Neuromedin and somatostatin receptor agonists

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention claims new compounds that elicit both high affinity and selectivity with respect to neuromedin B and somatostatin receptors. Compounds has the following formula: wherein α-atom in each group among AA1, AA2, AA3, AA4, AA5, AA6, AA7 and AA8 is substituted optionally and independently with (C1-4)-alkyl-(C3-4)-alkenyl, (C3-4)-alkynyl or (C1-6))-alkyl-C(O)-; AA1 is absent or means Ac-D-Phe or D- or L-isomer of R11, Pip, Pro or aromatic α-amino acid taken among the group consisting of Cpa, Dip, Nal and Phe; AA2 is absent or means Pal, Phe, Tyr; AA3 means D- or L-isomer of Cys; AA4 means D- or L-isomer of Trp; AA5 means Lys; AA6 means D- or L-isomer of Cys; AA7 is absent or means A3c, A4c, A5c, A6c, Abu, Aic, β-Ala, Gaba, Nle, Pro, Sar, Thr, Thr(Bzl) or Val; AA8 is absent or means R11, Nal, Thr, Tyr, Phe or Nle; each among R1 and R2 represents independently hydrogen atom (H) or absent; R5 means -NH2,; R11 means D- or L-amino acid independently in each case and AA3 and AA6 are bound by disulfide bond.

EFFECT: valuable biological properties of compounds.

9 cl, 2 tbl, 1 ex

 

Background of the invention

Peptides related bombezin (Bn) mammalian gastrin-releasing peptide (GRP) and neuromedin In (NMB), have a wide range of biological and pharmacological effects. These effects include stimulation of the release of numerous gastrointestinal hormones and peptides, stimulation of the secretion of exocrine glands, chemotaxis, contraction of smooth muscles, the effects in the Central nervous system, such as thermoregulation, behavioral effects, maintaining circadian rhythm, inhibition of TSH release and satiety. Peptides related Bn, also function as growth factors in many normal cells (for example, bronchial cells, endometrial cells of the stoma and the cells T) , as well as neoplastic cells, such as cells, small-cell lung cancer human cells hepatocellular tumors in rats, prostate cells and cells of adenocarcinomas of the mammary gland.

Recent studies of structure-function and cloning showed that at least two classes of receptors mediate the action of peptides, related to Bn. One class is a subtype, preferably linking fiberglass (GRP receptor or GRP-R), has a high affinity to the GRP and low affinity for NMB, while another class is a subtype, preferably linking NMB (NMB receptor or NMB-R), has the high affinity for NMB and low affinity to the GRP. Both classes of receptors are widely presented in the Central nervous system and gastrointestinal tract. Until recently it was unclear physiological significance of peptides related Bn, in mediating various processes, and which receptor subtype mediates various biological effects of the peptides related Bn reported.

Describes five different classes of antagonists Bn-receptor. Jensen, R.. et al. Trends Pharmacol. Sci. 12: 13 (1991). Representatives of this set of classes have high efficiency, long duration of action and selectivity with respect to the GRP receptor and, thus, suitable even for identifying the role of GRP or GRP receptors in mediating various physiological effects in vivo. Currently, however, described a few of the NMB receptor antagonists that are sufficiently selective or effective. (See, for example, Coy, D., and Taylor, J., U.S. patent 5462926). In addition, NMB was involved in the inhibition of lung cancer and glioma. Cancer Res 1991 Oct 1, 51: 19, 5205-11; J. Cell Biochem. Suppl. 1996, 24: 237-46, Peptides 1995, 16: 6, 1133-40; J. Pharmacol. Exp. Ther. 1992 Oct 263: 1, 311-7), stimulation of appetite (Eur. J. Pharmacol. 1994 Dec 12, 271: 1 R7-9; Am. J. Physiol. 1997 Jan. 272: 1 Pt 2 R433-7; Pharmacol. Biochem. Behav. 1996 Aug 54: 4 705-11), stimulation of the secretion of TSH (hypothyroidism) (Regul. Pept. 1996 Nov 14, 67: 1, 47-53) and inhibition of secretion of aldosterone (giperaldosteronizm) (Histol. Histopathol. 1996 Oct. 11: 4, 895-7). So about what atom, compounds according to this invention is suitable for studies of the physiological role played by the NMB, and for the development of therapeutic compositions for the treatment of symptoms associated with NMB.

As is well known in this field, agonists and antagonists of the somatostatin useful in the treatment of various medical conditions and diseases, such as inhibition of proliferation N. pylori, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external or internal false cyst and the pancreatic ascites, Vipoma, hyperplasia of pancreatic islets, hyperinsulinism, gastrinoma syndrome Zollinger - Ellison, diarrhea, diarrhea associated with AIDS, diarrhea associated with chemotherapy, scleroderma, irritable bowel syndrome, pancreatitis, obstruction of the small intestine, gastroesophageal reflux, duodenogastric reflux, and in the treatment of endocrinological diseases and/or conditions such as Cushing's syndrome, gonadotropinum, hyperparathyroidism, graves ' disease, diabetic neuropathy, Paget's disease, and polycystic disease ovary; in the treatment of various types of cancer such as thyroid cancer, hepatoma, leukemia, meningioma, and conditions associated with cancer, such as cancer cachexia; in the treatment of such conditions as hypotension, such as orthostatic hypotension and postprandial who ipotence, and States with the reaction of panic; adenomas secreting GH (acromegaly) and adenomas secreting TSH. Activation of the receptor subtype type 2 but not type 5, was associated with the treatment of adenomas secreting prolactin. Other manifestations associated with activation of subtypes of somatostatin, are inhibition of insulin and/or glucagon, and more specifically diabetes, hyperlipidemia, insensitivity to insulin, syndrome X, angiopathy, proliferative retinopathy, the phenomenon of "dawn" and nephropathy; inhibition of gastric secretion of acid, and more specifically, peptic ulcers, intestinal, skin and skin-pankreaticescoy fistula, dumping syndrome, water diarrhea, acute or chronic pancreatitis and tumor secreting gastrointestinal hormones; inhibition of angiogenesis, treatment of inflammatory diseases such as arthritis; chronic reaction rejection of allogeneic transplant; plastic surgery on vessels, the prevention of bleeding in vascular transplantation, and gastrointestinal bleeding. Agonists of somatostatin can also be used to reduce the body weight of the patient. Accordingly, the compounds according to the present invention is suitable for the above-mentioned methods.

Recently it was reported that native somatostatin (SS), somatostatin-14 (SS-14), inhibited cross with Azania 125I-GRP protein with 120 Mm CD in tritanopic extracts of cells T cell and small-cell lung cancer people who are known to have receptors bombezin. Recent studies have also shown that SS-14 may weakly inhibit binding to opiate receptors, and subsequent research on the interconnections between structure and function has led to the identification of various substituted D-amino acids and substituted limited amino acid cyclic analogues of somatostatin, which function as effective antagonists of opioid mu receptor.

Everything mentioned here patents and publications hereby incorporated by reference in full.

The INVENTION

This invention relates to a series of analogs with unique structural features and method of selective modulation of biochemical activity of cells induced by somatostatin and/or neuromedin Century

In one aspect the direction of the present invention is a compound of formula (1)

or its pharmaceutically acceptable salt, where α-nitrogen each AA1, AA2, AA3, AA3b, AA4, AA5, AA6, AA7, AA7band AA8independently optionally substituted C1-4)alkyl, (C3-4alkenyl, (C3-4)quinil or (C -6)alkyl-C(O)-;

AA1is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aac, Aic, Arg, Asn, Asp, Dip, Gln, Glu, Hca, Hyp, Lys, Mac, Macab, Orn, Pro, Ser, Ser(Bzl), Thr, Thr(Bzl), Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, lia, Alla, Aba, Gba, Car, Ipa, laa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua, the Ruhr, and optionally substituted aromatic α-amino acids;

where specified optionally substituted aromatic α-amino optionally substituted by one or more substituents, each of which is independently selected from the group consisting of halogen, NO2HE, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, (C1-6)alkoxygroup, Bzl, O-Bzl and NR9R10;

AA2is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aic, Arg, Hca, His, Hyp, Pal, F5-Phe, Phe, Pro, Trp, and X0-Phe, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, lia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua and the Ruhr;

AA3is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tpa, Tmpa, Mac, Macab, and optionally substituted aromatic α-amino acids;

where specified optionally substituted aromaticity the α -amino optionally substituted by one or more substituents, each of which is independently selected from the group consisting of halogen, NO2HE, CN, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)quinil, (C1-4)alkoxygroup, Bzl, O-Bzl, NR9R10, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, Iia, Alla, Aba, Gba, Car, Ipa, laa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua and the Ruhr; AA3bis missing or D - or L - isomer amino acids selected from the group consisting of Pal, 4-Pal, His, Arg, Nal, Trp, Bpa, F5-Phe, Phe, X0-Phe, R11, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala and Pala;

AA4is D - or L - isomer optionally substituted amino or optionally substituted aromatic α-amino acids ;

where specified optionally substituted amino acid selected from the group consisting of Trp, Lys, Orn, hLys, Cys-4-Acha, TRANS-4-Acha, TRANS-4-Amcha, 4-Pip-Gly, N-Met-Trp, β-Met-Trp, His, hHis, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and 4-Pip-Ala; where the amino group of the side chain of the specified optional substituted amino acids optionally substituted R3and R4;

and where specified optionally substituted aromatic α-amino optionally substituted by one or more substituents, each of which is independently selected from the group comprised the soup from halogen, NO2HE, CN, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)quinil, Bzl, O-Bzl and NR9R10;

AA5is missing, R11, Aic, As, As, As, As, Abu, Aib, β-Ala, Bpa, Cha, Deg, Gaba,Ile, Leu, Nal, Nle, Pro, Sar, Ser, Ser(Bzl), Thr, Thr(Bzl), Trp, Val, Pal, F5-Phe, Phe, X0-Phe or optionally substituted D - or L - isomer amino acids selected from the group consisting of 4-Pip-Gly, 4-Pip-Ala, Cys-4-Acha, TRANS-4-Acha, TRANS-4-Amcha, hLys, Lys, Orn, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala and Pala; where the amino group of the side chain of the specified optionally substituted by amino optionally mono - or tizamidine R3and R4;

AA6is missing or D - or L - isomer amino acids selected from the group consisting of R11, optionally substituted aromatic α-amino acids, Cys, hCys, Pen, Tpa, Tmpa, Thr, Thr(Bzl), Ser, Ser(Bzl), hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala and Pala;

AA7is missing or D - or L - isomer amino acids selected from the group consisting of R11, optionally substituted aromatic α-amino acids, As, As, As, As, Abu, Aib, Aic, β-Ala, Arg, Cha, Deg, Gaba, Ile, Leu, Nle, Pip, Pro, Sar, Ser, Ser (Bzl), Thr, Thr (Bzl), Val, Tic, Htic, Sala, Aala, Thza, Thia, Bal, Fala, Pala, hArg, Bip, Bpa, Dip, Pal, Sala and X0-Phe;

AA7bis missing or D - or L-isomer amino acids selected from the group consisting of R11, Bpa, Phe, F5Is Phe, X0-Phe, Nal, Pro, Ser, Ser (Bzl), Thr, Thr (Bzl), Trp, hArg, Bip, Tic, Htc, Dip, Sala, Aala, Thza, Thia, Bal, Fala and Pala;

AA8is missing or D - or L - isomer amino acids selected from the group consisting of R11, Maa, Maaab, Thr, Thr(Bzl), Ser, Ser(Bzl), Tyr, Phe(4-O-Bzl), F5-Phe, and X5-Phe, and optionally substituted aromatic α- amino acids;

each of R1and R2independently represents H, E-, E(O)2S-, E(O)C-, EOOC, R13or missing;

each of R3and R4independently is a (C1-12) alkyl, (C2-12)alkenyl, (C2-12)quinil, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)quinil, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)quinil, (cyclo(C3-7)alkyl)-(C1-6)alkyl, (cyclo(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(C2-6)quinil, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)quinil, 1-substituted, 2-substituted 9-fluorenylmethyl, dicyclopropyl, dimethylcyclopropene or benzhydryl;

R5is-OR6, -NR7R8or missing; where each R6, R7and R8independently represents H, (C1-12)alkyl, (C2-12)alkenyl, (C2-12)quinil, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)quinil, naphthyl-(C1-6)alkyl, n is ftil-(C 2-6)alkenyl, naphthyl-(C2-6)quinil, 1-substituted, 2-substituted 9-fluorenylmethyl, dicyclopropyl, dimethylcyclopropene or benzhydryl;

each R9and R10independently represents H, (C1-6)alkyl, (C3-4)alkenyl, (C3-4)quinil, 1-substituted or 2-substituted;

R11independently for each case is D - or L - amino acid of the formula:

where each of m and n independently is 1, 2 or 3, and p is 0, 1 or 2;

R12independently for each case is optionally substituted by a fragment of the formula

R13represents a fragment of formula:

where each of q, r, s and t independently are 0, 1, 2, 3, 4 or 5;

R19there is no means N, NH2HE, (C1-6)hydroxyalkyl, N(R27R28), SO3H or optionally substituted fragment selected from the group consisting of heterocyclyl, phenyl and naphthyl,

where the optionally substituted fragment defined for R19, optionally substituted by one or more substituents independently selected for each case from the group consisting of halogen, NO2HE, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, (C1-6)alkoxygroup, NH2mono - or di- (C-6 )alkylamino, Bzl and O-Bzl;

R20is O or is absent;

R21means (C1-6)alkyl or is absent;

R22is N, O, or CH;

R23means (C1-6)alkyl or is absent;

R24is N, CH or C;

R25is NH, O or absent;

R26is SO2, CO or SN;

each of R27and R28independently is H or (C1-6)alkyl;

E independently for each case represents an optionally substituted fragment selected from the group consisting of (C1-12)alkyl, (C2-12)alkenyl, (C2-12)quinil, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)quinil, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)quinil, (cyclo(C3-7)alkyl)-(C1-6)alkyl, (cyclo-(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(C2-6)quinil, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)quinil, 1-adamantyl, 2-adamantyl, dicyclopropyl, dimethylcyclopropene, 9-fluorenylmethyl and benzhydryl;

where the optionally substituted fragment described for E, optionally substituted by one or more substituents, each of which is independently selected from the group sotoyama is from halogen, HE, Bzl, O-Bzl, NO2, CN, COOH and SH;

X0means halogen, NO2HE, (C1-6)alkyl, (C2-6)alkoxygroup, mono - or di- (C1-6)alkylamino, Bzl, O-Bzl, NR9R10or CN;

X1means H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, indolyl, imidazolyl, 1-naphthyl, 3-pyridyl, optionally substituted in the benzyl ring or a fragment, which corresponds to a group of the side chain of Arg, Leu, Gln, Lys, Tyr, His, Thr, Trp, Phe, Val, Ala, Lys or His;

where specified optionally substituted in the ring benzyl optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-6)alkoxygroup, mono - or di- (C1-6)alkylamino, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)quinil and NR9R10;

each of X2and X3independently represents H, halogen, HE, =O, =S, (C1-12)alkyl, (C2-12)alkenyl, (C2-12)quinil, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)quinil, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)quinil, (cyclo(C3-7)alkyl)-(C1-6)alkyl, (cyclo(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(C2-6)quinil, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)-quinil, 1-substituted, 2-hell is mantil, dicyclopropyl or dimethylcyclopropene;

X4means N, HE or NH2and

X5means halogen, NO2CH3HE, Bzl or O-Bzl;

provided that

there are at least six amino acid residues;

in the case when AA3is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tra or Tmpa, and AA6is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tra or Tmpa, AA3and AA6linked by a disulfide bond;

in the case when AA1or AA3is D - or L - isomer amino acids selected from the group consisting of a Mac or Macab, AA8is D - or L - isomer amino acids selected from the group consisting of Maa and Maaab, and when AA8is D - or L-isomer amino acids selected from the group consisting of Maa and Maaab, AA1or AA3is D - or L-isomer Mac or Macab, and AA1or AA3linked by a disulfide bond with AA8;

AA2may be D - or L-Hca only in the case when AA1no;

in the case when one of R1or R2is E(O)2S-, S(O) -, EOOS - or R13, the other is N;

if R5no, one of R1or R2also absent, and N - terminal amino and C - terminal amino is iSlate together form an amide bond;

if one of X2or X3represents the C=O or C=S, the other is absent; and a specified compound of formula (I) has the formula:

D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Ac-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

L-4-NO2-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Ac-L-4-NO2-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Hca-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

D-Dip-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

D-4-NO2-Phe-Phe(4-O-Bzl)-cyclo(D-Cys-D-Trp-Lys-Cys)Cha-Nal-NH2or

D-4-NO2-Phe-cyclo(D-Cys-Phe(4-O-Bzl)-D-Trp-Lys-Cys)-Val-Tyr-NH2.

In another aspect, the direction of the present invention is a pharmaceutical composition, containing one or more compounds of the formula (I)defined above and a pharmaceutically acceptable carrier.

In another aspect the direction of the present invention is a method designed to induce agonistic action on the part of one or more subtypes of somatostatin receptors and/or neuromedin In the subject, which it should, which includes the introduction of the compounds of formula (I), which is described above, the specified entity.

In another aspect this invention is directed to a way to cause an antagonistic action on the part of one or more subtypes of the recipe is the moat somatostatin and/or neuromedin In the subject, which it should, which includes the introduction of the compounds of formula (I), which is described above, the specified entity.

In the following aspect this invention is directed to a method of binding one or more subtypes of somatostatin receptors and/or neuromedin In the subject who needs it, which includes the introduction of the compounds of formula (I), which is described above, a given patient.

In yet another additional aspect this invention is directed to the use of one or more compounds of formula I to bind to the receptor neuromedin In or with one or more somatostatin receptors, as in the performance analysis in vitro and in vivo.

DETAILED description of the INVENTION

The specialist will understand that some substituents listed in this invention can have low chemical stability in combination with another Deputy or heteroatoms in the connection. Such compounds with low chemical stability are not preferred.

In General, the compounds of formula (I) can be obtained by methods that include methods known in the field of chemistry for producing compounds. Some of the methods of manufacture of compounds of formula (I) are provided as additional parts of the invention and are illustrated by the schemes of reactions and examples included in this work.

In the above structural formulas and throughout this application the following terms have the specified values, unless otherwise noted.

It is implied that the term "alkyl" includes definitions of the alkyl groups of the specified length, either straight or branched configuration. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. In that case, when included in the definition of the term0is alkyl, it is understood that it refers to a single covalent bond.

It is implied that the term "alkoxygroup includes definitions alkoxygroup specified length, either straight or branched configuration. Examples of such alkoxygroup are methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, tert-butoxy-pentox, isopentane, hexose, isohexadecane and the like.

It is implied that the term "halogen" or "halogen atom" includes atoms of the Halogens: fluorine, chlorine, bromine and iodine.

It is implied that the term "cycloalkyl includes monocyclohexyl group or bicycloalkyl group with the specified number of carbon atoms known to specialists in this field.

The term "dimethylcyclopropene" from OSISA to the structure

The term "aryl" include aromatic rings, known in this area, which can be monocyclic, bicyclic or tricyclic, such as phenyl, naphthyl and antracol.

The term "heterocycle" includes monocyclic and bicyclic system having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur. Ring system may be aromatic, (e.g., pyridine, indole, quinoline, pyrimidine, thiophene (also known as Teenel), furan, benzothiophene, tetrazol, dihydroindol, indazole, N-formylindole, benzimidazole, thiazole and thiadiazole). The ring system can also be non-aromatic (e.g., pyrrolidine, piperidine, morpholine and the like).

Specialist chemist will understand that certain combinations of substituents containing heteroatoms listed in this invention, identify the connections that will be less stable under physiological conditions. Accordingly, such compounds are less preferred.

According to this definition here some remnants or fragments in alternative cases are missing in some of the peptides according to the invention. Wherever the relationship(zi) with the remnant or fragment is indicated by a solid line, it is understood that in the case when the remnant or fragment is missing, contact is established between the remaining N-terminal residue or fragment(s) and the remaining C-terminal residue or fragment(s). Wherever the relationship(zi) with the remnant or fragment is indicated by the dashed line(s) it is understood that in the case when the remnant or fragment is missing, no connection is formed between the remaining N-terminal residue or fragment(s) and the remaining C-terminal residue or fragment(s). For example, in the following structure:

no AA1in the result

and no AA1' in the result

In the following structure:

the lack of R23in the result

In that case, when the chemical structure is used here in the form has an arrow coming out of it, the arrow indicates the point of binding. For example, the structure

is Pintilei group. In the case where the line is drawn passing through a cyclic fragment, the line indicates that the Deputy may be associated with a cyclic fragment at any available point of binding. For example,

means that substituent X may be linked in the ortho-, meta - or para-position relative to the point of binding. Similarly, in the case when the line narisou is passing through bicyclic or tricyclic fragment, line indicates that the Deputy may be associated with a bicyclic or tricyclic fragment in any accessible point binding in any of the rings.

For all pictured here formulas N-end is on the left and the end on the right, in accordance with the traditional image of the polypeptide chain.

Symbol AA1, AA2or similar in the sequence of the peptide indicates amino acid residue, i.e. a =N-CH(R)-CO-, when it is located on the N-end, or-NH-CH(R)-CO-, when he is not at the N end, where R is a side chain of this amino acid residue. Thus, R for Val represents-CH(CH3)2. Also in the case when the amino acid residue is optically active, it is in the form of L-configuration, which means, if D-form is not specified.

Unless otherwise stated, where N is the end appears acetyl group, it is assumed that the acetyl group is preferable connected with αnitrogen, and not with the side chain of the N-terminal amino acids. For example, the structure of the amino acid sequence Ac-4-NO2-Phe-AA2-AACrepresents a

Where the Deputy Y, for example, has the form-OR5at the end of the peptide, it is understood that-OR5link directly to carbon of the carbonyl group instead-HE.

What is denoted by the term "aromatic α-amino acid, is an amino acid residue of the formula

where Z denotes the fragment containing aromatic ring. Examples of Z include, but are not limited to, benzene, or pyridine ring, and the following structures without substituent, or with one or more substituents X in the aromatic ring (where X independently for each case is halogen, NO2CH3HE, Bzl or O-Bzl):

Other examples of aromatic α-amino acids according to the invention is replaced by His, such as MeHis, His(τ-IU) or His(π-IU).

What is meant by the term "base nucleic acid is optionally substituted by a fragment of a nucleic acid of the formula:

where R1and R2represent radicals that are defined in the claims.

In some embodiments of the invention, the amino group of the side chain of one or more amino optionally mono - or tizamidine R3and R4.

For example, the introduction of the substituent R3in the amino group of the side chain 4-Pip-Gly would give the following structure:

The connection agreement is but the present invention have at least one asymmetric center. In the molecule may be additional asymmetric centers, depending on the nature of the various substituents in the molecule. Each such asymmetric center will produce two optical isomers and it is implied that all such optical isomers as separate purified or partially purified optical isomers, racemic mixtures or diastereomeric mixtures included in the scope of the present invention.

These compounds generally can be identified in the form of their pharmaceutically acceptable acid additive salts, such as salts derived from inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, propionic, maleic, succinic, D-tartaric, L - tartaric, malonic, methanesulfonate and the like. In addition, some compounds containing acidic functional group such as carboxyl group, can be identified in the form of inorganic salts, in which the counterion may be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as in the form of organic bases.

Pharmaceutically acceptable salt form, using about 1 equivalent of the compound of formula (I) and providing its contact with about 1 equivalent of the appropriate corresponding acid is you, salt which you want to receive. Receipt and allocation of the resulting salt is well known to specialists in this field.

Compounds according to this invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nazalnam, vaginal, rectal, sublingual, or local routes of administration, and can be prepared in compositions with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration. Thus, in the scope of this invention is included a pharmaceutical composition containing as active ingredient at least one compound of formula (I) in Association with a pharmaceutically acceptable carrier.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms can also contain - and this is normal practice, additional substances other than such inert diluents, such as lubricating agents such as magnesium stearate. In the case of capsules,tablets and pills dosage forms can also contain buffer means. Pills and tablets, in addition, can be prepared in intersolubility coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in this field, such as water. Besides such inert diluents, compositions can also include adjuvants, such as humectants, emulsifying and suspendresume agents, and sweeteners, corrigentov and fragrances.

Preparations for parenteral administration according to this invention include sterile aqueous and non-aqueous solutions, suspensions or emulsions. Examples of nonaqueous solvents or fillers are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and suitable for injection complex organic esters, such as etiloleat. Such dosage forms may also contain adjuvants such as preservatives, moisturizing, emulsifying and dispersing funds. Dosage forms can be sterilized, for example, by filtration through filters, inhibiting bacteria, by incorporating sterilizing means in the compositions, by irradiating the compositions, or by heating the compositions. Dosage forms also can produce is in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile, suitable for injection medium immediately prior to use.

Compositions for rectal or vaginal injection preferably are suppositories which may contain, besides the active substance, excipients such as cocoa butter or wax for suppositories.

Compositions for nasal or sublingual introduction also prepared with standard fillers are well known in this field.

In addition, the compounds according to the invention can be introduced in the form of a composition extended release, such as the compositions described in the following patents. In U.S. patent No. 5672659 reported compositions prolonged release containing a bioactive agent and a complex polyester. U.S. patent No. 5595760 introduces compositions prolonged release containing bioactive agent in gel form. The application for the grant of U.S. patent No. 08/929363 registered 9 September 1997, introduces polymer compositions prolonged release containing a bioactive agent and chitosan. Application for U.S. patent No. 08/740778 registered 1 November 1996, introduces the compositions prolonged release containing a bioactive agent and a cyclodextrin. Application for U.S. patent No. 09/01539, registered on January 29, 1998, introduces absorbable compositions prolonged release of bioactive funds. The message of the above-mentioned patents and applications are incorporated herein by reference.

In General, the effective dose of the active ingredient in the compositions according to this invention can vary; however, it is necessary that the amount of active ingredient was such that there was obtained a suitable dosage form. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment, and it all relates to the field of specialist knowledge in this area. As a rule, man and other animals, for example mammals, enter the dose levels from 0.0001 to 100 mg/kg of body weight daily.

The preferred dose limits range from 0.01 to 10.0 mg/kg of body weight daily which can be entered as a single dose or divided into multiple doses or give continuous introduction.

Compounds according to the present invention can be and were evaluated for their ability to bind with receptor subtype somatostatin in accordance with the following tests.

The affinity of compounds in relation to subtypes of somatostatin receptors with 1 to 5 (sst1sst2sst3sst4and sst5, respectively) was determined by MEAs the rhenium inhibition of binding of [ 125I-Tyr]SRIF-14 cells Cho - K1, transfitsirovannykh subtype receptor sst.

Gene receptor sst1human cloned in the form of a genomic fragment. The > PST fragment-XmnI length of 1.5 TPN containing 100 BP 5'-untranslated region, 1,17 TPN full coding region and 230 BP 3'-untranslated region, modified by adding a BglII linker. The resulting DNA fragment was subcloned into the BamHI site of the plasmid pCMV - 81 to get expressing plasmid mammals (provided by Dr. Graeme Bell, University of Chicago, Chicago, IL). Line clonal cells, stably expressing the receptor sst1received by transfection of cells Cho - K1 (American type collection of cultures, Manassas, VA) ("ATSS"), using the process of co-precipitation of calcium phosphate. The plasmid pRSV-neo (ATS) was included as a breeding marker. Breeding lines clonal cells was performed in medium RPMI 1640 (Sigma Chemical Co., St. Louis, MO)containing 0.5 mg/ml geneticin (Gibco BRL, Grand Island, NY), cloned on the ring circuit and multiplied to obtain the culture.

Gene receptor somatostatin sst2the man, identified as BamHI-HindIII fragment of genomic DNA with a length of 1.7 TPN and subcloned in the plasmid vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (University of Chicago, Chicago, IL). The vector expressing in mammalian cells, designed p is a means of embedding BamHI-HindIII fragment length 1,7 TPN in the compatible sites of the restriction endonucleases, plasmid pCMV5. Line clonal cells were obtained by transfection of cells Cho-K1, using the process of co-precipitation of calcium phosphate. The plasmid pRSV-neo included as breeding token.

Gene sst3the man was identified in the genomic fragment, and a complete coding sequence was enclosed within the BamHI/HindIII-fragment length of 2.4 TPN Expressing plasmid mammalian pCMV-h3 was designed by embedding NcoI-HindIII fragment length 2,0 TPN in the EcoR1 site of the vector pCMV after modification of the ends and add EcoR1 linkers. Line clonal cells, stably expressing the receptor sst3, was obtained by transfection of cells Cho-K1 (ATSS), using the process of co-precipitation of calcium phosphate. The plasmid pRSV-neo (ATS) was included as a breeding marker. Breeding lines clonal cells was performed in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned on the ring circuit and multiplied to obtain the culture.

Plasmid pCMV-HX expressing the receptor sst4man, was provided by Dr. Graeme Bell (University of Chicago, Chicago, IL). A vector containing the genomic NheI-NheI fragment length 1,4 TPN encoding sst4, 456 BP 5'-untranslated region and 200 BP 3'-untranslated region, cloned into the Xbal sites/EcoRl plasmids PCMV-HX. Line clonil the data cells, stably expressing the receptor sst4, was obtained by transfection of cells Cho-K1 (ATSS), using the process of co-precipitation of calcium phosphate. The plasmid pRSV-peo (ATS) was included as a breeding marker. Breeding lines clonal cells was performed in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned on the ring circuit and multiplied to obtain the culture.

Gene sst5man was obtained PCR using as template genomic clone λ and courtesy of Dr. Graeme Bell (University of Chicago, Chicago, IL). The resulting PCR fragment length 1.2 TPN contained 21 a couple of bases 5'-noncoding region, the full coding region and 55 BP 3'-untranslated region. The clone was built into the EcoR1 site of the plasmid pBSSK(+). The insert was recovered in the form of a HindIII-XbaI fragment length 1.2 KBP to sublimirovanny in expressing vector mammals pCVM5. Line clonal cells, stably expressing the receptor SST5, was obtained by transfection of cells Cho-K1 (ATSS), using the process of co-precipitation of calcium phosphate. The plasmid pRSV-neo (ATS) was included as a breeding marker. Breeding lines clonal cells was performed in medium RPMI 1640 containing 0.5 mg/ml G418 (Gibco), cloned on the ring circuit and multiplied to obtain the culture.

Cells Cho-K1, stably expressing one of receptora the sst person, grown in RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin. Cells are harvested using 0.5 mm EDTA and centrifuged at 500 g for about 5 minutes at a temperature of about 4°C. the Precipitate resuspended in 50 mm Tris hydrochloride [hydroxymethyl] aminomethane, pH of 7.4, at 25° ("Tris buffer") and centrifuged twice at 500 g for approximately 5 minutes at a temperature of about 4°C. the Cells are lysed by sonication and centrifuged at 39000 g for approximately 10 minutes at a temperature of about 4°C. the Precipitate resuspending in the same buffer and centrifuged at 50000 g for approximately 10 minutes at a temperature of about 4°and the membrane obtained from the sediment stored at -80°C.

Experiments on competitive inhibition of binding of [125I-Tyr11]SRIF-14 is carried out in duplicates in 96-well polypropylene plates. Cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (Dr. Tom Davis, Univ. Of Arizona, Tuscon, AZ) (0,05 nm) for approximately 60 minutes at a temperature of about 37°With 50 mm HEPES, 0.2% BSA, 2.5 mm MgCl2.

Bound and free [125I-Tyr11]SRIF-14 immediately separated by filtering through filter plate with glass fiber GF/C Unifilter, Packard, Meriden, CT), pre-soaked in 0.3% polyethylenimine (P.E.I)using the device to collect cells Filtermate 196 (Packard. The filters are washed with 50 mm Tris-HCl at a temperature of about 0-4°With approximately 4 seconds and analyze the radioactivity using a counter Packard Top Count.

The value of specific binding is obtained by subtracting nonspecific binding (determined in the presence of 0.1 μm SRIF-14) from the total binding. Results binding analyzed by analysis of nonlinear regression using the computer (Data Analysis Toolbox, v.1.0, Molecular Design Limited, San Leandro, CA), and determine the values of the inhibition constants (Ki).

Whether the connection of the present invention agonist SST or a somatostatin antagonist, determine when the next analysis.

Functional analysis. Inhibition of intracellular production of camp.

Cells Cho-K1 expressing the receptor subtypes of somatostatin (SRIF-14) man, seeded in 24-cell cups for tissue culture in medium RPMI 1640 with 10% fetal calf serum (FCS). Environment change the day before the experiment.

Cells in 105cells/well 2 times washed with 0.5 ml of RPMI medium 1640. Add fresh medium RPMI 1640 with 0.2% BSA and with the addition of 0.5 mm 3-isobutyl-1-methylxanthines ("IBMX), and cells incubated for approximately 5 minutes at a temperature of about 37°C. the Production of cyclic AMP stimulated by adding 1 mm of Forskolin ("FSK") (Sigma Chemical Co., St. Louis, MO) for about 15-30 minutes at a temperature of about 37°C.

the Agonistic activity of the compounds measured with the simultaneous addition of FSK (1 μm), SRIF-14 (Bachem, Torrence, CA), (10-12up to 10-6M) and test compounds (10-10up to 10-5M). Antagonistic action of the compounds measured with the simultaneous addition of FSK (1 μm) , SRIF-14 (from 1 to 10 nm) and test compound (10-10up to 10-5M).

Reaction medium was removed and added to 200 ml of 0.1 N HCl. camp is measured using a radioimmunoassay method (set FlashPlate SMP001A, New England Nuclear, Boston).

Compounds according to the present invention can be and were evaluated for their ability to bind with receptor neuromedin, in accordance with the following analysis.

Cell culture. Cells Balb T expressing the receptor NMB rats, received from Dr. R.T. Jensen (National Institutes of Health, Bethesda, MD) and cultured in medium Needle, modified, Dulbecco (DMEM)containing 10% fetal calf serum, 0.5 mg/ml G418 (Gibco). Cells were maintained at 37°C in a humid atmosphere of 5% CO2/95% air.

Linking radioligand. Membranes for studies linking radioligand was obtained by homogenization of the cells in 20 ml of ice-cold 50 mm Tris-HCl at Brinkman homogenizer transmitter station (Westbury, NY) (setting 6, 15 sec). The homogenates were twice washed by centrifugation (39000 g/10 min), and final precipitation re-suspended in 50 mm Tris - HCl, containing 5.0 mm MgCl2and 0.1% BSA. For analysis, aliquots (0.4 ml) were incubated from 0.05 nm [125I-Tyr4]bombezin the (2200 Curie/mmol, New England Nuclear, Boston, MA) in the presence and without 0.05 ml of its competing tested peptides. After incubation (30 minutes, 4° (C) associated with [125I-Tyr4]bombezin was separated from the free by rapid filtration through filters GF/C (Brandel, Gaithersburg, MD), which were pre-soaked in 0.3% polyethylenimine. Then the filters were washed three times with 5-ml-aliquot of ice-cold 50 mm Tris-HCl, and associated radioactivity trapped on the filters was positively gamma spectrometry (Wallac LKB, Gaithersburg, MD). Specific binding was defined as the total amount of bound peroxidase [125I-Tyr4]bombezin minus the amount of bound peroxidase in the presence of 1000 nm neuromedin In (Bachem, Torrence, CA).

One variant of the method includes a stage of contacting the cells with a peptide of the formula (2):

or its pharmaceutically acceptable salt,

where AA1is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aac, Aic, Arg, Asn, Asp, Dip, Gln, Glu, Hyp, Lys, Mac, Macab, Orn, Pip, Pro, Ser, Ser(Bzl), Thr, Thr(Bzl), Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, lia, Alla, Aba, Gba, Car, Ipa, laa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua, the Ruhr, and optionally substituted aromatic α-amino acids;

where specified optionally substituted aromatics is th α -amino optionally substituted by one or more substituents selected from the group consisting of halogen, NO2HE, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)-quinil and NR9R10;

AA2is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aic, Arg, NSA, His, Hyp, Pal, Fs-Phe, Phe, Pro, Trp, X°-Phe, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, Iia, Alla, Aba, Gba, Car, Ipa, laa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua and the Ruhr;

AA3is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tra and Tmpa;

AA4is D - or L - isomer amino acids selected from the group consisting of Trp, N-Met-Trp, β-Met-Trp, His, hHis, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and optionally substituted aromatic α-amino acids

where specified optionally substituted aromatic α-amino optionally substituted by one or more substituents, each of which is independently selected from the group consisting of halogen, NO2HE, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)quinil, Bzl, O-Bzl and NR9R10;

AA5is D - or L - isomer amino acids selected from the group consisting of 4-Pip-Gly, 4-Pip-Ala, Cys-4-Acha, TRANS-4-Acha, TRANS-4-Amcha, hLys, Lys, Or, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala and Pala,

where the amino group of the side chain of the specified amino optionally mono - or tizamidine R3and R4;

AA6is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tpa and Tmpa;

AA7is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aic, As, As, As, As, Abu, Aib, β-Ala, Arg, Bpa, Cha, Deg, Gaba, His, Ile, Leu, Nal, Nle, Pal, Phe, F5Is Phe, Pro, Sar, Ser, Ser(Bzl), Thr, Thr(Bzl), Trp, N-Me-Trp, Val, N-Me-Val, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and X0-Phe;

AA8is missing or D - or L - isomer amino acids selected from the group consisting of R11, optionally substituted aromatic α-amino acids, Maa, Maaab, Ser, Ser(Bzl), Thr, Thr(Bzl), Tyr, Phe(4-O-Bzl), Fs-Phe, and X5-Phe;

R13is a fragment in accordance with the formula:

where R21means (C1-4)alkyl and s is 1, 2, 3 or 4;

X0means halogen, NO2CH3HE, Bzl, O-Bzl or CN;

provided that there is at least one AA7or AA8.

Another variant of the method includes a stage of contacting the cells with a peptide of the formula (III):

or its pharmaceutically acceptable salt,

where AA1is missing or D - or L-isomer amino acids, selected from the group consisting of R11, Aac, Aic, Arg, Asn, Asp, Gln, Glu, Hca, His, Hyp, Lys, Mac, Macab, Orn, Pro, Ser, Ser(Bzl), Thr, Thr(Bzl), Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, lia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua, the Ruhr, and optionally substituted aromatic α-amino acids;

where specified optionally substituted aromatic α-amino optionally substituted by one or more substituents selected from the group consisting of halogen, NO2HE, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)-quinil and NR9R10;

AA3is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tpa and Tmpa;

AA3bis D - or L - isomer amino acids selected from the group consisting of R11, Arg, Bpa, F5-Phe, His, Nal, Pal, 4-Pal, Trp, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and X5-Phe;

AA4is D - or L-isomer amino acids selected from the group consisting of Trp, N-Met-Trp, β-Met-Trp, His, hHis, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and optionally substituted aromatic α-amino acids, where this optional substituted aromatic α-amino optionally substituted by one or more substituents, each of which is independently selected from the group consisting of the halogen, NO2HE, CN, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)quinil, Bzl, O-Bzl and NR9R10;

AA5is D - or L - isomer amino acids selected from the group consisting of 4-Pip-Gly, 4-Pip-Ala, Cys-4-Acha, TRANS-4-Acha, TRANS-4-Amcha, hLys, Lys and Orn, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala,

where the amino group of the side chain of the specified amino optionally mono - or tizamidine R3and R4;

AA6is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen, Tpa and Tmpa;

AA7is missing or D - or L - isomer amino acids selected from the group consisting of R11, Aic, As, As, As, As, Abu, Aib, β-Ala, Arg, Bpa, Cha, Deg, Gaba, His, Ile, Leu, Nal, Nle, Pal, Phe, F5Is Phe, Pro, Sar, Ser, Ser(Bzl), Thr, Thr(Bzl), Trp, N-Me-Trp, Val, N-Me-Val, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala and X0-Phe;

X0means halogen, NO2CH3HE, CN, Bzl or O-Bzl;

each of R1and R2independently represents H, E-, E(O2)S-, E(O)C-, EOOC, R13or missing;

R5is-OR6or NR7R8;

R13represents a fragment of formula:

where R21means (C1-4)alkyl and s is 1, 2, 3 or 4;

provided that there is at least one AA1or AA2;

in the case when AA1is D - or L - isomer Pro, Hyp Arg, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, Iia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua, Ruhr or His, AA2cannot be D - or L - isomer Pro, Hyp, Arg, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, lia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Ara, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, MFN, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α-Chpa, Cit, Nua, Ruhr or His;

in the case when AA7is D - or L - isomer of Thr, or Ser, AA8cannot be D - or L - isomer of Thr or Ser;

at least one AA1, AA2, AA3b, AA7, AA7bor AA8is D - or L-isomer R11and

in the case when X2or X3is =O or =S, the other is absent;

or its pharmaceutically acceptable salt.

Another variant of the method involves the step of contacting cells with a peptide of the formula (4) :

where AA1missing is D - or L - isomer amino acids selected from the group consisting of R11, Aic, Hyp, Pro, Ser, Ser(Bzl), Thr, Thr(Bzl), and optionally substituted aromatic α-amino acids;

where specified optionally substituted aromatic α-amino optionally substituted by one or more substituents, each of which is independently selected from the group consisting of halogen is, NO2HE, (C1-6)alkyl, (C2-6-alkenyl, (C2-6)quinil, (C1-6)alkoxygroup, Bzl, O-Bzl and NR9R10;

AA2is missing or D - or L-isomer amino acids selected from the group consisting of R11, Arg, F5-Phe, His, Pal, Phe, Trp and X0-Phe;

AA3is D - or L - isomer optionally substituted aromatic α-amino acids, where this optional substituted aromatic α-amino optionally substituted by one or more substituents selected from the group consisting of halogen, NO2HE, (C1-4)alkyl, (C2-4-alkenyl, (C2-4)quinil, Bzl, O-Bzl and NR9R10;

AA4is D - or L - isomer optionally substituted amino acid selected from the group consisting of Lys, Orn, hLys, Cys-4-Acha, TRANS-4-Acha, TRANS-4-Amcha, 4-Pip-Gly 4-Pip-Ala,

where the amino group of the side chain of the specified optionally substituted by amino optionally substituted by R3and R4;

AA5is missing or D - or L - isomer R11, As, As, As, As, Abu, Aib, Aic, β-Ala, Bpa, Cha, Deg, F5-Phe, Gaba, Ile, Leu, Nal, Nle, Pal, Phe, Pro, Sar, Ser, Ser(Bzl), Thr, Thr(Bzl), Trp, N-Me-Trp, Val, N-Me-Val or X0-Phe;

AA6missing is D - or L - isomer R11, aromatic α-aminosilane, F5-Phe, Phe, Thr, Thr(Bzl), Ser, Ser(Bzl) or X0-Phe;

AA7Otsu is there is D - or L - isomer R11or D - or L-isomer of an aromatic α-aminoacetate;

AA8is D - or L-isomer R11;

R1represents H, E-, E(O2)S-, S(O) -, EOOS - or R13;

R13represents a fragment of formula:

where R21means (C1-4) alkyl and s is 1, 2, 3 or 4;

X0in determining AA2and AA5means halogen, NO2HE, (C1-6)alkyl, (C1-6) alkoxygroup, mono - or di- (C1-6)alkylamino, Bzl or O-Bzl;

X0in determining AA6means halogen, NO2HE, (C1-6)alkyl, (C1-6)alkoxygroup, mono - or di- (C1-6)alkylamino, Bzl, O-Bzl or NR9R10;

provided that

there is at least one AA1or AA2;

in the case when AA1no, AA2and AA8together form a bond;

and there are at least two amino acids from AA5, AA6and AA7;

or its pharmaceutically acceptable salt.

Introduction what their pharmaceutically acceptable salts of the compounds, described by formula (I), the patient whose violation is the result of biochemical activity induced NMB or somatostatin, also included in the scope of this invention. In other words, the peptides may be provided in the form of pharmaceutically acceptable salts, for example acid additive salts, or complexes with metals such as zinc, iron and the like. Illustrative examples of acid additive salts are salts of organic acids such as acetic, lactic, Panova, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, subernova, salicylic, tartaric, methansulfonate or toluensulfonate acid, salts of polymeric acids such as tannic acid or carboxymethyl cellulose, and salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid or phosphoric acid.

Other features and advantages of this invention will be apparent from the following description of the preferred options, as well as from the claims. It is assumed that on the basis of the expert in this area uses the invention to the fullest extent. Therefore, the following specific options should be considered illustrative only and in no way limiting remained the ing part of the application. All cited here documents are hereby incorporated by reference.

Description of the PREFERRED OPTIONS

In a preferred embodiment, a feature of the invention is the compound according to the formula 2, where

AA1missing is Ac-D-Phe or D - or L - isomer R11, Pip, Pro or Ser, or an aromatic a-amino acids selected from the group consisting of CPA, Dip, Nal, Pal, and Phe;

AA2means Aic, Pal, Phe, F5-Phe, 4-NO2-Phe, Trp, Tyr, Phe (4-O-Bzl) or is missing;

AA3mean D - or L - isomer amino acids selected from the group consisting of a Pen, Cys, hCys and Tmpa;

AA4mean D - or L-isomer of Trp or His;

AA5is Lys, hLys, N-Me-Lys, Orn, Cys-4-Acha or 4-Pip-Ala;

AA6is D - or L - isomer amino acids selected from the group consisting of Cys, hCys, Pen and Tmpa;

AA7means As, As, As, As, Abu, Aic, β-Ala, Gaba, Nle, F5-Phe, Phe, Pro, Sar, Ser, Thr, Thr(Bzl), Tyr, Val, or absent;

AA8means R11, Nal, Thr, Thr(Bzl), Tyr, Phe(4-O-Bzl) or is missing;

or its pharmaceutically acceptable salt.

In a more preferred embodiment feature of the invention is the compound according to mentioned directly above, where

AA1is missing or D - or L - isomer R11, Pip or Pro or aromatic α-amino acids selected from the group consisting of CPA, Dip, Nal, Pal, Phe and AC-Phe;

AA 2means Tight, Pal, Phe, 4-NO2Is Phe, Trp or is absent;

AA3is D - or L - isomer of Cys or Pen;

AA4mean D-Trp;

AA5means Lys, Orn or Cys-4-Acha;

AA6mean D - or L - isomer of Cys or Pen;

AA7means As, As, As, As, Abu, Aic, β-Ala, Gaba, Nle, Phe, Pro, Sar, Thr, Thr(Bzl), Tyr, Val, or absent;

AA8means R11, Thr, Tight, Nal or missing;

or its pharmaceutically acceptable salt.

In another preferred embodiment, a feature of the invention is a compound according to formula III, where AA1means R11, Aic, Hca, Pro, Ser, Ser(Bzl), Trp, Tyr, or D - or L - isomer of an aromatic α-amino acids selected from the group consisting of CPA, Nal, Ac-Nal, Phe, Ac-Phe, 4-NO2-Phe and AU-4-NO2-Phe;

AA2means Pal, Phe, F5Is Phe, Tyr or is missing;

AA3is D - or L - isomer of Cys, hCys, Pen or Tmpa;

AA3bmeans Pal, 4-Pal, His, Trp, Tyr, Phe (4-O-Bzl), Phe or R11;

AA4is D - or L - isomer of Trp or His;

AA5means Lys, N-Me-Lys, Orn, hLys, cis-4-Acha or 4-Pip-Ala;

AA6is D - or L - isomer of Cys, hCys, Pen or Tmpa;

AA7means R11, A4c, A5c, Abu, β-Ala, Gaba, Phe, F5Is Phe, Ser(Bzl), Thr, Thr(Bzl), Phe(4-O-Bzl) or is missing;

AA7bmeans R11, Nal, F5Is Phe, X0Is Phe or is absent, where X0is halogen, NO2CH3HE, Bzl or O-Bzl;

The and 8means R11, Nal, Tight, Phe(4-O-Bzl) or is missing;

or its pharmaceutically acceptable salt.

In a more preferred embodiment feature of the invention is the compound according to mentioned directly above, where

AA1means R11, Aic, Hca, Pro, Ser(Bzl), or D - or L - isomer of an aromatic α-amino acids selected from the group consisting of CPA, Nal, Ac-Nal, Phe, Ac-Phe, 4-NO2-Phe and Ac-4-NO2-Phe;

AA2means Pal, Tyr or is missing;

AA3is D - or L - isomer of Cys or Pen;

AA3bmeans R11, Pal, 4-Pal, Trp, Tight, Phe(4-O-Bzl) or Phe, where R11is a (T)aeg;

AA4mean D-Trp;

AA5means Lys, N-Me-Lys, Orn or Cys-4-Acha;

AA6is D - or L - isomer of Cys or Pen;

AA7means R11, A5c, Abu, Ser(Bzl), Thr, Thr(Bzl), Phe(4-O-Bzl), Gaba or missing;

AA7bmean Nal, X0-Phe or absent;

AA8means Tyr or is missing;

or its pharmaceutically acceptable salt.

In another preferred embodiment, a feature of the invention is the compound according to the formula 4, where AA1means Aic, Hyp, Cpa, D-Cpa, Nal, Pal, Phe, Pro, R11, Tyr or is missing;

AA2means Phe, Trp, F5-Phe, His, Tyr, Phe(4-O-Bzl) or R11;

AA3is the D-isomer of Trp, His, or Pal;

AA4means Lys, N-Me-Lys, Orn, hLys, Cys-4-Acha or 4-Pip-Ala;

5means Pal, Phe (4-O-Bzl), Thr(Bzl), Thr, and Sar, Gaba, β-Ala, A4c, A5c, A6c, Abu, Aic or missing;

AA6means Thr, Tyr, Ser, F5-Phe, Cpa, Nal, or D - or L-Phe;

AA7mean Nal, Pal, or missing;

AA8means R11;

or its pharmaceutically acceptable salt.

In another preferred embodiment, a feature of the invention is the compound according to mentioned directly above, where AA1means Cpa, Nal, Pal, Phe, Tyr or is missing;

AA2means Phe, Tyr, Trp or R11;

AA3mean D-Trp;

AA4means Lys, N-Me-Lys or Cys-4-Acha;

AA5means Pal, Phe(4-O-Bzl), Aic, Gaba, A5c or missing;

AA6means Thr, Nal, or D-or L-Phe;

AA7no;

AA8means R11;

or its pharmaceutically acceptable salt.

In another preferred embodiment, a feature of the invention is a compound according to formula II, where R1and R5there are no N-terminal amino and C-terminal amino acid together form an amide bond; or its pharmaceutically acceptable salt.

In another preferred embodiment, a feature of the invention is a compound according to formula III, where R1and R5there are no N-terminal amino and C-terminal amino acid together form an amide bond; or its pharmaceutically acceptable salt.

Ac-D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

D-Dip-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

cyclo(D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr);

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-gas Stations-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A6c-Nal-NH2;

(G(z)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-β-Ala-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Sar-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Pro-Nal-NH2;

or its pharmaceutically acceptable salt.

In another most preferred embodiment, a feature of the invention is a compound according to formula II, where the aforementioned compound has the formula:

Phe-cyclo(Cys-D-Trp-Lys-Cys)-Thr-NH2;

Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Ac-D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-H 2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A3c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A6c-Nal-NH2;

(G(z)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

D-Cpa-cyclo(Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

CPA-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-β-Ala-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Sar-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Aic-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Pro-Nal-NH2;

(T)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-(A)aeg-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A4c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nal-NH2;

Pro-Phe-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-Cys)-Val-NH2;

Pip-4-NO2-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-NIe-NH2;

(G)aeg-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr(Bzl)-(C)aeg-NH2;

(C)aeg-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr(Bzl)-(G)aeg-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nle-Phe-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-Nle-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-Phe-NH2;

Cpa-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-NH2;

Cpa-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Tyr-NH2;

Pip-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-NH2;

Pip-Phe-cyclo(Cys-D-Trp-Lys-Cys)-Gaba-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-NH2;

or its pharmaceutically acceptable salt.

Another is the range of the preferred embodiment feature of the invention is a compound according to formula III, where the specified compound has the formula:

Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2

D-Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Cys)-Thr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

Ac-D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-4-NO2-Phe-Pal-cyclo(D-Cys-Phe(4-O-Bzl)-D-Trp-Lys-Cys)-Tyr-NH2;

CPA-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr-Tyr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2,

D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

D-Nal-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

Pro-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

CPA-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Nal-NH2;

Ser(Bzl)-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

(A)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(G)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-4-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Phe-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-(T)aeg-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Ser(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Phe(4-O-Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-A5c-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Abu-Tyr-NH2;

D-Cpa-CEC is about(D-Cys-(T)aeg-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH 2;

(C)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

D-Cpa-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(Pen-Pal-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Trp-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Orn-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-hLys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Iamp-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Cha(4-am)-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Ser(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)Thr(Bzl)-D-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)Thr(Bzl)-Trp-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Pen)Thr(Bzl)-Tyr-NH2;

(C)aeg-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

Ina-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

MFN-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

Inp-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

Nua-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

Ruhr-cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

cyclo(D-Cys-Phe-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-Pat-cyclo(D-Cys-D-Trp-Lys-D-Cys)Tyr(Bzl)-Thr-NH2;

(C)aeg-Phe-cyclo (D-Cys-D-Trp-Lys-D-Cys)Thr(Bzl)-Tyr-NH2;

(T)aeg-D-Trp-cyclo(D-Cys-Pal-Lys-D-Cys)Thr(Bzl)-Leu-NH2;

or its pharmaceutically acceptable salt.

In another most preferred embodiment, a feature of the invention is a compound according to formula III, where the aforementioned compound has the formula:

NSA-CEC is about(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH 2;

Ac-Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

Ac-D-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

Ac-D-Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-Nal-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Cys)-Thr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

Ac-D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Nal-NH2;

D-4-NO2-Phe-Pal-cyclo(D-Cys-Phe(4-O-Bzl)-D-Trp-Lys-Cys)-Tyr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

CPA-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

D-4-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

4-NO2-Phe-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

D-Nal-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

Pro-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

CPA-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Nal-NH2;

Ser(Bzl)-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(C)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

Aic-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(C(z)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(A(z)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2:

(A)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(G)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2:

(T)aeg-cyclo(D-Cs-4-Pal-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH 2;

(T)aeg-cyclo(D-Cys-Tyr-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Phe-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-(T)aeg-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Ser(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Phe(4-O-Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-A5c-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-Cys)-Abu-Tyr-NH2;

D-Cpa-cyclo(D-Cys-(T)aeg-D-Trp-Lys-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-p-Me-Phe-NHz;

Ac-(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

(T)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Nal-NH2;

D-Cpa-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Nal-NH2;

(A)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

(C)aeg-cyclo(D-Cys-Pal-D-Trp-Lys-D-Cys)-Thr(Bzl)-Tyr-NH2;

or its pharmaceutically acceptable salt.

In another most preferred embodiment, a feature of the invention is the compound according to the formula 4, where the aforementioned compound has the formula:

cyclo(Trp-D-Trp-Lys-Phe(4-O-Bzl)-Phe-(T)aeg);

cyclo(Trp-D-Trp-Lys-Pal-Phe-(T)aeg);

cyclo(Phe-Phe-D-Trp-Lys-Thr-(T)aeg);

or its pharmaceutically acceptable salt.

OBTAINING PEPTIDES

The peptide amide was synthesized on Rink resin, MVNA, (4-(2', 4'-acid-Fmoc-aminomethyl)phenoxyacetamide-MBNA-resin using standard solid-phase synthesis Protocol used in Fmoc-chemistry, and tsalala using a mixture TFU/phenol/N2About/triisopropylsilane (83 ml/5 g/10 ml/2 ml). The cyclization of Pat the species were carried out in CH 3CN/N2About (5 ml/5 ml), using the resin EKATIOX™ (EKAGEN Corporation, San Carlos, CA) and purified on a column of C18with silica (Rainin Instruments Co., Woburn, MA, now Varian Analytical, Walnut Creek, CA)using buffers acetonitrile / 0.1% of triperoxonane acid. Homogeneity was assessed by analytical HPLC and mass spectrometry, and identified that she was >95% for each peptide.

Peptides having the General structure

or

that is, having a cyclic Tetra - or pentapeptides basis, amide was synthesized on the resin MUNA Rink (4-(2',4'-acid-Fmoc-aminomethyl)phenoxyacetamide-MBNA-resin), following the standard solid-phase synthesis Protocol used in Fmoc-chemistry until then, until it was assembled to the desired peptide. The final elimination/removal of protective groups was achieved by treatment of the peptide bound to the resin, the mixture TFU/phenol/N2O/triisopropylsilane (83:5:10:2 ml/g/ml/ml).

The cyclization of (the formation of S-S-bond) was achieved by dissolving the linear peptide in 50 % mixture of CH3CN/N2O, except in those cases specifically provided otherwise, after which was added 2.5 EQ. resin EKATHIOXTM, then was stirred overnight.

The peptides were purified on a column of C18silica using buffer acetonitrile/0.1% of TFU. Homogeneity was assessed by analytical journal is Oh HPLC and mass spectrometry and identified, she was >95% for each peptide, unless otherwise stated.

Peptides with carboxyl function on the s-end, was synthesized on Wang resin (resin-based pair-benzyloxybenzyl alcohol), tsalala from the resin and removing the protective groups of the mixture (TFU: phenol: N2O: triisopropylsilane in the ratio 88:5:5:2).

Circular through education, communication "head-tail peptides having the General structure

first synthesized in the form of the fully protected linear peptide 2 horticulturally resin.

First remove the protective Fmoc group was performed using 5% piperidine in DMF/DCM (1:1) for about 10 minutes, after which 25% piperidine in DMF for about 15 minutes. All subsequent procedures for the removal of the protective groups were performed using standard solid-phase synthesis Protocol used in Fmoc-chemistry.

Protected linear peptides was obtained by treatment of the resin with a mixture of acetic acid/TFE/DCM (1:1:8 by volume) for approximately 60 minutes at room temperature.

The cyclization of the "head-tail" was achieved using as connecting/cyclisme reagent HATU/HOAT/DIPEA. Fully protected cyclic peptide was treated with a mixture of TFU/phenol/N2O/triisopropylsilane (83:5:10:2 ml/g/ml/ml) for approximately 21/2 hours to reach the end of the compulsory removal of the protective groups.

The peptides were purified on a column of C18with silica using as eluent buffer acetonitrile/0.1% of TFU. Homogeneity was assessed by analytical HPLC and mass spectrometry, and identified that the purity was >97% for each peptide.

As indicated above, some compounds according to the invention include one or more amino acid fragments of R11with the structure

where each of R12X1X2X3X4, m, n and R has the meaning defined in the claims. Specialist in the field of chemical synthesis will be clear that various amino acids R11it is easy to synthesize, using the appropriate starting materials and known methods of synthesis. Examples of suitable methods can be found in the following publications, which are thereby incorporated by reference: aminoacylation: Tetrahedron, vol.51, pp.6179 (1995); Bioorganic and Medicinal Chemistry Letters, vol.5, No.11, p.1159 (1995); Tetrahedron, vol.53, No.43, p.14671 (1997); Nucleosides, Nucleotides, vol.6 (10 & 11), R (1997); α,α-dialkylamino amino acid with a side chain represented by the nucleotide base, the OEWG. Natl. Acad. Sci. USA, vol.92, p.12013 (1995); aminocyclohexanol, Chem. Eur. J. vol.3, No.6, p.912 (1997); σ-N-Boc-α-N-(thymine-1-ylacetic)ornithine, Bioorganic and Medicinal Chemistry Letters, vol.6, No.1, p.793 (1996); substituted Proline, J. Chem. Soc. Perkin. Trans., vol. 1, pp.539, 547, 555 (197); N-(aminomethyl)-β-alanine, Tetrahedron Lett., vol.36, No.38, R (1995); substituted ornithine, Nucleosides and Nucleotides, vol. 17 (1-3), pp.219, 339 (1998); the structure vi, Tetrahedron Lett., vol.36, No.10, p.1713 (1995); Tetrahedron Lett., vol.38, No.48, p.8363 (1997); structure v, Tetrahedron Lett., vol. 39, p. 4707 (1998); compound iv, J. Amer. Chem. Soc., vol.119, p.11116 (1997); aminopropan, Bioorganic and Medicinal Chemistry Lett., vol.7, no.6, p.681 (1997); chiral poliolefinovoy acid, Tetrahedron Lett., vol.35, No.29, R (1994); Bioorganic and Medicinal Chemistry Lett., vol.4, no.8. p.1077 (1994).

Below is a detailed description of the synthesis of an analog of No. 1. Other peptides according to the invention can be obtained by making appropriate modifications within the ability of the specialist in the field of peptide synthesis.

Stage 1. Obtaining Fmoc-Nal-O-tert-butyl-Tyr-S-trityl-D-Cys-N-in-t-Boc-D-Trp-N-ε-t-Boc-Lys-S-trityl-D-Cys-Abu-Nal-4-(2',4'-dimethoxyphenethyl)phenoxyacetamide-4-methylbenzhydrylamine resin.

The amide resin MUNA Rink (Novabiochem, Inc., San Diego, CA), 1 g (of 0.53 mmol), was placed in the reaction vessel No. 1 (RV-1) peptide synthesizer model 90 (Advanced ChemTech, Louisville, KY). The peptide synthesizer was programmed to perform the next cycle of the reaction:

a) dimethylformamide;

b) 25% piperidine in dimethylformamide (2 times for 15 minutes each, with 1 DMF washing between them);

(C) washing DMF (3×10 ml, 1 min each).

The resin was mixed with Fmoc-Nal (2,12 mmol), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBT) (a 2.01 mmol) and diisopropylethylamine (4,24 mmol) in dimethylformamide for about 1 1/2hours and then the resulting resin with the amino acid were subjected to cyclic reactions (a) through (C) stages in the above program. Nal-resin was associated with Fmoc-Abu, and then was subjected to a cycle of reactions, as described above. The resin was dried in vacuum.

The following amino acids (1.4 mmol) was consistently associated with the peptide on the resin (0.35 mmol) by the same procedure: Fmoc-S-trityl-D-Cys, Fmoc-N-ε-t-Boc-Lys, Fmoc-N-in-t-Boc-D-Trp. After drying in vacuum, the resin peptide was divided and one part connected with Fmoc-S-trityl-AU-Cys, Fmoc-O-t-butyl-Tyr. Associated part was again divided and one part connected with Fmoc-Nal. After washing DMF (3×10 ml, 1 min each) and drying in vacuum filled resin weighed 0,242,

Stage 2. Getting

The resin with the peptide obtained in stage 1 (0.24 g, 0,087 mmol), was mixed with a freshly prepared solution of TFU (8,8 ml), phenol (0.5 g), N2About (0.5 ml) and triisopropylsilane (0.2 ml) at room temperature and was stirred for approximately 21/2hours. Excess TFU evaporated under reduced pressure to an oily residue. Then to the oily residue was added ether and precipitated free linear peptide was filtered, then washed with dry ether. Then the crude peptide was dissolved in 11 ml of CH3CN/N2O/a 0.1 N HOAc (5 ml/5 ml/1 ml), after which was added 200 mg see the crystals EKATHIOX® . The mixture was stirred overnight and then filtered. The filtrate was evaporated to small volume, then applied on a column (22-250 mm) with microturbines silicon oxide modified octadecylsilane (5 μm), followed by elution with a linear gradient from 30% to 80%, within 30 minutes of acetonitrile in water, where both solvents contain 0.1% of triperoxonane acid. Fractions were evaluated by analytical highly effective liquid chromatography (HPLC) and were combined to obtain maximum purity. Lyophilization of solutions to remove the water gave 10 mg of the product as a white, fluffy powder. By HPLC on a column of C18with silica using the same solvent that is listed directly above, found that the product is homogeneous (tR=16,646 minutes). Infusion mass spectrometry confirmed the structure of cyclic oktapeptid (Mm 1178,45).

OTHER OPTIONS

Based on the above description, the person skilled in the art will easily outline the main features of this invention and, without departing from the essence and without leaving the scope of the invention, can make various changes and modifications of the invention to adapt it to various uses and conditions. Thus, other options are also included in the invention.

1. The compound of formula (II)

or its pharmaceutically acceptable salt,

where α-nitrogen each AA1, AA2, AA3, AA4, AA5, AA6, AA7and AA8independently optionally substituted C1-4)alkyl, (C3-4-alkenyl, (C3-4)quinil or (C1-6)alkyl-C(O)-;

AA1missing is Ac-D-Phe or D - or L-isomer R11, Pip, Pro or aromatic α-amino acid selected from the group consisting of CPA, Dip, Nal and Phe;

AA2is missing, Pal, Phe, Tyr;

AA3is D - or L-isomer of Cys;

AA is D - or L-isomer Thr;

AA5means Lys;

AA6is D - or L - isomer of Cys;

AA7is As, As, As, As, Abu, Aic, β-Ala, Gaba, Nle, Pro, Sar, Thr, Thr(Bzl), Val or absent and

AA8is R11, Nal, Thr, Tight, Phe, Nle or missing;

each of R1and R2independently represents H or is absent;

R5is-NR7R8where each R7and R8independently represents H,

R11independently for each case is D - or L - amino acid formula

where each of m and n independently is 1, 2 or 3 and p is 0, 1 or 2;

R12independently for each case is optionally substituted by a fragment of the formula

;

X1means H, (C1-6)alkyl or a fragment, which corresponds to a group of the side chain of Arg, Leu, Gin, Lys, Tyr, His, Thr, Trp, Phe, Val, Ala, Lys or His;

each of X2and X3independently represents H, halogen, (C1-12)

alkyl, phenyl, phenyl-(C1-6)alkyl;

X4means N, HE or NH2;

provided that available is t, at least six

amino acid residues;

AA3and AA6linked by a disulfide bond;

and a specified compound of formula (II) has the formula:

D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Ac-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

L-4-NO2-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Ac-L-4-NO2-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Hca-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

D-Dip-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

D-4-NO2-Phe-Phe(4-O-Bzl)-cyclo(D-Cys-D-Trp-Lys-Cys)Cha-Nal-NH2;

or

D-4-NO2-Phe-cyclo(D-Cys-Phe(4-O-Bzl)-D-Trp-Lys-Cys)-Val-Tyr-NH2.

2. The compound according to claim 1, where AA1is missing or D - or L-isomer R11, Pip or Pro, or aromatic α-amino acid selected from the group consisting of CPA, Dip, Nal, Phe, and Ac-Phe; AA2is Tyr, Pal, Phe or absent; AA3is D - or L-isomer of Cys; AA4mean D-Trp; AA5means Lys; AA6is D - or L - isomer of Cys; AA7means the gas station, As, As, As, Abu, Aic, β-Ala, Gaba, Nle, Pro, Sar, Thr, Thr(Bzl), Val or absent; and AA8is R11, Thr, Nal, Tight or missing; or its pharmaceutically acceptable salt.

3. The compound according to claim 2, where the specified connection has the formula

Ac-D-Phe-Tyr-cyclo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-ValNal-NH 2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

D-Dip-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A3c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A6c-Nal-NH2;

(G(z)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-β-Ala-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Sar-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Pro-Nal-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nle-Phe-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-Nle-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-Phe-NH2;

Cpa-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-NH2;

Cpa-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Tyr-NH2;

Pip-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-NH2;

Pip-Phe-cyclo(Cys-D-Trp-Lys-Cys)-Gaba-NH2or

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr-NH2,

or its pharmaceutically acceptable salt.

4. The compound according to claim 2, where the specified compound corresponds to the formula

Phe-cyclo(Cys-D-Trp-Lys-Cys)-Thr-NH2,

Phe-Tyr-cyclo(D-Cys-D-Tip-Lys-Cys)-Abu-Thr-NH2;

Ac-D-Phe-Tyr-qi is lo(D-Cys-D-Trp-Lys-Cys)-Abu-Thr-NH 2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Tq)-Lys-D-Cys)-Val-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A3c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A6c-Nal-NH2;

(G(z)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

D-Cpa-cyclo(Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-β-Ala-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Sar-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Aic-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Pro-Nal-NH2;

(T)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-(A)aeg-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A4c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nal-NH2;

Pro-Phe-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-NH2;

Pro-Phe-cyclo(D-Cys-D-Trp-Lys-Cys)-Val-NH2;

Pip-4-NO2-Phe-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Nle-NH2;

(G)aeg-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr(Bzl)-(C)aeg-NH2or

(C)aeg-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Thr(Bzl)-(G)aeg-NH2,

or supplied the ski acceptable salt.

5. Way to call agonistic action on the part of the receptor neuromedin In the patient who needs it, thus this method includes the introduction of a specified subject an effective amount of a compound according to claim 3 or its pharmaceutically acceptable salt.

6. Way to call the agonistic action of somatostatin receptor in a patient who needs it, thus this method includes the introduction of a specified subject an effective amount of a compound according to claim 4 or its pharmaceutically acceptable salt.

7. Way to call agonistic action SSTR-1 in a patient who needs it, thus this method includes the introduction of a specified subject an effective amount of a compound according to claim 4 or pharmaceutically acceptable salts, provided that the specified connection is not

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Abu-Nal-NH2;

Dip-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Nal-Tyr-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Val-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A3c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A6c-Nal-NH2;

(G(z)aeg-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

D-Cpa-cyclo(Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-cyclo(D-Cys-D-Trp-Lys-D-Cys)-A5c-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-β-Ala-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Sar-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Aic-Nal-NH2;

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Gaba-Nal-NH2or

Cpa-Pal-cyclo(D-Cys-D-Trp-Lys-D-Cys)-Pro-Nal-NH2.

8. Pharmaceutical composition having the properties of somatostatin receptor comprising an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

9. A method of treating disease in a subject, comprising the introduction of a specified subject a therapeutically effective amount of a compound according to claim 1, where the disease is selected from the group consisting of lung cancer, glioma, anorexia, hypothyroidism, hyperaldosteronism, proliferation .pylori, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external or internal false cysts of the pancreas and liver, Vipoma, hyperplasia of pancreatic islets, hyperinsulinism, gastrinoma syndrome Zollinger - Ellison, diarrhoea, diarrhea, AIDS-related diarrhea associated with chemotherapy, scleroderma, irritable bowel syndrome, pancreat the obstruction of the small intestine, gastroesophageal reflux, duodenogastric reflux, Cushing's syndrome, gonadotropinum, hyperparathyroidism, graves ' disease, diabetic neuropathy, Paget's disease, and polycystic disease of the ovary, thyroid cancer, hepatoma, leukemia, meningioma, cancer cachexia, orthostatic hypotension, postprandial hypotension, panic States, adenomas secreting GH, acromegaly, adenomas secreting TSH, adenomas secreting prolactin, insulinoma, glucagonoma, diabetes, hyperlipidemia, insensitivity to insulin, syndrome X, angiopathy, proliferative retinopathy, the phenomenon of "dawn", nephropathy, secretion of gastric acid, peptic ulcers, bowel-skin fistula, skin - pankreaticheskoi fistula, dumping syndrome, syndrome water diarrhoea, pancreatitis, tumors secreting gastrointestinal hormones, angiogenesis, arthritis, rejection of allogeneic transplant, bleeding in vascular transplantation, portal hypertension, gastrointestinal bleeding, obesity and an overdose of opioids.



 

Same patents:

FIELD: organic chemistry, peptides, pharmacy.

SUBSTANCE: invention relates to biologically active compounds as antagonists of somatostatin. Invention represents compound of the formula (I): A1-cyclo-{D-Cys-A2-D-Trp-A3-A4-Cys}-A-Y1 wherein A1 represents aromatic α-amino acid taken among the group: Cpa, Tfm, 1-Nal, 2-Nal and 3-Pal and substituted optionally with one or some substitutes taken among halogen atom and (C1-6)-alkyl; A2 represents aromatic amino acid taken among the group: 3-Pal and Tyr and substituted optionally with one or some substituted taken among halogen atom, (C1-6)-alkyl, OH-group; A3 represents Lys, Dab, Dap, Orn; A4 represents Thr, β-hydroxyvaline, Ser, Hser; A5 represents D- or L-aromatic α-amino acid taken among the group: Dip, 2-Nal, Trp; Y1 represents -NH2 or -MHMe wherein amine nitrogen in each amide peptide bond and amino-group A1 are substituted optionally with methyl group under condition that at least one abovementioned methyl group presents; or its pharmaceutically acceptable salt.

EFFECT: valuable biological properties of compounds.

11 cl, 1 dwg, 3 tbl, 16 ex

FIELD: bioorganic chemistry.

SUBSTANCE: invention provides somatostatin agonists of general formula: A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1 (I), wherein A1 represents aromatic D- or L-α-amino acid selected from Phe, D-Phe, Tyr, D-Tyr, β-Nal, D-β-Nal, Cha, or D-Cha; A2 aromatic α-amino acid selected from Phe, Tyr, β-Nal, and Cha; A3 Lys or Orn; A4 β-hydroxyvaline, Ser, hSer, or Thr; A5 β-hydroxyvaline, Ser, hSer, or Thr; and Y1 represents NH2; amide nitrogen atoms of peptide groups and amine group of A1 in compound I are optionally substituted by methyl group, provided that at least one methyl group is available and that compound I cannot have following formula: D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH-2. pharmaceutically acceptable salts of compound I are also claimed.

EFFECT: expanded synthetic possibilities in peptide synthesis.

24 cl, 2 tbl, 18 ex

The invention relates to compounds of formula (I) or (II)

or their pharmaceutically acceptable salts, where Y and Z each for each case independently represents a D - or L-natural or unnatural-amino acid; n in each case independently is 0 or 4, (I) provided that both n cannot simultaneously be 0; and 0 or 4 (II)

moreover, these amino acids (I) are chain: X1-X2-X3-X4where X1represents Tyr or Trp, which may be protected by a BOC group; X2represents D-Trp; X3represents Lys, which may be protected by a BOC group; X4is a Nal, Tyr or Thr; m is 0; a represents N or R1b means HE or OR1; (II) X1is a natural or non-natural D - or L-isomer of Phe, Trp or Tyr, where in the case when X1is Tyr, an aromatic ring in its side chain optionally substituted by R6; X2is a D - or L-isomer of Trp; X3represents Lys; X4represents Opticheskie ring, disposed in its side chain may be optionally substituted by R6or in the case when X4is either Ser or Thr, the oxygen atom located in its side chain, optionally may be substituted by one or more R1

The invention relates to a production method of compound I with a slow release of the active ingredient, which comprises the compound (A):

< / BR>
and the polymer containing lactide, glycolide monomers and monomers of tartaric acid in the amount of 71-73%, 26-28% and 1-3%, respectively, and the amino group of the compound (A) is connected by means of ionic bonds with the carboxyl group of the acid monomers of the polymer, while this method involves the step of interacting an aqueous solution (A) with the polymer or its salt in a mixture of acetonitrile and water, in which the weight ratio of acetonitrile and water is approximately 3 : 1, respectively, at a temperature approximately equal to 0-5oWith, up until the formation of compound I is not completed; the method of producing microparticles of compound I by spraying a solution of compound I in ethyl acetate in isopropyl alcohol to obtain a dispersion of microparticles of compound I

The invention relates to somatostatinomas peptides, method for their production and pharmaceutical preparations containing them

The invention relates to medicine, in particular to the creation of analogues of hormonal drugs protein nature

FIELD: medicine, genetic engineering.

SUBSTANCE: invention proposes a method that involves construction of bacteriophage library of random peptides based on oligonuleotide fragments encoding their, selection of bacteriophages binding with target-cells but not binding with cells of other types that can be involves in pathological process or able to show effect on its diagnosis and therapy, and confirmation of specificity of selected bacteriophages by using combination of different tests. Oligonucleotide fragments encoding random peptides are prepared by reaction of reverse transcription by using random primers and total RNAs isolated from indicated target-cells and cells of other types. Applying this invention provides preparing bacteriophages binding with target-cells with high degree of selectivity. Invention can be used in diagnosis, therapy and pharmaceutical industry.

EFFECT: improved preparing method.

3 cl, 2 dwg, 8 ex

FIELD: chemistry of peptides, medicine.

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EFFECT: improved method for detecting, valuable medicinal properties of agent.

14 cl, 5 tbl, 5 dwg, 9 ex

FIELD: biotechnology, in particular epithelial cell growth factors useful in production of new keratinocyte growth factor (KGF).

SUBSTANCE: KGF protein is obtained by cultivation of recombinant host cell, transformed with vector containing DNA which encodes amini acid sequence of KGF protein. Obtained KGF protein in pharmaceutical composition is used for forcing of epithelial cell proliferation. Method of present invention makes it possible to produce KGF protein with specific mitogenic activity of 3.4 x 104 U/mg of protein in relation to keratinocyte cells.

EFFECT: new keratinocyte growth factor.

52 cl, 14 dwg, 3 tbl

FIELD: gene engineering, in particular purification and isolation of polynucleotides.

SUBSTANCE: invention relates to purification and isolation of polynucleotides regulating mammalian gene transcription and is useful in regulation of heterologous polynucleotide expression, obtaining transgene animals, and identification of affined regulatory DNA sequences. DNA containing transcriptional regulatory DNA of hamster gene EF-1α was isolated by screening of genome library to Chinese hamster ovary (CHO-K1). Chimeric polynucleotide including isolated regulatory DNA of hamster gene EF-1α operably bonded to gene sequence encoding target protein product other than protein encoded by hamster gene EF-1α was constructed. Obtained chimeric polynucleotide is used as component of expression plasmid for transformation or transfection of host cell. To increase target gene transcription in host cell DNA containing regulatory DNA of hamster gene EF-1α was integrated into host cell genome DNA in site operably bonded to target gene. Method of present invention make it possible to increase mRNA expression level for operably bonded heterologous polynucleotides by 3-11 times.

EFFECT: increased mRNA expression of operably bonded heterologous polynucleotides.

31 cl, 3 tbl, 7 ex

FIELD: biotechnology, molecular biology, medicine, genetic engineering, pharmacy.

SUBSTANCE: the hemopoietic protein comprises the amino acid sequence of the formula: R1-L1-R1, R2-L1-R1, R1-R2 or R2-R1 wherein R1 represents the modified ligand flt-3; R2 represents the modified human IL-3, the modified or unmodified colony-stimulating factor. Modification of R1 is carried out by addition of N-end with C-end directly or through linker (L2) that is able to join N-end with C-end to form new C- and N-ends. The modified human IL-3 is prepared by replacing amino acids at positions 17-123. The human G-CSF is modified by exchange of amino acids. The hemopoietic protein is prepared by culturing cells transformed with vector comprising DNA that encodes the hemopoietic protein. The hemopoietic protein stimulates producing hemopoietic cells and this protein is used as a component of pharmaceutical composition used in treatment of humans suffering with tumor, infectious or autoimmune disease. Invention provides preparing multifunctional hemopoietic proteins eliciting the enhanced activity with respect to stimulation of hemopoietic cells and eliciting the improved physical indices. Invention can be used for preparing chimeric multifunctional hemopoietic proteins.

EFFECT: improved preparing and producing method, valuable medicinal properties of protein.

22 cl, 19 dwg, 18 tbl, 117 ex

Thrombopoietin // 2245365

FIELD: medicine, molecular biology, polypeptides.

SUBSTANCE: invention describes homogenous polypeptide ligand mpI representing polypeptide fragment of the formula: X-hTPO-Y wherein hTPO has amino acid sequence of human fragments TPO (hML); X means a amino-terminal amino-group or amino acid(s) residue(s); Y means carboxy-terminal carboxy-group or amino acid(s) residue(s), or chimeric polypeptide, or polypeptide fragment comprising N-terminal residues of amino acid sequence hML. Also, invention relates to nucleic acid encoding polypeptide and expressing vector comprising nucleic acid. Invention describes methods for preparing the polypeptide using cell-host transformed with vector, and antibodies raised against to polypeptide. Invention describes methods and agents using active agents of this invention. The polypeptide ligand mpI effects on replication, differentiation or maturation of blood cells being especially on megacaryocytes and progenitor megacaryocyte cells that allows using polypeptides for treatment of thrombocytopenia.

EFFECT: valuable medicinal properties of polypeptide.

21 cl, 92 dwg, 14 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tocopherol, tocotrienol and other derivatives of chroman of the general formula (1): wherein X is taken among the group comprising oxygen and nitrogen atoms; Y is taken among the group comprising oxygen, nitrogen and sulfur atoms wherein if Y represents oxygen or nitrogen atom then n = 1 and if Y represents sulfur atom then n = 0; R1 represents residue of carboxylic acid, carboxamide, ester, alcohol, amine or sulfate; R2 represents methyl; R3 represents methyl; R4 represents methyl; R5 is taken among the group comprising alkyl, alkenyl, alkynyl, carboxyl and ester residue wherein if Y represents nitrogen atom then indicated nitrogen atom is replaced with group R6 wherein R6 represents hydrogen atom or methyl wherein if X represents oxygen atom, Y represents oxygen atom and R5 represents phytyl then R1 doesn't mean butanoic acid. Also, invention relates to a pharmaceutical composition based on these compounds, a method for treatment of cellular-proliferative disease and a method for induction of cells apoptosis. Invention provides preparing new compounds possessing the proliferative effect.

EFFECT: valuable medicinal properties of compounds.

36 cl, 4 tbl, 19 dwg, 19 ex

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