WO2009099171A1 - Produit pharmaceutique - Google Patents

Produit pharmaceutique Download PDF

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Publication number
WO2009099171A1
WO2009099171A1 PCT/JP2009/052029 JP2009052029W WO2009099171A1 WO 2009099171 A1 WO2009099171 A1 WO 2009099171A1 JP 2009052029 W JP2009052029 W JP 2009052029W WO 2009099171 A1 WO2009099171 A1 WO 2009099171A1
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Prior art keywords
methyl
acid
dpp
diabetes
compound
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PCT/JP2009/052029
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English (en)
Japanese (ja)
Inventor
Koji Takeuchi
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Takeda Pharmaceutical Company Limited
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Publication of WO2009099171A1 publication Critical patent/WO2009099171A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl]- Benzonitrile (referred to herein as “compound (A)”) or a salt thereof, and 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl -2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile (hereinafter referred to as “compound (B)”) or a salt thereof for the prevention or treatment of borderline diabetes, etc. About.
  • DPP-IV dipeptidyl peptidase-IV
  • DPP-IV specifically binds to a peptide containing proline (or alanine) second from the N-terminus. It is a serine protease that produces a dipeptide by cleaving the C-terminal side of proline (or alanine).
  • DPP-IV has also been shown to be the same molecule as CD26, and has been reported to be related to the immune system.
  • DPP-IV The role of DPP-IV in mammals has not been fully clarified, but it plays an important role in neuropeptide metabolism, T cell activation, cancer cell adhesion to endothelial cells, and HIV entry into cells. It is thought that he plays. Particularly in terms of sugar metabolism, DPP-IV is involved in inactivation of incretins GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-dependent insulinotropic peptide). GLP-1 has a short plasma half-life of 1-2 minutes, and GLP-1 (9-36) amide, a degradation product of DPP-IV, acts as an antagonist to the GLP-1 receptor.
  • GLP-1 glucagon-like peptide-1
  • GIP Gastric inhibitory peptide / Glucose-dependent insulinotropic peptide
  • the present inventor considers that the compounds (A) and (B) have an excellent DPP-IV inhibitory action, and thus can prevent or treat borderline diabetes. It came.
  • the present invention [1] 2-[[6-[(3R) -3-Amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -benzo
  • a preventive or therapeutic agent for borderline diabetes comprising nitrile or a salt thereof;
  • Nitrile or a salt thereof is 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl ]
  • the agent according to the above [1] which is a benzoate of benzonit
  • the compound of the present invention has an excellent DPP-IV inhibitory action and is useful as a preventive or therapeutic agent for borderline diabetes.
  • Examples of the salts of the compounds (A) and (B) include pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include benzoic acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid. And salts with p-toluenesulfonic acid and the like.
  • salt with basic amino acid include salts with arginine, lysine, ornithine and the like
  • preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • the salt of compound (A) include salts with benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and among them, the salt with benzoic acid is preferable.
  • the salt of compound (B) include salts with trifluoroacetic acid, succinic acid, hydrochloric acid and the like, and among them, the salt with succinic acid is preferable.
  • the compounds (A) and (B) or salts thereof may be “prodrugs” that are converted into an active form by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
  • Compounds (A) and (B) or salts thereof may be solvated (for example, hydrate) or non-solvated.
  • Compounds (A) and (B) or salts thereof may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I).
  • the compounds (A) and (B) or salts thereof also include a deuterium converter in which 1 H is converted to 2 H (D).
  • Compounds (A) and (B) can be produced according to the method described in US Patent Application Publication No. 2005/0261271, or a method analogous thereto.
  • Compounds (A) and (B) or a salt thereof, or a prodrug thereof are toxic (eg, acute toxicity, chronic toxicity, genetic Toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity) is low or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition, so that a mammal (eg, human, Mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys) can be used as preventive or therapeutic agents for various diseases described later, or insulin resistance improvers.
  • a mammal eg, human, Mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
  • the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethyl
  • the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
  • buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Benzyl alcohol etc. are mentioned as a suitable example of a soothing agent.
  • preservative examples include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • the antioxidant include sulfite and ascorbate.
  • Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, ⁇ -carotene, chlorophyll, bengara) and the like.
  • the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges.
  • Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.
  • Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration). These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.
  • controlled-release preparations eg, sustained-release microcapsules
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • DPP-IV can be involved in various pathological conditions or diseases.
  • enhancement of the physiological activity of GLP-1 may be useful for the treatment of various pathological conditions or diseases.
  • GLP-1 (7-36) is effectively decomposed into GLP-1 (9-36) by DPP-IV.
  • GLP-1 (9-36) is believed to act as a physiological antagonist to GLP-1 (7-36).
  • DPP-IV in vivo inhibition of DPP-IV is useful for increasing endogenous concentrations of GLP-1 (7-36) and reducing the production of its antagonist GLP-1 (9-36) It can be.
  • DPP-IV expression increases in T-cells when stimulated with mitogen or antigen (Scand. J. Immunol., 1991, 33: 737).
  • DPP-IV inhibitors and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated or antigen-stimulated T-cells in a dose-dependent manner (Biol. Chem., 1991, 372: 305).
  • T-lymphocytes eg, cytokine production, IL-2-mediated cell proliferation and B-cell helper activity
  • DPP-IV inhibitor based on boroproline (Proc. Natl. Acad. Sci.
  • DPP-IV has been reported to be essential for the invasion and infectivity of HIV-1 and HIV-2 viruses in CD4 + T-cells (24.sup.th European Peptide Symposium, 1996, Abstract P.44). . Furthermore, DPP-IV binds to the enzyme adenosine deaminase (ADA) on the surface of T-cells (Science, 193, 26) 466). ADA deficiency results in severe combined immunodeficiency (SCID) in humans.
  • ADA adenosine deaminase
  • DPP-IV Lung endothelial cells
  • DPP-IV have been reported to be adhesion molecules to lung-translocated rat breast and prostate cancer cells (J. Cell Biol., 1993, 121: 1423).
  • DPP-IV is known to bind to fibronectin and several metastatic tumor cells are known to have large amounts of fibronectin on their surface.
  • DPP-IV inhibitors may be useful, for example, as agents that prevent translocation of breast and prostate tumors to the lung.
  • High levels of DPP-IV expression have also been found in human skin fibroblasts from patients with psoriasis, rheumatoid arthritis (RA) and lichen planus (J. Cell Physiol., 1992). , 151: 378).
  • DPP-IV inhibitors can also act as male contraceptives because they can have the effect of suppressing sperm movement.
  • DPP-IV inhibitors may be useful in the treatment of infertility, particularly human female infertility due to polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome).
  • Polycystic ovary syndrome is a condition characterized by an increase in ovarian sac thickness and the formation of numerous follicular cysts, resulting in infertility and amenorrhea.
  • DPP-IV is thought to play a specific role in the cleavage of various cytokines (hematopoietic cell stimuli), growth factors and neuropeptides.
  • Stimulated hematopoietic cells are useful for the treatment of diseases characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions can occur in immunosuppressed patients, for example, as a result of cancer chemotherapy and / or radiation therapy.
  • DPP-IV inhibitors may be useful for stimulating hematopoietic cell growth (proliferation) and differentiation in the absence of exogenously added cytokines or other growth factors or substrate cells.
  • DPP-IV in human plasma cleaves N-terminal Tyr-Ala from growth hormone-releasing factor and also causes inactivation of this hormone.
  • DPP-IV inhibitors may be useful in the treatment of undergrowth (dwarfism) due to growth hormone deficiency and for promoting GH-dependent tissue growth or regrowth.
  • DPP-IV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptide substance P, neuropeptide Y and CLIP (Regul. Pept., 49, 133, 1993). Neuropeptides, 1997, 31: 41).
  • DPP-IV inhibitors may also be useful agents for ameliorating and / or treating neurological diseases.
  • GLP-1 receptors are widely expressed in the central nervous system, and GLP-1 may be useful for the treatment of Alzheimer's disease and other neurodegenerative diseases (Endcrinology, 2004, 145 (6 ): 2653-2659).
  • the compound of the present invention is useful for prevention or treatment of a disease state or disease involving DPP-IV, or a disease state or disease considered to be treatable by enhancing the physiological activity of GLP-1.
  • the compound of the present invention is, for example, diabetic [eg, type 1 diabetes, type 2 diabetes, type 1.5 diabetes (LADA (Latent Autoimmune Diabetes in Adults)), gestational diabetes, insulin secretion deficiency type diabetes, obesity.
  • Type diabetes childhood diabetes, secondary diabetes, diabetes due to genetic abnormalities], diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, arteriosclerosis, osteopenia, diabetic Hyperosmotic coma, infection (eg, respiratory infection, urinary tract infection, digestive tract infection, skin soft tissue infection, leg infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular Disorders, peripheral blood flow disorders, diabetic myopathy], obesity, hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia), arteriosclerosis (eg, atherosclerosis) Atherosclerosis), hypertension, myocardial infarction, narrow Disease, cerebrovascular disorders (e.g., cerebral infarction, stroke), insulin resistance syndrome, syndrome X, metabolic syndrome (Dysmetabolic syndrome) are useful for the prevention or treatment of such.
  • diabetic complications eg, neuropathy, nephropathy, retinopathy
  • the compound of the present invention also provides secondary prevention of the above-mentioned various diseases (eg, secondary prevention of cardiovascular events such as myocardial infarction) or progression inhibition [eg, diabetes to diabetic complications (preferably diabetic neuropathy, Inhibition of progression to diabetic nephropathy, diabetic retinopathy, arteriosclerosis).
  • various diseases eg, secondary prevention of cardiovascular events such as myocardial infarction
  • progression inhibition eg, diabetes to diabetic complications (preferably diabetic neuropathy, Inhibition of progression to diabetic nephropathy, diabetic retinopathy, arteriosclerosis).
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • glucose level in venous plasma is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
  • glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (ImpairedpairFasting Glucose).
  • the IFG is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia) Call.
  • the compound of the present invention is also used as a preventive or therapeutic agent for diabetes, borderline diabetes, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline diabetes, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
  • the compound of the present invention can also suppress pancreatic exhaustion caused by glucotoxicity, lipotoxicity, oxidative stress or endoplasmic reticulum stress due to diabetes, and retain the sugar-dependent insulin secretory ability, which is an important function of pancreatic ⁇ cells. Furthermore, the compound of the present invention can suppress pancreatic ⁇ cell death due to diabetes, and can promote the formation or replication of pancreatic ⁇ cells.
  • the compound of the present invention further induces sugar-dependent promotion of insulin secretion, but has side effects (eg, vascular complications, hypoglycemia) possessed by insulin preparations, side effects possessed by insulin secretory hypoglycemic agents that act on sulfonylurea receptors (
  • side effects eg, vascular complications, hypoglycemia
  • insulin secretory hypoglycemic agents that act on sulfonylurea receptors
  • the pancreatic protective agent of the present invention can be safely administered over a long period of time to a patient suffering from diabetes or the like.
  • the compounds of the present invention are also used in metabolic acidosis, ketosis, appetite regulation, organ transplant rejection, autoimmune diseases (eg, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, HIV infection), cancer (eg, colorectal) Cancer, prostate cancer, breast cancer, thyroid cancer, skin cancer, lung cancer, head and neck cancer), skin disease (eg, psoriasis, rheumatoid arthritis, lichen planus), infertility, amenorrhea, dwarfism, lymphocytes or A condition characterized by insufficient activation or concentration of hematopoietic cells (conditions resulting from chemotherapy, radiation therapy, renal failure, or bone marrow disease), Crohn's disease, intestinal disease induced by chemotherapy, oral cavity It is useful for the prevention or treatment of mucositis, short bowel syndrome, diabetic dyslipidemia.
  • autoimmune diseases eg, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, HIV infection
  • the compounds of the present invention may also be used in mental and neurodegenerative diseases [eg, dementia, Huntington's chorea, delayed dyskinesia, hyperactivity, gonorrhea, Parkinson's disease, Steel-Richard's syndrome, Down's syndrome, myasthenia gravis, nerves and Brain trauma, vascular amyloidosis, brain inflammation, Friedreich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis, glaucoma, Alzheimer's disease, anxiety, depression, insomnia, schizophrenia] Useful for prevention or treatment.
  • mental and neurodegenerative diseases eg, dementia, Huntington's chorea, delayed dyskinesia, hyperactivity, gonorrhea, Parkinson's disease, Steel-Richard's syndrome, Down's syndrome, myasthenia gravis, nerves and Brain trauma, vascular amyloidosis, brain inflammation, Friedreich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis, glaucoma, Alzheimer
  • the dose of the compound of the present invention varies depending on the nature of the compound, administration subject, administration route, target disease, symptom, etc.
  • the compound (A) or (B) (both free forms) is 0.01 to 1000 mg / day, preferably 1 to 50 mg / day, more preferably 3 to 25 mg / day.
  • the frequency of administration of the tablet containing the compound (A) or (B) as the pharmaceutically active ingredient to the mammal is preferably 1 to 3 times per day, more preferably once a day.
  • Compound (B) it may be administered at intervals exceeding 1 day (for example, once every 3 days to 1 week).
  • the dose in this case is 1 to 500 mg, preferably 1 to 400 mg, more preferably 1 to 250 mg, and still more preferably 25 to 200 mg as compound (B) (free form) per administration. .
  • the compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis, It can be used in combination with drugs (hereinafter abbreviated as concomitant drugs) such as dementia drugs, erectile dysfunction-improving drugs, urinary incontinence / frequent urination drugs, and dysuria drugs.
  • concomitant drugs may be low molecular weight compounds, and may be macromolecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), vaccines, and the like.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • Examples of the dosage form include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) 2 obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation
  • insulin resistance improving agent eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, ⁇ -glucosidase inhibitor, ⁇ -glucosidase inhibitor Acarbose, migli , Emiglitate), biguanides (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogues
  • biguanides eg
  • Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112, ranirestat (AS-3201)), neurotrophic factor and its Increase drug (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolepropanol, 4 -(4-Chlorophenyl) -2- (2-methyl-1-imidazolyl) -5-oxazolebutanol, 4- (4-chlorophenyl) -5- [3- (1-imidazolyl) propyl] -2- (2- Methyl-1-imidazolyl) oxazole, 4- (4-chlorophenyl) -2- ( -Methyl-1-imi
  • an HMG-CoA reductase inhibitor eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or a salt thereof (eg, sodium salt, calcium salt)
  • Squalene synthase inhibitors eg, lapaquistat acetate
  • fibrate compounds eg, bezafibrate, clofibrate, simfibrate, clinofibrate
  • ACAT inhibitors eg, Avasimibe), Eflucimibe
  • anion exchange resin eg, cholestyramine
  • nicotinic acid drugs eg, nicomol, niceritrol
  • ethyl icosapentate eg Soysterol (soysterol),
  • Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan, 1- [ 2 ′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7- Carboxylic acid), calcium channel blockers (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine), potassium channel openers (eg, levcromakalim, L-27152, AL0671, NIP-121),
  • Anti-obesity agents include, for example, central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist Drugs (eg, SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonists (eg, CP-422935); cannabinoid receptor antagonists (eg, SR-141716, SR-147778); ghrelin antagonists; 11 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498)), pancreatic lipase inhibitors (eg, orlistat, cetilistat (ATL-962)), ⁇ 3 agonists ( Examples, AJ-9777), peptidic appetite suppressants (eg,
  • diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • Methiclotiazide e.g., Methiclotiazide
  • anti-aldosterone preparations eg, spironolactone, triamterene
  • carbonic anhydrase inhibitors e.g, acetazolamide
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide
  • azosemide isosorbide
  • ethacrynic acid Piretanide
  • bumetanide ethacrynic acid
  • furosemide furosemide and the like
  • chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin) Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as flurtulon or neofluturon are preferred.
  • alkylating agents eg, cyclophosphamide, ifosfamide
  • antimetabolites eg, methotrexate, 5-fluorouracil and derivatives thereof
  • anticancer antibiotics eg, mitomycin, adriamycin
  • Plant-derived anticancer agents eg, vincristine, vindesine, taxol
  • cisplatin
  • immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like. Of these, interleukins such as IL-1, IL-2 and IL-12 are preferred.
  • IL-1, IL-2 and IL-12 are preferred.
  • antithrombotic agent examples include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban), thrombolytic agent (Eg, urokinase, tisokinase,reteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol) cilostazol), ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, Clopidogrel, and the like.
  • heparin eg, heparin sodium, heparin calcium, dalteparin sodium
  • warfarin eg, warfarin potassium
  • antithrombin drug eg, argatroban
  • thrombolytic agent Eg,
  • osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin (calcitonin salmon), estriol, ipriflavone, risedronate disodium (risedronate) disodium), disodium pamidronate disodium, alendronate sodium hydrate, minderonate disodium and the like.
  • Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
  • Examples of the erectile dysfunction ameliorating agent include apomorphine, sildenafil citrate, and the like.
  • Examples of the urinary incontinence / frequent urination therapeutic agent include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
  • Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).
  • Concomitant drugs include drugs that have been shown to improve cachexia in animal models and clinically, ie cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, Dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF- ⁇ , LIF, IL -6, an antibody against Oncostatin M, and the like.
  • cyclooxygenase inhibitors eg, indomethacin
  • progesterone derivatives eg, megesterol acetate
  • carbohydrate steroids eg, Dexamethasone
  • metoclopramide drugs etrahydrocannabinol drugs
  • fat metabolism improvers eg, eico
  • the concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), ⁇ 2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.
  • nerve regeneration promoters eg, Y-128,
  • the combination drug is preferably an insulin preparation, an insulin resistance improving agent, an ⁇ -glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
  • the insulin resistance improving agent, insulin secretagogue and biguanide can be reduced from the usual dose.
  • the adverse effects that would be caused by these agents can be safely prevented.
  • the dosage of diabetic complication therapeutics, hyperlipidemia therapeutics, antihypertensives can be reduced, and the adverse effects that would be caused by these agents can be effectively prevented.
  • the compound of the present invention has an excellent peptidase inhibitory action and is useful as a preventive or therapeutic agent for borderline diabetes.

Abstract

La présente invention concerne un agent destiné à prévenir et à traiter les diabètes limites. L'agent selon l'invention contient un 2-[[6-[(3R)-3-amino- 1-pipéridinyl]-3,4-dihydro-3-méthyl-2,4-dioxo-1(2H)-pyrimidinyl]méthyl]-benzonitrile, un 2-[[6-[(3R)-3-amino-1-pipéridinyl]-3,4- dihydro-3-méthyl- 2,4-dioxo-1(2H)-pyrimidinyl]méthyl]-4-fluorobenzonitrile, ou un sel d'un des composés.
PCT/JP2009/052029 2008-02-07 2009-02-06 Produit pharmaceutique WO2009099171A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005263780A (ja) * 2004-03-15 2005-09-29 Syrrx Inc ジペプチジルペプチダーゼ阻害剤
WO2007033350A1 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
WO2007035629A2 (fr) * 2005-09-16 2007-03-29 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidylpeptidase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005263780A (ja) * 2004-03-15 2005-09-29 Syrrx Inc ジペプチジルペプチダーゼ阻害剤
WO2007033350A1 (fr) * 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
WO2007035629A2 (fr) * 2005-09-16 2007-03-29 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidylpeptidase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

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