 The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
专利摘要:
The present invention provides the use of a compound of formula 1 and a pharmacologically active salt thereof for the treatment of a ligand for a melanocortin receptor and / or a disease of the melanocortin system: [Formula 1] In Chemical Formula 1, X is H or OH; R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different from one another and are an electron donating group such as hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms or hydroxy Electron acceptor selected from cyano, nitro, trifluoroalkyl, or amide, alkylamino, benzoyloxy, nitrooxy, phenyl, or sulfo. 公开号:KR20030022371A 申请号:KR10-2003-7001846 申请日:2001-08-07 公开日:2003-03-15 发明作者:룬드스테트토르브죄른；스코트네르안나；세이페르트엘리사벳 申请人:멜라큐어 테라퓨틱스 에이비； IPC主号:
专利说明:
The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands} [2] It is known in the art that numerous large linear peptides and cyclic peptides bind specifically to the melanocortin (MC) receptor. Promoting and / or antagonistic properties of such peptides are also known (see “Melanocortin Recepter ligands and methods of using same”, Dooley, Girten and Houghten (WO99 / 21571)). However, there remains a need to provide low molecular weight compounds that exhibit facilitating or antagonistic properties for the melanocrotin receptor. [3] It is already known in the art that hydroxyguanidine has a proven inhibitory effect on xanthine oxidase / xanthine dehydrogenase enzymes (eg WO98 / 23267). Another compound known in the art is benzylideneamino guanidine, which exhibits antidepressant effects (US 4060640). Other examples of pharmacologically active guanidines known in the art have been reported in patents US 3982020 and GB 1223491. Other applications are also known in the art and are reported in patents US 3896332, DE 1165013, and US 3941825. Guanabenz is a compound well known in the art as an antihypertensive drug (US Pharmacopeia, 1999, The United States Pharmacopeial Convention, Inc, ISBN 1-889788-03-1). Guanabenz appears to be structurally similar to the compounds of the present invention but does not exhibit affinity for the melanocortin receptor. Therefore, it is very surprising that the benzylideneamino guanidine compounds of the present invention show affinity for melanocortin receptors as promoters and / or antagonists. [1] FIELD OF THE INVENTION The present invention relates to the use of benzylideneaminoguanidine and hydroxyguanidine for treating obesity, anorexia, inflammation, mental illness, and other diseases associated with melanocortin receptors or related systems such as melanocyte stimulating hormone. . [4] Therefore, in one aspect, the present invention provides a low molecular weight compound that exhibits activity against the melanocortin receptor. The low molecular weight compound may be orally administered, and may well penetrate through the brain blood gateway. [5] The present invention provides the use of a compound of formula 1 and a pharmacologically active salt thereof for the treatment of a ligand for a melanocortin receptor and / or a disease of the melanocortin system: [6] [7] In Chemical Formula 1, [8] X is H or OH; [9] R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different from one another and are an electron donating group such as hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms or hydroxy Electron acceptor selected from cyano, nitro, trifluoroalkyl, or amide, alkylamino, benzoyloxy, nitrooxy, phenyl, or sulfo. [10] In the above definition, the term "alkyl" refers to aliphatic cyclic groups as well as straight or branched chain hydrocarbon groups; The term "alkoxy" is a straight or branched chain alkoxy group or heterocyclic group; And the term "halogen" includes fluoro, chloro, bromo, and iodo. [11] Preferably, the "alkyl having 1 to 5 carbon atoms" is lower alkyl such as methyl, ethyl, propyl, or isopropyl. [12] Preferably, the "alkoxy having 1 to 5 carbon atoms" is lower alkoxy such as methoxy, ethoxy, propoxy, or isopropoxy. [13] Preferably, said halogen is fluoro or chloro. [14] Preferably, the trifluoroalkyl is trifluoromethyl, trifluoroethyl, trifluoropropyl, or trifluoroisopropyl. [15] The term "alkylamino" preferably refers to a group having 2-6 carbon atoms, preferably a dialkylamino group, most preferably dimethylamino or diethylamino. [16] Two or more of R 1 -R 5 may be connected by a linker group such as —O— (CH 2 ) n —O—, wherein n is preferably 1, 2, or 3. Most preferably the linker is a methylenedioxy group, particularly preferably a 1,2-, 3,4-, or 4,5-methylenedioxy group. [17] More preferred compounds are those wherein R 1 is nitrooxy or sulfo; R 3 is phenyl; And R 1 , R 2 , and R 3 are all benzoyloxy. [18] Particularly preferred compounds are those wherein one or two of R 1 , R 2 , R 3 , R 4 , and R 5 are H. [19] Since the compound of formula 1 is basic, inorganic acids such as hydrochloric acid, bromic acid, iodic acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, propanoic acid, glycolic acid, lactic acid, malonic acid are suitable because they are basic. Can be converted to therapeutically active acid addition salts by treatment with organic acids such as succinic acid, fumaric acid, tartaric acid, citric acid, pamo acid, or p-toluene-sulfonic acid. [20] Conversely, the salt form can be converted to the free base form by treating with alkali. [21] The present invention relates to the use of benzylideneaminoguanidine and hydroxyguanidine. Biological testing of some of the compounds of the present invention in the melanocortin system has surprisingly shown that it is able to bind to the melanocortin receptor as well as exhibiting activity in a functional assay. [22] Some of the compounds of the invention are either promoters or antagonists of specific MC-receptors or numerous MC-receptors, such as the MC1, MC3, MC4 or / and MC5 receptors. [23] MC-receptors belong to the group of G-protein binding receptors formed from a single polypeptide that forms seven transmembrane domains. Five such receptor types have been reported called MC1, MC2, MC3, MC4 and MC5. Signals of the MC receptor are primarily mediated through cAMP, but other signal transduction pathways are also known. They are clearly distributed in the body. [24] MC-receptors are associated with various physiological actions that are believed to be mediated by several subtypes of MC-receptors. In many cases, however, it is not entirely clear which subtype is associated with which effect. [25] Motivation, learning, memory, behavior (including emotional and sexual behavior), inflammation (as well as other events related to delivery and natriuresis, including MSH-peptides include natriuresis (Lin et al., Hypertension. 1987, 10, 619-627)) Immune stimulation and immunosuppression), body temperature, pain perception, blood pressure, heart rate, vascular tone, cerebral blood flow, stimulating effects on other organs, nutritional effects on other organs, nerve growth, placental development, endocrine and exocrine functions, aldosterone Synthesis and secretion, thyroxine secretion, spermatogenesis, ovarian weight, prolactin and FSH secretion, effects on other hormones, uterine bleeding in women, sebum and pheromone secretion, plasma levels, intrauterine fetal growth It was known long ago that Eberle, AN: The melanotropins: Chemistry, phisiology and mechani are of action.Basel: Karger, Switzerland. 1998, ISBN 3-8055-4678-5; Gruber, and Cal lahan, Am. J. Physiol. 1989, 257, R681-R694; De Wildt et al., J. Cardiovascular Pharmacology. 1995, 25, 898-905). [26] It is also well known that the immunomodulatory action of α-MSH includes both immunostimulating and immunosuppressive effects. Several studies have shown that α-MSH antagonizes the effects of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6 and TNFα and induces the production of anti-inflammatory cytokines, IL-10 ( Catania & Lipton, 1993). [27] Eating behaviour is regulated by a complex network of physiological regulatory pathways involving both the central and peripheral nervous systems. Factors such as leptin, insulin, NPY (neupeptide Y), orexin, CRF (corticotropin-secreting factor, secretory hormone), and melanocortic peptide (Schwartz; Nature Medicine 1998, 4, 385-386) may be weight, It is known to regulate food intake in both short and long term, which can affect body fat mass and growth rate. Recent studies have revealed a food intake-regulatory role of the MC-receptor, particularly the MC4 receptor, and there is evidence indicating that melanocortin and MC4 receptors are important factors for downregulation of leptin. Intraventricular injections of the melanocortic peptides α-MSH and ACTH (1-24) have been shown to significantly limit food intake (Poggioli et al., Peptides, 1986, 7, 843-848; Vergoni et al., Neuropeptides, 1986, 7, 153-158). [28] MC5-receptors have recently been shown to play a role in regulating exocrine gland function (van der Kraan et al., Endocrinol, 1998, 139, 2348-2355; Chen et al., Cell. 1997, 91, 789-798). [29] In addition, melanocortic peptides have a clear effect on sexual function in inducing male erection (Donovan, Psychol. Med. 1978, 8, 305-316), which is the backbone of peptides for MC-receptors. It is assumed that it is mediated by the promoting effect. MC-receptor blockers can inhibit the erectogenic effects of melanocortic peptides (Vergoni et al., Eur. J. Pharmacol, 1998, 362; 95-101). [30] Compounds of formula (1) and / or pharmaceutically acceptable salts thereof are valuable pharmacological properties useful for treating mental disorders such as psychosis, depression, anxiety, senile dementia, Alzheimer's disease, substance abuse disorders, and eating disorders such as anorexia and bulimia. Has [31] Compounds of formula (1) and / or pharmaceutically acceptable salts thereof may include excessive menstruation, endometriosis, labor related events, prolactin-related dysfunction, growth hormone-related dysfunction, testosterone-related dysfunction, estrogen-related dysfunction, glucocorticoid-related function Has valuable pharmacological properties useful for treating endocrine and other hormone dysfunctions such as luteinizing hormone and follicle stimulating hormone-related dysfunction for disorders, miscarriage induction, prevention of miscarriage, and / or treatment of labor related events . [32] Compounds of formula (1) and / or pharmaceutically acceptable salts thereof have valuable pharmacological properties useful for treating sexual dysfunction / dysfunction such as causing male erections, making it difficult to induce or mate the breeding of animals. Facilitates sexual intercourse of animals, especially rare or valuable breeds, pets, cats, dogs, and horses, refrains from sexual behavior of animals, such as pets, cats, or erectile dysfunction, both male and female Treatment of diseases related to sexual desire, including lack of desire or abnormal sexual desire. [33] Compounds of formula (1) and / or pharmaceutically acceptable salts thereof include inflammation associated with the production of nitric oxide, inflammation associated with increased (upregulated amounts) of inducible nitric oxide synthase, activation of transcriptional activators and Associated inflammation, inflammation associated with nuclear factor kappa beta, macrophages, neutrophils, monocytes, keratinocytes, fibroblasts, melanocytes, pigment cells, and inflammation associated with endothelial cells, for example interleukin, in particular interleukin 1 (IL-1), It has valuable pharmacological properties useful for treating inflammation, such as inflammation associated with increased production and / or secretion of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). [34] As used herein, "increase in production" refers to an increase in the amount, increased secretion, or increased formation of endogenous compounds in a patient locally, locally, or systemically compared to the amount of endogenous compounds in a healthy individual. As used herein, "upregulation" refers to an increase in the activity and amount of a compound compared to healthy individuals. [35] As used herein, "reduced production" refers to a decrease in formation, a decrease in secretion, or a decrease in the amount of an endogenous compound in a patient as compared to the amount of an endogenous compound in a healthy individual. As used herein, "downregulation" refers to a decrease in the activity and amount of a compound compared to healthy individuals. [36] In particular, certain therapeutic and prophylactic effects include inflammation or inflammation-like conditions of allergy, hypertension, bacterial infections, viral infections, inflammation caused by toxic substances, fever, autoimmune diseases, UV-irradiation, X-ray irradiation, γ It may be caused by or associated with one or more of -irradiation, radiation damage from any cause, including α- or β-particles, solar burns, temperature rise or mechanical injury. In addition, inflammation caused by hypoxia is sometimes accompanied by reoxidation in the hypoxic region, typically leading to severe inflammation, and such conditions can have a definite effect by treating with a compound of the present invention. [37] In a very specific embodiment of the present invention, the compounds of the present invention may also be administered to prevent or treat inflammatory diseases of the skin (including the dermis or epidermis) caused by any cause, including skin diseases with inflammatory components. Specific examples of this embodiment of the invention include contact dermatitis, solar burns, burns of any cause, and dermatitis caused by chemicals, psoriasis, vasculitis, necrosis, plaque erythema, eczema, palmar plantar pyelitis, And vulgaris. [38] The invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat an inflammatory disease of the abdomen, including an abdominal disease having an inflammatory component. Specific examples of such diseases treatable with the compounds of the present invention include gastritis, malignant gastritis (atrophic gastritis), ulcerative colitis, Crohn's disease, systemic sclerosis, duodenal ulcer, colon disease, esophagitis, and gastric ulcer caused by one of the unknown causes. have. [39] The invention also provides for the administration of a compound of formula (1) or a pharmacologically acceptable salt thereof for the treatment of systemic or general and / or local immunological diseases, including diseases with autoimmune properties and other inflammatory diseases with general properties. It includes. Specific examples include rheumatoid arthritis, psoriatic arthritis, systemic sclerosis, rheumatoid polymyopathy, Wegener's granulomatosis, sarcoidosis, eosinophilic fasciitis, reactive arteritis, Beckerreb disease, systemic lupus erythematosus, temporal arteritis, Behcet's disease, Burger's disease, Goodyear There are treatments for Pasture syndrome, eosinophilic granulomas, fibromyalgia, myositis, and mixed connective tissue disease. It also includes arteritis, including arteritis caused by unknown causes. [40] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat peripheral and / or central nervous system diseases associated with inflammation. In this aspect of the invention, treatment of cerebrovascular disease, multiple sclerosis, autoimmune ophthalmitis, and multiple neuropathy is included. The invention also includes administering a compound of the invention to prevent apoptosis by treating inflammation of the central nervous system. Moreover, since some of the compounds of the present invention exhibit a pronounced ability to induce nerve regeneration, there is often a definite therapeutic effect on central nervous system diseases associated with cell damage at these sites. In this aspect, the invention also includes treating traumatic injuries of the central nervous system, brain edema, multiple sclerosis, Alzheimer's disease, bacterial and viral infections in the central nervous system, stroke, and bleeding in the central nervous system. [41] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat diseases of the eye and tear glands associated with inflammation. Specific examples of such diseases are anterior and posterior ophthalmitis, retinitis vasculitis, optic neuritis, optic nephritis, Wegener's granulomatosis, Sjogren's syndrome, episcleitis, sarcoidosis affecting the eye, and multiple chondritis affecting the eye. [42] The invention also includes administering a compound of formula (1) or a pharmacologically acceptable salt thereof to treat an ear disease associated with inflammation, with specific examples of such diseases being polychondritis and otitis which affect the ear. [43] The invention also includes administering a compound of formula (1) or a pharmacologically acceptable salt thereof to treat a disease of the nose associated with inflammation, specific examples of which include sarcoidosis, multiple chondritis, and nasal centerline granulomas have. [44] The present invention also includes administering a compound of formula 1 or a pharmaceutically acceptable salt thereof to treat diseases associated with inflammation of the mouth, pharynx and salivary glands. Specific examples include Wegener's granulomatosis, centerline granulomas, Sjogren's syndrome, and multiple chondritis at these sites. [45] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation in the lung. Specific examples include the treatment of idiopathic alveolitis, primary pulmonary hypertension, bronchitis, chronic bronchitis, sarcoidosis, alveolitis in inflammatory systemic disease, pulmonary hypertension in inflammatory systemic disease, Wegener's granulomatosis, and Goodpasture syndrome. [46] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the heart. Specific examples include treatment of pericarditis, idiopathic pericarditis, myocarditis, Takayasu's arteritis, Kawasaki disease, coronary arteryitis, pericarditis in inflammatory systemic disease, myocarditis in inflammatory systemic disease, endocarditis, and endocarditis in inflammatory systemic disease. have. [47] The invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the liver. Specific examples include treatment of hepatitis, chronic reactive hepatitis, cholangiopathy, liver damage caused by toxic substances, interferon induced hepatitis, hepatitis caused by viral infections, liver damage induced by anoxia, and mechanical injury caused by mechanical trauma. have. [48] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the pancreas. Specific examples include the treatment (and prevention) of diabetes mellitus, acute pancreatitis, and chronic pancreatitis. [49] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the thyroid gland. Specific examples of this embodiment of the invention include the treatment of thyroiditis, autoimmune thyroiditis, Hashimoto thyroiditis. [50] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the kidney. Specific examples include glomerulonephritis, glomerulonephritis in systemic lupus erythematosus, nodular periarteritis, Wegener's granulomatosis, Goodpasture syndrome, HLAb27-related diseases, IgA nephritis (IgA = immunoglobulin A), pyelonephritis, chronic pyelonephritis, and There is a treatment for interstitial nephritis. [51] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the joint. Specific examples include Bechtereb disease, psoriatic arthritis, rheumatoid arthritis, arthritis in ulcerative colitis, arthritis in Crohn's disease, joint disease in systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, reactive arthritis, lighters There is a treatment of the syndrome. Moreover, this embodiment of the present invention includes the treatment of any joint arthrosis, especially arthrosis of the finger joints, knees, and hips. [52] The present invention also includes administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to treat a disease associated with inflammation of the blood vessels. Specific examples include the treatment of temporal arteritis, nodular periarteritis, atherosclerosis, Takayasu's arteritis, and Kawasaki disease. The efficacy of some of the compounds of the present invention that are able to protect against and prevent atherosclerosis is particularly beneficial. This is partly due to the ability of the compound of formula 1 or its pharmacologically acceptable salt to prevent induction of inducible nitric oxide synthesis (iNOS) induced by the action of oxidized low density lipoprotein (LDL) on endothelial cells and blood vessel walls. It is due. [53] The present invention also provides a compound of the present invention for the treatment of drug-induced diseases of the vascular and lymphatic systems, including drug-induced hypertension (including drug hypertension) that affects blood cells and blood cell producing organs (e.g., bone marrow and lymphoid tissue). It includes administering. Specific examples of this aspect of the invention include the treatment of anemia, granulocytopenia, thrombocytopenia, leukopenia, aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune granulocytopenia. [54] In addition, the compounds of the present invention can be administered for the treatment of rapid allergic diseases (type I allergy). Such embodiments of the present invention include the treatment of anaphylactic reactions, anaphylactic reactions, asthma, allergic asthma, unknown asthma, rhinitis, hay fever, and pollen allergy. [55] The present invention also includes administering a compound of Formula 1 or a pharmacologically acceptable salt thereof to treat inflammation associated with infection by any cause. Specific examples include the treatment of secondary inflammation against infection by viruses, bacteria, rotifers, and protozoa. [56] The invention also includes administering a compound of Formula 1 or a pharmacologically acceptable salt thereof to treat inflammation associated with trauma and / or tissue injury due to any cause. [57] Compounds of formula (1) or pharmaceutically acceptable salts thereof include blood pressure related diseases, heart rate, vascular tone, natriuresis, bleeding, shock, ischemia related diseases, infarction, repercussion injury, cardiac arrhythmias, especially cardiac arrhythmias in ischemia It has valuable pharmacological properties useful for the treatment of or for the treatment of arrhythmias associated with re-extinguishment of the previous ischemic period of the heart. [58] Compounds of formula (1) or pharmaceutically acceptable salts thereof include: pain caused by a central cause, pain following damage to the CNS, stroke, infarction, pain caused by peripheral causes, chronic pain, neuropathy, and the pericardium periventral site It has valuable pharmacological properties that are useful for treating diseases that can be treated by stimulation. [59] In addition, the compounds of the present invention can stimulate pigmentation in the envelope cells, leading to tanning of the skin for cosmetic purposes, for the treatment of vitiligo, or for any other condition in which the skin color is desired to darken. This can be useful. Moreover, the compounds of the present invention may also be useful for inducing brighter skin color for cosmetic use or for any condition in which a brighter skin color is desired because it can inhibit pigmentation in skin cells. [60] The compound of formula (1) or a pharmaceutically acceptable salt thereof can be used to induce skin tanning to darken the skin color, to induce melanin synthesis in the skin, to reduce skin soot and lighten the skin color Disorders related to acne, injectable acne, skin glands (eg, sebaceous glands), to induce anti-inflammatory action in the skin, to control skin growth, to promote wound healing, to prevent or reduce And valuable pharmacological properties useful for treating excessive or reduced production of sebum. [61] Compounds of the invention are useful for inhibiting or promoting in vivo formation of secondary messenger elements such as cAMP. Such inhibition / promoting may be used in cells, or in cell systems that have been ground in vitro, for example for analysis or diagnostic purposes. [62] For analytical or diagnostic purposes, the compounds of the present invention can be used for quantitation as well as tissue localization of MC-receptors, for analysis of dissociation / binding constants, and for scintography, positron emission tomography (PET), or monoquantum release. One or more radiolabels or gamma or positron emission for use in radioligand binding for in vivo binding images by the use of computed tomography or for the diagnosis and treatment of any malignant tumor containing malignant cells. It may be used in radioactive form including isotopes. [63] Alternatively, the compounds of the invention may be capable of detecting each of these compounds, for example gamma-irradiation, photons, or biochemical treatments, or light or UV-rays (the latter being used in photoaffinity techniques). To obtain a compound useful for covalent labeling of the MC receptor), and any type of label such as fluorescence, biotin, NMR, MRI. [64] Toxins (e.g., doxorubicin, lysine, diphtheria toxin or other toxins) can also be attached to a compound of Formula 1 or a pharmacologically acceptable salt thereof for use in targeted delivery to malignant cells having an MC receptor, Malignant by attaching compounds capable of activating the endogenous immune system (eg, compounds capable of binding T-cell antigens such as CD3 or other antigens, monoclonal antibodies, or other substances) to stimulate the system It can be used to treat tumors and other MC receptor expressing diseases. The hybrid compound thus formed will inhibit cytotoxic cells by transferring them to malignant melanoma cells or malignant cells with MC1-receptors. [65] The compound of formula 1 and pharmacologically acceptable salts thereof can be chemically attached to the antibody by covalent or non-covalent bonds. [66] The compounds of the present invention can be used for the treatment and diagnosis of diseases, disorders, and / or pathological conditions in animals, especially humans. [67] The invention also relates to prodrugs that are converted to the compounds of the invention upon administration to an animal or human. The prodrugs of the compounds of formula (1) and their pharmacologically acceptable salts can be used for the same purposes as described herein for the compounds of the invention as well as those listed in the Examples below. [68] Compounds of the invention may be covalently or non-covalently bonded to other molecule (s) having one or several desired structure (s): the modified compounds or complexes thus formed are described herein with reference to the compounds of the invention. It can be used for the same purpose as described in. In a particularly important embodiment of the present invention, a radiolabeled molecule is covalently attached to a compound of formula 1 or a pharmacologically acceptable salt thereof to attach the radiolabel to a compound of formula 1 or a pharmacologically acceptable salt thereof. You can. [69] The invention also relates to the use of the compounds of the invention for various medical and veterinary practices related to melanocyte stimulating hormone receptors. [70] The compounds of the present invention have an effect on xanthine oxidase in mammals, including humans. [71] Manufacturing method [72] The compound of formula 1 may be prepared by the following general method. [73] Method 1. [74] [75] [76] The compound of formula 2 is reacted with aminoguanidine (formula 3) and then deprotected to produce the compound of formula 1 if necessary or desired. In Formula 2, X, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above, and in Formula 3, X is as defined above. [77] The following examples are intended to illustrate but not limit the scope of the present invention, although the named compounds are of particular interest for the intended purpose. These compounds were designated by the numeric code, a: b, where a means the number of the example in which the method for preparing the compound was described, and b means the order of the compound prepared according to the above example. Thus, Example 1: 2 refers to the second compound prepared according to Method 1. [78] Example 1 [79] The structure of the compound was confirmed by IR, NMR, MS, and elemental analysis. Given the melting point (m.p.), these are not corrected. [80] Preparation of Compound 1: 1 [81] A solution of 2-chloro-3,4-dimethoxybenzaldehyde (1.0 g, 5 mmol), aminoguanidine bicarbonate (0.68 g, 5 mmol) and acetic acid (1 ml) in 15 ml of methanol was heated to reflux for 10 minutes. The reaction mixture was cooled to 0 ° C. and the residue was filtered off. The filtrate was evaporated in vacuo and the product crystallized in ethanol. Yield of the title compound 1: 1 was 1.1 g (79%) and M.p was 198-200 ° C. [82] Preparation of Compound 1: 2-1: 164 [83] Compound 1: 2-1: 164 was prepared essentially using the same method as 1: 1 prepared using Method 1. The prepared compound is shown below with its data. [84] 1 N- (2-chloro-3,4-dimethoxybenzylideneamino) guanidine acetate, m.p. 198-200 ℃ [85] 2 N- (3-bromobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 177-178.5 ℃ [86] 3 N- (3-bromo-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 209-210.5 ℃ [87] 4 N- (5-chloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 180-181 ℃ [88] 5 N- (2,4-dihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 194-195 ℃ [89] 6 N- (2,3-dihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 108-109 ℃ [90] 7 N- (2,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine, m.p. 98.5-99.5 ℃ [91] 8 N- (3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 204.5-206 ℃ [92] 9 N- (4,5-methylenedioxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 108-111 ℃ [93] 10 N- (3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 139-141 ℃ [94] 11 N- (4-chloro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 184-187 ℃ [95] 12 N- (4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 175-177 ℃ [96] 13 N- (2-bromobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 148.5-150 ℃ [97] 14 N- (2,3,4-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 179-181 ℃ [98] 15 N- (2-hydroxy-4,6-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 133-135 ℃ [99] 16 N- (2,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 137-139 ℃ [100] 17 N- (2,3-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 91-93 ℃ [101] 18 N- (2,5-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 186-187.5 ℃ [102] 19 N- (5-bromo-2-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 217-218 ℃ [103] 20 N- (4-dimethylaminobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 185.5-187 ℃ [104] 21 N- (4-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 191-193 ℃ [105] 22 N- (2-hydroxy-3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 173-175 ℃ [106] 23 N- (3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 184-186 ℃ [107] 24 N- (2-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 172-174 ℃ [108] 25 N- (2,3,4-tribenzyloxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 147-149 ℃ [109] 26 N- (benzylideneamino) guanidine acetate, m.p. 196-198 ℃ [110] 27 N- (3,4,5-trimethoxybenzylideneamino) guanidine acetate, m.p. 223-225 ℃ [111] 28 N- (4-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 192-194 ℃ [112] 29 N- (3,4-methylenedioxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 204-206 ℃ [113] 30 N- (3,4-methylenedioxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 199-200 ℃ [114] 31 N- (4-diethylaminobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 100-102 ℃ [115] 32 N- (2-hydroxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 217-219 ℃ [116] 33 N- (4-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 83-85 ℃ [117] 34 N- (2,4,6-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 80-82 ℃ [118] 35 N- (2,3,4-trihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 100-102 ℃ [119] 36 N- (3-hydroxy-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 88-89 ℃ [120] 37 N- (2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 204-206 ℃ [121] 38 N- (2-bromo-3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 172-175 ℃ [122] 39 N- (2,4-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 208-211 ℃ [123] 40 N- (2-chloro-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 92-94 ℃ [124] 41 N- (3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 92-95 ℃ [125] 42 N- (5-hydroxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 182-183 ℃ [126] 43 N- (3,6-dimethoxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 101-102 ℃ [127] 44 N- (3,4-dimethoxy-2-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 95-97 ℃ [128] 45 N- (3,4-dimethoxy-2-chlorobenzylideneamino) guanidine, m.p. 198-200 ℃ [129] 46 N- (benzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 169-171 ℃ [130] 47 N- (3,4-dimethoxy-2-chlorobenzylideneamino) -N'-hydroxyguanidine 1.5 hydrochloride, m.p. 214-216 ℃ [131] 48 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, m. 174-176 ℃ [132] 49 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, m. 174-176 ℃ [133] 50 N- (2,3-dimethoxy-5,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.15 hydrate, m.p. 178-179 ℃ [134] 51 N- (2,6-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 69-71 ℃ [135] 52 N- (2,3-dimethoxy-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 81-83 ℃ [136] 53 N- (5-bromo-2,4-dimethoxybenzylideneamino) -N'-hydroxyguanidine, m.p. 102-105 ° C [137] 54 N- (2-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.1, m. 169-171 ℃ [138] 55 N- (2-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 79-82 ℃ [139] 56 N- (2,4,6-trimethoxybenzylideneamino) guanidine acetate, m.p. 66-68 ℃ [140] 57 N- (2,3-methylenedioxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 163-164.5 ℃ [141] 58 N- (4-bromo-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 201-202.5 ℃ [142] 59 N- (5-bromo-2-hydroxy-3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 131.5-134 ℃ [143] 60 N- (3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 151-153.5 ℃ [144] 61 N- (2,3-dinitro-6-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 170-172.5 ℃ [145] 62 N- (3,6-dichloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 183-184.5 ℃ [146] 63 N- (2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 91-93 ℃ [147] 64 N- (2-chloro-3,4-dimethoxy-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 104-106.5 ℃ [148] 65 N- (2,4-dinitrobenzylideneamino) guanidine acetate, m.p. 224-226 ℃ [149] 66 N- (4-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 156-158 ℃ [150] 67 N- (4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.25 hydrate, m.p. 182-184 ℃ [151] 68 N- (3-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, m. 170-171.5 ℃ [152] 69 N- (4-cyanobenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, m.p. 203-204 ℃ [153] 70 N- (3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, m.p. 131-133 ℃ [154] 71 N- (4-fluoro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 190-192.5 ℃ [155] 72 N- (2-chloro-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 189-191 ℃ [156] 73 N- (4-chloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.25 hydrate, m.p. 179-181.5 ℃ [157] 74 N- (3,4-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 200-202.5 ° C. [158] 75 N- (2,4-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, m.p. 158-161 ℃ [159] 76 N- (4-methoxy-3-nitrobenzylideneamino) -N'-hydroxyguanidine, m.p. 219-221 ℃ [160] 77 N- (2,3-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 197-199.5 ℃ [161] 78 N- (2-fluoro-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.4 hydrate, m.p. 172-175 ℃ [162] 79 N- (2-methoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.7 hydrate, m.p. 115-117 ℃ [163] 80 N- (4-hydroxy-3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.4 hydrate, m. 114-115 ℃ [164] 81 N- (2-bromo-5-chloro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 195-196.5 ℃ [165] 82 N- (3-bromo-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate 1.8 propanol, m.p. 91-93 ℃ [166] 83 N- (3,5-dinitro-2-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, m. 185-187 ℃ [167] 84 N- (5-bromo-2-hydroxy-3-nitrobenzylideneamino) -N'-hydroxyguanidinetosylate 0.1 hydrate, m. 186-189 ℃ [168] 85 N- (3-nitrobenzylideneamino) guanidine acetate, m.p. 147-148.5 ℃ [169] 86 N- (2-hydroxy-4,6-dimethoxybenzylideneamino) guanidine acetate, m.p. 115-118 ℃ [170] 87 N- (4-nitrobenzylideneamino) guanidine acetate, m.p. 184-186 ℃ [171] 88 N- (3-methoxy-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 123.5-125 ℃ [172] 89 N- (3-bromo-4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 204.5-206.5 ℃ [173] 90 N- (2,3-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 186.5-187 ℃ [174] 91 N- (4-chloro-3-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, m.p. 166.5-167.5 ℃ [175] 92 N- (4-bromo-3-fluurobenzylideneamino) -N'-hydroxyguanidine tosylate 0.6 hydrate, m.p. 183-185.5 ℃ [176] 93 N- (3-bromo-4-fluorobenzylideneamino) guanidine acetate, m.p. 172-173.5 ℃ [177] 94 N- (2,3-difluorobenzylideneamino) guanidine acetate, m.p. 149-151.5 ℃ [178] 95 N- (4-chloro-3-fluorobenzylideneamino) guanidine acetate, m.p. 165-171 ℃ [179] 96 N- (3-methoxy-2,6-dinitrobenzylideneamino) guanidine hydrochloride, m.p. 217-218 ℃ [180] 97 N- (3-bromo-2,6-dinitrobenzylideneamino) guanidine hydrochloride, m.p. 166.5-168 ℃ [181] 98 N- (2-chloro-5-nitrobenzylideneamino) guanidine acetate, m.p. 165-171 ℃ [182] 99 N- (2-chloro-5-nitrobenzylideneamino) guanidine acetate 0.5 hydrate, m.p. 221-224 ℃ [183] 100 N- (2,3-dimethoxy-5-nitrobenzylideneamino) guanidine acetate, m.p. 191-194 ℃ [184] 101 N- (3,4-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 199-201 ℃ [185] 102 N- (4-phenylbenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 171-173 ℃ [186] 103 N- (3-chloro-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 85-88 ℃ [187] 104 N- (4-phenylbenzylideneamino) guanidine acetate, m.p. 191-194 ℃ [188] 105 N- (3,4-difluorobenzylideneamino) guanidine tosylate, m.p. 176-178 ℃ [189] 106 N- (4-bromo-2-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, m. 176-179 ℃ [190] 107 N- (2-fluoro-5-nitrobenzylideneamino) guanidine acetate, m.p. 192-195 ℃ [191] 108 N- (4-bromo-2-fluorobenzylideneamino) guanidine acetate, m.p. 187-188 ℃ [192] 109 N- (2-bromo-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 148-150 ℃ [193] 110 N- (2,4-dinitrobenzylideneamino) -N'-hydroxyguanidine hydrochloride, m.p. 191-193 ℃ [194] 111 N- (2,6-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 176-179 ℃ [195] 112 N- (3-chloro-4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 198.5-201 ℃ [196] 113 N- (3,5-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 208-210.5 ℃ [197] 114 N- (2-bromo-4-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 170-173 ℃ [198] 115 N- (3,5-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, m.p. 202-207 ℃ [199] 116 N- (2,3-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 214-216 ℃ [200] 117 N- (3,5-dichlorobenzylideneamino) guanidine acetate, m.p. 131-134 ℃ [201] 118 N- (3,5-dinitrobenzylideneamino) guanidine acetate dihydrate, m.p. 251-254 ° C (decomposition) [202] 119 N- (2,6-difluorobenzylideneamino) guanidine acetate, m.p. 138.5-141 ℃ [203] 120 N- (3-chloro-4-fluorobenzylideneamino) guanidine acetate, m.p. 141-144 ℃ [204] 121 N- (2-bromo-4-nitrobenzylideneamino) guanidine acetate, m.p. 145-147 ℃ [205] 122 N- (2-bromo-5-nitrobenzylideneamino) guanidine acetate, m.p. 205-208 ° C (decomposition) [206] 123 N- (2-iodobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 136-139 ℃ [207] 124 N- (2-iodobenzylideneamino) guanidine acetate, m.p. 171-173 ℃ [208] 125 N- (2,3-dimethoxy-5-nitrobenzylideneamino) guanidine hydrochloride, m.p. 237-238 ℃ [209] 126 N- (2-hydroxy-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 174-176 ℃ [210] 127 N- (2-hydroxy-4-methoxybenzylideneamino) guanidine acetate, m.p. 161-164 ℃ [211] 128 N- (4-bromo-3-nitrobenzylideneamino) guanidine acetate, m.p. 152-153 ℃ [212] 129 N- (6-chloro-2,3-dinitrobenzylideneamino) guanidine hydrochloride, m.p. 153-154.5 ℃ [213] 130 N- (3-bromo-4-methoxybenzylideneamino) guanidine hydrochloride, m.p. 261-262.5 ℃ [214] 131 N- (3-iodobenzylideneamino) guanidine hydrochloride, m.p. 203-204 ℃ [215] 132 N- (3-iodobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 193.5-195 ℃ [216] 133 N- (2-sulfobenzylideneamino) guanidine hydrochloride, m.p. > 260 ℃ [217] 134 N- (2-sulfobenzylideneamino) -N'-hydroxyguanidine, m.p. 243.5-244 ℃ [218] 135 N- (3,4-dichlorobenzylideneamino) guanidine acetate, m.p. 138-140 ℃ [219] 136 N- (2-chloro-5-nitrobenzylideneamino) guanidine acetate, m.p. 222-224 ° C (decomposition) [220] 137 N- (4-chloro-3-nitrobenzylideneamino) guanidine acetate, m.p. 136-139 ° C (decomposition) [221] 138 N- (4-fluoro-3-nitrobenzylideneamino) guanidine acetate, m.p. 222-224 ° C. (decomposition) [222] 139 N- (4-methoxy-3-nitrobenzylideneamino) guanidine acetate, m.p. 144-147 ° C (decomposition) [223] 140 N- (2-chloro-3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 176-178 ℃ [224] 141 N- (3,5-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 210.5-213 ℃ [225] 142 N- (5-bromo-2,3,4-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 195-197 ℃ [226] 143 N- (3-chloro-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 204-207 ℃ [227] 144 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine hydrochloride, m.p. 196-197.5 ℃ [228] 145 N- (3,5-difluoro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 176-178 ℃ [229] 146 N- (3,5-dichloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, m.p. 205-207 ℃ [230] 147 N- (3,5-difluoro2-nitrobenzylideneamino) guanidine acetate, m.p. 231-233 ℃ [231] 148 N- (3,5-dichloro-2-nitrobenzylideneamino) guanidine acetate, m.p.88-91 ° C [232] 149 N- (2-hydroxy-3-methoxy-5-nitrobenzylideneamino) guanidine hydrochloride, m.p. 243-246 ℃ [233] 150 N- (2-hydroxy-4-methoxy-5-nitrobenzylideneamino) guanidine hemiacetate, m.p. 227-230 ℃ [234] 151 N- (3-chloro-4-methoxy-5-nitrobenzylideneamino) guanidine, m.p. 255-258 ℃ (decomposition) [235] 152 N- (3,5-dichloro-4-methoxybenzylideneamino) guanidine acetate, m.p. 185-190 ℃ [236] 153 N- (3-bromo-4-methoxy-5-methylbenzylideneamino) guanidine acetate, m.p. 163-166 ℃ [237] 154 N- (2,3,4-trimethoxybenzylideneamino) guanidine hydrochloride, m.p. 181-183 ℃ [238] 155 N- (4-chloro-2-methoxy-5-nitrobenzylideneamino) guanidine acetate, m.p. 196-199 ℃ [239] 156 N- (3,6-dichloro-2-nitrobenzylideneamino) guanidine acetate, m.p. 219.5-221 ℃ [240] 157 N- (2-hydroxy-4-methyl-5-nitrobenzylideneamino) guanidine hydrochloride, m.p. 229-230 ℃ [241] 158 N- (2-bromo-5-chloro-3-nitrobenzylideneamino) guanidine acetate, m.p. 136.5-137 ℃ [242] 159 N- (3-hydroxy-4-methyl-2-nitrobenzylideneamino) guanidine acetate, m.p. 240-241 ℃ [243] 160 N- (5-bromo-4-methyl-2-nitrobenzylideneamino) guanidine hydrochloride, m.p. 246.5-248 ℃ [244] 161 N- (5-bromo-2-hydroxy-3-nitrobenzylideneamino) guanidine hydrochloride, m.p. > 250 ℃ [245] 162 N- (5-bromo-2-methoxy-3-nitrobenzylideneamino) guanidine hydrochloride, m.p. 258-259 ℃ [246] 163 N- (2,4-dimethoxy-5-nitrobenzylideneamino) guanidine acetate, m.p. 207-210 ℃ [247] 164 N- (4-bromo-2-fluoro-5-nitrobenzylideneamino) guanidine acetate, m.p. 175-198 ° C (decomposition) [248] Example 2 [249] This example shows the efficacy of treating a mental disorder of a compound of Formula 1 and its therapeutically active acid addition salt. [250] Test 1. Affinity for MC1-receptors [251] A binding assay was performed using I 125 -NDP-αMSH as ligand, essentially following the method reported in Lunec et al., Melanoma Res 1992; 2; 5-12. [252] Test 2. Affinity for MC3-receptors, MC4-receptors, and MC5-receptors [253] Binding assays are essential in Szardenings et al., J Biol Chem 1997; 272; 27943-27948 and Schioth et al., FEBS Lett 1997; 410; According to the method described in 223-228, I 125 -NDP-αMSH was performed as ligand. [254] Test 3. cAMP [255] Testing for stimulating cAMP is essential for Schioth et al., Br J Pharmacol 1998; 124; It was carried out according to the method described in 75-82. [256] TABLE 1 [257] Affinity for MC-receptors [258] compoundKi (μM) MC1MC3MC4MC5 1: 342916247 1: 442686133 [259] TABLE 1b [260] Impact on cAMP [261] MC1cMC3cMC4cMC5c 1: 38.41631.84.7 1: 46.4One17.18.7 [262] Example 3 [263] The following formulations are representative of all of the pharmacologically active compounds of the present invention. [264] Examples of Formulations Including Capsules [265] Per capsule [266] Active ingredient as salt 5 mg [267] Lactose 250mg [268] Starch 120mg [269] Magnesium Stearate 5mg [270] Up to 385 mg [271] When using a larger amount of active ingredient, the amount of lactose used can be reduced. [272] Examples of Proper Tablet Formulation [273] Refined sugar [274] Active ingredient as salt 5 mg [275] Potato Starch 90mg [276] Colloidal Silica 10mg [277] Talc 20mg [278] Magnesium Stearate 2mg [279] 5% gelatin aqueous solution 25mg [280] Up to 385 mg [281] A solution for parenteral administration by injection may be prepared in an aqueous solution of a pharmaceutically acceptable acid addition salt of the water-soluble active ingredient, preferably at a concentration of 0.1% by weight to 5% by weight. This solution may also contain stabilizers and / or buffers.
权利要求:
Claims (45) [1" claim-type="Currently amended] Use of a compound of Formula 1 or a pharmacologically active salt thereof as a melanocortin receptor ligand and / or for the treatment of diseases related to the melanocortin system: [Formula 1] In Chemical Formula 1, X is H or OH; R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different from one another and are an electron donating group such as hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1-5 carbon atoms or hydroxy Electron acceptor selected from cyano, nitro, trifluoroalkyl, or amide, alkylamino, benzoyloxy, nitrooxy, phenyl, or sulfo. [2" claim-type="Currently amended] 2. Use according to claim 1, wherein X is H. [3" claim-type="Currently amended] 2. Use according to claim 1, wherein X is OH. [4" claim-type="Currently amended] 4. Use according to any one of claims 1 to 3, wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is alkyl having 1 to 5 carbon atoms. [5" claim-type="Currently amended] 4. Use according to any one of the preceding claims, characterized in that at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is alkoxy. [6" claim-type="Currently amended] 6. Use according to claim 5, wherein the alkoxy is methoxy. [7" claim-type="Currently amended] 7. Use according to any one of claims 1 to 6, wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is a halogen atom. [8" claim-type="Currently amended] 8. Use according to claim 7, wherein the halogen is fluoro or chloro. [9" claim-type="Currently amended] 1 N- (2-chloro-3,4-dimethoxybenzylideneamino) guanidine acetate, 2 N- (3-bromobenzylideneamino) -N'-hydroxyguanidine tosylate, 3 N- (3-bromo-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 4 N- (5-chloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 5 N- (2,4-dihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 6 N- (2,3-dihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 7 N- (2,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine, 8 N- (3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 9 N- (4,5-methylenedioxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 10 N- (3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 11 N- (4-chloro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 12 N- (4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 13 N- (2-bromobenzylideneamino) -N'-hydroxyguanidine tosylate, 14 N- (2,3,4-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 15 N- (2-hydroxy-4,6-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 16 N- (2,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 17 N- (2,3-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 18 N- (2,5-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 19 N- (5-bromo-2-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 20 N- (4-dimethylaminobenzylideneamino) -N'-hydroxyguanidine tosylate, 21 N- (4-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 22 N- (2-hydroxy-3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 23 N- (3-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 24 N- (2-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 25 N- (2,3,4-tribenzyloxybenzylideneamino) -N'-hydroxyguanidine tosylate, 26 N- (benzylideneamino) guanidine acetate, 27 N- (3,4,5-trimethoxybenzylideneamino) guanidine acetate, 28 N- (4-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 29 N- (3,4-methylenedioxybenzylideneamino) -N'-hydroxyguanidine tosylate, 30 N- (4-bromobenzylideneamino) -N'-hydroxyguanidine tosylate, 31 N- (4-diethylaminobenzylideneamino) -N'-hydroxyguanidine tosylate, 32 N- (2-hydroxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 33 N- (4-hydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 34 N- (2,4,6-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 35 N- (2,3,4-trihydroxybenzylideneamino) -N'-hydroxyguanidine tosylate, 36 N- (3-hydroxy-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 37 N- (2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 38 N- (2-bromo-3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 39 N- (2,4-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 40 N- (2-chloro-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 41 N- (3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 42 N- (5-hydroxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 43 N- (3,6-dimethoxy-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 44 N- (3,4-dimethoxy-2-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 45 N- (3,4-dimethoxy-2-chlorobenzylideneamino) guanidine, 46 N- (benzylideneamino) -N'-hydroxyguanidine tosylate, 47 N- (3,4-dimethoxy-2-chlorobenzylideneamino) -N'-hydroxyguanidine 1.5 hydrochloride, 48 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, 49 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, 50 N- (2,3-dimethoxy-5,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.15 hydrate, 51 N- (2,6-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 52 N- (2,3-dimethoxy-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 53 N- (5-bromo-2,4-dimethoxybenzylideneamino) -N'-hydroxyguanidine, 54 N- (2-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.1, 55 N- (2-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 56 N- (2,4,6-trimethoxybenzylideneamino) guanidine acetate, 57 N- (2,3-methylenedioxybenzylideneamino) -N'-hydroxyguanidine tosylate, 58 N- (4-bromo-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 59 N- (5-bromo-2-hydroxy-3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 60 N- (3-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 61 N- (2,3-dinitro-6-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 62 N- (3,6-dichloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 63 N- (2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 64 N- (2-chloro-3,4-dimethoxy-6-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 65 N- (2,4-dinitrobenzylideneamino) guanidine acetate, 66 N- (2-chlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 67 N- (4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.25 hydrate, 68 N- (3-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, 69 N- (4-cyanobenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, 70 N- (3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, 71 N- (4-fluoro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 72 N- (2-chloro-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, 73 N- (4-chloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.25 hydrate, 74 N- (3,4-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 75 N- (2,4-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, 76 N- (4-methoxy-3-nitrobenzylideneamino) -N'-hydroxyguanidine, 77 N- (2,3-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 78 N- (2-fluoro-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.4 hydrate, 79 N- (2-methoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.7 hydrate, 80 N- (4-hydroxy-3,5-dimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.4 hydrate, 81 N- (2-bromo-5-chloro-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 82 N- (3-bromo-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate 1.8 propanol, 83 N- (3,5-dinitro-2-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate 0.2 hydrate, 84 N- (5-bromo-2-hydroxy-3-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.1 hydrate, 85 N- (3-nitrobenzylideneamino) guanidine acetate, 86 N- (2-hydroxy-4,6-dimethoxybenzylideneamino) guanidine acetate, 87 N- (4-nitrobenzylideneamino) guanidine acetate, 88 N- (3-methoxy-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 89 N- (3-bromo-4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 90 N- (2,3-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 91 N- (4-chloro-3-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, 92 N- (4-bromo-3-fluurobenzylideneamino) -N'-hydroxyguanidine tosylate 0.6 hydrate, 93 N- (3-bromo-4-fluorobenzylideneamino) guanidine acetate, 94 N- (2,3-difluorobenzylideneamino) guanidine acetate, 95 N- (4-chloro-3-fluorobenzylideneamino) guanidine acetate, 96 N- (3-methoxy-2,6-dinitrobenzylideneamino) guanidine hydrochloride, 97 N- (3-bromo-2,6-dinitrobenzylideneamino) guanidine hydrochloride, 98 N- (2,3-dimethoxy-5,6-dinitrobenzylideneamino) guanidine acetate, 99 N- (5-bromo-2,4-dimethoxybenzylideneamino) guanidine acetate 0.5 hydrate, 100 N- (2,3-dimethoxy-5-nitrobenzylideneamino) guanidine acetate, 101 N- (3,4-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 102 N- (4-phenylbenzylideneamino) -N'-hydroxyguanidine tosylate, 103 N- (3-chloro-2,6-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 104 N- (4-phenylbenzylideneamino) guanidine acetate, 105 N- (3,4-difluorobenzylideneamino) guanidine tosylate, 106 N- (4-bromo-2-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate 0.3 hydrate, 107 N- (2-fluoro-5-nitrobenzylideneamino) guanidine acetate, 108 N- (4-bromo-2-fluorobenzylideneamino) guanidine acetate, 109 N- (2-bromo-5-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 110 N- (2,4-dinitrobenzylideneamino) -N'-hydroxyguanidine hydrochloride, 111 N- (2,6-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 112 N- (3-chloro-4-fluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 113 N- (3,5-dichlorobenzylideneamino) -N'-hydroxyguanidine tosylate, 114 N- (2-bromo-4-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 115 N- (3,5-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate 0.5 hydrate, 116 N- (2,3-dinitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 117 N- (3,5-dichlorobenzylideneamino) guanidine acetate, 118 N- (3,5-dinitrobenzylideneamino) guanidine acetate dihydrate, 119 N- (2,6-difluorobenzylideneamino) guanidine acetate, 120 N- (3-chloro-4-fluorobenzylideneamino) guanidine acetate, 121 N- (2-bromo-4-nitrobenzylideneamino) guanidine acetate, 122 N- (2-bromo-5-nitrobenzylideneamino) guanidine acetate, 123 N- (2-iodobenzylideneamino) -N'-hydroxyguanidine tosylate, 124 N- (2-iodobenzylideneamino) guanidine acetate, 125 N- (2,3-dimethoxy-5-nitrobenzylideneamino) guanidine hydrochloride, 126 N- (2-hydroxy-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 127 N- (2-hydroxy-4-methoxybenzylideneamino) guanidine acetate, 128 N- (4-bromo-3-nitrobenzylideneamino) guanidine acetate, 129 N- (6-chloro-2,3-dinitrobenzylideneamino) guanidine hydrochloride, 130 N- (3-bromo-4-methoxybenzylideneamino) guanidine hydrochloride, 131 N- (3-iodobenzylideneamino) guanidine hydrochloride, 132 N- (3-iodobenzylideneamino) -N'-hydroxyguanidine tosylate, 133 N- (2-sulfobenzylideneamino) guanidine hydrochloride, 134 N- (2-sulfobenzylideneamino) -N'-hydroxyguanidine, 135 N- (3,4-dichlorobenzylideneamino) guanidine acetate, 136 N- (2-chloro-5-nitrobenzylideneamino) guanidine acetate, 137 N- (4-chloro-3-nitrobenzylideneamino) guanidine acetate, 138 N- (4-fluoro-3-nitrobenzylideneamino) guanidine acetate, 139 N- (4-methoxy-3-nitrobenzylideneamino) guanidine acetate, 140 N- (2-chloro-3,4,5-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 141 N- (3,5-difluorobenzylideneamino) -N'-hydroxyguanidine tosylate, 142 N- (5-bromo-2,3,4-trimethoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 143 N- (3-chloro-4-methoxybenzylideneamino) -N'-hydroxyguanidine tosylate, 144 N- (2,3-dimethoxy-5-nitrobenzylideneamino) -N'-hydroxyguanidine hydrochloride, 145 N- (3,5-difluoro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 146 N- (3,5-dichloro-2-nitrobenzylideneamino) -N'-hydroxyguanidine tosylate, 147 N- (3,5-difluoro2-nitrobenzylideneamino) guanidine acetate, 148 N- (3,5-dichloro-2-nitrobenzylideneamino) guanidine acetate, 149 N- (2-hydroxy-3-methoxy-5-nitrobenzylideneamino) guanidine hydrochloride, 150 N- (2-hydroxy-4-methoxy-5-nitrobenzylideneamino) guanidine hemiacetate, 151 N- (3-chloro-4-methoxy-5-nitrobenzylideneamino) guanidine, 152 N- (3,5-dichloro-4-methoxybenzylideneamino) guanidine acetate, 153 N- (3-bromo-4-methoxy-5-methylbenzylideneamino) guanidine acetate, 154 N- (2,3,4-trimethoxybenzylideneamino) guanidine hydrochloride, 155 N- (4-chloro-2-methoxy-5-nitrobenzylideneamino) guanidine acetate, 156 N- (3,6-dichloro-2-nitrobenzylideneamino) guanidine acetate, 157 N- (2-hydroxy-4-methyl-5-nitrobenzylideneamino) guanidine hydrochloride, 158 N- (2-bromo-5-chloro-3-nitrobenzylideneamino) guanidine acetate, 159 N- (3-hydroxy-4-methyl-2-nitrobenzylideneamino) guanidine acetate, 160 N- (5-bromo-4-methyl-2-nitrobenzylideneamino) guanidine hydrochloride, 161 N- (5-bromo-2-hydroxy-3-nitrobenzylideneamino) guanidine hydrochloride, 162 N- (5-bromo-2-methoxy-3-nitrobenzylideneamino) guanidine hydrochloride, 163 N- (2,4-dimethoxy-5-nitrobenzylideneamino) guanidine acetate, Of a compound selected from 164 N- (4-bromo-2-fluoro-5-nitrobenzylideneamino) guanidine acetate, or a pharmacologically acceptable salt thereof, as a melanocortin receptor ligand and / or associated with a melanocortin system Use for the treatment of a disease. [10" claim-type="Currently amended] Use according to one of the preceding claims, characterized in that there is additionally a label, preferably a radioactive label or a toxic substance. [11" claim-type="Currently amended] Use of a prodrug in which the compound according to any one of claims 1 to 9 is formed in vivo as a melanocortin receptor ligand and / or for the treatment of diseases related to the melanocortin system. [12" claim-type="Currently amended] Use of a compound of any one of claims 1 to 10 or a prodrug of claim 11 for inclusion in a pharmaceutical composition with one or more adjuvants, carriers or excipients. [13" claim-type="Currently amended] Use of a compound of any one of claims 1 to 10 or a prodrug of claim 11 for the manufacture of a medicament for the treatment of inflammation. [14" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of mental disorders. [15" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of endocrine or hormonal dysfunction. [16" claim-type="Currently amended] Use of a compound of any one of claims 1 to 10 or a prodrug of claim 11 for the manufacture of a medicament for the treatment of sexual function and / or sexual dysfunction. [17" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of drug-induced or other diseases of the vascular and / or lymphatic system. [18" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for allergic diseases. [19" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of cardiovascular diseases. [20" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of pain. [21" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for inducing skin burn or lighter skin color. [22" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of type II diabetes. [23" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of obesity. [24" claim-type="Currently amended] A compound of any one of claims 1 to 10 or a prodrug of claim 11 for the manufacture of a medicament for treating anorexia such as caused by cancer, cachexia, old age, HIV, trauma, and physiological conditions. Usage. [25" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for inducing peripheral nerve regeneration. [26" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for inducing central nervous regeneration. [27" claim-type="Currently amended] A method of treating inflammation comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [28" claim-type="Currently amended] A method of treating a mental disorder comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [29" claim-type="Currently amended] A method of treating endocrine or hormonal dysfunction comprising using or administering the compound of any one of claims 1 to 10 or the prodrug of claim 11. [30" claim-type="Currently amended] A method of treating sexual function and / or sexual dysfunction comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [31" claim-type="Currently amended] A method of treating a vascular and / or lymphatic drug-induced disease comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [32" claim-type="Currently amended] A method for treating a cardiovascular disease comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [33" claim-type="Currently amended] A method of treating pain comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [34" claim-type="Currently amended] A method of inducing skin burn or lighter skin color comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [35" claim-type="Currently amended] A method of treating type II diabetes comprising using or administering the compound of any one of claims 1 to 10 or the prodrug of claim 11. [36" claim-type="Currently amended] A method of treating obesity comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [37" claim-type="Currently amended] 11. Such as caused by cancer, cachexia, old age, HIV, trauma, and physiological conditions, comprising using or administering the compound of any one of claims 1 to 10 or the prodrug of claim 11. How to treat anorexia. [38" claim-type="Currently amended] A method of inducing peripheral nerve regeneration comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [39" claim-type="Currently amended] A method of inducing central nervous regeneration comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [40" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of skin diseases including melanoma. [41" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for treating and / or diagnosing cancer such as melanoma and metastasis. [42" claim-type="Currently amended] A method for the treatment of skin diseases, including melanoma, comprising using or administering the compound of any one of claims 1 to 10 or the prodrug of claim 11. [43" claim-type="Currently amended] A method of treating and / or diagnosing cancer, such as melanoma and metastasis, comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11. [44" claim-type="Currently amended] Use of the compound of any one of claims 1 to 10 or the prodrug of claim 11 for the manufacture of a medicament for the treatment of ischemia and / or ischemia / reperfusion. [45" claim-type="Currently amended] A method of treating ischemia and / or ischemia / reperfusion comprising using or administering a compound of any one of claims 1 to 10 or a prodrug of claim 11.
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同族专利:
公开号 | 公开日 CA2417098A1|2002-02-14| JP5654190B2|2015-01-14| AU7652201A|2002-02-18| US8309609B2|2012-11-13| JP2011246471A|2011-12-08| JP5683396B2|2015-03-11| US20120178820A1|2012-07-12| US9227927B2|2016-01-05| GB0019357D0|2000-09-27| BR0113053A|2003-07-08| EP1313461A2|2003-05-28| ZA200300829B|2004-02-25| US20040024060A1|2004-02-05| IL154272D0|2003-09-17| US20070231267A1|2007-10-04| US8148429B2|2012-04-03| US8410174B2|2013-04-02| US20070088085A1|2007-04-19| IL154272A|2010-12-30| WO2002011715A3|2003-01-16| MXPA03001072A|2004-03-10| US20110015437A1|2011-01-20| JP2004505912A|2004-02-26| WO2002011715A2|2002-02-14| KR100929363B1|2009-12-02| US20130295009A1|2013-11-07|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2000-08-07|Priority to GB0019357A 2000-08-07|Priority to GB0019357.3 2001-08-07|Application filed by 멜라큐어 테라퓨틱스 에이비 2001-08-07|Priority to PCT/GB2001/003534 2003-03-15|Publication of KR20030022371A 2009-12-02|Application granted 2009-12-02|Publication of KR100929363B1
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申请号 | 申请日 | 专利标题 GB0019357A|GB0019357D0|2000-08-07|2000-08-07|Novel phenyl guanidines| GB0019357.3|2000-08-07| PCT/GB2001/003534|WO2002011715A2|2000-08-07|2001-08-07|The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands| 相关专利
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