 50 μl of m-cresol treated at 0oC for 30 min anhydrous hydrogen fluoride. The crude product is recrystallized from ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target compound in the form of solid pale yellow color (23 mg, 68.7 per cent of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 7 to 14% at a speed of 0,23%/min, and lyophilization obtained after chromatography was carried out product. Get triptorelin target compound as a fluffy solid white (output when cleaning up 31% of the total yield of 12.4% ). Mass spectrum: M+H 561,46.

Example 4

Cyclo- (D-Val-NMeArg-Gly-Asp-Mamb); J is D-Val, NMeArg, L Gly, M Asp, R1R2H

In HBTU (0,194 g, 0.5 mmol), oximo resin (0.52 g, degree of substitution, 0.96 mmol/g) and N-methylmorpholin (0,165 ml, 1.50 mmol). The resulting suspension is stirred at room temperature for 24 hours and Then the resin is thoroughly washed (by volume of 10-12 ml) and DMF (three times), MeOH (once), dichloromethane (three times), MeOH (twice) and dichloromethane (three times). The degree of substitution, certain quantitative ninhydrin analysis is 0,389 mmol/g of Unreacted Aksinya block group by treatment with a mixture of 0.5 M trimethylacetylchloride/0.5 M DIEA in DMF for 2 h

Then carry out the following stages: (stage 1) the Resin was washed with DMF (three times), MeOH (1 times), dichloromethane (three times), MeOH (twice) and dichloromethane (three times). (Stage 2) Remove the protective tert.-butoxycarbonyl group, using a 25% TFUCK. In dichloromethane for 30 minutes (stage 3) the Resin was washed with dichloromethane (three times), MeOH (once), dichloromethane (twice), MeOH (twice) and DMF (three times). (Stage 4) add To the resin 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), and conducting the reaction for 2.5 hours (stage 5) Quantitative ninhydrin analysis shows that the reaction of accession (doubling) was completely. Stage 1 - 5 repeat until, until at the Auteuil. After assembling the linear peptide tert. -Boc group of the N-Terminus is removed by processing 25% TFUK in dichloromethane (30 min). The resin is washed thoroughly with dichloromethane (3 times), MeOH (2 times) and dichloromethane (3 times), and then neutralized with 10% DIEA in dichloromethane (2 times for 1 min). The resin is washed thoroughly with dichloromethane (3 times) and MeOH (Once), and then dried. For cyclization take half of the resin (0,101 mmol); the cyclization is carried out, processing 6 ml of DMF containing HOAc (5,8 μl, 0,101 mmol) and heating at 50oC for 72 hours and Then the resin is filtered off and washed thoroughly with DMF. DMF-filtrate evaporated to the consistency of oil, dissolve it in a mixture of acetonitrile/water 1:1, and lyophilized, receiving the protected cyclic peptide (49 mg, 69%). This peptide (42 mg) at 0oC is treated with anhydrous hydrogen fluoride in the presence of m-cresol as a scavenger for 30 min, removing in this way the protective groups of the side chains. The crude product is planted with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target compound in the form of solid pale yellow color (23 mg, 70% calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) with the use of the compounds in the form of a solid fluffy white matter (output when cleaning up 24% of the total yield of 9.4%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 575,45.

Example 5

Cyclo-(D-Leu-NMeArg-Gly-Asp-Mamb);J is D-Leu, NMeArg, L Gly, M Asp, R1R2H

The target connection receive, using the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,115 mmol linear peptide cyclist in the protected cyclic peptide (92,4 mg, 98%). Peptide (92,4 mg) and 93 μl of m-cresol treated at 0oC for 20 min anhydrous hydrogen fluoride. The crude product is planted with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (of 45.7 mg, 63%), the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1 TFUK, from 7 to 21% at a speed of 0,23%/min, and lyophilization obtained by chromatographicaliy product. Get triptorelin target compound as a fluffy solid white (output when cleaning up 29% of the total yield of 16.5%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 589,48.

Example 13f

Cyclo-(D-Lys-NMeA-rg-Gly-Asp-Mamb); J is D-Lys, NMeArg, L Gly, M Asp, R1R2H

The target connection receive, using the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). For fixing Boc-Mamb resin COI is ical peptide (349 mg, 58,9%). Peptide (334 mg) and 334 μl of anisole at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude product is planted with ether, dissolved in aqueous acetonitrile and lyophilized, obtaining the target product in the form of a solid pale yellow color (168 mg, 79.1% the calculation for diferida). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 5.4 to 14.4% at the rate of 0.23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 33.6% of the total yield of 12.1%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 604,32.

Example 18

Cyclo-(NMeGly-NMeArg-Gly-Asp-Mamb); J NMeGly, NMeArg, L Gly, M Asp, R1R2H

(Identification of sequence No. 6)

The target connection receive, using the General method described above for cycle-(D-Val-NMeArg-Gly-Asp-Mamb). For fixing Boc-Mamb on oximes resin used method using DCC/DMAP. Receive 0.43 mmol linear peptide cyclist in the protected cyclic peptide (205 mg, 60%). The peptide (200 mg) and 200 μl of m-cresol at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude material planted ether, rest the t for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 7 to 22% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning 14.7% of the total yield of 7.9%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 547,34.

Example 24

Cyclo-(Pro-NMeArg-Gly-Asp-Mamb); J Pro, NMeArg, L Gly, M Asp, R1R2H

(Identification sequence N 3)

The target connection get in the way described above for cyclo - (D-Val-NMeArg-Gly-Asp-Mamb). For fixing Boc-Mamb on oximes resin using the method with DCC/DMAP. Receive 0.43 mmol linear peptide cyclist in the protected cyclic peptide (170 mg, 48,8%). Peptide (164 mg) and 164 mmol m-cresol at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude product is planted with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid, pale yellow (101 mg, 79% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 7 to 22% at a speed of 0,23%/min, and lio is ETA (output when cleaning 5.8% of the total yield of 2.1%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 573,46.

Example 25

Cyclo-(D-Pro-NMeArg-Gly-Asp-Mamb);J is D-Pro, NMeArg, L Gly, M Asp, R1R2H

The target connection get in the way described above for cyclo- (D-Val-NMeArg-Gly-Asp-Mamb). For fixing Boc-Mamb on oximes resin using the method with DCC/DMAP. Receive 0.43 mmol linear peptide cyclist in the protected cyclic peptide (211 mg, 60.8 per cent). The peptide (200 mg) and 200 μl of m-cresol at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude material is then precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid, pale yellow (145 mg, 93.3% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 7.0 to 22.0% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 6.4% of the total yield of 3.3%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 573,35.

Example 28C

Cyclo-(b-Ala-NMeArg-Gly-Asp-Mamb);J b-Ala, NMeArg, L Gly, M Asp, R1R2H

(Identification sequence N 2)

The target connection get the General method described above for cyclo-(D-V is putida, which cyclist in the protected cyclic peptide (264 mg, 57.5%, respectively). Peptide (258 mg) and 258 μl of anisole at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude material is planted with ether, dissolved in aqueous acetonitrile and lyophilized, obtaining the target product in the form of a solid pale yellow color (231 mg, yield exceeded quantitative calculation for fluoride). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 5.4 to 14.4% at the rate of 0.23%/min, and lyophilization. Get the target substance in the form of a fluffy solid white (output when cleaning 53.2% of the total yield of 32.5% triptorelin). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 547,28.

Example 29

Cyclo-(Gly-Arg-Gly-Asp-Mamb); J Gly, Arg, L-Gly, M Asp, R1R2H

(Identification of sequence No. 5)

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,283 mmol linear peptide; half of that amount cyclist, receiving the protected cyclic peptide (62 mg, 58% ). Peptide (60 mg) and 60 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product planted the th color (48 mg, output exceeds the quantitative calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 0 to 9% at a speed of 0.30%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 36% of the total output of 19.9 per cent ). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 519,26.

Example 30

Cyclo-(D-Ala-Arg-Gly-Asp-Mamb);J is D-Ala, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,189 mmol linear peptide cyclist, receiving the protected cyclic peptide (211 mg, yield exceeded quantitative). Peptide (195 mg) and 195 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product is planted with ether, dissolved in HOAc and lyophilized, obtaining the target product in the form of a solid pale yellow color (125 mg, 83% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 2 to 11% at a speed of 0,23%/min, and lyophilization. The floor is% of total output - 13,8%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 533,26.

Example 31

Cyclo-(Ala-Arg-Gly-Asp-Mamb); J Ala, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,324 mmol linear peptide cyclist in the protected cyclic peptide (191 mg, 76,4%). The peptide (100 mg) and 100 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product is planted with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target compound in the form of solid pale yellow color (75 mg, 97.4% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUCK. from 2 to 11% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning 15.5% of the total yield of 10.5%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 533,25.

Example 32

Cyclo-(D-Val-Arg-Gly-Asp-Mamb); J is D-Val, K. Arg, L-Gly, M Asp R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Receive rate of 0.193 mmol linear peptide cyclist in the protected cyclic peptide (199 m is one of fluoric hydrogen. The crude product is planted with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (130 mg, 86% calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 2 to 13% at the rate of 0.23%/min, and lyophilization. Get triptorelin compound as a fluffy solid white (output when cleaning up 57% of the total output to 58.1%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 561,22.

Example 33

Cyclo-(D-Leu-Arg-Gly-Asp-Mamb); J is D-Leu, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,202 mmol linear peptide cyclist in the protected cyclic peptide (152 mg, 93%). Peptide (150 mg) and 150 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product is precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (78 mg, 66% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of ACE what about the connection in the form of fluffy solid white (output when cleaning up 26% of the total yield of 14.8%). MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 575,45.

Example 34

Cyclo-(D-Abu-Arg-Gly-Asp-Mamb); J is D-Abu, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Receive rate of 0.193 mmol linear peptide cyclist in the protected cyclic peptide (210 mg, yield exceeded quantitative). Peptide (206 mg) and 206 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product is precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (158 mg, 99% calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUCK. from 2 to 11% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 57% of total output, accounting for 72.2%).

MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 547,21.

Example 35

Cyclo-(D-Ser-Arg-Gly-Asp-Mamb); J is D-Ser, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Receive rate of 0.193 mmol linear peptide cyclist in ZAR>C for 1 h, treated with anhydrous hydrogen fluoride. The crude product is precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid, pale yellow (145 mg, 89% calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 2 to 13% at the rate of 0.23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 22% of the total yield 27%).

MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 549,31.

Example 36

Cyclo-(D-Phe-Arg-Gly-Asp-Mamb); J is D-Phe, Arg, L-Gly, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,266 mmol linear peptide cyclist in the protected cyclic peptide (202 mg, 90%). Peptide (157 mg) and 157 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude product is precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (125 mg, yield exceeded quantitative calculation for the acetate salt). Cleaning is onitrile, containing 0.1% TFUK, from 7 to 23% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning 35% of the total yield for 29.3%).

MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H 609,25.

Example 37

Cyclo-(Phe-Arg-Gly-Asp-Mamb); J Phe, Arg, L-Gly, M Asp, R1R2H

(Identification sequence # 4)

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). Get 0,335 mmol linear peptide cyclist in the protected cyclic peptide (306 mg, yield exceeded quantitative). Peptide (275 mg) and 275 μl of m-cresol at 0oC for 1 h, treated with anhydrous hydrogen fluoride. The crude material is then precipitated with ether, dissolved in aqueous HOAc, and lyophilized, obtaining the target product in the form of a solid pale yellow color (214 mg, 98% of the calculation for the acetate salt). Cleanup is completed jhud with reversed phase preparative column (Vydac C18 (2.5 cm) using a gradient of acetonitrile containing 0.1% TFUK, from 9 to 230/0 at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning up 32% of the total yield of 31.5%).

< / BR>
Examples 42-45

The synthesis of compounds of examples 42-45 presented in figure 5.

Examples 46 and 47

Compounds of examples 46 and 47 receive, using standard methods, for example, described in Tett. Lett. (1990) 31:1969-1972 or patent Canada 2008311, in accordance with scheme 6. To avoid side reactions aspartic acid group may be protected, for example, finalley protecting group.

Example 54

Cyclo-(D-Val-NMeArg- -Ala-Asp-Mamb); J is D-Val, NMeArg, L b-Ala, M Asp, R1R2H

The target connection get the General method described above for cyclo-(D-Val-NMeArg-Gly-Asp-Mamb). For fixing Boc-Mamb on oximes resin using the method with DCC/DMAP. Get 0,586 mmol linear peptide cyclist in the protected cyclic peptide (227 mg, 46.9 per cent). Peptide (219 mg) and 219 μl of anisole at 0oC for 30 min, treated with anhydrous hydrogen fluoride. The crude material is planted with ether, dissolved in aqueous acetonitrile and lyophilized, obtaining the target product in the form of a solid pale yellow color (150 mg, 93.2% of the calculation for ftory the rate of acetonitrile, containing 0.1 TFUK, from 7.2 to 16.2% at a speed of 0,23%/min, and lyophilization. Get triptorelin target compound as a fluffy solid white (output when cleaning 43,6% of the total yield of 16.5%

MS-THE BELARUSIAN LIBRARY ASSOCIATION: M+H=589,32.

Examples 55-58

The synthesis of compounds of examples 55 to 58 shown in scheme 7.

Test platelet aggregation: Venous blood taken from the arm of a healthy person (the donor) who were not taking medication and aspirin for at least two weeks before blood sampling. Blood is taken in 10-ml nitrate test tube Vacutainer. The blood is centrifuged for 15 min at 150 x g at room temperature, after which select the platelet-rich plasma (BTP). The remaining blood is centrifuged for 15 min at 1500 x g, and then select the platelet-poor plasma (Bdtp). Samples tested on aragonite (PAP-4 Platelet Aggregation Profiler), using BDP as the zero reference point (100% transmittance). In each microprobing for testing add 200 ál of BTP, and take transmittance at 0% In each tube add 20 µl of various substances with affinity to receptors (ADP, collagen, arachidonate, epinephrine, thrombin), and log aggregation curves (dependence% transmission mi affinity to the receptors. To determine the IC50the test compound is added in different concentrations prior to activation of platelets.

Test the binding of Fibrinogen to platelets: Binding125I fibrinogen with platelets is carried out in accordance with the method described by Bennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, while introducing some modifications, which are described below. BTP person (h-BTP) is passed through a column of Sepharose purification fractions of platelets. Aliquots of platelets (5108cells) together with 1 mm of calcium chloride added to a Cup containing 96 deleted cells, before activating gel-purified human platelets (h-GOTH). The activation of h-THAT is carried out using ADP, collagen, arachidonate, epinephrine and/or thrombin in the presence of ligand -125I-fibrinogen. Associated with activated platelets fibrinogen is separated from unbound fibrinogen by centrifugation and determine the radioactivity of gamma counters. To determine the IC50the test compound is added in different concentrations prior to activation of platelets.

Dosing and dosage forms

Compounds of the present invention can be introduced into the body in any way that may create con is the future. They can be introduced by any known method, available for the use of drugs, as individual therapeutic agents or in combination with other therapeutic agents such as, for example, the second protivotrevozhny agent, such as aspirin or ticlopidine, which are specific for certain substances having affinity to the receptors. They can be introduced in pure form, but as a rule, are introduced together with a pharmaceutical carrier which determines, on the basis of the chosen route of administration and generally accepted pharmaceutical practice.

Enter the dose, of course, varies depending on a number of factors such as the pharmacodynamic characteristics of the particular agent and the path and method of administration; age, health and weight of the recipient; nature and extent of symptoms; kind of concomitant therapeutic treatment; the frequency of therapeutic effects and the desired effect. Daily dose of active ingredient may range from about 0.01 to about 10 mg per kilogram of body weight.

Dosage forms (compositions suitable for administration contain from about 1 mg to about 100 mg of the active ingredient at a dosage of a single the olo 95% of the total weight of the composition.

The active ingredient can enter the oral route in the form of solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. They can also enter parenterally, in the form of a sterile liquid dosage.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used for the manufacture of compressed tablets. And tablets, and capsules can be designed as a system of prolonged isolation, providing prolonged release of active ingredient for hours. Molded tablets may be coated with sugar or film for masking the unpleasant taste and protect the tablet from the weather, or covered intersolubility membrane, which is selectively destroyed in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain color and aromatic additives to make it more attractive.

Generally, suitable carriers for parenteral RA is market related sugars, as well as glycols, such as propylene glycol and polyethylene glycol. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffer compounds. Suitable stabilizing compounds are antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, individually or in combination with each other. Also used citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzylaniline, methyl - or propyl-paraben and chlorbutanol.

Suitable pharmaceutical carriers are listed in Remington's Pharmaceutical Sciences, Mack Publishing Company, which is widely cited source in this field of technology.

Preferred pharmaceutical dosage forms for administration of the compounds of the present invention are illustrated below.

Capsules

Prepare a large number of capsules, filling standard two-part hard gelatin capsules 100 mg of powdered active ingredient, 150 ml of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft butter, such as soybean oil, cotton or olive oil. This mixture is injected through the injection pump into gelatin, getting soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

Tablets

Standard methods of preparing a large number of tablets, each containing 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. The tablets can be coated, designed to improve the taste or to slow down the absorption of the active ingredient.

In the following table. 1-8 typical representatives of the compounds of the present invention.

The biological activity of all compounds listed as the definition of the IC50in the test for platelet aggregation. Determine the IC50expressed as + + + <1 μm, + + 1 ám + 10 ám and 100 ám, where µm denotes makromolekulare.

1. The cyclic peptides of the formula I

< / BR>
or their pharmaceutically acceptable salt,

where R1H, C1C4-alkyl, phenyl, benzyl;

R2H or lower alkyl;

R10H, halogen; n 1, n,0;

j D-Ala, D-Yal, anomalina acid, D - 2-aminopentanoic Gly, N-p-azidobenzoyl-D-Lys, N- p-benzoylbenzoate-D-Lys, N-p-azidobenzoyl-D-Lys, N- dansyl-D-Lys, N-t-butoxycarbonylmethyl-D-Lys, N-glycyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N-p-vinylbenzyl-D-Lys, N-m-benzoylmethyl-D-Lys or N-o-benzoylbenzoate-D-Lys;

K is NMeArg, NN-Dima-N-guanidino, N-MeLys or NN-Lys;

L is Gly;

M is chosen from Asp, - MeAsp or NMeAsp.

2. Peptides under item 1,

where R1H, C1C4-alkyl, phenyl, benzyl;

R2H or methyl;

R10H, halogen;

j D-Ala, D-Val, D - Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-Lys, D-Orn, D - Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D - Gly, D-Norvaline, D-2-aminobutyric acid, D-2-aminopentanoic Gly, N-p-azidobenzoyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N-p-azidobenzoyl-D-Lys, N-dansyl-D-Lys, N-t-butoxycarbonyl-glycyl-D-Lys, N-glycyl-D-Lys, N- p-benzoylbenzoate-glycyl-D-Lys, N-p-vinylbenzyl-D-Lys, N- m-benzoylmethyl-D-Lys and the n, N-MeLys or NN-MeLys;

L GIy;

M is selected from Asp-MeAsp or NMeAsp.

3. Peptides under item 2,

where R1H, C1C4-alkyl, phenyl, benzyl;

R2H or methyl;

R10H, halogen;

j D Ala, D-Val, D-Ile, D-Leu, D-Nle, D Gly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, N- p-azidobenzoyl-D-Lys, N-p-benzoylbenzoate-D - Lys, N- p-azidobenzoyl-D - Lys, N-dansyl-D - Lys, N-t-butoxycarbonyl glycyl-D-Lys, N-glycyl-D-Lys, N-p-benzoylbenzoate-D-Lys, N- p-vinylbenzyl-D-Lys, N-m-benzoylmethyl-D-Lys or N- O-benzoylbenzoate-D-Lys;

K is NMeArg,

L GIy;

M is selected from Asp - MeAsp or NMeAsp.

4. Peptides under item 2,

where R1and R2independently selected from H or methyl;

R10H;

j is selected from D-Val, D-2-aminobutyric acid, D Leu, D Ala, D - Pro, D-Ser, D-Lys-Ala, NMeGly, D-Nle, D-Gly, D-Ile, D-Phe, D - Tyr;

K is NMeArg;

L is Gly;

M is selected from Asp-MeAsp or NMeAsp.

5. Peptides under item 2, which is selected from the group of compounds in which R1, R2and R1P>, R2and R10represent H;

j D-2-aminobutyric acid;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D Leu;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D Ala;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D Pro;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1methyl (isomer I);

R2and R10H;

j D Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1methyl (isomer 2);

R2and R10H;

j D Yal;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I

where R1phenyl (isomer I);

R2and R10H;

j D Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D Met;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-2-aminomalonate formula I,

where R1, R2and R10H;

j D-2-aminobutyric acid;

K NN-MeLys,

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N- p-azidobenzoyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-n-benzoylmethyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-tryptophanyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-o-benzylbutyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N- p-acetylbenzoic-D-LyS;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-dansyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-glycyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R formula I,

where R1, R2and R10H;

j N- p-vinylbenzyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-m-benzoylmethyl-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N- o-benzoylbenzoate-D-Lys;

K is NMeArg;

L is Gly;

M Asp;

connection frmula I,

where R1, R2and R10H;

j D-Nle;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-Gly;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-Ile;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-Phe;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R104-Cl;

j D Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R104-J;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;


where R1and R2H;

R104-Me;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R106-Cl;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compound of formula I,

where R1and R2H;

R106-methoxy;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R106-Me;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R104-CI;

j D-2-aminobutyric acid;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R104-J;

j D-2-aminobutyric acid;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1and R2H;

R104-Me;

j D-2-aminobutyric acid;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-Tyr;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j is D-Val;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

inane formula I,

where R1, R2and R10H;

j D-Gly;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j N-t-butoxycarbonylmethyl-D-LyS;

K is NMeArg;

L is Gly;

M Asp;

the compounds of formula I,

where R1, R2and R10H;

j D-Ser;

K is NMeArg;

L is Gly;

M Asp.

6. Peptides under item 1,

where R1H, C1C4-alkyl, phenyl;

R2H or methyl;

R10H, halogen;

j D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-Gly, D-Phe, D-LyS, D-Orn, D-Met, D-Pro-Ala, D-Tyr, D-Ser, NMeGly, D-Gly, D-Gly, D-Norvaline, D-2-aminobutyric acid, D-2-aminopentanoic acid Gly, N- p-azidobenzoyl-D-Lys;

K NN-Dima-N-guanidino, N- MeLys;

L is Gly;

M from Asp-MeAsp or NMeAsp.

7. Peptides on p. 6,

where j denotes the D - Ala, D-Val, D-Ile, D-Leu, D-Pro, D-Ser or D-Lys.

8. Pharmaceutical composition having the ability to inhibit the action of platelets, comprising as active principle derived peptide, characterized in that the quality of the derived peptide it contains an effective amount of cyclic pepti

 

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,

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