US20040024060A1 - Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands - Google Patents

Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands Download PDF

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Publication number
US20040024060A1
US20040024060A1 US10/343,325 US34332503A US2004024060A1 US 20040024060 A1 US20040024060 A1 US 20040024060A1 US 34332503 A US34332503 A US 34332503A US 2004024060 A1 US2004024060 A1 US 2004024060A1
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Prior art keywords
compound
guanidine
nitrobenzylideneamino
prodrug
treatment
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US10/343,325
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Inventor
Torbjorn Lundstedt
Anna Skottner
Elisabeth Seifert
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AcurePharma AB
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Melacure Therapeutics AB
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Assigned to MELACURE THERAPEUTICS AB reassignment MELACURE THERAPEUTICS AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SEIFERT, ELISABETH, SKOTTNER, ANNA, LUNDSTEDT, TORBJORN
Publication of US20040024060A1 publication Critical patent/US20040024060A1/en
Assigned to STARTA EGET BOXEN 4637 AB/ACURE PHARMA CONSULTING AB reassignment STARTA EGET BOXEN 4637 AB/ACURE PHARMA CONSULTING AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MELACURE THERAPEUTICS AB
Assigned to ACURE PHARMA AB reassignment ACURE PHARMA AB CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: STARTA EGET BOXEN 4637 AB/ ACURE PHARMA CONSULTING AB
Priority to US11/639,190 priority Critical patent/US8148429B2/en
Priority to US11/798,669 priority patent/US20070231267A1/en
Priority to US12/892,402 priority patent/US8309609B2/en
Priority to US13/426,096 priority patent/US8410174B2/en
Priority to US13/803,555 priority patent/US9227927B2/en
Abandoned legal-status Critical Current

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    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
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    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to the use of benzylideneaminoguanidines and hydroxyguanidines for the treatment of obesity, anorexia, inflammation, mental disorders and other diseases associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
  • a number of large linear and cyclic peptides are known in the art which show high specific binding to melanocortin (MC) receptors.
  • the agonistic and/or antagonistic properties of these peptides are also known. See for example “Melanocortin Receptor ligands and methods of using same” by Dooley, Girten and Houghten (WO99/21571). There remains, however, a need to provide low molecular weight compounds showing agonistic or antagonistic properties to the melanocortin receptors.
  • hydroxyguanidines e.g. WO98/23267
  • Other compounds known in the art are benzylideneamino guanidines which have shown anti-depressive effects (U.S. Pat. No. 4,060,640).
  • Other examples of pharmacologically active guanidines known in the art are described in patent U.S. Pat. No. 3,982,020 and GB 1223491.
  • Other application areas are also known in the art and are described in patents U.S. Pat. No. 3,896,332, DE 1165013, and U.S. Pat. No. 3,941,825.
  • Guanabenz is compound which is well known in the art as an antihypertensive drug (US Pharmacopeia, 1999, The United States Pharmacopeial Convention, Inc, ISBN 1-889788-03-1). Whilst Guanabenz might appear to be structurally similar to the compounds in the present invention, it shows no affinity to the melanocortin receptors. Therefore it is very surprising that the benzylideneamino guanidine compounds in the present invention show affinity to the melanocortin receptors as agonist and/or antagonists.
  • One aspect of the present invention is therefore to provide low molecular weight compounds showing activity on melanocortin receptors and which may be taken up after per oral administration and which may penetrate well through the blood brain barrier.
  • the present invention provides the use of compounds of the general formula (1) as ligands to the melanocortin receptors and/or for treatment of disorders in the melanocortin system:
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, electron donor groups such as alkoxy having 1-5 carbon atoms or hydroxy, electron acceptor groups selected from cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl or sulpho; and the pharmacologically active salts thereof.
  • alkyl is meant to include straight or branched chain hydrocarbon groups as well as alicyclic groups
  • alkoxy is meant to include straight or branched chain alkoxy groups or heterocyclic groups
  • halogen includes fluoro, chloro, bromo and iodo.
  • the “alkyl having 1 to 5 carbon atoms” is a lower alkyl such as methyl, ethyl, propyl or isopropyl.
  • the “alkoxy having 1 to 5 carbon atoms” is a lower alkoxy such as methoxy, ethoxy, propoxy or iso-propoxy.
  • the halogen is fluoro or chloro.
  • the trifluoroalkyl is trifluoromethyl, trifluoroethyl, trifluoropropyl or trifluoroiso-propyl.
  • alkylamino refers preferably to groups having 2-6 carbon atoms, particularly dialkylamino groups, and most preferably dimethylamino or diethylamino.
  • R 1 -R 5 may be linked by a linker group such as —O—(CH 2 ) n —O—, where n is preferably 1, 2 or 3. Most preferably the linker is a methylenedioxy group, particularly preferably a 2,3- 3,4- or 4,5-methylenedioxy group.
  • a linker group such as —O—(CH 2 ) n —O—, where n is preferably 1, 2 or 3.
  • the linker is a methylenedioxy group, particularly preferably a 2,3- 3,4- or 4,5-methylenedioxy group.
  • R 1 is nitroxy or sulpho
  • R 3 is phenyl
  • R 1 , R 2 and R 3 are all benzoyloxy.
  • Particularly preferred compounds are those wherein 1 or 2 of R 1 , R 2 , R 3 , R 4 and R 5 are H.
  • the compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active acid addition salts by treatment with appropriate physiologically acceptable acids, e.g. inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, succinic, fumaric, tartaric, citric, pamoic or para-toluene-sulphonic acid.
  • physiologically acceptable acids e.g. inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, succinic, fumaric, tartaric, citric, pamoic or para-toluene-sulphonic acid.
  • the salt form may be converted into the free base form by treatment with alkali.
  • the present invention relates the use of benzylideneaminoguanidines and hydroxyguanidines.
  • Some of the compounds of the present invention have been biologically tested in the melanocortin system and have surprisingly been shown to be capable of binding to melanocortin receptors as well as showing activity in functional assays.
  • Some of the compounds of the present invention are either agonists or antagonists of a specific MC-receptor or of a number of MC-receptors, e.g. MC1, MC3, MC4 or/and MC5 receptors.
  • the MC-receptors belong to the class of G-protein coupled receptors which are all built from a single polypeptide forming 7 transmembrane domains. Five such receptors type, termed MC1, MC2, MC3, MC4 and MC5, have been described.
  • the MC receptor's signaling is mainly mediated via cAMP but also other signal transduction pathways are known. They are distinctly distributed in the body.
  • MC-receptors are linked to a variety of physiological actions that are thought to be mediated by distinct subtype of the MC-receptors. In many cases, however, it is not entirely clear which of the subtypes is responsible for the effect
  • MSH-peptides may affect many different processes such as motivation, learning, memory, behaviour (including feeding and sexual), inflammation (including immunostimulatory and immunosuppressive), body temperature, pain perception, blood pressure, heart rate, vascular tone, brain blood flow, trophic effects in different organs, nerve growth, placental development, endocrine and exocrine functions, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, effects on other hormones, uterine bleeding in women, sebum and pheromone secretion, blood glucose levels, intrauterine foetal growth, as well as other events surrounding parturition and natriuresis (Eberle, AN: The melanotropins: Chemistry, physiology and mechanisms of action.
  • ⁇ -MSH immunomodulatory action of ⁇ -MSH includes both immuno-stimulatory and immunosuppressive effects.
  • cytokines such as IL-1 ⁇ , IL-1 ⁇ , IL-6 and TNF ⁇
  • IL-10 pro-inflammatory cytokine
  • Eating behaviour is regulated by a complex network of physiological regulatory pathways that involve both the central nervous system and peripheral sites.
  • Factors such as leptin, insulin, NPY (neuropeptide Y), orexins, CRF (Corticotropin-Releasing Factor, release hormone) and melanocortic peptides (Schwartz; Nature Medicine 1998, 4, 385-386) are known to control the amount of food intake both during short and long term, which may affect body weight, body fat mass and growth rate.
  • MC-receptors especially the MC4 receptor, for control of food intake, and there is evidence indicating that the melanocortins and the MC4 receptor are important factors downstream of leptin.
  • Intracerebroventricular injections of the melanocortic peptides ⁇ -MSH and ACTH(1-24) have been shown to markedly inhibit feeding (Poggioli et al., Peptides, 1986, 7, 843-848; Vergoni et al., Neuropeptides, 1986, 7, 153-158).
  • the MC5-receptor has recently been attributed a role in control of exocrine gland function (van der Kraan, et al., Endocrinol. 1998, 139, 2348-2355; Chen et al., Cell. 1997, 91,789-798).
  • melanocortic peptides have distinct effects on sexual functions in that they cause erection in males (Donovan, Psychol. Med 1978, 8, 305-316), presumably mediated by a central agonistic effect of the peptide on MC-receptors. It has also been shown that a MC-receptor blocker could inhibit the erectogenic effect of melanocortic peptides (Vergoni et al., Bur. J. Pharmacol, 1998, 362; 95-101).
  • Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of mental disorders such as psychoses, depression, anxiety, senile dementia, Alzheimer's disease, drug abuse disorders and eating disorders such as anorexia and bulimia.
  • Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of dysfunctions of the endocrine system and other hormonal systems such as excessive menstruations, endometriosis, events related to parturition, dysfunctions related to prolactin, dysfunctions related to growth hormone, dysfunctions related to testosterone, dysfunctions related to estrogen, dysfunctions related to glucocorticoids, dysfunctions related to luteinizing hormone and follicle stimulating hormone, inducing abortion, for prevention of abortion and/or for treatment of events related to parturition.
  • dysfunctions of the endocrine system and other hormonal systems such as excessive menstruations, endometriosis, events related to parturition, dysfunctions related to prolactin, dysfunctions related to growth hormone, dysfunctions related to testosterone, dysfunctions related to estrogen, dysfunctions related to glucocorticoids, dysfunctions related to luteinizing hormone and follicle stimulating hormone, inducing abortion, for prevention of abortion and/or for treatment of events related to
  • Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of sexual functions/dysfunctions such as inducing erection in man, to induce erection in animal breeding, to stimulate intercourse in animals which are difficult to mate, in particular rare species or valuable strains, pets, cats, dogs, horses or to reduce sexual behaviour in animals, e.g. for pets, cats etc., to treat impotence and disorders related to sexual drive, including lack of sexual drive or abnormal sexual drive in both men and women.
  • Compounds of formula (I) and/or their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of inflammation such as inflammations related to the production of nitric oxide, inflammation related to increased amounts (upregulated amounts) of inducible nitric oxide synthase, inflammation related to activation of transcriptional activators, inflammation related to nuclear factor kappa beta, inflammation related to macrophages, neutrophils, monocytes, keratinocytes, fibroblasts, melanocytes, pigment cells and endothelial cells, inflammation related to increased production and/or release of inflammatory cytokines, such as e.g. interleukins, in particular interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor ⁇ (TNF- ⁇ ).
  • IL-1 interleukin 1
  • IL-6 interleukin 6
  • TNF- ⁇ tumor necrosis factor ⁇
  • “increased production” refers to increased formation, increased release, or increased amount of an endogenous compound locally, regionally or systemically in a patient compared to the amount of said endogenous compound in a healthy individual.
  • “upregulated” refers to an increased activity or amount of the compound compared with that in a healthy individual.
  • “decreased production” refers to decreased formation, decreased release, or decreased amount of an endogenous compound in a patient compared to the amount of said endogenous compound in a healthy individual.
  • “downregulated” refers to a decreased activity or amount of the compound compared with that in a healthy individual.
  • inflammation or an inflammatory-like condition is caused by or being associated with one or more of the following: allergy, hypersensitivity, bacterial infection, viral infection, inflammation caused by toxic agent, fever, autoimmune disease, radiation damage by any source including UV-radiation, X-ray radiation, ⁇ -radiation, ⁇ - or ⁇ -particles, sun burns, elevated temperature or mechanical injury.
  • inflammation due to hypoxia which is optionally followed by reoxygenation of the hypoxic area, is typically followed by severe inflammation, which condition may be positively affected by treatment with a compound of the invention.
  • a compound of the invention may be administered for the prevention or therapeutic treatment of inflammatory diseases of the skin (including the dermis and epidermis) of any origin, including skin diseases having an inflammatory component.
  • inflammatory diseases of the skin including the dermis and epidermis
  • this embodiment of the invention include treatment of contact dermatitis of the skin, sunburns of the skin, burns of any cause, and inflammation of the skin caused by chemical agents, psoriasis, vasculitis, pyoderma gangrenosum, discoid lupus erythematosus, eczema, pustulosis palmo-plantaris, and phemphigus vulgaris.
  • Also comprised by the invention is the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of an inflammatory disease in the abdomen, including an abdominal disease having an inflammatory component.
  • a compound of the invention include gastritis, including one of unknown origin, gastritis perniciosa (atrophic gastritis), ulcerous colitis (colitis ulcerosa), morbus Crohn, systemic sclerosis, ulcus duodeni, coeliac disease, oesophagitis and ulcus ventriculi.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of systemic or general and/or local immunological diseases, including those of an autoimmune nature, and other inflammatory diseases of a general nature.
  • Specific examples include treatment of rheumatoid arthritis, psoriatic arthritis, systemic sclerosis, polymyalgia rheumatica, Wegener's granulomatosis, sarcoidosis, eosinophilic fasceitis, reactive arthritis, Bechterew's disease, systemic lupus erythematosus, arteritis temporalis, Behcet's disease, morbus Burger, Good Pastures' syndrome, eosinophilic granuloma, fibromyalgia, myositis, and mixed connective tissue disease. Included therein is also arthritis, including arthritis of unknown origin.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of a disease of the peripheral and/or central nervous system related to inflammation.
  • a disease of the peripheral and/or central nervous system related to inflammation includes the treatment of cerebral vasculitis, multiple sclerosis, autoimmune ophthalmitis and polyneuropathia.
  • Comprised by the invention is also the administration of a compound of the invention for the treatment of an inflammation of the central nervous system to prevent apoptotic cell death.
  • positive treatment effects are often seen in central nervous system diseases involving damage of cells in this region.
  • This aspect of the invention also includes treatment of traumatic injuries to the central nervous system, brain edema, multiple sclerosis, Alzheimer's disease, bacterial and viral infections in the central nervous system, stroke, and haemorrhagia in the central nervous system.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases of the eye and tear glands related to inflammation.
  • diseases of the eye and tear glands related to inflammation comprise anterior and posterior uveitis, retinal vasculitis, optic neuritis, optic neuromyelitis, Wegener's granulomatosis, Sjögren's syndrome, episcleritis, scleritis, sarcoidosis affecting the eye and polychondritis affecting the eye.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases of the ear related to inflammation, specific examples of which include polychondritis affecting the ear and external otitis.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases of the nose related to inflammation, specific examples of which are sarcoidosis, polychondritis and mid-line granuloma of the nose.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation of the mouth, pharynx and salivary glands.
  • diseases related to inflammation of the mouth, pharynx and salivary glands include Wegener's granulomatosis, mid-line granuloma, Sjögren's syndrome and polychondritis in these areas.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation in the lung.
  • diseases related to inflammation in the lung include 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 Good Pastures' syndrome.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to the inflammation of the heart.
  • diseases related to the inflammation of the heart include treatment of pericarditis, idiopathic pericarditis, myocarditis, Takayasus' arteritis, Kawasaki's disease, coronary artery vasculitis, pericarditis in inflammatory systemic disease, myocarditis in inflammatory systemic disease, endocarditis and endocarditis in inflammatory systemic disease.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation of the liver.
  • diseases related to inflammation of the liver include treatment of hepatitis, chronic active hepatitis, biliary cirrhosis, hepatic damage by toxic agents, interferon induced hepatitis, hepatitis induced by viral infection, liver damage induced by anoxia and liver damage caused by mechanical trauma.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation of the pancreas.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation of the pancreas.
  • Specific examples include treatment (and prevention) of diabetes mellitus, acute pancreatitis and chronic pancreatitis.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to the inflammation of the thyroidea.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to the inflammation of the thyroidea.
  • Specific examples of these embodiments of the invention include treatment of thyreoiditis, autoimmune thyreoiditis and Hashimoto's thyreoiditis.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to inflammation of the kidney.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to the inflammation of the joints.
  • diseases related to the inflammation of the joints include treatment of Bechterew's disease, psoriatic arthritis, rheumatoid arthritis, arthritis in colitis ulcerosa, arthritis in morbus Crohn, affection of joints in systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, reactive arthritis, Reiter's syndrome.
  • included in this embodiment of the invention is treatment of arthrosis of any joint, in particular arthrosis of finger joints, the knee and the hip.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of diseases related to the inflammation of blood vessels.
  • diseases related to the inflammation of blood vessels include treatment of arteritis temporalis, periarteritis nodosa, arteriosclerosis, Takayasus' arteritis and Kawasaki's disease.
  • Particularly advantageous is the capacity of some compounds of the invention to afford protection against and prevention of arteriosclerosis.
  • Comprised by the invention is also the administration of a compound of the invention for the treatment of drug-induced disorders of the blood and lymphoid system, including the treatment of drug-induced hypersensitivity (including drug hypersensitivity) affecting blood cells and blood cell forming organs (e.g. bone marrow and lymphoid tissue).
  • drug-induced hypersensitivity including drug hypersensitivity
  • blood cells and blood cell forming organs e.g. bone marrow and lymphoid tissue.
  • Specific embodiments of this aspect of the invention include the treatment of anemia, granulocytopenia, thrombocytopenia, leukopenia, aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia and autoimmune granulocytopenia.
  • the compounds of the invention may also be administered for the treatment of fast allergic disorders (Type I allergy). Included in this embodiment of the invention is the treatment of anaphylactic reactions, anaphylactoid reactions, asthma, asthma of allergic type, asthma of unknown origin, rhinitis, hay fever and pollen allergy.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of inflammation related to infections of any origin.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of inflammation related to infections of any origin.
  • Specific examples include treatment of inflammation secondary to infection caused by virus, bacteria, helminths and protozoae.
  • Comprised by the invention is also the administration of a compound of formula (I) or a pharmacologically acceptable salt thereof for the treatment of inflammations related to trauma and/or tissue injury of any origin.
  • Compounds of formula (I) or pharmaceutically acceptable salts thereof have valuable pharmacological properties, making them useful for the treatment of disorders of the cardiovascular system such as disorders related to blood pressure, heart rate, vascular tone, natriuresis, bleeding, shock, disorders related to ischemia, infarction, repercussion injuries, arrhythmias of the heart, in particular during ischemia, or for the treatment of arrhythmias associated with reoxygenation of a previously ischemic period of the heart.
  • Compounds of formula (I) or the pharmaceutically acceptable salts thereof have valuable pharmacological properties, making them useful for the treatment of pain such as pain of central origin, pain seen after damage to the CNS, stroke, infarction, pain of peripheral origin, chronic pain, neuropathies and disorders where a treatment effect is achieved by stimulation of receptors in the periaqueductal grey area.
  • compounds of the invention may be also useful for inducing skin tanning for cosmetic reasons, for treatment of vitiligo, or any other condition where darkening of skin color is desired.
  • compounds of the invention to inhibit pigment formation in cells of the skin they may also be useful for inducing lighter skin color for cosmetic reasons, or during any condition where a lighter color of skin is desired.
  • Compounds of formula (I) or the pharmaceutically acceptable salts thereof have valuable pharmacological properties, making them useful to cause skin tanning, darkening the colour of the skin, to induce melanin synthesis in the skin, to reduce skin tanning, lightening the colour of the skin, to reduce or block melanin synthesis in the skin, to cause anti-inflammatory actions in the skin, to modulate epidermal growth, to improve wound healing, to treat acne, seborrhoea, acne roseacea, conditions related to malfunctions of the glands of the skin, e.g. sebacous glands and over or underproduction of sebum.
  • Compounds of the invention are useful for inhibiting or stimulating the in vivo formation of second messenger elements such as cAMP. Such inhibition/stimulation may be used in cells or crushed cell systems in vitro, e.g. for analytical or diagnostic purposes.
  • the compounds of the invention may be used in radioactive form where they comprise one or more radioactive labels or gamma or positron emitting isotopes, to be used in radioligand binding for the quantification as well as tissue localisation of MC-receptors, for analysis of dissociation/association constants, and for imaging of in vivo binding by the use of scintigraphy, positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for the diagnosis of disease and treatment of any malignancy where the malignant cells contain MC receptors.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the compounds of the invention can be labelled with any other type of label that allows detection of the respective compound, e.g. fluorescence, biotin, NMR, MRI, or labels activated by gamma-irradiation, light photons or biochemical processes, or by light or UV-light (the latter in order to obtain a compound useful for covalent labelling of MC receptors by a photoaffinity technique).
  • any other type of label that allows detection of the respective compound, e.g. fluorescence, biotin, NMR, MRI, or labels activated by gamma-irradiation, light photons or biochemical processes, or by light or UV-light (the latter in order to obtain a compound useful for covalent labelling of MC receptors by a photoaffinity technique).
  • Compounds of formula (I) or the pharmacologically acceptable salts thereof may also be tagged with a toxic agent (i.e. doxorubicin, ricin, diphtheria toxin or other) and used for targeted delivery to malignant cells bearing MC receptors, or tagged with a compound capable of activating the endogenous immune system for triggering the immune system (for example a compound, monoclonal antibody or other, capable of binding to a T-cell antigen, e.g. CD3 or other) for treatment of malignancies and other MC receptor expressing diseases.
  • a toxic agent i.e. doxorubicin, ricin, diphtheria toxin or other
  • a compound capable of activating the endogenous immune system for triggering the immune system for example a compound, monoclonal antibody or other, capable of binding to a T-cell antigen, e.g. CD3 or other
  • the thus formed hybrid compound will direct cytotoxic cells to the malignant melanoma
  • Compounds of the invention may be used for the treatment and diagnosis of diseases, disorders and/or pathological conditions in an animal, in particular in man.
  • the present invention also relates to a pro-drug which, upon administration to an animal or a human, is converted to a compound of the invention.
  • Pro-drugs of the compounds of formula (I) and their pharmacologically acceptable salts may be used for the same purposes as described in this specification for the compounds of the invention, as well as is disclosed in the Examples given below.
  • the compounds of the present invention may be bound covalently or non-covalently to one or several of other molecule(s) of any desired structure(s); the thus formed modified compound or complex may be used for the same purposes as described in this specification for the compounds of the invention, as well as is disclosed in the Examples given below.
  • a radioactively-labeled molecule is covalently bound to a compound of formula (I) or a pharmacologically acceptable salt thereof so as to make a compound of formula (I) or a pharmacologically acceptable salt thereof radioactively labeled.
  • the invention also relates to uses of compounds of the invention for various medical and veterinary practices related to melanocyte stimulating hormone receptors.
  • Compounds of the invention have an effect on xanthine oxidase in mammals, including humans.
  • the compounds having the general formula (I) may be prepared by the following general method.
  • Test 1 Affinity for the MC1-Receptor
  • the binding assay was carried out essentially as described by Lunec et al, Melanoma Res 1992; 2; 5-12, using I 125 -NDP- ⁇ MSH as ligand.
  • Test 2 Affinity for the MC3-Receptors, the MC4-Receptors and the MC5-Receptors
  • Example of a Suitable Tablet Formulation Per tablet Active ingredient, as salt 5 mg Potato starch 90 mg Colloidal Silica 10 mg Talc 20 mg Magnesium stearate 2 mg 5% aqueous solution of gelatine 25 mg Total up to 385 mg
  • a solution for parenteral administration by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt of the active substance preferably in a concentration of 0.1% to about 5% by weight.
  • These solutions may also contain stabilising agents and/or buffering agents.

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US11/639,190 US8148429B2 (en) 2000-08-07 2006-12-15 Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US11/798,669 US20070231267A1 (en) 2000-07-08 2007-05-16 Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US12/892,402 US8309609B2 (en) 2000-08-07 2010-09-28 Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US13/426,096 US8410174B2 (en) 2000-08-07 2012-03-21 Method for treating arthritis
US13/803,555 US9227927B2 (en) 2000-08-07 2013-03-14 Method of treating inflammation

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