Melanocortin receptor ligands

FIELD: medicine.

SUBSTANCE: present invention concerns a compound representing a selective agonist of a melanocortin-4 receptor of formula: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50) and its pharmaceutically acceptable salts, pharmaceutical compositions and methods for application thereof in preparation of drugs.

EFFECT: higher effectiveness of compound application.

20 cl, 8 dwg, 4 tbl, 4 ex

 

Description of the prior art

The present invention relates to peptides that are ligands of one or more receptors melanocortin (MC-R), their pharmaceutically acceptable salts, methods of using such peptides for the treatment of mammals and useful pharmaceutical compositions comprising these peptides.

Melanocortin are a family of regulatory peptides, which are formed by post-translational processing of Pro-hormone, Pro-opiomelanocortin (O.G. ROMs; length of 131 amino acids). O.G. ROMs processed in 3 classes of hormones: melanocortin, adrenocorticotropic hormone, and various endorphins (for example, lipotropin) (Cone, et al., Recent Prog. Horm. Res., 51:287-317, (1996); Cone et al., Ann. N.Y. Acad. Sci., 31:342-363, (1993)).

Melanocortin were found in a wide variety of normal human tissues, including brain, adrenal gland, skin, testes, spleen, kidneys, ovaries, lungs, thyroid, liver, large intestine, small intestine, and pancreas (Tatro, J. B. et al., Endocrinol. 121:1900-1907 (1987); Mountjoy, K. G. et al., Science 257:1248-1251 (1992); Chhajlani, V. et al., FEBS Lett. 309:417-420 (1992); Gantz, I. et al. J. Biol. Chem. 268:8246-8250 (1993) and Gantz, I. et al., J. Biol. Chem. 268:15174-15179 (1993)).

It was shown that peptides melanocortin display a wide diversity of physiological activity, including the regulation of behavior and memory effects on neuro is romnie and antipyretic properties, as well as effects on the modulation of the immune system. It was also shown that melanocortin, in addition to their well known effects on the adrenal cortex (adrenocorticotropic hormone, ACTH) and melanocyte (melanocyte-stimulating hormone, MSH), regulate the cardiovascular system, analgesia, thermoregulation and release of other neurohumoral agents, including prolactin, luteinizing hormone and biogenic amines (De Wied, D. et al., Methods Achiev. Exp. Pathol. 15:167-199 (1991); De Wied, D. et al., Physiol. Rev. 62:977-1059 (1982); Guber, K.A. et al., Am. J. Physiol. 257:R681-R694 (1989); Walker, J.M. et al., Science 210:1247-1249 (1980); Murphy, M. T. et al., Science 221:192-193 (1983); Ellerkmann, E. et al., Endocrinol. 130:133-138 (1992) and Versteeg, D. H. G. et al., Life Sci. 38:835-840 (1986)).

It was also shown that the binding sites of melanocortins distributed in many different types of tissues, including the lacrimal and submandibular glands, pancreas, adipose tissue, bladder, 12-dispersed intestine, spleen, brain and tissues of the genital glands, as well as in malignant melanoma tumors. Characterized to date 5 receptor melanocortin (MC-R). They include melanocyte-specific receptor (MC1-R), specific for adrenal ACTH receptor (MC2-R), the receptor melanocortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-5 (MC5-R). All receptors melanocortin respond to a class of peptide hormones that stimulate melanocyte (MSH) (Cone, R.D. et al., Ann. N.Y. Acad. Sci., 680:342-363 (1993); Cone, R. D. et al., Recent Prog. Horm. Res., 51:287-318 (1996)).

MC1-R, known in this area as the receptor for melanocyte-stimulating hormone (MSH-R), the receptor melanotropin or receptor melanocortin-1, is a transmembrane protein of 315 amino acids, belonging to the family of receptors associated with G-protein. MC1-R is a receptor for MSH and ACTH. The activity of MC1-R mediated by G-proteins that activate adenylate cyclase. Receptors MC1-R is found in melanocytes and tissue of the adrenal cortex, and also in various other tissues such as the adrenal glands, leukocytes, lung, lymph nodes, ovaries, testes, pituitary gland, placenta, spleen and uterus. MC2-R, also called adrenocorticotropic hormone receptor (ACTH-R), is a transmembrane protein of 297 amino acids found in melanocytes and tissue of the adrenal cortex. MC2-R mediates corticotropinby the effect of ACTH. People MC3-R is a protein of 360 amino acids found in the brain tissue; in mice and rat MC3-R is a protein of 323 amino acids. MC4-R is a transmembrane protein of 332 amino acids, which is also expressed in the brain, as well as in the tissues of the placenta and intestine. MC5-R is a transmembrane protein of 325 amino acids, expressed in adrenal glands, stomach, lung, and sales the NECS and at very low levels in the brain. MC5-R is also expressed in the three layers of the adrenal cortex, predominantly in cells glomerulosa zone, producing aldosterone.

However, five known receptors melanocortin different functions. For example, MC1-R is a G-protein that regulates pigmentation in response to α-MSH, a potent agonist MC1-R. Agonism receptor MC1-R leads to stimulation of melanocytes, which causes the formation of eumelanin and increases the risk of skin cancer. Agonism MC1-R can also have neurological effects. Stimulation of the activity of the MC2-R can lead to carcinoma tissue of the adrenal glands. Recent pharmacological proof established that the Central receptor MC4-R are primary mediators anorexically and orexigenic effects reported in relation to, respectively, agonists and antagonists melanocortin. Effects agonism MC3-R and MC5-R is not yet known.

There was also great interest in receptors melanocortin (MC-R) as targets for developing new therapeutic agents for the treatment of disorders of body weight, such as obesity and cachexia. Both genetic and pharmacological evidence points to the Central receptor MC4-R as its main target (Giraudo, S. Q. et al., Brain Res., 809:302 to 306 (1998); Farooqi, I. S. et al., NE J Med., 348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-157 (2002); MacNeil, D. J. et al., Eu. J. Pharm., 450:93-109 (2002); Kask, A.et al., NeuroReport, 10:707-711 (1999)). Modern achievements in the development of selective receptor agonists and antagonists indicates therapeutic potential of activated receptor melanocortin, in particular MC4-R.

Agonistic, antagonistically or other ligand compounds that activate one or more receptor melanocortin, could be used to treat a wide variety of indications in a subject in need of them, or risk of development, including acute and chronic inflammatory diseases, such as General inflammation (U.S. Patent No. 6613874; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), inflammatory bowel disease (U.S. patent No. 6713487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), encephalitis (Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), sepsis (U.S. patent No. 6613874; U.S. patent No. 6713487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)) and septic shock (U.S. patent No. 6613874; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)); diseases with an autoimmune component, such as rheumatoid arthritis (U.S. patent No. 6713487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), gouty arthritis (Catania, A. et al., Pharm. Rev., 56:1-29 (2004), Getting, S. J. et al., Curr. Opin. Investig. Drugs, 2:1064-1069 (2001)) and multiple sclerosis (U.S. patent No. 6713487); metabolic diseases and medical conditions associated with weight gain such as obesity (U.S. patent No. 6613874; U.S. patent No. 6600015; Fehm, H. L. et al., J. Clin. Endo. & Metab., 86:1144-1148 (2001); Hansen, M. J. et al., Brain Res., 1039:13-145 (2005); Ye, Z. et al., Peptides, 26:2017-2025 (2005); Farooqi, I. S. et al., NE J Med., 348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-157 (2002); MacNeil, D. J. et al., Eu. J. Pharm., 450:93-109 (2002); Kask, A. et al., NeuroReport, 10:707-711 (1999); Schwartz, A. W., J. Clin. Invest., 108:963-964 (2001), Gura, T., Science, 287:1738-1740 (2000), Raffin-Sanson, M. L., Eu. J. Endo., 144:207-208 (2001), Hamilton, B. S. et al., Obesity Res. 10:182-187 (2002)), feeding disorders (U.S. patent No. 6720324; Fehm, H. L. et al., J. Clin. Endo. & Metab., 86:1144-1148 (2001); Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-2546 (2005)) and Prader-Willi Syndrome (GE, Y. et al., Brain Research, 957:42-45 (2002)); metabolic disease or medical condition accompanied by weight loss such as anorexia (U.S. patent No. 6613874; Wisse, B.R. et al., Endo., 142:3292-3301 (2001)), bulimia (U.S. patent No. 6720324), depletion in AIDS (Marsilje, T. H. et al., Bioorg. Med. Chem. Lett., 14:3721-3725 (2004); Markison, S. et al., Endocrinology, 146:2766-2773 (2005)), cachexia (U.S. patent No. 6613874; Lechan, R. M. et al., Endo., 142:3288-3291 (2001); Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-2546 (2005)), cancer cachexia (U.S. patent No. 6639123) and malnutrition in malnourished older persons (U.S. patent No. 6639123); diabetes (U.S. patent No. 6713487) and diabetes-related conditions and complications of diabetes, such as retinopathy (U.S. patent No. 6525019); neoplastic proliferation (U.S. patent No. 6713487), such as skin cancer (Sturm, R.A., Melanoma Res., 12:405-416 (2002); Bastiens, M. T. et al., Am. J. Hum. Genet., 68:884-894 (2001)) and prostate cancer (Luscombe, C.J. et al., British J. Cancer, 85:1504-1509 (2001); reproductive or sexual health conditions such as endometriosis (U.S. patent No. 6713487) and uterine kr is vaticinia women (U.S. patent No. 6613874), sexual dysfunction (U.S. patent No. 6720324; Van der Ploeg, L. H. T. et al., PNAS, 99:11381-11386 (2002), Molinoff, P. B. et al., Ann. N.Y. Acad. Sci., 994:96-102 (2003), Hopps, C. V. et al., BJU International, 92:534-538 (2003)), erectile dysfunction (U.S. patent No. 6613874; Diamond, L. E. et al., Urology, 5:755-759 (2005), Wessells, H. et al., Int. J Impotence Res., 12:set S74-S79 (2000), Andersson, K-E. et al., Int. J Impotence Res., 14:S82-S92 (2002), Bertolini / Marian Fisher, A. et. al., Sexual Behavior: Pharmacology and Biochemistry, Raven Press, NY, p 247-257 (1975); Wessells, H. et al, Neuroscience, 118:755-762 (2003), Wessells, H. et al., Urology, 56:641-646 (2000), Shadiack, A. M. et al., Society for Neuroscience Abstract, (2003); Wessells, H. et al., J. of Urology, 160:389-393 (1998), Rosen, R. et al., Int. J Impotence Res., 16:135-142 (2004), Wessells, H. et al., Peptides, 26:1972-1977 (2005)) and decreased sexual response in women (U.S. patent No. 6713487; Fourcroy, J.L., Drugs, 63:1445-1457 (2003)); disease or condition resulting from treatment or damaging effects on the body, such as the rejection of organ transplant (U.S. patent No. 6713487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), ischemic and reperfusion injury (Mioni, C. et al., Eu. J. Pharm. 477:227-234 (2003); Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), treatment of spinal cord injury and accelerate wound healing (Sharma H. S. et al., Acta. Nerochir. Suppl., 86:399-405 (2003); Sharma, H. S., Ann. N.Y. Acad. Sci. 1053: 407-421 (2005); U.S. patent No. 6525019), and loss of body weight caused by chemotherapy, radiation therapy, temporary or permanent immobilization (Harris, R. B. et al., Physiol. Behav., 73:599-608 (2001)) or dialysis; cardiovascular diseases or conditions such as hemorrhagic shock (Catania, A. et al., Pharm. Rev., 56:1-29(2004)), cardiogenic shock (U.S. patent No. 6613874), hypovolemic shock (U.S. patent No. 6613874), cardiovascular disorders (U.S. patent No. 6613874) and cardiac cachexia (Markison, S. et al., Endocrinology, 146:2766-2773 (2005); pulmonary disease or condition, such as acute respiratory distress syndrome (U.S. patent No. 6350430; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), chronic obstructive pulmonary disease (U.S. patent No. 6713487), asthma (U.S. patent No. 6713487) and pneumovirus; to strengthen the immune tolerance (Luger, T. A. et al., Pathobiology, 67:point of 319-321 (1999)) and to combat attacks on the immune system, such as impacts associated with certain types of allergies (U.S. patent No. 6713487), or rejection of organ transplants (U.S. patent No. 6713487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), the treatment of dermatological diseases and conditions, such as psoriasis (U.S. patent No. 6713487), depletion of skin pigmentation (U.S. patent No. 6713487; Ye, Z. et al., Peptides, 26:2017-2025 (2005), eels (Hatta, N. et al., J. Invest. Dermatol., 116:564-570 (2001); Bohm, M. et al., J. Invest. Dermatol., 118:533-539 (2002)), the formation of keloids (U.S. patent No. 6525019) and skin cancer (Sturm, R.A., Melanoma Res., 12:405-416 (2002); Bastiens, M. T. et al., Am. J. Hum. Genet., 68:884-894 (2001)); behavioral disorders and conditions and disorders of the Central nervous system such as anxiety (U.S. patent No. 6720324; Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-2546 (2005)), depression (Chaki, S. et al., Peptides, 26:1952-1964 (2005), Bednarek, M. A. et al., Expert Opinion Ther. Patents, 14:327-336 (2004); U.S. patent No. 6720324, disorders and dysfunction of memory (U.S. patent No. 6613874; Voisey, J. et al., Curr. Drug Targets, 4:586-597 (2003)), the modulation of pain perception (U.S. patent No. 6613874; Bertolini / Marian Fisher, A. et al., J. Endocrinol. Invest, 4:241-251 (1981); Vrinten, D. et al., J. Neuroscience, 20:8131-8137 (2000)) and the treatment of neuropathic pain (Pontillo, J. Et al., Bioorganic & Med. Chem. Ltrs., 15:2541-2546 (2005)); conditions and diseases associated with alcohol consumption, alcohol abuse and/or alcoholism (WO 05/060985; Navarro, M. et al., Alcohol Clin. Exp. Res., 29:949-957 (2005)); and kidney condition or disease, such as treatment of renal cachexia (Markison, S. Et al., Endocrinology, 146:2766-2773 (2005) or nutrient (U.S. patent No. 6613874).

Ligand compounds that activate one or more receptor melanocortin, would be useful for modeling a wide variety of normalizing or homeostatic activity in need of the subject that includes the release of thyroxine (U.S. patent No. 6613874), synthesis and release of aldosterone (U.S. patent No. 6613874), body temperature (U.S. patent No. 6613874), blood pressure (U.S. patent No. 6613874), heart rate (U.S. patent No. 6613874), vascular tone (U.S. patent No. 6613874), cerebral blood flow (U.S. patent No. 6613874), the levels of glucose in the blood (U.S. patent No. 6613874), bone metabolism, the formation and development of bone tissue (Dumont, L. M. et al., Peptides, 26:1929-1935 (2005), the mass of the ovaries (U.S. patent No. 6613874), development of the placenta (U.S. patent No. 6613874), the secretion about the actin and FSH (U.S. patent No. 6613874), intrauterine fetal growth (U.S. patent No. 6613874), childbirth (U.S. patent No. 6613874), spermatogenesis (U.S. patent No. 6613874), the secretion of fat and pheromones (U.S. patent No. 6613874), neuroprotection (U.S. patent No. 6639123) and nerve growth (U.S. patent No. 6613874), and modulation of motivation (U.S. patent No. 6613874), training (U.S. patent No. 6613874) and other behaviors (U.S. patent No. 6613874).

Therefore, the aim of the present invention is to provide ligands for receptor melanocortin that exhibit greater stability and selectivity for receptors melanocortin than native ligands of receptors melanocortin.

A brief description of the invention

In one aspect of the present invention is directed to a compound in accordance with formula (I):

(R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1,

where

And1represents the ACC, HN-(CH2)m-C(O), L - or D-amino acid or subjected deletions;

And2represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

And3represents Gly, Ala, β-Ala, Gaba, Aib, D-amino acid or subjected deletions;

And4represents His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X1X2X3X4X5)Phe;

And5represents D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X1X2X3X4X5/sup> )Phe, L-Phe or D-(Et)Tyr;

And6represents Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O);

And7represents Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip;

And8represents Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)s-C(O) or subjected deletions;

And9represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;

And10represents the ACC, HN-(CH2)t-C(O), L - or D-amino acid or subjected deletions;

R1represents-OH or NH2;

each of R2and R3independently for each case selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)quinil, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C1-C30)acyl, substituted (C2-C30)alkenyl, substituted (C2-C30)quinil, substituted aryl(C1-C30)alkyl and substituted aryl(C1-C30)acyl;

each of R4and R5independently for each case represents H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)lceil, (C2-C40)quinil, aryl(C1-C40)alkyl, aryl(C1-C40)acyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C1-C40)acyl, substituted (C2-C40)alkenyl, substituted (C2-C40)quinil, substituted aryl(C1-C40)alkyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl or -- C(NH)-NH2;

m, independently for each case= 1, 2, 3, 4, 5, 6 or 7;

n is independently for each case = 1, 2, 3, 4 or 5;

s independently for each case= 1, 2, 3, 4, 5, 6 or 7;

t independently for each case= 1, 2, 3, 4, 5, 6 or 7;

each of X1X2X3X4and X5independently for each case represents H, F, Cl, Br, I, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C2-C10)alkenyl, substituted (C2-C10)alkenyl, (C2-C10)quinil, substituted (C2-C10)quinil, aryl, substituted aryl, OH, NH2, NO2or CN;

provided that

(I) when R4is a (C1-C40)acyl, aryl(C1-C40)acyl, substituted (C1-C40)acyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl or -- C(NH)-NH2then R5is a (C1-C40)alkyl, (C -C40)heteroalkyl, (C2-C40)alkenyl, (C2-C40)quinil, aryl(C1-C40)alkyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C2-C40)alkenyl, substituted (C2-C40)quinil or substituted aryl(C1-C40)alkyl;

(II) when R2is a (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C1-C30)acyl, or substituted aryl(C1-C30)acyl, then R3represents H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, (C2-C30)quinil, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)quinil or substituted aryl(C1-C30)alkyl;

(III) any And3and8or they both must be present in the specified connection;

(IV) when And2represents Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, And then9represents Cys, D-Cys, hCys, D-hCys, Pen or D-Pen;

(V) when And2represents Asp or Glu, And then9is a Dab, Dap, Orn or Lys;

(VI) when A8represents Ala or Gly, And then1is not a Nle; and

(VII) kohda 1subject to the deletion, then R2and R3can not both represent H;

or its pharmaceutically acceptable salt.

A preferred group of compounds is directly above formula represents one in which And1represents A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet, or Oic;

And2represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

And3represents Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or subjected deletions;

And4represents His;

And5represents D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(Et)Tyr;

And6represents Arg or hArg;

And7represents Trp, Bip, D-Trp, 1-Nal or 2-Nal;

And8represents A6c, Ala, β-Ala, Gaba, Apn or Ahx;

And9represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

And10represents Thr or subjected deletions

or its pharmaceutically acceptable salt.

A preferred group of compounds is directly above formula represents one in which each of R2and R3independently represents H, acyl, n-propanol or n-butanol, or its pharmaceutically acceptable salt.

More preferred compound of formula (I) represents where the specified connection has the formula:

And1represents the ACC, Arg, DArg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val, or subjected deletions;

And2represents Cys, D-Cys, Pen or Asp;

And3represents Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val, or subjected deletions;

And4represents His or 3-Pal;

And5represents D-Phe, D-2-Nal or D-(Et)Tyr;

And6represents Arg or hArg;

And7represents Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp;

And8represents Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha or subjected deletions;

And9represents Cys, D-Cys, Pen or Lys;

And10represents Thr or subjected deletions;

where at least one of the A3or And8subjected to deletions, but not both,

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound having the formula:

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:1

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO:1

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:2

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3

D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4

Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:5

Ac-D-2-Nal-c(Asp-Hi-D-Phe-Arg-Trp-Gaba-Lys)-NH 2; SEQ ID NO:6

Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hLeu-c(Asp-His-DPhe-Arg-Trp-Gaba-Lys)-NH 2; SEQ ID NO:11

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:12

Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2; SEQ ID NO:16

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:17

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:17

Ac-Nle-c(CysD-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH 2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:61

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; SEQ ID NO:19

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23

D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29

Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO33

Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36

Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39

Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40

Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; SEQ ID NO:41

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; SEQ ID NO:42

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; SEQ ID NO:43

D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; SEQ ID NO:43

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; SEQ ID NO:43

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; SEQ ID NO:42

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; SEQ ID NO:41

Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:29

Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; SQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:47

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48 or

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49,

or its pharmaceutically acceptable salt.

The preferred compound represented directly above group of compounds is a compound having the formula:

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:29

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 or

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48,

or its pharmaceutically acceptable salt.

More preferred compound of formula (I) is a compound having the formula:

And1represents Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val, or subjected deletions;

And2represents Cys, Pen or Asp;

And3represents the D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val, or subjected deletions;

And4represents His or 3-Pal;

And5represents D-Phe, D-2-Nal or D-(Et)Tyr;

And6represents Arg or hArg;

And7the submitted is a Trp, 2-Nal, Bal, Bip or D-Trp;

And8represents Gly, Ala, β-Ala, Gaba, Apn, Ahx or subjected deletions;

And9represents Cys, D-Cys, Pen or Lys;

And10represents Thr or subjected deletions;

each of R2and R3independently selected from the group consisting of H or acyl;

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53

Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:1

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:2

D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4

Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23

D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29

Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Val-c(Cys-His-D-Phe-ArgTrp-Gaba-Cys)-NH 2; SEQ ID NO:33

Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Ac-Nle-c(Cys-3Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36

Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39

Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40

Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 or

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49

or its pharmaceutically acceptable salt.

More preferred compound of formula (I) represents where the specified connection has the formula:

And1represents Arg, D-Arg, hArg, or D-hArg;

or its pharmaceutically acceptable salt.

The preferred connection directly above group of compounds is a compound having the formula:

And2represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

And3represents Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or subjected deletions;

And4represents His;

And5represents D-Phe, D-1-Nal, D-2-Nal, D-Trp D-Bal, or D-(Et)Tyr;

And6represents Arg or hArg;

And7represents Trp, Bip, D-Trp, 1-Nal or 2-Nal;

And8represents A6c, Ala, β-Ala, Gaba, Apn or Ahx;

And9represents Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

And10represents Thr or subjected deletions;

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is that in which each of R2and R3independently represents H, acyl, n-propanol or n-butanol, or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is that in which the indicated compound has the formula:

And2represents Cys or Asp;

And3represents the D-Ala or subjected deletions;

And4represents His;

And5represents D-Phe or D-2-Nal;

And6represents Arg;

And7represents Trp;

And8represents Ala, Gaba, or subjected deletions;

And9represents Cys, Pen, or Lys;

And10subject deletions;

or its pharmaceutically acceptable salt.

More preferable compound represented directly above the group of compounds represented is t a, in which each of R2and R3independently represents H or acyl; or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53

Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53 or

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 or

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

or its pharmaceutically acceptable salt.

More preferable compound represented by eposredstvenno above group of compounds is a compound of the formula:

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

or its pharmaceutically acceptable salt.

More preferable compound represented directly above group of compounds is a compound of the formula:

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49

or its pharmaceutically acceptable salt.

In one aspect of the present invention is directed to a compound in accordance with formula (II):

(R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-NH2,

where

And1represents Nle or subjected deletions;

And2represents Cys or Asp;

And3represents Glu or D-Ala;

And4represents His;

And5represents D-Phe;

And6represents Arg;

And7represents Trp, 2-Nal or Bal;

And8represents Gly, D-Ala, β-Ala, Gaba or Apn;

And9represents Cys or Lys;

each of R2and R3independently selected from the group consisting of H or (C1-C6)acyl;

provided that

(I) when R2is a (C1-C6)acyl, R3represents H; and

(II) when A2represents Cys, A9represents Cys,

or its pharmaceutically acceptable salt.

More predpochtitelnye presented directly above group of compounds is a compound of the formula:

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:54

Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55

Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:55

Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56

Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:56

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO:57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:57 or

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; SEQ ID NO:58

or its pharmaceutically acceptable salt.

Another more preferred compound of formula (I) or formula (II) represents each of the compounds, which in a certain way are numbered below in the Examples section of the present description, or their pharmaceutically acceptable salt.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt and farmatsevticheskii acceptable carrier or diluent.

In another aspect the present invention provides a pharmaceutical composition comprising effective to icesto the compounds of formula (I) or formula (II), as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, where the specified compound is a selective agonist of the receptor melanocortin-4.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, where the specified compound is a selective agonist of the receptor melanocortin-4 with a functional activity characterized EU50at least 15-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-1, human receptor melanocortin-3 and human receptor melanocortin-5.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, where the specified compound is a selective agonist of the receptor m is lineartime-4 functional activity, characterized EU50at least 17-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 90 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 200 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5, or EU50at least 3000 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of acute or chronic inflammatory disease or medical condition, such as General inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in esteem description or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of diseases or medical conditions with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of metabolic disease or medical condition accompanied by weight gain such as obesity, eating disorders and Prader-Willi. In another aspect of being treated for a disease or condition constitutes obesity. In another aspect of being treated with the disease or condition is a nutritional disorder.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the menichini food intake, for reducing body mass or combinations thereof. In a preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, which can be used to reduce food intake, body weight reduction, or combinations thereof, where the active ingredient is one or more of the following compounds: Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2SEQ ID NO:32, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:51, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2SEQ ID NO:49. In another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, which can be used to reduce food intake, body weight reduction, or combinations thereof, where Akti is hydrated ingredient is: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2SEQ ID NO:50. In another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, which can be used to reduce food intake, body weight reduction, or combinations thereof, where the active ingredient is: Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:51. In another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, which can be used to reduce food intake, body weight reduction, or combinations thereof, where the active ingredient is: Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2SEQ ID NO:49.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically who priemlemim carrier or diluent, used to reduce appetite without compromising weight. In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used to reduce food intake, at the same time increasing the weight of the body.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of metabolic disease or medical condition accompanied by weight loss such as anorexia, bulimia, malnutrition, AIDS, cachexia, cancer cachexia and malnutrition in malnourished older persons In another aspect being treated for a disease or condition is an anorexic. In another aspect of being treated with the disease or condition is a bulimia. In another aspect of being treated with the disease or condition is Istomina who AIDS or alimentary dystrophy in malnourished older persons. In another aspect of being treated with the disease or condition is a cachexia or cancer cachexia.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of neoplastic disease or medical condition such as skin cancer and cancer cachexia.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of reproductive or sexual health conditions, such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically PR is acceptable salt together with a pharmaceutically acceptable carrier or diluent, used for the treatment of a disease or medical condition arising out of the damaging effects on the body, such as the rejection of organ transplant, ischemic and reperfusion damage, injury and spinal cord injury and loss of body weight due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, used to treat cardiovascular diseases or medical conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of pulmonary diseases is whether the medical condition, such as acute respiratory distress syndrome, pneumovirus, chronic obstructive pulmonary disease and asthma.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, used to strengthen the immune tolerance for the treatment of allergic conditions.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of dermatological diseases or medical conditions, such as psoriasis, exhaustion, skin pigmentation, acne and the formation of keloid zone.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent, applies the controls for the treatment of behavioral disorders, or diseases or medical conditions of the Central nervous system, such as anxiety, depression, memory dysfunction and neuropathic pain.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the treatment of renal disease or medical condition, such as renal cachexia and natures.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used to modulate the mass of the ovaries, placenta development, prolactin secretion, FSH secretion, intrauterine fetal growth, birth, spermatogenesis, release of thyroxine synthesis and release of aldosterone, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, secretion of fat, the secretion of pheromones, motivation, learning and behavior, perception of pain, neuroprotection and nerve growth.

In another aspect of the brew is her invention provides a pharmaceutical composition, comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for modulation of bone metabolism, bone formation and bone development.

In another aspect the present invention provides a pharmaceutical composition comprising an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent used for the inhibition of alcohol to reduce alcohol use, alcoholism treatment, or for treatment of alcohol abuse. In another aspect the compound of the composition used for the inhibition of alcohol to reduce alcohol use, alcoholism treatment, or for treatment of alcohol abuse, is a selective agonist of the receptor melanocortin-4. In another aspect the compound of the composition used for the inhibition of alcohol, is a selective agonist of the receptor melanocortin-4 or its pharmaceutically acceptable salt with a functional activity characterized the EU 50at least 15-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-1, human receptor melanocortin-3 and human receptor melanocortin-5. In another aspect the compound of the composition used for the inhibition of alcohol, is a selective agonist of the receptor melanocortin-4 or its pharmaceutically acceptable salt with a functional activity characterized EU50at least 17-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 90 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 200 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5, or at least 3000 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5.

In another aspect the present invention provides the use of a therapeutically effective amount of an agonist of the receptor melanocortin-4 compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of alcoholism or for the treatment of alcohol abuse in in need of such treatment of the subject.

In another aspect the present invention provides a method of call agonistic or antagonistic effect on receptor melanocortin we need him as a subject, which includes the introduction of a specified subject an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of call agonistic or antagonistic effect on receptor melanocortin we need him as a subject, which includes the introduction of a specified subject an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt, where the specified compound is a selective agonist of the receptor melanocortin-4.

In another aspect the present invention provides a method of call agonistic or antagonistic effect on receptor melanocortin we need him as a subject, which includes the introduction of a specified subject an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt, where the specified compound is a selective agonist of the receptor melanocortin-4 with unctionally activity characterized EU50at least 15-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-1 to the human receptor melanocortin-3 and to the human receptor melanocortin-5.

In another aspect the present invention provides a method of call agonistic or antagonistic effect on receptor melanocortin we need him as a subject, which includes the introduction of a specified subject an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt, where the specified compound is a selective agonist of the receptor melanocortin-4 with a functional activity characterized EU50in 17 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 90 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 200 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5, or at least 3000 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin the a-5.

In another aspect the present invention provides a method of treating acute or chronic inflammatory disease or medical condition, such as General inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating diseases or medical conditions with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treatment of a disease or medical condition accompanied by weight gain such as obesity, eating disorders and Prader-Willi, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of efficient STA the VA compounds of formula (I) or formula (II), as defined above in the present description, or its pharmaceutically acceptable salt. In another aspect of the above method is subjected to treatment of the disease or condition is a obesity. In another aspect of the above method is subjected to treatment of the disease or condition is a nutritional disorder.

In another aspect the present invention provides a method of reducing food intake, reducing body weight or a combination of them by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt. In a preferred embodiment, the present invention provides a method of reducing food intake, reducing body weight or a combination of them by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, where the specified connection is an Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2SEQ ID NO:32, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:51, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:7 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:22, Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2SEQ ID NO:49. In another preferred embodiment, the present invention provides a method of reducing food intake, reducing body weight or a combination of them by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, where the specified connection is an Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50. In another preferred embodiment, the present invention provides a method of reducing food intake, reducing body weight or a combination of them by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, where the specified connection is an Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:51. In another preferred embodiment, the present invention provides a method of reducing food intake, reducing body weight or a combination of them by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or its pharmaceutically PR is acceptable salt, where the specified connection is an Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2SEQ ID NO:49.

In another aspect the present invention provides a method of reducing appetite without breaking the body mass by introducing an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt. In another aspect the present invention provides a method of reducing food consumption with a simultaneous increase in body mass by introducing an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating a metabolic disease or medical condition accompanied by weight loss such as anorexia, bulimia, malnutrition, AIDS, cachexia, cancer cachexia and malnutrition in malnourished older persons by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt. In another aspect of the above method is used for treatment of anorexia. In another aspect of the above method is applied is carried out for the treatment of bulimia nervosa. In another aspect of the above method is used for the treatment for AIDS wasting or malnutrition in malnourished older persons In another aspect of the above method is used for the treatment of cachexia or cancer cachexia.

In another aspect the present invention provides a method of treating a neoplastic disease or medical condition such as skin cancer and cancer cachexia, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating a reproductive or sexual health conditions, such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating diseases or medical conditions arising in the result of the damaging effects on the body, such as the rejection of organ transplant, ischemic and reperfusion damage, injury and spinal cord injury and loss of body weight due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating cardiovascular diseases or medical conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating a pulmonary disease or medical condition, such as acute respiratory distress syndrome, pneumovirus, chronic obstructive pulmonary disease and asthma, by cause is and agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II), as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of strengthening the immune tolerance or treatment of allergic conditions by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating a dermatological disease or medical condition, such as psoriasis, exhaustion, skin pigmentation, acne and the formation of keloid zone, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating behavioral disorders, or diseases or medical conditions of the Central nervous system such as anxiety, depression, memory dysfunction and neuropathic pain, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of compound f is rmula (I) or formula (II), as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of treating renal disease or medical condition, such as renal cachexia and natures, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of modulating normalizing or homeostatic activity, such as the mass of the ovaries, placenta development, prolactin secretion, FSH secretion, intrauterine fetal growth, birth, spermatogenesis, release of thyroxine synthesis and release of aldosterone, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, secretion of fat, the secretion of pheromones, motivation, learning and behavior, perception of pain, neuroprotection and nerve growth, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically pickup the integral of salt.

In another aspect the present invention provides a method of modulating normalizing or homeostatic activity, such as bone metabolism, bone formation and bone development by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt.

In another aspect the present invention provides a method of inhibiting the consumption of alcohol to reduce alcohol use, alcoholism treatment, or for treatment of alcohol abuse, by calling agonistic or antagonistic effect on receptor melanocortin the introduction of an effective amount of the compounds of formula (I) or formula (II)as defined above in the present description, or its pharmaceutically acceptable salt. In another aspect of the above method, the compound is a selective agonist of the receptor melanocortin-4. In another aspect presented directly above method, the compound of the composition used for inhibiting alcohol consumption, is a selective agonist of the receptor melanocortin-4 or its pharmaceutically acceptable salt, functional activity, caracterizamos EU 50at least 15-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-1 to the human receptor melanocortin-3 and to the human receptor melanocortin-5. In another aspect presented directly above method, the compound of the composition used for inhibiting alcohol consumption, is a selective agonist of the receptor melanocortin-4 or its pharmaceutically acceptable salt, with a functional activity characterized EU50at least 17-fold more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 90 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-3, EU50at least 200 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5, or EU50at least 3000 times more selective for the human receptor melanocortin-4 than to the human receptor melanocortin-5.

In another aspect the present invention provides the use of a therapeutically effective amount of an agonist or antagonist of the receptor melanocortin-4 in accordance with the formula (I) or the second (II), as defined above, or its pharmaceutically acceptable salt for the manufacture of a medicinal product used for the treatment of disease and/or acute medical condition selected from the group consisting of acute and chronic inflammatory diseases, such as General inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock; diseases with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis; metabolic diseases and medical disorders accompanied by weight gain such as obesity, eating disorders and Prader-Willi; metabolic diseases and medical disorders, accompanied by weight loss such as anorexia, bulimia, malnutrition, AIDS, cachexia, cancer cachexia and malnutrition in malnourished elderly; diabetes and diabetes-related conditions and complications of diabetes such as retinopathy; neoplastic proliferation, such as skin cancer and prostate cancer; reproductive or sexual health conditions such as endometriosis and uterine bleeding in women, sexual dysfunction, erectile dysfunction and decreased sexual response in women; diseases or conditions resulting from treatment or the damaging effects of the of conduct on the body, such as the rejection of organ transplant, ischemic and reperfusion injury, trauma, spinal cord injuries, and loss of body weight caused by chemotherapy, radiation therapy, temporary or permanent immobilization or dialysis; cardiovascular diseases or conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia; pulmonary diseases or conditions, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma, and pneumovirus; to strengthen the immune tolerance and to combat attacks on the immune system, such as impacts associated with certain types of allergies or rejection of organ transplants; dermatological diseases and conditions, such as psoriasis, exhaustion, skin pigmentation, acne, formation of keloids and skin cancer, behavioral disorders, disorders of the Central nervous system and neurogenic disorders such as anxiety, depression, memory dysfunction and neuropathic pain; and renal conditions or diseases, such as renal cachexia and nutrient.

In another aspect the present invention provides the use of a therapeutically effective amount of an agonist or antagonist of the receptor melanocortin the at-4 in accordance with the formula (I) or formula (II), as defined above, or its pharmaceutically acceptable salt for the manufacture of a medicinal drug used to modulate normalizing or homeostatic activity, such as the mass of the ovaries, the development of the placenta, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, the release of thyroxine synthesis and release of aldosterone, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, glucose levels in the blood, the secretion of sebum, the secretion of pheromones, motivation, learning, and behavior, perception, pain, neuroprotection, nerve growth, bone metabolism, bone formation and development of bones.

It should be understood that also provides therapeutic interventions and normal physiological and pathophysiological processes that use receptors melanocortin.

Additional objectives, advantages and features of the present invention will become apparent from the following description and appended claims, taken in conjunction with accompanying drawings.

Compounds of formula (I) or (II) represent ligands, at least one receptor melanocortin (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R), and their choice was tested for their ability to act as a ligand is described by the following in vitro assays.

Brief description of drawings

Figa: the Average difference in food intake from the carrier of starving rats at 6 h after injection of 100 nmol/kg of the selected compounds.

Figv. The average difference in food intake from the carrier of starving rats at 6 h after injection of 500 nmol/kg of the selected compounds.

Figa. The cumulative difference between the average food consumption of media in rats after administration of various concentrations of compound A.

Figv. The cumulative difference between the average body mass of the carrier in rats after administration of various concentrations of compound A.

Figa. The cumulative difference between the average food consumption of media in rats after administration of selected compounds.

Figv. The cumulative difference between the average body mass of the carrier in rats after administration of selected compounds.

Figa. The cumulative difference between the average food consumption of media in rats after administration of selected compounds.

Figv. The cumulative difference between the average body mass of the carrier in rats after administration of selected compounds.

Detailed description of the invention

The nomenclature used to define the peptides is that which is commonly used in this field, where the amino group of N-Terminus appears to the left and the carboxyl group at the C-end appears to the right. When the amino acid has some the forms, while there are no other clear indications, it presents an L-shape. Yet other definitions used in the present description of the technical and scientific terms have the same meaning, which usually understands the average expert in the field that applies the present invention. Also, all publications, patent applications, patents, and other references mentioned in the present description, is included as a reference.

Nomenclature and abbreviations

SymbolValue
Abuα-aminobutyric acid
AUAcyl group
ACC1-amino-1-cyclo(C3-C9)alkalicarbonate acid
As1-amino-1-cyclopropanecarbonyl acid
As1-amino-1-cyclobutanecarbonyl acid
As1-amino-1-cyclopentanecarbonyl acid
As1-amino-1-cyclohexanecarbonyl acid
Aha 7-aminoheptanoic acid
Ahx6-aminohexanoic acid
Aibα-aminoadamantane acid
Ala or Aalanine
β-Alaβ-alanine
Apn5-aminopentanoic acid (HN-(CH2)4-C(O)
Arg or Rarginine
hArghomoarginine
Asn or Nasparagine
Asp or Daspartic acid
Bal3-benzothiadiazin
Bip4,4'-biphenylene represented by the structure
Bpa4-benzylpenicillin
4-Br-Phe4-brompheniramine
Chaβ-cyclohexylamin
hCha Homecollection
Chgcyclohexylglycine
Cys or CCysteine
hCysHomocysteine
Dab2,4-diaminopentane acid
Dap2,3-diaminopropionic acid
Dipβ,β-diphenylalanine
Doc8-amino-3,6-dioxaoctyl acid with structure:
2-Fuaβ-(2-furyl)alanine
Gaba4-aminobutyric acid
Gln or QGlutamine
Glu or Eglutamic acid
Gly or GGlycine
His or HHistidine
3-HypTRANS-3-hydroxy-L-Proline, i.e. the (2S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid
4-Hyp4-hydroxyproline, i.e. the (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid
Ile or IIsoleucine
Leu or LLeucine
hLeuHemolysin
Lys or KLysine
Met or MMethionine
β-hMetβ-geomation
1-Nalβ-(1-naphthyl)alanine
2-Nalβ-(2-naphthyl)alanine
Nipnikotinova acid
NleNorleucine
Oicoctahedron-2-carboxylic acid
OrnOrnithine
2-Palβ-(2-pyridyl)alanine
3-Palβ-(3-pyridyl)alanine
4-Palβ-(4-pyridyl)alanine
PenPenicillamine
Phe or FPhenylalanine
hPheHomophenylalanine
Pro or PProline
hProGamopolis
Ser or SSerine
Tletert-leucine
Tazβ-(4-thiazolyl)alanine
2-Thiβ-(2-thienyl)alanine
3-Thiβ-(3-thienyl)alanine
Thr or TThreonine
Trp or WTryptophan
Tyr or YTyrosine
D-(Et)Tyrhas the structure:
Val or VValine

Some other abbreviations used in this description are defined below:

Boc:tert-butyloxycarbonyl
Bzl:Benzil
DCM:Dichloromethane
DIC:N,N-diisopropylcarbodiimide
DIEA:diisopropylethylamine
Dmab:4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methylbutyl)amino}benzyl
DMAP:4-(dimethylamino)pyridine
DMFDimethylformamide
DNP:2,4-dinitrophenyl
Fm:Fertility
Fmoc:fertilityscore
For:Formyl
HBTU:hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
cHexcyclohexyl
HOAT:hexaphosphate O-(7-ASABE striatal-1-yl)-1,1,3,3-tetramethyluronium
HOBt:1-hydroxybenzotriazole
MBHA4-methylbenzhydrylamine
Mmt:4-methoxytrityl
NMP:N-organic
O-tBuHydroxy-tert-butyl
Pbf:2,2,4,6,7-pentamethylcyclopentadiene-5-sulfonyl
PyBroPhexaphosphate bromo-Tris-pyrrolidinone
tBu:Tert-butyl
TIS:triisopropylsilane
TOS:Tosyl
TrtTrail
TFA:triperoxonane acid
TFFH:hexaphosphate tetramethylpiperidine
Z:benzyloxycarbonyl

Unless otherwise indicated, all abbreviations (e.g., Ala) of amino acids, except N-is Onaway amino acids, in the present description denotes the structure-NH-C(R)(R')-CO-, where each R and R' independently represents hydrogen or a side chain amino acids (for example, R=CH3and R'=H for Ala), or R and R' can be connected to form a ring system.

For N-terminal amino acid abbreviation refers to the structure:

The designation “NH2”for example, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2indicates that the end of the peptide amitirova. Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) or, alternatively, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH indicates that the end is a free acid.

“-c(Cys-Cys)-or cyclo(Cys-Cys)-“ refers to the structure:

“-c(Cys-Pen)-or cyclo(Cys-Pen)-“ refers to the structure:

“-c(Asp-Lys)-or cyclo(Asp-Lys)-“ refers to the structure:

"Acyl" refers to a R"-C(O)-, where R" represents H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, replaced alkenyl, aryl, alkylaryl or substituted alkylaryl, and is indicated in General formula specific implementation as "Ac".

"Alkyl" refers to a hydrocarbon group consisting of one or more carbon atoms, where multiple carbon atoms, if present, are connected by single bonds. Alkyl the traveler hydrocarbon group may be promotepatent or contain one or more branches or cyclic groups.

"Hydroxyalkyl" refers to an alkyl group where one or more hydrogen atoms of the hydrocarbon group substituted by one or more hydroxyadamantane, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl, hydroxyhexyl, and the like.

"Substituted alkyl" refers to alkyl wherein one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2and C1-20alkyl, where specified With1-20alkyl optionally may be substituted by one or more substituents, independently selected for each case from the group consisting of-CF3, -OCH3, -OCF3and -(CH2)0-20-COOH. In various embodiments, the implementation of the present 1, 2, 3, or 4 substituent. The presence of -(CH2)0-20-COOH leads to products alkilani acid. Non-limiting examples alilovic acids containing -(CH2)0-20-COOH, include 2-norbornanamine acid, tert-butyric acid, 3-cyclopentylpropionic acid and the like.

The term "halogen" includes fluorine-, chlorine-, bromine - and iodine.

"Heteroalkyl" refers to alkyl wherein one or more carbon atoms in the hydrocarbon group is substituted by one, and the and several of the following groups: amino, amido, -O-, -S -, or carbonyl. In various embodiments, the implementation contains 1 or 2 heteroatoms.

"Substituted heteroalkyl" refers to heteroalkyl, where one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2and C1-20of alkyl, where specified With1-20alkyl optionally may be substituted by one or more substituents, independently selected for each case from the group consisting of halogen, -CF3, -OCH3, -OCF3and -(CH2)0-20-COOH. In various embodiments, the implementation of the present 1, 2, 3, or 4 substituent.

"Alkenyl" refers to a hydrocarbon group composed of two or more carbons, where one or more mesopartner double bonds. Alchemilla hydrocarbon group may be remotemachine or contain one or more branches or cyclic groups.

"Replaced alkenyl" refers to alkenyl, where one or more hydrogens replaced with one or more substituents selected from the group consisting from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2and C1-20of alkyl, where specified With1-20alkyl n which can optionally be substituted by one or more substituents, independently selected for each case from the group consisting of-CF3, -OCH3, -OCF3and -(CH2)0-20-COOH. In various embodiments, the implementation of the present 1, 2, 3, or 4 substituent.

"Aryl" refers to optionally substituted aromatic group, at least one ring having a conjugate linked to a pi-electron system containing up to three conjugate linked or condensed ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and marilou group. Preferably, the aryl is a 5 - or 6-membered ring. Preferred atoms for heterocyclic aryl represents one or more of sulfur, oxygen and/or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene and the like. Aryl substituents selected from the group consisting of C1-20of alkyl, C1-20alkoxy, halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NO2- 1-20of alkyl, substituted with halogen, -CF3, -OCF3and -(CH2)0-20-COOH. In various embodiments, the implementation of the present 1, 2, 3, or 4 substituent.

"Alkylaryl" applies to "alkyl", connected with "aryl".

The term "(1-12)hydrocarbon portion" encompasses alkyl, alkenyl and quinil in the case of kanila and quinil include 2-12.

Used in the present description, the term "normalizing" function or activity refers to those types of functions that can be considered to be involved in normal function or homeostasis of the organism. Such functions include, without limitation, the activities and functions that affect body temperature, blood pressure, heart rate, vascular tone, brain blood flow, glucose levels in the blood and the like.

Used in this description of the compounds that are considered "selective" to a specific receptor melanocortin, are compounds having a functional activity characterized EU50at least about 2 times, at least about 5-fold, at least about 10 times, at least about 15-fold, at least about 17 times, at least about 90, at least about 200-fold, at least about 3000 times or at least about 10,000 times, or even greater selectivity with respect to any receptor melanocortin compared to any other receptor melanocortin. For example, a selective agonist of the receptor melanocortin-4 according to the invention shows a functional activity characterized EU50at least 15-fold more selective against human the ski receptor melanocortin-4, than in relation to human receptor melanocortin-1, human receptor melanocortin-3 and human receptor melanocortin-5. Also, for example, a selective agonist of the receptor melanocortin-4 according to the invention shows a functional activity characterized EU50at least 17-fold more selective with regard to the human receptor melanocortin-4 than in relation to human receptor melanocortin-3.

Synthesis

The peptides according to the invention can be obtained by standard solid-phase peptide synthesis. See, for example, Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R2and R3the above generic formula can be attached to the free amine N-terminal amino acids by standard methods known in this field. For example, alkyl groups such as a (C1-30)alkyl, can be attached using reductive alkylation. Hydroxyalkyl group, for example (C1-30)hydroxyalkyl, can also be attached using reductive alkylation, where the free hydroxyl group is protected complex tert-butyl ether. Acyl group, for example SOY1can be attached coupling of the free acid, for example E1COOH, with free amine N-terminal amino acid mixture is of full resin with 3 molar equivalent of the free acid, and diisopropylcarbodiimide in methylene chloride for 1 hour If the free acid contains a free hydroxyl group, such as p-hydroxyphenylpropionic acid, then the connection should be made with an additional 3 molar equivalents of HOBt.

When R1represents-NH2the synthesis of the peptide begins with Fmoc-amino acids, which connects to MBNA resin Rink amide. If R1is a HE, the synthesis of the peptide begins with Fmoc-amino acids, which is connected with Wang resin.

During the synthesis of the peptide of the present invention, containing A6c and/or Aib, the connection time is 2 h for these residues and residue immediately following them.

The following examples describe the synthesis methods for obtaining the peptides of the present invention, and these methods are well known to specialists in this field. Other methods well known to specialists in this field. Examples are presented for illustrative purposes and are in no way intended to limit the scope of the present invention.

EXAMPLES

Example 1: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:7

Specified in the title peptide was synthesized by multiple peptide synthesizer Advanced ChemTech (Louisville, KY 40228) model 396® using performancemonitoring (Fmoc) chemistry. Use the Lee 4-methylbenzhydrylamine (MVNA) resin Rink amide (Novabiochem®, San Diego, CA) with the substitution of 0.58 mmol/g was Used with Fmoc amino acids (Novabiochem®, CA and Chem-Impex®, IL) was an Fmoc-Nle-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-His(Trt)-OH, Fmoc-D-Phe-OH, Fmoc-Arg(Pbf)-OH and Fmoc-Trp(Boc)-OH. The synthesis was performed in the scale 0.035 mmol. The Fmoc group was removed by treatment of 25% piperidine in N,N-dimethylformamide (DMF) for 30 minutes At each stage of the connection Fmoc-amino acid (10 EQ., 0.35 mmol), N,N-diisopropylcarbodiimide (DIC) (10 EQ., 0.35 mmol) and 1-hydroxybenzotriazole (HOBt) (10 EQ., 0.35 mmol) was used in DMF (1.4 ml). After washing DMF did double connection with Fmoc-amino acid (10 EQ., 0.35 mmol), hexaflurophosphate 2-(1-N-benzotriazol-1-yl)-1,1,2,3-tetramethyluronium (HBTU) (8 EQ., 0.28 mmol), HOBT (10 EQ., 0.35 mmol) and diisopropylethylamine (DIEA) (20 EQ., 0.7 mmol) in DMF (1,26 ml). Multiple peptide synthesizer AST 396® was programmed to perform the next cycle of the reaction: (1) washing DMF, (2) removing the protective Fmoc group 25% piperidine in DMF, (4) connection with Fmoc-amino acid in the presence of DIC and HOBt for 1 h, (5) washing DMF, (6) double linking of the same with Fmoc-amino acid, which is stage 4, in the presence of HBTU, HOBt, and DIEA in a period of 1 h the Resin was coupled sequentially in accordance with the sequence specified in the header of the peptide. After Assembly of the peptide chain and the removal of the last Fmoc-protective group of the resin is fully washed by using DMF and dichloromethane is (DCM).

For splitting specified in the header of the peptide resin was treated with a solution (1.5 ml) TFA, H2O and triisopropylsilane (TIS) (about/about/about: 90/6,2/3,8) for 2 h at room temperature. The resin was filtered and the filtrate was poured into 30 ml of a simple ester. The precipitate was collected by centrifugation. This crude product was dissolved in water (~7 ml) and the pH of the aqueous solution was brought to ~7.5 Appendix 2 N. NH4HCO3. The solution was opened to air for 72 h at room temperature. The crude product was purified on a system of preparative HPLC in the reversed-phase column (4×43 cm) C18DYNAMAX-100® A0(Varian®, Walnut Creek, CA). The column was suirable for about 1 h using a linear gradient of 85% A:15% to 30% A:70% B, where a consisted of 0.1% TFA in water, and consisted of 0.1% TFA in acetonitrile. Fractions were checked by analytical HPLC and those that contained pure product were combined and liofilizirovanny to dryness to obtain to 10.3 mg (yield 27%) of white solids. The purity was analyzed using HPLC and found that it was approximately 88%. Analysis by electrospray ionization mass spectrometry (ESI-MS) gave the molecular weight at the level 1073,6 (which is consistent with the calculated molecular weight 1074,3).

Example 2: Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2SEQ ID NO:6

Specified in is the head of the peptide was synthesized on a peptide synthesizer, Applied Biosystems® (Foster City, CA) model A, which was modified to conduct accelerated solid-phase peptide synthesis using Boc-chemistry. Cm. Schnolzer, et al., Int. J. Peptide Protein Res., 40:180 (1992). Used 4-methylbenzhydrylamine (MVNA) resin (Peninsula®, Belmont, CA) with the substitution of 0.91 mmol/g Used the following BOC-amino acids (Novabiochem®, San Diego, CA and Chem-Impex®, Wood Dale, IL): Boc-Cha-OH, Boc-Asp(OFm)-OH, Boc-His(DNP)-OH, Boc-D-Phe-OH, Boc-Arg(Tos)-OH, Boc-Trp(For)-OH, Boc-Gaba-OH and Boc-Lys(Fmoc)-OH. The synthesis was performed in the scale of 0.20 mmol. The Boc group was removed by treatment with 100% TFA for 2×1 min BOC amino acid (2.5 mmol) pre-activated HBTU (2.0 mmol) and DIEA (1.0 ml) in 4 ml DMF and combined without prior neutralization of the TFA salt of the peptide-resin. Connection time was 5 minutes

At the end of the Assembly of Boc-Asp(OFm)-His(DNP)-D-Phe-Arg(Tos)-Trp(For)-Gaba-Lys(Fmoc)-MBHA the peptide-resin was transferred into a reaction vessel on a shaker. The resin was treated twice 25% piperidine in DMF for 15 min per procedure, washed with DMF and shaken with hexaphosphate bromo-Tris-pyrrolidinone (PyBrOP) (6 EQ., 0.3 mmol), DIEA (1 ml) and 4-(dimethylamino)pyridine (DMAP) (24 mg) in DMF (2 ml) within 12 hours After washing DMF, the resin was treated twice with 100% TFA for 2 min for processing, washed with DMF and DCM and then dried under reduced pressure. One-fourth of the peptide-resin (0.05 mmol) was used for the next connection with Boc-Cha-OH (10 EQ., 0.5 mmol) in the presence of HTU (9 equiv., 0.45 mmol) and DIEA (0.25 ml) in DMF for 10 minutes After removing protection 100% TFA two techniques, which lasts for approximately 2 min each, the peptide-resin was then washed with DMF. The final stage of capping carried out by shaking the resin with acetic anhydride (40 EQ., 2.0 mmol) and DIEA (20 equiv., 1.0 mmol) in DMF for 1 h After washing DMF, the resin was treated twice with a solution of 20% mercaptoethanol/10% DIEA in DMF, and each treatment lasted approximately 30 min, to remove the DNP group on the his-tag side-chain. Formyl group on the side chain of tryptophan is removed by shaking with a solution of 15% ethanolamine/15% water/70% DMF twice for 30 min on a shaking. The peptide-resin is washed with DMF and DCM and dried under reduced pressure. The final cleavage was performed by stirring the peptide-resin in 10 ml of HF containing 1 ml of anisole and dithiothreitol (30 mg) at 0°C for 75 min HF was removed by a stream of nitrogen. The residue was washed with a simple ether (6×10 ml) and was extracted with 4 N. HOAc (6×10 ml).

The peptide mixture in the aqueous extract was purified on preparative high performance liquid chromatography (HPLC) on reversed phase using obremenitve column VYDAC® C18(Nest Group®, Southborough, MA). The column was suirable linear gradient from 10% to 50% of solution b over 40 min) at a flow rate of 10 ml/min (solution A = water containing 0.1% TFA; Solution B = acetonitrile, with whom containing a series of 0.1% TFA). Fractions were collected and checked by analytical HPLC. The fractions containing the product were combined and liofilizirovanny to dryness. Received 5.1 mg of white solid. The yield was 8.9%. Purity amounted to 94.5% based on analysis analytical HPLC. Analysis of electrospray mass spectrometer (MS(ES))S gave the molecular weight at the level 1148,5 (which is consistent with the calculated molecular weight 1148,3).

Other peptides according to the invention, the average person skilled in the art can be obtained using synthetic procedures similar to those generally described above in the present description, and/or disclosed, in particular, in the above examples, and the compounds shown in tables 1A and 1B.

The following examples can be obtained in accordance with the appropriate procedures described above:

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:1

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO:1

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:2

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3

D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4

Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:5

Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6

Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cy)-NH 2; SEQ ID NO:7

Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7

Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9

Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10

Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-D-Chg-c(AspHis-D-Phe-Arg-Trp-Gaba-Lys)-NH 2; SEQ ID NO:11

n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:12

Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11

Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO:14

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO:15

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2; SEQ ID NO:16

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:17

n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:17

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO:18

Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:61

Ac-Nle-c(sp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH 2; SEQ ID NO:19

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22

D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23

D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24

D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:54

Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28

Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55

Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:55

Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56

Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:56

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO:57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:57

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29

Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Ile-His-DPhe-Arg-Trp-Cys)-NH 2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32

Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33

Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34

Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36

Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37

Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; SEQ ID NO:58

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:38

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39

Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39

Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40

Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; SEQ ID NO:41

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; SEQ ID NO:42

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; SEQ ID NO:43

D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; SEQ ID NO:43

D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; SEQ ID NO:43

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; SEQ ID NO:42

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-pn-Lys)-OH; SEQ ID NO:41

Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:29

Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; SEQ ID NO:45

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46

Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:47

Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50

Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52

Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51

Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53

Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:53

Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 and

Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH SEQ ID NO:48.

Other peptides according to the invention, the average person skilled in the art can be obtained using synthetic procedures similar to those generally described above in the present description, and/or the eat, disclosed, in particular, in the above examples, and the compounds shown in tables 1A and 1B.

Tables 1A and 1B - Molecular mass and purity of the selected options exercise

95,8
Table 1A
ConnectionThe calculated molecular massExperimental molecular weightPuritySEQ ID NO:
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH21095,271095,296,4SEQ ID NO:1
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH21149,361149,0596SEQ ID NO:1
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH21116,381115,898SEQ ID NO:2
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH21167,381167,399SEQ ID NO:3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-i> β-Ala-D-Cys)-Thr-NH21167,381167,593SEQ ID NO:3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH21181,411181,999SEQ ID NO:3
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH21102,35110399SEQ ID NO:2
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH21123,321123,999SEQ ID NO:4
Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21121,311121,293SEQ ID NO:5
Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21193,371193,292,6SEQ ID NO:6
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;1149,361149,494,5SEQ ID NO:6
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2 1109,31109,291,5SEQ ID NO:6
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21074,31074,698,3SEQ ID NO:7
Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH21074,31074,491SEQ ID NO:7
Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH21088,321088,493SEQ ID NO:7
Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH21088,321088,480SEQ ID NO:7
Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH21060,271060,490SEQ ID NO:7
Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH21074,31074,493SEQ ID NO:8
Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21074,3107,4 81SEQ ID NO:8
Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH21074,31074,492SEQ ID NO:8
Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH21088,321088,494SEQ ID NO:8
Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH21088,321088,491SEQ ID NO:8
Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH21060,271060,496SEQ ID NO:8
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH21074,31074,466SEQ ID NO:9
Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH21074,31074,294SEQ ID NO:9
Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH21088,321088,293 SEQ ID NO:9
Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH21088,321088,490SEQ ID NO:9
Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH21060,271060,491SEQ ID NO:9
Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH21074,31074,465SEQ ID NO:10
Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH21074,31074,293SEQ ID NO:10
Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH21074,31074,492SEQ ID NO:10
Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH21088,321088,490SEQ ID NO:10
Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH21088,32108895
Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21147,351147,497,5SEQ ID NO:11
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21135,331135,199SEQ ID NO:11
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21163,391163,499SEQ ID NO:11
Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21149,361149,299SEQ ID NO:11
Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21107,281107the 98.9SEQ ID NO:11
Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21107,281107,499SEQ ID NO:11
Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21123,321123,299SEQ ID NO:11
Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21163,391163,694SEQ ID NO:59
Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21143,311143,396,9SEQ ID NO:11
Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21143,311143,396,5SEQ ID NO:11
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21135,331135,499SEQ ID NO:11
n-butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21177,411177,588,6SEQ ID NO:60
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21157,341157,270SEQ ID NO:11
Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21141,361141,289SEQ ID NO:11
Ac-Gaba-c(Asp-His-D-Ph-Arg-Trp-Gaba-Lys)-NH 21081,241080,992,5SEQ ID NO:11
Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH21135,331135,285SEQ ID NO:13
Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH21149,361149,187SEQ ID NO:13
Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH21095,271095,498,6SEQ ID NO:13
Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH21109,31109,293,8SEQ ID NO:13
Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH21129,291129,281,9SEQ ID NO:13
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH21095,271095,397SEQ ID NO:14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2 1095,271095,382SEQ ID NO:14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH21109,31109,199SEQ ID NO:14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH21137,351137,498SEQ ID NO:14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH21123,321123,397,3SEQ ID NO:14
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH21102,35110299SEQ ID NO:15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH21088,321087,897SEQ ID NO:15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH21116,381116,299SEQ ID NO:15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH21074,3 1073,899,9SEQ ID NO:15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH21074,31073,899,9SEQ ID NO:15
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH21124,361123,696,1SEQ ID NO:16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH21135,381134,5of 99.1SEQ ID NO:16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH21135,381134,694,8SEQ ID NO:16
n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH21113,371112,695,7SEQ ID NO:17
n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21102,351101,599,9SEQ ID NO:17
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH21085,3297,7SEQ ID NO:18
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH21085,321084,596,6SEQ ID NO:18
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH21091,35of 1090.496,2SEQ ID NO:18
Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH21132,331131,599,9SEQ ID NO:61
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH21095,271094,699,9SEQ ID NO:19
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH21141,411140,595,6SEQ ID NO:20
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21102,351101,699,9SEQ ID NO:21
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH21102,351101,6 99,9SEQ ID NO:22
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH21130,41129,699,9SEQ ID NO:22
D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH21181,411181,796,9SEQ ID NO:23
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH21211,431211,7to 97.1SEQ ID NO:24
D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH21204,441204,699SEQ ID NO:25
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH21225,461225,797SEQ ID NO:24
D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH21218,471218,899SEQ ID NO:26
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH21262,521263 99SEQ ID NO:26
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH21131,351131,296,8SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH21145,371145,396,4SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH21145,371145,2of 98.2SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21159,41159,295,1SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH21173,431173,396,8SEQ ID NO:54
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH21060,311060,398,5SEQ ID NO:27
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH21095,271094,796,2 SEQ ID NO:28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH21112,321111,796,5SEQ ID NO:28
Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH21090,251089,699,9SEQ ID NO:55
Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH21101,271100,698,3SEQ ID NO:55
Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH21032,221031,5for 95.2SEQ ID NO:56
Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH21043,241042,595,6SEQ ID NO:56
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH21144,391144,6for 95.3SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH21145,371144,697,3SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21158,411158,696,5SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH1103,33110399,9SEQ ID NO:29
Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH21088,321087,699,9SEQ ID NO:30
Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH21102,351101,799,9SEQ ID NO:30
Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH21116,381115,799,9SEQ ID NO:30
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH21116,381115,897,4SEQ ID NO:30
Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH21116,381115,596,5SEQ ID NO:30
Ac-le-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 21156,441155,696,4SEQ ID NO:30
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21116,381115,795SEQ ID NO:31
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH21116,381115,599,9SEQ ID NO:32
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH21144,43114499,9SEQ ID NO:32
Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21088,32108896,7SEQ ID NO:33
Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21128,391128,495,8SEQ ID NO:33
Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21088,321088,495SEQ ID NO:33
Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2 1122,341122for 95.2SEQ ID NO:33
Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21074,31074,695,4SEQ ID NO:33
Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21172,41172,2for 95.2SEQ ID NO:33
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21046,291046,497,6SEQ ID NO:34
Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH21080,3108095,8SEQ ID NO:34
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH21099,351099,696,6SEQ ID NO:35
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH1075,281075,299,9SEQ ID NO:36
Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH21088,321088SEQ ID NO:37
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH21183,41182,8599,9SEQ ID NO:58
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH21145,33114599,99SEQ ID NO:38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-βAla-Lys)-NH21145,33114599,99SEQ ID NO:38
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH21138,381137,899,99SEQ ID NO:39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH21166,44116699SEQ ID NO:39
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH21207,41206,999SEQ ID NO:40
Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH21199,421198,8100 SEQ ID NO:40
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21117,31116,995,10SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH21117,331116,899,2SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH21145,381144,996,4SEQ ID NO:51
Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH21159,411158,999,9SEQ ID NO:52
Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH21159,411159,199SEQ ID NO:52
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH21145,38total area of 1,145 .199SEQ ID NO:51
Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH21138,31138,098,0SEQ ID NO:53
Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH21138,31138,199,0SEQ ID NO:53

Table 1B
ConnectionThe calculated molecular massExperimental molecular weightPuritySEQ ID NO:
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH21167,391167,4099,9SEQ ID NO:49

Example 3: in vitro Studies

Compounds of the present invention can be and were tested for the presence of activity as ligands of one or more receptors melanocortin in accordance with the following procedures. The person skilled in the art would be aware that procedures similar to those described in the present description, can be used to analyze the binding activity of the compounds according to the invention with molecules of receptor melanocortin.

Analyses of the binding of ligands, radiolabelled

The cell membrane, used for analysis of binding in vitro, is Uchali of transgenic cells Cho-K1, stably expressing the desired subtype 1, 3, 4 or 5 receptor hMC-R Cells Cho-K1 were treated with ultrasound (Branson®, the installation of 7, approximately 30 sec) in ice-cold 50 mm Tris-HCl at pH 7.4, and then centrifuged at 30,000 g for 10 minutes at approximately 4°C. the Pellets re-suspended in the same buffer and centrifuged at 50000g for 10 minutes at approximately 4°C. the Washed pellet containing cell membranes were stored at approximately-s.

Competitive inhibition of [125I](Tyr2)-(Nle4-D-Phe7)α-MSH ([125I]-NDP-α-MSH, Amersham Biosciences®) binding was performed in polypropylene 96-well plates. The cell membrane (1-10 μg protein/well), obtained as described above, were incubated in 50 mm Tris-HCl at pH 7.4, containing 0.2% bovine serum albumin (BSA), 5 mm MgCl2, 1 mm CaCl2and 0.1 mg/ml bacitracin with increasing concentrations of the test compound and 0.1-0.3 nm [125I]-NDP-α-MSH for about 90-120 minutes at approximately 37°C. the Bound ligand [125I]-NDP-α-MSH was separated from free [125I]-NDP-α-MSH by filtration through glass fiber filter plate GF/C (Unifiller®; Packard), pre-soaked in 0.1% (wt./about.) polyethylenimine (PEI)using the collector cells Packard Filtermate®. Filters were washed 3 times with 50 mm Tris-HCl at pH 7.4 at a temperature of about 0-4°C and then the analysis is whether the radioactivity using a scintillation counter Packard Topcount®. Data binding were analyzed by nonlinear regression analysis using the computer (selection XL; IDBS).

The selection of the preferred embodiments was tested using the above-discussed analysis and the binding constant (Ki in nm), presented in tables 2A, 2B and 2C.

Tables 2A, 2B and 2C - analysis Data binding ligands, labeled radioactive isotope, for selected compounds

Table 2A
ConnectionKi
hMC1-R
Ki
hMC3-R
Ki
hMC4-R
Ki
hMC5-R
Ki
hMC1-R/
MC4-R
SEQ ID NO:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2a 3.87the 10.12,094301,9SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH24,0112,11,763522,3SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 8,2913,32,788163,0SEQ ID NO:51
Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH23,9317211,05380,36SEQ ID NO:52
Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH21,8120,54,575020,4SEQ ID NO:52
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH29,6722,04,219002,3SEQ ID NO:51
Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH20,7945,51,214930,6SEQ ID NO:53
Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH20,6820,71,017830,7 SEQ ID NO:53

3,84
Table 2B
ConnectionKi
hMC1-R
Ki
hMC3-R
Ki
hMC4-R
Ki
hMC5-R
Ki
hMC1-R
/MC4-R
SEQ ID NO:
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH211463,9of 3.07165737,1SEQ ID NO:16
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH211267,618001,4SEQ ID NO:7
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH20,059,31,12,90,0SEQ ID NO:24
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH20,074,10,858,80,1SE ID NO:27
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH20,12100,430,420,3SEQ ID NO:32
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,051,30,470,20,1SEQ ID NO:34
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH20,099693180,61710,90,16SEQ ID NO:1
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2,013216,11,230,3590,11SEQ ID NO:2
D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH20,20743,22,583440,08SEQ ID NO:3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH20,42010 4,7512600,09SEQ ID NO:3
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH20,0951was 9.330,894the 13.40,11SEQ ID NO:2
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH20,99930011,14310,09SEQ ID NO:4
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,10611,81,491100,07SEQ ID NO:6
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,05069,891,0416,30,05SEQ ID NO:6
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,88422322,56090,04SEQ ID NO:11
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,72193,556,07470,01SEQ ID NO:11
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,22714,52,991640,08SEQ ID NO:11
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH20,27725,23,372030,08SEQ ID NO:11
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH20,32314,11,9624,00,16SEQ ID NO:15
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH234,1118of 17.055602,01SEQ ID NO:21
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH229,122,825507,58SEQ ID NO:22
D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH20,44212310,35210,04SEQ ID NO:23
D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH25,80337058311300,01SEQ ID NO:25
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH20,0567of 31.414,79,270SEQ ID NO:24
D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH21,68126017212200,01SEQ ID NO:26
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH20,12885,636,938,00SEQ ID NO:26
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH20,3521493,013390,12SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH23,9387648,049400,08SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH20,9952874,807660,21SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,8481843,769560,23SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH21,102287,588590,15SEQ ID NO:54
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH20,659 the 98.92,554,190,26SEQ ID NO:28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH24,1244550,643000,08SEQ ID NO:28
Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2111171047,76942,33SEQ ID NO:55
Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2262250096,414602,72SEQ ID NO:55
Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2199599096,7> 10000to 2.06SEQ ID NO:56
Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2132456040,788103,24SEQ ID O:56
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH29,12113022,128600,41SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH21,002275,554960,18SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,5361693,123580,17SEQ ID NO:57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH32,133017,41651,84SEQ ID NO:29
Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH210,641,1of 7.6954,91,38SEQ ID NO:30
Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH213,0104 the 10.1401,29SEQ ID NO:30
Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH24,28a 38.59,012,50,48SEQ ID NO:30
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH21,606,824,13to 5.570,39SEQ ID NO:30
Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2to 12.085,811,2401,07SEQ ID NO:30
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH20,3532,081,410,8570,25SEQ ID NO:30
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,53786,1of 5.892,560,09SEQ ID NO:31
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH20,7441783,512,690,21SEQ ID NO:32
Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,21617,40,9950,4860,22SEQ ID NO:33
Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,1079,110,8840,3540,12SEQ ID NO:33
Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,14813,91,060,4230,14SEQ ID NO:33
Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,25418,52,130,7140,12SEQ ID NO:33
Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,25629,9 1,980,8640,13SEQ ID NO:33
Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,56039,22,942,730,19SEQ ID NO:33
Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,18615,2is 4.930,5370,04SEQ ID NO:34
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH221,115110,492,62,03SEQ ID NO:35
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH30,7152the 15.61141,97SEQ ID NO:36
Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH25,2015013820,30,04SEQ ID NO:37
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH24,8929021,311,10,23SEQ ID NO:58
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH225,53,82to 7.611023,35SEQ ID NO:16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH232,55,852,5394,612,85SEQ ID NO:16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH222,2a 12.716,6125of 1.34SEQ ID NO:20
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH21,171,560,2773,244,22SEQ ID NO:38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH20,6482,78 0,3291,41,97SEQ ID NO:38
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH20,393to 1.860,3751,111,05SEQ ID NO:39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2of 0.3332,91is 0.9980,3660,33SEQ ID NO:39
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH20,4612,450,9311,370,50SEQ ID NO:40
Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH20,5763,982,823,910,20SEQ ID NO:40

Table 2C
ConnectionKi hMC1-RKi hMC3-RKi hMC4-R Ki hMC5-RKi hMC1-R
/MC4-R
SEQ ID NO:
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH217,91,680,25623,469,9SEQ ID NO:49

Biological analysis of cyclic AMP

The levels of intracellular cyclic AMP (camp) was determined by analysis of electrochemiluminescence (ECL) (Meso Scale Discovery®, Gaithersburg, MD; hereinafter referred to as MSD). Cells Cho-K1, stably expressing the receptor subtypes hMC, suspended in analytical buffer RMPI 1640® (buffer RMPI 1640 containing 0.5 mm isobutylmethylxanthine (IBMX) and 0.2% protein blend (blocker And MSD)). Transgenic cells Cho-K1, stably expressing subtypes 1, 3, 4 or 5 receptor hMC, was applied at a density of approximately 7,000 cells/well in 384-well tablets Multi-Array® (MSD)containing integrated carbon electrodes and coated with an antibody against the camp. Added increasing concentrations of the tested compounds and cells were incubated for approximately 40 minutes at approximately 37°C. After this incubation was added litany buffer (HEPES buffered saline with MgCl2and Triton X-100® at pH 7,3)containing 0.2% protein mixture and 2.5 nm TAGTMlabeled with ruthenium camp (MSD) and glue the key incubated for about 90 min at room temperature. At the end of the second incubation period is added to the read buffer (Tris buffered solution containing joint ECL reagent and Triton X-100 at pH 7,8) and immediately determined the levels of camp in cell lysates by ECL detection by the reader Sector Imager 6000 reader® (MSD). Data were analyzed using nonlinear regression analysis using the computer (selection XL; IDBS), and represented in the form or size EU50or size Kb.

EU50is the concentration of agonist required to obtain 50% of the maximum response, for example 50% of the maximum level of camp, according to the definition using the above analysis. Size Kb reflects the activity of the antagonist and is determined by Schild analysis. In short, the curves of reaction on the concentration of agonist receive in the presence of increasing concentrations of antagonist. The value of Kb is the concentration of antagonist, which would have caused a two-fold shift of the curve of the dependence of the reaction on the concentration of agonist. It is calculated by extrapolation of the line on the graph Schild to zero on the y-axis.

Selected compounds were tested using the above-discussed tests, and the results are presented in tables 3A, 3B and 3D.

Tables 3A, 3B, 3C and 3D biological Data analysis camp for selected compounds

Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2
Table 3A
ConnectionEC50
hMC1-R
EC50
hMC3-R
EC50
hMC4-R
EC50
hMC5-R
EC50
hMC1-R
/MC4-R
SEQ ID NO:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH25,79the 5.250,313163018,0SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH26,175,60,397102016,0SEQ ID NO:50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH226,510,50,493244054,0SEQ ID NO:51
Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH28,4332,40,95921409,0SEQ ID NO:52
4,238,090,71923,26,0SEQ ID NO:52
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH248,313,30,791000061,0SEQ ID NO:51
Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH21,485,760,07829719,0SEQ ID NO:53
Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH21,392,890,05546725,0SEQ ID NO:53
ND = not determined

Table 3B

td align="left"> 0,145
ConnectionEC50
hMC1-R
EC50
hMC3-R
EC50
hMC4-R
EC50
hMC5-R
EC50
hMC1-R
/MC4R
SEQ ID NO:
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH22,40,330,07842031SEQ ID NO:7
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH20,351,10,110,373SEQ ID NO:24
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH20,310,270,0183,117SEQ ID NO:27
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH20,280,240,028a 3.910SEQ ID NO:32
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH20,370,10,0211,718SEQ ID NO:34
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH20,8340,1282,796,52SEQ ID NO:1
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH20,760,1990,04921,7315,45SEQ ID NO:2
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH23,260,1890,094930,234,35SEQ ID NO:6
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH21,370,6280,1313,4810,46SEQ ID NO:6
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH22,273,327,244150,31SEQ ID NO:11
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2ND1,89mean HDI of 0.531NDNDSEQ ID N:21
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH214,32,030,1832240a 78.14SEQ ID NO:22
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH20,3452,7153762,380,06SEQ ID NO:24
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH20,68581,886,9of 31.80,01SEQ ID NO:26
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH20,9313,221,65>100000,56SEQ ID NO:28
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH23,240,4650,091578,535,41SEQ ID NO:30
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH20,819 0,5410,45345,31,81SEQ ID NO:30
ND = not determined

Table 3C
ConnectionEC50hMC1-RKb hMC3-RKb MC4-REC50hMC5-RSEQ ID NO:
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH217,612,438,811,8SEQ ID NO:16
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH20,6192,980,1090,189SEQ ID NO:38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH20,9130,5360,3460,489SEQ ID NO:38
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH20,23118,4 0,7820,153SEQ ID NO:39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH20,58110,80,9670,126SEQ ID NO:39
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH20,413to 9.320,8240,307SEQ ID NO:40
Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH21,273,020,4420,736SEQ ID NO:40
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH238361,553,62842SEQ ID NO:16

Table 3D

ConnectionEC50hMC1-RKb hMC3-RKb MC4-REC50hMC5-RSEQ ID NO:
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2193 5,721,581111SEQ ID NO:49

Example 4: in vivo Studies

Compounds of the present invention can be and were tested for the presence of effects on food intake and/or body weight in accordance with the following procedures. The person skilled in the art should know that to analyze the effect of the compounds according to the invention on the consumption of food and/or body weight, you can use procedures similar to those described in the present description.

Below is the connection of the ligand that activates the receptor melanocortin tested in vivo studies (table 4):

Table 4
Code of ligandStructure
Connection AAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:7
Compound BAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:22
Connection CAc-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2SEQ ID NO:32
Connection DD-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2SEQ ID NO:24
Connection EAc-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50
Connection FAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO:50
Connection GAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2SEQ ID NO:51

Experiments on acute feeding (after fasting)

Male rats Sprague Dawley (250 g) were kept in individual cages and maintained by the alternation of light and darkness for 12 hours, the Rats fasted for 18 h before the experiment with water access without restrictions. During 0 to rats subcutaneously (s/C) were injected with selected compounds in doses or 500, or 100 nmol/kg, or the media and gave them food. Individual feed intake was measured after about 1, 2, 3, 4, 5 and 6 h after injection. Data for selected compounds of the invention represented on figa and 1B.

Experiments on acute feeding (without starvation)

Male rats Sprague Dawley (250 g) were kept in individual cages and maintained by the alternation of light and darkness for 12 hours Feed and water were available without restriction throughout the entire experiment. At time 0 the rats s/C were injected with the compound in doses or 500, or 100 nmol/kg, or media. Individual feed intake was measured after about 1, 2, 3, 4, 5 and 6 h after injection.

Experiments on chronic the mu feeding

Male rats Sprague Dawley (250 g) were kept in individual cages and maintained by the alternation of light and darkness for 12 h with access to food and water without restrictions. Rats p/C 3/d (approximately 08:00 h 12:00 h and 16:00 h) were injected with the compound at various doses or the carrier within 7 days Daily measured individual body weight and food consumption. Data for selected compounds of the invention represented on figa and 2B, figa and 3B and figa and 4B.

Introduction and application

The peptides of the present invention can be obtained in the form of pharmaceutically acceptable salts. Examples of such salts include, without limitation salts formed with organic acids (e.g. acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluensulfonate or Paveway acid), inorganic acids (e.g. hydrochloric acid, sulfuric acid or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic or copolymers of polylactic-glycolic acid). A typical way to obtain the salt of the peptide of the present invention are well known in this field and can be carried out by standard methods salt exchange. Accordingly TFA salt of the peptide of the present invention (the ol TFA is obtained by purification of the peptide by using preparative HPLC, elution of TFA containing buffer solutions) can be converted into another salt, such as acetate, dissolving the peptide in a small amount of 0.25 N. aqueous solution of acetic acid. The resulting solution was applied on a column prepreparation HPLC (Bond®, SB 300, C-8). The column was suirable: (1) 0.1 N. aqueous solution of ammonium acetate for 0.5 h; (2) 0,25 N. aqueous solution of acetic acid for 0.5 h; and (3) a linear gradient (from 20% to 100% of solution b over 30 min) at a flow rate of 4 ml/min (solution a represents 0,25N aqueous solution of acetic acid; the solution is a 0,25N solution of acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide, collect and lyophilizer to dryness.

As is well known to specialists in this field, known and potential uses of the peptides with agonist activity or antagonist of the receptor melanocortin (MC-R) are varied and numerous; thus, the introduction of the compounds of the present invention to challenge the effect of the agonist can have the same effects and uses himself as melanocortin.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising as active ingredient at least one of the compounds of formula (I) in Association with a pharmaceutically acceptable carrier.

The dosage of the active ingredient in the compositions of the present invention may vary; however, it is necessary that the amount of active ingredient was such that there was obtained a suitable dosage. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment. In General, an effective dosage for the activities of the present invention is in the range from 1×10-7up to 200 mg/kg/d, preferably, from 1×10-4up to 100 mg/kg/d, which can be entered as a single dose or divided into multiple doses.

Compounds of the present invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), intranasal, vaginal, rectal, sublingual, or local routes of administration, and they may be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such lekarstvennayaforma may also include, as in normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also include tabularasa agents. Tablets and pills can additionally be obtained intersolubility the floor.

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 wetting agents, emulsifying and suspendresume agents, and sweetening, giving a pleasant taste and odor agents.

The preparations in accordance with the present invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of nonaqueous solvents or media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and complex injectable organic esters, such as etiloleat. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Drugs which s can be sterilized, for example, by filtration through a retaining bacteria filter, by incorporation of sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. Drugs can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

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

Compositions for intranasal or sublingual introduction also get with standard excipients, well known in this field.

In addition, the compound of the present invention can be enter in the composition of extended release, such as the compositions described in the following patents and patent applications. In U.S. patent No. 5672659 it comes to songs extended release, including a biologically active agent and a complex polyester. In U.S. patent No. 5595760 it comes to songs extended release, including a biologically active agent in forming the gel form. In U.S. patent No. 5821221 it comes to polymer compositions with prolonged release, including biologically as the active agent and chitosan. In U.S. patent No. 5916883 it comes to songs extended release, including a biologically active agent and a cyclodextrin. The provisions of the above patents and applications are incorporated into this description by reference.

1. The connection, which is a selective agonist of the receptor melanocortin-4, representing:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt.

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound which is a selective agonist of the receptor melanocortin-4, representing the Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.

3. The pharmaceutical composition according to claim 2, intended for the treatment of acute or chronic inflammatory diseases or medical conditions where the disease or condition selected from the group consisting of General inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock.

4. The pharmaceutical composition according to claim 2, intended for the treatment of diseases or medical conditions with an autoimmune component, the de specified disease or condition selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.

5. The pharmaceutical composition according to claim 2, intended for the treatment of metabolic disease or medical condition accompanied by weight gain, where the disease or condition selected from the group consisting of obesity, eating disorders and Prader-Willi.

6. The pharmaceutical composition according to claim 5, where the treatment is subjected to obesity or eating disorders.

7. The pharmaceutical composition according to claim 2, designed to reduce food intake, or intended for weight reduction, or designed to reduce food intake and weight loss.

8. The pharmaceutical composition according to claim 2, intended for the treatment of neoplastic disease or medical condition, where the disease or condition selected from the group consisting of skin cancer and cancer cachexia, or intended for the treatment of reproductive or sexual health status, where the disease or condition selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women, or intended for treatment of a disease or medical condition arising as a result of treatment or the surface is Idumea effects on the body, where the specified disease or condition selected from the group consisting of rejection of organ transplant ischemia and reperfusion damage, injuries and spinal cord injuries, and loss of body weight due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, or intended for the treatment of cardiovascular diseases or medical conditions where the disease or condition selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia, or intended for the treatment of pulmonary diseases or medical States, where the disease or condition selected from the group consisting of acute respiratory distress syndrome, pneumovirus, chronic obstructive pulmonary disease and asthma, or intended for treatment of a disease or medical condition, where the disease or condition selected from the group consisting of enhanced immune tolerance and allergic conditions, or intended for treatment of a dermatological disease or medical condition, where the disease or condition selected from the group consisting of psoriasis, isthose the Iya skin pigmentation, acne and education keloid zone, or intended for the treatment of behavioral or Central nervous system or neuronal disease or medical condition, where the disease or condition selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain, or intended for the treatment of renal disease or medical condition, where the disease or condition selected from the group consisting of renal cachexia and natriuresis, or designed to modulate the mass of the ovaries, placenta development, prolactin secretion, FSH secretion, intrauterine fetal growth, birth, spermatogenesis, release of thyroxine synthesis and release aldosterone, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, glucose levels in the blood, secretion of fat, the secretion of pheromones, motivation, learning and behavior, perception of pain, neuroprotection and nerve growth, or intended for modulation of bone metabolism, bone formation and bone development.

9. The pharmaceutical composition according to claim 2, intended for the inhibition of alcohol to reduce alcohol use, alcoholism treatment, or for treatment of alcohol abuse.

10. The use of therapeuti the Eski effective number of connections, which is a selective agonist of the receptor melanocortin-4, representing the Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt for the manufacture of a medicine for inhibiting alcohol consumption or to reduce alcohol consumption for alcohol treatment or for the treatment of alcohol abuse in in need of such treatment of the subject.

11. The connection, which is a selective agonist of the receptor melanocortin-4, representing the Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt for call agonistic effect of receptor melanocortin the need for this entity.

12. The connection 11 for the treatment of acute or chronic inflammatory diseases or medical conditions where the disease or condition selected from the group consisting of General inflammation, inflammatory bowel disease, encephalitis, sepsis and septic shock.

13. The connection 11 for the treatment of diseases or medical conditions with an autoimmune component, where the disease or condition selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.

14. The connection 11 for the treatment of metabolic disease or medical status is I, accompanied by weight gain, where the disease or condition selected from the group consisting of obesity, eating disorders and Prader-Willi.

15. The connection 14, where treatment is subjected to obesity or eating disorders.

16. The connection 11 to reduce food intake or to reduce weight or to decrease food intake and reduce the weight.

17. The connection 11 for the treatment of neoplastic disease or medical condition by calling the agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of skin cancer and cancer cachexia, or for the treatment of reproductive or sexual health status by calling agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women, or for the treatment of diseases or medical conditions arising as a result of treatment or damaging effects on the body by calling agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of rejection of organ transplant, ischemia and reperfusion damage, injuries and spinal cord injuries, and loss of body weight due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, or for the treatment of cardiovascular diseases or medical conditions by calling agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia, or for the treatment of pulmonary disease or medical condition by calling agonist or antagonist effect from receptor melanocortin, where the disease or condition selected from the group consisting of acute respiratory distress syndrome, pneumovirus, chronic obstructive pulmonary disease and asthma, or for the treatment of a disease or medical condition by calling the agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of enhanced immune tolerance and allergic conditions, or for the treatment of dermatological diseases or medical status is I by calling agonistic or antagonistic effect on receptor melanocortin, where the specified disease or condition selected from the group consisting of psoriasis, exhaustion, skin pigmentation, formation of acne and keloid zone, or to treat the behavioral or Central nervous system or neuronal disease or medical condition by calling the agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain or for the treatment of renal disease or medical condition by calling the agonistic or antagonistic effect on receptor melanocortin, where the disease or condition selected from the group consisting of renal cachexia and natriuresis, or to modulate the mass of the ovaries, placenta development, prolactin secretion, FSH secretion, intrauterine fetal growth, birth, spermatogenesis, release of thyroxine synthesis and release of aldosterone, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, glucose levels in the blood, secretion of fat, the secretion of pheromones, motivation, learning and behavior, perception of pain, neuroprotection and nerve growth by calling agonistic or antagonistic effect on receptor melanocortin, or on the I modulation of bone metabolism, bone formation and bone development by calling agonistic or antagonistic effect on receptor melanocortin.

18. The connection 11 for inhibiting alcohol consumption, reducing alcohol consumption, alcohol treatment or treatment of alcohol abuse by calling agonistic or antagonistic effect on receptor melanocortin.

19. The use of therapeutically effective amounts of compounds that are selective agonist of the receptor melanocortin-4, representing the Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of a disease or condition selected from the group consisting of General inflammation, inflammatory bowel disease, encephalitis, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, metabolic diseases and medical conditions associated with weight gain, obesity, eating disorders, Prader-Willi, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, cachexia, AIDS cachexia, cancer cachexia, malnutrition in malnourished the elderly, skin cancer, endometriosis, uterine bravoteen is, sexual dysfunction, erectile dysfunction, reduced sexual response in women, rejection of organ transplant ischemia and reperfusion damage, injury and spinal cord injury, weight loss, caused by a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pneumovirus, chronic obstructive pulmonary disease, asthma, increased immune tolerance, allergic conditions, eczema, exhaustion, skin pigmentation, acne, education keloid zone, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.

20. The use of therapeutically effective amounts of compounds that are selective agonist of the receptor melanocortin-4, representing the Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO:50), or its pharmaceutically acceptable salt for the manufacture of drugs to modulate the mass of the ovaries, placenta development, prolactin secretion, FSH secretion, intrauterine fetal growth, birth, spermatogenesis, release of thyroxine synthesis and release of aldosterone, the temperature of the body, blood pressure, heart rate, vascular tone, brain blood flow, glucose levels in the blood, secretion of fat, the secretion of pheromones, motivation, learning and behavior, perception of pain, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.



 

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43 cl, 79 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the method for preparation of the cyclic somostatin analogues of formula I and to the intermediates used in the claimed method. The method is implemented by the cyclisation of somostatin having formula II where R1 is -C2-C6 alkylene -NR3R4, R3 and R4 independently of each other are H or acyl, R2 is , where R5 is phenyl, R11 and R12 independently of each other are amino protective groups. If R1 contains the amino end-group the latter is also protected with amino protective group, if necessary the amino protective group(s) is (are) eliminated and thus obtained compound of formula I is reduced in free or salt form.

EFFECT: improvement of method for preparation of somostatin peptides.

6 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula (Ia) and their application in radiological pharmaceutical compositions for linking to receptors associated with angiogenesis.

EFFECT: possible application in diagnostics or therapy, eg for malignant or cardiac diseases, endometriosis, inflammatory diseases, rheumatoid arthritis and sarcoma Kaposi.

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds in the form of peptide agonists of vasopressin receptor V1a, of the general formula (I) , and treatment method for shock of hypovolemic or vasodilation origin, esophagus vein dilation with hemorrhage, hepatorenal syndrome, cardiopulmonary resuscitation, anesthesia-induced hypotension, orthostatic hypotension, blood circulation malfunction induced by paracentesis, blood loss during operation or in connection with burn treatment, or nosebleeding. Additionally invention concerns pharmaceutical compositions including claimed compounds as active component in therapeutically effective quantity, and application of claimed compounds in medicine manufacturing.

EFFECT: obtaining compounds with agonistic effect on vasopressin receptor V1a.

12 cl, 2 tbl

FIELD: chemistry, biochemistry.

SUBSTANCE: claimed invention relates to biologically active compounds and includes novel peptides containing to 15 amino acid residues, including sequence Thr-Ser-Asp-Xaa-Xaa, where Xaa represents optionally substituted biphenylalanine, and possessing activity of GLP-1 receptor.

EFFECT: obtaining peptides demonstrating higher resistance to proteolytic decomposition, which makes them candidates for therapy by oral or parenteral introduction.

6 cl, 7 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: proposed here is an isolated cyclic peptide, with amino acid sequence Cys-Ile-Xaa-Ser-Cys (SEQ ID NO:7); where Xaa is an amino acid residue, chosen from a group comprising Asp, Asn, Glu and Gin, and containing a disulphide bond between two Cys residues, which can be used as a selective antagonist of R-cadherin of mammals.

EFFECT: invented selective peptide-antagonists of R-cadherin can be used for inhibiting targeting of hematopoietic stem cells (HSC) on a developing vascular tree, for inhibiting cytoadherence caused by R-cadherin and inhibiting retina angiogenesis.

8 cl, 12 dwg, 7 ex

FIELD: biotechnologies.

SUBSTANCE: invention is related to the field of biotechnology and immunology. Separated and cleaned DNA is presented, which codes receptor CTLA-4 (CD 152) of cat. The following is also suggested - diagnostic oligonucleotide, cloning vector, vaccine, methods of induction, strengthening and suppression of immune response in cat.

EFFECT: creation of model cat for research of retroviral infection.

24 cl, 10 dwg, 6 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: there is provided DNA that codes protein able to transform a compound of formula (II) specified in description of invention into a compound of formula (III) specified in description of invention with an electron transport system containing an electron donor. Protein is able to metabolise herbicides.

EFFECT: introduction of DNA to plants with an expression of the specified protein provides herbicide resistance thereto.

26 cl, 66 dwg, 35 tbl, 75 ex

FIELD: chemistry; medicine.

SUBSTANCE: possibility of application in diagnostics of prostate gland cancer, and in differential diagnostics between prostate gland cancer and benign hyperplasia. Marker of prostate gland cancer consists of protein with molecular weight 28.5 kDa and visible isoelectric point 6.92, isolated from tumor tissue of prostate gland. Isolated marker protein includes peptides MPADLPSLAADFVESK; DVFLGMFLYEYAR; VFDEFKPLVEEPQNLIK; FQNALLVR; VPQVSTPTLVEVSR and AVMDDFAAFVEKCCK.

EFFECT: increase of accuracy of prostate gland cancer diagnostics.

2 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to immunology. β1-adrenoreceptor autoantibodies in human blood plasma/serum are bonded with a synthetic antigen containing nonapeptide (125-133) and tridecapeptide (208-218) of human β1-adrenoreceptor sequences interbinded with disulfide bridge. The antigen is characterised with higher affinity as compared to applied 1st and 2nd loop β1-adrenoreceptor sequences.

EFFECT: invention can be used for diagnostics and treatment of the patients suffering from dilated cardiomyopathy.

3 ex, 1 tbl, 1 dwg

FIELD: biotechnology.

SUBSTANCE: present invention relates to biotechnology. Description is given of a single-strand T-cell receptor (scTCR), containing an α segment, formed by a sequence of a variable region in a TCR chain, joined with the N end of the extracellular sequence with constant region in the TCR chain, a β segment, formed by a sequence of the variable region of the α TCR chain, joined with the N end of the extracellular sequence with constant region of the β TCR chain, and a linker sequence, joining the C end of the α segment with the N end of the β segment, or vice versa. Extracellular sequences of constant regions of α and β segments are joined by a disulphide bond. Extracellular sequences of constant regions can correspond to constant regions of α and β chains of native TCR, cut-off at their C ends such that, cysteic residues, which form the inter-chain native disulphide bond of the TCR, are excluded, or extracellular sequences of constant regions which are in the α and β segments, can correspond to constant regions of α and β chains of native TCR, in which cysteic residues, which form the native inter-chain disulphide bond, are replaced by another amino acid residue, or there is no uncoupled cysteic residue, which is in the β chain of the native TCR. This invention makes available a new class of alpha/beta analogues of scTCR, in which there is a disulphide bond between residues of a single amino acid, contributing to stability of the bond between the alpha and beta regions of the molecule.

EFFECT: such TCR are suitable for screening or for therapeutic purposes.

3 cl, 14 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: proposed here is an isolated cyclic peptide, with amino acid sequence Cys-Ile-Xaa-Ser-Cys (SEQ ID NO:7); where Xaa is an amino acid residue, chosen from a group comprising Asp, Asn, Glu and Gin, and containing a disulphide bond between two Cys residues, which can be used as a selective antagonist of R-cadherin of mammals.

EFFECT: invented selective peptide-antagonists of R-cadherin can be used for inhibiting targeting of hematopoietic stem cells (HSC) on a developing vascular tree, for inhibiting cytoadherence caused by R-cadherin and inhibiting retina angiogenesis.

8 cl, 12 dwg, 7 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: present invention pertains to biotechnology. Description is given of a phage particle, exposing on its surface, T-cell receptor (TCR), which is a human scTCR. The exposed dTCR polypeptide pair or exposed scTCR polypeptide contains a series of α and β chains of extra-cellular constant lg of the native TCR domain. A disulphide bond joins amino acid residues of the given series of chains of the constant lg domain, where the given disulphide bond is between cysteic residues. Presented is a library of polypeptide pairs of mutated TCR or scTCR polypeptides, exposed on the described phage particle. Nucleic acid, which encodes the described phage particle, is also presented. A method of identifying TCRs is invented. The invention can be used for making various TCR libraries, for identification of high-affinity TCRs.

EFFECT: possibility of making various TCR libraries for identification of high-affinity TCRs.

17 cl, 25 ex, 63 dwg, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: variants of the combined protein which contain the extracellular domain of a human receptor of a hormone of growth and the domain which includes alarm sequence for joining glycosylphosphatidylynozyte (GPI) anchors are offered.

EFFECT: effective medical product for acromegalia and gigantism treatment.

8 cl, 16 dwg

FIELD: genetic engineering.

SUBSTANCE: invention refers to polypeptides GPCR Drosophila melanogaster (DmGPCR) and polynucleotides detecting and coding such polypeptides. Construction of expressing vectors based on specified polynucleotides and production of containing host cells enables to apply DmGPCR as insecticides. Besides, invention refers to methods of DmGPCR-bindnig, method of DmGPCR expression and activity modulator identification, method of insect population control using DmGPCR-antibody, DmGPCR antisense polynucleotides, DmGPCR binding partner or modulator.

EFFECT: new application of polypeptides.

35 cl, 7 tbl, 10 ex

FIELD: technological processes.

SUBSTANCE: method suggests protein of adipocyte plasma membrane, method of its preparation and complex based on this protein. Protein has molecular mass of 115 kilodaltons and has the ability to start-up tyr-phosphorylation of insulin-receptor proteins substrate in adipocyte. Method of protein preparation provides for adipocytes preparation out of rat, mouse or human tissues and plasma membranes extraction out of them. Then plenty of domains are isolated with high content of cholesterol hcDIG, which are treated with solution trypsin/NaCl. Centrifugation is done and protein fraction SDS-polyacrylamide gel is segregated with electrophoresis. Prepared protein fraction in amount of 115 kilodaltons is eluated from this gel. Complex constitutes activated protein and is formed during its combination with one of compounds from group: YCN-PIG, YMN-PIG, YCN or lcGcel.

EFFECT: protein in its activated form allows regulating glucose utilization bypassing insulin signal chain.

7 cl, 20 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

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