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WO2013086980A1 - Sulfonylurée et guanidine, son procédé de préparation et son utilisation - Google Patents

Sulfonylurée et guanidine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2013086980A1
WO2013086980A1 PCT/CN2012/086431 CN2012086431W WO2013086980A1 WO 2013086980 A1 WO2013086980 A1 WO 2013086980A1 CN 2012086431 W CN2012086431 W CN 2012086431W WO 2013086980 A1 WO2013086980 A1 WO 2013086980A1
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Prior art keywords
group
alkyl
compound
pharmaceutically acceptable
formula
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Ceased
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PCT/CN2012/086431
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English (en)
Chinese (zh)
Inventor
柏俊
孙备
胡士高
程杰
田磊
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ANHUI BIOCHEM UNITED PHARMACEUTICAL Co Ltd
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ANHUI BIOCHEM UNITED PHARMACEUTICAL Co Ltd
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Publication of WO2013086980A1 publication Critical patent/WO2013086980A1/fr
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Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/61—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups further bound to another hetero atom
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides

Definitions

  • the present invention relates to the field of organic synthesis technology, and in particular to a transverse ureide guanidine compound, a preparation method and use thereof. Background technique
  • Diabetes is a genetic disease that is associated with genes such as infections and obesity. Its pathological basis is due to hyperglycemia due to insufficient insulin secretion and metabolic disorders caused by the use of disorders. Diabetic patients are prone to complications such as blindness, coronary heart disease, renal failure and related diseases. According to statistics, the mortality caused by diabetes is second only to cardiovascular diseases and tumors. Therefore, the development of effective, low-toxic, and economical drugs for treating diabetes has great social and economic benefits.
  • oral hypoglycemic agents mainly include ureide and biguanide. Both drugs can be used to control blood sugar when used alone, but all have different side effects, such as ureide drugs having hypoglycemia. Dangerous, nephrotoxicity, retinopathy and other side effects, while diterpene has side effects such as lactic acidosis and retinopathy.
  • ureide drugs having hypoglycemia
  • Dangerous, nephrotoxicity, retinopathy and other side effects while diterpene has side effects such as lactic acidosis and retinopathy.
  • insulin hypoglycemic agents there are insulin hypoglycemic agents, but the price of insulin-based hypoglycemic agents is expensive and will increase the weight of patients.
  • the present inventors considered designing a novel compound having a double structure of a sulfonylurea and an aminoguanidine, so that not only the use of the acid ureide structure enhances the secretion of endogenous insulin, but also achieves the purpose of lowering blood sugar, and
  • the aminoguanidine structure can be used to prevent and treat various complications of diabetic patients. Summary of the invention
  • the problem to be solved by the present invention is to provide a compound having the dual structure of a sulfonylurea and an aminoguanidine, the two structures acting separately with different targets in the metabolism of the human body;
  • the structure can enhance the secretion of endogenous insulin and achieve the effect of lowering blood sugar.
  • the aminoguanidine structure in the compound can prevent and treat diabetic complications.
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof having the structure represented by the formula (I):
  • X is selected from 0 or s
  • R 2 is selected from the group consisting of H, Cw 2 alkyl, and. a cycloalkyl group, a cyano group, wherein one or more hydrogen atoms in the alkyl group or cycloalkyl group are optionally substituted by a halogen, a hydroxyl group, an amino group or a carboxyl group;
  • R 3 and R 4 are each independently selected from H, Cw 2 alkyl, wherein one or more hydrogen atoms in the alkyl group are optionally halogen, hydroxy, amino, carboxy.
  • a cycloalkyl or phenyl group; or, R 3 and R 4 , or R 2 and R 4 together with the nitrogen atom to which they are attached constitute a five-, six- or seven-membered saturated or unsaturated heterocyclic ring.
  • the pharmaceutically acceptable salt according to the present invention may be a mineral acid salt or an organic acid salt, and if an acidic group is present, it may also form a salt with a base.
  • the present invention also provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises (A) an aminoguanidine represented by the formula (II)
  • the compound of formula (I) is obtained and optionally converted into a pharmaceutically acceptable salt; wherein, hydrazine is a compound, and X, Ri, R 2 , R 3 and R 4 are as defined above.
  • the present invention also provides a pharmaceutical composition comprising the compound of the formula (I) as an active ingredient, and a pharmaceutically acceptable carrier.
  • the invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of diabetes.
  • the invention also provides a method of treating diabetes, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and/or a medicament comprising a compound of formula (I) combination.
  • the compound provided by the invention has the dual structure of sulfonylurea and aminoguanidine, and the sulfonylurea can enhance the secretion of endogenous insulin and lower blood sugar; the aminoguanidine structure has various complications for diabetic patients. Has a significant preventive effect.
  • the definitions of X, R 2 , and R 4 are as described above.
  • the Ci 12 alkyl group is linear or branched, preferably having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably an anthracenyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or an isobutyl group.
  • Base sec-butyl, tert-butyl.
  • the alkyl group in the d- 12 alkoxy group is the same as the d- 12 alkyl group.
  • the C 2 -8 alkenyl group and the C 2 -8 alkynyl group are linear or branched and have one or more unsaturated bonds, preferably having 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms.
  • the Cwo cycloalkyl group is a monocyclic or fused ring structure, preferably having 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • the halogen in the present invention is preferably fluorine, chlorine, bromine or iodine.
  • R is ortho or para to the sulfonamide group, preferably in the para position.
  • R 3 and R 4 with the nitrogen atom to which they are attached together form dihydro-imidazole, imidazolidine, dihydro-pyrimidine 1 set, 11-tetrahydro-pyrimidin-set of heterocyclic.
  • R 2 is selected from H, Ci- 6 alkyl, preferably, R 2 is H; and R 3 and R 4 are each independently selected from H, C ⁇ 6 alkyl, preferably, R 3 and R 4 are both H.
  • the pharmaceutically acceptable salt may be a mineral acid salt or an organic acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, an acetate, a citrate, an oxalate, a succinate, or a rich Horse salt, maleate salt, citrate, malate, but not limited to this.
  • an acidic group when present in the structure of the compound of the formula (I), it may also form a salt with a base, and specific examples may be an alkali metal salt such as a sodium salt, a potassium salt, an alkaline earth metal salt such as a magnesium salt or a calcium salt.
  • an ammonium salt or an organic quaternary ammonium salt but is not limited thereto.
  • the aminoguanidine or its hydrochloride salt of the formula (II) is dissolved in an organic solvent to obtain an organic solution of the aminoguanidine (hydrochloride) of the formula (II).
  • the organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester organic solvent.
  • Specific examples of the alcohol organic solvent may be decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol, but are not limited thereto.
  • halogenated hydrocarbon organic solvent may be dichlorosilane, chloroform or 1,2-dichloroethane, but are not limited thereto.
  • ether organic solvent may be tetrahydrofuran, diethyl ether, isopropyl ether, benzoin ether, decyl tert-butyl ether, but are not limited thereto.
  • ketone organic solvent may be acetone, decyl isobutyl ketone, butanone, decyl butyl ketone, but are not limited thereto.
  • ester organic solvent may be ethyl acetate, isobutyl acetate, butyl acetate, or isopropyl acetate, but are not limited thereto.
  • the organic solvent should be inert to the reactants, and those skilled in the art have the ability to vary
  • the type of reactant is selected as a suitable solvent.
  • the organic solvent is acetone, and the concentration of the aminoguanidine (hydrochloride) organic solution is preferably 0.5 to 2 mol/L, more preferably 0.7 to 1.5 mol/L, and particularly preferably 0.9 to 1. /L.
  • the organic solution of the aminoguanidine which is an organic base or an inorganic base such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, but it is not limited to this.
  • the base is triethylamine.
  • the ratio of the amount of the base to the aminoguanidine is from 1:2 to 2:1, preferably from 1:1.5 to 1.5:1, more preferably from 1:1.
  • an aminoguanidine (hydrochloride) When preparing the organic solution of the aminoguanidine (hydrochloride), it is preferred to add an aminoguanidine (hydrochloride) to the organic solvent under a protective atmosphere, and the protective atmosphere may be nitrogen, argon, etc.;
  • the present invention is not particularly limited, and a mechanical stirring method well known to those skilled in the art is preferably used.
  • a base preferably triethylamine
  • an isocyanate represented by the formula (III) or an acyl group represented by the formula (IV) is added to the first mixed solution to obtain a second mixed solution.
  • the ratio of the amount of the isocyanate or acyl group to the aminoguanidine is from 1:2 to 2:1, preferably from 1:1.5 to 1.5:1, more preferably from 1:1.
  • the second mixed solution is heated to a reflux state for a reaction time of at least 1 hour, preferably 3 hours, more preferably 4 hours, particularly preferably 5 hours, to obtain a compound represented by the formula (I).
  • the reaction mixture was cooled, filtered, and recrystallized.
  • the present invention is not particularly limited for filtration and recrystallization, and can be carried out in a manner well known to those skilled in the art.
  • a compound represented by the formula (I) can be further used to prepare a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt thereof in particular, in the preparation of the hydrochloride, it is preferred to follow the following method:
  • the compound of the formula (I) is added to an organic solvent selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester organic solvent at room temperature.
  • an alcohol organic solvent may be decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol or t-butanol, but are not limited thereto.
  • Specific examples of the hydrocarbon-derived organic solvent may be dichlorosilane, chloroform or 1,2-dichloroethane, but are not limited thereto.
  • ether organic solvent may be, but are not limited to, tetrahydrofuran, diethyl ether, diisopropyl ether, benzoin ether, and mercapto tert-butyl ether.
  • ketone organic solvent may be acetone, decyl isobutyl ketone, butanone, decyl butyl ketone, but are not limited thereto.
  • ester organic solvent may be ethyl acetate, isobutyl acetate, butyl acetate or isopropyl acetate, but are not limited thereto; preferably, decyl alcohol.
  • the molar volume ratio of the compound of the formula (I) to the organic solvent is 0.5 to 2 mol/L, which is excellent It is selected to be 0.7 to 1.5 mol/L, more preferably 0.9 to 1.1 mol/L. Passing dry under agitation
  • the HC1 gas is stirred until the compound of formula (I) is completely dissolved to obtain its hydrochloride salt, which can then be filtered and concentrated.
  • the obtained hydrochloride salt can be added to acetone for refrigeration, and then filtered, dried and purified.
  • the pharmaceutical composition according to the present invention comprises a compound of the formula (I) as an active ingredient.
  • the pharmaceutical composition can be formulated into pharmaceutical preparations well known to those skilled in the art such as tablets, pills, powders, granules, capsules, syrups, emulsions and the like.
  • Pharmaceutically acceptable carriers well known to those skilled in the art may also be included in the pharmaceutical compositions, such as excipients, binders, disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, well known to those skilled in the art.
  • a cosolvent or the like is not particularly limited in the present invention.
  • the compound of the present invention can enhance the secretion of endogenous insulin, thereby achieving the effect of lowering blood sugar, and can prevent and treat various complications of diabetic patients (such as nephrotoxicity, eye disease, arteriosclerosis, etc.).
  • Example 2 The reaction route of Example 1 is as follows: Example 2
  • the starting material was 50.0 mg of Compound 1 (prepared from Example 1), 70.5 mg of D-mannitol, 16.0 mg of corn starch, 15.0 mg of sodium hydrogencarbonate, 3. Omg of hydroxypropyl decyl cellulose, 5.0 mg. Talc, 0.5 mg of magnesium stearate.
  • the starting material was 10% by weight of Compound 2 (prepared from Example 1), 89.5% by weight of D-mannitol, and 0.5% by weight of hydroxypropyl decyl cellulose.
  • the starting material was 50.0 mg of Compound 3 (prepared from Example 2), 30.0 mg of D-mannitol, 19.0 mg of corn starch, 15. Omg of sodium bicarbonate, 1.5 mg of hydroxypropyl decyl cellulose, 4.0 mg. Talc, 0.5 mg of magnesium stearate.
  • Compound 1 dose 43 mg/kg 21.5 mg/kg 10.75 mg/kg
  • Model group 8 23.3+3.50 26.1+3.46 25.8 ⁇ 1.78 27.1 ⁇ 1.36 24.1+3.10 Media Gleich 20.1 ⁇ 4.03 21.6 ⁇ 3.27 22.4+2.22 22.9+2.63 20.9 ⁇ 2.52
  • Table 4 shows that the endothelial cells proliferated significantly in the model group compared with the normal group, and the pericytes were significantly reduced. Compound 1 and Compound 2 were significantly less than this model group ( ⁇ 0.05).
  • the number of cytoplasmic vesicles in the retinal capillary endothelial cells increased, mitochondrial edema, partial mitochondrial sputum and membrane fusion disappeared, basement membrane thickened, treatment group compound 1, compound 2 retinal capillary lumen regulation, The nucleus of endothelial cells is intact, some mitochondrial edema in the cytoplasm, and the basement membrane is normal.
  • Compound 2 is 40.0 1.07 ⁇ 0.02* 0.29 ⁇ 0.01 dose
  • Table 5 shows that the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) of the model group were significantly higher than those of the normal group, and the medication groups were significantly improved compared with the model group.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un composé représenté par la formule (I). Par rapport à l'art antérieur, le composé selon la présente invention présente une structure double de sulfonylurée et d'aminoguanidine ; la sulfonylurée peut réduire le niveau de glycémie par l'activation de la sécrétion endogène d'insuline, et la structure d'aminoguanidine possède des effets significatifs de prévention et de traitement pour diverses complications de patients diabétiques. Chaque substituant de X, R1, R2, R3 et R4 est tel que défini dans la description.
PCT/CN2012/086431 2011-12-14 2012-12-12 Sulfonylurée et guanidine, son procédé de préparation et son utilisation Ceased WO2013086980A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110419180.3 2011-12-14
CN201110419180.3A CN103159651B (zh) 2011-12-14 2011-12-14 磺酰脲胍及其制备方法和用途

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WO2013086980A1 true WO2013086980A1 (fr) 2013-06-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017140778A1 (fr) * 2016-02-16 2017-08-24 The University Of Queensland Sulfonylurées et composés apparentés et leur utilisation
US12187702B2 (en) 2018-08-15 2025-01-07 Inflazome Limited Sulfonamideurea compounds

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104649944B (zh) * 2015-02-13 2016-08-31 佛山市赛维斯医药科技有限公司 一类甲氧苯磺酰肼类gpr119激动剂、制备方法及其用途
CN104649937B (zh) * 2015-02-13 2016-04-13 佛山市赛维斯医药科技有限公司 苯磺酰肼类gpr119激动剂、制备方法及其用途
CN113683584A (zh) * 2021-09-22 2021-11-23 无锡桑格尔生物科技有限公司 一种磺酰脲类化合物的合成方法

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US2968158A (en) * 1955-08-08 1961-01-17 Upjohn Co New benzene sulfonyl ureas; composition and process for lowering blood sugar therewith
US3501495A (en) * 1966-02-10 1970-03-17 Science Union & Cie N-phenylsulphonyl-n'-(3-azabicycloalkyl) urea derivatives
US3755587A (en) * 1967-11-25 1973-08-28 Bayer Ag Compositions and methods for lowering blood sugar using aryl sulphonylsemicarbazides containing heterocyclic acylamino groups
CN1244801A (zh) * 1997-02-19 2000-02-16 沃尼尔·朗伯公司 用于糖尿病的磺酰脲类－格列酮类协同联合给药
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US3501495A (en) * 1966-02-10 1970-03-17 Science Union & Cie N-phenylsulphonyl-n'-(3-azabicycloalkyl) urea derivatives
US3755587A (en) * 1967-11-25 1973-08-28 Bayer Ag Compositions and methods for lowering blood sugar using aryl sulphonylsemicarbazides containing heterocyclic acylamino groups
CN1244801A (zh) * 1997-02-19 2000-02-16 沃尼尔·朗伯公司 用于糖尿病的磺酰脲类－格列酮类协同联合给药
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017140778A1 (fr) * 2016-02-16 2017-08-24 The University Of Queensland Sulfonylurées et composés apparentés et leur utilisation
US11858922B2 (en) 2016-02-16 2024-01-02 The University Of Queensland Sulfonylureas and related compounds and use of same
US12187702B2 (en) 2018-08-15 2025-01-07 Inflazome Limited Sulfonamideurea compounds

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CN103159651A (zh) 2013-06-19

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