MX2007000311A - Cyclic peptides for treatment of cachexia. - Google Patents

Abstract

A highly selective melanocortin-4 receptor antagonist cyclic hexapeptideof the formula: (I) where R1, R2, R3a, R3b,R4, R5, x, y and z are as defined in the specification, anda method of treating body weight disorders, including cachexia, sarcopeniaand wasting syndrome or disease, and treating inflammation and immune disorders.

Description

CYCLICAL PEPTIDES FOR THE TREATMENT OF CAQUEXIA INTERREFERENCE WITH RELATED REQUESTS This application claims the priority and benefit of the provisional US patent application. UU Series No. 60 / 585,971, entitled "Cyclic Peptides for Treatment of Cachexia", filed July 6, 2004, and the specification and claimed claims thereof are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION The present invention relates to cyclic hexapeptides which are highly specific antagonists of the melanocortin 4 receptor (MC4-R), and which can be used in the treatment of a variety of body weight disorders, including cachexia, sarcopenia and syndrome or disease of consumption, and in the treatment of inflammation and immune disorders.

DESCRIPTION OF THE RELATED TECHNIQUE Note that in the following exhibition reference is made to several publications by author and year of publication, and that due to the recent publication dates, some publications are not considered as prior art with respect to the present invention. The disclosure of said publications herein is intended to provide a more complete basis, and is not considered an admission that such publications are prior art. Melanocortin receptors. A family of types and subtypes of melanocortin receptors has been identified, including melanocortin 1 (MC1-R) receptors expressed in normal human melanocytes and melanoma cells, melanocortin 2 (MC2-R) receptors for ACTH (adrenocorticotropin) , expressed in the cells of the adrenal gland, and the melanocortin 3 and melanocortin 4 receptors (MC3-R and MC4-R), expressed mainly in cells of the hypothalamus, mesoencephalon and brainstem, and melanocortin 5 receptors (MC5 -R), expressed in a wide distribution of peripheral tissues. Significant work has been done to determine the structure of melanocortin receptors, which include both the nucleic acid sequences encoding the receptors, and the amino acid sequences that make up the receptors. MC4-R is a 7-transmembrane receptor linked to G protein that is thought to be expressed primarily in the brain. It has been reported that inactivation of this receptor in mice by means of gene targeting results in obesity syndrome of onset at maturity, which is associated with hyperphagia, hyperinsulinemia and hyperglycemia (Huszar D., Lynch CA, Fairchild-Huntress V. and others, "Targeted disruption of the melanocortin-4 receptor results in obesity n mice", Cell 88: 131-141 (1997)). MC4-R is a molecular target of therapeutic intervention in energy homeostasis. It is generally believed that the compounds specific for MC4-R, and secondarily the compounds specific for MC3-R or MC5-R, are useful in the regulation of energy homeostasis in mammals, including the use as agents to attenuate ingestion of food and the gain of body weight. It is believed that MC4-R antagonists are useful in helping to gain weight, for example for use in the treatment of cachexia, sarcopenia, wasting syndrome and anorexia. In contrast, MC4-R agonists are believed to be useful in reducing food intake and body weight gain, for example for the treatment of obesity. Additionally, compounds that are specific antagonists for MC3-R and MC4-R are believed to be useful for regulating blood pressure, heart rate and other neurophysiological parameters. Cachexia and other diseases of consumption. Body weight disorders include one or more "wasting" disorders (e.g., wasting syndrome, cachexia, sarcopenia) that cause undesirable and pathological weight loss, or loss of body cell mass. In the elderly and in cancer and AIDS patients, wasting diseases can cause undesirable body weight loss, which includes both fat and lean compartments. Consumption diseases can be the result of inadequate food intake and / or metabolic changes related to the disease and / or the aging process. Cancer patients and AIDS patients, as well as patients who have undergone extensive surgery, or who have chronic infections, immune diseases, hyperthyroidism, Crohn's disease, psychogenic disease, chronic heart failure or other severe trauma, often they suffer from wasting disease. Sometimes the disease of consumption is also referred to as cachexia and is generally recognized as a metabolic disorder, and sometimes of feeding. Additionally, cachexia can be characterized by hypermetabolism and hypercatabolism. Although cachexia and wasting disease are often used interchangeably to refer to wasting conditions, there is at least one group of researchers who differentiate cachexia from wasting syndrome as a loss of lean mass, and particularly the body's cellular mass (Roubenoff R "The pathophysiology of wasting in the eiderly", J. Nutr. 129 (1S Suppl.): 256S-259 (1999)). Sarcopenia, another such disorder that can affect individual aging, is usually characterized by loss of muscle mass. End-stage diseased disease as described above can develop in individuals suffering from cachexia or sarcopenia. Melanocortin antagonist peptides. The antagonist peptides are based on modifications of the core sequence of the alpha-melanocyte stimulating hormone (α-MSH), His-Phe-Arg-Trp (SEQ ID NO: 1), and generally include a D-amino acid in the Phe position, most commonly a D-amino acid with a 1- or 2-naphthyl ring or a phenyl ring, which may optionally be a substituted ring. In this way, the US patent. UU No. 5,731, 408, discloses lactam cyclic heptapeptides which are nonspecific antagonists of the melanocortin receptors MC3-R and MC4-R, and contain D-Phe (4-I) or D-Nal 2 in place of the Phe residue. Of particular interest is a peptide commonly called SHU91 19 (Ac-Nle-cyclo (-Asp-His-D-NaI 2-Arg-Trp-Lys) -NH2), described in US Pat. UU No. 5,731, 408. SHU91 19 has been used extensively in research as a reference nonspecific melanocortin antagonist. Related lactam cyclic heptapeptides are described in U.S. Pat. UU No. 6,054,556, which are antagonists of the melanocortin receptors MC1-R, MC3-R, MC4-R and MC5-R. All these peptides contain a D-Phe or D-Nal 2 instead of the Phe residue. Other patents teach the use of melanocortin antagonists for the treatment of cachexia and other weight-related diseases. See, for example, U.S. Pat. UU Nos. 6,716,810; 6,699,873; 6,693,165; 6,613,874; 6,476,187; 6,284,729; 6,100,048; and 5,908,609. However, none of these describe the hexapeptides of the present invention. The US patent UU No. 6,693,165, discloses heptapeptides and cyclic hexapeptides that are assured to be selective antagonists of MC4-R. All these peptides include a D-amino acid containing a 1- or 2-naphthyl, 3-benzothienyl or phenyl, selected from the group consisting, instead of the Phe residue, in the core sequence His-Phe-Arg-Trp (SEQ ID NO: 1). However, the peptides described in U.S. Pat. UU No. 6,693,165 optionally omit His in the His-Phe-Arg-Trp sequence (SEQ ID NO: 1), and when the His position is present, it is limited to Lys or His. The published application of EE. UU 2003/01 13263, "Methods and Reagents for Using Mammalian Melanocortin Receptor Antagonists to Treat Cachexia", describes a method for characterizing a compound useful for the treatment of an animal with cachexia, which includes the use of an MC4-R antagonist to treat an animal with cachexia, and specifically describes SHU91 19. The published application of EE. UU 2003/01 05024, "Methods and Reagents for Discovering and Using Mammalian Melanocortin Receptor Agonists and Antagonists to Modulate Feeding Behavior in Animáis", describes SHU91 19 as an MC receptor antagonist used experimentally to stimulate feeding behavior. The US patent UU No. 6,476,187, "Methods and Reagents for Discovering and Using Mammalian Melanocortin Receptor Agonists and Antagonists to Modulate Feeding Behavior in Animáis", similarly describes SHU91 19 as an MC receptor antagonist used experimentally to stimulate feeding behavior. The published application of EE. UU 2003/0032791, "Novel Melanocortin-4 Receptor Sequences and Screening Assays to Identify Compounds Useful in Regulating Animal Appetite and Metabolic Rate", describes the experimental use of SHU91 19 in several tests. The published application of EE. UU 2002/0016291, "Cyclic Peptides as Potent and Selective Melanocortin-4 Receptor Antagonists", describes SHU91 19 as an antagonist of MC3 and MC4 receptors. In 1977, it was discovered that SHU91 19 enhances feeding behavior: Fan W., Boston BA, Kesterson RA, Hruby VJ, Cone RD, "Role of melanocorticergic neurons in feeding and the agouti obesity syndrome", Nature 385: 165-168 (1997); see also Rossi M., Kim MS, Morgan DG and others, "A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo", Endocrinology 139: 4428-31 (1998); Wisse B.E., Frayo R.S., Schwartz M.W., Cummings D.E., "Reversal of cancer anorexia by blockade of central melanocortin receptors in rats", Endocrinology 142: 3292-3301 (2001); Marks D. L., Ling N., Cone R. D., "Role of the central melanocortin system in cachexia", Cancer Research 61: 1432-1438 (2001). There remains a significant need for ligands with high specificity for separate melanocortin receptors, and specifically MC4-R, as well as ligand antagonists, or optionally inverse agonists of MC4-R. To reduce unwanted pharmacological responses, it is desirable that the ligand be highly specific to the target MC receptor, such as MC4-R. Thus, it is desirable that the binding affinity of a ligand for MC4-R be higher, for example about ten times higher for MC4-R, than for other MC receptors. High-affinity and highly specific peptide ligands of MC4-R can be used to take advantage of the various physiological responses associated with melanocortin receptors, particularly peptide ligands that are antagonists or inverse agonists. For example, MC4-R antagonists can be used to treat eating disorders, wasting diseases and cachexia. In addition, melanocortin receptors have an effect on the activity of several cytokines, and peptide ligands of high affinity melanocortin receptors can be used to regulate cytokine activity. In this manner, said peptide ligands can be used additionally for the treatment of inflammation and other immune disorders.

BRIEF DESCRIPTION OF THE INVENTION The invention provides a cyclic hexapeptide of the structural formula: where: R-, is H, NH2 or R2 is -C (= O) -NH-, -NH-C (= O) -, or -S-; 3a and R3b are each optional ring substituents, and when one or both are present, they are independently identical or different hydroxyl, halogen, alkyl or aryl groups, attached directly or via an ether linkage; R4 is -NH2 or -NH (C = NH) NH2; R5 is 1- or 2-naphthyl or 3-indolyl, optionally with one or two ring substituents, and when one or both of the ring substituents are present, they are independently hydroxyl, halogen, alkyl or aryl, the same or different, attached directly or through an ether link; R6 is H, NH2, a linear or branched lower aliphatic alkyl chain of Ci to C4, an aralkyl of CT to C4, or an omega-amino derivative of Ci to C4; x is 1 to 4, and y is from 1 to 5, provided that x + y is from 2 to 7; and z is from 2 to 5. The cyclic hexapeptide of formula (I) includes a hexapeptide of the structural formula: wherein R 4, R 5 and z are as defined in claim 1. In this manner, in one embodiment, the cyclic hexapeptide of formula (II) is Ac-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2 -Lys) -NH2 or Ac-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2. The cyclic hexapeptide of formula (I) also includes a hexapeptide of the formula: wherein R4, R5 and z are as defined in claim 1. In this embodiment the cyclic hexapeptide of formula (III) is H-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2 or H-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2. The invention also provides a pharmaceutical preparation comprising a cyclic hexapeptide of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention also provides a method of treating cachexia, which comprises administering to a mammal a pharmaceutically sufficient amount of the pharmaceutical preparation. The invention further provides a method of treating inflammation and immune disorders, which comprises administering to a mammal a pharmaceutically sufficient amount of the pharmaceutical preparation. The invention also provides a cyclic hexapeptide with an Ac group at the N-terminus or with an NH2 group at the N-terminus, and with an NH2 group at the C-terminus, the hexapeptide containing the nucleus sequence Trp-D-Nal 2-XY in positions 2 to 5, wherein X is an L-amino acid residue selected from the group consisting of Arg, Lys, Orn, Harg and Hlys, and V is an L- or D-amino acid residue selected from the group consists of Nal 1, Nal 2 and Trp, wherein any aromatic ring in the core sequence may optionally include one or two ring substituents, and when one or both of the ring substituents are present, they are independently hydroxyl, halogen, alkyl or aryl, the same or different, attached directly or via an ether linkage, and wherein the cyclic hexapeptide is cyclized by the amino acid residue at position 1 and the amino acid residue at position 6. The cyclic hexapeptide can be cyclized. cyclize p or formation of an amide bond between an amino group of a side chain of an amino acid residue at position 1, or an amino group of the N-terminal group of the amino acid residue at position 1, and a side chain carboxyl group of an amino acid residue in the 6-position. Alternatively, the cyclic hexapeptide can be cyclized by forming an amide bond between a side chain carboxyl group of an amino acid residue in the 1-position, and an amino group of a side chain of an amino acid residue at position 6. Alternatively, the cyclic hexapeptide can be cyclized by formation of a covalent bond comprising an amide, disulfide, thioether, Schiff base, reduced Schiff base, imide, secondary amine, carbonyl bond , urea, hydrazone or oxime. The cyclic hexapeptide may have a core sequence Trp-D-Nal 2-X-Nal 2. The cyclic hexapeptide includes Ac-cicio (-Asp-Trp-D-Nal-2-Arg-Nal 2-Lys) -NH2, Ac-Cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2, H-Cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2 and H -cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2. The invention also provides a method of treating a disorder of body weight, including cachexia, sarcopenia or wasting syndrome or disease, comprising the step of administering a pharmaceutically sufficient amount of a cyclic hexapeptide with an Ac group at the N-terminus or with an NH2 group at the N-terminus, and with an NH2 group at the C-terminus, the hexapeptide containing the nucleus sequence Trp-D-Nal 2-XY at positions 2 to 5, where X is a residue of L- amino acid selected from the group consisting of Arg, Lys, Orn, Harg and Hlys, and V is an L- or D-amino acid residue selected from the group consisting of Nal 1, Nal 2 and Trp, wherein any aromatic ring in the The core sequence may optionally include one or two ring substituents, and when one or both of the ring substituents are present, they are independently the same or different hydroxyl, halogen, alkyl or aryl groups, attached directly or by n ether linkage, and wherein the cyclic hexapeptide is cyclized by the amino acid residue at position 1 and the amino acid residue at position 6. An object of the present invention is to provide a specific peptide-based pharmaceutical agent. for the melanocortin receptor, wherein the peptide is a highly selective antagonist or inverse agonist of MC4-R for use in the treatment of cachexia. Another object of this invention is to provide peptides that are highly specific for the melanocortin receptor MC4-R, and which are antagonists or inverse agonists. Another object of the present invention is a peptide-based pharmaceutical agent, specific to a melanocortin receptor, for use in the treatment of inflammation and other disorders related to immunity. Another object of the present invention is to provide a pharmaceutical agent specific for the melanocortin receptor for use in a treatment, wherein the administration of the treatment is nasal administration. According to one embodiment of the present invention, there is provided a cyclic hexapeptide which is a highly specific MCR-4 antagonist, suitable for use as a specific pharmaceutical agent in the treatment of eating disorders, and which is effective at a dose low. Another aspect of the present invention provides a cyclic hexapeptide which is a highly specific inverse antagonist or agonist of MC4-R, which is effective on a significant dose scale. Another aspect of the present invention provides cyclic hexapeptides which are highly specific antagonists or inverse agonists of MC4-R, for use in the treatment of eating disorders, which, as have a higher efficacy at low doses, can be administered by different delivery of conventional intravenous, subcutaneous or intramuscular injections, including without limitation oral delivery systems, nasal delivery systems and mucus membrane delivery systems. Other novel objects, features and advantages and further scope of the application of the present invention will be set forth in part in the following detailed description, and in part will become apparent to the person skilled in the art upon examination of the following, or may be learned. by the practice of the present invention. The objects and advantages of the invention can be realized and obtained by means of the arrangements and combinations particularly pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION Definitions. Some terms used throughout the specification and the claims are defined as follows. The terms "unite", "unite", "complex" and "complex formation", as used throughout the specification and the claims, generally cover all types of physical and chemical union, reactions, complex formation, attraction , chelation and the like. The "peptides" of this invention can be a) natural, b) produced by chemical synthesis, c) produced by recombinant DNA technology, d) produced by biochemical or enzymatic fragmentation of larger molecules, e) produced by methods resulting from a combination of the above-mentioned methods a) -d), f) produced by any other means for the production of peptides. Using chemical synthesis, a preferred production medium, it is possible to introduce several amino acids that do not naturally occur in the chain, modify the N- or C- terminus, and the like, thereby improving stability and formulation, resistance to protease degradation and Similar. The term "peptide", as used throughout the specification and the claims, includes any structure comprised of two or more amino acids, including chemically modified peptides and amino acid derivatives. The amino acids that form part or all of a peptide can be natural amino acids, stereoisomers and modified amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, in such a manner that the term "peptide" includes pseudopeptides and peptidomimetics, which include structures having a non-peptide backbone. The term "peptide" also includes peptide dimers or multimers. A "manufactured" peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical or enzymatic fragmentation of larger molecules, combinations of the above or, in general, can be done by any other method. The term "amino acid side chain portion", used in this invention, including in the specification and claims, includes any side chain of any amino acid, as the term "amino acid" is defined herein. Thus, this includes the side chain portion present in the natural amino acids. In addition, it includes side chain portions of the modified natural amino acids, such as the glycosylated amino acids. In addition, it includes side chain portions of stereoisomers and modified natural protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derived amino acids, constructs or structures designed to mimic amino acids, and the like. For example, the side chain portion of any amino acid described herein is included in the definition. A "derivative" of an amino acid side chain portion is included in the definition of an amino acid side chain portion. The "derivative" of an amino acid side chain portion includes any modification or variation in any amino acid side chain portion, including a modification of the side chain portions of the naturally occurring amino acid. By way of example, derivatives of amino acid side chain portions include alkyl, aryl or aralkyl side-chain or branched, cyclic or non-cyclic, substituted or unsubstituted, saturated or unsaturated portions. The term "amino acids", used in the embodiments of the present invention, and the term used in the specification and claims, includes the naturally occurring known protein amino acids, which are referred to by their common abbreviation of three letters and their abbreviation of a single letter. See in general "Synthethic Peptides: A User's Guide", G. A. Grant, editor, W.H. Freeman & Co., New York (1992), whose teachings are incorporated herein by reference, including the text and table on pages 11 to 24. As discussed above, the term "amino acid" also includes stereoisomers and amino acids of modified natural proteins, amino acids non-protein, post-translationally modified amino acids, enzymatically synthesized amino acids, derived amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are generally described in "Synthethic Peptides: A User's Guide", cited above; Hruby V. J., Al-obeidi F., Kazmierski W., Biochem. J. 268: 249-262 (1990); and Toniolo C, Int J. Peptide Protein Res. 35: 287-300 (1990); the teachings of which are incorporated here as a reference. In addition, the following abbreviations have the meanings given: Harg Homoarginine Hlys Homolisine Nal 1 3- (1-naphthyl) alanine Nal 2 3- (2-naphthyl) alanine In the list of peptides according to the present invention, the residues of conventional amino acids have their conventional meaning as given in chapter 2400 of the "Manual of Patent Examining Procedure", 8th ed. Thus, "Nle" is norleucine, "Asp" is aspartic acid, "His" is histidine, "D-Phe" is D-phenylalanine, "Arg" is arginine, "Trp" is tryptophan, "Lys" is lysine, etc. . The term "hexapeptide" includes a peptide containing six amino acid residues, optionally with groups of non-amino acid residues at the N and C termini, said groups include the acyl, acetyl, alkenyl, alkyl, N-alkyl, amine or amide groups, among other groups. The term "alkene" includes unsaturated hydrocarbons that contain one or more carbon-carbon double bonds. Examples of said alkene groups include ethylene, propene and the like. The term "alkenyl" includes a linear monovalent hydrocarbon radical of two to six carbon atoms, or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond; examples thereof include ethenyl, 2-propenyl and the like. The "alkyl" groups specified herein include alkyl radicals of the designated length, in straight or branched configuration.

Examples of said alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, / sopentyl, hexyl, / sohexyl and the like. The term "alkynyl" includes a linear monovalent hydrocarbon radical of two to six carbon atoms, or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond; examples thereof include ethynyl, propynyl, butynyl, and the like. The term "aryl" includes a monovalent or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, nitro, acyl, cyano , amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy or alkoxycarbonyl. Examples of an aryl group include phenyl, biphenyl, naphthyl, 1-naphthyl and 2-naphthyl, derivatives thereof, and the like. The term "aralkyl" includes a radical -RaRb, wherein Ra is an alkylene group (a bivalent alkyl) and Rb is an aryl group as defined above. Examples of aralkyl groups include benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like. The term "aliphatic" includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes and derivatives thereof. The term "acyl" includes an RCO- group, wherein R is an organic group. An example is the acetyl group CH3CO-, referred to herein as "Ac". A peptide or aliphatic moiety is "acylated" when attached to an alkyl or substituted alkyl group as defined above, by one or more carbonyl groups. { - (C = 0) -} . A peptide is more usually acylated at the N-terminus. An "omega-amino derivative" includes an aliphatic moiety with a terminal amino group. Examples of omega-amino derivatives include aminoheptanoyl and the amino acid side chain portions of ornithine and lysine. The term "heteroaryl" includes monocyclic and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The 5- or 6-membered heteroaryl is a monocyclic heteroaromatic ring; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. Bicyclic heteroaromatic rings include, without limitation, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzoisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine and thienopyridine. An "amide" includes compounds having a trivalent nitrogen bonded to a carbonyl group (-CO.NH2), such as for example methylamide, ethylamide, propylamide, and the like. An "imide" includes compounds that contain an imido group (-CO.NH.CO-). An "amine" includes compounds that contain an amino group (-NH2). A "nitrile" includes compounds that are carboxylic acid derivatives and contain a group (-CN) attached to an organic group. The term "halogen" includes halogen atoms fluorine, chlorine, bromine and iodine, and groups that include one or more halogen atoms, such as -CF3 and the like. The term "composition", as a pharmaceutical composition, encompasses a product comprising one or more active ingredients and one or more inert ingredients that form the vehicle, as well as any product that results, directly or indirectly, from the combination, formation of complex or aggregation of any of two or more of the ingredients, or of the dissociation of one or more of the ingredients, or of other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing a peptide of the present invention and a pharmaceutically acceptable carrier. A single amino acid is sometimes referred to herein as "residue", and includes stereoisomers' and modified natural protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derived amino acids, constructs or structures designed to mimic amino acids, and the like, including all of the foregoing. By a melanocortin receptor "agonist" is meant a natural substance or a manufactured pharmaceutical substance or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. By "antagonist" of the melanocortin receptor is meant a natural substance or a manufactured substance or pharmaceutical composition that counteracts the responses associated with the melanocortin receptor normally induced by a melanocortin receptor agonist agent. By "inverse agonist" of the melanocortin receptor is meant a drug or compound that stabilizes the inactive conformation of the melanocortin receptor and inhibits its basal activity. "Eating disorders" are those associated with overweight, cachexia, anorexia or bulimia of any cause in humans. "Cachexia" refers to a general state of illness and malnutrition. It is frequently associated and induced by malignant cancer, cystic fibrosis or AIDS, and is characterized by loss of appetite, loss of body mass, especially lean body mass, and muscle wasting. "Anorexia" refers simply to a loss of appetite produced by medical, physiological or psychological factors. Anorexia is frequently associated with cachexia and generally contributes to the cachexia observed in patients with advanced cancer and other conditions.

Cyclic Hexapeptides of the Invention In one embodiment, the invention provides cyclic hexapeptides that include the core sequence Trp-D-Nal 2-XY, or homologs or analogs thereof, wherein X is an L-amino acid selected from the group consisting of in Arg, Lys, Orn, Harg and Hlys, and Y is an L- or D-amino acid selected from the group consisting of Nal 1, Nal 2 and Trp. The above definition includes hexapeptides with one or more ring groups substituted in the core sequence, for example where any of one or more aromatic rings in the core sequence optionally includes one or two ring substituents, and when one or more are present. the two ring substituents are independently identical or different hydroxyl, halogen, alkyl or aryl groups, attached directly or via an ether linkage. In a preferred embodiment, the peptide is a hexapeptide that is cyclized by the residues in positions 1 and 6, with the core sequence in positions 2 to 5. The positions are determined in the conventional manner, counting the residue positions of amino acid from the N-terminus to the C-terminus. Most preferably, the N-terminus is hydrogen or an acyl group, preferably an acetyl group, and the C-terminus is an amino group. Another aspect of the present invention provides cyclic hexapeptides that are highly specific for one or more melanocortin receptors, preferably MC4-R. Most preferably, the cyclic hexapeptides bind to MC4-R with high affinity, with a Ki value of at least 100 nM, preferably of at least 10 nM, and most preferably from about 0.01 nM to about 2 nM. In some embodiments, the cyclic hexapeptides can be functionally inverse agonists with respect to such a receptor or receptors. However, it is not necessary that the hexapeptides of this invention are inverse agonists. Preferably, such cyclic hexapeptides can be used in the treatment of eating disorders, and can be characterized in part by inducing weight gain in mammals, including without limitation rodents, canines and humans. The peptide is a cyclic hexapeptide. A cyclic peptide can be obtained by inducing the formation of a covalent bond between an amino group at the N-terminus of the peptide, if provided, and a carboxyl group at the C-terminus, if provided. A cyclic peptide can also be obtained by forming a covalent bond between a terminal reactive group and an amino acid side chain reactive portion, or between two reactive side chain amino acid portions. Peptides can also be formed with covalent bonds of lanthionine, cystathionine or pentionin, such as the cyclic bonds formed from the amino acid residues cysteine, homocysteine or penicillamine. These bonds are thioether bridge bonds. Galande A. K., Spatola A. F., Lett. Pept. Sci. 8: 247 (2001), which describe methods for making such links, is incorporated herein by reference. In this manner, a hexacyclic peptide can also be obtained by forming a covalent thioether bond between two reactive side chain amino acid portions, or between a terminal reactive group and an reactive side chain amino acid portion. The hexapeptides described in the various embodiments of the present invention are characterized in part because the hexapeptides are preferably highly selective for MC4-R. For example, for SHU91 19 the ratio of Ki values for MC4-R / MC3-R, under the test conditions used herein, is less than about 1: 6, the ratio for MC4-R / MC5-R is less than about 1: 3, and the ratio for MC4-R / MC1-R is less than about 1: 7. Other researchers (for example Schioth H. B. and others, Peptides 18: 1009-1013 (1997)), although they report different values, agree that SHU91 19 is not selective. In this way, it can be seen that SHU91 19 is not highly selective for MC4-R. By contrast, the cyclic hexapeptides of this invention are significantly more selective. In this way, the cyclic hexapeptide of Example 11, Ac-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2, under the same test conditions, has a ratio of Ki values for MC4-R / MC3-R of about 1: 62, for MC4-R / MC5-R of about 1: 93, and for MC4-R / MC1-R of more than about 1: 175,000. In this way, it can be seen that at all pharmaceutically relevant doses, the hexapeptides of this invention are highly selective for MC4-R. The hexapeptides of the invention are further characterized because they are preferably not agonists for any MC receptor, and preferably are inactive or antagonists of all other MC receptors.

MC different from MC4-R. All hexapeptides of the invention are functional antagonists of MC4-R.

Synthesis of peptides The cyclic hexapeptides of this invention can be easily synthesized by any conventional method known for the formation of a peptide bond between amino acids. Said conventional methods include, for example, any process in solution phase that allows a condensation between the free alpha-amino group of an amino acid or residue thereof, having its carboxyl group or another protected reactive group, and the primary carboxyl group free of another amino acid or residue thereof, which has its amino group or other protected reagent. In a preferred conventional process, the cyclic hexapeptides of this invention can be synthesized by solid phase synthesis and can be purified according to known methods. Any of several well-known procedures using a variety of resins and reagents can be used to prepare the peptides of this invention. The process of synthesizing the cyclic hexapeptides can be carried out by a method wherein each amino acid is added in succession to another amino acid or residue thereof in the desired sequence, one at a time, or by a procedure where the fragments are first synthesized conventionally. of peptide with the desired amino acid sequence and then condensed to provide the desired peptide. The resulting hexapeptide is then cyclized to produce a cyclic hexapeptide of the invention. The solid phase peptide synthesis methods are well known and practiced. In such methods, the synthesis of the peptides of the invention can be done sequentially by incorporating the desired amino acid residues one at a time into the growing peptide chain, according to the general principles of the solid phase methods. These methods are described in many references including Merrifeld R.B., "Solid phase synthesis (Nobel reading)", Angew Chem 24: 799-180 (1985) and Barany et al., "The Peptides, Analysis, Synthesis and Biology", vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980). In chemical peptide syntheses, the side chain reactive groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction at that site from occurring until the protecting group is removed. It is also common to protect the alpha-amino group from a residue or amino acid fragment, while the entity reacts at the carboxyl group, followed by the selective removal of the alpha-amino protecting group to allow a subsequent reaction to occur at this site. . Specific protecting groups have been described and are known in solid phase synthesis methods and solution phase synthesis methods. The alpha-amino groups can be protected by suitable protecting groups including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl , 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); protective aliphatic urethane type groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl and allyloxycarbonyl. Fmoc is preferred for the protection of alpha-amino. The guanidino groups can be protected with a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanosulfonyl (Pmc), adamantyloxycarbonyl, pentamethyl-dihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a preferred protecting group for Arg. The peptides of the invention described herein are prepared using solid phase synthesis, for example by means of an automatic peptide synthesizer Symphony Multiplex Peptide Synthesizer (Rainin Instrument Company), using programming modules provided by the manufacturer and following the protocols indicated in the manufacturer's manual. Solid phase synthesis starts from the C-terminal end of the peptide by coupling a protected alpha-amino acid with a suitable resin. This starting material is prepared by linking an amino-protected amino acid via an ester linkage with a p-benzyloxybenzyl alcohol resin (Wang), or a 2-chlorotryl chloride resin, via an amide bond between an Fmoc linker , such as p - [(R, S) -a- [1 - (.9H-fIuoren-9-yl) -methoxyformamide] -2,4-dimethyloxybenzyl] -phenoxyacetic acid (Rink linker) and a benzohydrylamine resin (BHA), or by any other known means. Fmoc-Binder-BHA resin supports are commercially available and are generally used when feasible. The resins are carried through repeated cycles as necessary to sequentially add the amino acids. The Fmoc alpha-amino protecting groups are removed under basic conditions. For this purpose, piperidine, piperazine, diethylamine or morpholine (20-40% v / v) can be used in N, N-dimethylformamide (DMF). After removal of the alpha-amino protecting group, the subsequent protected amino acids are stepped in the desired order to obtain a protected peptide resin intermediate. The activating reagents used for the coupling of the amino acids in the solid phase synthesis of the peptides are well known. After synthesizing the peptide, if desired, the orthogonally protected side chain protecting groups can be removed using known methods for further modification of the peptide. The reactive groups of a peptide can be modified selectively, either during synthesis in solid phase or after the removal of the resin. For example, the peptides can be modified to obtain modifications at the N-terminus, such as acetylation, while they are on the resin, or they can be separated from the resin using a separation reagent and then modified. Methods for modifying the N-terminus, such as acetylation, and for modifying the C-terminus, such as amidation, are known. Similarly, methods for modifying amino acid side chains are well known to those skilled in peptide synthesis. The choice of the modifications made to the reactive groups present in the peptide will be determined in part by the characteristics that are desired in the peptide. In one embodiment, the peptide can be cyclized before it is separated from the resin. For cyclization by reactive side chain portions, the desired side chains are deprotected and the peptide is suspended in a suitable solvent, and a cyclic coupling agent is added. Suitable solvents include, for example, DMF, dichloromethane (DCM) or 1-methyl-2-pyrroidone (NMP). Suitable cyclic coupling reagents include, for example, 2- (1H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (1 H-benzotriazole-1-hexafluorophosphate. il) -1, 1, 3,3-tetramethyluronium (HBTU), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris (pyrrolidin) phosphonium hexafluorophosphate (PyBOP), 2- (7-aza-1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate (TATU), 2- (2-oxo-1 (2H) tetrafluoroborate - pyridyl) -1, 1, 3,3-tetramethyluronium (TPTU), or N, N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole (DCCI / HOBt). The coupling is conventionally initiated using a suitable base such as N, N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). After separation of the peptides from the solid phase subsequent to their synthesis, the peptide can be purified by any method, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a Gis column- Other separation or purification methods can also be used, as the methods based on the size or charge of the peptide. Once purified, the peptide can be characterized by any method, such as high performance liquid chromatography (HPLC), amino acid analysis, mass spectrometry and the like.

Formulation and utility The cyclic hexapeptides described herein can be used both for medical application and for animal or veterinary breeding applications. Normally, the product is used in humans but can also be used in other mammals. The term "patient" denotes a mammalian individual and is thus used throughout the specification and the claims. Primary applications of this invention include human patients, but this invention can be applied to laboratory, farm, zoo, wild, pet, entertaining or other animal animals. In general, the hexapeptides of this invention can be synthesized by solid phase synthesis and purified according to known methods. Any known method can be used using a variety of resins and reagents to prepare the peptides of this invention. Salt formation of cyclic hexapeptides. The cyclic hexapeptides of this invention may be in the form of any pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" refers to salts prepared from innocuous pharmaceutically acceptable bases or acids including organic or inorganic bases and organic or inorganic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like salts. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include the primary, secondary and tertiary amine salts, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, resins of polyamine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the cyclic hexapeptide of the present invention is basic, acid addition salts can be prepared from innocuous pharmaceutically acceptable acids, including inorganic and organic acids. These acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic, and the like. The acid addition salts of the cyclic hexapeptides of this invention are prepared in a suitable solvent of the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic acid. or methanesulfonic. The acetate salt form is especially useful. When the hexapeptides of the embodiments of this invention include an acid portion, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts. Pharmaceutical compositions Another embodiment of the present invention provides a pharmaceutical composition that includes a cyclic hexapeptide of this invention and a pharmaceutically acceptable carrier. The vehicle can be a liquid formulation, and is preferably an aqueous buffer solution. Pharmaceutically acceptable carriers also include excipients such as diluents, vehicles and the like, and additives as stabilizing agents, preservatives, solubilizers, buffers and the like, as described below. The cyclic hexapeptide compositions of the embodiments of the present invention may be formulated or combined in pharmaceutical compositions that include at least one cyclic peptide of this invention together with one or more pharmaceutically acceptable carriers, including excipients such as dioliants, carriers and the like, and additives such as stabilizing agents, preservatives, solubilizers, buffers and the like, as required. The formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride and sodium citrate. For injection or other liquid administration formulations, water containing at least one or more buffering constituents is preferred, and stabilizing, preserving and solubilizing agents can also be used. For solid administration formulations a variety of thickening, filling, bulking agents, and additives such as starches, sugars, fatty acids and the like can be employed. For topical administration formulations any of a variety of creams, ointments, gels, lotions and the like can be used. For most pharmaceutical formulations, the inactive ingredients will constitute the majority by weight or volume of the preparation. For pharmaceutical formulations the use of any of a variety of controlled release, sustained release or sustained release formulations and additives is also contemplated, such that the dose can be formulated in order to release the hexapeptide of the embodiments of the present invention during a certain period. In general, the actual amount of the cyclic hexapeptides administered to a patient can vary within very broad scales depending on the mode of administration, the formulation used and the desired response. In practical use, the cyclic hexapeptides described herein can be combined as an active ingredient in a mixture with a pharmaceutical carrier according to conventional pharmaceutical composition techniques. The vehicle can have a wide variety of forms depending on the form of preparation desired for administration, for example, oral, parenteral (including intravenous), urethral, vaginal, nasal, buccal, sublingual, or the like. To prepare compositions of oral dosage forms, any of the usual pharmaceutical media, such as for example water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, can be used in the case of liquid oral preparations such as example suspensions, elixirs and solutions; or vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of solid oral preparations such as, for example, powders, hard and soft capsules and tablets. Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form. If desired, the tablets can be coated by standard techniques, aqueous or non-aqueous. In such therapeutically useful compositions, the amount of active hexapeptide is such that an effective dosage will be obtained. In another form of advantageous unit dose, sublingual devices, such as sheets, wafers, tablets or the like can be used. Active hexapeptides can also be administered intranasally, such as, for example, in liquid drops or spray preparations. The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as a fatty oil. Other materials can be used as coatings or to modify the physical form of the unit dose. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl- and propylparabens as preservatives, a colorant and a flavoring such as cherry or orange flavor. The cyclic hexapeptides can also be administered parenterally. Solutions or suspensions in water of these active hexapeptides, conveniently mixed with a surfactant such as hydroxypropylcellulose, can be prepared. . Dispersions in glycerol, liquid polyethylene glycols and mixtures thereof in oils can also be prepared. Optionally these preparations may contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be administered through a syringe. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing for example water, ethanol, polyol, for example glycerol, propylene glycol or liquid polyethylene glycol, suitable mixtures thereof and vegetable oils. The cyclic hexapeptides described herein can be applied therapeutically by nasal administration. By "nasal administration" is meant any form of intranasal administration of any of the cyclic hexapeptides of this invention. The hexapeptides may be in an aqueous solution, such as a solution including saline, citrate or other common excipient or preservative. The hexapeptides may also be in a dry or powder formulation. In an alternative embodiment, the cyclic hexapeptides can be administered directly in the lung. The intrapulmonary administration can be effected by means of a metered dose inhaler, a device that allows the self-administration of a dosed bolus of a peptide of this invention when it is operated by a patient during inspiration. The cyclic hexapeptides of the embodiments of the present invention can be formulated with any of a variety of agents that increase the effective nasal absorption of the drugs, including peptide drugs. These agents would increase nasal absorption without major damage to the mucous membrane. The US patents UU Nos. 5,693,608, 5,977,070 and 5,908,825, among others, teach various pharmaceutical compositions which may be employed, which include absorption enhancers, and teachings thereof, and all references and patents cited therein, are incorporated by reference. The aqueous solutions of the cyclic hexapeptides of the embodiments of the present invention can be appropriately buffered by means of saline, acetate, phosphate, citrate or other buffering agents, which can be at any physiologically acceptable pH, usually at a pH from about 4 to about 7. A combination of buffering agents, such as phosphate buffering saline, acetate buffering saline, and the like may also be employed. In the case of a saline solution, a 0.9% saline solution can be used. In the case of acetate, phosphate and citrate, a 50 mM solution can be used. In addition to the buffering agents, a suitable preservative can be used to prevent or limit the growth of bacteria and other microbes. One such preservative that can be employed is 0.05% benzalkonium chloride. It is also possible and contemplated that the cyclic hexapeptide may be in a dry and particulate form. In a preferred embodiment, the particles are from 0.5 μm to 6.0 μm, approximately, so that the particles have a mass sufficient to settle on the surface of the lung and not be exhaled, but are small enough so that they do not deposit on the surfaces of the respiratory passages before reaching the lung. Any of a variety of different techniques can be used to make dry powder microparticles, which include without limitation micropulverization, spray drying and rapid aerosol freezing, followed by lyophilization. The peptides can be deposited at the bottom of the lung as microparticles, thereby giving rapid and efficient absorption into the bloodstream. Furthermore, such an approach does not require penetration enhancers, as is sometimes the case in transdermal, nasal, or oral mucosal routes of administration. Any of a variety of inhalers can be used including propellant-based aerosols, nebulizers, single-dose dry powder inhalers and multiple dose dry powder inhalers. Common devices in current use include metered dose inhalers that are used to administer medications for the treatment of asthma, chronic obstructive pulmonary disease and the like. Preferred devices include dry powder inhalers designed to form a cloud or fine powder aerosol, with a particle size that is always less than about 6.0 μm. The size of the microparticle, including the average size distribution, can be controlled by means of the preparation method. For micropulverization, the size of the grinding head, the rotor speed, the treatment time and the like control the microparticle size. For spray drying, the size of the nozzle, the flow rate, the heat of the dryer and the like control the microparticle size. For preparation by rapid freezing of aerosol followed by lyophilization, the size of the nozzle, the flow rate, the concentration of the aerosol solution and the like, control the microparticle size. These and other parameters can be used to control the microparticle size. The cyclic peptides of this invention can be administered therapeutically by means of an injection, usually a deep intramuscular injection, for example in the gluteus or deltoid muscle, of a controlled release injectable formulation. In a modality, a cyclic peptide of this invention is formulated with a polyethylene glycol, such as polyethylene glycol 3350, and optionally one or more additional excipients and preservatives, including, without limitation, excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid for adjust the pH, and the like. In another embodiment, a cyclic peptide of this invention is formulated with a poly (ortho ester), which may be a poly (ortho ester) autocatalyzed with any variable percentage of lactic acid in the polymeric backbone, and optionally one or more excipients additional In one embodiment, the poly (D, L-lactide-co-glycolide) polymer (PLGA polymer), preferably a PLGA polymer with a hydrophilic end group, such as PLGA RG502H from Boehringer Ingelheim, Inc. (Ingelheim, Germany) is employed. ). These formulations can be made, for example, by combining a cyclic peptide of this invention in a suitable solvent, such as methanol, with a solution of PLGA in methylene chloride, and by adding thereto a continuous phase solution of polyvinyl alcohol under of suitable mixing in a reactor. In general, any of several injectable and biodegradable polymers, which preferably are also adhesive polymers, can be used in a controlled release injectable formulation. The teachings of the US patents UU Nos. 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and formulation methods described therein, are incorporated herein by reference. The formulation may be an injection for weekly, monthly or other periodic use, depending on the concentration and amount of the cyclic peptide, the rate of biodegradation of the polymer and other factors known to those skilled in the art. Routes of administration. If administered by injection, it may be intravenous, subcutaneous, intramuscular, intraperitoneal, or other known means. The hexapeptides of this invention may be formulated by any known means, including, without limitation, their formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, eye drops, skin patches, oral soluble formulations, formulations for atomizing, aerosols and the like, and can be mixed and formulated with buffers, binders, stabilizers, antioxidants and other known agents. In general, any administration route can be used by which the hexapeptides of the invention are introduced through an epidermal layer of cells. In this manner, the means of administration may include administration through mucous membranes, oral administration, oral administration, dermal administration, administration by inhalation, nasal administration, urethral administration, vaginal administration, and the like. Therapeutically effective amount. In general, the actual amount of the cyclic hexapeptide of this invention administered to a patient varies between quite broad scales depending on the mode of administration, the formulation used and the desired response. The dosage for the treatment is the administration, by any of the aforementioned means or any other known means, of an amount sufficient to produce the desired therapeutic effect. Thus, a therapeutically effective amount includes an amount of peptide or pharmaceutical composition of this invention that is sufficient to therapeutically alleviate the eating disorder in a patient, or to prevent or delay the onset or recurrence of the eating disorder, or to the management of eating disorder in patients with diseases or syndromes associated with cachexia, including secondary to immune disorders and cancer. In general, the cyclic peptides of this invention are very active. For example, the cyclic hexapeptide can be administered at a dose of about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, or 500 μg / kg of body weight, depending on the specific hexapeptide selected, the desired therapeutic response, the route of administration, the formulation and other known factors for the subject matter experts. Inflammation and immune disorders. The hexapeptides of this invention can also be used in the treatment of inflammation and immune disorders. See, for example, Catania A. and others, Endocrine Trends !. Metab. 11: 304-308 (2000); Gantz I. and Fong T. M., Am. J. Physiol. Endocrinol Metab. 284: E468-E474 (2003); and Catania A., Gatti S., Colombo G., Lipton J. M., Pharmacol. Rev. 56: 1-29 (2004), which are incorporated herein by reference.

Combination therapy It is also possible and contemplated that cyclic hexapeptides according to various embodiments of the present invention, are used in combination with other drugs or agents, particularly in the treatment of cachexia. These other drugs and agents may include weight-inducing agents, including corticosteroids and progestational agents. In a preferred embodiment of the invention, the cyclic hexapeptides of the invention are used in combination with a therapeutically effective amount of a second weight gain pharmaceutical agent. In accordance with another embodiment of the present invention, methods are provided for the treatment of cachexia. The method includes the step of administering to the patient having cachexia or at risk of having it, a therapeutically effective amount of a cyclic hexapeptide of this invention in combination with a therapeutically effective amount of another compound that is useful in the treatment of cachexia. . One embodiment of the present invention also provides pharmaceutical compositions comprising 1) a cyclic peptide of this invention, and 2) a second compound used for the treatment of cachexia. In one embodiment of the above composition, the second compound useful for the treatment of cachexia is preferably selected, without limitation, from the group consisting of inhibitors of ADP-ribose polymerase, ADP-ribose transferase inhibitors, NADase inhibitors, nicotinamide, benzamide, theophylline, thymine and analogs thereof; omega-3 fatty acids such as alpha-linolenic acid, stearidonic acid, eicosapentanoic acid (EPA), docosapentanoic acid, docosahexaenoic acid or mixtures thereof; branched chain amino acids such as valine, leucine, isoleucine or mixtures thereof, with or without minor amounts of tryptophan and 5-hydroxytryptophan; antioxidants selected from the group comprising beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof; L-glutamine, vitamin A, vitamin C, vitamin E, and selenium; Azaftig; quinine derivatives including 3,5,6-trimethyl-2- (3-pyridyl) methyl-1,4-benzoquinone hydrochloride; Interleukin 2; benzaldehyde; 4,6-O-benzylidene-D-glucose; friedelan-3-one; hydrazine sulfate; Medroxyprogesterone acetate; beta 2 adrenoceptor agonists; corticosteroids such as dexamethasone; Vítor ™; Pro-Stat ™; Megestrol acetate (Megace ™); dronabinol (Marino! ™); magestrol acetate (Megace ™); thalidomide (Thalidomid ™); Fluoxymesterone (Halotestin ™); pentoxifylline (Trental ™); cyproheptadine (Periactin ™); metoclopramide (Reglan ™); total parenteral nutrition; or other MC4-R antagonists. In another embodiment, the second compound useful for the treatment of cachexia is somatropin (Serostim ™), an injectable form of human growth hormone. Another embodiment of the present invention provides equipment for the treatment of cachexia. The kits include a first pharmaceutical composition that includes a cyclic hexapeptide according to one embodiment of the present invention, a second pharmaceutical composition comprising a second compound useful for the treatment of cachexia, and a container for the first and second compositions.

Industrial Application The invention is further illustrated by means of the following non-limiting examples.

EXAMPLE 1 Competitive binding test using p1251-NDP-a-MSH A competitive inhibition binding test is performed using membranes prepared with HEK-293 cells transfected with hMC3-R, hMC4-R or hMC5-R gene constructs, mouse melanoma cells B-16 (containing MC1-R), using respectively [l125] -NDP-a-MSH 0.4 nM, 0.2 nM, 0.4 nM or 0.1 nM (New England Nuclear), in 50 mM HEPES buffer containing 1 mM MgCl2, 2 mM CaCl2, and 5 mM KCl , at pH 7.2. The test tube also contains a chosen concentration of the test peptide of the invention, usually at a concentration of 1 μM, to determine its efficacy in inhibiting the binding of [125] -NDP-a-MSH to its receptor. Nonspecific binding is measured by complete inhibition of the binding of [125] -NDP-a-MSH in the assay, in the presence of 1 μM of NDP-a-MSH. The test mixture is incubated 90 minutes at room temperature and then filtered; The membranes are washed three times with an ice-cooled buffer. The filter is dried and a gamma count is made of the remaining radioactivity bound to the membranes. 100% specific binding is defined as the difference in radioactivity (cpm) bound to cell membranes in the absence and presence of 1 μM of NDP-a-MSH. The cpm obtained in the presence of the test peptides is normalized with respect to 100% specific binding, to determine the percentage of inhibition of the binding of [125] -NDP-a-MSH. Each test is done in triplicate. The Ki (nM) of some peptides of the invention is determined using protocols and test peptides at a larger dose scale.

EXAMPLE 2 General method to determine the CEgo in a functional activity test Functional evaluation of the peptides in melanocortin receptors is performed by measuring the accumulation of intracellular cAMP in HEK-293 cells expressing hMC3-R, hMC4-R or hMC5-R, and in mouse melanoma cells B-16 expressing MC1 -R. Cells suspended in Earle's balanced saline solution containing 10 mM HEPES (pH 7.5), 5 mM MgCl2, 1 mM glutamine, 0.1% albumin and 0.6 mM 3-isobutyl-1-methyl-xanthine, an inhibitor of phosphodiesterase, are seeded in 96-well plates at a density of 0.5 X 105 cells per well. The cells are incubated with the test peptides in the absence or in the presence of a-MSH for 1 hour at 37 ° C. The concentration of cAMP in the cell lysates is measured using the EIA equipment (Amersham). The data are analyzed and the CE5o values are determined using non-linear regression analysis with Prism Graph-Pad software.

EXAMPLE 3 Functional condition The agonist / antagonist condition is determined with respect to MC1-R, MC4-R and MC5-R of some peptides of the invention. The antagonist activity is determined by measuring the inhibition of cAMP concentration induced by a-MSH or induced by NDP-a-MSH, after exposure to the peptides as in the preceding descriptions. Agonist test An evaluation of agonist activity of the molecules is made to elicit a functional response in HEK-293 cells expressing hMC4-R, measuring the accumulation of intracellular cAMP after treatment. The confluent HEK-293 cells overexpressing MC4-R are lysed by means of a cell suspension buffer without enzyme. Cells are suspended in Earle's balanced salt solution containing 10 mM HEPES (pH 7.5), 1 mM MgCl2, 1 mM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-1-methyl-xanthine, a phosphodiesterase inhibitor. Cells are seeded in 96-well plates at a density of 0.5 X 105 cells per well and pre-incubated 30 minutes. The cells are then contacted with the test peptides dissolved in dimethyl sulfoxide (DMSO) at a concentration scale of 0.05-5000 nM, in a total test volume of 200 μL, for 1 hour at 37 ° C. The concentration of DMSO is always maintained at 1% in the test mixture. NDP-a-MSH is used as the reference agonist. At the end of the incubation period, the cells lysate adding 50 μL of lysis buffer from the cAMP EIA (Amersham). To ensure complete rupture of the cells, the cells are pipetted up and down many times. The concentration of cAMP in the cell lysates is measured after an appropriate dilution using the EIA (Amersham) method. The data analysis and the EC50 values are determined using non-linear regression analysis with the Prism Graph-Pad software. At a concentration of 5000 nM peptides with a response ratio of 0.7 and greater with respect to NDP-a-MSH are classified as full agonists. Peptides with a ratio of 0.1 to 0.7 are classified as partial agonists. Peptides with a response ratio of less than 0.1 are evaluated for their antagonist activity. Neutral antagonist test. Peptides with a high binding affinity for the MC4-R membranes but with less efficiency (EC50> 1000 nM) and lower response ratio (<0.1), are analyzed to determine their ability to antagonize the stimulatory effect of the agonist NDP-a-MSH. These studies are carried out on HEK-293 cells expressing hMC4-R. The cells are incubated with the peptides in the presence of the NDP-a-MSH agonist, and the magnitude of the antagonism is measured by the reduction of the intracellular concentration of cAMP. Examination of the peptides to determine their antagonist capacity is done at a single concentration of NDP-a-MSH (1.0 nM) on a peptide concentration scale of 0.5-5000 nM; the studies are further extended when the peptides exhibit strong antagonism to derive the pA2 value from a Schild analysis. The experimental details are similar to the analysis of agonist activity and are described above. Briefly, the cells are preincubated for 30 minutes with the test peptides at concentrations between 0.5 nM and 5000 nM. The cells are then stimulated with NDP-a-MSH at a concentration of 1 nM for 1 hour. For the Schild analysis, the interactions are studied using at least 3 concentrations of the peptides, separated by a logarithmic unit, on the full scale of the agonist (0.005-5000 nM). The concentration of cAMP in the cell lysates is measured after appropriate dilution. A non-linear regression analysis is used with the Prism Graph-Pad software for the Schild analysis and to obtain the EC50 values. The values of pA2 are derived from the Schild graph. Inverse agonist test. Peptides that have a weak activity (EC50 >; 1000 nM) or a low response ratio (<0.1) are also analyzed to determine their ability to act as inverse agonists, that is, to reduce the basal or constitutive concentration of cAMP in HEK-293 cells that express the hMC4- receptors R. The experimental protocol is essentially the same as described above. The cells are exposed to the test peptides in a concentration range of 0.05 nM to 5000 nM for 1 hour at 37 ° C. As the reference inverse agonist, the agouti-related protein (AgRP) or a biologically active fragment of the agouti protein is used, such as AgRP (83-132) (Ser-Ser-Arg-Arg-Cys-Val-Arg-Leu). -His-Glu-Ser-Cys-Leu-Gly-Gln-Gln-Val-Pro-Cys-Cys-Asp-Pro-Cys-Ala-Thr-Cys-Tyr-Cys-Arg-Phe-Phe-Asn-Ala -Phe-Cys-Tyr-Cys-Arg-Lys-Leu-Gly-Thr-Ala-Met-Asn-Pro-Cys-Ser-Arg-Thr (SEQ ID NO: 2)). The data analysis and the EC50 values are determined using non-linear regression analysis with the Prism Graph-Pad software.

EXAMPLE 4 Changes in ICV food intake and body weight The ingestion of food and body weight produced by selected peptides was evaluated. Rats with housed intracerebroventricular cannulae (ICV rats) are obtained from Hilltop Lab Animáis, Inc. (Scottdale, Pa.). The animals are housed individually in conventional plexiglass hanging cages and are maintained in a controlled cycle of 12 hours of on / off light. They are freely given water and food powder (LabDiet, 5P00 Prolab RMH 3000) or in pellets (rodent diet 18% protein, Harlan Teklad 2018). One week before treatment, food intake for 24 hours and body weight change are recorded to determine the baseline values of the group during vehicle treatment. The rats are dosed via ICV with vehicle or selected peptides (0.1-3 nmol). Changes in body weight and food intake are determined for the 24-hour period after dosing. Changes in body weight and food intake are also measured for periods of 48 hours and 72 hours after dosing, to determine the regression of changes in body weight and food intake with respect to baseline values.

EXAMPLE 5 Change in food intake i.v. and i.p. and body weight The change in food intake and body weight produced by selected peptides was evaluated. Male Sprague-Dawley rats are obtained from Taconic (Germantown, New York). The animals are housed individually in conventional plexiglass hanging cages and are maintained in a controlled cycle of 12 hours of on / off light. They are freely given water and food powder (LabDiet, 5P00 Prolab RMH 3000) or in pellets (rodent diet 18% protein, Harian Tekiad 2018). One week before treatment, 24-hour food intake and body weight change are recorded to determine the baseline values of the group during vehicle treatment. The rats are dosed via i.v. or i.p. with selected vehicle or peptides (0.5-3 mg / kg). Changes in body weight and food intake are determined for the 24-hour period after dosing. Changes in body weight and food intake are also measured for periods of 48 hours and 72 hours after dosing, to determine the regression of the effects of body weight and food intake with respect to baseline values.

EXAMPLE 6 Satiety behavior sequence Male Sprague-Dawley rats are maintained on a restricted diet of 20 g of powdered feed per day. The food is presented at the same time during the period of light on, dosed with saline solution or the test peptide, 2 hours before the presentation of the food and the beginning of the observation. The rats are presented previously weighed containers containing 20 g of food and their behavior is observed for one hour. Behavioral observations are divided into 3 categories: Feeding, Activity (includes grooming, drinking and smelling / exploring), and Rest (decreased activity and sleep). The amount of time spent on each behavior is recorded. The amount of food eaten is determined after the observation period.

EXAMPLE 7 Conditional Taste Abstinence Male Sprague-Dawley rats adapt to a water restriction period of 30 minutes during the period of light on and are given free food in pellets. In laboratory animals the administration of LiCI conditions an aversion to the novel and favorable taste of saccharin (Seeley RJ, Blake K. Rushing PA, Benoit S., Eng J., Woods SC and D'Alessio D: "The role of CNS glucagons -like peptide-1 (7-36) amide receptors in mediating the visceral illness effets of lithium chloride ", J. Neurosci 20 (4): 1616-1621 (2000)). To condition the animals, they are given an injection of LiCI or test peptide immediately after the initial presentation of a 0.1% solution of saccharin. Two days later, the saccharin solution is presented again, and fluid intake is determined. A reduction of the drink of the saccharin solution suggests the development of an aversion to conditioned palates.

EXAMPLE 8 Model of cachexia induced by lipopolysaccharide Rats with housed intracerebroventricular cannulae (ICV rats) are obtained from Hilltop Lab Animáis, Inc. (Scottdale, Pa.). The animals are housed individually in conventional plexiglass hanging cages and are maintained in a controlled cycle of 12 hours of on / off light. They are freely given water and food powder (LabDiet, 5P00 Prolab RMH 3000) or in pellets (rodent diet 18% protein, Harian Tekiad 2018). Lipopolysaccharide (LPS) (E. Coli 055: B5, Sigma Chemical Co.) is dissolved in normal saline and i.p. For the first injection of LPS, male animals 6-7 weeks of age are used. In an identical repeat experiment, female animals, 5 weeks old, are used. The basal feeding of the animals is monitored for two days, and then during each twelve-hour period after an i.p. of saline before the injection of 100 μg / kg of LPS. Some peptides of the invention are administered and 3 hours later 50 μg / kg of LPS are administered. Sixty hours after the first dose a second dose of 100 μg / Kg of LPS is given in the second experiment. No food is given between the administration of the peptide and the administration of LPS. Beginning after the administration of LPS, the feeding is measured every 6 hours for 24 hours; then every 12 hours for 48 more hours. In the false treatment group, basal feeding is measured every six hours in two groups of the same age and sex after the simulated ICV injection and i.p. of saline solution. Twenty-four hours later the selected peptides are administered and 3 hours later the LPS is administered i.p. The feeding is measured every 6 hours for 24 hours; then every 12 hours for 48 more hours. The difference between the feeding curves in the two groups is expressed as normalized ingestion by weight and as a percentage of basal feeding versus the subsequent injection of saline and false ICV.

EXAMPLE 9 Model of tumor-induced cachexia Lewis lung carcinoma cells (LLC) and Englebret-Holm-Swarm sarcoma tumors (EHS) are maintained as a primary culture in DMEM with 10% fetal bovine serum, or in vivo, respectively, as recommended by the provider . The LLC tumor cells are harvested during the exponential growth of the culture, washed in Hanks balanced salt solution, and the cells are injected subcutaneously into the upper side of the animals. The EHS sarcoma tissue is dissected from a donor animal and a tissue cube of approximately 3 mm is implanted subcutaneously above the posterior side. Fake-operated animals receive an implant of a similar amount of donor tissue. In all cases, the time of occurrence of a tumor mass is noted, and it is found that all animals have a palpable tumor within four days (CLL) or eight days (EHS) after the start of the experiment. At the time of sacrifice, the tumors are separated from the surrounding tissue and weighed. The general examination of all organs does not reveal the presence of any observable metastases. Blood is drawn from the arterial trunk at the time of sacrifice to measure serum leptin with a rat leptin radioimmunoassay kit. The animals are housed individually in conventional plexiglass hanging cages and are maintained in a controlled cycle of 12 hours of on / off light. The effects of the administration of some peptides of the invention in animals with hypophagia and weight loss due to the presence of a growing sarcoma are examined. In an initial experiment, the daily food intake and weight are monitored until the tumor-bearing animals have a food intake that is 75-80% of the basal level for three consecutive days. On average this occurs on day 12 after implantation or four days after a palpable tumor is present. The selected peptides are injected via ICV and the animals are monitored to determine the change in food intake. In a second experiment, the ability of selected peptides to prevent the appearance of cachexia and maintain normal feeding and growth is tested. The animals are examined daily to detect the presence of a palpable tumor, all animals having tumors by day 14 after implantation, and none before day 12. Then the selected peptides or a target are injected to the animals every 48 hours until their sacrifice. A group implanted with a false tumor is included for comparison and they are also given the peptides. The differences between the feeding, activity and water consumption curves of all the experiments are analyzed by ANOVA of two-factor repeated measurement, with time and treatment as the measured variables. The final weights of the tumor and the body are analyzed by Student's t-test when two groups are included, or one-way ANOVA with coincident correlation analysis when three groups are included. The statistical meaning of data series is analyzed using the PRISM software package (GraphPad) for ANOVA with repeated measurements, or in EXCEL (Microsoft) using the Student's t-test.

EXAMPLE 10 Mass Analysis and Nuclear Magnetic Resonance The mass values of the peptides of the invention are determined using a Waters MicroMass ZQ device, using a positive mode. The mass determinations are compared with calculated values and are expressed as mass weight plus one (M + 1 or M + H). The proton NMR data is obtained using a Bruker 300 MHz spectrometer. The spectra are obtained after dissolving the peptides in a deuterated solvent such as chloroform, DMSO or methanol, as appropriate.

EXAMPLE 11 Ac-cyclop-Asp-Trp-D-Nal 2-Arg-Nal 2-Lvs) -NH? Ac-cyclopentane hexapeptide (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2 was synthesized by conventional methods of peptide synthesis. The formula weight determined was 1135. The competitive inhibition activity and the Ki (nM) of the peptide were measured following the method of example 1. The functional condition of the peptide was determined following the methods of examples 2 and 3.

Ki (nM) MC1-R MC3-R MC4-R MC5-R 5680 2 0.03 3 In a cAMP test to determine the agonist / antagonist condition, the peptide was determined to be a partial agonist of MC1-R (mouse melanoma cells B-16), with an EC50 (nM) > 1000, was inactive for MC3-R, and an MC4-R antagonist. In tests of functional antagonism as those of example 3, a value of pA2 (M) for MC4-R of 8,852 was determined.

EXAMPLES 12-13 Additional peptides The following hexapeptides were synthesized by conventional methods of peptide synthesis: 12. H-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2 13. H-Cyclo (-Asp-Trp-D -Nal 2-Lys-Nal 2-Lys) -NH2. The competitive inhibition and Ki (nM) of the peptides of examples 12 and 13 were measured following the method of example 1. The functional condition of the peptides of examples 12 and 13 was determined following the methods of examples 2 and 3 .

EXAMPLE 14 Additional peptide Ac-cyclopentane hexapeptide (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2 was synthesized by conventional methods of peptide synthesis. The competitive inhibition and the Ki (nM) of the peptides of example 14 were measured following the method of example 1. The functional condition of the peptide of example 14 was determined following the methods of examples 2 and 3.

EXAMPLE 15 ICV Power Studies ICV feeding studies were carried out in rats following the general methods of example 4, using the hexapeptide of example 11. All animals were given the first day of saline solution via ICV, and given a pre-weighed food container, recording the weight at 2 and 21 hours after the ICV injection. On day 2, the animals were randomly distributed according to food consumption in 21 hours, eliminating animals with low feed intake or food spills. The animals were administered a vehicle (saline), a positive control (SHU91 19, 1 nmol), or the hexapeptide of example 11 (0.1, 0.2 and 1.0 nmol). The feed weights were again recorded at 2, 4, 21 and 24 hours after the ICV injection. In some cases, multiple different tests were performed, each group containing between 8 and 12 members; The average value is given. At 21 hours, the average increase in feed intake in the animals receiving the hexapeptide of example 11, was 4% at a dose of 0.1 nmol, 18% at a dose of 0.3 nmol, and 20% at a dose of 1.0 nmol.

EXAMPLE 16 Feeding studies IV The rats were administered 1 mg / kg of the peptide of example 11 as in example 5, and the food ingestion was measured at selected t over a period of 24 hours. Briefly, male Sprague-Dawley rats (300-350 g) were housed individually in shoe box cages with a 12-hour dark light period. Ingestion of food and body weights were monitored for 24 hours before the start of the study. The rats were randomly distributed by body weight and then the compound of example 11 or the same vehicle volume was administered., just before turning off the light. They were given a previously weighed amount of food and the food intake was determined at 2, 4, 20 and 24 hours. The hexapeptide of Example 11 caused an 8% increase in food intake in the 24 hour period. The preceding examples can be repeated with similar success by replacing the reagents and / or operating conditions described generically or specifically in this invention. Although the invention has been described in detail with particular reference to preferred embodiments, other embodiments may achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art, and it is considered that the invention covers all these modifications and equivalents. Full descriptions of all references, applications, patents and publications cited above are incorporated herein by reference.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - A cyclic hexapeptide of the structural formula: where: Ri is H, NH2 or

R2 is -C (= 0) -NH-, -NH-C (= 0) -, or -S-; R3a and R3b are each optional ring substituents, and when one or both are present, they are independently identical or different hydroxyl, halogen, alkyl or aryl groups, attached directly or via an ether linkage; R 4 is -NH 2 or -NH (C = NH) NH 2; R5 is 1- or 2-naphthyl or 3-undolyl, optionally with one or two ring substituents, and when one or both ring substituents are present, they are independently hydroxyl, halogen, alkyl or aryl groups,

Equal or different, attached directly or through an ether link; R6 is H, NH2, a linear or branched lower aliphatic alkyl chain of C-i to C4, an aralkyl of Ci to C4, or an omega-amino derivative of Ci to C4; x is 1 to 4, and y is from 1 to 5, provided that x + y is from 2 to 7; and z is from 2 to 5. 2. The cyclic hexapeptide according to claim 1, further characterized by having the structural formula: wherein R4, R5 and z are as defined in claim 1. 3. The cyclic hexapeptide according to claim 2, further characterized because it is: Ac-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2; or Ac-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2.

4. The cyclic hexapeptide according to claim 1, further characterized by having the structural formula: wherein R4, R5 and z are as defined in claim 1.

5. The cyclic hexapeptide according to claim 4, further characterized because it is: H-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2; or H-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2.

6. A pharmaceutical preparation comprising a cyclic hexapeptide as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The use of a pharmaceutical preparation of claim 6, in the manufacture of a medicament useful for the treatment of cachexia in a mammal.

8. The use of a pharmaceutical preparation of claim 6, in the manufacture of a medicament useful for the treatment of inflammation and immune disorders in a mammal.

9. A cyclic hexapeptide with an Ac group at the N-terminus or with an NH2 group at the N-terminus, and with an NH2 group at the C-terminus, the hexapeptide containing the nucleus sequence Trp-D-Nal 2 -XY at positions 2 to 5, wherein X is an L-amino acid residue selected from the group consisting of Arg, Lys, Orn, Harg and Hlys, and Yes a residue of L- or D-amino acid selected from the group consisting of Nal 1, Nal 2 and Trp, wherein any aromatic ring in the core sequence may optionally include one or two ring substituents, and when one or both of the ring substituents are present, they are independently hydroxyl, halogen, alkyl or aryl groups, equal or different, attached directly or via an ether linkage, and wherein the cyclic hexapeptide is cyclized by means of the amino acid residue in position 1 and the amino acid residue in position 6.

10. The cyclic hexapeptide in accordance with the reinvidication 9, further characterized in that the hexapeptide is cyclized by formation of an amide bond between an amino group of a side chain of an amino acid residue in the 1-position, or an amino group of the N-terminal group of the amino acid residue in the position 1, and a side chain carboxyl group of an amino acid residue in the 6-position.

11. The cyclic hexapeptide according to claim 9, further characterized in that the hexapeptide is cyclized by forming an amide bond between a carboxyl group of side chain of an amino acid residue at position 1, and an amine group of a side chain of an amino acid residue at position 6.

12. The cyclic hexapeptide according to claim 9, further characterized in that the hexapeptide is cyclizes by formation of a covalent bond, comprising an amide, disulfide, thioether, Schiff's base, reduced Schiff's base, amide, secondary amine bond, bonyl, urea, hydrazone or oxime.

13. The cyclic hexapeptide according to claim 9, further characterized in that the core sequence is Trp-D-Nal 2-X-Nal 2.

14. - The cyclic hexapeptide according to claim 9, further characterized in that it is Ac-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2.

15. The cyclic hexapeptide according to claim 9, further characterized in that it is Ac-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2.

16. The cyclic hexapeptide according to claim 9, further characterized in that it is H-cyclo (-Asp-Trp-D-Nal 2-Arg-Nal 2-Lys) -NH2.

17. The cyclic hexapeptide according to the claim 9, further characterized in that it is H-cyclo (-Asp-Trp-D-Nal 2-Lys-Nal 2-Lys) -NH2. 18.- The use of a cyclic hexapeptide with an Ac group at the N-terminus or with an NH2 group at the N-terminus, and with an NH2 group at the C-terminus, the hexapeptide containing the nucleus sequence Trp-D-Nal 2 -XY at positions 2 to 5, wherein X is an L-amino acid residue selected from the group consisting of Arg, Lys, Om, Harg and Hlys, and Y is a residue of L- or D-amino acid selected from the group consisting of Nal 1, Nal 2 and Trp, wherein any aromatic ring in the core sequence may optionally include one or two ring substituents, and when one or both of the ring substituents are present, they are independently hydroxyl, halogen, alkyl or aryl, identical or different, attached directly or via an ether linkage, and wherein the cyclic hexapeptide is cyclized by means of the amino acid residue in position 1 and the amino acid residue in position 6, in the preparation of a medicine useful for the treatment of and a body weight disorder that includes cachexia, sarcopenia or wasting syndrome or disease.