JP6048533B2 - Medicament containing 2-pyridone compound - Google Patents

Description

  The present invention relates to a novel 2-pyridone compound having a glucokinase activating action, a tautomer of the compound, or a pharmaceutically acceptable salt thereof (the 2-pyridone compound or the tautomerism of the compound). Or a pharmaceutically acceptable salt thereof is hereinafter referred to as “compound etc.”), or a preventive or therapeutic agent for diabetes or obesity containing a solvate of the compound or the like as an active ingredient.

  The number of patients with type 2 diabetes is on the rise worldwide, and a serious prognosis is brought about by the progression of the disease state and the onset of complications. Therefore, the development of new preventive or therapeutic agents is eagerly desired. Type 2 diabetes has a large risk of onset due to the development of a lifestyle in advanced countries, that is, excessive intake energy relative to the amount of physical activity, against the background of genetic predisposition and aging that are suggested to be related to its onset. It is thought to increase. In addition, metabolic abnormalities underlying the pathological conditions include decreased glucose utilization in skeletal muscle and adipose tissue, impaired insulin secretion from pancreatic beta cells, impaired suppression of hepatic glucose release, and the like. It is considered useful for the prevention and treatment of diabetes.

  Drug reduction with insulin sensitizers typified by thiazolidine derivatives (eg, pioglitazone) is considered effective for reducing glucose utilization in skeletal muscle and adipose tissue, but exacerbation of obesity, fluid retention, Increased risk of heart failure and increased incidence of bladder cancer have been reported, and careful judgment is required before use. In addition, sulfonylurea drugs (eg, glimepiride, glibenclamide, glipizide) are thought to be effective for insulin secretion disorders, but they often cause hypoglycemia and overweight, and the therapeutic effect is diminished during long-term use. Since it may lead to defects (secondary invalidity), problems remain in both safety and effectiveness. For postprandial hyperglycemia, α-glucosidase inhibitors (eg, acarbose, voglibose, miglitol) and glinide drugs (eg, nateglinide, repaglinide, mitiglinide) are used, but the therapeutic effect on diabetes is limited. Biguanides (eg, metformin) are effective in suppressing hepatic glucose release, but control of blood glucose becomes difficult as the disease progresses, and may be restricted due to gastrointestinal side effects, lactic acidosis risk, etc. . As is clear from the findings regarding the main drugs, existing drugs do not satisfy medical needs. In particular, there is substantially only metformin as a drug that directly corrects hepatic glucose metabolism, and there is a great need for drugs that can correct hepatic glucose metabolism by a novel mechanism of action.

Glucokinase (hereinafter referred to as GK) belongs to the hexokinase family, and catalyzes phosphorylation of glucose taken into cells in pancreatic beta cells and hepatocytes. GK of liver and pancreatic beta cells are identical in terms of enzyme, although their N-terminal 15 amino acid sequences differ due to differences in splicing. GK is affinity S _0.5 for glucose as high as before and after 10 mM, and, since by glucose 6-phosphate is a product inhibition is not subjected, the reaction rate is sensitive to physiological variation range of the blood glucose level To do. Pancreatic beta cells regulate glucose-dependent insulin secretion, while the liver regulates glycolysis or glycogen synthesis to maintain and regulate blood glucose levels. For this reason, GK is considered to function as a glucose sensor for maintaining blood glucose level homeostasis (see Non-Patent Document 1).

  The hypothesis that GK functions as an in vivo glucose sensor is supported by the discovery of genetically engineered mice and human genetic mutations. GK homo-deficient mice exhibit hyperglycemia soon after birth and die, and in hetero-deficient mice, hyperglycemia and impaired glucose tolerance have been observed (see Non-Patent Document 2). On the other hand, a decrease in blood glucose has been confirmed in GK overexpressing mice (see Non-Patent Document 3). Furthermore, diabetes occurs from a young age in human MODY2 (maturity onset diabetics of the young) in which a GK gene mutation is observed (see Non-Patent Document 4). This gene mutation has been confirmed to reduce GK activity. On the other hand, a family having a gene mutation that enhances GK activity has also been reported (see Non-Patent Document 5). With this gene mutation, the affinity of GK for glucose is enhanced, and a fasting hypoglycemia symptom accompanied by an increase in blood insulin concentration is observed.

  Thus, GK has been shown to function as a glucose sensor in mammals including humans.

  Substances that increase GK activity (hereinafter referred to as GK activators) may correct hyperglycemia by increasing glucose metabolism in the liver, glycogen synthesis, and glucose-responsive insulin secretion from pancreatic beta cells. It seems possible. Among them, it is considered that a substance that increases GK activity predominantly in the liver can correct hyperglycemia by enhancing glucose metabolism in the liver in an insulin-independent manner. Treatment and prevention of diabetic chronic complications such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis, and obesity, hyperlipidemia, hypertension, metabolic syndrome, etc. It can also be expected to lead to treatment and prevention of diabetes related diseases. Therefore, a compound that increases GK function is expected to be an effective therapeutic agent for diabetes.

  On the other hand, it has been reported that GK is expressed not only in the pancreas and liver but also in the feeding center and has an important function in the feeding-suppressing action by glucose (see Non-Patent Document 6). Therefore, it is considered that the GK activator acts on the feeding center and has a feeding-suppressing action, and can be expected not only as a treatment for diabetes but also as a therapeutic agent for obesity.

  In addition, although a compound having 2-pyridone has been reported as a GK activator, the structure is different from the compound of the present invention (see Patent Documents 1 and 2). Further, structurally similar 2-pyridone compounds have been reported, but there is no specific disclosure of the compounds of the present invention (see Patent Documents 3 and 4), and there is no description for medicinal use. This is different from the present invention in that it is a synthesis method of a pyridone compound (see Non-Patent Document 7). Furthermore, although certain acylurea compounds that can have a pseudo-ring structure have been reported as GK activators, they are non-cyclic compounds and are different from the compounds of the present invention (see Patent Documents 5 and 6).

Matschinsky F.M. M.M. and Magnnuson M. et al. A. , Frontiers in Diabetes, 16, 2004 Group A. et al. Cell, 83, 1, 69-78, 1995 Ferre T. et al. Proc. Natl. Acad. Sci. , 93, 14, 7225-7230, 1996 Vionnet N.M. et al. Nature, 356, 6371, 721-722, 1992 Glaser B. et al. N. Engl. J. et al. Med. 338, 4, 226-230, 1998 Kang L. et al, Diabetes, 55, 2, 412-420, 2006 Latif R.R. et al. J. et al. Chem. Soc. C. Organic, 17, 2140-2144, 1968

WO2008 / 079787 pamphlet WO2010 / 013161 pamphlet US4275069 specification WO2011 / 068211 pamphlet WO2000 / 58293 pamphlet WO2001 / 44216 pamphlet

  An object of the present invention is to provide a preventive or therapeutic agent for diabetes or obesity containing a compound having an excellent GK activation action as an active ingredient.

  In view of the situation described above, the present inventors have conducted extensive research to find a compound having a GK activating action, and as a result, the 2-pyridone compound represented by the following formula [1] (compound name: 3- Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine-2 (1H) -One) or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the like has been found to achieve this object, and the present invention has been completed.

(I) One aspect of the present invention is the compound represented by the formula [1]

で表される２−ピリドン化合物若しくは該化合物の互変異性体、又はそれらの薬学的に許容される塩、又は該化合物等の溶媒和物を有効成分として含有する糖尿病又は肥満の予防又は治療薬を提供することである。
（ＩＩ）本発明の他の態様としては、（Ｉ）に記載の、上記式［１］で表され、下記（ａ）の物性を有する３−シクロプロピル−６−｛（１Ｒ）−１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オンの結晶を有効成分として含有する糖尿病又は肥満の予防又は治療薬を提供することである；
（ａ）粉末Ｘ線回折図（Ｃｕ−Ｋα）において、回折角２θ＝ ８．５、１３．４、１９．１及び２４．５°にピークを有する。
（ＩＩＩ）本発明の他の態様としては、（Ｉ）に記載の、上記式［１］で表され、下記（ａ）〜（ｃ）の物性を有する３−シクロプロピル−６−｛（１Ｒ）−１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オンの結晶を有効成分として含有する糖尿病又は肥満の予防又は治療薬を提供することである；
（ａ）粉末Ｘ線回折図（Ｃｕ−Ｋα）において、回折角２θ＝ ８．５、１３．４、１９．１及び２４．５°にピークを有する；
（ｂ）赤外線吸収スペクトルにおいて、特性吸収帯が ９１６、１１４６、１１６７、１２９５、１６５１、１６６４、２９０９、２９５５、３００３及び３１４６ ｃｍ^−１にある；
（ｃ）融点が１９９〜２０１℃である。
（ＩＶ）本発明の他の態様としては、上記式［１］で表される３−シクロプロピル−６−｛（１Ｒ）−１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オンを、アルコール系溶媒に加熱溶解させた後、水溶媒を加え５℃以下に冷却して結晶化させ、得られた結晶を６０℃以下で乾燥させて製造することを特徴とする、下記（ａ）〜（ｃ）の物性を有する３−シクロプロピル−６−｛（１Ｒ）−１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オンの結晶を有効成分として含有する糖尿病又は肥満の予防又は治療薬を提供することである；
（ａ）粉末Ｘ線回折図（Ｃｕ−Ｋα）において、回折角２θ＝ ８．５、１３．４、１９．１及び２４．５°にピークを有する；
（ｂ）赤外線吸収スペクトルにおいて、特性吸収帯が ９１６、１１４６、１１６７、１２９５、１６５１、１６６４、２９０９、２９５５、３００３及び３１４６ ｃｍ^−１にある；
（ｃ）融点が１９９〜２０１℃である。

A prophylactic or therapeutic agent for diabetes or obesity comprising a 2-pyridone compound represented by the formula (1) or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate such as the compound as an active ingredient Is to provide.
(II) As another aspect of the present invention, 3-cyclopropyl-6-{(1R) -1- represented by the above formula [1] described in (I) and having the following physical properties (a): Diabetes containing crystals of [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient or To provide a preventive or therapeutic agent for obesity;
(A) In the powder X-ray diffraction pattern (Cu-Kα), the diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 ° having peaks.
(III) As another embodiment of the present invention, 3-cyclopropyl-6-{(1R) represented by the above formula [1] described in (I) and having the following physical properties (a) to (c) ) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient Providing a preventive or therapeutic agent for diabetes or obesity;
(A) In the powder X-ray diffraction pattern (Cu-Kα), peaks are observed at diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum, the characteristic absorption bands are at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199-201 degreeC.
(IV) As another embodiment of the present invention, 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2 represented by the above formula [1] -[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one was dissolved by heating in an alcohol solvent, then added with an aqueous solvent and cooled to 5 ° C. or lower for crystallization. And 3-cyclopropyl-6-{(1R) -1- [4 having the following physical properties (a) to (c), which is produced by drying the obtained crystal at 60 ° C. or lower: -(1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient Providing a prophylactic or therapeutic agent;
(A) In the powder X-ray diffraction pattern (Cu-Kα), peaks are observed at diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum, the characteristic absorption bands are at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199-201 degreeC.

(V) As another aspect of the present invention, as described in (I), the 2-pyridone compound represented by the above formula [1], a tautomer of the compound, or a pharmaceutically acceptable product thereof It is intended to provide a prophylactic or therapeutic agent for diabetes or obesity, which is an oral solid composition containing a salt or a solvate such as the compound as an active ingredient and further containing lactose and magnesium stearate.
(VI) As another aspect of the present invention, there is provided a prophylactic or therapeutic agent for diabetes or obesity according to (V), wherein the dosage is 0.01 to 1000 mg / day. It is to be.

(VII) As another aspect of the present invention, 3-cyclopropyl-6-{(1R) -1- represented by the above formula [1] described in (I) and having the following physical properties (a): Containing crystals of [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient; Providing a prophylactic or therapeutic agent for diabetes or obesity, which is an oral solid composition comprising lactose and magnesium stearate;
(A) In the powder X-ray diffraction pattern (Cu-Kα), the diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 ° having peaks.
(VIII) As another aspect of the present invention, there is provided a prophylactic or therapeutic agent for diabetes or obesity according to (VII), wherein the dosage is 0.01 to 1000 mg / day. It is to be.

(IX) As another embodiment of the present invention, 3-cyclopropyl-6-{(1R) represented by the above formula [1] described in (I) and having the following physical properties (a) to (c) ) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient And providing a prophylactic or therapeutic agent for diabetes or obesity, which is an oral solid composition containing lactose and magnesium stearate;
(A) In the powder X-ray diffraction pattern (Cu-Kα), peaks are observed at diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum, the characteristic absorption bands are at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199-201 degreeC.
(X) As another aspect of the present invention, there is provided a prophylactic or therapeutic agent for diabetes or obesity according to (IX), wherein the dosage is 0.01 to 1000 mg / day. It is to be.

(XI) As another aspect of the present invention, represented by the above formula [1], 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2 -[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one was dissolved by heating in an alcohol solvent, then added with an aqueous solvent and cooled to 5 ° C. or lower for crystallization. And 3-cyclopropyl-6-{(1R) -1- [4 having the following physical properties (a) to (c), which is produced by drying the obtained crystal at 60 ° C. or lower: -(1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one as an active ingredient Providing a prophylactic or therapeutic agent;
(A) In the powder X-ray diffraction pattern (Cu-Kα), peaks are observed at diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum, the characteristic absorption bands are at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199-201 degreeC.
(XII) As another aspect of the present invention, there is provided a prophylactic or therapeutic agent for diabetes or obesity according to (XI), wherein the dosage is 0.01 to 1000 mg / day. It is to be.

  According to the present invention, a prophylactic or therapeutic agent for diabetes or obesity containing a 2-pyridone compound having an excellent GK activation action as an active ingredient could be provided.

3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine of the present invention 2 shows a powder X-ray diffraction pattern of -2 (1H) -one crystals. 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine of the present invention 2 shows an infrared absorption spectrum (ATR method, crystal: diamond) of a -2 (1H) -one crystal. 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine of the present invention 2 shows a differential thermal analysis / thermal mass measurement curve of a -2 (1H) -one crystal.

  Hereinafter, the present invention will be described in detail, but the present invention is not particularly limited thereto.

  In the present invention, “n” is normal, “i” is iso, “s” and “sec” are secondary, “tert” is tertiary, “c” is cyclo, “o” is ortho. , “M” represents meta, and “p” represents para.

  First, the compound of the present invention will be described.

  In the present invention, the pharmaceutically acceptable salt is, for example, a mineral salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, Carboxylates such as mandelate, ascorbate, lactate, gluconate, malate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, aspartate; or Inorganic or ammonium salts such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diisopropylamine salt, cyclohexyl A salt with an organic base such as a ruamine salt, preferably hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate Citrate, acetate, lactate, glutamate, aspartate, sodium salt, potassium salt, ammonium salt, or triethylamine salt.

  The solvate in the present invention is a pharmaceutically acceptable solvate of the compound of the present invention or a salt thereof. The compound of the present invention and the salt thereof may absorb water or become adsorbed water or become a hydrate by exposure to the atmosphere or recrystallization. The compound in the present invention includes such a hydrate.

  Although the compound of the present invention has two asymmetric centers, the compound of the present invention is an optically active substance, and the absolute configuration of the two asymmetric centers of the compound of the present invention is both (R). The compounds of the invention can be obtained by optical resolution of the corresponding racemates or diastereomeric mixtures. As a method of optical resolution, a method well known to those skilled in the art, for example, a fractional crystallization method or chromatography using a chiral column can be used. The optically active compound of the present invention can also be obtained by an organic chemical method well known for this purpose. The synthetic intermediate for obtaining the compound of the present invention may have geometric isomers such as (E) isomer and (Z) isomer, but the ratio of these isomers is arbitrary.

  The compounds of the present invention include tautomers. The tautomer means a keto-enol tautomer of the compound represented by the formula [1]. As an example, the compound represented by the above formula [1] and its tautomer [1 ′] are shown below.

  The 2-pyridone compound of the present invention may be a pharmaceutically acceptable salt thereof, or a solvate such as the compound. Hereinafter, the 2-pyridone compound of the present invention or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the like is referred to as “the compound of the present invention”.

  Also, a compound that has a group that can be chemically or metabolically decomposed and forms the compound of the present invention that is pharmacologically active by solvolysis or in vivo under physiological conditions, usually a compound called a prodrug It is included in “the present compound”.

  The compound of the present invention has a GK activation action. Therefore, the compound of the present invention can correct hyperglycemia mainly by increasing sugar metabolism in the liver. Therefore, it can be used as a new drug therapy having a different mechanism of action from existing anti-diabetic drugs. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes. Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral artery occlusion, etc.), neuropathy (sensory nerve, motor Nerve, autonomic nerve, etc.), foot gangrene, infection and other diabetic complications.

  Furthermore, it can be used for the treatment and prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout.

  The compound of the present invention can also be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like having a different mechanism of action other than GK activation. . By combining the compound of the present invention with other drugs, an additive effect can be expected when used in combination with the above-mentioned diseases rather than the effects obtained with a single agent.

  Examples of the therapeutic agents for diabetes and diabetic complications that can be used in combination include insulin preparations, insulin resistance improving agents (PPARγ agonists, PPARα / γ agonists, PPARδ agonists, PPARα / γ / δ agonists, etc.) (eg, pioglitazone, rosi Glitazone, alegritazal, periglitazar, AVE-0897, MBX-8025), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol), biguanide (eg, metformin, buformin, phenformin), insulin secretagogue ( Eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide), glucagon receptor antagonist, insulin receptor kinase promoter, dipeptidyl peptidase IV inhibitor (eg, vildagliptin) , Alogliptin, sitagliptin, linagliptin, saxagliptin, teneligliptin, anagliptin), SGLT inhibitor (eg, dapagliflozin, ruseogliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin), PTP1b inhibitor (eg, vanadine) Acid sodium), glucose 6 phosphatase inhibitor, glycogen phosphorylase inhibitor (eg, PSN-357, FR-258900), FBPase inhibitor (eg, MB-07803), PEPCK inhibitor, pyruvate dehydrogenase kinase inhibitor, D- Kaileusitol, GSK3 inhibitor, GLP-1 agonist (eg, liraglutide, exenatide), amylin agonist (eg, pramlintide), glucocorticoid receptor Tagonist, 11 beta HSD1 inhibitor (eg, INCB-13739, LY-2523199, Ro-5027838, Ro-5093151, S-707106), protein kinase C inhibitor (eg, ruboxistaurin), beta 3 adrenergic receptor Agonist, phosphatidylinositol kinase inhibitor, phosphatidylinositol phosphatase inhibitor, ACC inhibitor, GPR40 receptor agonist (eg, TAK-875), GPR119 receptor agonist (eg, APD-597, PSN-821, MBX) -2982, DS-8500), GPR120 receptor agonist, TGR5 receptor agonist, AMPK activator, aldose reductase inhibitor (eg, epalrestat, ranirestat, fidarestat), AG Such as inhibitors, and the like.

  Examples of drugs for diabetes-related diseases that can be used in combination include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT inhibitors , MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, pancreatic lipase inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor increasing drug, angiotensin converting enzyme inhibitor, angiotensin II antagonist, renin receptor Antagonists, aldosterone antagonists, diuretics, calcium antagonists, alpha blockers, beta blockers, endothelin converting enzyme inhibitors, endothelin receptor antagonists, appetite suppressants, uric acid production inhibitors, uric acid excretion promoters and the like.

  The compound of the present invention can be administered alone or in combination with a pharmaceutically or pharmaceutically acceptable carrier or diluent.

  In order to use the compound of the present invention as a pharmaceutical, any form of a solid composition, a liquid composition and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable carrier. Specifically, conventional excipients, fillers, binders, disintegrants, coating agents, sugar coatings, pH adjusting agents, solubilizers or aqueous or non-aqueous solvents are added, and tablets are prepared by conventional pharmaceutical techniques. Pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Examples of excipients and extenders include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. it can.

  The compound of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.

  When the compound of the present invention is used as a GK activator, the compound of the present invention may be administered orally or parenterally as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom and the like. For example, when administered orally to an adult diabetic patient, the dose is usually about 0.01 to 1000 mg, preferably It is 0.1-100 mg, and it is desirable to administer this amount 1 to 3 times a day.

  Next, the manufacturing method of this invention compound is demonstrated.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

  The compound of the present invention can be synthesized by a method known per se in the chemical field, or a method that undergoes one or two or more processes similar thereto. Such methods include, for example, ORGANIC FUNCTIONAL GROUP PREPARATIONS 2nd edition Academic Press, Inc., 1986, Comprehensive Organic Transformation (Comprehensive Organic Transformation). Examples include the methods described in VCH Publishers Inc., 1989, peptide synthesis basics and experiments, published by Maruzen, 1985, and the like.

  In the synthesis of the compound of the present invention, a suitable method for protecting and deprotecting a functional group contained in a starting material or an intermediate is a method well known to those skilled in the art, for example, Green's Protective Groups in Organic Synthesis (Green's Protective Synthesis). (Groups in Organic Synthesis) John Willy and Sons (John Wily and Sons) 2006, etc., can be performed according to the method described.

  Although the general manufacturing method of this invention compound is shown to scheme 1-2, a manufacturing method is not limited. It is well known to those skilled in the art, such as changing the order in which the steps are performed, applying a protecting group to the hydroxy group, etc., carrying out the reaction and performing deprotection in the subsequent steps, adding new steps in the middle of each step, etc. The compound of the present invention can also be produced by using the method.

Scheme 1: Synthesis method of compound [1] of the present invention from compound (1-a)

(In the scheme, G ¹ represents a protecting group for a hydroxy group in the hydroxypyridyl group, and R ¹ represents a 2-benzothiazolyl group or a 1-phenyl-1H-tetrazol-5-yl group.)
The compound (1-g) used in the step (1-4) can be obtained as a commercially available compound, a known compound, or a compound synthesized from a compound that is easily available using various organic synthesis methods known to those skilled in the art. .

Step (1-1):
Production method of compound (1-b): N, N-dimethoxyethylaminosulfur trifluoride (bis (2-methoxyethyl) aminosulfur trifluoride, Deoxo-Fluor (registered trademark)) to compound (1-a) The compound (1-b) can be produced by performing a “fluorination reaction” using a fluorinating reagent such as

  Examples of the fluorination reaction include reacting a compound (1-a) with a fluorinating reagent such as Deoxo-Fluor (registered trademark) in a solvent-free or inert solvent at a temperature of 0 ° C. to 100 ° C. And a method of giving the compound (1-b).

Step (1-2):
Production method of compound (1-d): Compound (1-d) is reacted with compound (1-c) in the presence of a base such as potassium acetate and a palladium catalyst in an inert solvent. Can be manufactured.

Step (1-3):
Production method of compound (1-f): After reacting compound (1-e) with a base such as n-butyllithium or n-butylmagnesium chloride in an inert solvent, N, N-dimethylformamide is allowed to act. Thus, compound (1-f) can be produced.
In addition, the compound (1-e) which is a starting material can be obtained by the method described in WO2011 / 066821, or a method analogous thereto.

Step (1-4, 1-5):
Production method of compound (1-h): (5R) -5- [2- (5) obtained by carrying out “coupling reaction” using carbonyl compound (1-f) and compound (1-g) -Cyclopropyl-6-methoxypyridin-2-yl) ethenyl] pyrrolidin-2-one (E / Z mixture) with bromine in an inert solvent followed by 1,8-diazabicyclo [5.4.0]. Compound (1-h) can be produced by reacting a base such as undec-7-ene (DBU).

  Examples of the coupling reaction include a compound (1-g) as a substrate and an organic solvent such as n-butyllithium, sec-butyllithium, and tert-butyllithium in an inert solvent at a temperature of −78 ° C. to 100 ° C. Examples include a method in which a compound (1-h) is obtained by reacting a carbonyl compound (1-f) with an anion generated by using a base such as a metal reagent, lithium hexamethyldisilazide, or potassium hexamethyldisilazide. It is done. Although the obtained olefin compound is generally obtained as an E / Z mixture, it can be isolated by dividing it using silica gel column chromatography, HPLC or the like.

  In addition, the compound (1-g) used for coupling reaction can be obtained by the method described in WO2011 / 068211, or the method according to it.

Step (1-6):
Production method of compound (1-i): Compound (1-i) is prepared by performing “coupling reaction” with phenylboron compound (1-d) in the presence of palladium catalyst using compound (1-h) as a substrate. Can be manufactured.

  Examples of the coupling reaction include a method of reacting the compound (1-h) with a phenylboron compound in the presence of a palladium catalyst and a base in an inert solvent at a temperature of 20 ° C. to 160 ° C. The reaction can also use a microwave.

  Examples of the palladium catalyst used in the coupling reaction include tetrakistriphenylphosphine palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (triphenylphosphine) palladium ( II) Palladium known to those skilled in the art, such as dichloride, bis (triphenylphosphine) palladium (II) acetate or [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) A catalyst is mentioned. Further, tris (dibenzylideneacetone) dipalladium (0) and tri (2-furyl) phosphine can be used for the reaction in the presence of a base.

Step (1-7):
Production method of compound (1-j): palladium-activated carbon, rhodium-active in the presence or absence of an acid in an inert solvent at a temperature of 0 to 80 ° C. using compound (1-i) as a substrate Compound (1-j) can be produced by reduction by catalytic hydrogenation reaction using a catalytic amount of carbon, platinum-activated carbon, or the like.

Step (1-8):
Production method of compound (1-k): Compound (1-k) can be produced by carrying out “deprotection reaction” of protecting group G ¹ of compound (1-j).

As the deprotection reaction, for example, when (i) the protecting group G ¹ is an alkyl group or an allyl group, hydrolysis reaction is performed in the presence of an acid or a strong acid in an inert solvent at a temperature of 0 ° C. to 200 ° C. removal and methods for the deprotection reaction such as methods using a method or aluminum chloride and alkyl thiols with trimethylsilyl iodide and the like can be given, (ii) the protecting group G ¹ is benzyl, 4-methoxybenzyl group , 2,4-dimethoxybenzyl group, benzyloxycarbonyl group, benzhydryl (diphenylmethyl) group, etc., at a temperature of 0 ° C. to 80 ° C., in an inert solvent, in the presence or absence of an acid, palladium- A method of removing activated carbon or rhodium-activated carbon by a catalytic hydrogenolysis reaction, or cerium (IV) ammonium nitrate or 2,3-di How to use Rollo 5,6-dicyano -p- oxidant benzoquinone and the like.

Step (1-9):
Method for Obtaining Compound [1] of the Present Invention: Compound (1) of the present invention [1] can be obtained by resolving the diastereomer of compound (1-k) using, for example, HPLC.

  In addition, the compound (1-a) and the compound (1-c) used as raw material compounds in the above scheme 1 can be obtained commercially or by a method known per se.

Scheme 2: Synthesis method of compound [1] of the present invention from compound (2-a)

（スキーム中、Ｇ^１及びＲ^１は上記に同じである。Ｇ^２はオキソ基で置換されたピロリジニル基中の窒素原子の保護基を示す。）

(In the scheme, G ¹ and R ¹ are the same as above. G ² represents a protecting group for a nitrogen atom in a pyrrolidinyl group substituted with an oxo group.)

Step (2-1):
Production method of compound (2-b): Compound (2-b) can be obtained by the method described in WO2008 / 103185 pamphlet or a method analogous thereto.

Step (2-2, 2-3):
Production method of compound (2-c): Compound obtained by carrying out "addition reaction" using compound (2-b) and an anion such as a lithium reagent such as heteroaryl lithium and a Grignard reagent such as heteroaryl magnesium bromide Is treated with an acid such as hydrochloric acid to produce compound (2-c).

  Examples of the addition reaction include compound (1-e) as a substrate and n-butyllithium, sec-butyllithium, tert-butyllithium, isopropylmagnesium bromide in an inert solvent at a temperature of −78 ° C. to 100 ° C. A method of reacting an anion generated by using a metal reagent such as organometallic reagent such as magnesium, a base such as lithium hexamethyldisilazide and potassium hexamethyldisilazide with the compound (2-b).

Step (2-4):
Production method of compound (2-d): Compound (2-d) can be produced by carrying out a “coupling reaction” using carbonyl compound (2-c) and compound (1-g).

  Examples of the coupling reaction include the same reactions as the above-described “coupling reaction” in the step (1-4).

The compound (2-d) obtained as described above can be led to the compound [1] of the present invention by the method described in the steps (1-7) to (1-9) of the above-mentioned scheme 1.
Moreover, this invention compound [1] can be manufactured also by the method shown below.

Step (2-5):
Process for the preparation of a compound (2-e): a compound having a pyrrolidinyl group substituted by an oxo group (2-d) to by the action of di -tert- butyl, the compound having a protecting group G ² (2 -E) can be produced.

Step (2-6):
Production method of compound (2-f): Palladium-activated carbon, rhodium-active using compound (2-e) as a substrate at a temperature of 0 ° C. to 80 ° C. in an inert solvent in the presence or absence of an acid Compound (2-f) can be produced by reduction by catalytic hydrogenation reaction using a catalytic amount of carbon, platinum-activated carbon or the like.

Step (2-7):
Production method of compound (2-g): Compound (2-g) can be produced by carrying out a “deprotection reaction” of protecting group G ² of compound (2-f).

  Examples of the deprotection reaction include a method using an acid such as hydrochloric acid or trifluoroacetic acid.

Step (2-8):
Production method of the compound [1] of the present invention: The compound [1] of the present invention can be produced by carrying out a “deprotection reaction” of the protecting group G ¹ of the compound (2-g).

  Examples of the deprotection reaction include the same method as the aforementioned “deprotection reaction” in the step (1-8).

  In addition, the compound (2-a) used as a raw material compound in the above-mentioned scheme 2 can be obtained commercially or by a method known per se.

  Finally, 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] of the present invention The crystal | crystallization of ethyl} pyridin-2 (1H) -one and its manufacturing method are demonstrated.

  Compound of the Invention 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} Crystals of pyridine-2 (1H) -one (hereinafter sometimes referred to as “crystals of the present invention”) have the chemical structural formula shown in the above formula [1].

The crystal of the present invention has the following physical properties (a) to (c);
(A) In a powder X-ray diffraction diagram (Cu-Kα, measurement method: transmission method), diffraction angle 2θ = 8.5, 10.8, 11.2, 11.6, 13.4, 16.8, 17 0.0, 17.9, 18.5, 18.8, 19.1, 19.4, 22.6, 23.1, 23.2 and 24.5 °, and in particular the diffraction angle 2θ. = With characteristic peaks at 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum (ATR method, crystal: diamond), the characteristic absorption bands are 916, 1146, 1167, 1295, 1375, 1614, 1625, 1651, 1664, 2837, 2866, 2909, 2955, 2986, 3003, At 3088 and 3146 cm ⁻¹ , in particular characteristic absorption bands at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199 degreeC-201 degreeC.

  Note that the characteristic peak due to powder X-ray crystal diffraction may vary depending on the measurement conditions. Therefore, an error may occur or it may not be clear about the peak of the powder X-ray crystal diffraction of the compound of the present invention.

  The powder X-ray diffraction pattern of the crystal of the present invention is shown in FIG. 1, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in FIG. 2, and the differential thermal analysis / thermal mass measurement curve is shown in FIG.

  The crystal of the present invention is 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl. } It can be produced by crystallizing pyridin-2 (1H) -one using an alcohol solvent.

  Raw material 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidine- before dissolution in an alcohol solvent 2-yl] ethyl} pyridin-2 (1H) -one is amorphous or crystalline.

  3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2- when the crystal of the present invention is obtained by crystallization or recrystallization using an alcohol solvent. [(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one can be dissolved in an alcohol solvent and crystallized from an alcohol solution by a conventional method. For example, in an alcohol solvent, amorphous 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidine 2-yl] ethyl} pyridin-2 (1H) -one is heated and dissolved, and then cooled.

  Examples of the solvent having a property miscible with the alcohol solvent include water solvents and hydrocarbon solvents such as heptane.

  In addition, the mixing ratio in the mixed solvent of the solvent having the property of being mixed with the alcohol solvent and the alcohol solvent can be appropriately changed.

  The alcohol solvent used is preferably methanol, ethanol, 1-propanol, isopropyl alcohol, tert-butyl alcohol, 1-butanol, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, trifluoroethanol, ethylene glycol, An alcohol having 1 to 4 carbon atoms such as propylene glycol, more preferably methanol, ethanol, isopropyl alcohol, or propylene glycol, and still more preferably methanol or ethanol.

  3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine-2 ( The concentration at which 1H) -one is dissolved is 1 to 50% by mass, preferably 17 to 25% by mass. Here, the mass% means 3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidine- in the solution. 2-yl] ethyl} pyridin-2 (1H) -one.

3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine-2 ( The crystallization temperature of 1H) -one can be carried out at a temperature from −78 ° C. to the reflux temperature of the solvent, but preferably 3-cyclopropyl-6-{(1R) -1- [4- (1,1 -Difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one was dissolved in an alcohol solvent by heating from 55 ° C to 75 ° C. In some cases, there may be mentioned a method of adding a solvent miscible with an alcohol solvent such as water and cooling to 5 ° C. or lower to precipitate crystals.
The cooling time is not particularly limited as long as it is 10 seconds or more, but is usually 10 minutes to 24 hours, preferably 30 minutes to 5 hours. From the viewpoint of industrial production, it is preferably 2 to 4 hours.

  The precipitated crystals are dried at 60 ° C. or lower after the suspension is separated from the solution by filtration, centrifugation, or the like.

  A seed crystal can be used for crystallization. The seed crystal can be obtained by a method well known to those skilled in the art, such as rubbing the wall of a container containing a solution for crystallization with a spatula.

  The reaction temperature of the general production method of the compound of the present invention is −78 ° C. to 250 ° C., preferably −20 ° C. to 80 ° C. The reaction time is 5 minutes to 3 days, preferably 30 minutes to 18 hours. This production method can be carried out under normal pressure, under pressure, under microwave irradiation, or the like.

  The base, acid, and inert solvent in the description of the general production method of the compound of the present invention are more specifically described, but are not limited to the following examples. Moreover, although the isolation method which can be used is described concretely, it is not limited to the following illustrations similarly.

Examples of the “base” include alkali metal or alkaline earth metal hydrides (lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (lithium amide). , Sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal C ₁ -C ₆ alkoxide (sodium methoxide, sodium ethoxide) Potassium tert-butoxide), alkali metal or alkaline earth metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (carbonic acid) Sodium and potassium carbonate , Calcium carbonate, cesium carbonate, etc.), inorganic bases such as alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), alkali metal or alkaline earth metal phosphates (eg tripotassium phosphate), amines (Triethylamine, diisopropylethylamine, N-methylmorpholine, etc.), basic heterocyclic compounds (pyridine, 4-dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] nonane-5-ene), imidazole, 2,6-lutidine, etc.).

  Examples of the “acid” include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acids (p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, camphorsulfone). Acid), Lewis acid (boron trifluoride, boron tribromide, aluminum chloride, scandium triflate, ytterbium triflate, etc.).

  The “inert solvent” is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, nitrile solvents, amide solvents, halogenated carbon solvents, ether solvents, aromatics A group solvent, a hydrocarbon solvent, an ester solvent, an alcohol solvent, a sulfoxide solvent, and water may be mentioned, and two or more of these may be used in an appropriate ratio.

  Examples of the nitrile solvent include acetonitrile and propionitrile. Examples of the amide solvent include N, N-dimethylformamide (hereinafter sometimes abbreviated as DMF), N, N-dimethylacetamide, and N-methylpyrrolidone. Examples of the halogenated carbon solvent include dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride. Examples of the ether solvent include diethyl ether (hereinafter sometimes abbreviated as “ether”), tetrahydrofuran (hereinafter sometimes abbreviated as THF), 1,4-dioxane, and 1,2-dimethoxyethane. . Examples of the aromatic solvent include benzene, toluene, xylene, and pyridine. Examples of the hydrocarbon solvent include hexane, pentane, and cyclohexane. Examples of the ester solvent include ethyl acetate and ethyl formate. Examples of the alcohol solvent include methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and ethylene glycol. Examples of the sulfoxide solvent include dimethyl sulfoxide (hereinafter sometimes abbreviated as DMSO).

  The compound obtained by the above production method can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, and various chromatography.

  Protecting groups that can be used by the compounds in the general production of the compounds of the present invention are described below, but are not limited to the examples, and can be appropriately selected.

The protecting group G ² includes, for example, a C ₁ -C ₆ acyl group (formyl, acetyl, propionyl, etc.) generally used during peptide synthesis, a C ₂ -C ₁₅ alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert-butoxy). Carbonyl, benzyloxycarbonyl, 9-fluorenylmethylenoxycarbonyl, etc.), arylcarbonyl group (benzoyl, etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert- butyldiethylsilyl and the _like), C 2 -C ₆ alkenyl group (1-allyl and the like). These groups may be substituted with one or more substituents selected from a halogen atom, a C ₁ -C ₆ alkoxy group (methoxy, ethoxy, propoxy, etc.), and a nitro group.

  The present invention will be described in more detail with reference to the following examples and test examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.

  In the following examples, NH silica gel column chromatography refers to column chromatography separation and purification using NH2 type silica gel (Chromatolex (registered trademark) NH2 type, Biotage (registered trademark) SNAP KP-NH Cartridge). The ratio of elution solvent indicates a volume ratio unless otherwise specified.

For silica gel column chromatography, Kanto Chemical “silica gel 60” or Fuji Silysia “PSQ60B” or packed column (YAMAZEN Hi-Flash ^™ Column or MORITX Purif Pack or Biotage (registered trademark) SNAP KP-Sil Catridge) was used.

Abbreviations used in this specification have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
dd: double doublet (double doublet)
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform

¹ H-NMR (proton nuclear magnetic resonance spectrum) was measured by the following Fourier transform NMR.
300 MHz: JNM-ECP300 (JEOL), JNM-ECX300 (JEOL)
600 MHz: JNM-ECA600 (JEOL)
For analysis, ACD / SpecManager ver. 12.01 (trade name) or the like was used.

MS (mass spectrum) was measured with the following apparatus.
micromass ZQ (Waters)
LTQ XL (Thermo Fisher Scientific)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
Agilent 6150 (Agilent)
LCQ Deca XP (Thermo Fisher Scientific)
As an ionization method, an ESI (Electrospray Ionization) method or a dual ionization method of ESI and APCI (Atmospheric Pressure Chemical Ionization) method was used.

  The optical rotation was measured using a polarimeter (model number: P-1020) manufactured by JASCO Corporation.

  The powder X-ray diffraction measurement was performed using X'Pert PRO MPD (radiation source: Cu · Κα) manufactured by PANalytical.

  Infrared absorption spectrum measurement was performed by ATR method (attenuated total reflection, attenuated total reflection method) using Nicolet iS5 manufactured by Thermo Fisher Scientific.

  Melting points were measured using an MP90 automatic melting point measurement system manufactured by Mettler Toledo.

  Preparative HPLC columns include Daicel Chemical Industries, LTD. CHIRALPAK IB 5 μm (ID 20 mm, Length 250 mm) or the like was used.

  Analytical HPLC columns are available from Daicel Chemical Industries, LTD. CHIRALPAK IB 5 μm (ID 4.6 mm, Length 250 mm) or the like was used.

  The compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.

Example 1
3-cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine-2 ( 1H)-ON

(1) 1-bromo-4- (1,1-difluoroethyl) benzene

１−（４−ブロモフェニル）エタノン（２０．０ｇ）にＤｅｏｘｏ−Ｆｌｕｏｒ（登録商標）（２２．２ｇ）を加え、８５℃で１５時間撹拌した。氷冷下、反応液に氷水及び炭酸カリウム水溶液を加え、クロロホルムで抽出した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン）を用いて精製することにより、表題化合物（１３．０ｇ，収率５９％）を黄色油状物質として得た。
^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ １．９１（ｔ，Ｊ＝１８．２Ｈｚ，３Ｈ），７．５０（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）．
（２）２−［４−（１，１−ジフルオロエチル）フェニル］−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン

Deoxo-Fluor (registered trademark) (22.2 g) was added to 1- (4-bromophenyl) ethanone (20.0 g), and the mixture was stirred at 85 ° C. for 15 hours. Under ice-cooling, ice water and an aqueous potassium carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane) to give the title compound (13.0 g, yield 59%) as a yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.91 (t, J = 18.2 Hz, 3H), 7.50 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8 .3Hz, 2H).
(2) 2- [4- (1,1-difluoroethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

実施例１−（１）で合成した１−ブロモ−４−（１，１−ジフルオロエチル）ベンゼン（９．８０ｇ）の１，４−ジオキサン（６０ｍＬ）溶液に、ビスピナコールジボレート（２２．５ｇ）と［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド ジクロロメタン錯体（９０４ｍｇ）と酢酸カリウム（８．７０ｇ）を加えて、９０℃で１０時間撹拌した。反応液を水に加え、クロロホルムで抽出した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン）を用いて精製することにより、表題化合物（７．８７ｇ，収率６６％）を無色固体として得た。
^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ １．３５（ｓ，１２Ｈ）， １．９１（ｔ，Ｊ＝１８．２Ｈｚ，３Ｈ），７．５０（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ）．
（３）５−シクロプロピル−６−メトキシピリジン−２−カルバルデヒド

To a solution of 1-bromo-4- (1,1-difluoroethyl) benzene (9.80 g) synthesized in Example 1- (1) in 1,4-dioxane (60 mL) was added bispinacol diborate (22.5 g). ) And [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (904 mg) and potassium acetate (8.70 g) were added and stirred at 90 ° C. for 10 hours. The reaction solution was added to water and extracted with chloroform. The solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane) to give the title compound (7.87 g, yield 66%) as a colorless solid.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 1.35 (s, 12H), 1.91 (t, J = 18.2 Hz, 3H), 7.50 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 2H).
(3) 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde

トルエン（４３３ｍＬ）−テトラヒドロフラン（１１６ｍＬ）混合溶媒に、アルゴン雰囲気下、２Ｍ ｎ−ブチルマグネシウムクロリドのテトラヒドロフラン溶液（７４．５ｍＬ）を加えた。−１２℃で１．６Ｍ ｎ−ブチルリチウムのテトラヒドロフラン溶液（１８６ｍＬ）を滴下し４０分間撹拌した後、６−ブロモ−３−シクロプロピル−２−メトキシピリジン（３４．０ｇ）を加えた。さらに１時間撹拌した後、Ｎ，Ｎ−ジメチルホルムアミド（３２．７ｇ）を滴下した。さらに１時間半撹拌した後、反応液を１３％クエン酸水溶液に加え抽出した後に有機層を水で洗浄した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→９０：１０）を用いて精製することにより、表題化合物（２１．２ｇ，収率８０％）を黄色油状物質として得た。
^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ０．７３−０．７８（ｍ，２Ｈ），１．０３−１．０８（ｍ，２Ｈ），２．１４−２．２１（ｍ，１Ｈ），４．０７（ｓ，３Ｈ），７．１９（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），７．４９（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），９．９２（ｓ，１Ｈ）．
ＭＳ（＋）：１７８［Ｍ＋Ｈ］^＋．
（４），（５） （５Ｒ）−５−［（Ｚ）−２−ブロモ−２−（５−シクロプロピル−６−メトキシピリジン−２−イル）エテニル］ピロリジン−２−オン

To a mixed solvent of toluene (433 mL) -tetrahydrofuran (116 mL), a tetrahydrofuran solution (74.5 mL) of 2M n-butylmagnesium chloride was added under an argon atmosphere. A tetrahydrofuran solution (186 mL) of 1.6M n-butyllithium was added dropwise at −12 ° C. and stirred for 40 minutes, and then 6-bromo-3-cyclopropyl-2-methoxypyridine (34.0 g) was added. After further stirring for 1 hour, N, N-dimethylformamide (32.7 g) was added dropwise. After further stirring for 1 hour and a half, the reaction solution was added to a 13% citric acid aqueous solution and extracted, and then the organic layer was washed with water. The solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 90: 10) to give the title compound (21.2 g, yield 80%). ) Was obtained as a yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.73-0.78 (m, 2H), 1.03-1.08 (m, 2H), 2.14-2.21 (m, 1H), 4.07 (s, 3H), 7.19 (d, J = 7.4 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 9.92 (s, 1H).
MS (+): 178 [M + H] ^< +>.
(4), (5) (5R) -5-[(Z) -2-bromo-2- (5-cyclopropyl-6-methoxypyridin-2-yl) ethenyl] pyrrolidin-2-one

(4) Tetrahydrofuran solution (1.2 L) of (5R) -5-[(1,3-benzothiazol-2-ylsulfonyl) methyl] pyrrolidin-2-one (30.0 g) and lithium chloride (8.58 g) After adding dropwise 1M potassium hexamethyldisilazide tetrahydrofuran solution (405 mL) to -78 ° C, the mixture was stirred for 1 hour. A tetrahydrofuran solution (600 mL) of 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (17.9 g) synthesized in Example 1- (3) was added dropwise, and the mixture was further stirred for 0.5 hour. Saturated aqueous ammonium chloride solution (500 mL) was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure. did. The obtained residue was purified twice by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 70: 30), and (5R) -5-[(Z) -2- (5-cyclopropyl-6). -Methoxypyridin-2-yl) ethenyl] pyrrolidin-2-one (8.40 g, 34% yield) was obtained as a yellow oil.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.62-0.68 (m, 2H), 0.93-0.99 (m, 2H), 1.89-1.97 (m, 1H), 2.03 to 2.09 (m, 1H), 2.33 to 2.56 (m, 3H), 3.98 (s, 3H), 5.53 to 5.55 (m, 1H), 5. 70 (dd, J = 11.56, 7.84 Hz, 1H), 5.94-6.03 (br.s., 1H), 6.34 (dd, J = 11.56, 1.24 Hz, 1H), 6.70 (d, J = 7.43 Hz, 1H), 7.07 (d, J = 7.43 Hz, 1H).
MS (+): 259 [M + H] ^< +>.
(5) (5R) -5-[(Z) -2- (5-Cyclopropyl-6-methoxypyridin-2-yl) ethenyl] pyrrolidin-2-one synthesized in Example 1- (4) (8) Bromine (1.33 mL) was added dropwise at 0 ° C. to a solution of .40 g) in chloroform (126 mL). After stirring for 1 hour, a chloroform solution (42 mL) of 1,8-diazabicyclo [5.4.0] undec-7-ene (9.7 mL) was added dropwise over 30 minutes and stirred for 15 minutes. To the reaction solution was added 1M hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 0: 100) to give the title compound (7.50 g, yield 68%) as a yellow solid.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.65-0.68 (m, 2H), 0.95-1.00 (m, 2H), 1.96-2.10 (m, 2H), 2.40-2.59 (m, 3H), 4.00 (s, 3H), 4.80 (q, J = 7.4 Hz, 1H), 5.68-5.70 (br.s., 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H).
MS (+): 337 [M + H] ^< +>.
(6) (5R) -5-{(E) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethenyl} pyrrolidine -2-one

窒素雰囲気下、実施例１−（５）で合成した（５Ｒ）−５−［（Ｚ）−２−ブロモ−２−（５−シクロプロピル−６−メトキシピリジン−２−イル）エテニル］ピロリジン−２−オン（１．０ｇ）の１，４−ジオキサン（５０ｍＬ）溶液に、実施例１−（２）で合成した２−［４−（１，１−ジフルオロエチル）フェニル］−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（１．５９ｇ）、炭酸セシウム（１．９２ｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（２７１ｍｇ）、トリ（２−フリル）ホスフィン（４１２ｍｇ）、蒸留水（１０ｍＬ）を加えて、９０℃で２時間撹拌した。反応液を水に加え、酢酸エチルで抽出した後、有機層に無水硫酸マグネシウムを加え乾燥させ、乾燥剤をろ別後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）、さらにＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、表題化合物（１．１３ｇ，収率９６％）を無色アモルファス状物質として得た。
^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ０．５６−０．６４（ｍ，２Ｈ），０．９０−０．９７（ｍ，２Ｈ），１．９３−２．０９（ｍ，５Ｈ），２．２０−２．３４（ｍ，２Ｈ），２．３７−２．４５（ｍ，１Ｈ），４．０４（ｓ，３Ｈ），４．０７−４．１６（ｍ，１Ｈ），５．７３−５．７５（ｂｒ．ｓ．，１Ｈ），６．２３（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），６．９０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），６．９２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２４（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ）．
ＭＳ（＋）：３９９［Ｍ＋Ｈ］^＋．
（７） （５Ｒ）−５−｛２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エチル｝ピロリジン−２−オン

(5R) -5-[(Z) -2-Bromo-2- (5-cyclopropyl-6-methoxypyridin-2-yl) ethenyl] pyrrolidine- synthesized in Example 1- (5) under nitrogen atmosphere 2- [4- (1,1-difluoroethyl) phenyl] -4,4, synthesized in Example 1- (2) was added to a solution of 2-one (1.0 g) in 1,4-dioxane (50 mL). 5,5-tetramethyl-1,3,2-dioxaborolane (1.59 g), cesium carbonate (1.92 g), tris (dibenzylideneacetone) dipalladium (0) (271 mg), tri (2-furyl) phosphine (412 mg) and distilled water (10 mL) were added, and the mixture was stirred at 90 ° C. for 2 hours. The reaction solution was added to water and extracted with ethyl acetate, and then anhydrous magnesium sulfate was added to the organic layer for drying. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) and further purified by NH silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to give the title compound (1.13 g, yield 96%) was obtained as a colorless amorphous substance.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.56-0.64 (m, 2H), 0.90-0.97 (m, 2H), 1.93-2.09 (m, 5H), 2.20-2.34 (m, 2H), 2.37-2.45 (m, 1H), 4.04 (s, 3H), 4.07-4.16 (m, 1H), 5. 73-5.75 (br.s., 1H), 6.23 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 9.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H).
MS (+): 399 [M + H] ^< +>.
(7) (5R) -5- {2- (5-Cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethyl} pyrrolidin-2-one

窒素雰囲気下、実施例１−（６）で合成した（５Ｒ）−５−｛（Ｅ）−２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エテニル｝ピロリジン−２−オン（１．１ｇ）のメタノール（４４ｍＬ）溶液に、１０％パラジウム−活性炭素（１１０ｍｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をセライト（登録商標）ろ過後、減圧下溶媒を留去し表題化合物（１．１０ｇ，収率９９％）を無色アモルファス状物質として得た。
ＭＳ（＋）：４０１［Ｍ＋Ｈ］^＋．
（８）３−シクロプロピル−６−｛１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オン

(5R) -5-{(E) -2- (5-cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1) synthesized in Example 1- (6) under nitrogen atmosphere. , 1-Difluoroethyl) phenyl] ethenyl} pyrrolidin-2-one (1.1 g) in methanol (44 mL) was added 10% palladium-activated carbon (110 mg) and stirred at room temperature for 1 hour under hydrogen atmosphere. . The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give the title compound (1.10 g, yield 99%) as a colorless amorphous substance.
MS (+): 401 [M + H] ^< +>.
(8) 3-Cyclopropyl-6- {1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine-2 (1H ) -On

実施例１−（７）で合成した（５Ｒ）−５−｛２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エチル｝ピロリジン−２−オン（１．１ｇ）のアセトニトリル（３０ｍＬ）溶液に、クロロトリメチルシラン（７０７μＬ）及びヨウ化カリウム（１．３７ｇ）を加え、６０℃で１時間撹拌した。反応液を水にあけて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムを加え乾燥させ、乾燥剤をろ別後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→８０：２０）で精製し、表題化合物（８８０ｍｇ，収率８３％）を無色アモルファス状物質として得た。
ＭＳ（＋）：３８７［Ｍ＋Ｈ］^＋．
（９）３−シクロプロピル−６−｛（１Ｒ）−１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オン

(5R) -5- {2- (5-Cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] synthesized in Example 1- (7) To a solution of ethyl} pyrrolidin-2-one (1.1 g) in acetonitrile (30 mL) were added chlorotrimethylsilane (707 μL) and potassium iodide (1.37 g), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 80: 20) to give the title compound (880 mg, yield 83%) as a colorless amorphous substance.
MS (+): 387 [M + H] ^< +>.
(9) 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridine -2 (1H) -ON

実施例１−（８）で合成した３−シクロプロピル−６−｛１−［４−（１，１−ジフルオロエチル）フェニル］−２−［（２Ｒ）−５−オキソピロリジン−２−イル］エチル｝ピリジン−２（１Ｈ）−オンのＲＳ混合物（１８０ｍｇ）をキラルＨＰＬＣカラム（ＣＨＩＲＡＬＰＡＫ ＩＢ，ヘキサン：エタノール＝７０：３０ ｖ／ｖ，４０℃，１２ｍＬ／ｍｉｎ，２５４ｎｍ）で分取して、表題化合物（７０ｍｇ）を無色アモルファス状物質として、表題化合物のジアステレオマー（６７ｍｇ）を無色アモルファス状物質として得た。
^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ０．５４−０．６７（ｍ，２Ｈ），０．９０−０．９８（ｍ，２Ｈ），１．６８−１．７５（ｍ，１Ｈ），１．８８（ｔ，Ｊ＝１８．２Ｈｚ，３Ｈ），２．０７−２．１４（ｍ，１Ｈ），２．１４−２．４０（ｍ，５Ｈ），３．４３−３．５２（ｍ，１Ｈ），４．０７−４．１２（ｍ，１Ｈ），６．００（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ），６．９２（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ），７．４１−７．４７（ｍ，４Ｈ），７．６０−７．６８（ｍ，１Ｈ），１２．２８−１２．４９（ｂｒ．ｓ．，１Ｈ）．
ＭＳ（＋）：３８７［Ｍ＋Ｈ］^＋．
ＣＨＩＲＡＬＰＡＫ ＩＢ ４．６×２５０ｍｍ ５μｍ （ＤＡＩＣＥＬ），ヘキサン：エタノール＝７０：３０ ｖ／ｖ，４０ ℃，１．０ｍＬ／ｍｉｎ，２１０ｎｍ，Ｒｔ＝７．５ｍｉｎ．

ジアステレオマー

3-cyclopropyl-6- {1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] synthesized in Example 1- (8) Ethyl} pyridin-2 (1H) -one RS mixture (180 mg) was fractionated on a chiral HPLC column (CHIRALPAK IB, hexane: ethanol = 70: 30 v / v, 40 ° C., 12 mL / min, 254 nm) The title compound (70 mg) was obtained as a colorless amorphous substance, and the diastereomer (67 mg) of the title compound was obtained as a colorless amorphous substance.
¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.54-0.67 (m, 2H), 0.90-0.98 (m, 2H), 1.68-1.75 (m, 1H), 1.88 (t, J = 18.2 Hz, 3H), 2.07-2.14 (m, 1H), 2.14-2.40 (m, 5H), 3.43-3.52 (m , 1H), 4.07-4.12 (m, 1H), 6.00 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H), 7.41. -7.47 (m, 4H), 7.60-7.68 (m, 1H), 12.28-12.49 (br.s., 1H).
MS (+): 387 [M + H] ^< +>.
CHIRALPAK IB 4.6 × 250 mm 5 μm (DAICEL), hexane: ethanol = 70: 30 v / v, 40 ° C., 1.0 mL / min, 210 nm, Rt = 7.5 min.

Diastereomer

^１Ｈ ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ０．５４−０．６６（ｍ，２Ｈ），０．９５−１．０５（ｍ，２Ｈ），１．７５−１．８４（ｍ，１Ｈ），１．９０（ｔ，Ｊ＝１８．０Ｈｚ，３Ｈ），２．１５−２．４１（ｍ，６Ｈ），３．５４−３．６４（ｍ，１Ｈ），４．１６（ｄｄ，Ｊ ＝１０．１，５．５７Ｈｚ，１Ｈ），６．０１（ｓ，１Ｈ），６．９６（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ），７．３９（ｄ，Ｊ＝８．２６Ｈｚ，２Ｈ），７．４７（ｓ，２Ｈ），７．８３−７．９２（ｍ，１Ｈ），１３．１４−１３．３４（ｂｒ．ｓ．，１Ｈ）．
ＭＳ（＋）：３８７［Ｍ＋Ｈ］^＋．
ＣＨＩＲＡＬＰＡＫ ＩＢ ４．６×２５０ｍｍ ５μｍ （ＤＡＩＣＥＬ），ヘキサン：エタノール＝７０：３０ ｖ／ｖ，４０ ℃，１．０ｍＬ／ｍｉｎ，２１０ｎｍ，Ｒｔ＝１８．９ｍｉｎ．

¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 0.54-0.66 (m, 2H), 0.95-1.05 (m, 2H), 1.75-1.84 (m, 1H), 1.90 (t, J = 18.0 Hz, 3H), 2.15-2.41 (m, 6H), 3.54-3.64 (m, 1H), 4.16 (dd, J = 10) .1, 5.57 Hz, 1H), 6.01 (s, 1H), 6.96 (d, J = 7.0 Hz, 1H), 7.39 (d, J = 8.26 Hz, 2H), 7 .47 (s, 2H), 7.83-7.92 (m, 1H), 13.14-13.34 (br.s., 1H).
MS (+): 387 [M + H] ^< +>.
CHIRALPAK IB 4.6 × 250 mm 5 μm (DAICEL), hexane: ethanol = 70: 30 v / v, 40 ° C., 1.0 mL / min, 210 nm, Rt = 18.9 min.

Example 2
(5R) -5- {2- (5-Cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethenyl} pyrrolidin-2-one

(1) (5-Cyclopropyl-6-methoxypyridin-2-yl) [4- (1,1-difluoroethyl) phenyl] methanone

窒素雰囲気下、−７８℃において、６−ブロモ−３−シクロプロピル−２−メトキシピリジン（４１．５ｇ）のテトラヒドロフラン（２７３ｍＬ）溶液に１．６Ｍ ｎ−ブチルリチウムのテトラヒドロフラン溶液（１２７ｍＬ）を５０分かけて滴下した後、−７８℃で１時間攪拌した。続いて−７８℃のまま反応溶液に４−（１，１−ジフルオロエチル）ベンゾニトリル（２４．３ｇ）のテトラヒドロフラン（１３７ｍＬ）溶液を７５分かけて滴下し、さらに１時間攪拌した。反応溶液を０℃に昇温後、１Ｍ塩酸（４３７ｍＬ）、テトラヒドロフラン（３６５ｍＬ）、１Ｍ塩酸（１４６ｍＬ）の順に滴下した。
反応液を有機層と水層に分離後、水層を酢酸エチル（１０００ｍＬ）で抽出した。あわせた有機層に無水硫酸マグネシウムを加え乾燥させ、乾燥剤をろ別後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→９５：５）で精製し、表題化合物（３４．０ｇ，収率７４％）を無色油状物質として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ ｐｐｍ ０．７２-０．８１（ｍ，２Ｈ），１．００-１．１０（ｍ，２Ｈ），１．９６（ｔ，Ｊ＝１８．２Ｈｚ，３Ｈ），２．１０-２．２５（ｍ，１Ｈ），３．９５（ｓ，３Ｈ），７．２４（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），７．５９（ｄ，Ｊ＝９．０Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）．
ＭＳ（＋）：３１８［Ｍ＋Ｈ］^＋．
（２） （５Ｒ）−５−｛２−（５−シクロプロピル−６−メトキシピリジン−２−イル）−２−［４−（１，１−ジフルオロエチル）フェニル］エテニル｝ピロリジン−２−オン

Under a nitrogen atmosphere at −78 ° C., a solution of 6-bromo-3-cyclopropyl-2-methoxypyridine (41.5 g) in tetrahydrofuran (273 mL) was added with 1.6M n-butyllithium tetrahydrofuran solution (127 mL) for 50 minutes. After dropwise addition, the mixture was stirred at -78 ° C for 1 hour. Subsequently, a solution of 4- (1,1-difluoroethyl) benzonitrile (24.3 g) in tetrahydrofuran (137 mL) was added dropwise to the reaction solution over 75 minutes, and the mixture was further stirred for 1 hour. The temperature of the reaction solution was raised to 0 ° C., and 1M hydrochloric acid (437 mL), tetrahydrofuran (365 mL), and 1M hydrochloric acid (146 mL) were added dropwise in this order.
The reaction solution was separated into an organic layer and an aqueous layer, and then the aqueous layer was extracted with ethyl acetate (1000 mL). To the combined organic layers, anhydrous magnesium sulfate was added and dried. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 95: 5) to give the title compound (34.0 g, yield 74%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 0.72-0.81 (m, 2H), 1.00-1.10 (m, 2H), 1.96 (t, J = 18.2 Hz, 3H ), 2.10-2.25 (m, 1H), 3.95 (s, 3H), 7.24 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 9.0 Hz) , 2H), 7.67 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.6 Hz, 2H).
MS (+): 318 [M + H] ^< +>.
(2) (5R) -5- {2- (5-Cyclopropyl-6-methoxypyridin-2-yl) -2- [4- (1,1-difluoroethyl) phenyl] ethenyl} pyrrolidin-2-one

窒素雰囲気下、−７８℃において、実施例２−（１）で得られた（５−シクロプロピル−６−メトキシピリジン−２−イル）［４−（１，１−ジフルオロエチル）フェニル］メタノン（３３．５ｇ）と（５Ｒ）−５−[（１，３−ベンゾチアゾール−２−イルスルホニル）メチル]ピロリジン−２−オン（３７．５ｇ）のジクロロメタン（１００７ｍＬ）溶液に１．０Ｍリチウムヘキサメチルジシラジドのテトラヒドロフラン溶液（３１７ｍＬ）を５０分かけて滴下し、−７８℃で４時間４０分攪拌した。
反応液を０℃に昇温後、飽和塩化アンモニウム水溶液（３３５ｇ）を滴下して反応を停止させた。反応液を有機層と水層に分離後、水層をクロロホルム（３３９ｍＬ）で抽出し、合わせた有機層を水（５０２ｇ）で洗浄した。有機層に無水硫酸マグネシウムを加え乾燥させ、乾燥剤をろ別後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：５０→０：１００）で精製し、表題化合物を淡黄色アモルファス状物質の混合物（４２．７ｇ，Ｅ：Ｚ＝５０：５０）として得た。
但し、混合比は液体クロマトグラフィーの面積百分率にて決定した。
液体クロマトグラフィーの条件を以下に示す。
Ｌ−Ｃｏｌｕｍｎ ＯＤＳ， ＣＨ_３ＣＮ：０．０１Ｍ ａｃｅｔａｔｅ ｂｕｆｆｅｒ（０．０１Ｍ酢酸水溶液：０．０１Ｍ酢酸ナトリウム水溶液＝８：１） ＝８０：２０ ｖ／ｖ，１．０ｍＬ／ｍｉｎ，４０℃，２５４ｎｍ,
Ｅ：Ｒｔ＝５．４０ｍｉｎ、Ｚ：Ｒｔ＝５．０８ｍｉｎ．
ＭＳ（＋）：３９９［Ｍ＋Ｈ］^＋．

(5-Cyclopropyl-6-methoxypyridin-2-yl) [4- (1,1-difluoroethyl) phenyl] methanone obtained in Example 2- (1) at −78 ° C. under a nitrogen atmosphere ( 33.5 g) and (5R) -5-[(1,3-benzothiazol-2-ylsulfonyl) methyl] pyrrolidin-2-one (37.5 g) in dichloromethane (1007 mL) in 1.0 M lithium hexamethyl A solution of disilazide in tetrahydrofuran (317 mL) was added dropwise over 50 minutes, and the mixture was stirred at -78 ° C for 4 hours and 40 minutes.
After raising the temperature of the reaction solution to 0 ° C., a saturated aqueous ammonium chloride solution (335 g) was added dropwise to stop the reaction. The reaction solution was separated into an organic layer and an aqueous layer, the aqueous layer was extracted with chloroform (339 mL), and the combined organic layer was washed with water (502 g). Anhydrous magnesium sulfate was added to the organic layer for drying, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 0: 100), and the title compound was mixed with a pale yellow amorphous substance (42.7 g, E: Z = 50: 50). Got as.
However, the mixing ratio was determined by the area percentage of liquid chromatography.
The conditions for liquid chromatography are shown below.
L-Column ODS, CH ₃ CN: 0.01 M acetate buffer (0.01 M acetic acid aqueous solution: 0.01 M sodium acetate aqueous solution = 8: 1) = 80: 20 v / v, 1.0 mL / min, 40 ° C., 254 nm ,
E: Rt = 5.40 min, Z: Rt = 5.08 min.
MS (+): 399 [M + H] ^< +>.

  Hereinafter, the title compound can be led to compound [1] by the method described in (7) to (9) of Example 1 or a method analogous thereto.

Example 3
Crystallization Method of Compound [1] Crystalline Compound [1] 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-difluoroethyl) phenyl] -2-[(2R) at 75 ° C. Water (29 g) was added dropwise to a solution of) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one (14.4 g) in ethanol (72 g). The mixture was gradually cooled from 75 ° C, and when the internal temperature reached 40 ° C, a piece of seed crystal was added and cooled to room temperature. The mixture was further cooled to 0 ° C. and stirred overnight to form a suspension.
After returning to room temperature, the obtained solid was collected by filtration, washed with water, and dried (50 ° C., 6 hours) to obtain 8.7 g (60% recovery rate) of colorless crystals.
(A) In a powder X-ray diffraction diagram (Cu-Kα, measurement method: transmission method), diffraction angle 2θ = 8.5, 10.8, 11.2, 11.6, 13.4, 16.8, 17 0.0, 17.9, 18.5, 18.8, 19.1, 19.4, 22.6, 23.1, 23.2 and 24.5 °.
(B) In the infrared absorption spectrum (ATR method, crystal: diamond), the characteristic absorption bands are 916, 1146, 1167, 1295, 1375, 1614, 1625, 1651, 1664, 2837, 2866, 2909, 2955, 2986, 3003, At 3088 and 3146 cm ⁻¹ .
(C) Melting | fusing point is 199 degreeC-201 degreeC.
(D) Specific rotation is [α] _D ²³ = + 36 (c 0.1, MeOH).

  Evaluation of the GK activation action of the compound of the present invention can be performed according to a known method such as the method described in Test Examples.

  The GK activating action of the compound [1] of the present invention and the compound A (Example 4-302), the compound B (Example 4-248) and the compound C (Example 4-340) disclosed in the pamphlet of WO2011 / 066821 The measurement was performed using the method described in the following test examples.

  In addition, the structure of the compound A, the compound B, and the compound C disclosed in WO2011 / 068211 pamphlet is shown below.

(Test Example 1.) -GK activation test-
The GK activation test of the test compound was performed by partially modifying the method of Van Schafftingen et al. (Eur. J. Biochem. 179: 179-184, 1989). GK activity is converted from thio-NAD + (thionicotinamide adenine dinucleotide) when glucose 6-phosphate produced by GK using glucose as a substrate is dehydrogenated by G6PDH (glucose 6-phosphate dehydrogenase). It was measured as a change in absorbance based on the amount of thio-NADH which is a reduced product.

  The enzyme source human liver type GK used in this assay was expressed in E. coli as a fusion protein with GST (Glutathione S-transferase) added to the amino terminus, and purified using Glutathione Sepharose 4B (Amersham Biosciences).

The test was conducted using a flat-bottomed 96-hole half-area microplate (Corning). A dimethyl sulfoxide (DMSO) solution of the test compound and DMSO as a control were added to each well of the plate to a final DMSO concentration of 1%. Furthermore, as final concentrations, 25 mM Hepes-KOH (pH = 7.1), 25 mM KCl, 2 mM MgCl ₂ , 2 mM thio-NAD +, 4 mM glucose, 1 mM DTT (dithiothreitol), 0.01 units / μL G6PDH, 2 μg / ML Human liver type GK was added. Next, ATP was added to a final concentration of 2 mM to initiate the reaction, and the mixture was allowed to stand at room temperature. 15 minutes after the start of the reaction, the absorbance at 405 nm was measured using a microplate absorptiometer.

The GK activity that was maximized by the test compound was defined as the maximum activation ability, and the test compound concentration (nM) required to activate 50% of the activity was expressed as the EC ₅₀ value.

  The results are shown below.

(Test Example 2.)-Blood glucose lowering test using C57BL6 / J mice-
The test for confirming the hypoglycemic effect of the test compound was carried out in accordance with a commonly used method represented by the method of Grimsby et al. (Science 301: 370-373, 2003).

The body weight of C57BL6 / J mice (N = 6) fed freely before the test was measured. The test compound was suspended or dissolved in the administration base (0.5% methylcellulose) at a concentration of 0.06-20 mg / mL. Mice were orally administered with 5 mL / kg of a drug solution (equivalent to 0.3-100 mg / kg of the test compound) or control (administration base alone). Approximately 60 μL of blood was collected from the tail vein with a capillary immediately before administration of the test compound and 0.5, 1, 2, 4, and 6 hours after administration of the test compound. After the collected blood was centrifuged, the plasma glucose concentration was measured. The area under the curve (AUC) was calculated from the time course of plasma glucose concentration after administration of the test compound, and the reduction rate (%) relative to AUC in the control group was calculated. A dose (ED ₂₀ value; mg / kg) showing an AUC reduction rate of 20% was calculated from a dose response curve with the AUC reduction rate on the vertical axis and the dose on the horizontal axis.

  The results are shown below.

  From the above test results, it was confirmed that the compound of the present invention exhibits a good hypoglycemic effect from a low dose range. Therefore, it can be said that the compound of the present invention is useful as a prophylactic / therapeutic agent for diabetes and the like, and its therapeutic range is clearly wider than other compounds.

  And it turned out that this invention compound has a stronger blood glucose lowering effect compared with 3 compound disclosed by WO2011 / 068211 pamphlet.

  In addition, this invention compound has a desirable property as a pharmaceutical. For example, by exhibiting good physical properties and pharmacokinetics (for example, liver metabolism stability, etc.), properties such as a good blood glucose lowering effect can be mentioned.

  The compound of the present invention has an excellent GK activation action, and not only diabetes treatment but also diabetes-related diseases such as obesity treatment and hyperlipidemia, or diabetic chronic complications such as retinopathy, nephropathy and arteriosclerosis Can be provided.

Claims (4)

Formula [1]

A 2-pyridone compound or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or the like as an active ingredient , and lactose and magnesium stearate A preventive or therapeutic agent for diabetes or obesity, which is a solid composition for oral use . The preventive or therapeutic agent for diabetes according to claim 1, wherein the dosage is 0.01 to 1000 mg / day. 3-Cyclopropyl-6-{(1R) -1- [4- (1,1-, 1-), which is represented by the above formula [1] and has the following physical properties (a) to (c) according to claim 1. Oral containing crystals of difluoroethyl) phenyl] -2-[(2R) -5-oxopyrrolidin-2-yl] ethyl} pyridin-2 (1H) -one , and further containing lactose and magnesium stearate A preventive or therapeutic agent for diabetes or obesity, which is a solid composition for use ;
(A) In the powder X-ray diffraction pattern (Cu-Kα), peaks are observed at diffraction angles 2θ = 8.5, 13.4, 19.1, and 24.5 °;
(B) In the infrared absorption spectrum, the characteristic absorption bands are at 916, 1146, 1167, 1295, 1651, 1664, 2909, 2955, 3003 and 3146 cm ⁻¹ ;
(C) Melting | fusing point is 199 degreeC-201 degreeC. The preventive or therapeutic agent for diabetes according to claim 3, wherein the dosage is 0.01 to 1000 mg / day.

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