Melanocortin receptor ligands

Abstract

The present invention relates to compounds according to the formula (R2R3)-A1-c (A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1, and pharmaceutically acceptable salts thereof, as ligands for one or more melanocortin receptors, to methods of using such compounds in the treatment of mammals and to pharmaceutical compositions comprising said compounds.

Description

[0001] The present application is a divisional application of Chinese patent application No. 201610168908.2, whose application date is July 10, 2006 and whose invention name is “Melanocortin Receptor Ligands”, in which Chinese patent application No. 201610168908.2 is a divisional application of Chinese patent application No. 201310495024.4, whose invention name is “Melanocortin Receptor Ligands”, in which Chinese patent application No. 201310495024.4 is a divisional application of Chinese patent application No. 200910174061.9, whose invention name is “Melanocortin Receptor Ligands”, in which Chinese patent application No. 200910174061.9 is a divisional application of Chinese patent application No. 200680032423.5 (International Application No. PCT / US2006 / 026586), whose invention name is “Melanocortin Receptor Ligands”. Background of the Invention

[0003] The present invention relates to peptides which are ligands for one or more melanocortin receptors (MC-R), to pharmaceutically acceptable salts of said peptides, to methods of using such peptides to treat mammals, and to useful pharmaceutical compositions comprising said peptides.

[0004] Melanocortins belong to a family of regulatory peptides that are formed by post-translational processing of the prohormone proopiocortin (POMC; 131 amino acids long). POMC is processed into three classes of hormones: melanocortins, adrenocorticotropic hormone, and a variety of endorphins (e.g., lipotropin) (Cone, et al., Recent Prog. Horm. Res., 51: 287-317, (1996); Cone et al., Ann. NY Acad. Sci., 31: 342-363, (1993)).

[0005] Melanocortins have been found in a variety of normalized human tissues, including the brain, adrenal glands, skin, testes, spleen, kidney, ovary, lung, thyroid, liver, colon, small intestine, and pancreas (Tatro, JB et al., Endocrinol. 121: 1900-1907 (1987); Mountjoy, KG 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)).

[0006] Melanocortin peptides have been shown to exhibit a variety of physiological activities, including control of behavior and memory, effects on neurotrophic and antipyretic properties, and effects on the regulation of the immune system. In addition to their well-known effects on adrenocortical function (adrenocorticotropic hormone, ACTH) and melanocytes (melanocyte stimulating hormone, MSH), melanocortins have also been shown to control the cardiovascular system, analgesia, temperature regulation, and the release of other neuronal mediators, 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, KA et al., Am. J. Physiol. 257: R681-R694 (1989); Walker JM et al., Science 210:1247-1249 (1980); Murphy, MT et al., Science 221:192-193 (1983); Ellerkmann, E. et al., Endocrinol. 130:133-138 (1992) and Versteeg, DHG et al., Life Sci. 38:835-840 (1986)).

[0007] It has also been shown that the binding sites of melanocortins are distributed in many different tissue types, including the lacrimal and submandibular glands, pancreas, fat, bladder, duodenum, spleen, brain and gonadal tissues, as well as malignant melanoma tumors. Five melanocortin receptors (MC-R) have been characterized to date. These include the melanocyte-specific receptor (MC 1-R), the adrenal cortex-specific ACTH receptor (MC2-R), melanocortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-5 receptor (MC5-R). All melanocortin receptors respond to the peptide hormone class melanocortin (MSH) (Cone, RD et al., Ann. NY Acad. Sci., 680: 342-363 (1993); Cone, RD et al., Recent Prog. Horm. Res., 51: 287-318 (1996)).

[0008] MC1-R, which is called melanocyte stimulating hormone receptor (MSH-R), melanocyte stimulating hormone receptor or melanocortin-1 receptor in the art, is a transmembrane protein of 315 amino acids, which belongs to the G-protein coupled receptor family. MC1-R is a receptor for MSH and ACTH. The activity of MC1-R is mediated by G-protein, which activates adenylate cyclase. MC1-R receptors are found in melanocytes and adrenal cortical tissues and various other tissues, such as adrenal glands, leukocytes, lungs, lymph nodes, ovaries, testes, pituitary glands, placenta, spleen and uterus. MC2-R, also known as adrenocorticotropic hormone receptor (ACTH-R), is a trans-modal protein of 297 amino acids found in melanocytes and adrenal cortical tissues. MC2-R mediates the adrenocorticotropic effect of ACTH. In humans, MC3-R is a 360AA protein found in brain tissue; in mice and rats, MC3-R is a 323AA protein. MC4-R is a 332 amino acid transmembrane protein that is also expressed in the brain as well as placenta and intestinal tissue. MC5-R is a 325 amino acid transmembrane protein expressed in the adrenal glands, stomach, lungs and spleen and is expressed at very low levels in the brain. MC5-R is also expressed in the three layers of the adrenal cortex, mainly in the zona glomerulosa cells that produce aldosterone.

[0009] However, the functions of these five known melanocortin receptors are different. For example, MC1-R is a G protein-coupled receptor that regulates pigment formation in response to α-MSH, a strong agonist of MC1-R. Activation of the MC1-R receptor leads to stimulation of melanocytes, which cause eumelanin and increase the risk of skin cancer. Activation of MC1-R also has neurological effects. Stimulation of MC2-R activity can lead to adrenal tissue cancer. Recent pharmacological evidence has determined that the important MC4-R receptor is the main mediator of the anorectic and anorectic effects reported for melanocortin agonists and antagonists, respectively. The agonistic effects of MC3-R and MC5-R are still unknown.

[0010] There is great interest in melanocortin (MC-R) receptors as targets for designing novel therapeutic agents for treating weight disorders such as obesity and cachexia. Genetic and pharmacological evidence points to the major MC4-R receptor as a primary target (Giraudo, SQ et al., Brain Res., 809:302-306 (1998); Farooqi, IS et al., NE J Med., 348:1085-1095 (2003); MacNeil, DJ et al., Eu. J. Pharm., 44:141-157 (2002); MacNeil, DJ et al., Eu. J. Pharm., 450:93-109 (2002); Kask, A. et al., Neuro Report, 10:707-711 (1999)). Current advances using receptor-selective agonists and antagonists demonstrate the therapeutic potential of melanocortin receptor activation, particularly MC4-R.

[0011] Compounds that activate one or more melanocortin receptors as agonists, antagonists or other ligands will be useful in treating a variety of indications for which they are needed or at risk, including acute and chronic inflammatory diseases, such as systemic inflammation (U.S. Pat. No. 6,613,874; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), inflammatory bowel disease (U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), and inflammatory bowel disease (U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)). , 56: 1-29 (2004)), brain inflammation (Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), sepsis (U.S. Pat. No. 6,613,874; U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), and septic shock (U.S. Pat. No. 6,613,874; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)). m. Rev., 56: 1-29 (2004)); diseases with autoimmune components such as rheumatoid arthritis (U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), gouty arthritis (Catania, A. et al., Pharm. Rev., 56: 1-29 (2004), Getting, SJ et al., Curr. Opin. Invest. ig.Drugs, 2:1064-1069 (2001)), and multiple sclerosis ((U.S. Patent No. 6,713,487); metabolic diseases and medical conditions associated with weight gain such as obesity (U.S. Patent No. 6,613,874; U.S. Patent No. 6,600,015; Fehm, HL et al., J. Clin. Endo. & Metab., 86:1144-1148 (2001); Hansen, MJ et al., Brain Res., 1039: 137-145 (2005); Ye, Z. et al., Peptides, 26: 2017-2025 (2005); Farooqi, IS et al., NE J Med., 348: 1085-1095 (2003); MacNeil, DJ et al., Eu. J. Pharm., 44: 141-157 (2002); MacNeil, DJ et al., Eu. J. Pharm., 450: 93-109 (2002); Kask, A. et al., NeuroReport, 10: 707-711 (1999); Schwartz, MW, J. Clin. Invest., 108: 963-964 (2001), Gura, T., Science, 287: 1738-1740 (2000), Raffin-Sanson, ML, Eu. J. Endo., 144: 207-208 (2001), Hamilton, BS et al., Obesity Res. 10: 182-187 (2002)), eating disorders (U.S. Pat. No. 6,720,324; Fehm, HL 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 diseases and medical conditions associated with weight loss, such as anorexia (U.S. Pat. No. 6,613,874; Wisse, BR et al., Endo., 142: 3292-3301 (2001)), bulimia (U.S. Pat. No. 6,720,324), AIDS wasting (Marsilje, TH et al., Bioorg. Med. Chem. Lett., 14: 3721-3725 (2004); Markison, S et al., Endocrinology, 146: 2766-2773 (2005)), cachexia (U.S. Pat. No. 6,613,874; Lechan, RM 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. 6,639,123) and wasting in frail elderly people (U.S. Patent No. 6,639,123); diabetes (U.S. Patent No. 6,713,487) and diabetes-related diseases and complications of diabetes, such as retinopathy (U.S. Patent No. 6,525,019); neoplastic hyperplasia (U.S. Patent No. 6,713,487) such as skin cancer (Sturm, RA, Melanoma Res., 12:405-416 (2002); Bastiens, MT et al., Am. J. Hum. Genet., 68:884-894 (2001)), and prostate cancer (Luscombe, CJ et al., British J. Cancer, 85:1504-1509 (2001); reproductive or sexual medical conditions, such as endometriosis (U.S. Pat. No. 6,713,487) and uterine bleeding in women (U.S. Pat. No. 6,613,874), sexual dysfunction (U.S. Pat. No. 6,720,324; Van der Ploeg, LH.T. et al., PNAS, 99: 11381-11386 (2002), Molinoff, PB et al., Ann. NY Acad. Sci., 994: 96-102 (2003), Hopps, CV et al., BJU International, 92: 534-538 (2003)), erectile dysfunction ((U.S. Pat. No. 6,613,874; Diamond, LE et al., Urology, 65: 755-759 (2005), Wessells, H. et al., Int. J. Impotence Res., 12: S74-S79 (2000), Andersson, KE. et al., Int. J. Impotence Res., 14: S82-S92 (2002), Bertolini, 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, AM et al., Society for Neuroscience Abstract, (2003); Wessells, H. et al., J. Urology, 160:389-393 (1998), Rosen, RC 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. Pat. No. 6,713,487; Fourcroy, JL, Drugs, 63:1445 -1457 (2003)); treatment or diseases or conditions caused by organ damage such as organ transplant rejection (U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), ischemia and reperfusion injury (Mioni, C. et al., Eu. J. Pharm., 477: 227-234 (2003); Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), spinal cord injury treatment and accelerated wound healing (Sharma HS et al., Acta. Nerochir. Suppl., 86: 399-405 (2003); Sharma HS, Ann. NY Acad. Sci.1053:407-421 (2005); U.S. Pat. No. 6,525,019), and weight loss caused by chemotherapy, radiation therapy, temporary or permanent immobilization (Harris, RB et al., Physiol. Behav., 73:599-608 (2001)) or dialysis; cardiovascular disease or condition, such as hemorrhagic shock (Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), cardiogenic shock (U.S. Pat. No. 6,613,874), hypovolemic shock (U.S. Pat. No. 6,613,874), and pulmonary hypertension (U.S. Pat. No. 6,613,874). No. 6,613,874), cardiovascular disorders (U.S. Pat. No. 6,613,874) and cardiac cachexia (Markison, S. et al., Endocrinology, 146: 2766-2773 (2005); pulmonary diseases or disorders, such as acute respiratory distress syndrome (U.S. Pat. No. 6,350,430; Catania, A. et al., Pharm. Rev., 56: 1-29 (2004)), chronic obstructive pulmonary disease (U.S. Pat. No. 6,713,487), asthma (U.S. Pat. No. 6,7 13,487) and pulmonary fibrosis; enhancing immune tolerance (Luger, TA et al., Pathobiology, 67:318-321 (1999)) and resisting attacks on the immune system, such as those associated with certain allergens (U.S. Pat. No. 6,713,487) or organ transplant rejection (U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)); treatment of skin diseases and conditions such as psoriasis (U.S. Pat. No. 6,713,487), skin pigmentation The research progress has been reported in the fields of skin failure (U.S. Pat. No. 6,713,487; Ye, Z. et al., Peptides, 26: 2017-2025 (2005)), acne (Hatta, N. et al., J. Invest. Dermatol., 116: 564-570 (2001); Bohm, M. et al., J. Invest. Dermatol., 118: 533-539 (2002)), keloid formation (U.S. Pat. No. 6,525,019) and skin cancer (Sturm, R. A., Melanoma Res., 12: 405-416 (2002); Bastiens, MT et al., Am. J. Hum. Genet., 68: 884-894 (2001)); behavioral, central nervous system or neuronal conditions and disorders, such as anxiety (U.S. Pat. No. 6,720,324; Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)), depression (Chaki, S.et al., Peptides, 26: 1952-1964 (2005), Bednarek, MA et al., Expert Opinion Ther. Patents, 14: 327-336 (2004); U.S. Patent No. 6,720,324), memory and memory dysfunction (U.S. Patent No. 6,613,874; Voisey, J. et al., Curr. Drug Targets, 4: 586-597 (2003)), modulation of pain perception (U.S. Patent No. 6,613,874; Bertolini, A. et al., J. Endocrinol. Invest., 4: 241-251 (1981); Vrinten, D. et al., J. Neuroscience, 20: 8131-8137 (2000)) and treatment of neuropathic pain (Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15: 2541-2546 (2005)); conditions and diseases related to alcohol consumption, alcohol abuse and / or alcohol intoxication (WO 05 / 060985; Navarro, M. et al., Alcohol Clin. Exp. Res., 29:949-957 (2005)); and treatment of renal disorders or diseases, such as renal cachexia (Markison, S. et al., Endocrinology, 146:2766-2773 (2005)) or natriuresis (U.S. Pat. No. 6,613,874).

[0012] Compounds that activate one or more melanocortin receptor ligands will be useful for modulating a variety of normalizing or homeostatic activities in a subject in need thereof, including thyroxine release (U.S. Pat. No. 6,613,874), aldosterone synthesis and release (U.S. Pat. No. 6,613,874), body temperature (U.S. Pat. No. 6,613,874), blood pressure (U.S. Pat. No. 6,613,874), heart rate (U.S. Pat. No. 6,613,874), vascular tone (U.S. Pat. No. 6,613,874), cerebral blood flow (U.S. Pat. No. 6,613,874), blood glucose levels (U.S. Pat. No. 6,613,874), bone metabolism, bone formation or development (Dumont, LM et al., Peptides, 26: 1929-1935 (20 05), ovarian weight (U.S. Patent No. 6,613,874), placental development (U.S. Patent No. 6,613,874), prolactin and FSH secretion (U.S. Patent No. 6,613,874), intrauterine fetal growth (U.S. Patent No. 6,613,874), parturition (U.S. Patent No. 6,613,874), spermatogenesis (U.S. Patent No. 6,613,874), sebum and pheromone secretion (U.S. Patent No. 6,613,874), neuroprotection (U.S. Patent No. 6,639,123) and nerve growth (U.S. Patent No. 6,613,874) and regulation of movement (U.S. Patent No. 6,613,874), learning (U.S. Patent No. 6,613,874) and other behaviors (U.S. Patent No. 6,613,874).

[0013] Therefore, one object of the present invention is to provide melanocortin receptor ligands which show greater stability and selectivity for melanocortin receptors than natural melanocortin receptor ligands. SUMMARY OF THE INVENTION

[0015] In one aspect, the present invention relates to compounds according to formula (I):

[0016] (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1

[0017] in:

[0018] A 1 Acc, HN-(CH2) m-C(O), L- or D-amino acids, or absence thereof;

[0019] A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

[0020] A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or missing;

[0021] A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;

[0022] A 5 It is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, L-Phe or D-(Et)Tyr;

[0023] A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O);

[0024] A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip;

[0025] A 8 It is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or missing;

[0026] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;

[0027] A 10 Acc, HN-(CH2)t -C(O), L- or D-amino acids, or absence thereof;

[0028] R 1 is -OH, or -NH2;

[0029] R 2 and R 3 Each is independently selected from H, (C1-C 30 )alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) acyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl group;

[0030] R 4 and R 5 each in each case H, (C1-C 40 )alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) acyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl, or -C(NH)-NH2;

[0031] m is independently at each occurrence 1, 2, 3, 4, 5, 6 or 7;

[0032] n is independently in each instance 1, 2, 3, 4 or 5;

[0033] s is independently in each instance 1, 2, 3, 4, 5, 6, or 7;

[0034] t is independently at each occurrence 1, 2, 3, 4, 5, 6, or 7;

[0035] X 1 , X 2 , X 3 , X 4 and X 5 each independently represents at each occurrence H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 )alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN;

[0036] The condition is

[0037] (I).When R 4 Yes (C1-C 40 ) acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl, or -C(NH)-NH2, then R 5 is H or (C1-C 40 )alkyl, (C1-C 40 )heteroalkyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 )alkyl;

[0038] (II). When R 2 is (C1-C 30 ) acyl, aryl (C1-C 30) acyl, substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1-C 30 )alkyl, (C1-C 30 )heteroalkyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 )alkyl;

[0039] (III).A 3 or A 8 or both must be present in the compound;

[0040] (IV).When A 2 When Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen;

[0041] (V).When A 2 When it is Asp or Glu, A 9 It is Dab, Dap, Orn, or Lys;

[0042] (VI). When A 8 When it is Ala or Gly, A 1 Not Nle;

[0043] (VII).When A 1 When missing, R 2 and R 3 It can’t all be H;

[0044] or a pharmaceutically acceptable salt thereof.

[0045] A preferred group of compounds of the foregoing general formula is that wherein A 1 Is A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet or Oic;

[0046] A 2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

[0047] A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or absent;

[0048] A 4 It is His;

[0049] A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, or D-(Et)Tyr;

[0050] A 6 is Arg, or hArg;

[0051] A 7 is Trp, Bip, D-Trp, 1-Nal, or 2-Nal;

[0052] A 8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

[0053] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

[0054] A 10 is Thr, or missing,

[0055] or a pharmaceutically acceptable salt thereof.

[0056] A preferred group of compounds of the preceding group are those wherein R 2 and R 3 Each is independently H, acyl, n-propionyl or n-butyryl, or a pharmaceutically acceptable salt thereof.

[0057] A more preferred compound of formula (I) is one wherein the compound is of the formula:

[0058] A 1 is Acc, Arg, D-Arg, 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 absent;

[0059] A 2 is Cys, D-Cys, Pen or Asp;

[0060] A3 is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val, or absent;

[0061] A 4 is His or 3-Pal;

[0062] A 5 is D-Phe, D-2-Nal or D-(Et)Tyr;

[0063] A 6 is Arg or hArg;

[0064] A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp;

[0065] A 8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, or absent;

[0066] A 9 is Cys, D-Cys, Pen or Lys;

[0067] A 10 is Thr or missing;

[0068] Among them A 3 or A 8 At least one but not both of the

[0069] or a pharmaceutically acceptable salt thereof.

[0070] More preferred compounds of the foregoing group are those wherein the compound is of the formula:

[0071] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 1

[0072] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO: 1

[0073] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 2

[0074] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0075] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:3

[0076] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;SEQ ID NO:3

[0077] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:2

[0078] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;SEQ ID NO:4

[0079] Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:5

[0080] Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0081] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0082] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0083] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0084] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0085] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0086] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0087] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0088] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0089] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0090] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0091] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0092] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0093] Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0094] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0095] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0096] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0097] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0098] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0099] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0100] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0101] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0102] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0103] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0104] Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0105] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0106] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0107] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0108] Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0109] Ac-hPr0-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0110] Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0111] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0112] Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0113] Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0114] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0115] n-Butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 12

[0116] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0117] Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0118] Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0119] Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO: 13

[0120] Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO: 13

[0121] Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0122] Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0123] Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0124] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2;SEQ ID NO:14

[0125] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2;SEQ ID NO:14

[0126] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2;SEQ ID NO:14

[0127] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2;SEQ ID NO:14

[0128] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2;SEQ ID NO:14

[0129] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2;SEQ ID NO:15

[0130] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2;SEQ ID NO:15

[0131] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2;SEQ ID NO:15

[0132] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2;SEQ ID NO:15

[0133] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO: 15

[0134] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 16

[0135] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 16

[0136] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2; SEQ ID NO: 16

[0137] n-Butyryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 17

[0138] n-Butyryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 17

[0139] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 18

[0140] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2; SEQ ID NO: 18

[0141] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO: 18

[0142] Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 61

[0143] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; SEQ ID NO: 19

[0144] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2;SEQ ID NO:20

[0145] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:21

[0146] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0147] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0148] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ IDNO:23

[0149] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ IDNO:24

[0150] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ IDNO:25

[0151] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:24

[0152] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0153] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0154] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:27

[0155] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;SEQ ID NO:28

[0156] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;SEQ ID NO:28

[0157] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0158] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0159] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0160] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0161] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0162] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0163] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0164] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:31

[0165] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0166] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0167] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0168] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0169] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0170] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0171] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0172] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0173] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0174] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0175] Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:35

[0176] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:36

[0177] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2;SEQ ID NO:37

[0178] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2;SEQ ID NO:38

[0179] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2;SEQ ID NO:38

[0180] Ac-Nle-c(Cys-His-D-2-NaI-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:39

[0181] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:39

[0182] Ac-hPhe-c(Asp-His-D-2-NaI-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:40

[0183] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:40

[0184] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-AIa-Lys)-OH;SEQ ID NO:41

[0185] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;SEQ ID NO:42

[0186] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;SEQ ID NO:43

[0187] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;SEQ ID NO:43

[0188] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;SEQ ID NO:43

[0189] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;SEQ ID NO:42

[0190] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;SEQ ID NO:41

[0191] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0192] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0193] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:29

[0194] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0195] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0196] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0197] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0198] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0199] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;SEQ ID NO:45

[0200] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;SEQ ID NO:45

[0201] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;SEQ ID NO:45

[0202] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;SEQ ID NO:45

[0203] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO: 46

[0204] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO: 46

[0205] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; SEQ ID NO: 46

[0206] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO: 46

[0207] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 47

[0208] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO: 29

[0209] 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

[0210] or a pharmaceutically acceptable salt thereof.

[0211] The compounds of the preceding group are more preferably compounds of the formula:

[0212] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 7

[0213] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 22

[0214] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 32

[0215] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 29

[0216] 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

[0217] or a pharmaceutically acceptable salt thereof.

[0218] A more preferred compound of formula (I) is one wherein the compound is of the formula:

[0219] A 1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val, or absent;

[0220] A 2 is Cys, Pen or Asp;

[0221] A 3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or absent;

[0222] A 4 is His or 3-Pal;

[0223] A 5 is D-Phe, D-2-Nal or D-(Et)Tyr;

[0224] A 6 is Arg or hArg;

[0225] A 7 is Trp, 2-Nal, Bal, Bip or D-Trp;

[0226] A 8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx, or absent;

[0227] A 9 is Cys, D-Cys, Pen or Lys;

[0228] A 10 is Thr or missing;

[0229] R 2 and R3 are each independently selected from H or acyl;

[0230] or a pharmaceutically acceptable salt thereof.

[0231] More preferred of the former group of compounds are compounds of the formula:

[0232] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0233] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0234] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0235] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0236] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0237] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0238] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[0239] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[0240] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 7

[0241] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 24

[0242] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:27

[0243] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0244] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0245] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2;SEQ ID NO:1

[0246] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:2

[0247] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:3

[0248] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;SEQ ID NO:3

[0249] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:2

[0250] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;SEQ ID NO:4

[0251] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0252] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0253] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0254] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0255] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0256] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0257] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2;SEQ ID NO:15

[0258] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:21

[0259] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0260] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:23

[0261] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:25

[0262] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:24

[0263] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0264] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0265] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;SEQ ID NO:28

[0266] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;SEQ ID NO:28

[0267] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0268] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0269] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0270] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0271] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0272] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0273] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0274] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:31

[0275] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0276] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0277] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0278] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0279] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0280] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0281] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0282] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0283] Ac-Nle-c(Cys-3Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:35

[0284] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:36

[0285] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2;SEQ ID NO:37

[0286] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2;SEQ ID NO:16

[0287] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2;SEQ ID NO:16

[0288] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2;SEQ ID NO:20

[0289] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 38

[0290] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 38

[0291] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 39

[0292] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 39

[0293] Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40

[0294] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40 or

[0295] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49

[0296] or a pharmaceutically acceptable salt thereof.

[0297] A more preferred compound of formula (I) is one wherein the compound is of the formula:

[0298] A 1 is Arg, D-Arg, hArg or D-hArg;

[0299] or a pharmaceutically acceptable salt thereof.

[0300] A more preferred compound of the preceding group of compounds is one wherein the compound is of the formula:

[0301] A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

[0302] A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or absent;

[0303] A 4 It is His;

[0304] A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, or D-(Et)Tyr;

[0305] A 6 is Arg, or hArg;

[0306] A 7 is Trp, Bip, D-Trp, 1-Nal, or 2-Nal;

[0307] A 8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

[0308] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

[0309] A 10 is Thr, or missing;

[0310] or a pharmaceutically acceptable salt thereof.

[0311] A more preferred compound of the preceding group of compounds is one in which R 2 and R 3 Each is independently H, acyl, n-propionyl, or n-butyryl or a pharmaceutically acceptable salt thereof.

[0312] A more preferred compound of the preceding group of compounds is one wherein the compound is of the formula:

[0313] A 2 is Cys or Asp;

[0314] A 3 It is D-Ala or missing;

[0315] A 4 It is His;

[0316] A 5 It is D-Phe or D-2-Nal;

[0317] A 6 is Arg;

[0318] A 7 It is Trp;

[0319] A 8 It is Ala, Gaba or missing;

[0320] A 9is Cys, Pen or Lys;

[0321] A 10 missing;

[0322] or a pharmaceutically acceptable salt thereof.

[0323] A more preferred compound of the preceding group of compounds is one in which R 2 and R 3 Each is independently H or acyl; or a pharmaceutically acceptable salt thereof.

[0324] More preferred of the foregoing group of compounds are compounds of the formula:

[0325] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0326] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0327] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0328] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0329] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0330] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0331] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[0332] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53 or

[0333] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49

[0334] or a pharmaceutically acceptable salt thereof.

[0335] The compounds of the preceding group are more preferably compounds of the formula:

[0336] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0337] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51 or

[0338] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ IDNO: 49

[0339] or a pharmaceutically acceptable salt thereof.

[0340] The compounds of the preceding group are more preferably compounds of the formula:

[0341] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0342] or a pharmaceutically acceptable salt thereof.

[0343] The compounds of the preceding group are more preferably compounds of the formula:

[0344] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0345] or a pharmaceutically acceptable salt thereof.

[0346] The compounds of the preceding group are more preferably compounds of the formula:

[0347] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49

[0348] or a pharmaceutically acceptable salt thereof.

[0349] In one aspect, the present invention relates to compounds according to formula (II):

[0350] (R 2 R 3 , -A 1 -c(A 2 -A 3 -A 4 -A5 -A 6 -A 7 -A 8 -A 9 )-NH2

[0351] in:

[0352] A 1 is Nle or missing;

[0353] A 2 is Cys or Asp;

[0354] A 3 is Glu or D-Ala;

[0355] A 4 It is His;

[0356] A 5 It is D-Phe;

[0357] A 6 is Arg;

[0358] A 7 is Trp, 2-Nal or Bal;

[0359] A 8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;

[0360] A 9 is Cys or Lys;

[0361] R 2 and R 3 Each is independently selected from H or (C1-C6) acyl;

[0362] The condition is

[0363] (I).When R 2 When it is (C1-C6) acyl, R 3 It is H;

[0364] (II).When A 2 When it is Cys, A 9 It's Cys.

[0365] or a pharmaceutically acceptable salt thereof.

[0366] The compounds of the preceding group are more preferably compounds of the formula:

[0367] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO: 54

[0368] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO: 54

[0369] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 54

[0370] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 54

[0371] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO: 54

[0372] Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 55

[0373] Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO: 55

[0374] Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 56

[0375] Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO: 56

[0376] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 57

[0377] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 57

[0378] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 57 or

[0379] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; SEQ ID NO: 58

[0380] or a pharmaceutically acceptable salt thereof.

[0381] Another more preferred compound of formula (I) or formula (II) is each compound specifically listed in the Examples section below of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0382] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0383] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, wherein the compound is a selective melanocortin 4 receptor agonist.

[0384] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, wherein the compound is a selective melanocortin 4 receptor agonist, which is selective for melanocortin 4 receptor agonist via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[0385] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, wherein the compound is a selective melanocortin 4 receptor agonist, which is selective for melanocortin 4 receptor agonist via EC 50 The functional activity characterized was at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The functional activity characterized is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The functional activity is characterized by being at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[0386] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for the treatment of acute or chronic inflammatory diseases or medical conditions, such as systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.

[0387] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for use in the treatment of a disease or medical condition with an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis.

[0388] On the other hand, the invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for treating a metabolic disease or medical condition accompanied by weight gain, such as obesity, eating disorders and Prader-Willi syndrome. On the other hand, the disease or condition treated is obesity. On the other hand, the disease or condition treated is an eating disorder.

[0389] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing food intake, reducing body weight or a combination thereof. In a preferred embodiment, the present invention provides a composition comprising an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for reducing food intake, reducing body weight or a combination thereof, wherein the active ingredient is one or more of the following compounds: Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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: NO: 51, 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, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing food intake, reducing body weight, or a combination thereof, wherein the active ingredient is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50. In another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing food intake, reducing body weight, or a combination thereof, wherein the active ingredient is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51.In another preferred embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing food intake, reducing body weight or a combination thereof, wherein the active ingredient is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49.

[0390] On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing appetite without impairing body weight. On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for reducing food consumption and increasing body weight.

[0391] On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for the treatment of metabolic diseases or medical conditions associated with weight loss, such as anorexia, bulimia, AIDS emaciation, cachexia, cancer cachexia, and emaciation in the frail elderly. On the other hand, the disease or condition treated is anorexia. On the other hand, the disease or condition treated is bulimia. On the other hand, the disease or condition treated is emaciation in AIDS or emaciation in the frail elderly. On the other hand, the disease or condition treated is cachexia or cancer cachexia.

[0392] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for use in treating a neoplastic disease or medical condition, such as skin cancer and cancer cachexia.

[0393] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for the treatment of reproductive or sexual medical conditions such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and reduced sexual response in women.

[0394] On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for treating a disease or medical condition caused by treatment or injury to an organism, such as organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss caused by a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent fixation and dialysis.

[0395] On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for the treatment of cardiovascular disease or medical conditions such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disease and cardiac cachexia.

[0396] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for the treatment of pulmonary diseases or medical conditions such as acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[0397] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for enhancing immune tolerance and treating allergic reactions.

[0398] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for use in treating skin diseases or medical conditions such as psoriasis, skin pigmentation failure, acne and keloid formation.

[0399] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for the treatment of behavioral or central nervous system or neuronal diseases or medical conditions, such as anxiety, depression, memory dysfunction and neuropathic pain.

[0400] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for use in treating kidney disease or medical conditions, such as renal cachexia and natriuresis.

[0401] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.

[0402] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent for regulating bone metabolism, bone formation and bone development.

[0403] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for inhibiting drinking, reducing drinking, treating alcoholism or treating alcohol abuse. In another aspect, the compound of the composition for inhibiting drinking, reducing drinking, treating alcoholism or treating alcohol abuse is a selective melanocortin 4 receptor agonist. In yet another aspect, the compound of the composition for inhibiting drinking is a selective melanocortin 4 receptor agonist or a pharmaceutically acceptable salt thereof, which is regulated by EC 50 The functional activity characterized is at least 15 times more selective for human melanocortin 4 receptor than for human melanocortin 1 receptor, human melanocortin 3 receptor and human melanocortin 5 receptor. In yet another aspect, the compound of the composition for inhibiting alcohol consumption is a selective melanocortin 4 receptor agonist or a pharmaceutically acceptable salt thereof, which is selectively activated by EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The functional activity is characterized to be at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or as measured by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[0404] In another aspect, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, for the production of a medicament for inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism or treating alcohol abuse in a subject in need of such treatment.

[0405] In yet another aspect, the present invention provides a method for eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0406] In another aspect, the present invention provides a method for causing an agonist or antagonist effect on a melanocortin receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist.

[0407] In another aspect, the present invention provides a method for causing an agonist or antagonist effect on a melanocortin receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist, which is selective for melanocortin 4 receptor agonist via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[0408] In another aspect, the present invention provides a method for causing an agonist or antagonist effect on a melanocortin receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is a selective melanocortin 4 receptor agonist, which is selective for melanocortin 4 receptor agonist via EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The functional activity is characterized to be at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or as measured by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[0409] In another aspect, the present invention provides a method for treating acute or chronic inflammatory diseases or medical conditions, such as systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock, which comprises administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect from a melanocortin receptor.

[0410] In another aspect, the present invention provides a method for treating a disease or medical condition having an autoimmune component, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis, which comprises eliciting an agonist or antagonist effect at a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0411] In another aspect, the present invention provides a method for treating a metabolic disease or medical condition associated with weight gain, such as obesity, eating disorders and Prader-Willi syndrome, comprising causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect of the foregoing method, the disease or condition treated is obesity. In yet another aspect of the foregoing method, the disease or condition treated is an eating disorder.

[0412] In another aspect, the present invention provides a method for reducing food intake, reducing body weight or a combination thereof, comprising eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or (II) as defined above or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method for reducing food intake, reducing body weight or a combination thereof, comprising eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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. 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-NH2 SEQ 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 method for reducing food intake, reducing body weight, or a combination thereof, comprising causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50. In another preferred embodiment, the present invention provides a method for reducing food intake, reducing body weight, or a combination thereof, comprising causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51.In another preferred embodiment, the present invention provides a method for reducing food intake, reducing body weight or a combination thereof, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to induce an agonist or antagonist effect from a melanocortin receptor, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2SEQ ID NO:49.

[0413] On the other hand, the present invention provides a method for reducing appetite without compromising body weight, comprising administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. On the other hand, the present invention provides a method for reducing food consumption and increasing body weight, comprising administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0414] In another aspect, the present invention provides a method for treating metabolic diseases or medical conditions associated with weight loss, such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in the frail elderly, comprising causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, the aforementioned method is used to treat anorexia. In another aspect, the aforementioned method is used to treat bulimia. In another aspect, the aforementioned method is used to treat AIDS wasting or wasting in the frail elderly. In another aspect, the aforementioned method is used to treat cachexia or cancer cachexia.

[0415] In another aspect, the present invention provides a method for treating neoplastic diseases or medical conditions, such as skin cancer and cancer cachexia, comprising administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect at a melanocortin receptor.

[0416] In another aspect, the present invention provides a method for treating reproductive or sexual medical conditions, such as endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and reduced sexual response in women, comprising administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect from a melanocortin receptor.

[0417] In another aspect, the present invention provides a method for treating a disease or medical condition caused by treatment or injury to an organism, such as organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss caused by a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization and dialysis, which comprises administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect from a melanocortin receptor.

[0418] In another aspect, the present invention provides a method for treating cardiovascular disease or medical conditions, such as hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia, which comprises administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect from a melanocortin receptor.

[0419] In another aspect, the present invention provides a method for treating lung diseases or medical conditions, such as acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma, which comprises administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, to induce an agonist or antagonist effect at a melanocortin receptor.

[0420] In another aspect, the present invention provides a method for enhancing immune tolerance or treating allergy, which comprises inducing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt thereof.

[0421] In another aspect, the present invention provides a method for treating skin diseases or medical conditions, such as psoriasis, skin pigmentation failure, acne and keloid formation, which comprises eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0422] In another aspect, the present invention provides a method for treating behavioral or central nervous system or neuronal diseases or medical conditions, such as anxiety, depression, memory dysfunction and neuropathic pain, which comprises eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0423] In another aspect, the present invention provides a method for treating kidney disease or medical conditions, such as renal cachexia and natriuresis, comprising eliciting an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0424] In another aspect, the present invention provides a method for regulating normalization or homeostatic activities such as ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth, which comprises causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0425] In another aspect, the present invention provides a method for regulating normalization or homeostatic activities such as bone metabolism, bone formation and bone development, which comprises inducing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof.

[0426] In another aspect, the present invention provides a method for inhibiting drinking, reducing drinking, treating alcoholism or treating alcohol abuse, which comprises causing an agonist or antagonist effect from a melanocortin receptor by administering an effective amount of a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect of the aforementioned method, the compound is a selective melanocortin 4 receptor agonist. In another aspect of the aforementioned method, the compound of the composition for inhibiting drinking is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, which is selectively administered by EC 50 The functional activity characterized is at least 15 times more selective for human melanocortin 4 receptor than for human melanocortin 1 receptor, human melanocortin 3 receptor and human melanocortin 5 receptor. In another aspect of the aforementioned method, the compound of the composition for inhibiting alcohol consumption is a selective melanocortin 4 receptor agonist or a pharmaceutically acceptable salt thereof, which is selectively inhibited by EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor, as measured by EC 50 The functional activity is characterized to be at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor, or as measured by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[0427] On the other hand, one invention provides a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist: the use of a compound of formula (I) or formula (II) as defined above or a pharmaceutically acceptable salt thereof, for the production of a medicament for treating a disease and / or a medical condition selected from: acute and chronic inflammatory diseases, such as systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock; diseases with autoimmune components, such as rheumatoid arthritis, gouty arthritis and multiple sclerosis; metabolic diseases and medical conditions associated with weight gain, such as obesity, eating disorders and Prader-Willi syndrome; metabolic diseases and medical conditions associated with weight loss, such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in the frail elderly; diabetes, diabetes-related conditions and diabetic complications, such as retinopathy; neoplastic hyperplasia, such as skin cancer and prostate cancer; reproductive or sexual medical conditions, such as endometriosis, uterine effusions, blood, sexual dysfunction, erectile dysfunction and decreased sexual response in women; diseases or conditions caused by treatment or injury to the organism, such as organ transplant rejection, ischemia and reperfusion injury, spinal cord injury and trauma, and weight loss 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 pulmonary fibrosis; enhancing immune tolerance and combating attacks on the immune system, such as those associated with certain allergies or organ transplant rejection; treating skin diseases and conditions, such as psoriasis, skin pigmentation failure, acne, keloid formation and skin cancer; behavioral, central nervous system and neuronal disorders, such as anxiety, depression, memory dysfunction and neuropathic pain; renal disorders or diseases, such as treatment of renal cachexia and natriuresis.

[0428] On the other hand, the present invention provides the use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist: a compound of formula (I) or formula (II) as defined above, or a pharmaceutically acceptable salt thereof, for the production of a medicament for regulating normalization or homeostatic activities such as ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.

[0429] It will be appreciated that therapeutic interventions utilizing melanocortin receptors that address normal physiological and pathophysiological processes are also contemplated.

[0430] Additional objects, advantages and features of the present invention will become apparent from the following description and appended claims, taken in conjunction with the accompanying drawings.

[0431] Compounds of formula (I) or (II) are ligands for at least one melanocortin receptor (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R) and a panel of compounds were tested for their ability to act as ligands in the in vitro assays described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0433] Figure 1A Mean difference in food consumed compared to vehicle in fasted rats 6 hours after administration of 100 nmole / Kg of selected compounds.

[0434] Figure 1B Mean difference in food consumed compared to vehicle in fasted rats 6 hours after administration of 500 nmole / Kg of selected compounds.

[0435] Figure 2A Cumulative difference in mean food intake in rats after administration of different concentrations of Compound A compared to vehicle.

[0436] Figure 2B Cumulative mean body weight difference in rats after administration of different concentrations of Compound A compared with vehicle.

[0437] Figure 3A Cumulative difference in mean food intake in rats following administration of selected compounds compared to vehicle.

[0438] Figure 3B Cumulative mean body weight difference in rats following administration of selected compounds compared to vehicle.

[0439] Figure 4A Cumulative difference in mean food intake in rats following administration of selected compounds compared to vehicle.

[0440] Figure 4B Cumulative mean body weight difference in rats following administration of selected compounds compared to vehicle. DETAILED DESCRIPTION OF THE INVENTION

[0442] The terms used to define peptides are those commonly used in the art, with the N-terminal amino group appearing on the left and the C-terminal carboxyl group appearing on the right. When an amino acid has isomeric forms, unless expressly indicated to the contrary, it is the L form of the amino acid represented. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the invention belongs. Furthermore, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.

[0443] Terms and abbreviations

[0444]

[0445]

[0446]

[0447]

[0448] Certain other abbreviations used in this document are defined below:

[0449] Boc: tert-Butyloxycarbonyl

[0450] Bzl: benzyl

[0451] DCM: dichloromethane

[0452] DIC: N, N-diisopropylcarbodiimide

[0453] DIEA: Diisopropylethylamine

[0454] Dmab: 4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)-amino}benzyl

[0455] DMAP: 4-(dimethylamino)pyridine

[0456] DMF dimethylformamide

[0457] DNP: 2,4-Dinitrophenyl

[0458] Fm: Fluorenylmethyl

[0459] Fmoc: fluorenylmethoxycarbonyl

[0460] For:Formyl

[0461] HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

[0462] cHex cyclohexyl

[0463] HOAT: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate

[0464] HOBt: 1-Hydroxy-benzotriazole

[0465] MBHA 4-Methylbenzhydrylamine

[0466] Mmt: 4-methoxytrityl

[0467] NMP: N-methylpyrrolidone

[0468] O-tBu tert-Butoxy

[0469] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0470] PyBroP Bromo-tris-pyrrolidine- Hexafluorophosphate

[0471] tBu: tert-butyl

[0472] TIS: Triisopropylsilane

[0473] TOS: Tosyl

[0474] Trt trityl

[0475] TFA: trifluoroacetic acid

[0476] TFFH: Tetramethylfluoroformimidic acid amide Hexafluorophosphate

[0477] Z: benzyloxycarbonyl

[0478] Unless indicated to the contrary, except for the N-terminal amino acid, all abbreviations of amino acids in the present disclosure (e.g., Ala) represent the structure of -NH-C(R)(R′)-CO-, wherein R and R′ are each independently hydrogen or the side chain of an amino acid (e.g., for alanine, R=CH3 and R′=H), or R and R′ can be combined to form a ring system.

[0479] For the N-terminal amino acid, the abbreviation represents the structure:

[0480]

[0481] The designation "NH2'" in, for example, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 indicates that the N-terminus of the peptide is amidated. 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 C-terminus is a free acid.

[0482] “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” indicates the structure:

[0483]

[0484] "-c(Cys-Pen)-" or "-cyclo(Cys-Pen)-" indicates the structure:

[0485]

[0486] "-c(Asp-Lys)-" or "-cyclo(Asp-Lys)-" indicates the structure:

[0487]

[0488] "Acyl" refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl, and is represented in the general formula of specific embodiments as "Ac".

[0489] "Alkyl" refers to a hydrocarbon group containing one or more carbon atoms, wherein the carbon atoms (if present) are connected by single bonds. The alkyl hydrocarbon group may be straight chain or contain one or more branches or cyclic groups.

[0490] "Hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the hydrocarbon group are replaced with one or more hydroxy groups, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.

[0491] "Substituted alkyl" refers to an alkyl group in which one or more of the hydrogen atoms of the hydrocarbon group is replaced by a halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2 and -C 1-20 The alkyl group is substituted with one or more substituents, wherein: 1-20 The alkyl group may optionally be selected independently at each occurrence from halogen, -CF3, -OCH3, -OCF3 and -(CH2). -20 -COOH is substituted with one or more substituents. In different embodiments, there are 1, 2, 3 or 4 substituents. -(CH2)0 -20 The presence of -COOH results in the production of alkyl acids. -20 Non-limiting examples of alkyl acids of -COOH include 2-norbornaneacetic acid, tert-butyric acid, 3-cyclopentylpropionic acid, and the like.

[0492] The term "halo" includes fluorine, chlorine, bromine and iodine.

[0493] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms in the hydrocarbon group are substituted with one or more selected from the following groups: amino, amido, -O-, -S- or carbonyl. In various embodiments, there are 1 or 2 heteroatoms.

[0494] "Substituted heteroalkyl" refers to a heteroalkyl group in which one or more of the hydrogen atoms of the hydrocarbon group is selected from halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2 and -C1-20 The alkyl group is substituted with one or more substituents, wherein the -C 1-20 The alkyl group may optionally be selected independently at each occurrence from halogen, -CF3, -OCH3, -OCF3 and -(CH2) 0-20 In various embodiments, there are 1, 2, 3 or 4 substituents.

[0495] "Alkenyl" refers to a hydrocarbon group consisting of two or more carbons in which one or more carbon-carbon double bonds are present. Alkenyl hydrocarbon groups can be straight chain or contain one or more branches or cyclic groups.

[0496] "Substituted alkenyl" refers to an alkenyl group in which one or more hydrogen atoms are replaced by a radical selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2 and -C1- 20 The alkyl group is substituted with one or more substituents, wherein the -C 1-20 The alkyl group may optionally be selected independently at each occurrence from halogen, -CF3, -OCH3, -OCF3 and -(CH2) 0-20 In various embodiments, there are 1, 2, 3 or 4 substituents.

[0497] "Aryl" refers to an optionally substituted aromatic group having at least one ring with a conjugated π electron system containing up to three conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, aryl is a 5- or 6-membered ring. Preferred atoms of heterocyclic aryl are one or more 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 are selected from -C 1-20 Alkyl, -C 1-20 Alkoxy, halogen (i.e., fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NO2, -C substituted with halogen 1-20 Alkyl, -CF3, -OCF3, and -(CH2) 0-20 -COOH. In various embodiments, the aryl group contains 0, 1, 2, 3 or 4 substituents.

[0498] "Alkylaryl" refers to an "alkyl" group attached to an "aryl" group.

[0499] The term "(C1-C 12 The "hydrocarbon moiety" includes alkyl, alkenyl and alkynyl groups, and in the case of alkenyl and alkynyl groups, there is a C2-C 12 .

[0500] As used herein, the term "normalizing" function or activity refers to those types of functions that can be considered to be involved in normalizing body function or homeostasis of an organism. Such functions include, but are not limited to, activities and functions that affect body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood sugar levels, etc.

[0501] As used herein, a compound considered to be "selective" for a particular melanocortin receptor is one that is expressed by an EC 50 The functional activity characterized is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 17-fold, at least about 90-fold, at least about 200-fold, at least about 3000-fold, or at least about 10,000-fold, or even greater, selective for any one melanocortin receptor over any other melanocortin receptor. For example, the selective melanocortin 4 receptor agonists of the invention exhibit selective melanocortin 4 receptor agonism via EC 50 The functional activity is characterized by at least about 15-fold selectivity for human melanocortin 4 receptor over human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor. Moreover, for example, the selective melanocortin 4 receptor agonists of the invention show that the selective melanocortin 4 receptor agonists of the invention are selective for human melanocortin 4 receptor over human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor. 50 The functional activity is characterized as being at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[0502] synthesis

[0503] The peptides of the present invention can be prepared by standard solid phase peptide synthesis. See, for example, Stewart, JM, et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). 2 and R 3 The free amine of the N-terminal amino acid can be attached by standard methods known in the art. For example, an alkyl group such as (C1-C 30 ) alkyl. Reductive alkylation can be used to connect hydroxyalkyl groups, such as (C1-C 30 ) hydroxyalkyl, wherein the free hydroxyl group is protected with a tert-butyl ester. By reacting the free acid, e.g., E 1 COOH is coupled to the free amine of the N-terminal amino acid and an acyl group can be attached, e.g., COE 1 The coupling was achieved by mixing the finished resin with 3 molar equivalents of the free acid and diisopropylcarbodiimide in dichloromethane for 1 hour. If the free acid contained free hydroxyl groups, e.g., p-hydroxyphenylpropionic acid, the coupling was performed with an additional 3 molar equivalents of HOBt.

[0504] When R 1When R is -NH2, peptide synthesis begins with an Fmoc-amino acid coupled to Rink Amide MBHA resin. 1 is -OH, then peptide synthesis started with Fmoc-amino acid coupled to Wang resin.

[0505] In the synthesis of peptides of the invention containing A6c and / or Aib, the coupling time for these residues and the residues immediately following them was 2 hours.

[0506] The following examples describe synthetic methods for preparing the peptides of the present invention, which methods are well known to those skilled in the art. Other methods are also known to those skilled in the art. These examples are provided for illustrative purposes and are not intended to limit the scope of the present invention in any way. Example

[0507] Example 1: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 7

[0508] At Advanced ChemTech The title peptide was synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry on a 1000MW multi-peptide synthesizer (Louisville, KY 40228). Rink Amide 4-methylbenzhydrylamine (MBHA) resin ( San Diego, CA). The Fmoc amino acids used ( CA and Chem- 1L) is 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 carried out on a 0.035 mmol scale. The Fmoc group was removed by treatment with 25% piperidine in N,N-dimethylformamide (DMF) for 30 minutes. In each coupling step, Fmoc amino acid (10 eq, 0.35 mmol), N,N-diisopropylcarbodiimide (DIC) (10 eq, 0.35 mmol), and 1-hydroxy-benzotriazole (HOBt) (10 eq, 0.35 mmol) were used in DMF (1.4 mL). After washing with DMF, the mixture was stirred at 4 ℃ for 2 h in DMF (1.26 mL) using Fmoc-amino acid (10 eq, 0.35 mmol), 2-(1-H-benzotriazol-1-yl)-1,1,2,3-tetramethylurea hexafluorophosphate, and 1,2-dihydro-1,3 ... (HBTU) (8 eq, 0.28 mmol), HOBT (10 eq, 0.35 mmol), and diisopropylethylamine (DIEA) (20 eq, 0.7 mmol) were used for double coupling. The various peptide synthesizers were programmed to perform the following reaction cycles: (1) washing with DMF, (2) removal of the Fmoc protecting group by treatment with 25% piperidine in DMF for 30 minutes, (3) washing with DMF, (4) coupling with an Fmoc amino acid in the presence of DIC and HOBT for 1 hour, (5) washing with DMF, (6) double coupling with the same Fmoc amino acid in step 4 in the presence of HBTU, HOBt and DIEA for 1 hour. The resin was successfully coupled according to the sequence of the title peptide. After the peptide chain was assembled and the last Fmoc-protecting group was removed, the resin was washed extensively with DMF and dichloromethane (DCM).

[0509] To cleave the title peptide, the resin was treated with a solution (1.5 mL) of TFA, H2O and triisopropylsilane (TIS) (v / v / v: 90 / 6.2 / 3.8) at room temperature for 2 hours. The resin was filtered and the filtrate was poured into 30 mL of ether. The precipitate was collected by centrifugation. The crude product was dissolved in water (~7 mL) and the pH of the aqueous solution was adjusted to ~7.5 by adding 2N NH4HCO3. The solution was opened to air at room temperature for 72 hours. The reaction mixture was purified by C HPLC on a reverse phase preparative HPLC system. 18 DYNAMAX- A0 column (4x43cm) The crude product was purified by HPLC (Walnut Creek, CA). The column was eluted with a linear gradient of 85% A:15% B to 30% A:70% B for about 1 hour, wherein A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were analyzed by analytical HPLC and those containing the pure product were combined and lyophilized to give 10.3 mg (27% yield) of a white solid. The purity was analyzed by HPLC and found to be about 88%. Electrospray ionization mass spectrometry (ESI-MS) analysis gave a molecular weight of 1073.6 (consistent with the theoretical molecular weight of 1074.3).

[0510] Example 2: Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 SEQ ID NO: 6

[0511] In Applied The title peptide was synthesized on a 430A peptide synthesizer (Foster City, CA) modified for accelerated Boc chemistry solid phase peptide synthesis. See Schnolzer, et al., Int. J. Peptide Protein Res., 40:180 (1992). The 4-methylbenzhydrylamine (MBHA) resin with 0.91 mmol / g substitution was used ( Belmont, CA). The Boc amino acids used ( San Diego, CA andChem- The peptides were synthesized using the following 1:1 peptide (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 on a 0.20 mmol scale. The Boc group was removed by treatment with 100% TFA 2x 1 min. The Boc amino acid (2.5 mmol) was preactivated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL DMF and coupled without prior neutralization of the peptide-resin TFA salt. The coupling time was 5 min.

[0512] exist

[0513] At the end of the Boc-Asp(OFm)-His(DNP)-D-Phe-Arg(ToS)-Trp(For)-Gaba-Lys(Fmoc)-MB HA assembly, the peptide-resin was transferred to a reaction vessel on a shaker. The resin was treated with 25% piperidine in DMF for 15 min each, washed with DMF, and stirred with bromo-tris-pyrrolidine-hexafluorophosphate in DMF (2 mL). (PyBrOP) (6 eq, 0.3 mmol), DIEA (1 mL), and 4-(dimethylamino)pyridine (DMAP) (24 mg) were shaken for 12 hours. After washing with DMF, the resin was washed twice with 100% TFA, each treatment for 2 hours, washed with DMF and DCM, and then dried under reduced pressure. 1 / 4 of the peptide-resin (0.05 mmol) was used for the next coupling with Boc-Cha-OH (10 eq, 0.5 mmol) in the presence of HBTU (9 eq, 0.45 mmol) and DIEA (0.25 mL) in DMF for 10 minutes. Deprotection was performed twice with 100% TFA, each time for about 2 minutes, and then the peptide-resin was washed with DMF. The final end-capping step was performed by shaking the resin with acetic anhydride (40 eq, 2.0 mmol) and DIEA (20 eq, 1.0 mmol) in DMF for 1 hour. After washing with DMF, the resin is treated with 20% mercaptoethanol / 10%DIEA solution in DMF, and each treatment lasts about 30 minutes, to remove the DNP group on the histidine side chain. By shaking twice with 15% ethanolamine / 15% water / 70%DMF solution, each shaking 30 minutes, remove the formyl group on the side chain of tryptophan. Peptide-resin is washed with DMF and DCM and dried under reduced pressure. By stirring peptide-resin at 0 ℃ and carrying out the final cleavage in 10mL HF containing 1mL anisole and dithiothreitol (30mg) for 75 minutes. Remove HF by nitrogen gas stream. Wash resin with ether (6x 10mL) and extract with 4N HOAc (6x 10mL).

[0514] Reversed-phase preparative high pressure liquid chromatography (HPLC) C 18 Column The peptide mixture in the aqueous extract was purified by HPLC (Southborough, MA). The column (solution A = water containing 0.1% TFA; solution B = acetonitrile containing 0.1% TFA) was eluted with a linear gradient (10% to 50% solution B in 40 minutes) at a flow rate of 10 mL / min. Fractions were collected and checked by analytical HPLC. Fractions containing pure product were combined and lyophilized. 5.1 mg of white solid was obtained. The yield was 8.9%. The purity based on analytical HPLC analysis was 94.5%. Electrospray mass spectrometer (MS(ES))S analysis gave a molecular weight of 1148.5 (consistent with the theoretical molecular weight of 1148.3).

[0515] Other peptides of the present invention, such as the compounds described in Tables 1A and 1B, can be prepared by one skilled in the art using synthetic procedures analogous to those generally disclosed above and / or specifically disclosed in the preceding Examples.

[0516] Other peptides of the present invention, such as the compounds described in Tables 1A and 1B, can be prepared by one skilled in the art using synthetic procedures analogous to those generally disclosed above and / or specifically disclosed in the preceding Examples.

[0517] According to the above appropriate steps, the following example can be obtained:

[0518] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 1

[0519] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO: 1

[0520] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 2

[0521] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0522] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0523] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0524] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO: 2

[0525] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO: 4

[0526] Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 5

[0527] Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 6

[0528] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0529] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0530] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0531] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0532] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0533] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0534] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0535] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0536] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0537] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0538] Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0539] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0540] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0541] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0542] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0543] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0544] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0545] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0546] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0547] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ IDNO:10

[0548] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0549] Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0550] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0551] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0552] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0553] Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0554] Ac-hPr0-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0555] Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0556] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0557] Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0558] Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0559] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0560] n-Butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 12

[0561] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0562] Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0563] Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0564] Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0565] Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0566] Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0567] Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0568] Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0569] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2;SEQ ID NO:14

[0570] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2;SEQ ID NO:14

[0571] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2;SEQ ID NO:14

[0572] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2;SEQ ID NO:14

[0573] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2;SEQ ID NO:14

[0574] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2;SEQ ID NO:15

[0575] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO: 15

[0576] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; SEQ ID NO: 15

[0577] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 15

[0578] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO: 15

[0579] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 16

[0580] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 16

[0581] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2; SEQ ID NO: 16

[0582] N-butryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 17

[0583] N-butryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 17

[0584] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 18

[0585] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2; SEQ ID NO: 18

[0586] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2;SEQ ID NO:18

[0587] Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:61

[0588] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2;SEQ ID NO:19

[0589] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2;SEQ ID NO:20

[0590] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:21

[0591] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0592] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0593] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:23

[0594] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:24

[0595] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:25

[0596] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQID NO:24

[0597] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ IDNO:26

[0598] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQID NO:26

[0599] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2;SEQ ID NO:54

[0600] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2;SEQ ID NO:54

[0601] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2;SEQ ID NO:54

[0602] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:54

[0603] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:54

[0604] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:27

[0605] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;SEQ ID NO:28

[0606] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;SEQ ID NO:28

[0607] Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2;SEQ ID NO:55

[0608] Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2;SEQ ID NO:55

[0609] Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2;SEQ ID NO:56

[0610] Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2;SEQ ID NO:56

[0611] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2;SEQ ID NO:57

[0612] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2;SEQ ID NO:57

[0613] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:57

[0614] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0615] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0616] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0617] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0618] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0619] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0620] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0621] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:31

[0622] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0623] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0624] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0625] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0626] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0627] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0628] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0629] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0630] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0631] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0632] Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:35

[0633] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:36

[0634] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2;SEQ ID NO:37

[0635] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2;SEQ IDNO:58

[0636] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2;SEQ ID NO:38

[0637] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2;SEQ ID NO:38

[0638] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:39

[0639] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:39

[0640] Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:40

[0641] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:40

[0642] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH;SEQ ID NO:41

[0643] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;SEQ ID NO:42

[0644] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;SEQ IDNO:43

[0645] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;SEQ ID NO:43

[0646] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;SEQ ID NO:43

[0647] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;SEQ ID NO:42

[0648] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;SEQ ID NO:41

[0649] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0650] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0651] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:29

[0652] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0653] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0654] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0655] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0656] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0657] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;SEQ ID NO:45

[0658] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;SEQ ID NO:45

[0659] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;SEQ ID NO:45

[0660] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;SEQ ID NO:45

[0661] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;SEQ ID NO:46

[0662] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;SEQ ID NO:46

[0663] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH;SEQ ID NO:46

[0664] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;SEQ ID NO:46

[0665] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:47

[0666] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0667] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0668] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0669] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0670] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0671] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0672] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0673] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[0674] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[0675] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49 and

[0676] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH SEQ ID NO: 48.

[0677] Other peptides of the present invention, such as the compounds described in Tables 1A and 1B, can be prepared by one skilled in the art using synthetic procedures analogous to those generally disclosed above and / or specifically disclosed in the preceding Examples.

[0678] Table 1A and 1B - Molecular Weight and Purity of Selected Embodiments

[0679] Table 1A

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697] Table 1B

[0698]

[0699] Example 3: In vitro studies

[0700] The activity of the compounds of the present invention as ligands for one or more melanocortin receptors can be tested according to the following method. One skilled in the art will know that procedures similar to those described herein can be used to determine the binding activity of the compounds of the present invention to melanocortin receptor molecules.

[0701] Radioligand binding assay

[0702] Cell membranes for in vitro receptor binding assays were obtained from transgenic CHO-K1 cells stably expressing hMC-R receptor subtypes 1, 3, 4, or 5. CHO-K1 cells expressing the hMC-R receptor type of interest were sonicated in ice-cold 50 mM Tris-HCl (pH 7.4) ( Setting 7, about 30 seconds) followed by centrifugation at 39,000 g for 10 minutes at about 4° C. The pellet was resuspended in the same buffer and centrifuged at 50,000 g for 10 minutes at about 4° C. The washed pellet containing the cell membranes was stored at about -80° C.

[0703] In polypropylene 96-well plates [ 125 I](Tyr 2 )-(Nle 4 -D-Phe 7 )α-MSH([ 125 I]-NDP-α-MSH, Amersham ) binding. Cell membranes prepared as above (1-10 μg protein / well) were incubated in a flask containing 0.2% bovine serum albumin (BSA), 5 mM MgCl2, 1 mM CaCl2, and 0.1 mg / mL bacitracin with increasing concentrations of the test compound and 0.1-0.3 nM [ 125 I]-NDP-α-MSH in 50 mM Tris-HCl (pH 7.4) at about 37°C for about 90-120 minutes. Collector, through the GF / C glass fiber filter plate pre-soaked with 0.1% (w / v) polyethyleneimine (PEI) ( Packard) filtration separation of the combined [ 125 I]-NDP-α-MSH ligand and free [ 125 The filter was washed three times with 50 mM Tris-HCl (pH 7.4) at a temperature of about 0-4°C and then washed with a Packard Radioactivity was measured by scintillation counter.Binding data were analyzed by computer-assisted nonlinear regression analysis (XL Fit; IDBS).

[0704] A set of preferred embodiments were tested using the assay described above and the binding constants (Ki, in nM) are reported in Tables 2A, 2B and 2C.

[0705] Table 2A, 2B and 2C - Radioligand Binding Assay Data for Selected Compounds

[0706] Table 2A

[0707]

[0708]

[0709] Table 2B

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718] Table 2C

[0719]

[0720] Cyclic AMP bioassay

[0721] Electrochemiluminescence (ECL) assay (Meso Scale Intracellular cyclic AMP (cAMP) levels were measured by MSD (Gaithersburg, MD; hereinafter referred to as MSD). CHO-K1 cells stably expressing hMC receptor subtypes were suspended in RMPI Transgenic CHO-K1 cells stably expressing hMC receptor subtypes 1, 3, 4, or 5 were plated at a density of approximately 7,000 cells / well in a 384-well Multi- Plates (MSD) containing integrated carbon electrodes and coated with anti-cAMP antibodies were added. Increasing concentrations of the test compound were added and the cells were incubated at about 37°C for about 40 minutes. After this incubation, a 5% protein mix containing 0.2% protein and 2.5 nM TAG TM Ruthenium-labeled cAMP (MSD) lysis buffer (containing MgCl2 and Triton X- At the end of the second incubation period, read buffer (Tris buffer containing ECL co-reactants and Triton X-100, pH 7.8) was added and the cells were imaged using a Sector Imager 6000. (MSD) cAMP levels in cell lysates were immediately measured by ECL detection. Data were analyzed using computer-assisted nonlinear regression analysis (XL Fit; IDBS) and reported as EC 50 Value or Kb value.

[0722] EC 50 Represents the concentration of agonist compound required to obtain 50% of the maximum response, for example, 50% of the maximum level of cAMP as determined using the above assay. The Kb value reflects the potency of the antagonist and is determined by Schild analysis. Briefly, a concentration response curve of the agonist is performed in the presence of increasing concentrations of the antagonist. The Kb value is the antagonist concentration that will produce a two-fold shift in the concentration response curve of the agonist. Kb is calculated by extrapolating the line on the Schild curve to 0 on the y-axis.

[0723] A panel of compounds was tested using the above assay and the results are reported in Tables 3A, 3B, 3C, and 3D.

[0724] Tables 3A, 3B, 3C and 3D - cAMP Bioassay Data for Selected Compounds Table 3A

[0725]

[0726]

[0727] ND = Not Determined

[0728] Table 3B

[0729]

[0730] ND = Not Determined

[0731] Table 3C

[0732] Table 3D

[0733] Example 4: In vivo studies

[0734] The compounds of the invention can be tested for their effects on food intake and / or body weight according to the following methods. One skilled in the art will appreciate that similar procedures to those described herein can be used to determine the effects of the compounds of the invention on food intake and / or body weight.

[0735] The ligand compounds that activate melanocortin receptors tested in the in vivo studies are as follows (Table 4): Table 4

[0736]

[0737] Acute feeding experiment (fasting)

[0738] Male Sprague Dawley rats (250 g) were housed in individual cages and maintained under 12:12 h light:dark conditions. Rats were fasted for 18 h prior to the start of the experiment with unlimited access to water. At time 0, rats were injected subcutaneously (sc) with the selected compound at a dose of 500 or 100 nmole / kg or with vehicle and provided food. Individual food consumption was measured approximately 1, 2, 3, 4, 5, and 6 h after injection. Figure 1A and 1B Data for selected compounds of the present invention are reported in .

[0739] Acute feeding experiment (non-fasting)

[0740] Male Sprague Dawley rats (250 g) were placed in individual cages and maintained under 12:12 hour light:dark conditions. Food and water were available ad libitum throughout the experiment. At time 0, rats were injected subcutaneously with the compound at a dose of 500 or 100 nmole / kg or with vehicle. Individual food consumption was measured approximately 1, 2, 3, 4, 5, and 6 hours after injection.

[0741] Chronic feeding experiment

[0742] Male Sprague Dawley rats (250 g) were housed in individual cages and maintained under 12:12 h light:dark conditions with unlimited access to food and water. Rats were injected subcutaneously with different doses of compound or with vehicle for 7 days, three times daily (approximately 0800 h, 1200 h, and 1600 h). Individual body weights and food consumption were measured daily. Figure 2A and 2B , Figure 3A and 3B ,and Figure 4A and 4B Data for selected compounds of the invention are reported in .

[0743] Application and use

[0744] The peptides of the present invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, salts formed with organic acids (e.g., acetic acid, lactic acid, maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid or primic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid) and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic acid, polyglycolic acid or polylactic acid-glycolic acid copolymers). Typical methods for preparing salts of the peptides of the present invention are well known in the art and can be accomplished by standard methods of salt exchange. Therefore, by dissolving the peptides of the present invention in a small amount of 0.25N acetic acid aqueous solution, the TFA salt of the peptides of the present invention (the TFA salt obtained by eluting the peptide with a buffer containing TFA using preparative HPLC to purify the peptide) can be converted into another salt, such as acetate. The resulting solution is applied to a semi-preparative HPLC column ( 300SB, C-8). The column was eluted with: (1) 0.1N ammonium acetate aqueous solution for 0.5 h; (2) 0.25N acetic acid aqueous solution for 0.5 h; and (3) a linear gradient (20% to 100% solution B in 30 min) at a flow rate of 4 ml / min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile / water (80:20)). Fractions containing the peptide were collected and lyophilized.

[0745] As is well known to those skilled in the art, the known and potential uses of peptides having melanocortin receptor (MC-R) agonist or antagonist activity are different and varied, so that administration of the compounds of the present invention for the purpose of eliciting an agonist effect may have the same effects and uses as melanocortin itself.

[0746] The present invention therefore includes within its scope pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I) together with a pharmaceutically acceptable carrier.

[0747] The dosage of the active ingredient in the composition of the present invention can be varied; however, the amount of active ingredient must be such that a suitable dosage form is obtained. The selected dosage depends on the desired therapeutic effect, the route of administration, and the duration of treatment. Generally, the effective dosage of the active ingredient of the present invention is 1x10 -7 to 200 mg / kg / day, preferably 1x10 -4 To 100 mg / kg / day, which may be administered as a single dose or divided into multiple doses.

[0748] The compounds of the present invention may be administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection or implant), nasal, vaginal, rectal, sublingual or topical administration routes and may be formulated with pharmaceutically acceptable carriers to provide dosage forms suitable for each administration route.

[0749] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms may also include (as in conventional practice) additional substances in addition to such inert diluents, such as lubricants, such as magnesium stearate. For capsules, tablets and pills, the dosage form may also include a buffer. Tablets and pills may be prepared additionally with enteric coatings.

[0750] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, which contain inert diluents commonly used in the art, such as water. In addition to such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweeteners, flavoring agents and aromatics.

[0751] Preparations according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin and injectable organic esters, such as ethyl oleate. Such dosage forms can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. By, for example, filtering through a filter that stops bacteria, by mixing disinfectants into the composition, by radiating the composition, or by heating the composition, the preparation can be sterilized. Preparations can also be produced in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable media before use.

[0752] Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.

[0753] Compositions for nasal or sublingual administration may also be prepared using standard excipients well known in the art.

[0754] In addition, the compounds of the present invention can be administered in sustained release compositions such as those described in the following patents and patent applications. U.S. Patent No. 5,672,659 teaches a sustained release combination field comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,760 teaches a sustained release composition comprising a bioactive agent in a gelatinizable form. U.S. Patent No. 5,821,221 teaches a sustained release composition comprising a polymerized bioactive agent and chitosan. U.S. Patent No. 5,916,883 teaches a sustained release composition comprising a bioactive agent and a cyclodextrin. The teachings of the previous patents and applications are incorporated herein by reference.

[0755] Embodiment of the present invention:

[0756] 1. Compounds of formula (I):

[0757] (R2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1

[0758] in:

[0759] A 1 Acc, HN-(CH2) m -C(O), L- or D-amino acids, or absence thereof;

[0760] A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

[0761] A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or missing;

[0762] A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;

[0763] A 5 It is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe or D-(Et)Tyr;

[0764] A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O);

[0765] A 7is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip;

[0766] A 8 It is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or missing;

[0767] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;

[0768] A 10 Acc, HN-(CH2) t -C(O), L- or D-amino acids, or absence thereof;

[0769] R 1 is -OH or -NH2;

[0770] R 2 and R 3 is independently H, (C1-C 30 )alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) acyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, or substituted aryl (C1-C 30 ) acyl group;

[0771] R 4 and R 5 In each case H, (C1-C 40 )alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) acyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C40 ) alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl, or -C(NH)-NH2;

[0772] m is independently at each occurrence 1, 2, 3, 4, 5, 6 or 7;

[0773] n is independently in each instance 1, 2, 3, 4 or 5;

[0774] s is independently in each instance 1, 2, 3, 4, 5, 6, or 7;

[0775] t is independently at each occurrence 1, 2, 3, 4, 5, 6, or 7;

[0776] X 1 , X 2 , X 3 , X 4 and X 5 each independently represents at each occurrence H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 )alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN;

[0777] The condition is

[0778] (I).When R 4 Yes (C1-C 40 ) acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl, or -C(NH)-NH2, then R 5 is H, (C1-C 40 )alkyl, (C1-C40 )heteroalkyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 )alkyl;

[0779] (II). When R 2 is (C1-C 30 ) acyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1-C 30 )alkyl, (C1-C 30 )heteroalkyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 )alkyl;

[0780] (III).A 3 or A8 or both must be present in the compound;

[0781] (IV).When A 2 When Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen;

[0782] (V).When A 2 When it is Asp or Glu, A 9 It is Dab, Dap, Orn, or Lys;

[0783] (VI). When A 8 When it is Ala or Gly, A 1 Not Nle;

[0784] (VII).When A 1 When missing, R 2 and R 3 It can’t all be H;

[0785] or a pharmaceutically acceptable salt thereof.

[0786] 2. A compound according to embodiment 1, wherein:

[0787] A 1 Is A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet or Oic;

[0788] A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

[0789] A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or absent;

[0790] A 4 It is His;

[0791] A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr;

[0792] A 6 is Arg or hArg;

[0793] A 7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal;

[0794] A 8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

[0795] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys;

[0796] A 10 is Thr or missing;

[0797] or a pharmaceutically acceptable salt thereof.

[0798] 3. A compound according to embodiment 2, wherein:

[0799] R 2 and R 3is independently at each occurrence H, acyl, n-propionyl or n-butyryl;

[0800] or a pharmaceutically acceptable salt thereof.

[0801] 4. A compound according to embodiment 1, wherein:

[0802] A 1 is Acc, Arg, D-Arg, 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 absent;

[0803] A 2 is Cys, D-Cys, Pen or Asp;

[0804] A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val, or absent;

[0805] A 4 is His or 3-Pal;

[0806] A 5 is D-Phe, D-2-Nal or D-(Et)Tyr;

[0807] A 6 is Arg or hArg;

[0808] A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp;

[0809] A 8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, or absent;

[0810] A 9 is Cys, D-Cys, Pen or Lys;

[0811] A 10 is Thr or missing;

[0812] The condition is A 3 or A 8 One but not both are missing;

[0813] or a pharmaceutically acceptable salt thereof.

[0814] 5. The compound according to embodiment 4, wherein the compound is:

[0815] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 1

[0816] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO: 1

[0817] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 2

[0818] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0819] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0820] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO: 3

[0821] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO: 2

[0822] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO: 4

[0823] Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 5

[0824] Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 6

[0825] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 6

[0826] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0827] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0828] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0829] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0830] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0831] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0832] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0833] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0834] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0835] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0836] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0837] Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:8

[0838] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0839] Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0840] Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0841] Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0842] Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:9

[0843] Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0844] Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0845] Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0846] Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0847] Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;SEQ ID NO:10

[0848] Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0849] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0850] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0851] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0852] Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0853] Ac-hPr0-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0854] Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0855] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0856] Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0857] Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0858] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0859] n-Butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 12

[0860] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11

[0861] Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0862] Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0863] Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0864] Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0865] Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0866] Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0867] Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;SEQ ID NO:13

[0868] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2;SEQ ID NO:14

[0869] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2;SEQ ID NO:14

[0870] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2;SEQ ID NO:14

[0871] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2;SEQ ID NO:14

[0872] Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2;SEQ ID NO:14

[0873] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO: 15

[0874] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO: 15

[0875] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; SEQ ID NO: 15

[0876] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 15

[0877] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO: 15

[0878] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 16

[0879] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 16

[0880] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2; SEQ ID NO: 16

[0881] N-butryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 17

[0882] N-butryl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 17

[0883] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 18

[0884] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2;SEQ ID NO:18

[0885] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2;SEQ ID NO:18

[0886] Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:61

[0887] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2;SEQ ID NO:19

[0888] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2;SEQ ID NO:20

[0889] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:21

[0890] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0891] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[0892] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:23

[0893] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:24

[0894] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:25

[0895] D-Phe-c(Cys-His-D(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:24

[0896] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0897] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[0898] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:27

[0899] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;SEQ ID NO:28

[0900] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;SEQ ID NO:28

[0901] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0902] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0903] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0904] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0905] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0906] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0907] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[0908] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:31

[0909] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0910] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0911] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0912] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0913] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0914] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0915] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0916] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[0917] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0918] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0919] Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 35

[0920] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 36

[0921] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO: 37

[0922] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 38

[0923] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 38

[0924] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 39

[0925] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 39

[0926] Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40

[0927] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40

[0928] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; SEQ ID NO: 41

[0929] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; SEQ ID NO: 42

[0930] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;SEQ ID NO:43

[0931] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;SEQ ID NO:43

[0932] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;SEQ ID NO:43

[0933] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;SEQ ID NO:42

[0934] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;SEQ ID NO:41

[0935] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0936] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0937] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:29

[0938] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0939] Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0940] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0941] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0942] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44

[0943] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;SEQ ID NO:45

[0944] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;SEQ ID NO:45

[0945] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;SEQ ID NO:45

[0946] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;SEQ ID NO:45

[0947] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;SEQ ID NO:46

[0948] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;SEQ ID NO:46

[0949] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH;SEQ ID NO:46

[0950] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;SEQ ID NO:46

[0951] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;SEQ ID NO:47

[0952] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[0953] 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

[0954] or a pharmaceutically acceptable salt thereof.

[0955] 6. The compound according to embodiment 5, wherein the compound is:

[0956] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 7

[0957] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 22

[0958] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 32

[0959] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 29

[0960] 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

[0961] or a pharmaceutically acceptable salt thereof.

[0962] 7. A compound according to embodiment 1, wherein:

[0963] A 1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val, or absent;

[0964] A 2 is Cys, Pen or Asp;

[0965] A 3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or absent;

[0966] A 4 is His or 3-Pal;

[0967] A 5 is D-Phe, D-2-Nal or D-(Et)Tyr;

[0968] A 6 is Arg or hArg;

[0969] A 7 is Trp, 2-Nal, Bal, Bip or D-Trp;

[0970] A 8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx, or absent;

[0971] A 9 is Cys, D-Cys, Pen or Lys;

[0972] A 10 is Thr or missing;

[0973] R 2 and R 3 is independently H or acyl at each occurrence;

[0974] or a pharmaceutically acceptable salt thereof.

[0975] 8. The compound according to embodiment 7, wherein the compound is:

[0976] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0977] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[0978] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[0979] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0980] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[0981] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:51

[0982] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2;SEQ ID NO:53

[0983] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2;SEQ ID NO:53

[0984] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:7

[0985] D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ IDNO:24

[0986] Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:27

[0987] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[0988] Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[0989] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-AIa-Lys)-NH2;SEQ ID NO:1

[0990] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2;SEQ ID NO:2

[0991] D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-AIa-D-Cys)-Thr-NH2;SEQ ID NO:3

[0992] D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;SEQ ID NO:3

[0993] Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;SEQ ID NO:2

[0994] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;SEQ ID NO:4

[0995] Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0996] Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:6

[0997] Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0998] Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[0999] Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[1000] Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;SEQ ID NO:11

[1001] Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2;SEQ ID NO:15

[1002] Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:21

[1003] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;SEQ ID NO:22

[1004] D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:23

[1005] D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:25

[1006] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2;SEQID NO:24

[1007] D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[1008] D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2;SEQ ID NO:26

[1009] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;SEQ ID NO:28

[1010] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;SEQ ID NO:28

[1011] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;SEQ ID NO:29

[1012] Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1013] Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1014] Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1015] Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1016] Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1017] Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;SEQ ID NO:30

[1018] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:31

[1019] Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;SEQ ID NO:32

[1020] Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1021] Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1022] Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1023] Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1024] Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1025] Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:33

[1026] Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;SEQ ID NO:34

[1027] Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 35

[1028] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO: 36

[1029] Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO: 37

[1030] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 16

[1031] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 16

[1032] Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO: 20

[1033] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 38

[1034] Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO: 38

[1035] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 39

[1036] Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO: 39

[1037] Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40

[1038] Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 40 or

[1039] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49 or a pharmaceutically acceptable salt thereof.

[1040] 9. The compound according to embodiment 1, wherein:

[1041] A 1 is Arg, D-Arg, hArg or D-hArg;

[1042] or a pharmaceutically acceptable salt thereof.

[1043] 10. The compound according to embodiment 9, wherein

[1044] A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;

[1045] A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or absent;

[1046] A 4 It is His;

[1047] A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr;

[1048] A 6 is Arg or hArg;

[1049] A 7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal;

[1050] A 8 is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

[1051] A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys;

[1052] A 10 is Thr or missing;

[1053] or a pharmaceutically acceptable salt thereof.

[1054] 11. The compound according to embodiment 10, wherein:

[1055] R 2 and R3 is independently H, acyl, n-propionyl or n-butyryl at each occurrence; or a pharmaceutically acceptable salt thereof.

[1056] 12. The compound according to embodiment 11, wherein

[1057] A 2 is Cys or Asp;

[1058] A 3 It is D-Ala or missing;

[1059] A 4 It is His;

[1060] A 5 It is D-Phe or D-2-Nal;

[1061] A 6 is Arg;

[1062] A 7 It is Trp;

[1063] A 8 It is Ala, Gaba or missing;

[1064] A 9 is Cys, Pen or Lys;

[1065] A 10 missing;

[1066] or a pharmaceutically acceptable salt thereof.

[1067] 13. The compound according to embodiment 12, wherein:

[1068] R 2 and R 3 is independently H or acyl at each occurrence;

[1069] or a pharmaceutically acceptable salt thereof.

[1070] 14. The compound according to embodiment 13, wherein the compound is:

[1071] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[1072] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[1073] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[1074] Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[1075] Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO: 52

[1076] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51

[1077] Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53

[1078] Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO: 53 or

[1079] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49

[1080] or a pharmaceutically acceptable salt thereof.

[1081] 15. The compound according to embodiment 14, wherein the compound is:

[1082] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[1083] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51 or

[1084] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ IDNO: 49

[1085] or a pharmaceutically acceptable salt thereof.

[1086] 16. The compound according to embodiment 15, wherein the compound is:

[1087] Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO: 50

[1088] or a pharmaceutically acceptable salt thereof.

[1089] 17. The compound according to embodiment 15, wherein the compound is:

[1090] Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO: 51 or a pharmaceutically acceptable salt thereof.

[1091] 18. The compound according to embodiment 15, wherein the compound is:

[1092] Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO: 49

[1093] or a pharmaceutically acceptable salt thereof.

[1094] 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[1095] 20. The pharmaceutical composition according to embodiment 19, wherein the compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof.

[1096] 21. The pharmaceutical composition according to embodiment 20, wherein the compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof, which is selective for melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof. 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1097] 22. A pharmaceutical composition according to embodiment 21, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1098] 23. A pharmaceutical composition according to embodiment 21, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1099] 24. A pharmaceutical composition according to embodiment 21, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1100] 25. A pharmaceutical composition according to embodiment 21, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1101] 26. The pharmaceutical composition according to embodiment 19, for use in the treatment of an acute or chronic inflammatory disease or medical condition, wherein the disease or condition is selected from systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.

[1102] 27. A pharmaceutical composition according to embodiment 19 for use in the treatment of a disease or medical condition with an autoimmune component, wherein the disease or condition is selected from rheumatoid arthritis, gouty arthritis and multiple sclerosis.

[1103] 28. The pharmaceutical composition according to embodiment 19, for use in the treatment of a metabolic disease or medical condition associated with weight gain, wherein the disease or condition is selected from obesity, eating disorders and Prader-Willi syndrome.

[1104] 29. The pharmaceutical composition according to embodiment 28, wherein the obesity is treated.

[1105] 30. The pharmaceutical composition according to embodiment 28, wherein the eating disorder is treated.

[1106] 31. The pharmaceutical composition according to embodiment 19, for use in reducing food intake.

[1107] 32. The pharmaceutical composition according to embodiment 19, for use in reducing body weight.

[1108] 33. The pharmaceutical composition according to embodiment 19, for use in reducing food intake and losing body weight.

[1109] 34. A pharmaceutical composition according to embodiment 31 for reducing food intake, wherein the compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.

[1110] 35. The pharmaceutical composition according to embodiment 34, for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1111] 36. A pharmaceutical composition according to embodiment 34 for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1112] 37. A pharmaceutical composition according to embodiment 34 for reducing food intake, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1113] 38. A pharmaceutical composition according to embodiment 32 for use in reducing body weight, wherein the compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.

[1114] 39. The pharmaceutical composition according to embodiment 38, for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1115] 40. The pharmaceutical composition according to embodiment 38, for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1116] 41. A pharmaceutical composition according to embodiment 38, for use in reducing food intake, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1117] 42. A pharmaceutical composition according to embodiment 33, for reducing food intake and reducing body weight, wherein the compound is selected from Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, Ac-Arg-c(Cys-D-AIa-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-AIa-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, Ac-NIe-c(Cys-D-AIa-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: NO: 7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-AIa-D-Cys)-Thr-NH2 SEQ ID NO: 24, Ac-NIe-c(Cys-D-AIa-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 22 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1118] 43. A pharmaceutical composition according to embodiment 42 for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1119] 44. A pharmaceutical composition according to embodiment 42 for use in reducing food intake, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1120] 45. The pharmaceutical composition according to embodiment 42, for reducing food intake, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1121] 46. ​​The pharmaceutical composition according to embodiment 19, for use in the treatment of a metabolic disease or medical condition associated with weight loss, wherein the disease or condition is selected from anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and frail elderly wasting.

[1122] 47. A pharmaceutical composition according to embodiment 46 for use in the treatment of anorexia.

[1123] 48. A pharmaceutical composition according to embodiment 46 for use in the treatment of bulimia.

[1124] 49. The pharmaceutical composition according to embodiment 46, for use in treating AIDS-related wasting or wasting in frail elderly people.

[1125] 50. The pharmaceutical composition according to embodiment 46, for use in the treatment of cachexia or cancer cachexia.

[1126] 51. The pharmaceutical composition according to embodiment 19, for use in the treatment of a neoplastic disease or a medical condition, wherein the disease or condition is selected from the group consisting of skin cancer and cancer cachexia.

[1127] 52. The pharmaceutical composition according to embodiment 19, for use in the treatment of a reproductive or sexual medical disorder, wherein the disease or disorder is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women.

[1128] 53. A pharmaceutical composition according to embodiment 19 for use in the treatment of a disease or medical condition caused by treatment or injury to an organism, wherein the disease or condition is selected from organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss due to a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization and dialysis.

[1129] 54. The pharmaceutical composition according to embodiment 19, for use in the treatment of a cardiovascular disease or medical condition, wherein the disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.

[1130] 55. The pharmaceutical composition according to embodiment 19, for use in the treatment of a pulmonary disease or medical condition, wherein the disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[1131] 56. The pharmaceutical composition according to embodiment 19, for use in the treatment of a disease or medical condition, wherein the disease or condition is selected from enhanced immune tolerance and allergic response.

[1132] 57. The pharmaceutical composition according to embodiment 19, for use in the treatment of a skin disease or medical condition, wherein the disease or condition is selected from psoriasis, skin pigmentation failure, acne and keloid formation.

[1133] 58. A pharmaceutical composition according to embodiment 19 for use in the treatment of a behavioral or central nervous system or neuronal disease or medical condition, wherein the disease or condition is selected from anxiety, depression, memory dysfunction and neuropathic pain.

[1134] 59. The pharmaceutical composition according to embodiment 19, for use in the treatment of a kidney disease or medical condition, wherein the disease or condition is selected from renal cachexia and natriuresis.

[1135] 60. A pharmaceutical composition according to embodiment 19, for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.

[1136] 61. The pharmaceutical composition according to embodiment 19, for use in regulating bone metabolism, bone formation and bone development.

[1137] 62. The pharmaceutical composition according to embodiment 19, for use in inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism or treating alcohol abuse.

[1138] 63. A pharmaceutical composition according to embodiment 62 for use in suppressing alcohol consumption, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1139] 64. The pharmaceutical composition according to embodiment 62, for use in suppressing alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1140] 65. The pharmaceutical composition according to embodiment 62, for use in the treatment of alcoholism, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1141] 66. The pharmaceutical composition according to embodiment 62, for use in the treatment of alcohol abuse, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1142] 67. A pharmaceutical composition according to embodiment 63 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1143] 68. A pharmaceutical composition according to embodiment 67 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1144] 69. A pharmaceutical composition according to embodiment 67 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1145] 70. A pharmaceutical composition according to embodiment 67 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1146] 71. A pharmaceutical composition according to embodiment 67 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1147] 72. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting alcohol consumption in a subject in need of such treatment.

[1148] 73. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for reducing alcohol consumption in a subject in need of such treatment.

[1149] 74. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcoholism in a subject in need of such treatment.

[1150] 75. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol abuse in a subject in need of such treatment.

[1151] 76. A method of eliciting an agonist or antagonist effect at a melanocortin receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof.

[1152] 77. The method according to embodiment 76, wherein the compound is a selective melanocortin 4 receptor agonist.

[1153] 78. The method according to embodiment 77, wherein the compound is a selective melanocortin 4 receptor agonist which acts via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1154] 79. The method according to embodiment 78, wherein the functional activity of the melanocortin 4 receptor agonist is determined by EC 50 The selectivity of the agonist for human melanocortin 4 receptor is at least 17-fold higher than that for human melanocortin 3 receptor.

[1155] 80. The method according to embodiment 78, wherein the functional activity of the melanocortin 4 receptor agonist is determined by EC 50 The selectivity of the agonist for human melanocortin 4 receptor is at least 90-fold higher than that for human melanocortin 3 receptor.

[1156] 81. The method according to embodiment 78, wherein the functional activity of the melanocortin 4 receptor agonist is determined by EC 50 The selectivity of the agonist for human melanocortin 4 receptor is at least 200-fold higher than that for human melanocortin 5 receptor.

[1157] 82. The method according to embodiment 78, wherein the functional activity of the melanocortin 4 receptor agonist is determined by EC 50 The selectivity of the agonist for human melanocortin 4 receptor is at least 3000-fold higher than that for human melanocortin 5 receptor.

[1158] 83. A method of treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.

[1159] 84. A method of treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect from a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from rheumatoid arthritis, gouty arthritis and multiple sclerosis.

[1160] 85. A method for treating a metabolic disease or medical condition associated with weight gain by eliciting an agonist or antagonist effect from a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from obesity, eating disorders and Prader-Willi syndrome.

[1161] 86. The method according to embodiment 85, wherein the obesity is treated.

[1162] 87. The method according to embodiment 85, wherein the eating disorder is treated.

[1163] 88. The method of reducing food intake according to embodiment 76.

[1164] 89. The method for reducing body weight according to embodiment 76.

[1165] 90. A method of reducing food intake and body weight by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76.

[1166] 91. A method for reducing food intake by eliciting an agonist or antagonist effect from a melanocortin receptor according to embodiment 88, wherein the compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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: NO:51, 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, Ac-NIe-c(Cys-D-AIa-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.

[1167] 92. The method according to embodiment 91, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1168] 93. The method according to embodiment 91, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1169] 94. The method according to embodiment 91, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1170] 95. The method of reducing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to embodiment 89, wherein the compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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: NO: 51, 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, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1171] 96. The method according to embodiment 95, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1172] 97. The method according to embodiment 95, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1173] 98. The method according to embodiment 95, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1174] 99. The method of reducing food intake and weight loss by eliciting an agonist or antagonist effect from a melanocortin receptor according to embodiment 90, wherein the compound is Ac-Nle-C(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2 SEQ ID NO: 32, 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: NO:51, 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, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO:22, or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.

[1175] 100. The method according to embodiment 99, wherein the compound is 22493Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO: 50, or a pharmaceutically acceptable salt thereof.

[1176] 101. The method according to embodiment 99, wherein the compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2 SEQ ID NO: 49, or a pharmaceutically acceptable salt thereof.

[1177] 102. The method according to embodiment 99, wherein the compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 51, or a pharmaceutically acceptable salt thereof.

[1178] 103. A method for treating a metabolic disease or medical condition associated with weight loss by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, and wasting in frail elderly people.

[1179] 104. The method according to embodiment 103, wherein anorexia is treated.

[1180] 105. The method according to embodiment 103, wherein bulimia is treated.

[1181] 106. The method according to embodiment 103, wherein AIDS wasting or frail elderly wasting is treated.

[1182] 107. The method according to embodiment 103, wherein cachexia or cancer cachexia is treated.

[1183] 108. The method for treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or medical condition is selected from the group consisting of skin cancer and cancer cachexia.

[1184] 109. A method for treating a reproductive or sexual medical disorder by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or medical disorder is selected from endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, and decreased sexual response in females.

[1185] 110. A method for treating a disease or medical condition caused by treatment or injury in an organism by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or medical condition is selected from organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss due to a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization and dialysis.

[1186] 111. A method for treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from hemorrhagic shock, cardiogenic shock, hypovolemic shock, a cardiovascular disorder, and cardiac cachexia.

[1187] 112. A method for treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[1188] 113. A method for treating a disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from the group consisting of enhanced immune tolerance and allergic reactions.

[1189] 114. A method for treating a skin disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from the group consisting of psoriasis, skin pigmentation failure, acne and keloid formation.

[1190] 115. A method for treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from anxiety, depression, memory dysfunction and neuropathic pain.

[1191] 116. A method of treating a kidney disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 76, wherein the disease or condition is selected from renal cachexia and natriuresis.

[1192] 117. A method according to embodiment 76 for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor.

[1193] 118. A method according to embodiment 76 for regulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect at a melanocortin receptor.

[1194] 119. A method according to embodiment 76 for inhibiting alcohol consumption, reducing alcohol consumption, treating alcohol intoxication or treating alcohol abuse by eliciting an agonist or antagonist effect at a melanocortin receptor.

[1195] 120. The method of inhibiting alcohol consumption according to embodiment 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1196] 121. The method for reducing alcohol consumption according to embodiment 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1197] 122. The method for treating alcoholism according to embodiment 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1198] 123. The method for treating alcohol abuse according to embodiment 119, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1199] 124. The method for inhibiting alcohol consumption according to embodiment 120, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which acts via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1200] 125. The method according to embodiment 124, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1201] 126. A method according to embodiment 124, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1202] 127. The method according to embodiment 124, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1203] 128. The method according to embodiment 124, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1204] 129. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of embodiments 1-19 or a pharmaceutically acceptable salt thereof for producing a composition for treating a disease selected from systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, metabolic diseases or medical conditions associated with weight gain, obesity, eating disorders, Prader-Willi syndrome, metabolic diseases or medical conditions associated with weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction , decreased sexual response in women, organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, weight loss due to a medical procedure selected from chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation failure, acne, keloid formation, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.

[1205] 130. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, for the production of a medicament for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.

[1206] 131. A compound according to formula II:

[1207] (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH2

[1208] in:

[1209] A 1 is Nle or missing;

[1210] A 2 is Cys or Asp;

[1211] A 3 is GIu or D-AIa;

[1212] A 4 It is His;

[1213] A 5 It is D-Phe;

[1214] A 6 is Arg;

[1215] A 7 is Trp, 2-Nal or Bal;

[1216] A 8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;

[1217] A 9 is Cys or Lys;

[1218] R 2 and R 3 Each is independently selected from H or (C1-C6) acyl;

[1219] The condition is

[1220] (I).When R 2 When it is (C1-C6) acyl, R 3 is H; and

[1221] (II).When A 2 When it is Cys, A 9 It's Cys.

[1222] or a pharmaceutically acceptable salt thereof.

[1223] 132. The compound according to embodiment 131, wherein the compound is:

[1224] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO: 54

[1225] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO: 54

[1226] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 54

[1227] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 54

[1228] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO: 54

[1229] Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 55

[1230] Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO: 55

[1231] Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 56

[1232] Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO: 56

[1233] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO: 57

[1234] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO: 57

[1235] Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO: 57 or

[1236] Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2; SEQ ID NO: 58 or

[1237] its pharmaceutically acceptable salts.

[1238] 133. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[1239] 134. The pharmaceutical composition according to embodiment 133, wherein the compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof.

[1240] 135. A pharmaceutical composition according to embodiment 134, wherein the compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, which is selective for melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1241] 136. A pharmaceutical composition according to embodiment 135, wherein the melanocortin 4 receptor agonist is 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1242] 137. A pharmaceutical composition according to embodiment 135, wherein the melanocortin 4 receptor agonist is administered via EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1243] 138. A pharmaceutical composition according to embodiment 135, wherein the melanocortin 4 receptor agonist is 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1244] 139. A pharmaceutical composition according to embodiment 135, wherein the melanocortin 4 receptor agonist is administered via EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1245] 140. A pharmaceutical composition according to embodiment 133 for use in the treatment of an acute or chronic inflammatory disease or medical condition, wherein the disease or condition is selected from systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.

[1246] 141. A pharmaceutical composition according to embodiment 133 for use in the treatment of a disease or medical condition with an autoimmune component, wherein the disease or condition is selected from rheumatoid arthritis, gouty arthritis and multiple sclerosis.

[1247] 142. The pharmaceutical composition according to embodiment 133, for use in the treatment of a metabolic disease or medical condition associated with weight gain, wherein the disease or condition is selected from obesity, eating disorders and Prader-Willi syndrome.

[1248] 143. The pharmaceutical composition according to embodiment 142, wherein the obesity is treated.

[1249] 144. The pharmaceutical composition according to embodiment 142, wherein the eating disorder is treated.

[1250] 145. The pharmaceutical composition according to embodiment 133, for use in reducing food intake.

[1251] 146. The pharmaceutical composition according to embodiment 133, for use in reducing body weight.

[1252] 147. A pharmaceutical composition according to embodiment 133 for use in reducing food intake and losing body weight.

[1253] 148. The pharmaceutical composition according to embodiment 133, for use in the treatment of a metabolic disease or medical condition associated with weight loss, wherein the disease or condition is selected from anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and frail elderly wasting.

[1254] 149. The pharmaceutical composition according to embodiment 148, for use in the treatment of anorexia.

[1255] 150. The pharmaceutical composition according to embodiment 148, for use in the treatment of bulimia.

[1256] 151. The pharmaceutical composition according to embodiment 148, for use in treating AIDS wasting or frail elderly wasting.

[1257] 152. The pharmaceutical composition according to embodiment 148, for use in the treatment of cachexia or cancer cachexia.

[1258] 153. The pharmaceutical composition according to embodiment 133, for use in the treatment of a neoplastic disease or a medical condition, wherein the disease or condition is selected from skin cancer and cancer cachexia.

[1259] 154. A pharmaceutical composition according to embodiment 133 for use in the treatment of a reproductive or sexual medical disorder, wherein the disease or disorder is selected from endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in women.

[1260] 155. A pharmaceutical composition according to embodiment 133 for use in the treatment of a disease or medical condition caused by treatment or injury to an organism, wherein the disease or condition is selected from organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss due to a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization and dialysis.

[1261] 156. A pharmaceutical composition according to embodiment 133 for use in the treatment of a cardiovascular disease or medical condition, wherein the disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.

[1262] 157. A pharmaceutical composition according to embodiment 133 for use in the treatment of a pulmonary disease or medical condition, wherein the disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[1263] 158. The pharmaceutical composition according to embodiment 133, for use in the treatment of a disease or medical condition, wherein the disease or condition is selected from enhanced immune tolerance and allergic response.

[1264] 159. The pharmaceutical composition according to embodiment 133, for use in the treatment of a skin disease or medical condition, wherein the disease or condition is selected from psoriasis, skin pigmentation failure, acne and keloid formation.

[1265] 160. A pharmaceutical composition according to embodiment 133 for use in the treatment of a behavioral or central nervous system or neuronal disease or medical condition, wherein the disease or condition is selected from anxiety, depression, memory dysfunction and neuropathic pain.

[1266] 161. The pharmaceutical composition according to embodiment 133, for use in the treatment of a kidney disease or medical condition, wherein the disease or condition is selected from renal cachexia and natriuresis.

[1267] 162. A pharmaceutical composition according to embodiment 133, which is used to regulate ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth.

[1268] 163. A pharmaceutical composition according to embodiment 133, for use in regulating bone metabolism, bone formation and bone development.

[1269] 164. A pharmaceutical composition according to embodiment 133, for use in inhibiting alcohol consumption, reducing alcohol consumption, treating alcohol intoxication or treating alcohol abuse.

[1270] 165. A pharmaceutical composition according to embodiment 164 for use in suppressing alcohol consumption, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1271] 166. The pharmaceutical composition according to embodiment 164, for use in reducing alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1272] 167. The pharmaceutical composition according to embodiment 164, for use in the treatment of alcoholism, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1273] 168. The pharmaceutical composition according to embodiment 164, for use in treating alcohol abuse, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1274] 169. A pharmaceutical composition according to embodiment 165 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1275] 170. A pharmaceutical composition according to embodiment 169 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1276] 171. A pharmaceutical composition according to embodiment 169 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1277] 172. A pharmaceutical composition according to embodiment 169 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1278] 173. A pharmaceutical composition according to embodiment 169 for inhibiting alcohol consumption, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which inhibits alcohol consumption via EC50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1279] 174. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting alcohol consumption in a subject in need of such treatment.

[1280] 175. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for reducing alcohol consumption in a subject in need of such treatment.

[1281] 176. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcoholism in a subject in need of such treatment.

[1282] 177. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating alcohol abuse in a subject in need of such treatment.

[1283] 178. A method of eliciting an agonist or antagonist effect at a melanocortin receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof.

[1284] 179. The method according to embodiment 178, wherein the compound is a selective melanocortin 4 receptor agonist.

[1285] 180. The method according to embodiment 179, wherein the compound is a selective melanocortin 4 receptor agonist which acts via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1286] 181. A method according to embodiment 180, wherein the melanocortin 4 receptor agonist is administered via EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1287] 182. The method according to embodiment 180, wherein the melanocortin 4 receptor agonist is 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1288] 183. The method according to embodiment 180, wherein the melanocortin 4 receptor agonist is 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1289] 184. The method according to embodiment 180, wherein the melanocortin 4 receptor agonist is 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1290] 185. A method for treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis, and septic shock.

[1291] 186. A method for treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from rheumatoid arthritis, gouty arthritis and multiple sclerosis.

[1292] 187. A method for treating a metabolic disease or medical condition associated with weight gain by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from obesity, eating disorders and Prader-Willi syndrome.

[1293] 188. The method according to embodiment 187, wherein the obesity is treated.

[1294] 189. The method of embodiment 187, wherein the eating disorder is treated.

[1295] 190. The method of reducing food intake according to embodiment 178.

[1296] 191. The method for reducing body weight according to embodiment 178.

[1297] 192. A method of reducing food intake and losing body weight according to embodiment 178 by eliciting an agonist or antagonist effect at a melanocortin receptor.

[1298] 193. A method for treating a metabolic disease or medical condition associated with weight loss by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, and wasting in frail elderly people.

[1299] 194. The method according to embodiment 193, wherein anorexia is treated.

[1300] 195. The method according to embodiment 193, wherein bulimia is treated.

[1301] 196. The method according to embodiment 193, wherein AIDS wasting or frail elderly wasting is treated.

[1302] 197. The method according to embodiment 193, wherein cachexia or cancer cachexia is treated.

[1303] 198. The method for treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from the group consisting of skin cancer and cancer cachexia.

[1304] 199. A method for treating a reproductive or sexual medical disorder by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or disorder is selected from endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, and decreased sexual response in women.

[1305] 200. A method for treating a disease or medical condition caused by treatment or injury in an organism by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, and weight loss due to a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization, and dialysis.

[1306] 201. A method for treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, and cardiac cachexia.

[1307] 202. A method for treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.

[1308] 203. A method for treating a disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from the group consisting of enhanced immune tolerance and allergic reactions.

[1309] 204. A method for treating a skin disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from the group consisting of psoriasis, skin pigmentation failure, acne and keloid formation.

[1310] 205. A method for treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from anxiety, depression, memory dysfunction and neuropathic pain.

[1311] 206. The method of treating a kidney disease or medical condition by eliciting an agonist or antagonist effect at a melanocortin receptor according to embodiment 178, wherein the disease or condition is selected from renal cachexia and natriuresis.

[1312] 207. A method according to embodiment 178 for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor.

[1313] 208. A method according to embodiment 178 for regulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect at a melanocortin receptor.

[1314] 209. A method of inhibiting alcohol consumption, reducing alcohol consumption, treating alcohol intoxication or treating alcohol abuse according to embodiment 178 by eliciting an agonist or antagonist effect at a melanocortin receptor.

[1315] 210. The method of inhibiting alcohol consumption according to embodiment 209, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1316] 211. The method for reducing alcohol consumption according to embodiment 209, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1317] 212. The method for treating alcoholism according to embodiment 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1318] 213. The method for treating alcohol abuse according to embodiment 209, wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.

[1319] 214. The method for inhibiting alcohol consumption according to embodiment 210, wherein the compound of the pharmaceutical composition is a selective melanocortin 4 receptor agonist which acts via EC 50 The characterized functional activity is at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, human melanocortin 3 receptor, and human melanocortin 5 receptor.

[1320] 215. A method according to embodiment 214, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1321] 216. A method according to embodiment 214, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.

[1322] 217. A method according to embodiment 214, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1323] 218. A method according to embodiment 214, wherein the melanocortin 4 receptor agonist is expressed by EC 50 The characterized functional activity is at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.

[1324] 219. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of embodiments 131 or 132, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of systemic inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, metabolic diseases or medical conditions associated with weight gain, obesity, eating disorders, Prader-Willi syndrome, metabolic diseases or medical conditions associated with weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in the frail elderly, skin cancer, endometriosis, uterus Bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, trauma and spinal cord injury, weight loss due to a medical procedure selected from chemotherapy, radiotherapy, temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, increased immune tolerance, allergic reactions, psoriasis, skin pigmentation failure, acne, keloid formation, anxiety disorders, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.

[1325] 220. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist or a pharmaceutically acceptable salt thereof according to any one of embodiments 131 or 132 for the production of a medicament for regulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxine release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, cerebral blood flow, blood glucose level, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection, nerve growth, bone metabolism, bone formation and bone development.

Claims

1. Compounds of formula (I): (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 in: A 1 Acc, HN-(CH2) m -C(O), L- or D-amino acids, or absence thereof; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or missing; A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 , X 4 , X 5 )Phe; A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, L-Phe or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O); A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip; A 8 It is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or missing; A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L- or D-amino acids, or absence thereof; R 1 is -OH or -NH2; R 2 and R 3 is independently H, (C1-C 30 )alkyl, (C1-C 30 )heteroalkyl, (C1-C 30 ) acyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, or substituted aryl (C1-C 30 ) acyl group; R4 and R 5 In each case H, (C1-C 40 )alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) acyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl or -C(NH)-NH2; m is independently at each occurrence 1, 2, 3, 4, 5, 6 or 7; n is independently in each instance 1, 2, 3, 4 or 5; s is independently in each instance 1, 2, 3, 4, 5, 6, or 7; t is independently at each occurrence 1, 2, 3, 4, 5, 6, or 7; X 1 , X 2 , X 3 , X 4 and X 5 each independently represents at each occurrence H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 )alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; The condition is (I). When R4 is (C1-C 40 ) acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 )alkylsulfonyl, or -C(NH)-NH2, then R 5 is H, (C1-C 40 )alkyl, (C1-C 40 )heteroalkyl, (C2-C 40 )alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 )heteroalkyl, substituted (C2-C 40 )alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 )alkyl; (II). When R2 is (C1-C 30 ) acyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R3 is H, (C1-C 30 )alkyl, (C1-C 30 )heteroalkyl, (C2-C 30 )alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 )heteroalkyl, substituted (C2-C 30 )alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 )alkyl; (III).A 3 or A8 or both must be present in the compound; (IV).When A 2 When Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen; (V).When A 2 When it is Asp or Glu, A 9 It is Dab, Dap, Orn, or Lys; (VI). When A 8 When it is Ala or Gly, A 1 Not Nle; (VII).When A 1 When missing, R 2 and R 3 It can’t all be H; or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

3. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to claim 1 or a pharmaceutically acceptable salt thereof for the production of a medicament for inhibiting alcohol consumption in a subject in need of such treatment.

4. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to claim 1 or a pharmaceutically acceptable salt thereof for the production of a medicament for reducing alcohol consumption in a subject in need of such treatment.

5. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of alcoholism in a subject in need of such treatment.

6. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of alcohol abuse in a subject in need of such treatment.

7. A method for eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. Compounds according to formula II: (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH2 in: A 1 is Nle or missing; A 2 is Cys or Asp; A 3 is Glu or D-Ala; A 4 It is His; A 5 It is D-Phe; A 6 is Arg; A 7 is Trp, 2-Nal or Bal; A8 is Gly, A1a, D-Ala, β-A1a, Gaba, or Apn; A 9 is Cys or Lys; R 2 and R3 are each independently selected from H or (C1-C6) acyl; The condition is (I) When R2 is (C1-C6) acyl, R3 is H; and (II).When A 2 When it is Cys, A 9 It's Cys. or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. Use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to claim 8 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting alcohol consumption in a subject in need of such treatment.

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