WO2003059871A1 - Derives de n-alkylsulfonyle amide - Google Patents

Derives de n-alkylsulfonyle amide Download PDF

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WO2003059871A1
WO2003059871A1 PCT/JP2003/000098 JP0300098W WO03059871A1 WO 2003059871 A1 WO2003059871 A1 WO 2003059871A1 JP 0300098 W JP0300098 W JP 0300098W WO 03059871 A1 WO03059871 A1 WO 03059871A1
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substituted
group
unsubstituted
alkylsulfonyl
pharmaceutically acceptable
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PCT/JP2003/000098
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English (en)
Japanese (ja)
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Nobuyasu Suzuki
Yukio Nihei
Hidehiro Ichinose
Toshihiro Hatanaka
Katsumi Maezono
Koji Ohsumi
Nobuo Kondo
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Ajinomoto Co.,Inc.
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Priority to AU2003201850A priority Critical patent/AU2003201850A1/en
Publication of WO2003059871A1 publication Critical patent/WO2003059871A1/fr

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    • 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
    • C07C311/51—Y being a hydrogen or a carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • the present invention relates to an N-alkylsulfonyl-substituted amide derivative, and more particularly to a novel N-alkylsulfonyl-substituted amide derivative having acetyl CoA carboxylase (hereinafter sometimes abbreviated as ACC) inhibitory activity.
  • ACC acetyl CoA carboxylase
  • drugs used as anti-obesity drugs include central appetite suppressants such as mazindol and sibutramine, and orlythate, a Teng lipase inhibitor.
  • Cerebral agonists may cause severe side effects such as bile, constipation, stomach discomfort, and sometimes hallucinations and visual hallucinations. In Orlisto evening, diarrhea, incontinence, flatus, etc. Vascular side effects have been observed. In general, the effects of these antiobesity drugs are moderate at doses that do not produce side effects, the safety of long-term use has not yet been established, and their beneficial effects on insulin resistance, which is closely related to obesity, are not significant. At present, it is rarely recognized.
  • PPAR peroxisome proliferator-associated receptor Yuichi '(hereinafter abbreviated as PPAR) gamma agonist
  • biguanides show a hypoglycemic effect and a amelioration of hyperlipidemia, mainly in patients with non-insulin-dependent diabetes mellitus, in addition to improving insulin resistance.
  • the therapeutic effect of the drug alone is insufficient, and in addition to gastrointestinal symptoms such as upper abdominal discomfort, nausea and diarrhea, it is evident that it shows life-threatening side effects such as lactate acidosis. It has become.
  • P A R cancer As with biguanides, non-insulin dependent 'I, improve insulin resistance, hyperglycemia, hyperlipidemia and hypertension in patients with diabetes mellitus, similar to biguanides, but have side effects
  • ACC is an enzyme that catalyzes the synthesis of Malonyl CoA from Acetyl CoA, and is the rate-limiting enzyme in the synthesis of long-chain fatty acids. It is also known that Malonyl CoA itself synthesized from Acetyl CoA by ACC negatively controls Carnitine acyltransferase involved in the consumption of free long-chain fatty acids as an energy source. Furthermore, activation of fatty acid synthesis in visceral adipose tissue is thought to involve ACC activation.
  • drugs that inhibit ACC are not suitable for long-chain fatty acids and Obesity and obesity-induced hyperlipidemia and various diseases based on insulin resistance by reducing existing adipose tissue, as well as inhibiting new synthesis of triglycerides and neutral fats Has potential as a therapeutic and prophylactic agent. Disclosure of the invention
  • An object of the present invention is to provide obesity and obesity-induced hyperlipidemia, fatty liver and various diseases based on insulin resistance (impaired glucose tolerance, diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetes) It is an object of the present invention to provide a novel compound having ACC activity inhibition that is effective for the treatment of retinopathy, diabetic macroangiopathy, hypertension, and arteriosclerosis. It is a further object of the present invention to provide a pharmaceutical composition containing the compound.
  • the present invention provides a pharmaceutical composition comprising a novel N-alkylsulfonyl-substituted amide derivative represented by the following general formula (1) as an active ingredient, particularly an ACC activity inhibitor and a therapeutic pharmaceutical composition using the same. I will provide a.
  • N-alkylsulfonyl-substituted amide derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
  • Substituted or unsubstituted C1-C20 alkyl group substituted or unsubstituted C2-C20 alkenyl group, substituted or unsubstituted C2-C20 alkynyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted Or unsubstituted aromatic heterocyclic group, substituted amino group, substituted or unsubstituted C1-C20 alkoxyl group, substituted or unsubstituted C2-C20 alkenyloxy group, substituted or unsubstituted C2-C20 alkynyl An alkoxy group or a group represented by R 20 — (wherein R 2 is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group) Or or or
  • R 1 -SO 2- is a group substituted with a substituted or unsubstituted heterocyclic group
  • R 1, R 2, R 3, R 4, R 5, and R 6 may be the same or different,
  • a substituted or unsubstituted aromatic hydrocarbon group a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, a substituted or unsubstituted C2-C12 alkynyl group, or Substituted or unsubstituted C1-C12 alkoxy group, hydrogen atom, hydroxyl group, mercapto group, substituted or unsubstituted C1-C12 A substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a nitro group, a logen atom or a cyano group;
  • Part A is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group, a substituted or unsubstituted group.
  • X is represented by any of the general formulas (2), (3), (4), (5), and R 20;
  • R7, R8, R9, R10, Rl1, R12, R13, R14, R15, R16, R17, R18, R19 in the general formulas (2), (3), (4), (5) are Each may be the same or different; substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted C1-C12 alkyl group, substituted or unsubstituted C2-C12 alkenyl group, substituted or unsubstituted C2-C12 alkynyl group, or substituted or unsubstituted C1-C12 alkoxyl group, hydrogen atom, hydroxyl group, mercapto group, substituted or unsubstituted C1-C12 substituted amino group, substituted or unsubstituted ( ⁇ ⁇ ( 6 is an alkylthio group, a nitro group, a halogen atom, or a cyano group,
  • a substituted or unsubstituted aromatic hydrocarbon group a substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, an unsubstituted or substituted cyclic alkyl group, an unsubstituted or substituted cyclic alkenyl group,
  • a substituted or unsubstituted aromatic complex ring group excluding a pyridine ring, a furan ring, and a thiophene ring, a substituted or unsubstituted cyclic alkyl group, and an unsubstituted or substituted cyclic alkenyl group;
  • Substituted or unsubstituted C1-C12 alkyl group substituted or unsubstituted C2-C12 Lucenyl group, substituted or unsubstituted C2-C12 alkynyl group, or substituted or unsubstituted C1-C12 alkoxyl group, hydrogen atom, hydroxyl group, mercapto group, substituted or unsubstituted C1-C12 substituted amino group
  • R 7 and R 8 are R 3, R 4, R 5, and R 6 in the general formula (1) or R 9, a in the general formulas (2), (3), (4), and (5).
  • R 10, R 11, R 12, R 13, R 14;; covalently bond to any of 15, R 16, R 17, R 18, R 19 to form a ring structure Includes what you take. )
  • the present invention provides an ACC activity inhibitor and a pharmaceutical composition comprising the above N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to obesity, hyperlipidemia, fatty liver, impaired glucose tolerance, diabetes, and diabetic complications comprising the N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • N-alkylsulfonyl-substituted amide derivative of the present invention will be described in more detail.
  • the “C 1 -C 12 alkyl group” may be any of linear, branched or cyclic, and may be methyl, ethyl, n-propyl, n-butyl, 2-methyl Provir, 1-methylpropyl, 1,1-dimethylethyl, cyclobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopentyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl , 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3,3-dimethylbutyl, cyclohexyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 4,4-dimethyl Pentyl, 1-propylbutyl, 2-ethylpentyl, cyclohexylmethyl,
  • alkyl group having 1 to 9 carbon atoms is preferred. Further, these alkyl groups may be further substituted with various substituents. Examples of such a substituent include halogen atoms such as chlorine, bromine, iodine, and fluorine, silyl groups, nitro groups, amino groups, cyano groups, and water. Examples thereof include aromatic hydrocarbon groups such as an acid group, an alkoxy group, a thiol group, a trichloromethyl group, a trifluoromethyl group, a phenyl and a naphthyl group, and aromatic heterocyclic groups such as a chenyl, a frill and a pyridyl group. Can be.
  • aromatic hydrocarbons and aromatic heterocyclic groups further include the above-mentioned halogen atoms, halogenated alkyl groups, amino groups, halogenated alkoxy groups, alkyl groups, alkoxy groups, thiol groups, nitro graves, and alkylamino groups.
  • the ⁇ C 1 -C 20 alkyl group '' may be linear, branched, or cyclic.
  • dodecyl, tetradecyl, pencil decyl, hexadecyl, pencil decyl, octyl decyl, nonadecyl, icosyl, etc. can be exemplified.
  • the alkyl group is further substituted with various substituents. It may be done. Examples of the substituent include the same substituents as those described above for the “C 1 to C 12 alkyl group”.
  • alkenyl group, alkynyl group, alkoxyl group and alkylthio group examples include the following.
  • substituted amino group includes a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group as described herein for a nitrogen atom.
  • substituted or unsubstituted aromatic heterocyclic group refers to a 4-membered ring, a 5-membered ring containing at least one heteroatom such as a nitrogen atom, a sulfur atom, an oxygen atom, and a phosphorus atom as a constituent atom.
  • Ring 6-membered, 7-membered, 8-membered or 9-membered ring, It may be condensed with a benzene ring, and may further have one or more various substituents on the ring, for example, pyridyl, furyl, chenyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, imidazolyl, Penzimidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrimidyl, virazinyl, homopiperazinyl, isooxazolyl, isoindolyl, bivalyl and thiazole.
  • substituents on the ring for example, pyridyl, furyl, chenyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, imidazolyl, Penzimidazolyl
  • substituted or unsubstituted non-aromatic heterocyclic group refers to a 4- to 9-membered ring containing at least one heteroatom such as nitrogen, sulfur, oxygen and phosphorus as a constituent atom. And examples thereof include thiazolidinyl and the like. Those containing a nitrogen atom and / or a sulfur atom as a heteroatom atom are preferred.
  • heterocycle includes both an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • Cyclic alkyl groups such as hexyl, cyclic alkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl cyclohexenyl, phenyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, dinitrophenyl, trifluoromethylphenyl , Dimethylaminophenyl, mercaptophenyl, aromatic hydrocarbon groups such as naphthyl and?
  • benz I Mi Dazo Lil may thiazolyl, Okisazoriru, pyrazolyl, Pirimi Jill, pyrazinyl, homopiperazinyl, Isookisazoriru, isoindolyl, and the like and aromatic heterocyclic groups such as a pin hole drill and Chiazo Ichiru.
  • Part A is preferably a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted cyclic alkyl group, or an unsubstituted or substituted cyclic alkenyl group. .
  • the A portion is an aromatic hydrocarbon group having a 1,2-position or a 1,3-position as a substitution position, an aromatic heterocyclic group having a 1,2-position, or a 1,3-position as a substitution position, 1 Cyclic alkenyl group substituted at the 1, 2 or 1- or 3-position, substituted or unsubstituted acyclic amino acid, partial structure of amino acid (part of amino acid excluding amino and carboxy groups) Or a cyclic alkyl group having a substituent at the 1,1,1,2 or 1,3 position.
  • an N-alkylsulfonyl-substituted amide derivative in which the A portion is a substituted or unsubstituted phenyl group is also preferable.
  • the substituent in the substituted phenyl group is preferably a nitrogen atom, and particularly preferably ring A is an unsubstituted phenyl group.
  • X is preferably a group represented by any of formulas (2), (3), (4), (5) and R 20, and particularly preferably a group represented by formula (2) or R 20 .
  • R9 and 110 are hydrogen atoms.
  • the aryl group is mono- or di-substituted by a substituent containing a halogen atom.
  • the position at which the cyclic group containing Y is bonded to the carbon atom constituting the amide bond is not particularly limited, but the following are also preferred.
  • R5 and R6 each represent a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C2-C12 alkenyl group, or a substituted or unsubstituted C1-C12 alkoxyl group, a hydrogen atom, It is preferably a hydroxyl group, a mercapto group, a substituted or unsubstituted C1 to C12 substituted amino group, a substituted or unsubstituted C1 to C6 alkylthio group, a nitro group, a halogen atom, or a cyano group, particularly preferably a hydrogen atom or Is preferably a halogen atom.
  • ring B is a ring as shown in the following (6).
  • Ring C is a substituted or unsubstituted aromatic heterocyclic group excluding a pyridine ring, a furan ring, and a thiophene ring, a substituted or unsubstituted cyclic alkyl group, and an unsubstituted or substituted cyclic alkenyl group. After these, a 5- to 6-membered aromatic heterocyclic group is preferable.
  • R 1 is a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted C1-C20 And a substituted or unsubstituted C2-C20 alkenyloxy group is preferred, and a substituted or unsubstituted C1-C10 alkyl group is particularly preferred.
  • the alkyl group may include a hetero atom such as a zeo atom in the main chain, and may be a cyclic alkyl group having 3 to 6 carbon atoms.
  • R 1 -S 02- is a substituted or unsubstituted heterocyclic group
  • the heterocyclic group is preferably a thiazole group, a pyridyl group, or a phenyl group.
  • Rl, R5, R6, A and X are as defined above, and J is a normal ester protecting group used in the synthesis reaction, for example, methyl group, ethyl group, benzyl group, aryl group
  • D is a fluorine, chlorine, bromine, hydroxyl, N-hydroxysuccinimide group, or a like, such as a 4-12 trophenoxy group or a penfluorofluorooxy group.
  • the reaction temperature and the reaction time are not particularly limited depending on the type of the compound, etc., but the reaction can be carried out at a temperature of about 0 ° C. to about the boiling point of the solvent to be used for about 0.1 to 25 hours.
  • the desired compound can be obtained.
  • the amount of the condensing agent used is preferably approximately 1.2 times the equivalent of the carbonyl compound (8).
  • Examples of the base to be used include alkaline metal hydrides such as sodium hydride and potassium hydride; alkaline metal hydroxides such as sodium hydroxide and hydroxyladium; sodium carbonate, carbonated lithium.
  • Alkali metal carbonates such as sodium hydrogen carbonate and sodium bicarbonate; alkali metal carbonates such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium tert-butoxide Alkoxides; trialkylamines such as trimethylamine and triethylamine; and organic or inorganic bases such as pyridines such as pyridine, dimethylaminopyridine, picoline and lutidine.
  • the amount of the base used is preferably 1 to 10 times the equivalent of the carboxylic acid compound.
  • Step 2 is a step of deprotecting the protecting group of the carboxyl group in the ester compound (9).
  • the ester compound (9) is dissolved in methanol and THF, lithium hydroxide monohydrate is added, and the mixture is stirred at room temperature for about 10 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and 1 N hydrochloric acid is added to the residue. An appropriate amount of an aqueous solution is added, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a desired carboxylic acid.
  • Steps 1, 2, and 3 described above can be carried out in an inert solvent.
  • a solvent examples include ethers such as diethyl ether, tetrahydrofuran (THF) dioxane; benzene; Aromatic hydrocarbons such as toluene and xylene; hydrocarbons such as cyclopentane and cyclohexane; halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloroethane, and chloroform; nitriles such as acetonitrile and propionitrile Esters such as ethyl acetate; N, N-dimethylformamide, dimethylsulfoxide and the like, and mixtures of these with water.
  • ethers such as diethyl ether, tetrahydrofuran (THF) dioxane
  • benzene Aromatic hydrocarbons such as toluene and xylene
  • hydrocarbons such
  • N-alkylsulfonyl-substituted amide derivatives represented by the general formula (I) include those in the form of various salts, hydrates and solvates, and structural isomers or stereoisomers thereof, especially Includes those in pharmaceutically acceptable form. .
  • the present invention relates to obesity and obesity-induced hyperlipidemia and various diseases based on insulin resistance, which comprise the compound represented by the general formula (I) (abnormal glucose tolerance, diabetes Or diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hypertension, arteriosclerosis).
  • the present invention relates to obesity and obesity-induced hyperlipidemia and various diseases based on insulin resistance (impaired glucose tolerance, $ karauria, diabetic peripheral neuropathy, diabetic nephropathy, It is a drug and treatment for the prevention, treatment, and prevention of progression of diabetic retinopathy, diabetic macroangiopathy, hypertension, and arteriosclerosis.
  • the compound represented by the general formula (I) and another pharmaceutical agent such as an antidiabetic agent or a hypoglycemic agent may be mixed as a mixed preparation, or two preparations containing each component separately.
  • the present invention also includes those in the form of a combination.
  • Examples of the drug which can be used in combination with the compound represented by the general formula (I) include insulin, for example, insulin analogues such as risp mouth, glargine, etc., and insulin secretion such as glibenclamide, torppumid, glipizide, glimepiride, etc.
  • Enhancers for example, fast-acting insulin secretagogues such as nateglinide, repaglidide, etc., for example alpha-glycosidase inhibitors such as acarbose, voglibose, miglitol, etc.
  • Insulin resistance such as PPAR-gammaagonist and PPAR-gammaantagonist with a thiazolidine skeleton such as oral diglyuzone, piogliyuzone, or trogliyuzone or a non-thiazolidine skeleton such as GI-262570, JTT-501, or YM-440.
  • a thiazolidine skeleton such as oral diglyuzone, piogliyuzone, or trogliyuzone or a non-thiazolidine skeleton such as GI-262570, JTT-501, or YM-440.
  • the compound of the general formula (I) When a medicament containing the compound represented by the general formula (I) is administered to a human, it varies depending on the age, the symptoms of the target disease, etc., but preferably, the compound of the general formula (I) is 0.01 to 1000 mg per preparation. A degree can be included. The actual preferred mode of administration, order and intervals will depend on the particular drug formulation used, the time of onset of the effect, and the condition of the individual patient being treated (weight, body fat percentage, body mass index, blood biochemical index, etc.). It can be selected as appropriate using conventional techniques, and in view of the information provided herein. That is, more preferably, the compound represented by the general formula (I) is orally administered in an effective amount, for example, usually 1 to 1 Orn is divided into 1 to 3 times a day.
  • both can be administered simultaneously or at different times.
  • Each drug is preferably administered up to three times a day, and treatment can be repeated as long as no contraindications associated with continuous dosing are observed and until the goals set in individual patients are achieved.
  • the medicament of the present invention can be prepared as an injection.
  • This formulation may be dispersed or dissolved in a water carrier such as physiological saline in advance with a surfactant or a dispersant, or may be dispersed or dissolved as needed. Dissolution It may be in the form of a crystalline preparation for injection or a lyophilized preparation so that it can be converted into a pharmaceutical preparation.
  • a pH adjuster or a stabilizer may be added as an optional component to the water carrier.
  • the dose and route of administration of such an injection are not particularly limited, and the safe and necessary amount is administered at a time or by infusion, for example, intravenously, intraarterially, subcutaneously or intraperitoneally according to the disease state and the characteristics of the patient. can do.
  • each component or a plurality of components can be contained in one or more appropriate preparations.
  • it can be prepared into various forms of pharmaceutical preparations known or developed in the future, for example, oral administration preparations, injections, etc. Can be adopted.
  • Example 1 Illustrates the synthesis of 9 compounds ⁇
  • the benzoic acid moiety having a thiazole ring was synthesized by the method of synthesizing the synthesis intermediate of Synthesis Example 2 and used as a raw material for synthesis. Under an argon atmosphere, 3 ml of thionyl chloride was added to 598 mg of the obtained benzoic acid, and the mixture was stirred at 60 ° C. for 2 hours, and then thionyl chloride was distilled off under reduced pressure.
  • the benzoic acid having thiazole ⁇ used in Synthesis Example 23 was synthesized by the synthesis method of the synthesis intermediate in Synthesis Example 2 and used as a synthesis raw material. Under an argon atmosphere, 6 ml of thionyl chloride was added to 1418 mg of the obtained benzoic acid, and the mixture was stirred at 60 ° C. for 2 hours, and then thionyl chloride was distilled off under reduced pressure.
  • Example 23 21 mg of a Benzo [d] [1,3] oxazin-4-one derivative, which is a synthetic intermediate of 3, was dissolved in 3 ml of pyridine, and 5 mg of 2-amino-3-methylthiazole and 2-tert-butyl imino-2 were dissolved.
  • MS (ESI) m / z: 581 (MH +). The synthesis of the compound of Example 37 is illustrated.
  • the male SD rats were fasted for 2 days, then a high sucrose diet (component) was given for 2 days, the inferior vena cava was incised under ether anesthesia, blood was exsanguinated, and the liver was immediately removed.
  • Ice-cold buffer A 225 mM mannitol, 75 mM sucrose, 10 mM Tris-HCl (pH 7.5), 0.05 mM EDTA, 5 mM potassium citrate, 2.5 mM MgC12, 10 mg / L pepstatin A ⁇ 10 mg / L Homogenized in 1 eupeptic 1 mM PMSF
  • a 9-fold amount of buffer A was added to the liver weight, and the mixture was centrifuged at 1000 g for 10 minutes. The supernatant was collected, and further centrifuged at 17,000 g for 10 minutes.
  • Ammonium sulfate was added to the obtained supernatant so as to be 35% saturated, stirred for 45 minutes, and then centrifuged at 17,000 g for 10 minutes.
  • Buffer B 100 mM Tris-HCl (pH 7.5), 500 mM NaCl, 1 mM EDTA 0.1 mM DTT 10% glycerol, 10 mg / L pepstatin A, 10 mg / L leupeptin, 0.5 mg mM PMSF was added and dissolved, followed by centrifugation at 4000 g for 20 minutes.
  • reaction solution 1 containing ACC (40 mM Tris-HCl (pH 7.5), 40 mM MgC12, 40 mM sodium citrate, 2 mM DTT), and the mixture was heated at 37 ° C. for 30 minutes in a thermostat, and then cooled on ice.
  • reaction solution 2 40 mM Tris-HCl (pH 7.5), 2 mM DTT ⁇ 8 mM ATP, 0.5 mM acetyl CoA) containing [14C] -NaHC03, and 37.
  • mice Male KK-Ay mice were divided into groups for blood glucose and plasma triglyceride levels so that there was no difference between groups, and the compound prepared in the above example was forcibly administered at 58.3 to 175 mg / kg twice daily for 4 days. Oral administration. As a control, KK-Ay mice received vehicle alone. Plasma triglyceride, blood glucose and body weight were measured on the last day of administration under food intake. In addition, after an overnight fast after administration, an oral glucose tolerance test (gavage of 2 g / kg glucose by oral gavage and blood glucose measurement over time until 180 minutes after administration) was performed to evaluate glucose tolerance. did.
  • the anti-obesity effect was evaluated by determining the relative body weight at the end of administration as a percentage, with the body weight on the first day of administration being 100% (Table 2).
  • Table 3 Hyperlipidemia improving effect
  • Table 4 Hypoglycemic effect
  • Plasma triglyceride (or blood glucose) reduction rate (%) ⁇ 1-a / b ⁇ x 100a: Plasma triglyceride concentration (or whole blood glucose concentration) in compound administration group
  • ⁇ AUC (average value of AUC in control group) (average value of AUC in i-conjugated group) Table 1 ACC inhibitory activity
  • the N-alkylsulfonyl-substituted amide derivative of the present invention provides a different mechanism from the conventional anti-obesity drugs and insulin-sensitizing drugs, to obesity and hyperlipidemia induced by obesity, fatty liver, and insulin resistance.
  • Treatment of impaired glucose tolerance, diabetes, diabetic complications diabetic peripheral neuropathy, diabetic nephropathy, sugar. Uremic retinopathy, diabetic macroangiopathy
  • hypertension and arteriosclerosis that may be based on It is extremely useful as a therapeutic agent for these diseases.

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Abstract

La présente invention concerne un inhibiteur d'activité ACC qui est efficace dans le traitement de l'obésité, de l'hyperlipidémie et du gros foie apparemment induit par l'obésité, de l'intolérance au glucose, du diabète et des complications diabétiques (neuropathie périphérique diabétique, néphropathie diabétique, rétinopathie diabétique, maladie des gros vaisseaux diabétiques, etc.) apparemment basés sur la résistance à l'insuline, sur l'hypertension et sur l'artériosclérose. Les dérivés de N-alkylsulfonyle amide, leurs analogues ou leurs sels pharmaceutiquement acceptables présentent un effet inhibiteur d'activité ACC efficace.
PCT/JP2003/000098 2002-01-09 2003-01-09 Derives de n-alkylsulfonyle amide WO2003059871A1 (fr)

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US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
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US8153808B2 (en) 2008-12-23 2012-04-10 Roche Palo Alto Llc Dihydropyridone amides as P2X7 modulators
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EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
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US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
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