WO2003059871A1

WO2003059871A1 - N-alkylsulfonyl-substituted amide derivatives

Info

Publication number: WO2003059871A1
Application number: PCT/JP2003/000098
Authority: WO
Inventors: Nobuyasu Suzuki; Yukio Nihei; Hidehiro Ichinose; Toshihiro Hatanaka; Katsumi Maezono; Koji Ohsumi; Nobuo Kondo
Original assignee: Ajinomoto Co.,Inc.
Priority date: 2002-01-09
Filing date: 2003-01-09
Publication date: 2003-07-24
Also published as: JP2005170790A; AU2003201850A1

Abstract

It is intended to provide ACC activity inhibitor which are efficacious in treating obesity, hyperlipemia and fat liver seemingly induced by obesity, glucose tolerance failure, diabetes and diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic great vessel disease, etc.) seemingly based on insulin resistance, hypertension and arteriosclerosis. N-Alkylsulfonyl-substituted amide derivatives, analogs thereof or pharmaceutically acceptable salts thereof have an efficacious ACC activity inhibitory effect.

Description

Specification

N-alkylsulfonyl-substituted amide derivatives Background of the invention

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.

In recent years, obesity has emerged as one of the major risk factors for atherosclerotic disease, especially coronary artery disease. That is, in an obese individual, accumulated visceral fat releases various factors such as fatty acids and TNF-fiber, which cause insulin resistance in skeletal muscle, liver and adipose tissue, and neutral fat in liver. It has been reported to promote the synthesis of liposomes, leading to hyperlipidemia. In addition, blood insulin, which has been compensated by insulin resistance, not only causes impaired glucose tolerance and diabetes, but also enhances renal Na ion reabsorption and activation of sympathetic nerves in the periphery. It increases vascular resistance and eventually forms a hypertensive state. Hyperlipidemia, diabetes and hypertension caused by hypertrophy can cause arterial sclerosis-based vascular disorders such as cerebrovascular disease and coronary artery disease and have a profound effect on life prognosis. It is considered.

Exercise therapy and diet are the basis of obesity treatment.However, due to various factors such as conflict with fundamental human needs, work time, and increased stress, it is enormous to achieve the set goals. With difficulty. Surgical treatments such as gastric reduction and gastric bypass may be indicated for patients with extreme obesity.However, obese patients often have infections, fat melting and other wound complications during laparotomy. At present, it is lossy and painful. Therefore, a doctor who can safely and easily supplement dietary exercise There is a need for a combination of drugs. At present, 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.

Regarding insulin resistance, treatment using a biguanide agent, the peroxisome proliferator-associated receptor Yuichi '(hereinafter abbreviated as PPAR) gamma agonist, is widely used. It has been reported that 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. However, 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

In terms of (obesity, fulminant hepatitis), it is still not satisfactory.

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. Therefore, 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 inventors of the present invention have conducted intensive studies in order to solve such a problem, and as a result, it has been found that an N-alkylsulfonyl-substituted amide derivative having a novel skeleton represented by the following general formula (I) has excellent ACCP and harmful activity. It was found that this was recognized, and the present invention was completed. Accordingly, 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.

An N-alkylsulfonyl-substituted amide derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

(Where R 1 is

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

R 1 -SO 2-is a group substituted with a substituted or unsubstituted heterocyclic group, and Y is -CR3 = CR4-, -C0-NR3-, -NR3-C0-, -N = CR3- Or a group represented by -CR3 = N- or. Is a sulfur atom or an oxygen atom,

—In the general formula (1), R 1, R 2, R 3, R 4, R 5, and R 6 may be the same or different,

R3, R4, R5, are

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. A non-aromatic heterocyclic group or an alkylene group having a cyclic substituent,

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,

Z is a group represented by -CR9 = CR10-, -N = CR9- or -CR9 = N-, or a sulfur atom or an oxygen atom;

Q is a group represented by -CR9 = N- or a sulfur atom or an oxygen atom, and ring B is

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,

Ring C is

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;

R 20 is

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 A substituted or unsubstituted C1-C6 alkylthio group, nitro group, halogen atom, or cyano 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. Provide a preventive and / or therapeutic agent for hypertension and arteriosclerosis or (1) a hypoglycemic agent.

The present invention also provides an obesity or hyperlipidemia comprising the above N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof and one or two of the following Group A drugs as active ingredients: The present invention provides a preventive and / or therapeutic agent for hypotension, fatty liver, impaired glucose tolerance, diabetes, diabetic complications, high blood pressure, and arteriosclerosis, or a hypoglycemic agent.

A: Insulin, sulfonylurea agent, alpha-glycosidase inhibitor, biguanide, PPM-gammaagonist, PPA-gammaangone gonist, PPAR-alphagonist, SGLT inhibitor, GLP-1 receptor antagonist Gonist, DPP-IV inhibitor, aldose reductase inhibitor, diabetic neuropathy drug, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor Body antagonist, Bayer blocker, αΐ blocker, diuretic, anti-obesity drug, low energy BEST MODE FOR CARRYING OUT THE INVENTION

The N-alkylsulfonyl-substituted amide derivative of the present invention will be described in more detail.

In the present specification, 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, 1,1-getylpropyl, cycloheptyl, n-octyl, 1-methyloctyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 2-hexylethyl, 5,5-dimethylhexyl, cyclooctyl, n-nonyl, 1-methyloctyl, 7-methyloctyl, 6, 6 dimethylheptyl, n-decyl, 1-methylnonyl, 8-methylylnonyl, 7,7-dimethyloctyl, n-ndedecyl, 1-methyldecyl, 1-methyldecyl, 9-methyldecyl, 8,8-dimethylnonyl, n- Examples include dodecyl, 1-methyl-decyl, 10-methyl-dec-decyl, 5-methyl-dec-decyl, 9,9-dimethyl-decyl, bicyclo [2.2.1] heptyl, cyclooctyl, 6,6-dimethyl-bicyclo [3.1.1] heptyl, etc. can do. Of these, an 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. Further, these 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. , An amino group, a cyano group, a hydroxyl group, or other substituents.The `` C 1 -C 20 alkyl group '' may be linear, branched, or cyclic. In addition to the above examples, 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”.

The “alkenyl group such as C 2 to C 20 and C 2 to C 12, alkynyl group, alkoxy group, and alkylthio group” may be any of a linear cyclic group and a branched chain group. The alkenyl group, alkynyl group and alkoxyl group may be further substituted with various substituents. : Examples of the substituent include the same substituents as those described above for the C1 to C12 alkyl group substituent.

Examples of the alkenyl group, alkynyl group, alkoxyl group and alkylthio group include the following.

Examples of alkenyl groups include 1-methyl-11-propenyl, 1-hexenyl, ethenyl, 4,4-dimethyl-11-pentenyl, decenyl, icosenyl and the like. Examples of alkyninole groups: 1-propynyl, 2-propynyl, 1,3-hexazinyl, 2-hexynyl, icosatriynyl and the like. Examples of alkoxy groups: methoxy, ethoxy, n-hexyloxy, 3-methylbutoxy, icosyloxy, nonadesoxy, phenoxy, penzyloxy and the like. Examples of alkylthio groups: methylthio, ethylthio, 2-methyl-2-propylthio, 3-methylbutylthio, n-hexylthio and the like.

In addition, the “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. Group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted aromatic heterocyclic group substituted by 1 or 2 groups.Also, these alkyl and alkenyl groups are integrated with the nitrogen atom to be bonded. It can also form heterocycles which may contain a 6, 6 or 7 membered nitrogen, oxygen or sulfur atom. Examples of the substituted amino group include methylamino, ethylamino, propylamino, acetylamino, 2-propenylanino, 1-piperazinyl, morpholino, thiomorpholino, perhydroazepinyl, phenylamino, naphthylamino, pyridylamino, furylamino, and furylamino. / Rare amino, piperidino, upper. 1-pyrrolidinyl, 3-butenylamino, and the like. .

The “substituted or unsubstituted aromatic hydrocarbon” is a mono- or polycyclic aromatic hydrocarbon which may have one or more various substituents in a ring. Phenyl, methylphenyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, dinitrophenyl, trifluoromethylphenyl, dimethylaminophenyl, mercaptophenyl, hinaphthyl,? -Naphthyl And the like.

The term “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.

The term “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.

In the present specification, the term “heterocycle” includes both an aromatic heterocyclic group and a non-aromatic heterocyclic group.

The term "alkylene group having a cyclic substituent" refers to a C1- (12, preferably C1-C6 alkylene group, and examples of the cyclic substituent include cyclopropyl, cyclobutyl, cyclopentyl, and cycloalkyl. 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? -Naphthyl groups, and pyridyl, furyl, chenyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, benzozoenyl, imidazo Le, 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.

The N-alkylsulfonyl substitution represented by the general formula (1) provided by the present invention In amide derivatives,

1 is a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted C2-C20 alkynyl group, a substituted or unsubstituted aromatic carbonized Hydrogen 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 A C2-C20 alkynyloxy group or a group represented by R2-0- (wherein R2 is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group) ,

Y is a group represented by -CR3 = CR4-, -N = CR3- or -CR3 = N-, or a sulfur atom or an oxygen atom;

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. .

Further, 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.

A moiety is an aromatic hydrocarbon group having 1,2-position substitution position, an aromatic heterocyclic group having 1,2-position substitution position, a cyclic alkenyl group having 1,2-position substitution position, or L Also preferred are any of the cyclic alkyl groups having a substituent at the 1-position.

Further, 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 . Further, in the case of the general formula (2), a group in which Z is represented by -CR9 = CR10- is preferable. Here, it is particularly preferred that R9 and 110 are hydrogen atoms. In the case of R 20, an ethynyl group substituted by an aryl group is preferable. The aryl group bonded to the ethynyl group preferably has a substituent containing a fluorine atom or a fluorine atom bonded thereto. In the case of R 2◦, an alkoxy group such as a phenoxy group or a pendoxy group is also preferable. It is preferable that a fluorine atom or a substituent containing a fluorine atom is bonded to the alkoxy group. The number of substituents is not particularly limited.

R 9 ~! Preferably, 118 is a halogen atom-substituted C1-C12 alkyl group or alkoxyl group, and particularly preferably a fluorine atom-substituted C1-C12 alkyl group or alkoxyl group.

Further, Y in the formula (1) is preferably a group represented by -CR3 = CR4-, -N = CR3- or -CR3N-, or a sulfur atom or an oxygen atom. Y is preferably -CR3 = CM-, or any group represented by a sulfur atom or an oxygen atom, and particularly preferably -3 = 4-. Here, it is particularly preferred that R 3 and R 4 are hydrogen atoms. When Y is a group represented by -C0-NR3-, -NR3-C0-, R3 is preferably a substituted or unsubstituted C1-C12 alkyl group, particularly preferably an aryl substituted alkyl group. At this time, it is preferable that 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.

Three

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

It includes 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, and an unsubstituted or substituted cyclic alkenyl group. For example, ring B is a ring as shown in the following (6).

U> Q 1} OO Ο 1} _N QQQ} O

(6)

Four Among these, ring B is preferably a group represented by a substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, particularly a group represented by a heterocyclic ring having 5 ring members, and furthermore, a thiazo group. A group represented by a monocyclic ring or an oxaziazole ring is preferred.

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. Here, 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.

When 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.

The substituents in the above-mentioned R 1 to R 20, such as the substituted alkyl group, include a carboxyl group, a hydroxyl group, a halogen atom, a fluoromethyl group, a perfluoromethyl group, a fluoromethoxy group, a perfluoromethoxy group. And a methoxy group. In the present invention, the pharmaceutically acceptable salts include sodium salts and potassium salts.

Preferred examples of the compound represented by the above general formula (1) include the following compounds.

The N-alkylsulfonyl-substituted amide derivative of the general formula (1) can be synthesized, for example, by a production method represented by the following chemical formula.

(7) (8)

(Wherein 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 And D is a fluorine, chlorine, bromine, hydroxyl, N-hydroxysuccinimide group, or a like, such as a 4-12 trophenoxy group or a penfluorofluorooxy group.

Step 1 (Step 1) is a step of producing an ester compound (9) by condensing the amine (7) and the carbonyl compound (8). For example, when (8) is an acid chloride, a method of condensing with an amine (7) in the presence of a suitable base, or when (8) is a carboxylic acid, p-toluenesulfonic acid chloride, A method of forming an acid anhydride with ethyl, pivaloyl chloride, or the like, condensing with an amine (7) in the presence of an appropriate base, or the like.

For the reaction, the amine (7) and the carbonyl compound (8) were used in approximately equimolar amounts.

8 Preferably. 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 (Step 2) is a step of deprotecting the protecting group of the carboxyl group in the ester compound (9). Usually, 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. Using the obtained carboxylic acid as a raw material for step 3 and dissolving it in 1.4-dioxane under an argon atmosphere, adding an appropriate carbodiimide-based condensing agent, stirring at about 100 ° C for 30 minutes, and adding R 1 —Add the sulfonamide derivative and an appropriate base, stir at about 100 ° C for about 20 hours, evaporate the solvent under reduced pressure after the reaction, dilute the residue with ethyl acetate, 2N hydrochloric acid aqueous solution and saturated saline And then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized by general formula (1). A compound can be obtained.

Steps 1, 2, and 3 described above can be carried out in an inert solvent. Examples of such a solvent 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.

In all of the above-mentioned steps, if necessary, subject to purification methods commonly used, for example, filtration, decantation, extraction, washing, solvent evaporation, column or thin-layer chromatography, recrystallization, distillation, etc. Thus, it can be isolated and purified. The 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). In addition, 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.

In addition, 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. Anti-improvement agent, PPAR-alphaagonists such as clofibrate, SGLT inhibitors such as T-1095, GLP-1 receptor antagonists, and hypoglycemic agents such as DPP-IV inhibitors, such as epalles evening, fidales evening Aldose reductase inhibitors, e.g., citrate and generales, e.g., diabetic nervous disorders such as mecobalamin, mexitylene, e.g., pravasin, simbas, flubas, seripastatin, HMG-CoA reductase inhibitors such as atorbasitin and itabassin, antioxidants such as lipoic acid and probucol, such as calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Overnight blockers, << 1 blockers, antihypertensives such as diuretics, etc., anti-obesity drugs such as orlistu, sibutramine, etc. If there is such a low-energy diet, such as O Petit fast. Existing medicines and developments that are not illustrated, including diet therapy and exercise therapy, as well as medicines under basic research, are similar to the above-mentioned medicines, and include obesity, hyperlipidemia induced by obesity, and insulin. Various diseases based on resistance (Impaired glucose tolerance, diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, hyperlipidemia, hypertension, arteriosclerosis) Combined use with a compound of general formula (I) for therapeutic purposes Case is included in the present invention.

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.

When the general formula (I) and another drug are used in combination, 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 containing the general formula (I) ′ can be prepared into various dosage forms, for example, oral administration preparations such as tablets, capsules, granules, powders, troches and solutions. These formulations can be prepared by a method known per se. For example, the compound of the general formula (I) of the present invention may be used in combination with excipients such as starch, mannitol and lactose; binders such as carboxymethylcellulose sodium and hydroxypropylcellulose; Disintegrators; tablets, capsules, granules, powders, troches, etc. are prepared by appropriately combining disintegrants; lubricants such as talc, magnesium stearate, etc .; be able to. Further, 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.

When the general formula (I) and another drug are used in combination, it is not necessary to include all the active ingredients in the same preparation, and each component or a plurality of components can be contained in one or more appropriate preparations. In such a case, 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

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The synthesis example and the pharmacological test example are described below.

Synthesis Example 1 (Synthesis example of compound shown below).

4-3-D-Ethyl benzoate (l. Llg, 4.03 t) was dissolved in getylamine (10 ml). 下 Under an argon atmosphere, 3-ethynyl-hi, hi, hi-hi-trifluorotoluene (1.03 g, 6.05 employment / 1) ), Dichlorobistriphenylphosphine palladium (28.3 mg, 0.0403 dl) and Then, copper iodide (15.4 mg, 0.0806 alcohol) was added, and the mixture was stirred at 50 ° C for 1 hour. After the reaction was completed, getylamine was distilled off under reduced pressure, 1N-hydrochloric acid was added to the residue, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.28 g (yield> 99%) of the ethyl ester which was a synthetic intermediate of Example 1.

1H-NMR (CDC13): 1.42 (3H, t, J = 7.2Hz), 4.40 (2H, q, J = 7.2), 7.50 (1H, dd, J = 7.5), 7.58-7.6K 3H, m), 7.60 (2H, d, J2 8.7), 7.71 (1H, d, J = 7.5), 7.81 (1H, S), 8.05 (2H, d, J = 8.7)

continue,

The resulting Echiruesuteru (1.28 g, 4.03舰ol) in methanol (10 ml), was dissolved in THF (15ml), 2 N- NaOH (3.0ml, 6.05 Awakening: ₀ 1) 1.511 stirred pressurized tut room temperature _<3 reaction After completion, the reaction solution was acidified by adding 1N-HC1, the solvent was distilled off under reduced pressure, a large amount of H20 was added to the residue, and the mixture was allowed to stand overnight. The precipitated crystals were filtered to obtain 1.06 g (yield: 91%) of carboxylic acid which was a synthetic intermediate of Example 1.

1H-NMR (DMS0): 7.70-7.73 (1H, m), 7.72 (2H, d, J = 8A), 7.82 (lH, dd, J = 8.7), 7.91 (1H, dd, J = 7.5), 7.97 (1H, S), 7.99 (2H, d, J = 8A) Then, in an argon atmosphere, 3 ml of thionyl chloride was added to 517 mg (1.78 liter) of the obtained carboxylic acid, and the mixture was stirred at 60 ° C for 2 hours. Then, thionyl chloride was distilled off under reduced pressure. The residue was dissolved in 6 ml of methylene chloride, and this was added dropwise to a solution of Anthranilic acid methyl ester 0.230 ml (1.78 liters) in 10 ml of pyridine at 0 ° C. After stirring at room temperature for 20 hours, pyridine was distilled off under reduced pressure. did. The residue was dissolved in ethyl acetate, washed sequentially with a 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After the bow 1, the residue was dissolved in methanol (10 ml) and THF (15 ml), and a large excess of LiOH.H20 was added, followed by stirring at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid was added to the residue, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain 556 mg (yield: 76%) of the corresponding carboxylic acid.

Subsequently, under an argon atmosphere, 502 mg (L23 bandol) of the obtained carboxylic acid was dissolved in 20 ml of 1.4-dioxane, and 280 mg (1.47 tmol) of WSC'HCl was added.The mixture was stirred at 94 ° C for 30 minutes, and then Butane-1 -Add sulfonic acid amide 202mg (1.47 t1) and DBUO .368ml (2.46) and add 94. The mixture was stirred at C for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was diluted with 25 ml of ethyl acetate, washed successively with 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by PTLC to obtain 479 mg (yield 74%) of the target compound of Example 1.

1H-NMR (DMS0): 0.88 (3H, t, J = 7.2Hz), 1.34-1.40 (2Η, m), 1.60-1.65 (2H, m), 2.93 (2H, t, J = 7.5), 6.69-3.70 (1H, m.), 7.18-7.23 (1H, m), 7.44-7.96 (6H, m), 8.04-8.26 (2H, m), 8.61-8.64 (1H 5 m), 8.88 -8.89 ( 1H ₃ m), 12.73 (1H, s)

MS (ESI) m / z: 529.31 (MH +)

Synthesis Example 2 (Synthesis example of the compound shown below)

Synthesis of the following benzoic acid having a thiazole ring which is a synthetic intermediate of Synthesis Example 2

2.0 g of Wang resin (0.91 t ol / g) was suspended in NMP and left at room temperature for 3 hours. Excess solvent was removed, and NMP 30 ml, 4-cyanobenzoic acid 1.6 g, pyridine 1.45 ml, 2,6-dichlorobenzozoyl chloride 1.56 ml were added thereto, and the mixture was stirred at room temperature for 20 hours. The solvent was removed and the resin was further washed twice with 30 ml of NMP. After removing the solvent, the residue was washed three times with 30 ml each of dichloromethane, .NMP, and dichloromethane in that order, and the resin was further dried. 50 ml of 1 solution was added, and 10 ml of 0,0-diethyl dithiophosphoride ester was further added, followed by stirring at 80 for 12 hours. The solvent was removed, and the resin was washed twice with 30 ml of NMP. After removing the solvent, dichloromethane, NMP, and dichloromethane were washed three times with 30 ml each in this order, and the resin was further dried.

continue,

50 ml of NMP was added to the obtained thioamide resin, and 2.5 g of 4- (trifluoromethoxy) phenanthyl bromide was added thereto. The mixture was stirred at 80 ° C. for 12 hours. The solvent was removed and the resin was further washed twice with 30 ml of NMP. After removing the solvent, dichloromethane, NMP, and dichloromethane were washed three times each in the order of 30 ml each, and the resin was further dried. 100 to the resin obtained After addition of 50 ml of trifluoroacetic acid at 50% for 1 hour, the reaction solution and the resin were separated by filtration, and the reaction solution was concentrated under reduced pressure, and a benzoic acid having a thiazole ring, which was a synthetic intermediate of Synthesis Example 2 93 g was obtained.

Subsequently, in an argon atmosphere, 3 ml of thionyl chloride was added to 679 mg (1.86 mol) of the obtained benzoic acid, and the mixture was stirred at 60 ° C. for 3 hours, and then thionyl chloride was distilled off under reduced pressure. The residue was dissolved in 6 ml of methylene chloride, and this was added dropwise at 0 ° C. to a solution of 0.240 ml (1.86 mol) of anthranilic acid methyl ester at 0 ° C., stirred at room temperature for 15 hours, and pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain an ester compound (568 m, yield 61%).

Subsequently, under an argon atmosphere, 568 mg (1.14 t ol) of the obtained ester was dissolved in methanol (20 ml) and THF (20 ml), and 239 mg (5.70 g ol) of LiOH / H20 was added, and the mixture was added at room temperature for 16 hours. Stirred. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added a 1N-HC1 aqueous solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain carboxylic acid (549 mg, yield: 99%). .

Subsequently, under an argon atmosphere, 395 mg (0.816 t) of the obtained carboxylic acid was dissolved in 20 ml of 1.4-dioxane, and 187 mg (0.979 t) of WSC-HGI was added.After stirring at 100 ° C for 30 minutes, Butane-sulfonic acid was added. Acid amide (34 mg, 0.979 mmol), 08110.182] 111 (1.22%) and a low catalytic amount of 6D2-t-Butylimino-2-diethylamino-1.3-dimethylperhydro-1.3.2-diazaphosphorine were added, and the mixture was stirred at 100 ° C. for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was diluted with 25 ml of ethyl acetate, washed sequentially with a 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain the desired compound of Example 2 (380 mg, yield 77%).

1H-NMR (DMS0): 0.84 (3H, t, J = 7.2Hz), 1.33-1.43 (2Η, m), 1.61-1. 76 (H, m), 2.92-2.97 (2H, m), 6.70-6 1H, m), 7.25 to 7.30 (1H, m), 7.48-7.52 (2H, m), 7.58-7.64 (1H, m, 7.77-7.82 (1H, m), 8.08-8.28 (7H, m), 8.37 (1H, s)

MS (ESI) m / z: 604 (MH +) Synthesis Example 3 (Synthesis example of compound having the following structure)

In an argon atmosphere, 3 ml of thionyl chloride was added to 703 mg (2.35 mol) of rubonic acid synthesized using the corresponding raw materials in the same manner as in Example 2, and the mixture was stirred at 60 ° C for 2 hours, and then thionyl chloride was added. The solvent was distilled off under reduced pressure. The residue was dissolved in 6 ml of methylene chloride, and the solution was added dropwise to a 10 ml pyridine solution of 0.304 ml (2.35 ol) of Anthranilic acid methyl ester at 0 ° C. After stirring at room temperature for 2 hours, pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (50 ml) and lightning (5 (M), a large excess of 4N-NaOH was added, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, 1 N hydrochloric acid was added, and the organic solvent was removed under reduced pressure. The solvent was distilled off under reduced pressure, the residue was purified by recrystallization, and 713 mg of rubonic acid (73% yield) was obtained. Obtained.

Then, under argon atmosphere, 713 mg (1.70 t ol) of the obtained carboxylic acid was added to 1,4-dioxa dissolved in 20 ml of ne, added 421 mg (2.21 t) of WSC-HCl, stirred at 100 ° C for 30 minutes, and butane-1-sulfonic acid amide 280 mg (2.04 t), 08110.432] 111 (2.89 t) and catalyst amount Was added to the mixture, and the mixture was stirred at 100 ° C for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 25 ml of ethyl acetate, washed sequentially with 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain the target compound of Example 2 (659 mg, yield 72%).

1H-NMR (DMS0):. 0.82 (3H, t, J = 7.2Hz), 1.31-1.38 (2Η, m), 1.66-1 74 (2Η 3 m), 2.80-2.97 (2Η, m), 6.69- 6.72 (1Η, m), 7.25-7.35 (3Η, m), 7.55-7.62 (1Η ₅ m), 7.75-7.77 (1Η, m), 8.0.9-8.35 (9Η, m)

MS (ESI) m / z: 538.22 (MH +) Synthesis Example 4 (Synthesis example of compound having the structure shown below)

4- (3-Trifluoromethylphenylethenyl) benzoic acid 872 mg (3.00 mmol) s 1-Aminocyclopentanecarboxylic acid methyl ester hydrochloride 851 mg (4.74 mol) synthesized in Synthesis Example 1 -1160 mg (4.54 liters) of 1-methylbilizinodimoxide and 1.3 ml of triethylamine were dissolved in 5 ml of dry dichloromethane, and the mixture was stirred at room temperature overnight. The organic layer extracted by adding 20 ml of 1M hydrochloric acid and 30 ml of ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add 5 ml of ethyl acetate and 25 ml of hexane. The precipitated solid was collected by filtration to obtain 955 mg (2.30 ol) of the ester compound as a white powder (yield: 77%).

Subsequently, 955 mg (2.30 thigh) of the ester compound was dissolved in 10 ml of ethanol and 10 ml of 1,4-dioxane, and 10 ml of a 4 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 8 hours. The organic layer extracted by adding 50 ml of 1 M hydrochloric acid and 150 ml of ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to obtain 920 mg (2.29 mol) of carboxylic acid as a white powder (yield 99 %).

Subsequently, the obtained carboxylic acid (598 mg, 1.49 t ol), n-pentynesulfonamide 309 mg (2.04 mmol) s 1,8-diazabicyclo [5.4.0] pentadec-7-ene 0.50 ml (3.34 mmol) ), 469 mg of WSC hydrochloride (2.45 thigh 01) were dissolved in 5 ml of dried 1,4-dioxane, and the mixture was stirred at 80 ° C for 1 minute. After cooling, 5 ml of 1 M hydrochloric acid and 5 ml of ethyl acetate were added, and the mixture was stirred and separated. The organic layer was washed with 2 ml of 1 M hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (silica gel, dichloromethane: THF = 30: 1), concentration under reduced pressure to dryness, suspension in ethyl acetate: hexane (1:10), filtration, and 486 mg (0.909 ol) The compound of Synthesis Example 4 was obtained as a white powder (yield: 61%). MS (ESI) m / z: 535 (MH +)

Synthetic Examples 5 to 8 (Synthetic examples of the compound shown below)

Example No.R1 MS (ESI) (MH +)

5 n-Butyl 535

6 n-Pentyl 549

n-Propyl 521

8 n-Hexvl 563

Synthesized using the corresponding raw materials in the same manner as in Example 4.

Synthesis Example ^{9 (} Synthesis example of compound having the structure shown below)

It was synthesized in the same manner as in Example 4 using the corresponding raw materials. MS (ESI) m / z: 509 (M H +) Synthesis Example 10 (Synthesis example of the compound shown below)

It was synthesized in the same manner as in Example 4 using the corresponding raw materials. MS (ESI) m / z: 507 (MH +)

Synthesis Example 1 1 (Synthesis example of the compound shown below)

Three It was synthesized in the same manner as in Example 4 using the corresponding raw materials. MS (ESI) m / z: 650 (MH +)

Synthesis Example 1 2 (Synthesis example of compound having the following structure)

In the same manner as in Example 4, it was synthesized using the following benzoic acid having a thiazol ring, which is a synthetic intermediate of Synthesis Example 2. MS (ESI) m / z: 6 24 (MH +) Synthesis Examples 13 to 7 1 (Synthesis examples of the compound shown below)

Except for the compounds specifically shown below, two carboxylic acid derivatives each corresponding to the target compound were obtained in the same manner as in Example 19 compound or Example 23 compound.

It was synthesized using one kind of mid derivative. 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 residue was dissolved in methylene chloride, and this was added dropwise to a 110 ml pyridine solution of 311m of methyl 4-aminothiophene-3-carboxylate at 0 ° C. After stirring at room temperature for 2 hours, pyridine was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran and ethyl acetate, washed successively with a 2N-HC1 aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (80 ml) and THF (80 ml), a large excess of 2N-NaOH was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, 1 N-hydrochloric acid was added, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained carboxylic acid (292 mg) was added with THF (15 ml) and chloroform (15 ml), and 2-CHL0R0-1-METHYLPYRIDINIUM I0DID E 18Zmg, Butane-1-sulfonic acid amide 90 mg, 1,8-DIAZABICYCLO [5,4 , 0] -7-UNDECENE (DBU) (0.178 ml) was added, stirred at room temperature overnight, stirred at 55 ° C, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 1: 1), and concentrated under reduced pressure to dryness to obtain 189 mg of Synthesis Example 19 compound. MS (ESI) m / z: 562 (MH +). The synthesis of the compound of Example 23 will be exemplified.

The benzoic acid having thiazole で 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. The residue was dissolved in methylene chloride, and this was added dropwise to a solution of 0.631 ml of anthra nilic acid ethylester in 20 ml of pyridine at 0 ° C., stirred at room temperature for 2 hours, and pyridine was distilled off under reduced pressure. Dissolve the residue in ethyl acetate and add 2N-HC1 water After sequentially washing with a solution and saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (50 ml) and THF (50 ml), a large excess of 2N-NaOH was added, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, 1 N-hydrochloric acid was added, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to obtain a carboxylic acid. Dissolve 542 mg of the obtained cataphoric acid in THF (15 ml) and chloroform (15 ml), add 2-CHLORO-1-MET HYLPYRIDINIUM IODIDE 342m, stir overnight, concentrate under reduced pressure, and add ethyl acetate. After suspension in n-hexane and filtration, 466 mg of Benzo [d] [l, 3] oxazin-4-one derivative was obtained as a powder. MS (ESI) m / z: 467 (MH +). 466 mg of the obtained Benzo [d] [l, 3] oxazin-4-one derivative was dissolved in 1,4-dioxane (20 ml), and 157 mg of benzenesulfonamide, 1,8-DIAZABICYCL0 [5,4,0 ] -7- Add 0.299 ml of UNDECENE (DBU), stir at 90 ° C overnight, concentrate under reduced pressure, add 5 ml of 1 M hydrochloric acid and 5 ml of ethyl acetate, stir and separate the organic layer. After washing with 2 ml of M hydrochloric acid, the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, ethyl acetate: n-hexane = 1: 1), the mixture was concentrated to dryness under reduced pressure to give Synthesis Example 2. 3. Compound (410 mg) as a powder. MS (ESI) m / z: '624 (MH +). The synthesis of the compound of Example 36 is illustrated.

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. -diethlyamino-1, 3-dimethyl-perhydro 1,3,2-aiazaphospnorine (Β ΜΡ)), add a few drops, stir at 108 ° C for 30 minutes, concentrate under reduced pressure, and chromatograph (silica gel, ethyl acetate). : N-hexane = 1: 2), and then concentrated under reduced pressure to dryness to obtain the compound of Synthesis Example 36. MS (ESI) m / z: 581 (MH +). The synthesis of the compound of Example 37 is illustrated.

Example 23 21m of Benzo [d] [1,3] oxazin-4-one derivative which is a synthetic intermediate of 3 was dissolved in 3ml of pyridine, and 5mg of 6-amino-3-picoline, 2-tert-Butyli mmo-2- Add a few drops of dietnlyainino-丄, 3-dimethyl-perhydro 1,3,2-diazaphosphorine (BE MP), stir at 108 ° C for 30 minutes, concentrate under reduced pressure, and chromatograph (silica gel, ethyl acetate: n After purification with -hexane = 1: 2), the mixture was concentrated under reduced pressure to dryness to obtain the compound of Synthesis Example 37. MS (ESI) m / z: 575 (MH +).

The structural formula of the obtained compound is shown below.

[Example 3 1]

[Example 4 1] [Example 4 2]

[Example 6 7]

The mass spectrometry data of the obtained compound is shown below.

ε

86000 / C0df / X3d 1.86S0 / C0 OAV Pharmacological test example 1: Measurement of ACC inhibitory activity

1. Purification of ACC

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 ヽ 10 mg / L Homogenized in 1 eupeptic 1 mM PMSF) using a Polytron homogenizer. 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. The supernatant was dialyzed against buffer C (100 mM Tris-HCl (pH 7.5), 500 mM NaCl, 1 mM EDTA, 0.1 mM DTT, 5% glycerol). The dialyzed supernatant was filtered through a 5〃M filter overnight, applied to a monomeric avidin sepharose column, washed with buffer B, and eluted with AC B with buffer B containing 2 mM d-biotin. .

2. Measurement of ACC inhibitory activity

Each of the compounds prepared in the above Examples was dissolved in DMS0, placed in a glass vial, and contained 250 〃 of the 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. To reaction solution 1 was added 250〃1 of reaction solution 2 (40 mM Tris-HCl (pH 7.5), 2 mM DTT ヽ 8 mM ATP, 0.5 mM acetyl CoA) containing [14C] -NaHC03, and 37. 1 in C After heating for 0 minutes, 100 1 of INHC1 was added to stop the reaction. Centrifugal evaporator-After removing the water in the reaction solution in the evening, the scintillator was added overnight to dissolve the solid components, and the radioactivity of WC was measured with a liquid scintillation counter. The ACC inhibitory activity of each compound was calculated from the following formula, and the concentration (IC50) at which 50% inhibition was obtained was determined. The results are shown in Table 1. Tables 12 and 12 show the results of evaluating the ACC inhibitory concentration at the compound concentration.

Table 1-2 Example No. ACC Inhibition (%) Example No. ACC Inhibition (%)

13 12 43 13

14 5 44 21

15 99 45 96

16 63 46 35

17 27 47 38

18 50 48 24

19 78 49 49

20 71 50 28

21 11 51 13

22 58 52 38

23 97 53 100

24 46 54 96

25 97 55 34

27 19 56 66

28 28 57 54

29 34 58 80

30 100 59 80

31 100 60 46

32 100 61 33

33 100 62 29

34 16 63 32

35 14 64 61

36 30 65 24

37 46 66 9

38 24 67 28

39 18 68 32

40 12 69 29

41 6 70 28

42 4 71 42 ACC inhibition rate (%) = {1 — (ac) / (bc)} x 100 a: Radioactivity when test drug is added

: Radioactivity without test drug added

c: Blankne

* Before adding Reaction Solution 1 and Reaction Solution 2, IN HC1 100 1 was added to Reaction Solution 1 in advance. Pharmacological Test Example 2: Anti-obesity effect in diabetic model KK-Ay mouse, hyperlipidemia improving effect, Hypoglycemic effect and glucose tolerance improving effect

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). For the effect of improving hyperlipidemia and the effect of lowering blood glucose, the rate of reduction after the end of administration was determined and evaluated according to the following formula (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

b: Plasma triglyceride concentration (or whole blood glucose concentration) in the control group The body weight glucose tolerance improving effect was evaluated using ΔΑΐ after calculating the AUC of blood glucose from the blood glucose transition curve up to 180 minutes after administration of gnorecose. . AAUC is calculated by the following equation. It was calculated from: _C The results are shown in Table 5

ΔAUC = (average value of AUC in control group) (average value of AUC in i-conjugated group) Table 1 ACC inhibitory activity

Table 2 Anti-obesity effect

Table ³ Effect of improving hyperlipidemia

Compound name Dose Plasma triglyceride

(mg / kg) Reduction rate (%)

Example 1 Compound 175 31.7 Table 4 Hypoglycemic effect

Table 5 Effect of improving glucose tolerance

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.

Claims

The scope of the claims

1. An N-alkylsulfonyl-substituted amide derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

(Where R 1 is

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 2-0 — (wherein R 2 is a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group) Or or

R 1-SO 2- is a substituted or unsubstituted heterocyclic group, and Y is -CR3 = CR4- -C0-NR3-, -NR3-C0-,-N = CR3- or- CR3 is a group represented by N- or a sulfur atom or an oxygen atom;

In the general formula (1), R1, R2, R3, R4, R5, and R6 may be the same or different,

R 3 R4, 5 R6

Substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted ~ C1 2 alkyl group, substituted or unsubstituted C2-C12 alkenyl group, substituted or unsubstituted C2-C12 alkynyl group, or substituted or unsubstituted C1-C12 alkoxy group, hydrogen atom, hydroxyl group, mercapto group A substituted or unsubstituted C1-C12 substituted amino group, a substituted or unsubstituted C1-C6 alkylthio group, a nitro group, a halogen 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 A non-aromatic heterocyclic group or an alkylene group having a cyclic substituent,

X is represented by any of the general formulas (2), (3), (4), (5), and R 20;

R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 in the general formulas (2), (3), (4), and (5) And R 19 may be the same or different, and each represents 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 a substituted or unsubstituted C1-C12 alkoxyl group, a hydrogen atom, a hydroxyl group, a mercapto group, a substituted or unsubstituted C1-C12 substituted amino group, substituted or An unsubstituted C- _S alkylthio, nitro, halogen, or cyano group;

Z is a group represented by -CR9-CR10-, -N = CR9- or -CR9 = N-, or a sulfur atom or an oxygen atom;

Q is a group represented by -CR9 = N- or a sulfur atom or an oxygen atom;

Including substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted heterocyclic ring having 4 to 9 ring members, unsubstituted or substituted cyclic alkyl group, unsubstituted or substituted cyclic alkenyl group ,

Ring C is

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 璟 -alkenyl group;

R 20 is 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 a substituted or unsubstituted C1-C12 alkoxyl group Group, hydrogen atom, hydroxyl group, mercapto group, substituted or unsubstituted C1-C12 substituted amino group, substituted or unsubstituted C1-C6 alkylthio group, nitro group, halogen atom, or cyano group,

R 7 and R 8 are R 3, R 4, R 5 and R 6 in the general formula (1) or R 9 and R 9 in the general formulas (2), (3), (4) and (5) R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19 are covalently bonded to form a ring structure Includes what you take. )

2. In equation (1),

R1 is a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted C2-C20 alkynyl group, a substituted or unsubstituted aromatic group Hydrocarbon group, substituted or unsubstituted aromatic heterocyclic group, substituted amino group, substituted or unsubstituted C20 alkoxyl group, substituted or unsubstituted C2-C20 alkenyloxy group, substituted or unsubstituted A C2-C20 alkynyloxy group or a group represented by R 2-0— wherein R 2 is a substituted or unsubstituted aromatic or aromatic heterocyclic group; ),

Y is a group represented by -CR3 = CR4-, -N = CR3- or -3 = N-, or a sulfur atom or an oxygen atom;

2. The component A is 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 derivative of the above-mentioned N-alkylsulfonyl-substituted amide or a pharmaceutically acceptable salt.

3. A moiety is an aromatic hydrocarbon group having a 1,2- or 1,3-position as a substitution position, an aromatic heterocyclic group having a 1,2- or 1,3-position as a substitution position, 1, Second or , A cyclic alkenyl group having a substitution position at the 1,3-position, a substituted or unsubstituted acyclic group, a partial structure of one amino acid (a part of an amino acid excluding an amino group and a carboxyl group), or 3. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt according to claim 1 or 2, which is represented by a cyclic alkyl group having a substituent at position 1, 1, 2, or 1,3.

4. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the A portion is a substituted or unsubstituted phenyl group.

5. The N-alkylsulfonyl-substituted amide derivative according to any one of claims 2 to 4, wherein X is represented by any one of the general formulas (2), (3), (4), and (5): Pharmaceutically acceptable salts.

6. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein X is represented by R20.

7. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to claim 6, wherein X is represented by R 20, wherein R 20 is an ethynyl group substituted with an aryl group. Salt.

8. The N-alkylsulfonyl substitution according to claim 6, wherein X is represented by R 20, wherein R 20 is an ethynyl group substituted by a fluorine atom or an aryl group to which a substituent containing a fluorine atom is bonded. An amide derivative or a pharmaceutically acceptable salt thereof.

9. The N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein X is represented by the general formula (2).

10. An N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable compound according to claim 4, wherein X is represented by the general formula (2), and Z in the formula (2) is represented by -CR9 = CillO-. salt.

X is represented by the general formula (2), Z in the formula (2) is represented by -CR9 = CR10-, and Y in the formula (1) is -CR3 = CR4- or a sulfur atom or an oxygen atom. Claim 4 indicated Or an N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof.

12. The N-alkylsulfonyl-substituted amide derivative or the N-alkylsulfonyl-substituted amide derivative according to claim 9, wherein the ring B in the general formula (2) is a substituted or unsubstituted ring having 4 to 9 heterocyclic groups. Pharmaceutically acceptable salts.

13. The N-alkylsulfonyl-substituted amide derivative or its derivative according to claim 9, wherein ring B in the general formula (2) is a substituted or unsubstituted heterocyclic ring having 5 members. Pharmaceutically acceptable salts.

14. The N-alkylsulfonyl-substituted amide derivative or pharmaceutically acceptable salt according to claim 9, wherein ring B in the general formula (2) is represented by a thiazole ring or an oxaziazole ring.

15. An ACC activity inhibitor comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

16. A prophylactic and / or therapeutic agent for obesity, comprising the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient.

17. A preventive and / or therapeutic agent for hyperlipidemia comprising an N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient. .

18. A preventive and / or therapeutic agent for fatty liver containing the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient. .

19. A hypoglycemic agent comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

20. An impaired glucose tolerance or diabetes containing the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient. Preventive and / or therapeutic drugs for the disease.

21. A prophylactic and / or therapeutic agent for diabetic complications comprising the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient.

22. An agent for preventing and / or treating hypertension and arteriosclerosis, comprising an N-alkylsulfonyl-substituted amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 as an active ingredient. .

23. Effectively using the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and one or two of the following Group A drugs: Preventive and / or therapeutic agent for obesity, hyperlipidemia, and fatty liver as a component.

A: Insulin, sulfonylide agent, alpha-glycosidase inhibitor, biguanide agent, PPAR-gammaagonist, PPM-gammaangonist, PPM-alphagonist, SGLT inhibitor, GLP-1 receptor antagonist, DPP -IV inhibitor, Aldose reductase inhibitor, Diabetic neuropathy drug, HMG-CoA reductase inhibitor, Antioxidant, Calcium antagonist, Angiotensin converting enzyme inhibitor, Angiotensin II receptor Antagonists, base blockers, sperm blockers, diuretics, anti-obesity drugs, low energy one meal.

24. Effectively using the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and one or two of the following Group A drugs: Preventive and / or therapeutic drug for impaired glucose tolerance, diabetes, and diabetic complications.

A: Insulin, sulfonylurea agent, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPM-gamma antagonist, PPM-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist Gonist, DPP-IV inhibitor, Al Dose reductase inhibitor, diabetic neuropathy drug, G-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, Beiyu blocker, α ΐ blocker, diuretic, anti-obesity drug, low energy

25. The Ν-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and one or two of the following drugs of the group 薬剤 are effective: Prevention and / or treatment of hypertension and arteriosclerosis as an ingredient

A: Insulin, sulfonylurea, alpha-glycosidase inhibitor, biguanide, PPAR-gamma agonist, PPAR-gamma-angonist, PPAR-alpha-gonist, SGLT inhibitor, GLP-1 receptor angonist , DPP-IV inhibitor, aldose reductase inhibitor, diabetic neuropathy drug, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin II receptor Antagonists, pet blockers, sperm blockers, diuretics, anti-obesity drugs, low energy

• —meal o

26. Effectively using the N-alkylsulfonyl-substituted amide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 and one or two of the following Group A drugs: Hypoglycemic agent as a component.

A: Insulin, sulfonylurea agent, alpha-glycosidase inhibitor, biguanide, PPM-gamma agonist, PPM-gamma anion gonist, PPM-alpha agonist, SGLT inhibitor, GLP-1 receptor antagonist Evening gonist, DPP-IV inhibitor, aldose reductase inhibitor, therapeutic agent for diabetic neuropathy, HMG-CoA reductase inhibitor, antioxidant, calcium antagonist, angiotensin converting enzyme inhibitor, angiodensin Π Receptor antagonists, Beethoyl blockers, 1 blockers, diuretics, anti-obesity drugs, low energy.

27. A pharmaceutical composition comprising the N-alkylsulfonyl-substituted amide derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.