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WO2007009389A2 - Derives de propanamide substitues, preparation et utilisation de ces derives - Google Patents

Derives de propanamide substitues, preparation et utilisation de ces derives Download PDF

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Publication number
WO2007009389A2
WO2007009389A2 PCT/CN2006/001784 CN2006001784W WO2007009389A2 WO 2007009389 A2 WO2007009389 A2 WO 2007009389A2 CN 2006001784 W CN2006001784 W CN 2006001784W WO 2007009389 A2 WO2007009389 A2 WO 2007009389A2
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Prior art keywords
group
carboxamide
aldehyde
amide
ethylthio
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Chinese (zh)
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WO2007009389A3 (fr
Inventor
Mingwei Wang
Qing Liu
Caihong Zhou
Bin Wu
Xin Hui
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid

Definitions

  • the present invention relates to a class of peroxisome proliferator-activated Receptor- ⁇ (PPAR- ⁇ ) agonists, specifically A small molecule organic compound that is substituted with a propylene (olefin) amide derivative, which serves as a PPAR-gamma agonist for medical use in the treatment and prevention of diabetes and its complications.
  • PPAR- ⁇ peroxisome proliferator-activated Receptor- ⁇
  • Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2.
  • the basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin.
  • Type 2 diabetes accounts for more than 95% of the diseased population.
  • Clinical studies have found that most patients with type 2 diabetes can synthesize normal or excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"). , leading to relatively insufficient insulin. Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • Diabetes can cause a variety of fatal complications, including stroke, blindness, diabetic nephropathy, hypertension, and coronary heart disease. In diabetic patients, about 60 to 70% of people have a certain degree of neurological damage, and severe shellfish (J causes gangrene in the extremities. Statistics show that diabetes has become the third largest human after cancer and cardiovascular disease Killer. Based on the study of insulin signal transduction pathway, designing and developing insulin sensitizer to improve insulin resistance is the focus of new drugs for the treatment of type 2 diabetes, and it is also one of its main directions [Saltiel AR New perspectives into the Molecular pathogenesis and treatment of type 2 diabetes. Cell, 2001, 104(4): 517-29].
  • the research on insulin sensitizers mainly focuses on the following aspects: 1) Thiazolidinediones (TZD), such as Troglitazone, Rosiglitazone and pioglitazone ( PiogHtazone); 2) biguanides, such as metformin, phenformin and buformin; 3) ⁇ 3-adrenoreceptor agonists and glucagon receptor antagonists; 4) fatty acid metabolism interfering agents, such as relying on Etomoxir and so on.
  • ZD Thiazolidinediones
  • biguanides such as metformin, phenformin and buformin
  • ⁇ 3-adrenoreceptor agonists and glucagon receptor antagonists such as relying on Etomoxir and so on.
  • TZD drugs can significantly improve insulin resistance and correct abnormalities in sugar and lipid metabolism during clinical application, thus showing great market value.
  • TZD was originally discovered as an analog of Clofibmte (hypolipidemic), and subsequent studies have shown that TZD significantly enhances insulin-targeted tissue reactivity to insulin, whereas in the absence of insulin, TZD does not lower blood glucose. .
  • Lehmann et al. found that the molecular target of TZD drugs in vivo is peroxisome proliferator activation.
  • ⁇ Peroxisome Proliferator Activated Receptor- ⁇ , PPAR- ⁇
  • An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 1995, J. Biol. Chem., Vol. (270): 12953-12956].
  • the PPAR- ⁇ single copy gene is encoded on human chromosome 3 and has 468, 441 and 479 amino acids, respectively, consisting of six domains from A to F (Fig. 1).
  • the A/B domain at the amino terminus is the activated transcribed region
  • the C domain is the DNA binding region (DBD)
  • the E/F domain at the carboxy terminus is the ligand binding region (LBD) [Desvergne B., Wahli W. Peroxisome proliferator-activated Receptors: nuclear control of metabolism. Endocr Rev. 1999, 20(5): 649-88].
  • PPAR- ⁇ Upon activation of small molecule ligands, PPAR- ⁇ forms a heterodimer with retinoic acid receptor X (RXR) and then binds to a specific DNA sequence called PPAR Response Element (PPRE). Transcriptional factors regulate the transcription of target genes [Blanquart C., Barbier O., Frachart JC, et al. Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation. J Steroid Biochem Mol Biol. 2003, 85 ( 2-5): 267-73].
  • PPRE is present upstream of multiple genes involved in regulation of lipid metabolism and glucose metabolism [Juge-Aubry C, Pernin A., Favez T” et al. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance Of the 5'-flanking region. J Biol Chem. 1997, 272(40): 25252-9].
  • PPAR- ⁇ is mainly distributed in tissues such as fat, immune system, large intestine and retina.
  • PPAR- ⁇ is a key regulator of adipocyte differentiation, which positively regulates the differentiation of adipocytes, induces the formation of adipocytes, inhibits the expression of leptin, and promotes the end of 3T3-L1 preadipocytes.
  • End stage fat cell transformation [Chawla A., Schwarz EJ., Dimaculangan DD, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology.
  • PPAR- ⁇ knockout mice die early in embryonic development. In vitro experiments confirmed that PPAR- ⁇ is essential for the differentiation of embryonic stem cells into adipocytes. In terms of insulin resistance and glucose metabolism, activation of PPAR- ⁇ promotes glucose uptake and transport by adipocytes and skeletal muscle cells, regulates adipocyte signal transduction, induces differentiation of brown adipose tissue, and increases uncoupling protein UCP1 and Expression of UCP2, which in turn increases energy expenditure, lowers blood sugar and blood lipids, and improves insulin resistance in people with type 2 diabetes [Motojima K., Passilly P., Peters JM, et al.
  • PPAR-gamma agonists currently used in the treatment of type 2 diabetes have multiple drug JHs in preclinical or clinical research, including Darglitazone of TZD and Farglitazar of non-TZD. They all showed good hypoglycemic effects without obvious side effects.
  • these drugs are ubiquitous, including side effects leading to obesity and edema [Lebovitz HE Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev. 2002 , 18 (Suppl 2): S23-9] limits their widespread use [Gershell L. Type 2 diabetes market. Nature Reviews Drug Discovery 2005, 4(5): 367-368]. Therefore, the use of PPAR- ⁇ as a target to find insulin sensitizers with less toxic side effects has become a hot spot for major multinational pharmaceutical companies.
  • the present invention discovers and synthesizes a series of small molecule compounds substituted with propylene (acrylamide) derivatives by applying various PPAR- ⁇ -based high-throughput drug screening models and structure-activity relationship studies of active samples. Both the receptor binding activity assay and the reporter gene activation assay demonstrated that these compounds specifically bind to PPAR- ⁇ and are agonists of PPAR- ⁇ , suggesting their potential to be further developed into novel insulin sensitizers. Summary of the invention
  • Another object of the present invention is to provide a process for the preparation of a derivative of formula I;
  • Another object of the present invention is to provide a pharmaceutical composition comprising a derivative of formula I;
  • a further object of the present invention is to provide the use of a derivative of the formula I for the treatment or prevention of a peroxisome proliferator-activated receptor gamma agonist for diabetes and its complications.
  • the present invention provides a peroxisome proliferator-activated receptor gamma agonist that increases the membership of an insulin sensitizer.
  • the present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:
  • substituents including d-(alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, d-Cd decyloxy, amine, amide, carboxamide, Sulfhydryl, methylthio, ethylthio and any one, two or three substituents including: '
  • Ar is: aryl; 2-, 3-, or 4-position of the pyridine group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; ⁇ contains include - (4 alkyl group, a nitro group, a carboxyl group, an ester group Any one, two or three substituted aryl groups, an aldehyde group, a halogen, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; (: 4 thiol, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, etc.
  • C 2 -C 3 is a saturated or unsaturated double bond.
  • such a compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a kit comprising the above compounds for use in the treatment or prevention of diabetes and its complications.
  • the present invention relates to a combination preparation comprising a selective agonistic peroxisome proliferator gamma activating receptor, in particular a compound which activates the function of the receptor, or a pharmaceutically acceptable compound thereof
  • the salt either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • This compound has the following formula I:
  • R is any one of the following substituents: including a fluorenyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group of dC 4 , an amine group, an amide group, a carboxamide group, a fluorenyl group , methylthio, ethylthio and any, two or three substituents including:
  • Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxyl, ester, aldehyde including C 4 Any one, two or three substituted aryl groups including a halogen, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; any alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including a 4, two Or three substituted 2-, 3-, or 4-position pyridyl groups;
  • ⁇ contains include - C 4 alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, hydroxy, alkoxy, amine, amide, carboxamide, mercapto, a Any one, two or three substituted pyranyl groups including a thio group or an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group including Cr ( 4 ) Any one, two or three substituted thienyl groups, an
  • C 2 -C 3 is a saturated or unsaturated double bond.
  • the present invention provides a kit comprising the above combined preparation.
  • the present invention still further provides a method and a kit for treating or preventing diabetes and its complications by using the above combined preparation, to selectively activate the peroxisome proliferator ⁇ -activated receptor
  • the efficacy of the drug improves the insulin resistance of patients with diabetes.
  • the human PPAR- ⁇ expression plasmid is the product of the Addgene company of Australia [Addgene. . A S USA); the human cervical cancer epithelial cell HeLa is purchased from the American Type Culture Collection (American Type Culture Collection). , ATCC); Biotin-PPRE deoxynucleotide fragments are synthetic.
  • Fetal bovine serum FBS, GIBCO/BRL, USA
  • activated carbon and dextran treatment of fetal bovine serum CD-FBS, Hyclone, USA
  • DMEM medium GIBCO/BRL, USA
  • luciferase assay kit Promega 'Corporation, USA
  • Fugene 6 Fugene 6 (Roche Ltd., USA)
  • PPAR- ⁇ protein is an insect cell transfected PPAR- ⁇ gene expression product; positive control BRL4965 (Cayman, USA); [ 3 H] BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA); Biotin-binding protein-coated SPA microspheres (Amersham, USA); 96-well isotope assay plate (FlashPlateTM, PerkinElmer, USA).
  • Walkc 1420 plate reader PeridnEImer, USA; carbon dioxide incubator (Forma, USA); Wallac MicroBeta® liquid scintillation counter (TriLux 1450, PerkinElmer, USA).
  • DTT, CHAPS ⁇ EDTA, aprotinin, leupeptin and [ 3 H]BRL49653 were added to a certain amount of reaction buffer to achieve concentrations of 1 mmoI/L, 5 mmol/L, 1 mmol/L, 2 mg/L, respectively. , 100 mol/L and 10 nmol/L, then add the receptor PPAR-y (73 g/mL) and RXRa (6 g/niL), mix well, add 195 above solution to FlashPlateTM, incubate at 4 °C The data was read on a MicroBeta liquid scintillation counter after a certain period of time.
  • the compound concentration was set to 0, 0.003 ⁇ , 0.016 ⁇ , 0.08 ⁇ , 0.4 ⁇ , 2 ⁇ , ⁇ ⁇ , 100 ⁇ eight gradients, and the positive drug concentration was set to 0, 0.3 ⁇ , 1.6 nM, 8 ⁇ , 40 ⁇ , 200 ⁇ , 1000 ⁇ , 10000 ⁇ eight gradients.
  • the experimental results are shown in Table 1.
  • the compound mwwl 073 has better receptor binding activity and its IC 5Q value is less than 1 ⁇ .
  • Table 1 Binding activity of active compound to PPAR- ⁇
  • HeLa cells were cultured in DMEM medium containing 10% FBS and 2 mM L-glutamine. The day before transfection, the cells were replaced with DMEM medium containing 10% CD-FBS, and transfected with Fugene6 transfection reagent.
  • the human PPAR- ⁇ expression plasmid, the RXRct expression plasmid and the luciferase reporter plasmid were mixed at a ratio of 1: 1:10, and the ratio of the plasmid to Fugene 6 was 1:3, and the mixture was uniformly mixed and added dropwise to the cells. Incubation was carried out for 6 hours at 37 ° C and 5% CO 2 .
  • the cells were inserted into a 96-well culture plate at 5000 cells/100 ⁇ M/well, and cultured in DMEM medium containing 10% CD-FBS at 37 ° C for 2 hours.
  • the test compound was added and cultured for 24 hours, and the activity of the compound against PPA- ⁇ was evaluated by measuring the enzyme activity using a luciferase assay kit.
  • the positive drug and compound concentrations were set to 4 ⁇ , 20 ⁇ and 100 ⁇ , and the results are shown in Figure 2.
  • Compound mwwl073 showed agonistic activity.
  • Compound mwwl073 can compete with rosiglitazone (BRL49653) for binding to PPAR- ⁇ receptor with an IC 50 value of less than 1 ⁇ ;
  • Figure 1 is the protein domain of PPAR- ⁇ .
  • Figure 2 Effect of compounds on luciferase reporter gene expression regulated by PPAR- ⁇ response elements: The test compound produced an agonistic effect on PPAR- ⁇ at 100 ⁇ .
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic blood sugar, accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function.
  • the metabolic disorders in the body are not well controlled, leading to chronic complications of tissues such as the eyes, kidneys, nerves, blood vessels and heart, resulting in blindness, gangrene in the lower limbs, Uremic, stroke or myocardial infarction, even life-threatening.
  • plication refers to the pathological symptoms of related tissues and organs that occur with some major diseases.
  • an "effective amount" of a compound for treating a particular disease as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives includes any salt, ester or organism readily available to those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine. '
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant application.
  • substantially pure means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis, and High performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the substance, such as enzymatic activity and biological activity.
  • Methods for producing substantially chemically pure compounds for purification are well known to those skilled in the art. However, a substantially chemically pure compound can be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound.
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form.
  • the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • composition refers to any mixture. It may be a solution, a suspension, a liquid, a powder, an oil, an aqueous, a non-aqueous or any combination thereof.
  • object as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like. Experienced practitioners should understand that the subject is suitable and willing to treat and prevent diabetes and its complications.
  • the present invention provides an agonist of peroxisome proliferator gamma activating receptor function, which increases members of an insulin sensitizer.
  • the present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:
  • R is any of the following substituents: including C"C 4 thiol, nitro, carboxyl, ester, aldehyde, hydroxy, hydroxy, CrC 4 alkoxy, amine, amide, carboxamide Base, thiol, methylthio, ethylthio and any, two or three substituents including -
  • Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing fluorenyl, nitro, carboxyl, ester including d- (: 4 ) Base, aldehyde group, halogen, hydroxyl group, decyloxy group, amine group, amide group, carbon amide Any one, two or three substituted aryl groups including a thiol group, a thiol group, an alkylthio group, an ethylthio group, and an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups including a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group
  • the compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • the compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain different amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method.
  • the compound is prepared by the synthetic method cited in Section D below.
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • suitable acid for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.;
  • a sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the invention also relates to a combination formulation comprising a compound that selectively agonizes the function of a peroxisome proliferator gamma activating receptor, or a pharmaceutically acceptable salt thereof, and one or more Diabetes treatments include insulin sensitizers.
  • such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents for diabetes, including an insulin sensitizer, which has the following formula I:
  • any one of the following substituents a C "(alkyl, nitro, carboxyl, cool, aldehyde,, hydroxy, CrC 4 alkoxy, amine, amide, carboxamide group 4, Sulfhydryl, methylthio, ethylthio and any one, two or three substituents including:
  • Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing ("C 4 alkyl, nitro, carboxyl, ester group” Any one, two or three substituted aryl groups, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; ⁇ _( 4 alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, etc.
  • C 2 - C 3 is a saturated or unsaturated double bond.
  • any suitable therapeutic agent for diabetes including insulin sensitizers, can be used in the combination formulations of the invention.
  • the above-mentioned diabetes therapeutic agent, including an insulin sensitizer may be included in the combined preparation of the present invention. One or more.
  • a method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above diseases or symptoms.
  • kits comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction.
  • kits comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular, intradermal Injection, oral or topical.
  • the method can be administered by injection in a single dose in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical preparation of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • the frequency of dosing and medication will vary depending on age, weight, health status and individual patient response.
  • Dosage forms include tablets, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin. Finely mixed.
  • a special carrier a special carrier for the local or parenteral route can be used.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml.
  • the amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • a pharmaceutically acceptable solution preferably a sterile solution
  • Typical pharmaceutically acceptable solutions are physiological saline and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.

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  • Obesity (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention se rapporte à des composés représentés par la formule (I), à leur préparation et à leur utilisation en tant qu'agoniste du récepteur Ϝ activé par les proliférateurs de peroxysomes (PPAR-Ϝ) dans le traitement du diabète et des complications diabétiques.
PCT/CN2006/001784 2005-07-22 2006-07-20 Derives de propanamide substitues, preparation et utilisation de ces derives Ceased WO2007009389A2 (fr)

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CNB2005100280554A CN100562514C (zh) 2005-07-22 2005-07-22 一类取代丙酰胺衍生物、其制备方法和用途

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US9221756B2 (en) 2011-12-05 2015-12-29 University Of Leicester Pyrrole derivatives
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US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
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US20050004164A1 (en) * 2003-04-30 2005-01-06 Caggiano Thomas J. 2-Cyanopropanoic acid amide and ester derivatives and methods of their use

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US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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CN1900054A (zh) 2007-01-24
CN100562514C (zh) 2009-11-25

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