WO2009131065A1 - アリールスルホニル誘導体を有効成分とする長鎖脂肪酸伸長酵素阻害剤 - Google Patents
アリールスルホニル誘導体を有効成分とする長鎖脂肪酸伸長酵素阻害剤 Download PDFInfo
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- WO2009131065A1 WO2009131065A1 PCT/JP2009/057725 JP2009057725W WO2009131065A1 WO 2009131065 A1 WO2009131065 A1 WO 2009131065A1 JP 2009057725 W JP2009057725 W JP 2009057725W WO 2009131065 A1 WO2009131065 A1 WO 2009131065A1
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- alkyl
- heteroaryl
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- 0 CC(C)(CC(C)(C)NC(C)=O)*(C)(C)S Chemical compound CC(C)(CC(C)(C)NC(C)=O)*(C)(C)S 0.000 description 3
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Definitions
- the present invention is useful in the field of medicine. More specifically, the arylsulfonyl derivative of the present invention is a long chain fatty acid elongase (hereinafter, sometimes abbreviated as LCE) inhibitor, and is used as an inhibitor for various cardiovascular diseases, nervous system diseases, metabolism. It is useful as a preventive or therapeutic agent for hereditary diseases, reproductive system diseases, gastrointestinal diseases, neoplasms, infections, etc., or as a herbicide.
- LCE long chain fatty acid elongase
- Obesity is a condition in which neutral fat accumulates in adipocytes due to the persistence of excessive intake energy compared to energy consumption, resulting in a marked increase in body weight compared to standard weight (Itagaki). Eiji, “STEP Metabolism / Endocrine”, Kaiba Shobo, 1st Edition, 1998, p. 105). It is known that excessive accumulated fat causes insulin resistance, diabetes, hypertension, hyperlipidemia, etc., and the risk of developing arteriosclerosis is greatly increased by combining these factors. Such symptoms are called metabolic syndrome.
- hypertriglyceridemia or obesity is, for example, pancreatitis, liver dysfunction, cancer such as breast cancer / uterine cancer / ovarian cancer / colon cancer / prostate cancer, menstrual abnormality, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity It is known to increase the risk of hypoventilation syndrome (Pickwick syndrome), sleep apnea syndrome, and the like.
- diabetes is likely to cause, for example, angina pectoris, heart failure, stroke, lameness, retinopathy, decreased visual acuity, renal failure, neuropathy, skin ulcer, infection, etc. [The Merck Manual of Medical Information, Home 2nd Edition, Merck & Co, 2003].
- LCE is an enzyme that exists in the endoplasmic reticulum in the cell, and is an enzyme that catalyzes the rate-limiting condensation step in an enzyme group that catalyzes the carbon chain elongation reaction of fatty acids having 12 or more carbon chains.
- many of the fatty acids newly synthesized in vivo have a chain length of 16-18 carbons.
- These long chain fatty acids are over 90% of the total fatty acids present in the cell. They are an important component of the membrane and a major component of adipose tissue, the largest energy storage organ in animals. It is the liver that has the highest rate of new fatty acid synthesis, and this synthesis converts excess glucose in the body into fatty acids.
- Glycolysis converts glucose to pyruvate, which is converted to citrate by mitochondria and transported to the cytosol.
- Cytosolic ATP citrate lyase produces acetyl CoA, a precursor of fatty acids and cholesterol.
- Acetyl CoA is carboxylated by acetyl CoA carboxylase (ACC) to form malonyl CoA.
- the multifunctional enzyme fatty acid synthase (FAS) uses malonyl CoA, acetyl CoA, and NADPH to elongate fatty acids by two carbons.
- the main end product of FAS in rodents is palmitoyl CoA with 16 carbon chains, which is extended by two carbons by LCE [Journal of Biological Chemistry (J.
- Patent Document 1 shows a direct relationship between LCE and obesity.
- LCE mouse FACE
- LCE is also present in protozoa and nematodes, and is known to be involved in cell growth.
- Trypanosomiasis protozoa that causes African trypanosomiasis (popular name: African sleeping sickness)
- long-chain fatty acids are synthesized by the fatty acid elongation pathway including LCE, and inhibition of intracellular fatty acid elongation reaction contributes to the growth of Trypanosoma protozoa.
- arylsulfonyl derivative having an LCE inhibitory action has been known so far.
- Some of the arylsulfonyl derivatives of the present invention are novel compounds that have not been known so far. J. et al. Lipid Res. 43 (6), 911-920 (2002) Cell, 126: 691-699 (2006)
- An object of the present invention is to provide a compound having an LCE inhibitory action.
- the present inventors have found that a compound in which aryl, heteroaryl, etc. are bonded to the 3-position of a sulfonyl-substituted six-membered ring via amide or urea (hereinafter referred to as “the compound of the present invention”) is excellent.
- the present invention was completed by finding that it has an inhibitory action.
- W represents C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or —N (R 1 ) (R 2 );
- R 1 and R 2 each independently represent a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, or R 1 and R 2 together Forming a nitrogen-containing heterocycle with the nitrogen atom to which they are attached
- the alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or nitrogen-containing heterocycle is hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cyclo Alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C
- any hydrogen atom in the formulas (II-1) to (II-4) may be substituted with C 1-6 alkyl, halo C 1-6 alkyl or C 3-8 cycloalkyl
- Z is a hydrogen atom, hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino (wherein the amino is optionally substituted by C 1-6 alkyl, aryl or heteroaryl ), Carbamoyl (the carbamoyl may be 1 to 2 substituted with C 1-6 alkyl, aryl or heteroaryl), sulfanyl (the sulf
- the present invention provides (2) a pharmaceutical composition comprising an inhibitor represented by formula (I), (3) A preventive or therapeutic agent for diabetes, obesity or non-alcoholic fatty liver, comprising an inhibitor represented by formula (I) as an active ingredient, (4)
- the inhibitor according to (1) which is used as a therapeutically active substance for the treatment of a disease associated with a long-chain fatty acid elongation enzyme, (5)
- a compound represented by the formula (I-1) described later is also provided.
- LCE LCE inhibitory action
- various diseases involving LCE such as hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy, visual acuity Decrease, electrolyte abnormality, arteriosclerosis and other cardiovascular diseases such as bulimia, diabetic neuropathy, etc.
- Central nervous system diseases such as metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, high cholesterol Metabolic disorders such as dyslipidemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fatty liver, abnormal hormone secretion, gout, fatty liver, etc.
- reproductive system diseases such as menstrual disorders, sexual dysfunction, liver dysfunction , Pancreatitis, cholecystitis, gastrointestinal tract disease such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory apnea syndrome such as sleep apnea syndrome, infection by bacteria, fungi, parasites Disease, malignant neoplasms, arthritis, preventive agents such as inflammatory diseases such as skin ulcers, therapeutic agents, or are useful as herbicides.
- reproductive system diseases such as menstrual disorders, sexual dysfunction, liver dysfunction , Pancreatitis, cholecystitis, gastrointestinal tract disease such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory apnea syndrome such as sleep apnea syndrome, infection by bacteria, fungi, parasites Disease, malignant neoplasms, arthritis, preventive agents such as inflammatory diseases such as skin ulcers, therapeutic agents, or are useful as herbicides.
- Halogen means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- C 1-6 alkyl means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl. , Isopentyl, hexyl, isohexyl and the like.
- HaloC 1-6 alkyl means the above C 1-6 alkyl substituted at one or more, preferably 1 to 3, identical or different halogen atoms at any substitutable position, for example, Examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, bromomethyl, iodomethyl and the like.
- C 3-8 cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- alkyl is optionally halogen, cyano, nitro, oxo, —OR 51 , —R 51 , —COR 51 , —CO 2 R 51 , —NR 61 R 71 , -SR 51 , -SOR 51 , -SO 2 R 51 , -CONR 61 R 71 , -NR 51 COR 61 , -NR 51 CO 2 R 61 , -OCONR 61 R 71 , -NR 51 SO 2 R 61 ,- Optionally substituted with a substituent selected from the group consisting of SO 2 NR 61 R 71 and —NR 51 CONR 61 R 71 , and R 51 , R 61 and R 71 may be the same or different and represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heterocyclyl or heteroaryl, or R 61 and R 71 are In
- C 1-6 alkoxy means straight or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, Examples include pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like.
- Halo C 1-6 alkoxy substitutable or differently one, preferably means the C 1-6 alkoxy substituted with 1 to 3 same or different aforementioned halogen atoms, e.g. Examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy, iodomethoxy and the like.
- C 1-6 alkoxycarbonyl is a group in which the C 1-6 alkoxy is bonded to carbonyl, and examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl and the like.
- C 1-6 alkoxycarbonylamino is a group in which one of the hydrogen atoms of the amino group (—NH 2 ) has been substituted with the C 1-6 alkoxycarbonyl, such as methoxycarbonylamino, ethoxycarbonylamino, n -Propyloxycarbonylamino and the like.
- C 1-6 alkylcarbonyl is a group in which the above C 1-6 alkyl is bonded to carbonyl, and examples thereof include acetyl, propionyl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
- C 1-6 alkylcarbonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the C 1-6 alkylcarbonyl.
- acetylamino, propionylamino, isobutyrylamino, valerylamino examples include valerylamino and pivaloylamino.
- C 1-6 alkylsulfonyl is a group in which the C 1-6 alkyl is bonded to sulfonyl, and examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and the like.
- C 1-6 alkylsulfonylamino is a group in which one hydrogen atom of an amino group is substituted with the above C 1-6 alkylsulfonyl, such as methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, etc. Is mentioned.
- C 1-6 alkylsulfinyl is a group in which the above C 1-6 alkyl is bonded to sulfinyl, and examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and the like.
- aryl examples include phenyl, naphthyl and the like.
- Heteroaryl is a 5-membered or 6-membered monocyclic ring containing 1 or 2 or more, preferably 1 to 3 heteroatoms, which are the same or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom.
- a fused cyclic heteroaryl in which the monocyclic heteroaryl is fused with the aryl, or the same or different monocyclic heteroaryl is fused with each other, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2 , 4-Triazini 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzo
- aryl or “heteroaryl” is, for example, hydroxy, cyano, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, haloC 1-6 Alkoxy, C 3-8 cycloalkoxy, amino, C 1-6 alkylamino, diC 1-6 alkylamino, halo C 1-6 alkylamino, dihalo C 1-6 alkylamino, C 3-8 cycloalkylamino, DiC 3-8 cycloalkylamino, carbamoyl, C 1-6 alkylcarbamoyl, diC 1-6 alkylcarbamoyl, haloC 1-6 alkylcarbamoyl, dihaloC 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, di C 3-8 cycloalkylcarbamoyl, thiol
- Arylcarbonyl is a group in which the aryl is bonded to carbonyl.
- Heteroarylcarbonyl is a group in which the heteroaryl is bonded to carbonyl.
- Arylcarbonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the arylcarbonyl.
- Heteroarylcarbonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the heteroarylcarbonyl.
- Aryloxy is a group in which the aryl is bonded to an oxygen atom.
- Heteroaryloxy is a group in which the heteroaryl is bonded to an oxygen atom.
- Aryloxycarbonyl is a group in which the aryloxy is bonded to carbonyl.
- Heteroaryloxycarbonyl is a group in which the heteroaryloxy is bonded to carbonyl.
- Aryloxycarbonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the aryloxycarbonyl.
- Heteroaryloxycarbonyl is a group in which one of the hydrogen atoms of the amino group is substituted with the heteroaryloxycarbonyl.
- Arylsulfinyl is a group in which the aryl is bonded to sulfinyl.
- Heteroarylsulfinyl is a group in which the heteroaryl is bonded to sulfinyl.
- Arylsulfonyl is a group in which the aryl is bonded to sulfonyl.
- Heteroarylsulfonyl is a group in which the heteroaryl is bonded to sulfonyl.
- Arylsulfonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the arylsulfonyl.
- Heteroarylsulfonylamino is a group in which one of the hydrogen atoms of the amino group is substituted with the heteroarylsulfonyl.
- “Aralkyl” means a group in which the aryl and the C 1-6 alkyl are bonded, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
- Heteroaralkyl means a group in which the heteroaryl is bonded to the C 1-6 alkyl.
- Alkyloxy means a group in which the aralkyl is bonded to an oxygen atom.
- Heteroaralkyloxy means a group in which the heteroaralkyl is bonded to an oxygen atom.
- Heterocyclyl means a monocyclic or monocyclic containing 4 to 10 atoms containing 1, 2 or 3 heteroatoms selected from saturated, partially saturated or unsaturated nitrogen, oxygen and sulfur.
- a bicyclic ring, wherein the ring nitrogen atom may be substituted by a group selected from C 1-6 alkyl, amino-C 1-6 alkyl, aryl, aryl-C 1-6 alkyl and acyl Represents a ring in which the ring carbon atom can be substituted by C 1-6 alkyl, amino-C 1-6 alkyl, aryl, aryl-C 1-6 alkyl, heteroaryl, C 1-6 alkoxy, hydroxy or oxo, for example Pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl and tetrahydropyranyl.
- the “salt” of the compound of the present invention means a conventional pharmaceutically acceptable salt, for example, when it has a carboxyl group, a base addition salt at the carboxyl group or an amino group or a basic heterocyclic group And acid addition salts in the basic heterocyclic group.
- the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine.
- organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N′-dibenzylethylenediamine salts.
- the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, and the like.
- inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
- maleate, fumarate, tartrate, citrate, ascorbate Organic acid salts such as trifluoroacetates
- sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, and the like.
- Any substitutable position means a hydrogen atom that can be chemically substituted on a carbon atom, nitrogen atom, oxygen atom and / or sulfur atom, and is chemically stable as a result of the substitution. Represents the position to give the compound.
- the compounds of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituents or the salt form.
- the compound also includes all these stereoisomers, tautomers and mixtures thereof.
- the present invention includes various crystals, amorphous, salts, hydrates and solvates of the compounds according to the present invention.
- prodrugs of the compounds of the invention are also within the scope of the invention.
- such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted into the required compounds in vivo. Therefore, in the method for treating various diseases according to the present invention, the term “administration” refers not only to the administration of the specified compound but also to the administration of a compound that is converted into the specified compound in vivo after being administered to a patient. including. Conventional means for selection and production of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985, etc., the entire description of which is incorporated herein by reference. Metabolites of these compounds include active compounds produced by placing the compounds of the present invention in a biological environment and are within the scope of the present invention.
- W represents C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or —N (R 1 ) (R 2 ).
- R 1 and R 2 each independently represent a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or R 1 and R 2 are taken together Thus, a nitrogen-containing heterocycle is formed together with the nitrogen atom to which they are bonded.
- the alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or nitrogen-containing heterocycle is hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cyclo Alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino (the amino is C 1-6 Optionally substituted with alkyl, aryl or heteroaryl), carbamoyl (the carbamoyl may be substituted with C 1-6 alkyl, aryl or heteroaryl), sulfanyl (the sulfanyl is 1 is substituted with C 1-6 alkyl, aryl or heteroaryl May be), C 1-6 alkylsulfinyl, arylsulfinyl, heteroaryl
- W include C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and n-pentyl; C 3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- Aryl such as phenyl and naphthyl; heteroaryl such as pyridyl, pyrimidinyl and pyridazinyl; aralkyl such as benzyl and phenylethyl; heteroaralkyl such as pyridylmethyl, pyridylethyl and pyrimidylmethyl; —N (such as amino, methylamino and ethylamino; R 1 ) (R 2 ) are exemplified, and R 1 and R 2 together form a nitrogen-containing heterocycle with the nitrogen atom to which they are bonded, such as azetidine, pyrrolidine, piperidine, azepan, morpholine, etc.
- W is preferably —N (R 1 ) (R 2 ) such as amino, methylamino, ethylamino, cyclopropylamino; C 1-6 alkyl; C 3-8 cycloalkyl; aryl such as phenyl or naphthyl; pyridyl , Pyrimidinyl, pyridazinyl and the like; or —N (R 1 ) (R 2 ), wherein R 1 and R 2 are taken together, together with the nitrogen atom to which they are attached, a nitrogen-containing heterocycle
- C 3-8 cycloalkyl; aryl; heteroaryl; R 1 and R 2 together form a nitrogen-containing heterocycle with the nitrogen atom to which they are attached, pyrrolidine 5- to 7-membered monocycles such as piperidine and azepane, 2-azabicyclo [2.2.1] heptane, octahydropyrrolo [1,2-a] pyrazine
- X represents aryl, heteroaryl, aralkyl or heteroaralkyl, and these groups are hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino (wherein the amino is C 1-6 alkyl, Optionally substituted with aryl or heteroaryl), carbamoyl (the carbamoyl may be substituted with C 1-6 alkyl, aryl or heteroaryl), sulfanyl (the sulfanyl is C 1-6 alkyl, aryl or heteroaryl may be monosubstituted), C 1-6 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C
- X is specifically aryl such as phenyl and naphthyl; heteroaryl such as pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrrolyl, diazolyl and triazolyl; aralkyl such as benzyl and naphthylmethyl; pyridylmethyl And heteroaralkyl such as pyridazinylmethyl and pyrimidinylmethyl.
- X is preferably formula (X-1), formula (X-2) or formula (X-3)
- R 3a represents a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl
- R 3b represents a hydrogen atom, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, provided that R 3a —O— is Bonded on a carbon atom
- R 4 represents a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Represents aryloxy or heteroaryloxy
- R 5 represents isopropyl or isopropyloxy
- R 6 represents a hydrogen atom or C
- R 3a and R 3b are preferably the same or different and are C 1-6 alkyl such as methyl, ethyl, n-propyl, n-butyl, n-hexyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo Examples include C 3-8 cycloalkyl such as octyl; aryl such as phenyl and naphthyl; and heteroaryl.
- R 4 is preferably a hydrogen atom, C 1-6 alkyl such as methyl, ethyl, n-propyl, n-butyl or n-hexyl; heteroaryl such as aryl such as phenyl or naphthyl; methoxy, ethoxy, n-propyl C 1-6 alkoxy such as oxy, n-butoxy; aryloxy such as phenoxy, naphthyloxy; or heteroaryloxy is recommended.
- C 1-6 alkyl such as methyl, ethyl, n-propyl, n-butyl or n-hexyl
- heteroaryl such as aryl such as phenyl or naphthyl
- methoxy, ethoxy, n-propyl C 1-6 alkoxy such as oxy, n-butoxy
- aryloxy such as phenoxy, naphthyloxy
- heteroaryloxy is recommended.
- R 5 is exemplified by isopropyl or isopropyloxy.
- R 6 is preferably a hydrogen atom, methyl, ethyl, isopropyl or the like.
- R 7 is preferably a hydrogen atom; hydroxy; halogen such as fluorine and chlorine; cyano; C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl; methoxy, ethoxy, n-propyloxy, C 1-6 alkoxyalkyl methoxymethyl like; isopropyloxy, n-C 1-6 alkoxy butoxy fluoromethyl, trifluoromethyl, halo C 1-6 alkyl such as chloromethyl, hydroxymethyl, hydroxyethyl, 1 Hydroxy C 1-6 alkyl such as hydroxymethylethyl; C 3-8 cycloalkyl such as cyclopropyl, cyclobutyl; halo C 1-6 alkoxy such as fluoromethoxy, trifluoromethoxy, chloromethoxy; C such as thiomethyl, thioethyl, etc.
- C halogen such as fluor
- alkylsulfinyl such as phenylthio; aryloxy such as phenoxy arylsulfonyl such as phenylsulfonyl and the like.
- R 3a is the same as defined above.
- R 4 is the same as defined above.
- R 7 is the same as defined above.
- Y represents formula (II-1), formula (II-2), formula (II-3) or formula (II-4).
- n1, n2, n3 and n4 each represents 0 or 1).
- any hydrogen atom in the formulas (II-1) to (II-4) may be substituted with C 1-6 alkyl, halo C 1-6 alkyl or C 3-8 cycloalkyl.
- Y is preferably formula (II-2) or formula (II-3).
- Z is a hydrogen atom, hydroxy, cyano, carboxyl, sulfo, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino (wherein the amino may be 1 to 2 substituted with C 1-6 alkyl, aryl or heteroaryl Carbamoyl (the carbamoyl may be 1 to 2 substituted with C 1-6 alkyl, aryl or heteroaryl), sulfanyl (the sulfanyl is monosubstituted with C 1-6 alkyl, aryl or heteroaryl) C 1-6 alkylsulfinyl, arylsulfinyl, heteroary Rusulfinyl, C 1-6 alkylsulfonyl, aryls
- Z include halogen such as hydrogen atom, fluorine and chlorine; C 1-6 alkyl such as methyl, ethyl and n-propyl; C 1-6 alkoxy such as methoxy and ethoxy; methylamino, ethylamino and the like C 1-6 alkylamino; methyl; C 1-6 alkylsulfanyl, such as methylsulfanyl, ethylsulfanyl; methylsulfonyl, C 1-6 alkylsulfonyl such as ethylsulfonyl; dimethylamino, di-C 1-6 alkylamino diethylamino Examples thereof include C 1-6 alkylcarbonyl such as carbonyl and ethylcarbonyl; sulfamoyl; diC 1-6 alkylsulfamoyl such as dimethylsulfamoyl.
- C 1-6 alkylcarbonyl such as carbonyl
- Z is preferably a hydrogen atom, chloro, methyl, ethyl, methoxy, ethoxy or the like, and particularly preferably a hydrogen atom.
- the bonding position of Z preferably a A 4.
- a 1 , A 2 , A 3 and A 4 each independently represent CH or N, provided that at least three represent CH.
- a 1 , A 2 , A 3 and A 4 , A 1 , A 2 and A 3 are CH, A 4 is N, A 1 , A 2 and A 4 and CH are CH, A 3 is N, A 1 , A 3 and A 4 are CH, A 2 is N, A 2 , A 3 and A 4 and CH are CH, A 1 is N, All of A 1 , A 2 , A 3 and A 4 are CH, Are illustrated, preferably CH is recommended for all of A 1 , A 2 , A 3 and A 4 .
- the compound represented by the formula (I) is preferably the formula (I-1)
- Y 1 represents the formula (II-2) or the formula (II-3)
- X 1 represents formula (X-1), formula (X-2) or formula (X-3);
- W, Z, A 1 , A 2 , A 3 and A 4 are the same as described above].
- the compound represented by the formula (I) is preferably 3- (2-azabicyclo [2.2.1] hept-2-ylsulfonyl) -N- (4-isopropoxyphenyl) benzamide, 3- ⁇ [3- (1H-benzimidazol-2-yl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropoxyphenyl) benzamide, 3- ⁇ [3- (1,3-benzoxazol-2-yl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropoxyphenyl) benzamide, 1-[(3- ⁇ [(4-isopropylphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide, 3- ⁇ [3- (hydroxymethyl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropylphenyl) benzamide, 3- (2-
- the compound according to the present invention can be produced , for example, by the following production method or the method shown in Examples. However, the method for producing the compound according to the present invention is not limited to these examples.
- Manufacturing method 1 The compound represented by the formula (I) can be prepared by the following method.
- Process 1 Compound 1 and Compound 2 are mixed with a base, tris (dibenzylideneacetone) dipalladium (0) (hereinafter referred to as “Pd 2 (dba) 3 ”) and (9,9-dimethyl-9H-xanthene-4) in an organic solvent. , 5-diyl) bis (diphenylphosphine) (hereinafter referred to as “Xantphos”) to give compound 3.
- Examples of the base include N, N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate and the like, preferably N, N-diisopropylethylamine is recommended.
- the amount of base used is recommended to be 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of compound 1.
- the amount of compound 2 used is 1 to 5 moles per mole of compound 1, and the amount of Pd 2 (dba) 3 used is 0.1 to 1 mole per mole of compound 1. 0 mol is exemplified, and the amount of Xantphos used is 0.2 to 2.0 mol with respect to 1 mol of Compound 1.
- reaction solvent examples include tetrahydrofuran (hereinafter referred to as “THF”), 1,4-dioxane (hereinafter referred to as “dioxane”), and the like.
- reaction temperature 20 to 150 ° C. is exemplified, and the reaction is usually completed in 1 to 24 hours.
- the amount of thionyl chloride used is, for example, from 1 mol to a large excess of mol with respect to compound 3, and preferably 1 to 5 mol is recommended.
- the reaction temperature is from room temperature to 60 ° C., preferably 0 to 100 ° C., and the reaction is usually completed in 1 to 24 hours.
- the oxidation method is not particularly limited, for example, m-chloroperbenzoic acid, potassium permanganate or the like can be used.
- reaction is carried out in a solvent such as methylene chloride or chloroform.
- Examples of the amount of m-chloroperbenzoic acid used include 2 to 10 moles with respect to 1 mole of compound 4, and the reaction may usually be carried out at room temperature for 1 to 24 hours.
- potassium permanganate when used, it is carried out in a mixed solvent of acetone / water.
- acetic acid may be added to the reaction system.
- Examples of the amount of potassium permanganate used include 2 to 6 moles with respect to 1 mole of compound 4, and the reaction may usually be performed at room temperature for 1 to 24 hours.
- Examples of the amount of acetic acid used include 1 to 10 mol per 1 mol of compound 4.
- reaction temperature 20 to 80 ° C. is exemplified, preferably 20 to 50 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
- the ester of Compound 5 is hydrolyzed to Compound 6.
- the method of hydrolysis is not particularly limited, and may be carried out in a lower alcohol such as methanol or ethanol using an alkali such as sodium hydroxide or potassium hydroxide in an equimolar to excess molar amount.
- the reaction temperature at the time of hydrolysis is exemplified by 0 to 100 ° C., preferably 20 to 50 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
- the amidation method can be carried out by a conventionally known method.
- the compound 6 and the compound 7 are reacted in the presence of a condensing agent, or the carboxylic acid moiety of the compound 6 is activated by a conventionally known method. And then amidating the derivative with compound 2 (both methods are described in “Peptide Synthesis Fundamentals and Experiments” (Nobuo Izumiya et al., Maruzen Co., Ltd., 1983)). See
- the following method is exemplified as the reaction using a condensing agent.
- the compound 6 and the compound 7 are condensed in a reaction solvent in the presence of a base using a condensing agent to obtain a compound represented by the formula (Ia).
- Examples of the base include N, N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate and the like, preferably N, N-diisopropylethylamine is recommended.
- the amount of the base used is recommended to be 1 to 10 mol, preferably 1 to 3 mol with respect to 1 mol of compound 6.
- Examples of the amount of compound 7 used include 1 to 3 moles per mole of compound 6.
- condensing agent examples include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and the amount used is 1 to 3 moles per mole of compound 1.
- hydroxybenzotriazole (hereinafter referred to as “HOBT”) or the like may be added to the reaction system for the purpose of promoting the reaction.
- HOBT hydroxybenzotriazole
- Examples of the amount of HOBT used include 1 to 3 moles per mole of Compound 1.
- reaction solvent examples include THF, dioxane, N, N-dimethylformamide (hereinafter referred to as “DMF”), dimethyl sulfoxide (hereinafter referred to as “DMSO”), dichloromethane, or a mixed solvent thereof.
- reaction temperature 20 to 100 ° C. is exemplified, preferably 20 to 50 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
- the compound represented by the formula (Ia) obtained by the above method can be easily isolated and purified by ordinary separation means.
- Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography and the like (the same applies in the following methods).
- examples of compound 1 include 3-mercaptobenzoic acid and 3-mercapto-2-methoxybenzoic acid
- examples of compound 2 include 2-iodopyridine, 2-bromopyrimidine, 2-iodopyrazine and the like.
- examples of the compound 7 include 5-isopropoxypyridin-2-amine, 4-isopropylaniline, 1- (4-aminophenyl) ethanone and the like.
- Manufacturing method 2 is a method for producing a compound represented by formula (Ib).
- Step 6 Compound 9 is amidated with Compound 7 in the presence of a base in an organic solvent to give Compound 9.
- Examples of the base include N, N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate and the like, preferably N, N-diisopropylethylamine is recommended.
- the amount of base used is 1 to 10 moles, preferably 1 to 3 moles per mole of Compound 8.
- the amount of compound 7 used is 1 to 5 moles with respect to 1 mole of compound 8, and preferably 1 to 2 moles.
- organic solvent examples include methylene chloride, carbon tetrachloride, THF, dioxane, DMF, DMSO and the like.
- reaction temperature 0 to 80 ° C. is exemplified, preferably 0 to 20 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
- Examples of compound 7 include 4-isopropoxyaniline, 4-isopropylaniline, 2-methoxyaniline, 4-methoxyaniline, 3-methoxypyridin-2-amine, 2-amino-5-isopropoxypyridine and the like.
- Step 7 Compound 9 and Compound 10 are condensed in an organic solvent according to Step 5 to obtain a compound represented by the formula (Ib).
- the amount of compound 10 used is, for example, 1 to 5 moles per mole of compound 9, preferably 1 to 2 moles.
- organic solvent examples include methylene chloride, carbon tetrachloride, THF, dioxane, DMF, DMSO and the like.
- reaction temperature 0 to 80 ° C. is exemplified, preferably 0 to 20 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
- Compound 10 includes (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane, 2-azabicyclo [2.2.1] heptane, 4,5,6,7-tetrahydro-1H. -Pyrazolo [4,3-c] pyridine, 4-azatricyclo [4.3.1.1 3,8 ] undecane, 2-piperidin-3-yl-1H-benzimidazole and the like.
- Process 8 Compound 5 is reduced using a reducing agent to give compound 11.
- the ester moiety may be reduced by a conventionally known method using a reducing agent such as lithium aluminum hydride.
- lithium aluminum hydride when lithium aluminum hydride is used, compound such as THF is used as a reaction solvent, 1-5 mol of lithium aluminum hydride is used per 1 mol of compound 5, and the reaction is carried out at room temperature for 1-6 hours. Is obtained.
- Step 9 Compound 11 and phthalimide are condensed by Mitsunobu reaction to obtain compound 12.
- Examples of the azo compound include dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidide, and the triarylphosphine includes triphenylphosphine, Examples include trilylphosphine, and examples of trialkylphosphine include triethylphosphine and tributylphosphine. Among them, a combination of diisopropyl azodicarboxylate and triphenylphosphine, or a combination of 1,1 '-(azodicarbonyl) dipiperidide and tributylphosphine is recommended.
- the amount of phthalimide used is, for example, 1 to 10 mol, preferably 1 to 1.5 mol based on 1 mol of compound 11.
- the amount of the azo compound and the organophosphorus compound used is, for example, 1 to 3 mol of the azo compound with respect to 1 mol of the compound 11, preferably 1 to 1.5 mol is recommended.
- 1 to 3 moles of an organophosphorus compound is exemplified, and preferably 1 to 1.5 moles is recommended.
- reaction solvent examples include halogenated carbons such as methylene chloride, chloroform, dichloroethane and carbon tetrachloride; aliphatic hydrocarbons such as n-heptane and n-hexane; aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as diethyl ether, THF, dioxane, ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; acetonitrile, N-methylpyrrolidone (hereinafter referred to as “NMP”), DMF, DMSO, or a mixed solvent thereof Is exemplified.
- halogenated carbons such as methylene chloride, chloroform, dichloroethane and carbon tetrachloride
- aliphatic hydrocarbons such as n-heptane and n-hexane
- aromatic hydrocarbons such as benz
- reaction temperature 0 to 100 ° C. is exemplified, preferably 0 to 50 ° C. is recommended, and the reaction is usually completed in 2 to 24 hours.
- Step 10 Compound 12 is treated with hydrazine in a reaction solvent to give compound 13.
- Examples of the amount of hydrazine used include 1 to 10 mol, preferably 2 to 5 mol per mol of compound 12.
- reaction solvent examples include methanol, ethanol, n-propanol and the like.
- the reaction temperature is 0 to 80 ° C., preferably 20 to 50 ° C.
- the reaction is usually completed in 1 to 24 hours.
- Step 11 Compound 13 and Compound 14 are reacted according to Step 5 to obtain a compound represented by the formula (Ic).
- Step 12 Compound 13 and Compound 15 are reacted according to Step 6 to obtain the compound represented by the formula (Id).
- Step 13 The compound 13 and the compound 16 are reacted according to the step 6 to obtain a compound represented by the formula (Ie).
- amino-protecting group examples include aralkyl such as benzyl, p-methoxybenzyl and trityl; C 1-6 alkanoyl such as formyl, acetyl, propionyl, butyryl and pivaloyl; eg benzoyl; aryl alkanoyl and the like; for example, methoxycarbonyl, ethoxycarbonyl, tert- butoxy C 1-6 alkoxycarbonyl such as carbonyl; for example benzyloxycarbonyl, aralkyloxycarbonyl such as p- nitrobenzyloxycarbonyl; such as trimethylsilyl, tert- butyldimethylsilyl C 1-6 alkylsilyl such as acetyl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl and the like are particularly preferable.
- aralkyl such as benzyl, p
- Examples of the “carboxyl-protecting group” include C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl and tert-butyl; C 1-6 haloalkyl such as 2,2,2-trichloroethyl; C 1-6 alkenyl such as propenyl; for example, aralkyl such as benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl, trityl and the like, in particular, methyl, ethyl, tert-butyl, 2-propenyl, benzyl, p- Methoxybenzyl, benzhydryl and the like are preferable.
- C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl and tert-butyl
- C 1-6 haloalkyl such as 2,2,2-trichloroethyl
- the introduction and removal of the protecting group can be carried out according to the method described in the above document [Protective Groups in Organic Synthesis] or a method analogous thereto.
- the compounds according to the invention can be administered orally or parenterally and can be formulated into a form suitable for such administration, for example hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, Diabetic nephropathy, diabetic retinopathy, vision loss, electrolyte abnormalities, cardiovascular diseases such as arteriosclerosis, for example central nervous system diseases such as bulimia, diabetic neuropathy, such as metabolic syndrome, obesity, diabetes, Metabolic diseases such as insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceremia, dyslipidemia, nonalcoholic fatty liver, abnormal hormone secretion, gout, fatty liver, such as menstrual disorders, sex Reproductive system diseases such as dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal tract disease such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory apnea such as sleep apnea syndrome Disease, can be subjecte
- One aspect of the present invention is a method for treating a disease, illness or condition resulting from modulation of LCE comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound according to the present invention. To provide a cure or prevention.
- Another aspect of the present invention includes metabolic syndrome, fatty liver, hyperlipidemia, comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof. It is to provide a method for treating or preventing dyslipidemia, non-alcoholic fatty liver disease, obesity, diabetes, bulimia, malignant neoplasms or infectious diseases.
- Another aspect of the present invention is to provide a therapeutic or prophylactic method for diabetes comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof. It is.
- Another aspect of the present invention provides a method for treating or preventing obesity comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound according to the present invention. That is.
- Another aspect of the present invention includes overeating, bulimia, hypertension, plasma insulin levels comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof.
- Another aspect of the invention is the treatment of hyperlipidemia or dyslipidemia comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound according to the invention. Is to provide a law or prevention.
- Another aspect of the present invention is to provide a caloric intake method comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof.
- Another aspect of the present invention is to provide a method of reducing food intake comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof. .
- Another aspect of the present invention is to provide a method of increasing satiety comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof. .
- Another aspect of the present invention is to provide a method for reducing appetite, comprising administering a therapeutically or prophylactically effective amount of a compound according to the present invention to a subject in need thereof.
- the invention also treats obesity comprising administering a compound according to the invention in combination with a therapeutically or prophylactically effective amount of another agent known to be useful in the treatment or prevention of the condition.
- a compound according to the invention in combination with a therapeutically or prophylactically effective amount of another agent known to be useful in the treatment or prevention of the condition.
- the present invention also provides a method for treating diabetes comprising administering a compound according to the present invention in combination with a therapeutically or prophylactically effective amount of another drug known to be useful in the treatment or prevention of the condition. Or it relates to prevention methods.
- the present invention also provides a therapeutically or prophylactically effective compound (I) or a pharmaceutically acceptable salt thereof according to the present invention for other drugs known to be useful for the treatment or prevention of the condition.
- the present invention relates to a method for treating or preventing hyperlipidemia or dyslipidemia comprising administration in combination with an amount.
- Another aspect of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to the present invention and a pharmaceutically acceptable carrier.
- Still another aspect of the present invention relates to a compound according to the present invention for use as a medicament.
- Still another aspect of the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament useful for the treatment, prevention, or suppression of diseases caused by LCE in a subject in need thereof.
- Yet another aspect of the invention is the metabolic syndrome, hyperlipidemia, dyslipidemia, non-alcoholic fatty liver, obesity, diabetes, bulimia, malignant neoplasm or infection of the subject in need thereof It relates to the use of a compound according to the invention for the manufacture of a medicament useful for the treatment or prevention of sexually transmitted diseases.
- Still another aspect of the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament useful for the treatment or prevention of obesity in a subject in need thereof.
- Still another aspect of the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament useful for the treatment or prevention of diabetes in a subject in need thereof.
- Yet another aspect of the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament useful for the treatment or prevention of hyperlipidemia or dyslipidemia in a subject in need thereof.
- a therapeutically effective amount of a compound according to the present invention an insulin sensitizer, an insulin analog, a sulfonylurea, an ⁇ -glucosidase inhibitor, dipeptidyl peptidase 4 (DPP- 4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, ⁇ 3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 Agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, ghrelin antagonist, PYY, I from PYY 3-36 and NK-1 antagonist
- a therapeutically effective amount of a compound according to the present invention an insulin sensitizer, an insulin analog, a sulfonylurea, an ⁇ -glucosidase inhibitor, dipeptidyl peptidase 4 (DPP- 4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, ⁇ 3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 Agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, ghrelin antagonist, PYY, I from PYY 3-36 and NK-1 antagonist
- a therapeutically effective amount of a compound according to the present invention an insulin sensitizer, an insulin analog, a sulfonylurea, an ⁇ -glucosidase inhibitor, dipeptidyl peptidase 4 (DPP- 4 or DP-IV) inhibitor, glucagon-like peptide 1 (GLP-1) agonist, HMG-CoA reductase inhibitor, serotonin-like substance, ⁇ 3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 Agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, ghrelin antagonist, PYY, I from PYY 3-36 and NK-1 antagonist A combination for the simultaneous, separate or sequential use of obesity,
- Yet another aspect of the present invention comprises a therapeutically effective amount of a compound according to the present invention and simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa (trade name) and phentermine.
- a therapeutically effective amount of an agent selected from the group or a pharmaceutically acceptable salt thereof for the treatment of obesity, diabetes, diabetes-related diseases or obesity-related diseases in a subject in need thereof; The above use for the manufacture of a medicament useful for management or prevention.
- a pharmaceutically acceptable additive in accordance with its administration form and administer it after various preparations.
- various additives that are usually used in the pharmaceutical field can be used.
- dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field.
- a liquid preparation it may be dissolved or suspended in water or other appropriate medium at the time of use.
- injections they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.
- the compound according to the present invention is effective for animals and plants including humans or other mammals that require treatment with the compound.
- the mammal is preferably a human and may be male or female.
- mammals other than humans include pets such as dogs and cats.
- the compound according to the present invention is also effective against obesity such as dogs and cats or diseases related to obesity. Whether or not treatment with the compound is required can be readily determined by a regular physician, veterinarian or clinician.
- the dose and the number of administrations vary depending on the sex, age, weight, degree of symptoms of the patient, and the type and range of the intended treatment effect.
- 0.01 to 100 mg / kg, preferably 0.03 to 1 mg / kg per day for an adult is divided into 1 to several times, and in the case of parenteral administration, 0.001 to 10 mg / kg.
- 1.0-1000 mg of active ingredient especially 1.0, 5.0, 10.0, 15.0, 20 to adjust the dosage to the condition of the patient being treated.
- 0.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0 800.0, 900.0 and 1000.0 mg tablets containing 1000.0 mg of the active ingredient are preferred.
- the compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- the compounds according to the invention are applied for the treatment or prevention of obesity and / or diabetes and / or hyperlipidemia and / or dyslipidemia and / or non-alcoholic fatty liver, or other diseases
- the daily dose of the compound of the present invention is about 0.1 mg to about 100 mg per kg body weight of the animal, it is more preferable to administer a single dose or divided dose of 2 to 6 times per day, or gradually. Satisfactory results can generally be obtained when using a releasable formulation.
- the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg.
- the total daily dose will usually be from about 7 mg to about 350 mg.
- This dosage regimen can be adjusted to provide the best therapeutic effect. Ordinary physicians, veterinarians or clinicians can easily determine and handle the effective amount of drug needed to treat, prevent, prevent, inhibit or stop disease progression.
- These preparations can contain the compound according to the present invention in a ratio of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
- cardiovascular diseases such as hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy, vision loss, electrolyte abnormalities, arteriosclerosis, such as bulimia
- Central nervous system diseases such as diabetic neuropathy, eg metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fat Metabolic diseases such as liver, hormonal secretion abnormalities, gout, fatty liver, reproductive system diseases such as menstrual disorders, sexual dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal diseases such as gastroesophageal reflux, low obesity
- respiratory diseases such as ventilation syndrome (Pickwick syndrome), sleep apnea syndrome, infectious diseases caused by bacteria, fungi, and parasites, malignant neoplasms, arthritis, inflammatory diseases such as skin ulcers, etc.
- the present invention should be construed to include all simultaneous or timed administrations, and administration in the present invention should be construed as such.
- the range of combinations of the compounds of the present invention with other agents useful for the treatment of the above-mentioned diseases includes, in principle, combinations with any pharmaceutical preparations useful for the treatment of the above-mentioned diseases.
- the combination includes not only one other active substance but also two or more other active substances in combination with the composition of the present invention.
- combinations of the composition of the present invention with one, two or more activators selected from the above therapeutic agents For example, for the purpose of treatment / management / prevention of metabolic syndrome, one, two or more activators selected from the composition of the present invention and a hyperlipidemic agent, a lipid-reducing agent and an anti-diabetic agent The combination with is beneficial.
- compositions comprising anti-obesity agents and anti-hypertensive agents have a synergistic effect on the treatment, management or prevention of metabolic syndrome To do.
- drugs combined with this drug include ACAT inhibitor, ⁇ -procker, aldose reductase inhibitor, ⁇ -amylase inhibitor, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist, anion exchange resin, appetite suppressant, antioxidant Agent, antiplatelet agent, beta blocker, biguanide agent, calcium antagonist, CB1 receptor inverse agonist / antagonist, CETP inhibitor, cholesterol absorption inhibitor, DGAT inhibitor, DP-IV inhibitor, diuretic, eicosapentaenoic acid , Endothelin antagonist, FLAP inhibitor, FXR modulator, ghrelin antagonist, GLP-1 agonist, GLP-1 secretion agent, glucagon antagonist, glucokinase activator, glucocorticoid receptor ligand, ⁇ -glycosidase inhibitor, GPAT inhibition Agent, histami H3 receptor ligand, HMG-CoA reductase inhibitor, HSD inhibitor, insulin and its similar drugs, kinase
- the compound according to the present invention has an excellent LCE inhibitory action, and various diseases involving LCE such as cardiovascular disease, nervous system disease, metabolic disease, reproductive system disease, gastrointestinal disease, neoplasm, infection It is useful as a therapeutic agent for diseases, etc., or as a herbicide.
- Thin-layer chromatography used Silica gel 60 F 254 (Merck) as a plate and a UV detector as a detection method.
- column silica gel Wakogel TM C-300 or C-200 (Wako Pure Chemical Industries), FLASH + cartridge (Biotage) or Chromatorex (FUJI SILYSIA CHEMICAL) was used.
- MS spectra were measured using ZQ2000 (Waters). When NMR spectra are measured with a deuterated dimethyl sulfoxide solution, dimethyl sulfoxide is used as an internal standard, and JNM-AL400 (JEOL), Mercury 400 (400 MHz; Varian), or Inova 400 (400 MHz; Varian) type spectrometer. The total ⁇ value was expressed in ppm.
- Example 1 N- (4-Isopropoxyphenyl) -3-[(1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylsulfonyl] benzamide
- Compound obtained in Reference Example 1 80.0 mg) in THF (3.0 mL) was added (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane monohydrochloride (76.6 mg) and triethylamine (0.16 mL).
- Ethyl acetate was added to the reaction solution, which was then washed 3 times with water and dried over sodium sulfate.
- Example 2 3- (2-Azabicyclo [2.2.1] hept-2-ylsulfonyl) -N- (4-isopropoxyphenyl) benzamide
- the compound obtained in Reference Example 1 and 2-azabicyclo [2.2.1] The title compound was obtained by the method according to Example 1 using heptane as a raw material.
- Example 3 N- (4-Isopropoxyphenyl) -3- (1,4,6,7-tetrahydro-5H-pyrazolo [4,3-c] pyridin-5-ylsulfonyl) benzamide trifluoroacetate obtained in Reference Example 1
- the title compound was obtained by the method according to Example 1 using the obtained compound and 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine as raw materials.
- Example 4 3- (4-Azatricyclo [4.3.1.1 3,8 ] undec-4-ylsulfonyl) -N- (4-isopropoxyphenyl) benzamide
- the title compound was obtained by the method according to Example 1 using undecane as a raw material.
- Example 5 3- ⁇ [3- (1H-benzimidazol-2-yl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropoxyphenyl) benzamide
- the compound obtained in Reference Example 1 and 2-piperidine-3- The title compound was obtained by a method according to Example 1 using yl-1H-benzimidazole as a starting material.
- Example 6 3- ⁇ [(Dicyclopropylmethyl) amino] sulfonyl ⁇ -N- (4-isopropoxyphenyl) benzamide Examples using the compound obtained in Reference Example 1 and 1,1-dicyclopropylmethanamine as raw materials The title compound was obtained by a method according to 1.
- Example 7 3- ⁇ [3- (1,3-Benzoxazol-2-yl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropoxyphenyl) benzamide
- the compound obtained in Reference Example 1 and 2-piperidine- The title compound was obtained by a method according to Example 1 using 3-yl-1,3-benzoxazole as a starting material.
- Example 8 N- (4-Isopropoxyphenyl) -3- ⁇ [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] sulfonyl ⁇ benzamide trifluoroacetate Reference The title compound was obtained by the method according to Example 1 using the compound obtained in Example 1 and (1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptane as raw materials.
- Example 9 N- (4-Isopropoxyphenyl) -3- ⁇ [2- (phenoxymethyl) morpholin-4-yl] sulfonyl ⁇ benzamide Using the compound obtained in Reference Example 1 and 2- (phenoxymethyl) morpholine as raw materials, The title compound was obtained by the method according to Example 1.
- Example 10 N- (4-Isopropoxyphenyl) -3-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylsulfonyl] benzamide
- the compound obtained in Reference Example 1 and The title compound was obtained by a method according to Example 1 using (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane as a starting material.
- Example 11 N- (4-Isopropoxyphenyl) -3- ⁇ [3- (4-Methyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] sulfonyl ⁇ benzamide trifluoroacetate Reference Example Using the compound obtained in 1 and 3- (4-methyl-4H-1,2,4-triazol-3-yl) piperidine as raw materials, the title compound was obtained by the method according to Example 1.
- Example 12 3- (Octahydropyrrolo [1,2-a] pyrazin-2 (1H) -ylsulfonyl) -N- (4-isopropoxyphenyl) benzamide trifluoroacetate Compound obtained in Reference Example 1 and octahydropyrrolo The title compound was obtained by the method according to Example 1 using [1,2-a] pyrazine as a starting material.
- Example 13 N- (4-Isopropoxyphenyl) -3- (octahydro-2H-pyrido [1,2-a] pyrazin-2-ylsulfonyl) benzamide trifluoroacetate Compound obtained in Reference Example 1 and octahydro-2H- The title compound was obtained by the method according to Example 1 using pyrido [1,2-a] pyrazine as a starting material.
- Example 14 N- (4-Isopropoxyphenyl) -3- ⁇ [3- (morpholin-4-ylmethyl) piperidin-1-yl] sulfonyl ⁇ benzamide trifluoroacetate Compound obtained in Reference Example 1 and 4- (piperidine- The title compound was obtained by the method according to Example 1 using 3-ylmethyl) morpholine as a raw material.
- Example 15 3-[(4-Fluoropiperidin-1-yl) sulfonyl] -N- (4-isopropoxyphenyl) benzamide According to Example 1, using the compound obtained in Reference Example 1 and 4-fluoropiperidine as raw materials The title compound was obtained by the method.
- Example 16 3- (2-Azabicyclo [2.2.2] oct-2-ylsulfonyl) -N- (4-isopropoxyphenyl) benzamide
- the compound obtained in Reference Example 1 and 2-azabicyclo [2.2.2] The title compound was obtained by a method according to Example 1 using octane as a starting material.
- Example 17 3-[(4,4-Difluoropiperidin-1-yl) sulfonyl] -N- (4-isopropoxyphenyl) benzamide
- Example using the compound obtained in Reference Example 1 and 4,4-difluoropiperidine as raw materials The title compound was obtained by a method according to 1.
- Example 18 N- (4-Isopropoxyphenyl) -3-[(3-methoxypiperidin-1-yl) sulfonyl] benzamide According to Example 1, using the compound obtained in Reference Example 1 and 3-methoxypiperidine as raw materials The title compound was obtained by the method.
- Example 19 3-[(3,3-Difluoropiperidin-1-yl) sulfonyl] -N- (4-isopropoxyphenyl) benzamide
- Example using the compound obtained in Reference Example 1 and 3,3-difluoropiperidine as raw materials The title compound was obtained by the method according to 1.
- Example 20 N- (4-Isopropoxyphenyl) -3- ⁇ [3- (pyridin-3-ylmethoxy) piperidin-1-yl] sulfonyl ⁇ benzamide trifluoroacetate The compound obtained in Reference Example 1 and 3-[(piperidine The title compound was obtained by the method according to Example 1 using -3-yloxy) methyl] pyridine as a starting material.
- Example 21 N- (4-Isopropoxyphenyl) -3- ⁇ [3- (pyridin-2-ylmethoxy) piperidin-1-yl] sulfonyl ⁇ benzamide trifluoroacetate
- the title compound was obtained by the method according to Example 1 using -3-yloxy) methyl] pyridine as a starting material.
- Example 22 N- (4-Isopropoxyphenyl) -3-[(3-oxo-2,3,6,7-tetrahydroisoxazolo [4,5-c] pyridin-5 (4H) -yl) sulfonyl] benzamide Reference The title compound was obtained by the method according to Example 1 using the compound obtained in Example 1 and 4,5,6,7-tetrahydroisoxazolo [4,5-c] pyridin-3 (2H) -one as raw materials. Got.
- Example 23 N- (4-Isopropoxyphenyl) -3- ⁇ [(2S) -2-methylpyrrolidin-1-yl] sulfonyl ⁇ benzamide Using the compound obtained in Reference Example 1 and (2S) -2-methylpyrrolidine as raw materials And the title compound was obtained by the method according to Example 1.
- Example 24 N- (4-Isopropoxyphenyl) -3- ⁇ [(2R) -2-methylpyrrolidin-1-yl] sulfonyl ⁇ benzamide Using the compound obtained in Reference Example 1 and (2R) -2-methylpyrrolidine as raw materials And the title compound was obtained by the method according to Example 1.
- Example 25 3-( ⁇ [2- (1H-benzimidazol-2-yl) propyl] amino ⁇ sulfonyl) -N- (4-isopropoxyphenyl) benzamide
- the compound obtained in Reference Example 1 and 2- (1H-benzimidazole) The title compound was obtained by the method according to Example 1 using -2-yl) propan-1-amine as a starting material.
- Example 27 3- (Azepan-1-ylsulfonyl) -N- (4-isopropylphenyl) benzamide
- the title compound was obtained by a method according to Example 26 using the compound obtained in Reference Example 2 and hexamethyleneamine as raw materials. .
- Example 28 N- (4-Isopropylphenyl) -3- (pyrrolidin-1-ylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 26 using the compound obtained in Reference Example 2 and pyrrolidine as raw materials.
- Example 29 N- (4-Isopropylphenyl) -3- (morpholin-4-ylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 26 using the compound obtained in Reference Example 2 and morpholine as raw materials.
- Example 30 N- (4-Isopropylphenyl) -3-[(2-methylpiperidin-1-yl) sulfonyl] benzamide A method according to Example 26 using the compound obtained in Reference Example 2 and 2-methylpiperidine as starting materials. Gave the title compound.
- Example 31 3- ⁇ [(2R, 6S) -2,6-dimethylpiperidin-1-yl] sulfonyl ⁇ -N- (4-isopropylphenyl) benzamide
- the compound obtained in Reference Example 2 and (2R, 6S) -2, The title compound was obtained by a method according to Example 26 using 6-dimethylpiperidine as a starting material.
- Example 32 3-[(3-Hydroxypiperidin-1-yl) sulfonyl] -N- (4-isopropylphenyl) benzamide A method according to Example 26 using the compound obtained in Reference Example 2 and 3-hydroxypiperidine as starting materials. Gave the title compound.
- Example 33 (3R) -3-fluoropyrrolidin-1-yl] sulfonyl ⁇ -N- (4-isopropylphenyl) benzamide
- Example 26 using the compound obtained in Reference Example 2 and (3R) -3-fluoropyrrolidine as raw materials The title compound was obtained by a method according to.
- Example 34 1-[(3- ⁇ [(4-Isopropylphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide Conducted using the compound obtained in Reference Example 2 and (3R) -3-fluoropyrrolidine as raw materials The title compound was obtained by a method according to Example 26.
- Example 35 1-[(3- ⁇ [(4-Isopropylphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-4-carboxamide
- Example 26 the compound obtained in Reference Example 2 and piperidine-3-carboxamide were used as raw materials.
- the title compound was obtained by a similar method.
- Example 36 3- ⁇ [(3R) -3-hydroxypiperidin-1-yl] sulfonyl ⁇ -N- (4-isopropylphenyl) benzamide
- Example 37 3- ⁇ [3- (hydroxymethyl) piperidin-1-yl] sulfonyl ⁇ -N- (4-isopropylphenyl) benzamide Examples using the compound obtained in Reference Example 2 and piperidin-3-ylmethanol as raw materials The title compound was obtained by a method according to No. 26.
- Example 38 3-[(Cyclohexylamino) sulfonyl] -N- (4-isopropylphenyl) benzamide
- the title compound was obtained by a method according to Example 26 using the compound obtained in Reference Example 2 and cyclohexaneamine as raw materials.
- Example 39 3- (Anilinosulfonyl) -N- (4-isopropylphenyl) benzamide
- the title compound was obtained by a method according to Example 26 using the compound obtained in Reference Example 2 and aniline as raw materials.
- Example 40 N- (4-Isopropylphenyl) -3- ⁇ [(2R) -2- (methoxymethyl) pyrrolidin-1-yl] sulfonyl ⁇ benzamide
- the title compound was obtained by the method according to Example 26 using pyrrolidine as a starting material.
- Example 41 3- ⁇ [(3R) -3-hydroxypiperidin-1-yl] sulfonyl ⁇ -N- (2-methoxyphenyl) benzamide
- Example 42 3- ⁇ [3- (Hydroxymethyl) piperidin-1-yl] sulfonyl ⁇ -N- (2-methoxyphenyl) benzamide
- Example using the compound obtained in Reference Example 3 and piperidin-3-ylmethanol as raw materials The title compound was obtained by a method according to 1.
- Example 43 1-[(3- ⁇ [(2-methoxyphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide
- Example 1 was prepared using the compound obtained in Reference Example 3 and piperidine-3-carboxamide as raw materials. The title compound was obtained by a similar method.
- Example 44 5- ⁇ [(3- ⁇ [(4-Methoxyphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] amino ⁇ pentanoic acid (Step 1) 3- ⁇ [(5-hydroxypentyl) amino] sulfonyl ⁇ -N- (4 Synthesis of -methoxyphenyl) benzamide Using the compound obtained in Reference Example 4 and 5-aminopentan-1-ol as raw materials, the target compound was obtained by the method according to Example 1.
- Step 2 Synthesis of 5- ⁇ [(3- ⁇ [(4-methoxyphenyl) amino] carbonyl ⁇ phenyl) sulfonyl] amino ⁇ pentanoic acid
- acetone 10 mL
- Jones reagent mixed solution of chromic acid (280 mg), sulfuric acid (0.25 mL) and water (0.50 mL)
- the residue was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate.
- the desiccant was filtered off and the solvent was distilled off under reduced pressure.
- Example 45 3-[(tert-Butylamino) sulfonyl] -N- (4-methoxyphenyl) benzamide A method according to Example 1 using the compound obtained in Reference Example 4 and 2-methylpropan-2-amine as starting materials. Gave the title compound.
- Example 46 N- (4-Methoxyphenyl) -3- (piperidin-1-ylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 1 using the compound obtained in Reference Example 4 and piperidine as raw materials.
- Example 47 N- (3-methoxypyridin-2-yl) -3- (morpholin-4-ylsulfonyl) benzamide
- THF 2.0 mL
- triethylamine 0.13 mL
- morpholine 41.2 mg
- Example 48 N- (3-methoxypyridin-2-yl) -3- ⁇ [(2S) -2-methylpyrrolidin-1-yl] sulfonyl ⁇ benzamide
- the compound obtained in Reference Example 5 and (2S) -2-methylpyrrolidine was used as a starting material to give the title compound by the method according to Example 47.
- Example 49 3- (2-Azabicyclo [2.2.1] hept-2-ylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide
- the compound obtained in Reference Example 5 and 2-azabicyclo [2.2 .1] The title compound was obtained by a method according to Example 47 using heptane as a starting material.
- Example 50 3- ⁇ [3- (1H-benzimidazol-2-yl) piperidin-1-yl] sulfonyl ⁇ -N- (3-methoxypyridin-2-yl) benzamide
- the compound obtained in Reference Example 5 and 2-piperidine The title compound was obtained by the method according to Example 47 using -3-yl-1H-benzimidazole as a starting material.
- Example 51 3- (2-Azabicyclo [2.2.2] oct-2-ylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide
- the title compound was obtained by a method according to Example 47 using octane as a starting material.
- Example 52 3- (7-azabicyclo [2.2.1] hept-7-ylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide
- the compound obtained in Reference Example 5 and 7-azabicyclo [2.2 .1] The title compound was obtained by a method according to Example 47 using heptane as a starting material.
- Example 53 N- (3-methoxypyridin-2-yl) -3-[(1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylsulfonyl] benzamide obtained in Reference Example 5
- the title compound was obtained by the method according to Example 47 using the compound and (1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane monohydrochloride as raw materials.
- Example 54 3- (8-Azabicyclo [3.2.1] oct-8-ylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide
- the compound obtained in Reference Example 5 and 8-azabicyclo [3.2 .1] The title compound was obtained by a method according to Example 47 using octane as a starting material.
- Example 55 Ethyl 1-[(3- ⁇ [(3-methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxylate (Step 1) 3- ⁇ [3- (ethoxycarbonyl) piperidine-1 Synthesis of —yl] sulfonyl ⁇ benzoic acid Using 3- (chlorosulfonyl) benzoic acid (5.00 g) and ethylpiperidine-3-carboxylate (7.04 mL) as raw materials, the target compound was prepared by a method according to Reference Example 1. (7.12 g, 92%) was obtained as a colorless solid.
- Step 2 Synthesis of ethyl 1-[(3- ⁇ [(3-methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxylate Compound (4.00 g) obtained in Step 1 ) And 2-amino-3-methoxypyridine (1.45 g) as starting materials, and the target compound (3.66 g, 70%) was obtained as a colorless oil by the method according to Example 92.
- Example 56 1-[(3- ⁇ [(3-Methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxylic acid
- the compound (50 mg) obtained in Example 55 was dissolved in methanol (1.0 mL). 2M sodium hydroxide aqueous solution (0.056 mL) was added, and the mixture was stirred at room temperature for 17 hours.
- Example 57 1-[(3- ⁇ [(3-Methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide
- the compound (50 mg) obtained in Example 56 was added to DMF (1.0 mL).
- DMF 1.0 mL
- N, N-diisopropylethylamine 0.030 mL
- ammonium chloride 8 mg
- 1-hydroxybenzotriazole hydrate 22 mg
- N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride 27 mg was sequentially added, and the mixture was stirred at room temperature for 3 days.
- Example 58 1-[(3- ⁇ [(5-Isopropoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide Conducted using the compound obtained in Reference Example 6 and piperidine-3-carboxamide. The title compound was obtained by a method according to Example 47.
- Example 60 1-[(3- ⁇ [(3-Methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] -N-methylpiperidine-3-carboxamide Using the compound obtained in Example 56 and methylamine as raw materials The title compound was obtained by a method according to Example 57.
- Example 61 N-benzyl-1-[(3- ⁇ [(3-methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxamide Using the compound obtained in Example 56 and benzylamine as raw materials The title compound was obtained by a method according to Example 57.
- Example 62 Benzyl 1-[(3- ⁇ [(3-methoxypyridin-2-yl) amino] carbonyl ⁇ phenyl) sulfonyl] piperidine-3-carboxylate
- Example 63 3-Isopropoxy-5- ⁇ [3- (morpholin-4-ylsulfonyl) benzoyl] amino ⁇ -1H-pyrazole hydrochloride
- the compound (100 mg) obtained in Reference Example 7 was dissolved in THF (2.0 mL).
- Morpholine (0.10 mL) was added, and the mixture was stirred at room temperature for 18 hours.
- Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- Example 64 3-Isopropoxy-5-( ⁇ 3-[(2-methylpyrrolidin-1-yl) sulfonyl] benzoyl ⁇ amino) -1H-pyrazole hydrochloride Using the compound obtained in Reference Example 7 and 2-methylpyrrolidine as raw materials And the title compound was obtained by a method analogous to Example 63.
- Example 65 5-[(3- ⁇ [3- (hydroxymethyl) piperidin-1-yl] sulfonyl ⁇ benzoyl) amino] -3-isopropoxy-1H-pyrazole hydrochloride
- the compound obtained in Reference Example 7 and piperidine-3- The title compound was obtained by the method according to Example 63 using ilmethanol as a starting material.
- Example 66 5-( ⁇ 3-[(3-hydroxypiperidin-1-yl) sulfonyl] benzoyl ⁇ amino) -3-isopropoxy-1H-pyrazole hydrochloride
- the compound obtained in Reference Example 7 and 3-hydroxypiperidine hydrochloride The title compound was obtained by a method according to Example 63 using as a raw material.
- Example 67 5-( ⁇ 3-[(4-fluoropiperidin-1-yl) sulfonyl] benzoyl ⁇ amino) -3-isopropoxy-1H-pyrazole hydrochloride
- the compound obtained in Reference Example 7 and 4-fluoropiperidine hydrogen bromide The title compound was obtained by a method according to Example 63 using the acid salt as a starting material.
- Example 68 5-( ⁇ 3-[(4,4-Difluoropiperidin-1-yl) sulfonyl] benzoyl ⁇ amino) -3-isopropoxy-1H-pyrazole hydrochloride
- the compound obtained in Reference Example 7 and 4,4-difluoro The title compound was obtained by a method according to Example 63 using piperidine hydrobromide as a starting material.
- Example 69 3-Isopropoxy-5- ⁇ [3- (piperidin-1-ylsulfonyl) benzoyl] amino ⁇ -1H-pyrazole hydrochloride
- Example 63 using the compound obtained in Reference Example 7 and piperidine as raw materials.
- the title compound was obtained by the method.
- Example 70 N- (3-Isopropoxy-1H-pyrazol-5-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide hydrochloride According to Example 63, using the compound obtained in Reference Example 7 and pyrrolidine as raw materials The title compound was obtained by the method described above.
- Example 71 N- (4-Fluorophenyl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (Piperidin-1-ylsulfonyl) benzoic acid (100 mg) in DMF (2.0 mL) was added to 4-fluoro Aniline (41 mg), pyridine (0.060 mL) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (107 mg) were sequentially added and stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution, washed twice with 2M hydrochloric acid, and dried over sodium sulfate.
- Example 72 3- (Piperidin-1-ylsulfonyl) -N- [4- (trifluoromethyl) phenyl] benzamide 3- (Piperidin-1-ylsulfonyl) benzoic acid (100 mg) and 4-aminobenzotrifluoride (59 mg)
- the title compound was obtained by a method according to Example 71 using as a raw material.
- Example 74 2- ⁇ [3- (Piperidin-1-ylsulfonyl) benzoyl] amino ⁇ pyridine trifluoroacetate salt According to Example 73, using 3- (piperidin-1-ylsulfonyl) benzoic acid and 2-aminopyridine as raw materials The title compound was obtained by the method described above.
- Example 75 6- ⁇ [3- (Piperidin-1-ylsulfonyl) benzoyl] amino ⁇ quinoline trifluoroacetate According to Example 73, using 3- (piperidin-1-ylsulfonyl) benzoic acid and 7-aminoquinoline as raw materials The title compound was obtained by the method described above.
- Example 76 5- ⁇ [3- (piperidin-1-ylsulfonyl) benzoyl] amino ⁇ isoquinoline trifluoroacetate
- Example 73 using 3- (piperidin-1-ylsulfonyl) benzoic acid and 5-aminoisoquinoline hydrochloride as raw materials
- Example 77 N- (4-Isopropylphenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 4-isopropylaniline as raw materials, a method according to Example 73 The title compound was obtained.
- Example 78 N- (2-Phenylethyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 2-phenylethylamine as raw materials, a method according to Example 73 The title compound was obtained.
- Example 79 N- [4- (Methylthio) phenyl] -3- (piperidin-1-ylsulfonyl) benzamide According to Example 73, using 3- (piperidin-1-ylsulfonyl) benzoic acid and 4-methylthioaniline as raw materials The title compound was obtained by the method.
- Example 80 N- (2-methoxyphenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 2-methoxyaniline as raw materials, a method according to Example 73 The title compound was obtained.
- Example 81 N- (3-methoxyphenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-methoxyaniline as raw materials, a method according to Example 73 The title compound was obtained.
- Example 82 N-isoxazol-3-yl-3- (piperidin-1-ylsulfonyl) benzamide Method according to Example 73 using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-aminoisoxazole as raw materials Gave the title compound.
- Example 83 3- (Piperidin-1-ylsulfonyl) -N-[(1S) -1,2,3,4-tetrahydronaphthalen-1-yl] benzamide 3- (Piperidin-1-ylsulfonyl) benzoic acid and (S)
- the title compound was obtained by a method according to Example 73 using-(+)-1,2,3,4-tetrahydro-1-naphthylamine as a starting material.
- Example 84 N- (4-Methylphenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 4-methylaniline as raw materials, a method according to Example 73 The title compound was obtained.
- Example 85 N- (2,3-dihydro-1H-inden-1-yl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 1-aminoindan as raw materials The title compound was obtained by a method according to Example 73.
- Example 86 N- (3-Phenylpropyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-phenylpropylamine as raw materials, a method according to Example 73 The title compound was obtained.
- Example 87 N- (4-Phenoxyphenyl) -3- (piperidin-1-ylsulfonyl) benzamide Method according to Example 73 using 3- (piperidin-1-ylsulfonyl) benzoic acid and 4-phenyloxyaniline as raw materials Gave the title compound.
- Example 88 N-phenyl-3- (piperidin-1-ylsulfonyl) benzamide The title compound was obtained by a method according to Example 73 using 3- (piperidin-1-ylsulfonyl) benzoic acid and aniline as raw materials.
- Example 89 N- (2-Chlorophenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 2-chloroaniline as raw materials, the title was prepared by a method according to Example 73. A compound was obtained.
- Example 90 N- (3-Chlorophenyl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-chloroaniline as raw materials, the title was prepared by a method according to Example 73. A compound was obtained.
- Example 91 N- (4-Isopropoxyphenyl) -3- (piperidin-1-ylsulfonyl) benzamide According to Example 73, using 3- (piperidin-1-ylsulfonyl) benzoic acid and 4-isopropoxyaniline as raw materials The title compound was obtained by the method.
- Example 92 N- (4-acetylphenyl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid (200 mg) in DMF (4.0 mL) was added to 1- ( 4-aminophenyl) ethanone (151 mg), O-(-7-azabenzotriazol-1-yl) -1,1,3,3-tetra-methyluronium hexafluorophosphate (565 mg) and N, N -Diisopropylethylamine (0.39 mL) was sequentially added, and the mixture was stirred at room temperature for 2 hours.
- Example 93 N- [4- (1-hydroxyethyl) phenyl] -3- (piperidin-1-ylsulfonyl) benzamide Hydrogenated into a solution of the compound obtained in Example 92 (30.0 mg) in ethanol (2.0 mL) Sodium boron (8.8 mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- Example 94 N- [4- (1-hydroxy-1-methylethyl) phenyl] -3- (piperidin-1-ylsulfonyl) benzamide Diethyl ether (1.0 mL) of the compound (50.0 mg) obtained in Example 92 Methyl lithium (0.66 mL, 0.98 M diethyl ether solution) was added dropwise to the solution under ice cooling, and the mixture was stirred for 1 hour under ice cooling. After raising the temperature to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate three times. After drying with sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
- Example 95 N- [5- (Difluoromethoxy) pyridin-2-yl] -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 5- (difluoromethoxy) pyridine-
- the title compound was obtained by a method according to Example 92 using 2-amine as a starting material.
- Example 96 N- (2,6-dimethoxypyridin-3-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 2,6-dimethoxypyridine-3-
- the title compound was obtained by a method according to Example 92 using amine as a starting material.
- Example 98 N- (3-hydroxypyridin-2-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 2-aminopyridin-3-ol as raw materials And the title compound was obtained by a method analogous to Example 92.
- Example 99 N- (3-methoxypyridin-2-yl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-methoxypyridin-2-amine as raw materials And the title compound was obtained by a method analogous to Example 92.
- Example 100 N- (6-Isopropoxypyridin-3-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 6-isopropoxypyridin-3-amine
- the title compound was obtained by a method according to Example 92, using as a raw material.
- Example 101 N- (6-phenoxypyridin-3-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 6-phenoxypyridin-3-amine as raw materials And the title compound was obtained by a method analogous to Example 92.
- Example 102 N- (6-methoxypyridin-3-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 6-methoxypyridin-3-amine as raw materials And the title compound was obtained by a method analogous to Example 92.
- Example 103 N- (3-Methylpyridin-2-yl) -3- (piperidin-1-ylsulfonyl) benzamide Using 3- (piperidin-1-ylsulfonyl) benzoic acid and 3-methylpyridin-2-amine as raw materials And the title compound was obtained by the method according to Example 92.
- Example 104 N- (3-methoxypyridin-2-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide Using 3- (pyrrolidin-1-ylsulfonyl) benzoic acid and 3-methylpyridin-2-amine as raw materials, The title compound was obtained by a method according to Example 92.
- Example 105 N- (3-cyclopropyl-1H-pyrazol-5-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 5-cyclopropyl-1H-
- the title compound was obtained by a method according to Example 92 using pyrazol-3-amine as a starting material.
- Example 106 N- (5-Bromo-3-methoxypyridin-2-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (piperidin-1-ylsulfonyl) benzoic acid and 5-bromo-3-methoxy
- the title compound was obtained by a method according to Example 92 using pyridine-2-amine as a starting material.
- Example 107 N- (3-methoxy-5-vinylpyridin-2-yl) -3- (piperidin-1-ylsulfonyl) benzamide n-propanol (1.0 mL) of the compound obtained in Example 106 (30.0 mg) To the solution, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (9.7 mg), potassium vinyl trifluoroborate (10.6 mg), and triethylamine (0.010 mL) were sequentially added at room temperature. In addition, the mixture was stirred at 80 ° C. for 10 hours.
- Example 109 N- (3-methoxy-5-phenylpyridin-2-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide (step 1) N- (5-bromo-3-methoxypyridin-2-yl) -3 Synthesis of-(pyrrolidin-1-ylsulfonyl) benzamide According to a method according to Example 92, using 3- (pyrrolidin-1-ylsulfonyl) benzoic acid and 5-bromo-3-methoxypyridin-2-amine as raw materials The desired product was obtained.
- Step 2 Synthesis of N- (3-methoxy-5-phenylpyridin-2-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide
- Example 110 N- (3-methoxy-5-phenoxypyridin-2-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide N-methylpyrrolidinone of the compound (50.0 mg) obtained in Example 109 (Step 1) (1.0 mL) solution was added phenol (21.4 mg), cesium carbonate (74.0 mg), copper (I) chloride (11.2 mg) and 2,2,6,6-tetramethylheptane-3,5- Dione (2.1 mg) was added, and the mixture was stirred at 180 ° C. for 20 minutes under microwave irradiation. The reaction solution was diluted with ethyl acetate and washed with water.
- Example 111 N- [3-methoxy-5- (phenylthio) pyridin-2-yl] -3- (pyrrolidin-1-ylsulfonyl) benzamide Using the compound obtained in Example 109 (Step 1) and benzenethiol as raw materials, The title compound was obtained by a method according to Reference Example 8 (Step 1).
- Example 112 N- [3-Methoxy-5- (phenylsulfonyl) pyridin-2-yl] -3- (pyrrolidin-1-ylsulfonyl) benzamide chloroform (1.0 mL) of the compound (51.0 mg) obtained in Example 111 ) M-Chloroperbenzoic acid (28.0 mg) was added to the solution and stirred overnight at room temperature. After the reaction solvent was concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography (NH silica gel, ethyl acetate 100%) to obtain the title compound (14.0 mg, 28%) as a white solid.
- Example 113 N- (3-Ethoxypyridin-2-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide Using 3- (pyrrolidin-1-ylsulfonyl) benzoic acid and 3-ethoxypyridin-2-amine as raw materials, The title compound was obtained by a method according to Example 92.
- Example 114 N- (4-Cyano-1H-imidazol-5-yl) -3- (piperidin-1-ylsulfonyl) benzamide 3- (Piperidin-1-ylsulfonyl) benzoic acid and 5-amino-1H-imidazole-
- the title compound was obtained by a method according to Example 92 using 4-carbonitrile as a starting material.
- Example 115 N- (3-cyclopropyl-1H-pyrazol-5-yl) -3- (pyrrolidin-1-ylsulfonyl) benzamide 3- (pyrrolidin-1-ylsulfonyl) benzoic acid and 5-cyclopropyl-1H-pyrazole-
- the title compound was obtained by a method according to Example 92 using 3-amine as a starting material.
- Example 116 N- (3-Isopropoxy-1H-pyrazol-5-yl) -3- (pyridin-2-ylsulfonyl) benzamide (Step 1) N- (5-Isopropoxy-1- ⁇ [2- (trimethylsilyl) ethoxy Synthesis of methyl ⁇ -1H-pyrazol-3-yl) -3- (pyridin-2-ylsulfonyl) benzamide To a solution of the compound obtained in Reference Example 8 (2.43 g) in chloroform (50 mL) in oxalyl dichloride (50 mL) 0.88 mL) and DMF (0.20 mL) were sequentially added, and the mixture was stirred at room temperature for 2 hours.
- Step 2 Synthesis of N- (3-isopropoxy-1H-pyrazol-5-yl) -3- (pyridin-2-ylsulfonyl) benzamide
- the compound (3.38 g) obtained in Step 1 was converted into trifluoroacetic acid. It was dissolved in a mixed solvent of (27 mL) -distilled water (3.0 mL) and stirred at room temperature for 4 hours.
- Example 117 N- (3-Ethoxy-1H-pyrazol-5-yl) -3- (pyridin-2-ylsulfonyl) benzamide Reference Example 9 (Step 1) using ethanol and 3-amino-5-hydroxypyrazolamine as raw materials
- Example 116 Example 116 was prepared using 5-ethoxy-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-3-amine obtained by a similar method and the compound obtained in Reference Example 8 as raw materials. The title compound was obtained by the method according to step 1).
- Example 118 N- (3-propoxy-1H-pyrazol-5-yl) -3- (pyridin-2-ylsulfonyl) benzamide Reference Example 9 (step 1) using 1-propanol and 3-amino-5-hydroxypyrazolamine as raw materials
- Example 5 Using 5-propoxy-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-3-amine obtained by a method according to) and the compound obtained in Reference Example 8 as raw materials, The title compound was obtained by a method according to 116 (Step 1).
- Example 119 N- (3-butoxy-1H-pyrazol-5-yl) -3- (pyridin-2-ylsulfonyl) benzamide Reference Example 9 (step 1) using 1-butanol and 3-amino-5-hydroxypyrazolamine as raw materials
- Example 5 Using 5-butoxy-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-3-amine obtained by the method according to) and the compound obtained in Reference Example 8 as raw materials, The title compound was obtained by a method according to 116 (Step 1).
- Example 120 N- (3-methoxypyridin-2-yl) -3- (pyridin-2-ylsulfonyl) benzamide
- Example 92 was carried out using the compound obtained in Reference Example 8 and 3-methoxypyridin-2-amine as raw materials. The title compound was obtained by a similar method.
- Example 121 N- (4-Isopropylphenyl) -3- (pyridin-2-ylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 92 using the compound obtained in Reference Example 8 and 4-isopropylaniline as raw materials. It was.
- Example 122 N- (5-Isopropoxypyridin-2-yl) -3- (pyridin-2-ylsulfonyl) benzamide
- the title compound was obtained by a method according to 92.
- Example 123 N- [2-fluoro-4- (2-methoxy-1-methylethoxy) phenyl] -3- (pyridin-2-ylsulfonyl) benzamido 1-methoxypropan-2-ol (29.0 mg) in ethyl acetate ( 1 mL) solution, triethylamine (0.045 mL) and methanesulfonyl chloride (0.025 mL) were sequentially added at room temperature. After stirring at room temperature for 15 minutes, the precipitated solid was collected by filtration.
- Example 124 N- ⁇ 2-Fluoro-4- [2-fluoro-1- (fluoromethyl) ethoxy] phenyl ⁇ -3- (pyridin-2-ylsulfonyl) benzamide
- the compound obtained in Reference Example 11 and 1,3-difluoro The title compound was obtained by a method according to Example 123 using propan-2-ol as a starting material.
- Example 125 N- [4- (cyclopentyloxy) -2-fluorophenyl] -3- (pyridin-2-ylsulfonyl) benzamide
- DMF 1.0 mL
- Cyclopentane bromide 40.0 mg
- potassium carbonate 55.7 mg
- the reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate.
- Example 126 N- (2-Fluoro-4-isopropoxyphenyl) -3- (pyridin-2-ylsulfonyl) benzamide A method according to Example 125 using the compound obtained in Reference Example 11 and 2-bromopropane as raw materials. Gave the title compound.
- Example 127 N- (2-Fluoro-4-isobutoxyphenyl) -3- (pyridin-2-ylsulfonyl) benzamide
- Example 128 N- (4-sec-butoxy-2-fluorophenyl) -3- (pyridin-2-ylsulfonyl) benzamide According to Example 125, using the compound obtained in Reference Example 11 and 2-butane chloride as raw materials The title compound was obtained by the method.
- Example 129 N- (6-Bromo-5-isopropoxypyridin-2-yl) -3- (pyridin-2-ylsulfonyl) benzamide
- Example 131 N- (4-Isopropoxyphenyl) -3-[(4-methylpyridin-2-yl) sulfonyl] benzamide Reference example using the compound obtained in Reference Example 14 and 2-bromo-4-methylpyridine as raw materials The title compound was obtained by a method according to 8 (Step 1) and Example 112.
- Example 132 N- (4-Isopropoxyphenyl) -3-[(6-methylpyridin-2-yl) sulfonyl] benzamide Reference Example Using the compound obtained in Reference Example 14 and 2-bromo-6-methylpyridine as raw materials The title compound was obtained by a method according to 8 (Step 1) and Example 112.
- Example 133 N- (4-methoxyphenyl) -3- (phenylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 92 using 3- (phenylsulfonyl) benzoic acid and 4-methoxyaniline as raw materials.
- 1 H-NMR (CDCl 3 ) ⁇ : 3.83 (3H, s), 6.93 (2H, d, J 8.8 Hz), 7.50-7.68 (6H, m), 7.78 (1H, s), 7.94-8.01 (2H, m), 8.07-8.14 (2H, m), 8.38 (1H, s)
- Example 134 N- (2-methoxyphenyl) -3- (phenylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 92 using 3- (phenylsulfonyl) benzoic acid and 2-methoxyaniline as raw materials.
- Example 135 N- (3-methoxypyridin-2-yl) -3- (phenylsulfonyl) benzamide Using 3- (phenylsulfonyl) benzoic acid and 3-methoxypyridin-2-amine as raw materials, a method according to Example 92 The title compound was obtained.
- Example 136 N- (4-Isopropylphenyl) -3- (phenylsulfonyl) benzamide
- the title compound was obtained by a method according to Example 92 using 3- (phenylsulfonyl) benzoic acid and 4-isopropylaniline as raw materials.
- Example 137 3-[(4-Fluorophenyl) sulfonyl] -N- (4-isopropylphenyl) benzamide
- the title compound was obtained by a method according to Example 92 using the compound obtained in Reference Example 15 and 4-isopropylaniline as raw materials. Obtained.
- Example 138 N- (5-isopropoxypyridin-2-yl) -3- (pyrimidin-2-ylsulfonyl) benzamide
- the title compound was obtained by a method according to 116 (Step 1).
- Example 139 N- (4-Isopropoxyphenyl) -3- (pyrimidin-2-ylsulfonyl) benzamide According to Example 116 (Step 1) using the compound obtained in Reference Example 16 and 4-isopropoxyaniline as raw materials The title compound was obtained by the method.
- Example 140 N- (3-Cyclopropyl-1H-pyrazol-5-yl) -3- (pyrimidin-2-ylsulfonyl) benzamide
- the compound obtained in Reference Example 16 and 5-cyclopropyl-1H-pyrazol-3-amine The title compound was obtained by a method according to Example 116 (Step 1) using as a raw material.
- Example 141 N- (4-Isopropoxyphenyl) -3- (pyrazin-2-ylsulfonyl) benzamide
- Step 1 using the compound obtained in Reference Example 17 and 4-isopropoxyaniline as raw materials
- the title compound was obtained by the method.
- Example 142 N- (4-Isopropoxyphenyl) -3- (1H-1,2,4-triazol-3-ylsulfonyl) benzamide
- the compound obtained in Reference Example 18 and 1H-1,2,4-triazole-3- The title compound was obtained by a method according to Reference Example 8 (Step 1) and Example 112 using thiol as a starting material.
- Example 143 N- (4-Isopropoxyphenyl) -3- (1H-pyrazol-4-ylsulfonyl) benzamide Reference Example 8 (Step 1) using the compound obtained in Reference Example 14 and 4-iodo-1H-pyrazole as raw materials ) And the method according to Example 112 to give the title compound.
- Example 144 3- (Cyclohexylsulfonyl) -N- (4-isopropoxyphenyl) benzamide
- the title compound was obtained by a method according to Example 73 using the compound obtained in Reference Example 19 and 4-isopropoxyaniline as raw materials.
- the title compound was obtained by a method according to Example 73 using the compound obtained in Reference Example 19 and 2-methoxyaniline as raw materials.
- Example 146 3- (Cyclohexylsulfonyl) -N- (4-methoxyphenyl) benzamide Using 3-iodo-N- (4-methoxyphenyl) benzamide and cyclohexanethiol as raw materials, according to Reference Example 8 (Step 1) and Example 112 The title compound was obtained by the method described above.
- Example 147 3- (Cyclohexylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide (Step 1) 3- (Cyclohexylsulfonyl) -N- [3- (cyclohexylsulfonyl) benzoyl] -N- (3-methoxypyridine Synthesis of -2-yl) benzamide
- the compound (100 mg) obtained in Reference Example 19 was dissolved in chloroform (2.0 mL), and 2-amino-3-methoxypyridine (46 mg), triethylamine (0.156 mL), 25 % 2-chloro-1,3-dimethylimidazolinium chloride dichloromethane solution (0.200 mL) was sequentially added, and the mixture was stirred at room temperature for 30 minutes.
- Step 2 3- (Cyclohexylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide
- the compound (25 mg) obtained in Step 1 was dissolved in methanol (2.0 mL), and 2M aqueous sodium hydroxide solution was dissolved. (0.20 mL) was added, followed by stirring at room temperature for 4 hours. Ethyl acetate was added, washed successively with water and saturated brine, and dried over sodium sulfate.
- Example 148 3- (butylsulfonyl) -N- (3-methoxypyridin-2-yl) benzamide Reference Example 8 (Step 1) and Example 112 using the compound obtained in Reference Example 20 and butane-1-thiol as raw materials
- the title compound was obtained by a method according to.
- Example 149 2-methoxy-N- (4-methoxyphenyl) -5- (piperidin-1-ylsulfonyl) benzamide Using 2-methoxy-5- (piperidin-1-ylsulfonyl) benzoic acid and 4-methoxyaniline as raw materials, The title compound was obtained by a method according to Example 92.
- Example 150 N- (4-Isopropylphenyl) -2-methoxy-5- (piperidin-1-ylsulfonyl) benzamide Using 2-methoxy-5- (piperidin-1-ylsulfonyl) benzoic acid and 4-isopropylaniline as raw materials, The title compound was obtained by a method according to Example 92.
- Example 151 2-hydroxy-N- (4-isopropoxyphenyl) -5- (piperidin-1-ylsulfonyl) benzamide 2-hydroxy-5- (piperidin-1-ylsulfonyl) benzoic acid (470 mg) and chlorobenzene (2.0 mL) ) And phosphorus trichloride (0.072 mL) was added, and the mixture was stirred at 130 ° C. for 1 hour. 4-Isopropylaniline (249 mg) was added, and the mixture was stirred at 130 ° C. for 16 hr.
- Example 152 2-Ethoxy-N- (4-isopropoxyphenyl) -5- (piperidin-1-ylsulfonyl) benzamide
- DMF dimethyl methoxymethyl
- potassium carbonate 30 mg
- iodoethane 0.030 mL
- Example 153 2- (Cyanomethoxy) -N- (4-isopropoxyphenyl) -5- (piperidin-1-ylsulfonyl) benzamide According to Example 152, using the compound obtained in Example 151 and bromoacetonitrile as raw materials The title compound was obtained by the method.
- Example 154 [2- ⁇ [(4-Isopropoxyphenyl) amino] carbonyl ⁇ -4- (piperidin-1-ylsulfonyl) phenoxy] acetic acid
- the compound (100 mg) obtained in Example 151 was dissolved in DMF (2.0 mL).
- Potassium carbonate (50 mg) and tert-butyl bromoacetate (0.047 mL) were sequentially added, and the mixture was stirred at room temperature for 21 hours.
- Ethyl acetate was added to the reaction solution, washed successively with water and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- Example 155 N- (4-Isopropylphenyl) -4-methoxy-3- (piperidin-1-ylsulfonyl) benzamide Using 4-methoxy-3- (piperidin-1-ylsulfonyl) benzoic acid and 4-isopropylaniline as raw materials, The title compound was obtained by a method according to Example 92.
- Example 156 2-methoxy-N- (3-methoxypyridin-2-yl) -5- (piperidin-1-ylsulfonyl) benzamide 2-methoxy-5- (piperidin-1-ylsulfonyl) benzoic acid and 3-methoxypyridine-
- the title compound was obtained by a method according to Example 92 using 2-amine as a starting material.
- Example 157 N- (4-Isopropylphenyl) -6- (phenylsulfonyl) pyridine-2-carboxamide (Step 1) Synthesis of 6-chloro-N- (4-isopropylphenyl) pyridine-2-carboxamide 6-Chloropyridine-2- The target compound was obtained by the method according to Example 92 using carboxylic acid and 4-isopropylaniline as raw materials.
- Step 2 Synthesis of N- (4-isopropylphenyl) -6- (phenylthio) pyridine-2-carboxamide
- NMP 4.0 mL
- cesium carbonate 889 mg
- ethyl acetate was added to the reaction solution, washed three times with a saturated aqueous sodium hydrogen carbonate solution, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- Step 3 Synthesis of N- (4-isopropylphenyl) -6- (phenylsulfonyl) pyridine-2-carboxamide To a solution of the compound obtained in Step 2 (100 mg) in chloroform (3.0 mL) was added m-chloroperoxide. Benzoic acid (99.0 mg) was added, and the mixture was stirred at room temperature for 3 hr.
- Example 158 N- (4-Isopropylphenyl) -5- (phenylsulfonyl) nicotinamide
- Step 1 Synthesis of 5-bromo-N- (4-Iropropylphenyl) nicotinamide 5-bromonicotinic acid and 4-isopropylaniline as raw materials
- Step 2 Synthesis of N- (4-isopropylphenyl) -5- (phenylthio) nicotinamide Using the compound obtained in Step 1 and benzenethiol as raw materials, the target was prepared by a method according to Reference Example 8 (Step 1) A compound was obtained.
- Step 3 Synthesis of N- (4-isopropylphenyl) -5- (phenylsulfonyl) nicotinamide
- the title compound was obtained by the method according to Example 112 using the compound obtained in Step 2 as a starting material.
- Example 159 4-Isopropoxy-N- [3- (piperidin-1-ylsulfonyl) benzyl] benzamide
- the obtained colorless oily compound (200 mg) was dissolved in methanol (4.0 mL), 10% palladium carbon (60 mg) was added, and the mixture was stirred at room temperature for 23 hours under hydrogen atmosphere.
- the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a colorless oily compound (181 mg).
- the target compound 172 mg, 57%) was obtained as a colorless solid by the method according to Example 92.
- Example 161 4-Isopropoxy-N- ⁇ 2- [3- (piperidin-1-ylsulfonyl) phenyl] ethyl ⁇ benzamide
- the compound (100 mg) obtained in Reference Example 23 was dissolved in methanol (2.0 mL), and hydrochloric acid- After adding a methanol solution (0.50 mL) and 10% palladium carbon (50 mg), the mixture was stirred at room temperature for 22 hours in a hydrogen atmosphere.
- the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a yellow oily compound (120 mg).
- Example 162 N- (4-Isopropoxyphenyl) -3- [3- (piperidin-1-ylsulfonyl) phenyl] propanamide (Step 1) Synthesis of 3- (piperidin-1-ylsulfonyl) benzaldehyde Obtained in Reference Example 21 The compound (1.00 g) was dissolved in acetone (10 mL), manganese dioxide (500 mg) was added, and the mixture was stirred at 55 ° C. for 5 days. After allowing to cool, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure.
- Step 2 Synthesis of ethyl (2E) -3- [3- (piperidin-1-ylsulfonyl) phenyl] acrylate Triethylphosphonoacetate (398 mg) was dissolved in THF (3.0 mL) and hydrogenated at 0 ° C. Sodium chloride (62 mg) was added, and the mixture was stirred at 0 ° C. for 10 minutes.
- Step 3 Synthesis of (2E) -3- [3- (piperidin-1-ylsulfonyl) phenyl] acrylic acid
- the compound (380 mg) obtained in Step 2 was dissolved in methanol (6.0 mL), and 2M water An aqueous sodium oxide solution (1.10 mL) was added, and the mixture was stirred at room temperature for 1 day.
- the pH was adjusted to 3 using 2M hydrochloric acid at 0 ° C., water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
- Step 4 Synthesis of (2E) -N- (4-isopropoxyphenyl) -3- [3- (piperidin-1-ylsulfonyl) phenyl] acrylamide
- the compound obtained in Step 3 150 mg
- 4-iso A target compound (193 mg, 89%) of propoxyaniline (77 mg) was obtained as a colorless solid by the method according to Example 92.
- Step 5 Synthesis of N- (4-isopropoxyphenyl) -3- [3- (piperidin-1-ylsulfonyl) phenyl] propanamide
- Reference example 2 3- ⁇ [(4-Isopropylphenyl) amino] carbonyl ⁇ benzenesulfonyl chloride
- the title compound was obtained by a method according to Reference Example 1 using 4-isopropylaniline and 3- (chlorosulfonyl) benzoyl chloride as raw materials.
- Reference example 4 3- ⁇ [(4-Methoxyphenyl) amino] carbonyl ⁇ benzenesulfonyl chloride
- the title compound was obtained by a method according to Reference Example 1 using 4-methoxyaniline and 3- (chlorosulfonyl) benzoyl chloride as raw materials.
- Step 2 Synthesis of tert-butyl 5- ⁇ [3- (chlorosulfonyl) benzoyl] amino ⁇ -3-isopropoxy-1H-pyrazole-1-carboxylate Compound obtained in Step 1 and m-chlorosulfonylbenzoyl
- the title compound was obtained by the method according to Reference Example 1 using chloride.
- Step 1 Synthesis of 3- (pyridin-2-ylthio) benzoic acid 2-Iodopyridine (7.31 g), 3-mercaptobenzoic acid (5.0 g), Xantphos (3.75 g) and Pd 2 (dba) 3 (2.97 g) were sequentially added to a solution of N, N-diisopropylethylamine (11.30 mL) in dioxane (150 mL), and overnight at 100 ° C. under a nitrogen atmosphere. Stir.
- Step 2 Synthesis of 3- (pyridin-2-ylthio) benzoic acid methyl ester
- methanol 100 mL
- thionyl chloride 2.34 mL
- the reaction solution was evaporated under reduced pressure, and ethyl acetate was added to the residue.
- the extract was washed twice with water, then with saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- Step 3 Synthesis of 3- (pyridin-2-ylsulfonyl) benzoic acid methyl ester To a mixed solution of the compound obtained in Step 2 (3.64 g) in acetone (50 mL) -distilled water (50 mL), acetic acid ( 4.25 mL) and potassium permanganate (7.04 g) were added, and the mixture was stirred overnight at room temperature.
- Step 4 Synthesis of 3- (pyridin-2-ylsulfonyl) benzoic acid
- methanol 50 mL
- 5M aqueous sodium hydroxide solution 12.4 mL
- Methanol Methanol was added to the residue and stirred.
- the solid was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (2.83 g, 87%) as a white solid.
- Step 1 5-isopropoxy-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-3-amine
- Step 1 Synthesis of 5-isopropoxy-1H-pyrazol-3-amine 3-amino-5- Methanesulfonic acid (25 mL) was added to a solution of hydroxypyrazoleamine (25 g) in 2-propanol (250 mL), and the mixture was stirred at 120 ° C. for 2 days. After allowing the reaction solution to cool, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate and dried over sodium sulfate.
- Step 2 Synthesis of 5-isopropoxy-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-3-amine DMF (100 mL) solution of the compound (4.84 g) obtained in Step 1
- sodium hydride (1.44 g) was added under ice cooling, and the mixture was stirred for 2 hours under ice cooling.
- the reaction solution was cooled to ⁇ 18 ° C., and 2- (trimethylsilyl) ethoxymethyl chloride (6.38 mL) was added dropwise. After stirring at ⁇ 18 ° C.
- Step 2 Synthesis of N- (2-fluoro-4-hydroxyphenyl) -3- (pyridin-2-ylsulfonyl) benzamide
- a THF (40 mL) solution of the compound obtained in Step 1 (1.58 g)
- 5 M hydrochloric acid After adding 5 M hydrochloric acid, the mixture was stirred at 60 ° C. for 5 hours.
- saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- the organic layer was dried over sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
- Step 2 Synthesis of 6-bromo-5- (methoxymethoxy) pyridin-2-amine To a solution of the compound obtained in Step 1 (482 mg) in ethanol (20 mL), saturated aqueous ammonium chloride solution (2.0 mL) and iron Powder (4.0 g) was added, and the mixture was stirred with heating under reflux for 12 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- Step 2 Synthesis of 3-[(4-fluorophenyl) sulfonyl] benzoic acid
- acetonitrile 46 mL
- manganese sulfate pentahydrate 20.0 mg
- a mixed solution of 30% aqueous hydrogen peroxide 34 mL
- -0.2M aqueous sodium hydrogen carbonate solution was added dropwise, and the mixture was stirred overnight at room temperature.
- 0.1M hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure.
- the obtained residue was suspended in a mixed solvent of chloroform-hexane, and the solid was collected by filtration to give the title compound (921 mg, 82%) as a white solid.
- Step 1 Synthesis of 3- (cyclohexylthio) benzoic acid ethyl ester 3-Iodobenzoic acid ethyl ester (5.00 g) was dissolved in dioxane (100 mL) and cyclohexanethiol (2 .32 mL), N, N-diisopropylethylamine (6.29 mL), Xantphos (2.09 g) and Pd 2 (dba) 3 (1.66 g) were sequentially added, and the mixture was stirred at 100 ° C. for 7 hours under a nitrogen atmosphere. .
- Step 2 Synthesis of 3- (cyclohexylsulfonyl) benzoic acid ethyl ester
- the compound (5.11 g) obtained in Step 1 was dissolved in chloroform (100 mL), and m-chloroperbenzoic acid (15.
- Step 3 Synthesis of 3- (cyclohexylsulfonyl) benzoic acid
- Chloroform was added to the reaction solution, which was then washed with a saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. Ethyl acetate (about 50 mL) was added to the residue for suspension, and then the solid was collected by filtration to obtain a colorless solid (5.96 g). Methanol (50 mL) and 2M aqueous sodium hydrogen carbonate solution (3.42 mL) were added to the obtained solid (2.00 g), and the mixture was stirred at room temperature for 18 hours.
- Reference Example 23 [3- (Piperidin-1-ylsulfonyl) phenyl] acetonitrile
- Pharmacological test example 1 (LCE enzyme activity inhibition test) The test compound was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM and further diluted with DMSO to prepare a 1000-fold concentrated solution of the evaluation concentration.
- DMSO dimethyl sulfoxide
- the LCE enzyme activity inhibition test was performed by improving the method of Moon (J. Biol. Chem., 276, 45358-45366 (2001)).
- phosphate buffer solution 100 mM potassium phosphate buffer solution (pH 6.5)
- substrate solution 100 mM potassium phosphate buffer (pH 6.5)
- 4.0 ⁇ M rotenone 80 ⁇ M fatty acid-free bovine serum albumin, 160 ⁇ M palmitoyl CoA, 80 ⁇ M malonyl CoA, 3.5 ⁇ M [ 14 C] -malonyl CoA ( 1.92 GBq / mmol, manufactured by Amersham) was added to each well, and 25 ⁇ L of enzyme solution (100 mM potassium phosphate buffer (pH 6.5), 100 ⁇ g / mL human LCE) was added and the top of the plate was sealed with a seal And mild at 37 ° C for 90 minutes It was incubated with stirring crab shaking.
- the compound according to the present invention has an excellent LCE inhibitory action, and various diseases involving LCE such as cardiovascular disease, nervous system disease, metabolic disease, reproductive system disease, gastrointestinal disease, neoplasm, infection It is useful as a preventive or therapeutic agent for diseases, etc., or as a herbicide.
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Abstract
Description
J.Lipid Res.,43(6),911-920頁(2002年) Cell,126:691-699頁(2006年)
(1) 式(I)
Wは、C1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル又は-N(R1)(R2)を表し、
R1及びR2は、各々独立して、水素原子、C1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表すか、又はR1及びR2が一緒になって、それらが結合する窒素原子とともに含窒素複素環を形成し、
前記アルキル、シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル又は含窒素複素環は、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される置換基で置換されていてもよく、
Xは、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、該基は、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される置換基で置換されていてもよく、
Yは、式(II-1)、式(II-2)、式(II-3)又は式(II-4)を表し、
ここで、式(II-1)から式(II-4)における任意の水素原子は、C1-6アルキル、ハロC1-6アルキル又はC3-8シクロアルキルで置換されていてもよく、
Zは、水素原子、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される基を表し、
A1、A2、A3及びA4は、各々独立して、CH又はNを表し、但し、A1、A2、A3及びA4のうち少なくとも3つはCHである]で表される化合物又は薬学的に許容されるその塩を有効成分とする長鎖脂肪酸伸長酵素(LCE)阻害剤を提供する。
(2) 式(I)で表される阻害剤を含有する医薬組成物、
(3) 式(I)で表される阻害剤を有効成分とする、糖尿病、肥満症又は非アルコール性脂肪肝の予防剤又は治療剤、
(4) 長鎖脂肪酸伸長酵素に関連する疾患の治療のために治療活性物質として使用される、(1)に記載の阻害剤、
(5) 後述する式(I-1)で表される化合物、をも提供する。
R3aは、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、
R3bは、水素原子、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、但し、R3a-O-は、炭素原子上に結合しており、
R4は、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、C1-6アルコキシ、ハロC1-6アルコキシ、アリールオキシ又はヘテロアリールオキシを表し、
R5は、イソプロピル又はイソプロピルオキシを表し、
R6は、水素原子又はC1-6アルキルを表し、
R7は、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、C1-6アルコキシ、ハロC1-6アルコキシ、アリールオキシ、ヘテロアリールオキシ、ヘテロアラルキルオキシ、C1-6アルキルチオ、C1-6アルキルスルファニル、C1-6アルキルスルホニル、アリールチオ、アリールスルファニル又はアリールスルホニルを表し、
A1、A2及びA3及がCHであり、A4がN、
A1、A2及びA4及がCHであり、A3がN、
A1、A3及びA4及がCHであり、A2がN、
A2、A3及びA4及がCHであり、A1がN、
A1、A2、A3及びA4のいずれもCH、
が例示され、好ましくは、
A1、A2、A3及びA4のいずれもCHが推奨される。
Y1は、式(II-2)又は式(II-3)を表し、
X1は、式(X-1)、式(X-2)又は式(X-3)を表し、
W、Z、A1、A2、A3及びA4は、前記に同じである]で表される化合物が挙げられる。
3-(2-アザビシクロ[2.2.1]ヘプト-2-イルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド、
3-{[3-(1H-ベンズイミダゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロポキシフェニル)ベンズアミド、
3-{[3-(1,3-ベンズオキサゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロポキシフェニル)ベンズアミド、
1-[(3-{[(4-イソプロピルフェニル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド、
3-{[3-(ヒドロキシメチル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド、
3-(2-アザビシクロ[2.2.1]ヘプト-2-イルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド、
3-{[3-(1H-ベンズイミダゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(3-メトキシピリジン-2-イル)ベンズアミド、
N-ベンジル-1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド、
3-イソプロポキシ-5-{[3-(モルホリン-4-イルスルホニル)ベンゾイル]アミノ}-1H-ピラゾール 塩酸塩、
3-イソプロポキシ-5-({3-[(2-メチルピロリジン-1-イル)スルホニル]ベンゾイル}アミノ)-1H-ピラゾール 塩酸塩、
5-[(3-{[3-(ヒドロキシメチル)ピペリジン-1-イル]スルホニル}ベンゾイル)アミノ]-3-イソプロポキシ-1H-ピラゾール 塩酸塩、
5-({3-[(3-ヒドロキシピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩、
5-({3-[(4-フルオロピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩、
5-({3-[(4,4-ジフルオロピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩、
3-イソプロポキシ-5-{[3-(ピペリジン-1-イルスルホニル)ベンゾイル]アミノ}-1H-ピラゾール 塩酸塩、
N-(3-イソプロポキシ-1H-ピラゾール-5-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド、
N-(4-イソプロピルフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(2-メトキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(4-イソプロポキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(3-メトキシピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(6-イソプロポキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド、
N-(3-イソプロポキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド、
N-(3-エトキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド、
N-(3-プロポキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド、
N-(3-ブトキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド、
3-(シクロヘキシルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド、
N-(4-イソプロピルフェニル)-2-メトキシ-5-(ピペリジン-1-イルスルホニル)ベンズアミド、
4-イソプロポキシ-N-[3-(ピペリジン-1-イルスルホニル)ベンジル]ベンズアミド、及び
N-(4-イソプロポキシフェニル)-2-[3-(ピペリジン-1-イルスルホニル)フェニル]アセトアミド等が例示される。
本発明に係る化合物は、例えば下記の製造方法又は実施例に示す方法により製造することができる。ただし、本発明に係る化合物の製造方法はこれらの例に限定されるものではない。
式(I)で表される化合物は、以下の方法で調製可能である。
化合物1と化合物2とを有機溶媒中、塩基、トリス(ジベンジリデンアセトン)ジパラジウム(0)(以下、「Pd2(dba)3」という)及び(9,9-ジメチル-9H-キサンテン-4,5-ジイル)ビス(ジフェニルホスフィン)(以下、「Xantphos」という)の存在下で反応を行うことにより、化合物3を得る。
化合物3をメタノール中で塩化チオニルと反応を行い、化合物4を得る。
化合物4を、酸化することにより化合物5を得る。
2~10モルが例示され、通常、室温で1~24時間反応を行えばよい。
2~6モルが例示され、通常、室温で1~24時間反応を行えばよい。
化合物5のエステルを加水分解して化合物6とする。加水分解の方法は、特に限定されないが、水酸化ナトリウム、水酸化カリウム等のアルカリを、等モルから過剰モル用い、メタノール、エタノール等の低級アルコール中で行えばよい。
化合物6と化合物7とを、塩基の存在下、アミド化することにより、式(I-a)で表される化合物を得る。
製造方法2は、式(I-b)で表される化合物の製造方法である。
化合物8を有機溶媒中、塩基存在下で化合物7とアミド化反応を行い、化合物9を得る。
化合物9と化合物10とを工程5に準じて有機溶媒中で縮合を行い、式(I-b)で表される化合物を得る。
化合物5を還元剤を用いて還元を行い、化合物11を得る。還元の方法は、水素化リチウムアルミニウム等の還元剤を用いて従来公知の方法によりエステル部分の還元を行えばよい。
化合物11とフタルイミドとを、光延反応により縮合し化合物12を得る。
化合物12を反応溶媒中、ヒドラジン処理を行い化合物13とする。
化合物13と化合物14とを工程5に準じて反応を行い、式(I-c)で表される化合物を得る。
化合物13と化合物15とを工程6に準じて反応を行い、式(I-d)で表される化合物を得る。
化合物13と化合物16とを工程6に準じて反応を行い、式(I-e)で表される化合物を得る。
また本発明は本発明に係る化合物(I)又はそれらの薬学的に許容されうる塩を、その状態の治療又は予防に有用であるとして知られた他の薬剤の治療的又は予防的に有効な量と組み合わせて投与することからなる高脂血症又は異常脂質血症の治療法又は予防法に関する。
通常の内科医、獣医又は臨床医は病状進行を治療し、予防し、阻止し、抑制し又は停止させるに必要な効果的薬物量を容易に決定し処理することができる。
NMR測定における略号の意味を以下に示す。
s:シングレット
d:ダブレット
dd:ダブル ダブレット
t:トリプレット
dt:ダブル トリプレット
q:クァルテット
m:マルチプレット
br:ブロード
J:カップリング定数
Hz:ヘルツ
DMSO-d6:重ジメチルスルホキシド
N-(4-イソプロポキシフェニル)-3-[(1R,4R)-2-オキサ-5-アザビシクロ[2.2.1]ヘプト-5-イルスルホニル]ベンズアミド
参考例1で得られた化合物(80.0mg)のTHF(3.0mL)溶液に、(1R,4R)-2-オキサ-5-アザビシクロ[2.2.1]ヘプタン・1塩酸塩(76.6mg)およびトリエチルアミン(0.16mL)を順次加え、室温にて一終夜攪拌した。反応液に酢酸エチルを加えた後、水にて3回洗浄し、硫酸ナトリウムで乾燥した。硫酸ナトリウムをろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(NHバイオタージカラム、酢酸エチル/ヘキサン=0%-80%、グラジェント)にて精製し、表題化合物(80.0mg、85%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.23-1.39(7H,m),1.66-1.78(1H,m),3.19(1H,d,J=9.8Hz),3.38(1H,d,J=9.8Hz),3.65(1H,d,J=7.8Hz),3.82(1H,d,J=7.8Hz),4.41-4.59(3H,m),6.88(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.63(1H,t,J=7.8Hz),7.95(1H,d,J=7.8Hz),8.13(1H,d,J=7.8Hz),8.26(1H,s),8.29(1H,s)
3-(2-アザビシクロ[2.2.1]ヘプト-2-イルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および2-アザビシクロ[2.2.1]ヘプタンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.95-1.04(1H,m),1.18-1.27(1H,m),1.34(6H,d,J=6.3Hz),1.53-1.66(3H,m),1.69-1.78(1H,m),2.49(1H,s),3.01-3.13(2H,m),4.22(1H,s),4.49-4.57(1H,m),6.90(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.64(1H,t,J=7.8Hz),7.97(1H,d,J=7.8Hz),8.03(1H,s),8.14(1H,d,J=7.8Hz),8.26(1H,s)
N-(4-イソプロポキシフェニル)-3-(1,4,6,7-テトラヒドロ-5H-ピラゾロ[4,3-c]ピリジン-5-イルスルホニル)ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および4,5,6,7-テトラヒドロ-1H-ピラゾロ[4,3-c]ピリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.35(6H,d,J=5.9Hz),2.80-2.87(2H,m),3.50-3.56(2H,m),4.31(2H,s),4.50-4.58(1H,m),6.92(2H,d,J=8.8Hz),7.35(1H,s),7.53(2H,d,J=8.8Hz),7.63-7.69(1H,m),7.76-7.80(1H,m),7.96-8.01(1H,m),8.08-8.12(1H,m),8.22-8.25(1H,m)
3-(4-アザトリシクロ[4.3.1.13,8]ウンデク-4-イルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および4-アザトリシクロ[4.3.1.13,8]ウンデカンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.39-1.63(7H,m),1.76-1.96(6H,m),2.21-2.29(1H,m),3.41-3.47(2H,m),4.40-4.46(1H,m),4.49-4.58(1H,m),6.91(2H,d,J=8.8Hz),7.55(2H,d,J=8.8Hz),7.64(1H,t,J=7.8Hz),7.92-8.00(2H,m),8.11(1H,d,J=7.8Hz),8.26(1H,s)
3-{[3-(1H-ベンズイミダゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および2-ピペリジン-3-イル-1H-ベンズイミダゾールを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.28(6H,d,J=5.9Hz),1.36-1.50(1H,m),1.60-1.78(2H,m),2.00-2.10(1H,m),2.27-2.39(1H,m),2.83-2.94(1H,m),3.34-3.48(2H,m),3.89-3.98(1H,m),4.40-4.48(1H,m),6.76(2H,d,J=8.8Hz),7.31-7.37(2H,m),7.41(1H,t,J=8.0Hz),7.50(2H,d,J=8.8Hz),7.53-7.58(2H,m),7.61(1H,d,J=8.0Hz),7.99(1H,d,J=8.0Hz),8.09(1H,s)
3-{[(ジシクロプロピルメチル)アミノ]スルホニル}-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および1,1-ジシクロプロピルメタンアミンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.06-0.16(2H,m),0.21-0.33(4H,m),0.41-0.50(2H,m),0.75-0.86(2H,m),1.34(6H,d,J=5.9Hz),4.49-4.56(1H,m),4.99(1H,d,J=7.0Hz),6.89(2H,d,J=9.0Hz),7.54(2H,d,J=9.0Hz),7.60(1H,t,J=7.8Hz),8.00-8.05(2H,m),8.10(1H,d,J=7.8Hz),8.37-8.39(1H,m)
3-{[3-(1,3-ベンズオキサゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および2-ピペリジン-3-イル-1,3-ベンズオキサゾールを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.63-1.76(1H,m),1.76-1.90(1H,m),1.91-2.00(1H,m),2.25-2.33(1H,m),2.46-2.57(1H,m),2.75-2.84(1H,m),3.24-3.35(1H,m),3.78-3.88(1H,m),4.16-4.24(1H,m),4.49-4.58(1H,m),6.91(2H,d,J=7.8Hz),7.29-7.35(2H,m),7.47-7.57(3H,m),7.62-7.71(2H,m),7.79-7.85(1H,m),7.93-7.98(1H,m),8.11-8.17(1H,m),8.22(1H,s)
N-(4-イソプロポキシフェニル)-3-{[(1S,4S)-5-メチル-2,5-ジアザビシクロ[2.2.1]ヘプト-2-イル]スルホニル}ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および(1S,4S)-2-メチル-2,5-ジアザビシクロ[2.2.1]ヘプタンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.17-4.32(8H,m),1.33(6H,d,J=6.3Hz),2.83(3H,s),4.46-4.56(1H,m),6.82-6.91(2H,m),7.48-7.69(3H,m),7.92-8.00(1H,m),8.12-8.19(1H,m),8.31(1H,s)
N-(4-イソプロポキシフェニル)-3-{[2-(フェノキシメチル)モルホリン-4-イル]スルホニル}ベンズアミド
参考例1で得られた化合物および2-(フェノキシメチル)モルホリンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),2.33-2.41(1H,m),2.48-2.58(1H,m),3.57-3.64(1H,m),3.70-3.84(2H,m),3.87-4.03(4H,m),4.49-4.57(1H,m),6.84-6.92(4H,m),6.93-6.98(1H,m),7.24-7.30(2H,m),7.53(2H,d,J=8.6Hz),7.69(1H,t,J=7.8Hz),7.87-7.94(2H,m),8.16(1H,d,J=7.8Hz),8.20(1H,s)
N-(4-イソプロポキシフェニル)-3-[(1S,4S)-2-オキサ-5-アザビシクロ[2.2.1]ヘプト-5-イルスルホニル]ベンズアミド
参考例1で得られた化合物および(1S,4S)-2-オキサ-5-アザビシクロ[2.2.1]ヘプタンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.62-1.69(1H,m),1.71-1.77(1H,m),3.19-3.25(1H,m),3.41(1H,d,J=9.8Hz),3.68(1H,dd,J=7.8,1.6Hz),3.85(1H,d,J=7.8Hz),4.47-4.57(3H,m),6.90(2H,d,J=9.0Hz),7.54(2H,d,J=9.0Hz),7.66(1H,t,J=7.8Hz),7.98(1H,d,J=7.8Hz),8.01(1H,s),8.14(1H,d,J=7.8Hz),8.29(1H,s)
N-(4-イソプロポキシフェニル)-3-{[3-(4-メチル-4H-1,2,4-トリアゾール-3-イル)ピペリジン-1-イル]スルホニル}ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および3-(4-メチル-4H-1,2,4-トリアゾール-3-イル)ピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(6H,d,J=6.3Hz),1.52-1.65(1H,m),1.68-1.82(1H,m),1.83-1.92(1H,m),1.95-2.04(1H,m),2.33-2.42(1H,m),2.73(1H,t,J=11.3Hz),2.98-3.09(1H,m),3.70(3H,s),3.81-3.89(1H,m),3.92-4.00(1H,m),4.47-4.55(1H,m),6.86(2H,d,J=8.8Hz),7.53(2H,d,J=8.8Hz),7.61(1H,t,J=7.8Hz),7.84(1H,d,J=7.8Hz),8.12(1H,d,J=7.8Hz),8.16-8.21(2H,m),8.73(1H,s)
3-(オクタヒドロピロロ[1,2-a]ピラジン-2(1H)-イルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物およびオクタヒドロピロロ[1,2-a]ピラジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(6H,d,J=6.3Hz),1.83-2.31(4H,m),2.51-4.24(9H,m),4.47-4.57(1H,m),6.88(2H,d,J=8.8Hz),7.58(2H,d,J=8.8Hz),7.65(1H,t,J=7.8Hz),7.89(1H,d,J=7.8Hz),8.02-8.13(2H,m),9.27(1H,s)
N-(4-イソプロポキシフェニル)-3-(オクタヒドロ-2H-ピリド[1,2-a]ピラジン-2-イルスルホニル)ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物およびオクタヒドロ-2H-ピリド[1,2-a]ピラジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(6H,d,J=5.9Hz),1.42-2.05(6H,m),2.62-2.73(1H,m),2.92-3.06(2H,m),3.13-3.27(2H,m),3.39-3.49(2H,m),3.76-3.86(2H,m),4.47-4.55(1H,m),6.87(2H,d,J=8.8Hz),7.58-7.65(3H,m),7.88(1H,d,J=7.8Hz),8.03-8.08(2H,m),9.35(1H,s)
N-(4-イソプロポキシフェニル)-3-{[3-(モルホリン-4-イルメチル)ピペリジン-1-イル]スルホニル}ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および4-(ピペリジン-3-イルメチル)モルホリンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.12-1.80(8H,m),1.33(6H,d,J=6.3Hz),2.17-2.30(1H,m),2.60-2.82(3H,m),3.06-3.14(1H,m),3.47-3.56(1H,m),3.66-3.76(1H,m),3.92-4.04(4H,m),4.47-4.56(1H,m),6.88(2H,d,J=9.0Hz),7.58-7.68(3H,m),7.87(1H,d,J=7.8Hz),8.25(1H,d,J=7.8Hz),8.37(1H,s),9.23(1H,s)
3-[(4-フルオロピペリジン-1-イル)スルホニル]-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および4-フルオロピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.81-2.03(4H,m),2.84-2.98(2H,m),3.34-3.44(2H,m),4.49-4.58(1H,m),4.66-4.85(1H,m),6.91(2H,d,J=9.0Hz),7.54(2H,d,J=9.0Hz),7.68(1H,t,J=7.8Hz),7.85-7.95(2H,m),8.13(1H,d,J=7.8Hz),8.20(1H,s)
3-(2-アザビシクロ[2.2.2]オクト-2-イルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および2-アザビシクロ[2.2.2]オクタンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.44-1.91(9H,m),3.32(2H,s),3.87(1H,s),4.49-4.58(1H,m),6.91(2H,d,J=9.0Hz),7.55(2H,d,J=9.0Hz),7.64(1H,t,J=7.8Hz),7.94-8.02(2H,m),8.12(1H,d,J=7.8Hz),8.27(1H,s)
3-[(4,4-ジフルオロピペリジン-1-イル)スルホニル]-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および4,4-ジフルオロピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),2.00-2.14(4H,m),3.17-3.28(4H,m),4.48-4.59(1H,m),6.91(2H,d,J=9.0Hz),7.53(2H,d,J=9.0Hz),7.68(1H,t,J=7.8Hz),7.85-7.96(2H,m),8.13(1H,d,J=7.8Hz),8.22(1H,s)
N-(4-イソプロポキシフェニル)-3-[(3-メトキシピペリジン-1-イル)スルホニル]ベンズアミド
参考例1で得られた化合物および3-メトキシピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22-1.38(1H,m),1.34(6H,d,J=5.9Hz),1.45-1.65(1H,m),1.74-1.92(2H,m),2.52-2.71(2H,m),3.28-3.41(2H,m),3.36(3H,s),3.51-3.61(1H,m),4.47-4.60(1H,m),6.91(2H,d,J=9.0Hz),7.54(2H,d,J=9.0Hz),7.66(1H,t,J=7.8Hz),7.88-7.99(2H,m),8.11-8.17(1H,m),8.21(1H,s)
3-[(3,3-ジフルオロピペリジン-1-イル)スルホニル]-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および3,3-ジフルオロピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.73-1.82(2H,m),1.83-1.97(2H,m),3.11-3.19(2H,m),3.31-3.41(2H,m),4.48-4.58(1H,m),6.90(2H,d,J=9.0Hz),7.53(2H,d,J=9.0Hz),7.67(1H,t,J=7.8Hz),7.90-7.98(2H,m),8.14(1H,d,J=7.8Hz),8.21(1H,s)
N-(4-イソプロポキシフェニル)-3-{[3-(ピリジン-3-イルメトキシ)ピペリジン-1-イル]スルホニル}ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および3-[(ピペリジン-3-イルオキシ)メチル]ピリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(6H,d,J=5.9Hz),1.46-1.64(2H,m),1.77-1.93(2H,m),2.86-3.00(2H,m),3.16-3.25(1H,m),3.35-3.43(1H,m),3.57-3.66(1H,m),4.47-4.57(1H,m),4.62(1H,d,J=12.9Hz),4.70(1H,d,J=12.9Hz),6.87(2H,d,J=8.6Hz),7.55(2H,d,J=8.6Hz),7.60-7.67(2H,m),7.84-7.91(1H,m),8.07-8.15(2H,m),8.24(1H,s),8.52(1H,s),8.57-8.62(1H,m),8.66(1H,s)
N-(4-イソプロポキシフェニル)-3-{[3-(ピリジン-2-イルメトキシ)ピペリジン-1-イル]スルホニル}ベンズアミド トリフルオロ酢酸塩
参考例1で得られた化合物および2-[(ピペリジン-3-イルオキシ)メチル]ピリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(6H,d,J=5.9Hz),1.49-1.63(2H,m),1.78-1.93(2H,m),2.88-3.01(2H,m),3.13-3.22(1H,m),3.33-3.41(1H,m),3.62-3.70(1H,m),4.47-4.56(1H,m),4.85(2H,s),6.88(2H,d,J=9.0Hz),7.49-7.66(4H,m),7.74-7.78(1H,m),7.86-7.91(1H,m),8.06-8.12(1H,m),8.12-8.18(1H,m),8.26(1H,s),8.57(1H,s),8.64-8.69(1H,m)
N-(4-イソプロポキシフェニル)-3-[(3-オキソ-2,3,6,7-テトラヒドロイソオキサゾロ[4,5-c]ピリジン-5(4H)-イル)スルホニル]ベンズアミド
参考例1で得られた化合物および4,5,6,7-テトラヒドロイソオキサゾロ[4,5-c]ピリジン-3(2H)-オンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.25(6H,d,J=6.3Hz),2.64-2.74(2H,m),3.42-3.50(2H,m),3.98(2H,s),4.52-4.62(1H,m),6.91(2H,d,J=8.8Hz),7.63(2H,d,J=8.8Hz),7.78(1H,t,J=7.8Hz),8.01(1H,d,J=7.8Hz),8.26(1H,d,J=7.8Hz),8.34(1H,s),10.38(1H,s),11.46(1H,s)
N-(4-イソプロポキシフェニル)-3-{[(2S)-2-メチルピロリジン-1-イル]スルホニル}ベンズアミド
参考例1で得られた化合物および(2S)-2-メチルピロリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.30(3H,d,J=6.3Hz),1.34(6H,d,J=6.3Hz),1.46-1.62(2H,m),1.65-1.77(1H,m),1.79-1.92(1H,m),3.10-3.21(1H,m),3.40-3.51(1H,m),3.69-3.81(1H,m),4.47-4.58(1H,m),6.90(2H,d,J=8.6Hz),7.55(2H,d,J=8.6Hz),7.64(1H,t,J=7.8Hz),7.94-8.04(2H,m),8.12(1H,d,J=7.8Hz),8.26(1H,s)
N-(4-イソプロポキシフェニル)-3-{[(2R)-2-メチルピロリジン-1-イル]スルホニル}ベンズアミド
参考例1で得られた化合物および(2R)-2-メチルピロリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.30(3H,d,J=6.3Hz),1.34(6H,d,J=6.3Hz),1.46-1.62(2H,m),1.65-1.77(1H,m),1.79-1.92(1H,m),3.10-3.21(1H,m),3.40-3.51(1H,m),3.69-3.81(1H,m),4.47-4.58(1H,m),6.90(2H,d,J=8.6Hz),7.55(2H,d,J=8.6Hz),7.64(1H,t,J=7.8Hz),7.94-8.04(2H,m),8.12(1H,d,J=7.8Hz),8.26(1H,s)
3-({[2-(1H-ベンズイミダゾール-2-イル)プロピル]アミノ}スルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド
参考例1で得られた化合物および2-(1H-ベンズイミダゾール-2-イル)プロパン-1-アミンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25-1.33(9H,m),3.16-3.37(3H,m),4.43-4.55(1H,m),6.23(1H,s),6.80-6.88(2H,m),7.10-7.21(2H,m),7.35-7.46(3H,m),7.52(2H,d,J=7.8Hz),7.75-7.85(1H,m),7.99(1H,d,J=7.8Hz),8.26(1H,s),8.64-8.84(1H,m)
3-{[(2R,5R)-2,5-ジメチルピロリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド
(2R,5R)-2,5-ジメチルピロリジン(50mg)のクロロホルム(1.0mL)溶液に、トリエチルアミン(0.050mL)、参考例2で得られた化合物(50mg)を順次加え、室温にて1時間攪拌した。反応液を濃縮後、逆相HPLC(0.1%TFAアセトニトリル:H2O)=10%-95%、グラジェント)で精製し、表題化合物(59mg、100%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.17(6H,d,J=6.3Hz),1.22(6H,d,J=7.0Hz),1.45-1.60(2H,m),2.02-2.16(2H,m),2.82-2.95(1H,m),3.98-4.09(2H,m),7.18-7.26(2H,m),7.54(2H,d,J=8.2Hz),7.55-7.65(1H,m),7.91(1H,s),7.94-8.01(1H,m),8.03(1H,d,J=7.4Hz),8.25(1H,s)
3-(アゼパン-1-イルスルホニル)-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物およびヘキサメチレンアミンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.26(6H,d,J=6.8Hz),1.54-1.78(8H,m),2.86-2.98(1H,m),3.30(4H,t,J=5.9Hz),7.25(2H,d,J=7.8Hz),7.57(2H,d,J=8.3Hz),7.64(1H,t,J=7.8Hz),7.92(1H,s),7.95(1H,d,J=7.8Hz),8.10(1H,d,J=7.3Hz),8.22(1H,s)
N-(4-イソプロピルフェニル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
参考例2で得られた化合物およびピロリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=7.0Hz),1.74(4H,t,J=6.6Hz),2.82-2.96(1H,m),3.22(4H,t,J=6.6Hz),7.21(2H,d,J=8.6Hz),7.55(2H,d,J=8.6Hz),7.63(1H,t,J=7.8Hz),7.94(1H,d,J=7.8Hz),8.07(1H,s),8.11(1H,d,J=7.8Hz),8.23(1H,s)
N-(4-イソプロピルフェニル)-3-(モルホリン-4-イルスルホニル)ベンズアミド
参考例2で得られた化合物およびモルホリンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=7.0Hz),2.81-2.94(1H,m),2.99(4H,t,J=4.7Hz),3.70(4H,t,J=4.7Hz),7.22(2H,d,J=8.2Hz),7.53(2H,d,J=8.2Hz),7.66(1H,t,J=7.8Hz),7.87(1H,d,J=7.8Hz),7.93(1H,s),8.12(1H,d,J=7.8Hz),8.17(1H,s)
N-(4-イソプロピルフェニル)-3-[(2-メチルピペリジン-1-イル)スルホニル]ベンズアミド
参考例2で得られた化合物および2-メチルピペリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.08(3H,d,J=7.0Hz),1.26(6H,d,J=7.0Hz),1.29-1.60(6H,m),2.85-2.96(1H,m),3.01(1H,td,J=13.0,2.6Hz),3.69-3.78(1H,m),4.21-4.31(1H,m),7.23-7.28(2H,m),7.58(2H,d,J=8.6Hz),7.63(1H,t,J=7.8Hz),7.93-8.01(2H,m),8.09(1H,d,J=7.8Hz),8.26(1H,s)
3-{[(2R,6S)-2,6-ジメチルピペリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物および(2R,6S)-2,6-ジメチルピペリジン、を原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.17-1.78(6H,m),1.22(6H,d,J=6.6Hz),1.33(6H,d,J=7.0Hz),2.81-2.95(1H,m),4.11-4.22(2H,m),7.19-7.26(2H,m),7.53(2H,d,J=8.6Hz),7.59(1H,t,J=7.8Hz),7.84(1H,s),7.92-7.97(1H,m),8.05(1H,d,J=7.8Hz),8.23(1H,s)
3-[(3-ヒドロキシピペリジン-1-イル)スルホニル]-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物および3-ヒドロキシピペリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=7.0Hz),1.32-1.45(1H,m),1.48-1.63(1H,m),1.65-1.88(2H,m),2.72-2.96(3H,m),3.06-3.16(1H,m),3.30(1H,dd,J=11.3,2.7Hz),3.78-3.88(1H,m),7.20(2H,d,J=8.2Hz),7.53(2H,d,J=8.6Hz),7.63(1H,t,J=7.8Hz),7.87(1H,d,J=7.8Hz),8.05(1H,s),8.11(1H,d,J=7.8Hz),8.18(1H,s)
(3R)-3-フルオロピロリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物および(3R)-3-フルオロピロリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=6.6Hz),1.82-2.04(1H,m),2.06-2.22(1H,m),2.81-2.94(1H,m),3.22-3.33(1H,m),3.40-3.66(3H,m),5.13(1H,dt,J=52.5,3.4Hz),7.18-7.24(2H,m),7.53(2H,d,J=8.2Hz),7.64(1H,t,J=7.8Hz),7.92-7.99(2H,m),8.11(1H,d,J=7.8Hz),8.23(1H,s)
1-[(3-{[(4-イソプロピルフェニル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
参考例2で得られた化合物および(3R)-3-フルオロピロリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.19-1.30(1H,m),1.19(6H,d,J=6.6Hz),1.39-1.53(1H,m),1.66-1.82(2H,m),2.14-2.29(2H,m),2.30-2.43(1H,m),2.81-2.92(1H,m),3.56-3.71(2H,m),6.92(1H,s),7.23(2H,d,J=8.6Hz),7.41(1H,s),7.66(2H,d,J=8.6Hz),7.81(1H,t,J=7.8Hz),7.93(1H,d,J=7.8Hz),8.22-8.32(2H,m),10.45(1H,s)
1-[(3-{[(4-イソプロピルフェニル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-4-カルボキサミド
参考例2で得られた化合物およびピペリジン-3-カルボキサミドを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.19(6H,d,J=6.6Hz),1.45-1.60(2H,m),1.69-1.83(2H,m),1.99-2.11(1H,m),2.27-2.39(2H,m),2.81-2.92(1H,m),3.54-3.66(2H,m),6.79(1H,s),7.19(1H,s),7.23(2H,d,J=8.6Hz),7.66(2H,d,J=8.6Hz),7.80(1H,t,J=7.8Hz),7.93(1H,d,J=7.8Hz),8.23-8.30(2H,m),10.45(1H,s)
3-{[(3R)-3-ヒドロキシピペリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物および(R)-3-ヒドロキシピペリジン塩酸塩を原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=7.0Hz),1.31-1.46(1H,m),1.48-1.89(3H,m),2.70-2.93(3H,m),3.06-3.16(1H,m),3.30(1H,dd,J=11.7,3.1Hz),3.77-3.87(1H,m),7.18-7.23(2H,m),7.53(2H,d,J=8.2Hz),7.63(1H,t,J=7.8Hz),7.87(1H,d,J=7.8Hz),8.02(1H,s),8.10(1H,d,J=7.8Hz),8.18(1H,s)
3-{[3-(ヒドロキシメチル)ピペリジン-1-イル]スルホニル}-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物およびピペリジン-3-イルメタノールを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.94-1.10(1H,m),1.22(6H,d,J=7.0Hz),1.48-1.87(4H,m),2.27-2.38(1H,m),2.40-2.54(1H,m),2.82-2.94(1H,m),3.43(1H,dd,J=10.9,7.8Hz),3.48-3.59(2H,m),3.62-3.72(1H,m),7.21(2H,d,J=8.6Hz),7.54(2H,d,J=8.6Hz),7.63(1H,t,J=7.8Hz),7.88(1H,d,J=7.8Hz),8.06-8.21(3H,m)
3-[(シクロヘキシルアミノ)スルホニル]-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物およびシクロヘキサンアミンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.00-1.25(4H,m),1.22(6H,d,J=6.6Hz),1.41-1.54(2H,m),1.54-1.65(2H,m),1.65-1.77(2H,m),2.81-2.94(1H,m),3.05-3.21(1H,m),4.71(1H,d,J=7.8Hz),7.17-7.25(2H,m),7.53(2H,d,J=8.2Hz),7.60(1H,t,J=7.8Hz),7.95-8.05(2H,m),8.08(1H,d,J=8.2Hz),8.32(1H,s)
3-(アニリノスルホニル)-N-(4-イソプロピルフェニル)ベンズアミド
参考例2で得られた化合物およびアニリンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.21(6H,d,J=6.6Hz),2.80-2.92(1H,m),7.04-7.15(4H,m),7.15-7.27(4H,m),7.44-7.52(3H,m),7.80(1H,d,J=7.8Hz),7.89(1H,s),8.03(1H,d,J=7.8Hz),8.25(1H,s)
N-(4-イソプロピルフェニル)-3-{[(2R)-2-(メトキシメチル)ピロリジン-1-イル]スルホニル}ベンズアミド
参考例2で得られた化合物および(2R)-2-(メトキシメチル)ピロリジンを原料として用い、実施例26に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.22(6H,d,J=7.0Hz),1.50-1.65(2H,m),1.75-1.90(2H,m),2.76-2.97(2H,m),3.07-3.18(1H,m),3.31-3.36(1H,m),3.32(1H,s),3.37-3.45(1H,m),3.56(2H,dd,J=9.6,3.7Hz),3.70-3.80(1H,m),7.18-7.25(2H,m),7.54(2H,d,J=8.2Hz),7.62(1H,t,J=7.8Hz),7.96(1H,d,J=7.8Hz),8.03(1H,s),8.11(1H,d,J=7.8Hz),8.25(1H,s)
3-{[(3R)-3-ヒドロキシピペリジン-1-イル]スルホニル}-N-(2-メトキシフェニル)ベンズアミド
参考例3で得られた化合物および(R)-3-ヒドロキシピペリジン塩酸塩を原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(1H,m),1.57-1.70(1H,m),1.72-1.82(1H,m),1.82-1.94(1H,m),2.80(1H,dd,J=11.2,7.3Hz),2.84-2.93(1H,m),3.10-3.23(2H,m),3.38(1H,dd,J=11.2,3.4Hz),3.85-3.93(1H,m),3.94(3H,s),6.95(1H,dd,J=8.0,1.2Hz),7.04(1H,td,J=7.8,1.0Hz),7.13(1H,td,J=7.8,1.5Hz),7.69(1H,t,J=7.8Hz),7.95(1H,dt,J=8.1,1.3Hz),8.12(1H,dt,J=7.8,1.5Hz),8.25(1H,t,J=1.7Hz),8.43-8.50(1H,m),8.54(1H,s)
3-{[3-(ヒドロキシメチル)ピペリジン-1-イル]スルホニル}-N-(2-メトキシフェニル)ベンズアミド
参考例3で得られた化合物およびピペリジン-3-イルメタノールを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.98-1.13(1H,m),1.54-1.97(4H,m),2.30-2.39(1H,m),2.51(1H,td,J=10.9,2.9Hz),2.66(1H,s),3.46-3.75(4H,m),3.94(3H,s),6.95(1H,dd,J=8.0,1.2Hz),7.04(1H,td,J=7.8,1.5Hz),7.13(1H,td,J=7.8,2.0Hz),7.69(1H,t,J=7.8Hz),7.94(1H,dt,J=8.0,1.5Hz),8.10(1H,dt,J=7.6,1.5Hz),8.24(1H,t,J=1.5Hz),8.42-8.50(1H,m),8.55(1H,s)
1-[(3-{[(2-メトキシフェニル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
参考例3で得られた化合物およびピペリジン-3-カルボキサミドを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.18-1.32(1H,m),1.39-1.55(1H,m),1.66-1.81(2H,m),2.15-2.31(2H,m),2.31-2.44(1H,m),3.57-3.72(2H,m),3.83(3H,d,J=12.2Hz),6.90-7.01(2H,m),7.08-7.13(1H,m),7.18-7.25(1H,m),7.42(1H,s),7.65(1H,d,J=6.8Hz),7.80(1H,t,J=7.6Hz),7.91-7.96(1H,m),8.21-8.33(2H,m),9.88(1H,s)
5-{[(3-{[(4-メトキシフェニル)アミノ]カルボニル}フェニル)スルホニル]アミノ}ペンタン酸
(工程1)3-{[(5-ヒドロキシペンチル)アミノ]スルホニル}-N-(4-メトキシフェニル)ベンズアミドの合成
参考例4で得られた化合物および5-アミノペンタン-1-オールを原料として用い、実施例1に準じた方法により目的化合物を得た。
(工程2)5-{[(3-{[(4-メトキシフェニル)アミノ]カルボニル}フェニル)スルホニル]アミノ}ペンタン酸の合成
工程1で得られた化合物(500mg)のアセトン(10mL)溶液に、攪拌下、Jones試薬(クロム酸(280mg)、硫酸(0.25mL)および水(0.50mL)の混合溶液)を室温で滴下し加えた。室温下終夜攪拌後、過剰量のメタノールを加えた。室温下10分攪拌後、溶媒を減圧下留去した。残渣を酢酸エチルにて希釈後、水および飽和食塩水で洗浄し、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し(クロロホルム/メタノール=9/1)表題化合物(58mg、11%)を薄紫固体として得た。
1H-NMR(DMSO-d6)δ:1.35-1.50(4H,m),2.15(2H,t,J=7.1Hz),2.75(2H,q,J=6.3Hz),3.75(3H,s),6.95(2H,d,J=9.3Hz),7.67(2H,d,J=8.8Hz),7.72-7.75(1H,brm),7.75(1H,t,J=7.8Hz),7.97(1H,d,J=8.8Hz),8.19(1H,d,J=7.8Hz),8.33(1H,s),10.41(1H,s)
3-[(tert-ブチルアミノ)スルホニル]-N-(4-メトキシフェニル)ベンズアミド
参考例4で得られた化合物および2-メチルプロパン-2-アミンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.11(9H,s),3.75(3H,s),6.95(2H,d,J=9.3Hz),7.66-7.69(3H,m),7.73(1H,t,J=7.8Hz),8.02(1H,d,J=7.8Hz),8.16(1H,d,J=7.8Hz),8.37(1H,s),10.37(1H,s)
N-(4-メトキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
参考例4で得られた化合物およびピペリジンを原料として用い、実施例1に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.47(2H,m),1.57-1.69(4H,m),2.95-3.06(4H,m),3.83(3H,s),6.92(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.66(1H,t,J=7.8Hz),7.90(1H,d,J=7.8Hz),7.95(1H,s),8.14(1H,d,J=7.8Hz),8.18(1H,s).
N-(3-メトキシピリジン-2-イル)-3-(モルホリン-4-イルスルホニル)ベンズアミド
参考例5で得られた化合物(50.0mg)のTHF(2.0mL)溶液に、トリエチルアミン(0.13mL)およびモルホリン(41.2mg)を順次加え、室温にて一終夜攪拌した。反応液を減圧留去し、残渣を逆相HPLC(0.1%TFAアセトニトリル:H2O=10%-90%、グラジェント)にて精製し表題化合物(32mg、90%)を白色固体として得た。
1H-NMR(CDCl3)δ:3.03(4H,t,J=4.6Hz),3.75(4H,t,J=4.6Hz),3.94(3H,s),7.13(1H,dd,J=8.3,4.9Hz),7.23-7.28(1H,m),7.71(1H,t,J=7.8Hz),7.93(1H,d,J=7.8Hz),8.11(1H,d,J=4.9Hz),8.19(1H,d,J=7.8Hz),8.26(1H,s)
N-(3-メトキシピリジン-2-イル)-3-{[(2S)-2-メチルピロリジン-1-イル]スルホニル}ベンズアミド
参考例5で得られた化合物および(2S)-2-メチルピロリジンを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.33(3H,d,J=6.5Hz),1.47-1.63(2H,m),1.68-1.78(1H,m),1.82-1.93(1H,m),3.14-3.22(1H,m),3.44-3.52(1H,m),3.71-3.80(1H,m),3.94(3H,s),7.14(1H,dd,J=8.2,4.9Hz),7.23-7.28(1H,m),7.68(1H,t,J=7.7Hz),8.01-8.05(1H,m),8.10-8.14(1H,m),8.15-8.20(1H,m),8.30-8.33(1H,m)
3-(2-アザビシクロ[2.2.1]ヘプト-2-イルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例5で得られた化合物および2-アザビシクロ[2.2.1]ヘプタンを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.77-1.85(6H,m),2.47(1H,s),3.01-3.12(2H,m),3.91(3H,s),4.20(1H,s),7.09-7.14(1H,m),7.21-7.27(1H,m),7.64(1H,t,J=7.8Hz),7.99(1H,d,J=7.8Hz),8.09(1H,d,J=4.7Hz),8.15(1H,d,J=7.8Hz),8.27(1H,s)
3-{[3-(1H-ベンズイミダゾール-2-イル)ピペリジン-1-イル]スルホニル}-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例5で得られた化合物および2-ピペリジン-3-イル-1H-ベンズイミダゾールを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.63-1.84(2H,m),1.92-2.10(2H,m),2.80-2.91(1H,m),3.11-3.20(1H,m),3.25-3.34(1H,m),3.41-3.51(1H,m),3.69-3.78(1H,m),3.88(3H,s),7.11(1H,dd,J=7.8,4.9Hz),7.19-7.28(3H,m),7.54-7.60(2H,m),7.65(1H,t,J=7.8Hz),7.89-7.93(1H,m),8.03-8.07(1H,m),8.12-8.17(1H,m),8.26-8.29(1H,m)
3-(2-アザビシクロ[2.2.2]オクト-2-イルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例5で得られた化合物および2-アザビシクロ[2.2.2]オクタンを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.47-1.92(9H,m),3.31-3.38(2H,m),3.88(1H,s),3.94(3H,s),7.14(1H,dd,J=8.3,4.9Hz),7.23-7.28(1H,m),7.66(1H,t,J=7.8Hz),8.03(1H,d,J=7.8Hz),8.13(1H,d,J=4.9Hz),8.16(1H,d,J=7.8Hz),8.33(1H,s)
3-(7-アザビシクロ[2.2.1]ヘプト-7-イルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例5で得られた化合物および7-アザビシクロ[2.2.1]ヘプタンを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.46(4H,m),1.77-1.85(4H,m),3.94(3H,s),4.20-4.26(2H,m),7.14(1H,dd,J=8.3,4.9Hz),7.23-7.28(1H,m),7.64(1H,t,J=7.8Hz),8.08-8.19(3H,m),8.40(1H,t,J=1.7Hz)
N-(3-メトキシピリジン-2-イル)-3-[(1R,4R)-2-オキサ-5-アザビシクロ[2.2.1]ヘプト-5-イルスルホニル]ベンズアミド
参考例5で得られた化合物および(1R,4R)-2-オキサ-5-アザビシクロ[2.2.1]ヘプタン・1塩酸塩を原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.35(1H,d,J=10.7Hz),1.75(1H,d,J=10.2Hz),3.22(1H,d,J=9.8Hz),3.42(1H,d,J=9.8Hz),3.67-3.73(1H,m),3.89(1H,d,J=7.8Hz),3.93(3H,s),4.52(2H,d,J=11.7Hz),7.13(1H,dd,J=7.8,4.9Hz),7.24(1H,d,J=7.8Hz),7.68(1H,t,J=7.8Hz),8.03(1H,d,J=7.8Hz),8.11(1H,d,J=4.9Hz),8.17(1H,d,J=7.8Hz),8.34(1H,s),8.57(1H,s)
3-(8-アザビシクロ[3.2.1]オクト-8-イルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例5で得られた化合物および8-アザビシクロ[3.2.1]オクタンを原料として用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.45-1.68(8H,m),1.76-1.89(2H,m),3.93(3H,s),4.24(2H,s),7.11(1H,dd,J=8.3,4.9Hz),7.23(1H,dd,J=8.3,1.5Hz),7.63(1H,t,J=7.8Hz),8.03-8.08(1H,m),8.10-8.17(2H,m),8.35(1H,s),8.49(1H,s)
エチル1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキシレート
(工程1)3-{[3-(エトキシカルボニル)ピペリジン-1-イル]スルホニル}安息香酸の合成
3-(クロロスルホニル)安息香酸(5.00g)及びエチルピペリジン-3-カルボキシレート(7.04mL)を原料として用い、参考例1に準じた方法により目的化合物(7.12g、92%)を無色固体として得た。
(工程2)エチル1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキシレートの合成
工程1で得られた化合物(4.00g)及び2-アミノ-3-メトキシピリジン(1.45g)を原料として用い、実施例92に準じた方法により目的化合物(3.66g、70%)を無色油状物として得た。
1H-NMR(CDCl3)δ:1.25(3H,t,J=7.1Hz),1.35-1.50(1H,m),1.59-1.73(1H,m),1.76-1.87(1H,m),1.94-2.03(1H,m),2.44(1H,td,J=11.3,3.3Hz),2.56-2.68(2H,m),3.55-3.66(1H,m),3.78-3.88(1H,m),3.93(3H,s),4.14(2H,q,J=7.2Hz),7.12(1H,dd,J=8.3,4.9Hz),7.24(1H,dd,J=8.3,1.5Hz),7.69(1H,t,J=7.8Hz),7.94(1H,dt,J=7.8,1.5Hz),8.09-8.13(1H,m),8.18(1H,d,J=7.8Hz),8.25(1H,s),8.59(1H,s)
1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボン酸
実施例55で得られた化合物(50mg)をメタノール(1.0mL)に溶解し、2M水酸化ナトリウム水溶液(0.056mL)を加えた後、室温にて17時間攪拌した。反応液を濃縮後、逆相HPLC(0.1%TFAアセトニトリル:H2O)=10%-95%、グラジェント)で精製し、表題化合物(6mg、13%)を無色油状物として得た。
1H-NMR(DMSO-d6)δ:1.12-1.54(3H,m),1.59-1.81(2H,m),2.38-2.69(2H,m),3.23-3.37(1H,m),3.43-3.54(1H,m),3.76(3H,s),7.31(1H,dd,J=8.3,4.9Hz),7.50-7.55(1H,m),7.76(1H,t,J=8.0Hz),7.88-7.94(1H,m),7.99(1H,dd,J=4.9,1.5Hz),8.20-8.28(2H,m),10.61(1H,s)
1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
実施例56で得られた化合物(50mg)をDMF(1.0mL)に溶解し、N,N-ジイソプロピルエチルアミン(0.030mL)、塩化アンモニウム(8mg)、1-ヒドロキシベンゾトリアゾール水和物(22mg)、N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド塩酸塩(27mg)を順次加え、室温にて3日間攪拌した。反応液に水を加え、酢酸エチルにて4度抽出した。有機層を併せ飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)で精製し、表題化合物(37mg、74%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.56-1.73(2H,m),1.74-1.89(2H,m),2.45-2.57(1H,m),2.62-2.73(1H,m),2.79-2.91(1H,m),3.50(1H,d,J=11.5Hz),3.60-3.69(1H,m),3.94(3H,s),5.54(1H,s),5.97(1H,s),7.13(1H,dd,J=8.0,4.9Hz),7.22-7.27(1H,m),7.69(1H,t,J=7.8Hz),7.94(1H,d,J=8.0Hz),8.11(1H,d,J=4.4Hz),8.17(1H,d,J=8.0Hz),8.27(1H,s),8.63(1H,s)
1-[(3-{[(5-イソプロポキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
参考例6で得られた化合物およびピペリジン-3-カルボキサミドを用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.18-1.26(8H,m),1.28(6H,d,J=5.9Hz),1.38-1.52(1H,m),1.68-1.82(2H,m),2.15-2.43(3H,m),3.57-3.73(2H,m),4.63-4.69(1H,m),6.92(1H,s),7.41(1H,s),7.49(1H,dd,J=9.3,2.9Hz),7.78(1H,t,J=7.9Hz),7.89-7.95(1H,m),8.05-8.11(2H,m),8.28-8.35(2H,m),11.07(1H,s)
(3S)-1-[(3-{[(5-イソプロポキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド、及び、(3R)-1-[(3-{[(5-イソプロポキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
実施例58で得られた化合物(10mg)を、分取HPLC(ChiralpakAD)(ヘキサン/エタノール=70/30)で分離した。
先の溶出物((3S)-1-[(3-{[(5-イソプロポキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド)を無色固体(5.0mg)として得た(実施例59)。後の溶出物((3R)-1-[(3-{[(5-イソプロポキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド)を無色固体(5.0mg)として得た。(実施例59’)
1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]-N-メチルピペリジン-3-カルボキサミド
実施例56で得られた化合物およびメチルアミンを原料として用い、実施例57に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.55-1.84(4H,m),2.43-2.54(1H,m),2.81(3H,d,J=4.4Hz),2.81-2.90(1H,m),2.93-3.02(1H,m),3.42-3.52(1H,m),3.54-3.64(1H,m),4.04(3H,s),6.28(1H,s),7.50(1H,dd,J=8.0,5.4Hz),7.66-7.75(2H,m),7.97-8.05(2H,m),8.26(1H,d,J=8.0Hz),8.36(1H,s)
N-ベンジル-1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキサミド
実施例56で得られた化合物およびベンジルアミンを原料として用い、実施例57に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.56-1.90(4H,m),2.45-2.56(1H,m),2.68-2.80(1H,m),2.94(1H,dd,J=11.7,9.8Hz),3.47-3.60(1H,m),3.65-3.77(1H,m),4.02(3H,s),4.35-4.51(2H,m),6.31-6.43(1H,m),7.21-7.36(6H,m),7.43-7.50(1H,m),7.65(1H,d,J=8.3Hz),7.71(1H,t,J=7.8Hz),7.96-8.02(2H,m),8.25(1H,d,J=7.8Hz),8.35(1H,s)
ベンジル1-[(3-{[(3-メトキシピリジン-2-イル)アミノ]カルボニル}フェニル)スルホニル]ピペリジン-3-カルボキシレート
参考例5で得られた化合物およびベンジルピペリジン-3-カルボキシレートを用い、実施例47に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.53(1H,m),1.57-1.73(1H,m),1.75-1.89(1H,m),1.93-2.06(1H,m),2.38-2.54(1H,m),2.58-2.77(2H,m),3.54-3.68(1H,m),3.81-3.90(1H,m),3.93(3H,s),5.10(1H,d,J=12.2Hz),5.14(1H,d,J=12.2Hz),7.12(1H,dd,J=8.3,4.9Hz),7.23(1H,dd,J=8.3,1.5Hz),7.29-7.41(5H,m),7.63-7.74(1H,m),7.92-7.97(1H,m),8.12(1H,dd,J=4.9,1.5Hz),8.15-8.20(1H,m),8.22-8.25(1H,m),8.48(1H,s)
3-イソプロポキシ-5-{[3-(モルホリン-4-イルスルホニル)ベンゾイル]アミノ}-1H-ピラゾール塩酸塩
参考例7で得られた化合物(100mg)をTHF(2.0mL)に溶解し、モルホリン(0.10mL)を加え、室温にて18時間攪拌した。反応液に酢酸エチルを加えた後、水、飽和食塩水にて順次洗浄し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、無色固体(63mg)を得た。得られた個体(61mg)を酢酸エチル(2.0mL)に溶解し、4M塩酸-酢酸エチル溶液(2.0mL)を加えた後、室温にて18時間攪拌した。生じた固体をろ取することにより、表題化合物(50mg、59%)を無色固体として得た。
1H-NMR(DMSO-d6)δ:1.28(6H,d,J=6.1Hz),2.90(4H,t,J=4.6Hz),3.63(4H,t,J=4.6Hz),4.52-4.66(1H,m),5.82(1H,s),6.43(1H,brs),7.81(1H,t,J=7.8Hz),7.93(1H,dt,J=8.0,1.3Hz),8.25-8.35(2H,m),11.24(1H,s)
3-イソプロポキシ-5-({3-[(2-メチルピロリジン-1-イル)スルホニル]ベンゾイル}アミノ)-1H-ピラゾール 塩酸塩
参考例7で得られた化合物および2-メチルピロリジンを原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.23(6H,d,J=6.3Hz),1.28(3H,d,J=6.1Hz),1.34-1.49(2H,m),1.51-1.65(1H,m),1.69-1.85(1H,m),3.14(1H,dt,J=12.8,5.2Hz),3.30-3.40(1H,m),3.63-3.75(1H,m),4.51-4.66(1H,m),5.81(1H,s),6.07(1H,brs),7.77(1H,t,J=7.9Hz),8.02(1H,d,J=7.9Hz),8.27(1H,d,J=7.9Hz),8.35(1H,s),11.22(1H,s)
5-[(3-{[3-(ヒドロキシメチル)ピペリジン-1-イル]スルホニル}ベンゾイル)アミノ]-3-イソプロポキシ-1H-ピラゾール 塩酸塩
参考例7で得られた化合物およびピペリジン-3-イルメタノールを原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:0.81-0.95(1H,m),1.28(6H,d,J=6.1Hz),1.38-1.74(4H,m),1.94-2.04(1H,m),2.18-2.29(1H,m),3.14(1H,dd,J=10.7,7.8Hz),3.30(1H,dd,J=10.7,4.9Hz),3.50-3.60(1H,m),3.62-3.72(1H,m),4.52-4.65(1H,m),5.31(1H,brs),5.81(1H,s),7.79(1H,t,J=8.0Hz),7.88-7.94(1H,m),8.24-8.32(2H,m),11.20(1H,s)
5-({3-[(3-ヒドロキシピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩
参考例7で得られた化合物および3-ヒドロキシピペリジン塩酸塩を原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:0.99-1.26(1H,m),1.28(6H,d,J=6.1Hz),1.38-1.61(2H,m),1.61-1.80(2H,m),2.87-3.07(2H,m),3.13-3.23(1H,m),4.53-4.64(1H,m),4.69-4.78(1H,m),5.81(1H,s),7.79(1H,t,J=8.0Hz),7.89-7.96(1H,m),8.25-8.33(2H,m),11.17(1H,s)
5-({3-[(4-フルオロピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩
参考例7で得られた化合物および4-フルオロピペリジン臭化水素酸塩を原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.28(6H,d,J=6.1Hz),1.69-2.00(4H,m),2.89-2.99(2H,m),3.04-3.15(2H,m),4.53-4.64(1H,m),4.64-4.84(1H,m),5.82(1H,s),6.09(1H,brs),7.80(1H,t,J=8.0Hz),7.93-7.98(1H,m),8.26-8.32(2H,m),11.22(1H,s)
5-({3-[(4,4-ジフルオロピペリジン-1-イル)スルホニル]ベンゾイル}アミノ)-3-イソプロポキシ-1H-ピラゾール 塩酸塩
参考例7で得られた化合物および4,4-ジフルオロピペリジン臭化水素酸塩を原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.28(6H,d,J=6.1Hz),1.99-2.14(4H,m),3.12(4H,t,J=5.6Hz),4.54-4.64(1H,m),5.83(1H,s),6.75(1H,brs),7.81(1H,t,J=7.8Hz),7.98(1H,dt,J=7.8,1.5Hz),8.27-8.34(2H,m),11.25(1H,s)
3-イソプロポキシ-5-{[3-(ピペリジン-1-イルスルホニル)ベンゾイル]アミノ}-1H-ピラゾール 塩酸塩
参考例7で得られた化合物およびピペリジンを原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.29(6H,d,J=6.1Hz),1.32-1.41(2H,m),1.49-1.61(4H,m),2.92(4H,t,J=5.4Hz),4.53-4.70(1H,m),5.77-5.92(1H,m),7.76-7.86(1H,m),7.90-7.99(1H,m),8.25-8.39(2H,m),11.08-11.61(2H,m)
N-(3-イソプロポキシ-1H-ピラゾール-5-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド 塩酸塩
参考例7で得られた化合物およびピロリジンを原料として用い、実施例63に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.36(6H,d,J=6.1Hz),1.74-1.84(4H,m),3.27(4H,t,J=6.8Hz),4.50-4.63(1H,m),5.99(1H,s),7.66(1H,t,J=7.8Hz),7.99(1H,dt,J=8.0,1.5Hz),8.14(1H,dt,J=7.8,1.5Hz),8.30(1H,t,J=1.5Hz),10.24(1H,s)
N-(4-フルオロフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸(100mg)のDMF(2.0mL)溶液に、4-フルオロアニリン(41mg)、ピリジン(0.060mL)およびN-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド塩酸塩(107mg)を順次加え、室温にて14時間攪拌した。反応液に酢酸エチルを加え、2M塩酸にて2回洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=5%-50%、グラジェント)で精製し、表題化合物(87mg、65%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.37-1.48(2H,m),1.54-1.69(4H,m),2.93-3.08(4H,m),7.09(2H,t,J=8.7Hz),7.61-7.67(2H,m),7.68(1H,t,J=7.8Hz),7.86-7.96(1H,m),8.15(2H,d,J=7.8Hz),8.19(1H,s)
3-(ピペリジン-1-イルスルホニル)-N-[4-(トリフルオロメチル)フェニル]ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸(100mg)及び4-アミノベンゾトリフルオリド(59mg)を原料として用い、実施例71に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.47(2H,m),1.57-1.67(4H,m),3.01(4H,t,J=5.5Hz),7.66(2H,d,J=8.5Hz),7.69(1H,t,J=7.8Hz),7.85(2H,d,J=8.5Hz),7.92(1H,d,J=7.8Hz),8.15-8.20(1H,m),8.21(1H,s),8.35(1H,s)
N-ベンジル-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸(30mg)のクロロホルム(0.30mL)溶液に、ベンジルアミン(12mg)、トリエチルアミン(0.047mL)、2-クロロ-1,3-ジメチルイミダゾリニウムクロリドジクロロメタン25%溶液(0.11mL)を順次加え、室温にて1時間攪拌した。反応液を濃縮後、逆相HPLC(0.1%TFAアセトニトリル:H2O)=10%-95%、グラジェント)で精製し、表題化合物(26mg、65%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.37-1.48(2H,m),1.52-1.70(4H,m),3.00(4H,t,J=5.5Hz),4.66(2H,d,J=5.5Hz),6.54(1H,brs),7.28-7.41(5H,m),7.62(1H,t,J=7.8Hz),7.85-7.90(1H,m),8.06(1H,d,J=7.8Hz),8.10(1H,s)
2-{[3-(ピペリジン-1-イルスルホニル)ベンゾイル]アミノ}ピリジン トリフルオロ酢酸塩
3-(ピペリジン-1-イルスルホニル)安息香酸および2-アミノピリジンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.31-1.41(2H,m),1.49-1.60(4H,m),2.93(4H,t,J=5.5Hz),7.17-7.24(1H,m),7.78(1H,t,J=7.8Hz),7.83-7.97(2H,m),8.18(1H,d,J=8.2Hz),8.28-8.35(2H,m),8.39-8.44(1H,m),11.24(1H,s)
6-{[3-(ピペリジン-1-イルスルホニル)ベンゾイル]アミノ}キノリン トリフルオロ酢酸塩
3-(ピペリジン-1-イルスルホニル)安息香酸および7-アミノキノリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.30-1.44(2H,m),1.49-1.61(4H,m),2.94(4H,t,J=5.5Hz),7.70-7.78(1H,m),7.85(1H,t,J=7.6Hz),7.97(1H,d,J=7.8Hz),8.10-8.25(2H,m),8.30-8.38(2H,m),8.64-8.76(2H,m),8.96-9.03(1H,m),10.97(1H,s)
5-{[3-(ピペリジン-1-イルスルホニル)ベンゾイル]アミノ}イソキノリン トリフルオロ酢酸塩
3-(ピペリジン-1-イルスルホニル)安息香酸および5-アミノイソキノリン塩酸塩を原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.33-1.43(2H,m),1.51-1.61(4H,m),2.95(4H,t,J=5.1Hz),7.83-7.93(2H,m),7.99(1H,d,J=8.2Hz),8.03-8.14(2H,m),8.21-8.28(1H,m),8.36-8.45(2H,m),8.60(1H,dd,J=6.3,1.2Hz),9.61(1H,d,J=4.7Hz),10.93(1H,s)
N-(4-イソプロピルフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および4-イソプロピルアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.26(6H,d,J=7.0Hz),1.39-1.49(2H,m),1.56-1.74(4H,m),2.87-2.98(1H,m),3.03(4H,t,J=5.3Hz),7.23-7.29(2H,m),7.58(2H,d,J=8.0Hz),7.68(1H,t,J=8.0Hz),7.86-7.96(2H,m),8.14(1H,d,J=8.0Hz),8.18(1H,s)
N-(2-フェニルエチル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および2-フェニルエチルアミンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.48(2H,m),1.61-1.70(4H,m),2.93-3.02(6H,m),3.74(2H,q,J=6.5Hz),6.23(1H,brs),7.21-7.28(3H,m),7.30-7.37(2H,m),7.57-7.63(1H,m),7.86(1H,d,J=8.2Hz),7.94-8.00(2H,m)
N-[4-(メチルチオ)フェニル]-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および4-メチルチオアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.61-1.69(4H,m),2.50(3H,s),3.02(4H,t,J=5.5Hz),7.30(2H,d,J=8.6Hz),7.61(2H,d,J=8.6Hz),7.68(1H,t,J=7.8Hz),7.89-7.99(2H,m),8.14(1H,d,J=7.8Hz),8.17(1H,s)
N-(2-メトキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および2-メトキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.61-1.76(4H,m),3.04(4H,t,J=5.5Hz),3.94(3H,s),6.94(1H,d,J=7.8Hz),7.04(1H,t,J=7.6Hz),7.09-7.16(1H,m),7.68(1H,t,J=7.8Hz),7.94(1H,d,J=7.8Hz),8.11(1H,d,J=7.8Hz),8.23(1H,s),8.48(1H,d,J=8.2Hz),8.54(1H,s)
N-(3-メトキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および3-メトキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.60-1.77(4H,m),3.02(4H,t,J=5.5Hz),3.85(3H,s),6.71-6.78(1H,m),7.16(1H,d,J=8.2Hz),7.26-7.33(1H,m),7.42(1H,s),7.68(1H,t,J=7.8Hz),7.92(1H,d,J=7.8Hz),7.96(1H,s),8.14(1H,d,J=8.2Hz),8.18(1H,s)
N-イソオキサゾール-3-イル-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および3-アミノイソオキサゾールを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.62-1.73(4H,m),3.04(4H,t,J=5.5Hz),7.23(1H,d,J=1.6Hz),7.72(1H,t,J=7.8Hz),7.99(1H,d,J=7.8Hz),8.18(1H,d,J=7.8Hz),8.28-8.32(1H,m),8.38(1H,d,J=1.6Hz),9.25(1H,s)
3-(ピペリジン-1-イルスルホニル)-N-[(1S)-1,2,3,4-テトラヒドロナフタレン-1-イル]ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および(S)-(+)-1,2,3,4-テトラヒドロ-1-ナフチルアミンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.50(2H,m),1.60-1.70(4H,m),1.84-2.05(3H,m),2.11-2.23(1H,m),2.75-2.95(2H,m),3.01(4H,t,J=5.5Hz),5.36-5.46(1H,m),6.34-6.43(1H,m),7.14-7.25(3H,m),7.31-7.35(1H,m),7.62(1H,t,J=7.8Hz),7.85-7.90(1H,m),8.01-8.06(1H,m),8.07-8.11(1H,m)
N-(4-メチルフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および4-メチルアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.61-1.70(4H,m),2.36(3H,s),3.03(4H,t,J=5.1Hz),7.20(2H,d,J=8.2Hz),7.54(2H,d,J=8.2Hz),7.68(1H,t,J=7.8Hz),7.85(1H,s),7.92(1H,d,J=7.8Hz),8.14(1H,d,J=7.8Hz),8.17(1H,s)
N-(2,3-ジヒドロ-1H-インデン-1-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および1-アミノインダンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.49(2H,m),1.61-1.70(4H,m),1.91-2.04(1H,m),2.66-2.78(1H,m),2.89-3.13(2H,m),3.01(4H,t,J=5.5Hz),5.71(1H,q,J=7.6Hz),6.40(1H,d,J=9.0Hz),7.21-7.33(3H,m),7.36(1H,d,J=7.4Hz),7.63(1H,t,J=7.8Hz),7.88(1H,d,J=7.8Hz),8.06(1H,d,J=7.8Hz),8.09(1H,s)
N-(3-フェニルプロピル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および3-フェニルプロピルアミンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.36-1.47(2H,m),1.61-1.67(4H,m),1.96-2.04(2H,m),2.74(2H,t,J=7.4Hz),3.00(4H,t,J=5.5Hz),3.53(2H,q,J=6.6Hz),6.17(1H,brs),7.16-7.34(5H,m),7.60(1H,t,J=7.8Hz),7.86(1H,d,J=7.8Hz),7.92(1H,d,J=7.8Hz),8.02(1H,s)
N-(4-フェノキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および4-フェニルオキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.49(2H,m),1.60-1.71(4H,m),3.03(4H,t,J=5.1Hz),6.98-7.08(4H,m),7.09-7.14(1H,m),7.31-7.38(2H,m),7.63(2H,d,J=8.6Hz),7.69(1H,t,J=7.8Hz),7.89-7.99(2H,m),8.15(1H,d,J=7.8Hz),8.18(1H,s)
N-フェニル-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸およびアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.48(2H,m),1.59-1.71(4H,m),3.02(4H,t,J=5.1Hz),7.19(1H,t,J=7.4Hz),7.40(2H,t,J=7.8Hz),7.63-7.73(3H,m),7.92(1H,d,J=7.8Hz),7.97(1H,s),8.15(1H,d,J=7.8Hz),8.19(1H,s)
N-(2-クロロフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および2-クロロアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.40-1.49(2H,m),1.62-1.71(4H,m),3.05(4H,t,J=5.4Hz),7.13(1H,td,J=7.8,1.5Hz),7.33-7.39(1H,m),7.45(1H,dd,J=7.8,1.5Hz),7.71(1H,t,J=7.8Hz),7.97(1H,dt,J=8.0,1.5Hz),8.12(1H,dt,J=7.8,1.5Hz),8.28(1H,t,J=1.7Hz),8.43(1H,s),8.51(1H,dd,J=8.3,1.5Hz)
N-(3-クロロフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および3-クロロアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.48(2H,m),1.59-1.69(4H,m),3.01(4H,t,J=5.6Hz),7.15-7.19(1H,m),7.32(1H,t,J=8.0Hz),7.50-7.55(1H,m),7.69(1H,t,J=7.8Hz),7.82-7.85(1H,m),7.92(1H,dt,J=7.8,1.5Hz),8.13-8.17(2H,m),8.17-8.20(1H,m)
N-(4-イソプロポキシフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピペリジン-1-イルスルホニル)安息香酸および4-イソプロポキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=5.9Hz),1.38-1.48(2H,m),1.59-1.69(4H,m),3.01(4H,t,J=5.1Hz),4.48-4.60(1H,m),6.91(2H,d,J=8.8Hz),7.55(2H,d,J=8.8Hz),7.67(1H,t,J=7.8Hz),7.90(1H,d,J=7.8Hz),7.98(1H,s),8.14(1H,d,J=7.8Hz),8.17(1H,s)
N-(4-アセチルフェニル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸(200mg)のDMF(4.0mL)溶液に、1-(4-アミノフェニル)エタノン(151mg)、O-(-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラ-メチルウロニウムヘキサフルオロリン酸塩(565mg)およびN、N-ジイソプロピルエチルアミン(0.39mL)を順次加え、室温にて2時間攪拌した。反応液に酢酸エチルを加え、水にて3回洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、表題化合物(117mg、41%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.38-1.47(2H,m),1.58-1.67(4H,m),2.61(3H,s),2.97-3.04(4H,m),7.68(1H,t,J=7.8Hz),7.83(2H,d,J=8.8Hz),7.89-7.93(1H,m),8.00(2H,d,J=8.8Hz),8.15-8.19(1H,m),8.20-8.23(1H,m),8.43(1H,s)
N-[4-(1-ヒドロキシエチル)フェニル]-3-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例92で得られた化合物(30.0mg)のエタノール(2.0mL)溶液に、水素化ホウ素ナトリウム(8.8mg)を加え、室温にて一終夜攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて3回抽出後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、表題化合物(29.7mg、98%)を白色固体として得た。
1H-NMR(CDCl3)δ:1.40-1.47(2H,m),1.51(3H,d,J=6.7Hz),1.57-1.75(4H,m),2.98-3.06(4H,m),4.89-4.97(1H,m),7.40(2H,d,J=8.2Hz),7.60-7.74(3H,m),7.91(1H,d,J=8.2Hz),8.05(1H,s),8.15(1H,d,J=7.8Hz),8.18(1H,s)
N-[4-(1-ヒドロキシ-1-メチルエチル)フェニル]-3-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例92で得られた化合物(50.0mg)のジエチルエーテル(1.0mL)溶液に、氷冷下、メチルリチウム(0.66mL、0.98Mジエチルエーテル溶液)を滴下し、氷冷下1時間攪拌した。室温まで昇温後、反応液に水を加えた後、酢酸エチルにて3回抽出した。硫酸ナトリウムで乾燥した後、乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、表題化合物(51.1mg、99%)を白色固体として得た。
1H-NMR(CDCl3)δ:1.40-1.47(2H,m),1.59(6H,s),1.59-1.67(4H,m),2.98-3.04(4H,m),7.49-7.52(2H,m),7.60-7.69(3H,m),7.90(1H,d,J=7.6Hz),8.14-8.19(3H,m)
N-[5-(ジフルオロメトキシ)ピリジン-2-イル]-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および5-(ジフルオロメトキシ)ピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.47(2H,m),1.57-1.68(4H,m),2.97-3.03(4H,m),7.48(2H,d,J=8.8Hz),7.65-7.72(1H,m),7.69(2H,d,J=8.8Hz),7.88-7.93(1H,m),8.12-8.20(3H,m)
N-(2,6-ジメトキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および2、6-ジメトキシピリジン-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.48(2H,m),1.59-1.70(4H,m),3.04(4H,t,J=5.6Hz),3.92(3H,s),4.04(3H,s),6.38(1H,d,J=8.8Hz),7.68(1H,t,J=7.8Hz),7.90-7.96(1H,m),8.06-8.14(2H,m),8.19-8.23(1H,m),8.59(1H,d,J=8.8Hz)
N-(2-メトキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および2-メトキシピリジン-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.40-1.49(2H,m),1.62-1.71(4H,m),3.04(4H,t,J=5.6Hz),4.08(3H,s),6.98(1H,dd,J=7.8,4.9Hz),7.70(1H,t,J=7.8Hz),7.91-7.98(2H,m),8.07-8.13(1H,m),8.22-8.25(1H,m),8.39(1H,s),8.72(1H,dd,J=7.8,1.5Hz)
N-(3-ヒドロキシピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および2-アミノピリジン-3-オールを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.47(2H,m),1.58-1.69(4H,m),2.99(4H,t,J=5.4Hz),7.17(1H,dd,J=8.0,4.6Hz),7.44(1H,dd,J=8.3,1.5Hz),7.70(1H,t,J=7.8Hz),7.83-7.88(1H,m),7.95-8.00(1H,m),8.21-8.26(1H,m),8.34-8.39(1H,m)
N-(3-メトキシピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.48(2H,m),1.59-1.69(4H,m),3.01(4H,t,J=5.4Hz),3.93(3H,s),7.12(1H,dd,J=8.3,4.9Hz),7.21-7.26(1H,m),7.67(1H,t,J=7.8Hz),7.90-7.95(1H,m),8.08-8.13(1H,m),8.15-8.19(1H,m),8.21-8.25(1H,m)
N-(6-イソプロポキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および6-イソプロポキシピリジン-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.35(6H,d,J=6.3Hz),1.39-1.47(2H,m),1.58-1.69(4H,m),3.02(4H,t,J=5.4Hz),5.22-5.33(1H,m),6.73(1H,d,J=8.8Hz),7.68(1H,t,J=7.8Hz),7.88-7.94(1H,m),7.95-8.04(1H,m),8.16(1H,d,J=7.8Hz),8.20(1H,s),8.30-8.35(1H,m).
N-(6-フェノキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および6-フェノキシピリジン-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.35-1.45(2H,m),1.54-1.64(4H,m),2.98(4H,t,J=5.4Hz),6.93(1H,d,J=8.8Hz),7.09-7.14(2H,m),7.16-7.22(1H,m),7.35-7.42(2H,m),7.66(1H,t,J=7.8Hz),7.85-7.90(1H,m),8.13-8.24(3H,m),8.39(1H,d,J=2.4Hz),8.54(1H,s)
N-(6-メトキシピリジン-3-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および6-メトキシピリジン-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.36-1.46(2H,m),1.56-1.65(4H,m),2.98(4H,t,J=5.4Hz),3.94(3H,s),6.78(1H,d,J=8.8Hz),7.66(1H,t,J=7.8Hz),7.86-7.90(1H,m),8.03(1H,dd,J=8.8,2.9Hz),8.17(1H,d,J=7.8Hz),8.23(1H,s),8.39(1H,d,J=2.9Hz),8.44(1H,s)
N-(3-メチルピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および3-メチルピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.47(2H,m),1.57-1.67(4H,m),2.35(3H,s),2.95(4H,t,J=5.6Hz),7.11-7.21(1H,m),7.61-7.68(2H,m),7.91(1H,dt,J=7.8,1.5Hz),8.14-8.31(2H,m),8.34(1H,s),9.36(1H,s)
N-(3-メトキシピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
3-(ピロリジン-1-イルスルホニル)安息香酸および3-メチルピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.75-1.82(4H,m),3.24-3.31(4H,m),3.94(3H,s),7.13(1H,dd,J=8.3,4.9Hz),7.25(1H,dd,J=8.3,1.0Hz),7.68(1H,t,J=7.8Hz),8.02(1H,d,J=7.8Hz),8.12(1H,dd,J=4.9,1.0Hz),8.18(1H,d,J=7.8Hz),8.30(1H,s)
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および5-シクロプロピル-1H-ピラゾール-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.72-0.80(2H,m),0.94-1.03(2H,m),1.38-1.49(2H,m),1.60-1.71(4H,m),1.83-1.94(1H,m),3.03(4H,t,J=5.6Hz),6.43(1H,s),7.66(1H,t,J=7.8Hz),7.90(1H,d,J=7.8Hz),8.15(1H,d,J=7.8Hz),8.24(1H,s)
N-(5-ブロモ-3-メトキシピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および5-ブロモ-3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.39-1.49(2H,m),1.59-1.74(4H,m),3.01(4H,t,J=5.4Hz),3.94(3H,s),7.36(1H,d,J=2.0Hz),7.69(1H,t,J=7.8Hz),7.94(1H,d,J=7.8Hz),8.12-8.23(3H,m),8.43(1H,s)
N-(3-メトキシ-5-ビニルピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例106で得られた化合物(30.0mg)のn-プロパノール(1.0mL)溶液に、室温にて[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(9.7mg)、カリウムビニルトリフルオロボレート(10.6mg)、トリエチルアミン(0.010mL)を順次加え、80℃にて10時間撹拌した。放冷後、反応液に酢酸エチルを加えた後、水にて3回洗浄し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(NHバイオタージカラム、酢酸エチル/ヘキサン=0%-80%、グラジェント)にて精製し、表題化合物(11.0mg、42%)を無色油状物質として得た。
1H-NMR(CDCl3)δ:1.38-1.48(2H,m),1.59-1.69(4H,m),3.01(4H,t,J=5.1Hz),3.96(3H,s),5.37(1H,d,J=10.7Hz),5.78(1H,d,J=17.6Hz),6.72(1H,dd,J=17.6,10.7Hz),7.28(1H,s),7.68(1H,t,J=7.8Hz),7.93(1H,d,J=7.8Hz),8.09(1H,s),8.17(1H,d,J=7.8Hz),8.22(1H,s)
N-(5-エチル-3-メトキシピリジン-2-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例107で得られた化合物(9.0mg)のエタノール(2.0mL)溶液に、触媒として10%パラジウム-炭素(3.0mg)を加え、水素雰囲気下、室温にて一終夜撹拌した。触媒をろ過後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)にて精製し、表題化合物(8.5mg、94%)を無色油状物質として得た。
1H-NMR(CDCl3)δ:1.28(3H,t,J=7.6Hz),1.39-1.47(2H,m),1.61-1.69(4H,m),2.68(2H,q,J=7.6Hz),3.01(4H,t,J=5.4Hz),3.92(3H,s),7.09(1H,d,J=1.5Hz),7.67(1H,t,J=7.8Hz),7.93(1H,d,J=7.8Hz),7.96(1H,d,J=1.5Hz),8.18(1H,d,J=7.8Hz),8.22(1H,s)
N-(3-メトキシ-5-フェニルピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
(工程1)N-(5-ブロモ-3-メトキシピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミドの合成
3-(ピロリジン-1-イルスルホニル)安息香酸および5-ブロモ-3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により目的物を得た。
(工程2)N-(3-メトキシ-5-フェニルピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミドの合成
工程1で得られた化合物(50mg)のエチレングリコールジメチルエーテル(1.0mL)溶液に、室温にてテトラキストリフェニルホスフィンパラジウム(13.1mg)、フェニルボロン酸(18.0mg)、2M炭酸ナトリウム水溶液(0.2mL)を順次加え、マイクロ波照射下、180℃で20分間攪拌した。反応液を酢酸エチルにて希釈した後、飽和炭酸水素ナトリウム水溶液にて洗浄した。有機層を硫酸ナトリウムにて乾燥後、ろ過、減圧下濃縮した。残渣を逆相HPLC(0.1%TFAアセトニトリル:H2O=10%-90%、グラジェント)で精製した後、さらに分取用薄層クロマトグラフィー(NHシリカゲル、メタノール/クロロホルム=10%)にて精製し、表題化合物(14.0mg,28%)を白色固体として得た。
1H-NMR(CDCl3)δ:1.75-1.82(4H,m),3.25-3.32(4H,m),4.00(3H,s),7.38-7.44(2H,m),7.46-7.52(2H,m),7.56-7.61(2H,m),7.69(1H,t,J=7.8Hz),8.02(1H,dt,J=8.0,1.5Hz),8.20(1H,dt,J=7.8,1.5Hz),8.33(1H,t,J=1.5Hz),8.35(1H,d,J=2.0Hz)
N-(3-メトキシ-5-フェノキシピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
実施例109(工程1)で得られた化合物(50.0mg)のN-メチルピロリジノン(1.0mL)溶液に、フェノール(21.4mg)、炭酸セシウム(74.0mg)、塩化銅(I)(11.2mg)および2,2,6,6-テトラメチルヘプタン-3,5-ジオン(2.1mg)を加え、マイクロ波照射下、180℃で20分間攪拌した。反応液を酢酸エチルにて希釈した後、水にて洗浄した。有機層を硫酸ナトリウムにて乾燥後、ろ過、減圧下濃縮した。残渣を逆相HPLC(0.1%TFAアセトニトリル:H2O=10%-90%、グラジェント)で精製した後、さらに分取用薄層クロマトグラフィー(NHシリカゲル、メタノール/クロロホルム=10%)にて精製し、表題化合物(4.0mg,8%)を無色油状物質として得た。
1H-NMR(CDCl3)δ:1.70-1.83(4H,m),3.27-3.33(4H,m),3.88(3H,s),7.00-7.06(3H,m),7.16-7.19(1H,m),7.37-7.41(2H,m),7.69(1H,t,J=7.4Hz),7.87(1H,s),8.02(1H,d,J=7.4Hz),8.17(1H,d,J=7.4Hz),8.30(1H,s),8.45(1H,brs)
N-[3-メトキシ-5-(フェニルチオ)ピリジン-2-イル]-3-(ピロリジン-1-イルスルホニル)ベンズアミド
実施例109(工程1)で得られた化合物およびベンゼンチオールを原料として用い、参考例8(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.70-1.83(4H,m),3.20-3.33(4H,m),3.87(3H,s),7.18-7.37(6H,m),7.69(1H,t,J=7.8Hz),8.02(1H,d,J=7.8Hz),8.10(1H,d,J=2.0Hz),8.17(1H,d,J=7.8Hz),8.29(1H,s),8.55(1H,brs)
N-[3-メトキシ-5-(フェニルスルホニル)ピリジン-2-イル]-3-(ピロリジン-1-イルスルホニル)ベンズアミド
実施例111で得られた化合物(51.0mg)のクロロホルム(1.0mL)溶液に、m-クロロ過安息香酸(28.0mg)を加え、室温にて一終夜攪拌した。反応溶媒を減圧濃縮した後、残渣を分取用薄層クロマトグラフィー(NHシリカゲル、酢酸エチル100%)にて精製し、表題化合物(14.0mg,28%)を白色固体として得た。
1H-NMR(CDCl3)δ:1.74-1.84(4H,m),3.21-3.32(4H,m),4.02(3H,s),7.51-8.00(7H,m),8.02-8.07(1H,m),8.14(1H,d,J=7.8Hz),8.26(1H,d,J=1.5Hz),8.62(1H,d,J=2.0Hz),8.67(1H,s)
N-(3-エトキシピリジン-2-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
3-(ピロリジン-1-イルスルホニル)安息香酸および3-エトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.49(3H,t,J=7.0Hz),1.75-1.83(4H,m),3.25-3.31(4H,m),4.17(2H,q,J=7.0Hz),7.10(1H,dd,J=7.8,4.9Hz),7.22(1H,dd,J=8.3,1.5Hz),7.69(1H,t,J=7.8Hz),8.02(1H,dt,J=7.8,1.5Hz),8.10(1H,dd,J=4.9,1.5Hz),8.18(1H,dt,J=7.8,1.5Hz),8.30(1H,t,J=1.5Hz)
N-(4-シアノ-1H-イミダゾール-5-イル)-3-(ピペリジン-1-イルスルホニル)ベンズアミド
3-(ピぺリジン-1-イルスルホニル)安息香酸および5-アミノ-1H-イミダゾール-4-カルボニトリルを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.38-1.47(2H,m),1.59-1.68(4H,m),3.03(4H,t,J=5.4Hz),7.61(1H,s),7.70(1H,t,J=7.8Hz),7.95(1H,d,J=7.8Hz),8.23(1H,d,J=7.8Hz),8.37(1H,s),10.42(1H,s)
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-3-(ピロリジン-1-イルスルホニル)ベンズアミド
3-(ピロリジン-1-イルスルホニル)安息香酸および5-シクロプロピル-1H-ピラゾール-3-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.72-0.80(2H,m),0.94-1.03(2H,m),1.74-1.84(4H,m),1.85-1.95(1H,m),3.20-3.34(4H,m),6.41(1H,s),7.64(1H,t,J=7.8Hz),7.97(1H,d,J=7.8Hz),8.12(1H,d,J=7.8Hz),8.30(1H,s),11.36(1H,s)
N-(3-イソプロポキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
(工程1)N-(5-イソプロポキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミドの合成
参考例8で得られた化合物(2.43g)のクロロホルム(50mL)溶液に二塩化オキサリル(0.88mL)およびDMF(0.20mL)を順次加え、室温にて2時間攪拌した。反応溶媒を減圧留去した後、残渣をクロロホルム(50mL)に溶解した。トリエチルアミン(4.68mL)及び参考例9で得られた5-イソプロポキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミン(2.28g)を順次加え室温にて10分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、クロロホルムにて抽出し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-60%、グラジェント)で精製し、目的化合物(3.38g、78%)を淡黄色油状物質として得た。
(工程2)N-(3-イソプロポキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミドの合成
工程1で得られた化合物(3.38g)をトリフルオロ酢酸(27mL)-蒸留水(3.0mL)の混合溶媒に溶解し、室温にて4時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)で精製した後、得られた化合物を再結晶(ヘプタン/エタノール)にて精製し、表題化合物(1.42g、56%)を白色結晶として得た。
1H-NMR(CDCl3)δ:1.36(6H,d,J=6.3Hz),4.54-4.66(1H,m),5.94(1H,s),7.48-7.52(1H,m),7.67(1H,t,J=7.8Hz),7.97(1H,td,J=7.8,1.5Hz),8.18-8.27(3H,m),8.56-8.60(1H,m),8.66-8.69(1H,m),9.91(1H,s)
N-(3-エトキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
エタノールおよび3-アミノ-5-ヒドロキシピラゾールアミンを原料として用い参考例9(工程1)に準じた方法により得られた5-エトキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミンおよび参考例8で得られた化合物を原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.40(3H,t,J=7.2Hz),4.19(2H,q,J=7.2Hz),5.87(1H,s),7.48-7.54(1H,m),7.69(1H,t,J=7.8Hz),7.98(1H,td,J=7.8,1.6Hz),8.18-8.28(3H,m),8.53-8.57(1H,m),8.65-8.70(1H,m),9.54(1H,s)
N-(3-プロポキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
1-プロパノールおよび3-アミノ-5-ヒドロキシピラゾールアミンを原料として用い参考例9(工程1)に準じた方法により得られた5-プロポキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミンおよび参考例8で得られた化合物を原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.99(3H,t,J=7.6Hz),1.72-1.82(2H,m),4.06(2H,t,J=6.6Hz),5.93(1H,s),7.46-7.54(1H,m),7.66(1H,t,J=7.8Hz),7.97(1H,td,J=7.8,2.0Hz),8.16-8.27(3H,m),8.58(1H,s),8.64-8.70(1H,m),10.10(1H,s).
N-(3-ブトキシ-1H-ピラゾール-5-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
1-ブタノールおよび3-アミノ-5-ヒドロキシピラゾールアミンを原料として用い参考例9(工程1)に準じた方法により得られた5-ブトキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミンおよび参考例8で得られた化合物を原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:0.91(3H,t,J=7.3Hz),1.32-1.47(2H,m),1.59-1.71(2H,m),4.04(2H,t,J=6.6Hz),5.50-6.11(1H,m),7.70(1H,ddd,J=7.7,4.8,1.1Hz),7.80(1H,brs),8.12-8.20(2H,m),8.24-8.31(2H,m),8.51(1H,s),8.69-8.72(1H,m)
N-(3-メトキシピリジン-2-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例8で得られた化合物および3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:3.93(3H,s),7.12(1H,dd,J=8.3,4.9Hz),7.23(1H,dd,J=8.3,1.5Hz),7.47-7.51(1H,m),7.69(1H,t,J=7.8Hz),7.96(1H,td,J=7.8,2.0Hz),8.10(1H,d,J=4.4Hz),8.19-8.28(3H,m),8.49-8.58(2H,m),8.66-8.70(1H,m)
N-(4-イソプロピルフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例8で得られた化合物および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.24(6H,d,J=6.8Hz),2.83-2.95(1H,m),7.21(2H,d,J=8.8Hz),7.45-7.49(1H,m),7.56(2H,d,J=8.8Hz),7.63(1H,t,J=7.8Hz),7.93(1H,td,J=7.8,1.8Hz),8.15-8.21(3H,m),8.32(1H,s),8.49-8.53(1H,m),8.62-8.67(1H,m)
N-(5-イソプロポキシピリジン-2-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例8で得られた化合物および5-イソプロポキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.36(6H,d,J=5.9Hz),4.48-4.61(1H,m),7.30(1H,dd,J=9.3,2.9Hz),7.46-7.52(1H,m),7.70(1H,t,J=7.8Hz),7.93-8.00(2H,m),8.21(1H,d,J=7.8Hz),8.23-8.31(3H,m),8.53-8.56(1H,m),8.60(1H,s),8.66-8.70(1H,m)
N-[2-フルオロ-4-(2-メトキシ-1-メチルエトキシ)フェニル]-3-(ピリジン-2-イルスルホニル)ベンズアミド
1-メトキシプロパン-2-オール(29.0mg)の酢酸エチル(1mL)溶液に室温にて、トリエチルアミン(0.045mL)、塩化メタンスルホニル(0.025mL)を順次加えた。室温にて15分間撹拌した後、析出した固体をろ取した。ろ液を濃縮した後、得られた残渣をDMF(1.0mL)に溶解し、参考例11で得られた化合物(80.0mg)および炭酸カリウム(89.0mg)を順次加えた。反応液を60℃にて一終夜撹拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥し、乾燥剤をろ別後、溶媒を減圧留去した。残渣を分取用薄層クロマトグラフィー(NHシリカゲル、酢酸エチル/ヘキサン=20%)にて精製し、表題化合物(37.0mg,39%)を淡赤色油状物質として得た。
1H-NMR(CDCl3)δ:1.31(3H,d,J=6.3Hz),3.41(3H,s),3.49(1H,dd,J=10.2,4.4Hz),3.58(1H,dd,J=10.2,6.3Hz),4.46-4.55(1H,m),6.72-6.79(2H,m),7.46-7.52(1H,m),7.68(1H,t,J=7.8Hz),7.92-8.01(2H,m),8.07(1H,t,J=8.8Hz),8.16(1H,d,J=7.8Hz),8.21-8.28(2H,m),8.49-8.54(1H,m),8.65-8.70(1H,m)
N-{2-フルオロ-4-[2-フルオロ-1-(フルオロメチル)エトキシ]フェニル}-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例11で得られた化合物および1,3-ジフルオロプロパン-2-オールを原料として用い、実施例123に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:4.57-4.78(5H,m),6.79-6.87(2H,m),7.47-7.53(1H,m),7.69(1H,t,J=7.8Hz),7.96(1H,td,J=7.8,2.0Hz),8.03(1H,s),8.12-8.20(2H,m),8.22-8.29(2H,m),8.51-8.55(1H,m),8.65-8.70(1H,m)
N-[4-(シクロペンチルオキシ)-2-フルオロフェニル]-3-(ピリジン-2-イルスルホニル)ベンズアミド
実施例11で得られた化合物(50.0mg)のDMF(1.0mL)溶液に、室温にて臭化シクロペンタン(40.0mg)、炭酸カリウム(55.7mg)を順次加え、60℃にて5時間撹拌した。反応液を酢酸エチルにて希釈した後、飽和重曹水にて洗浄した。有機層を硫酸ナトリウムにて乾燥後、有機層を、硫酸ナトリウムで乾燥し、乾燥剤をろ別後、溶媒を減圧留去した。残渣を分取用薄層クロマトグラフィー(メタノール/クロロホルム=1%)にて精製し、表題化合物(37.5mg,63%)を淡赤色油状物質として得た。
1H-NMR(CDCl3)δ:1.58-1.69(2H,m),1.74-1.96(6H,m),4.68-4.77(1H,m),6.65-6.72(2H,m),7.47-7.52(1H,m),7.68(1H,t,J=7.8Hz),7.92-7.99(2H,m),8.06(1H,t,J=8.8Hz),8.16(1H,d,J=7.8Hz),8.22-8.28(2H,m),8.51(1H,s),8.68(1H,d,J=4.9Hz)
N-(2-フルオロ-4-イソプロポキシフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例11で得られた化合物および2-ブロモプロパンを原料として用い、実施例125に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),4.45-4.57(1H,m),6.68-6.74(2H,m),7.47-7.52(1H,m),7.70(1H,t,J=7.8Hz),7.91(1H,s),7.96(1H,td,J=7.8,2.0Hz),8.10(1H,t,J=9.0Hz),8.16(1H,d,J=7.8Hz),8.23-8.29(2H,m),8.51(1H,s),8.66-8.70(1H,m)
N-(2-フルオロ-4-イソブトキシフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例11で得られた化合物および1-ブロモ-2-メチルプロパンを原料として用い、実施例125に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.03(6H,d,J=6.8Hz),2.04-2.15(1H,m),3.71(2H,d,J=6.8Hz),6.68-6.75(2H,m),7.46-7.52(1H,m),7.68(1H,t,J=7.8Hz),7.92-8.01(2H,m),8.07(1H,t,J=8.8Hz),8.16(1H,d,J=7.8Hz),8.21-8.27(2H,m),8.52(1H,s),8.65-8.70(1H,m)
N-(4-sec-ブトキシ-2-フルオロフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例11で得られた化合物および2-塩化ブタンを原料として用い、実施例125に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.98(3H,t,J=7.3Hz),1.30(3H,d,J=6.3Hz),1.58-1.81(2H,m),4.21-4.31(1H,m),6.67-6.75(2H,m),7.46-7.54(1H,m),7.69(1H,t,J=7.8Hz),7.90(1H,s),7.96(1H,td,J=7.8,1.5Hz),8.09(1H,t,J=9.3Hz),8.16(1H,d,J=7.8Hz),8.23-8.29(2H,m),8.49-8.53(1H,m),8.66-8.70(1H,m)
N-(6-ブロモ-5-イソプロポキシピリジン-2-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例13で得られた化合物および2-ヨードプロパンを原料として用い、実施例125に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.41(6H,d,J=5.9Hz),4.50-4.60(1H,m),7.29(1H,d,J=8.8Hz),7.47-7.52(1H,m),7.71(1H,t,J=7.8Hz),7.97(1H,td,J=7.8,1.5Hz),8.19(1H,d,J=7.8Hz),8.23-8.33(3H,m),8.51-8.55(1H,m),8.62(1H,s),8.68(1H,d,J=4.9Hz)
N-(4-イソプロポキシフェニル)-3-(ピリジン-3-イルスルホニル)ベンズアミド
参考例14で得られた化合物及び3-ヨードピリジンを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.1Hz),4.49-4.59(1H,m),6.91(2H,d,J=8.8Hz),7.45-7.56(3H,m),7.65-7.73(1H,m),7.81(1H,s),8.09-8.17(2H,m),8.24(1H,d,J=8.0Hz),8.40(1H,s),8.82(1H,dd,J=4.9,1.7Hz),9.17(1H,d,J=2.0Hz)
N-(4-イソプロポキシフェニル)-3-[(4-メチルピリジン-2-イル)スルホニル]ベンズアミド
参考例14で得られた化合物及び2-ブロモ-4-メチルピリジンを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.1Hz),2.49(3H,s),4.48-4.59(1H,m),6.90(2H,d,J=8.8Hz),7.27-7.31(1H,m),7.53(2H,d,J=8.8Hz),7.67(1H,t,J=7.8Hz),7.96-8.04(1H,m),8.05(1H,s),8.20(2H,d,J=7.8Hz),8.49(1H,s),8.51(1H,d,J=4.9Hz)
N-(4-イソプロポキシフェニル)-3-[(6-メチルピリジン-2-イル)スルホニル]ベンズアミド
参考例14で得られた化合物及び2-ブロモ-6-メチルピリジンを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.1Hz),2.57(3H,s),4.48-4.59(1H,m),6.86-6.95(2H,m),7.30-7.36(1H,m),7.54(2H,d,J=9.0Hz),7.67(1H,t,J=7.8Hz),7.81(1H,t,J=7.8Hz),7.98(1H,s),8.03(1H,d,J=7.8Hz),8.17-8.24(2H,m),8.49(1H,s)
N-(4-メトキシフェニル)-3-(フェニルスルホニル)ベンズアミド
3-(フェニルスルホニル)安息香酸および4-メトキシアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:3.83(3H,s),6.93(2H,d,J=8.8Hz),7.50-7.68(6H,m),7.78(1H,s),7.94-8.01(2H,m),8.07-8.14(2H,m),8.38(1H,s)
N-(2-メトキシフェニル)-3-(フェニルスルホニル)ベンズアミド
3-(フェニルスルホニル)安息香酸および2-メトキシアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:3.93(3H,s),6.93(1H,d,J=8.0Hz),7.00-7.03(1H,m),7.11(1H,dt,J=7.8,1.4Hz),7.51-7.55(2H,m),7.63(1H,d,J=7.8Hz),7.64(1H,d,J=7.8Hz),7.98(2H,d,J=7.2Hz),8.06-8.11(2H,m),8.43-8.52(3H,m)
N-(3-メトキシピリジン-2-イル)-3-(フェニルスルホニル)ベンズアミド
3-(フェニルスルホニル)安息香酸および3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:3.93(3H,s),7.12(1H,dd,J=8.3,4.9Hz),7.23(1H,dd,J=8.3,1.5Hz),7.50-7.68(4H,m),7.94-8.00(2H,m),8.07-8.17(3H,m),8.41(1H,s),8.44(1H,s)
N-(4-イソプロピルフェニル)-3-(フェニルスルホニル)ベンズアミド
3-(フェニルスルホニル)安息香酸および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25(6H,d,J=7.0Hz),2.86-2.97(1H,m),7.22(2H,d,J=8.4Hz),7.49-7.63(6H,m),7.95(2H,d,J=8.4Hz),8.06-8.11(3H,m),8.40(1H,s)
3-[(4-フルオロフェニル)スルホニル]-N-(4-イソプロピルフェニル)ベンズアミド
参考例15で得られた化合物および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25(6H,d,J=6.8Hz),2.84-2.97(1H,m),7.15-7.23(4H,m),7.55(2H,d,J=8.4Hz),7.62(1H,t,J=7.8Hz),7.94-7.98(2H,m),8.04(1H,d,J=7.8Hz),8.09-8.10(2H,m),8.39(1H,s)
N-(5-イソプロポキシピリジン-2-イル)-3-(ピリミジン-2-イルスルホニル)ベンズアミド
参考例16で得られた化合物および5-イソプロポキシピリジン-2-アミンを原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.36(6H,d,J=5.9Hz),4.50-4.60(1H,m),7.31(1H,dd,J=9.3,2.9Hz),7.50(1H,t,J=4.9Hz),7.74(1H,t,J=7.8Hz),7.98(1H,d,J=2.9Hz),8.24-8.29(2H,m),8.30-8.35(1H,m),8.59(1H,s),8.61-8.64(1H,m),8.92(2H,d,J=4.9Hz)
N-(4-イソプロポキシフェニル)-3-(ピリミジン-2-イルスルホニル)ベンズアミド
参考例16で得られた化合物および4-イソプロポキシアニリンを原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=5.9Hz),4.46-4.59(1H,m),6.86-6.93(2H,m),7.47-7.56(3H,m),7.72(1H,t,J=7.8Hz),7.98(1H,s),8.24-8.31(2H,m),8.53(1H,s),8.89(2H,t,J=5.4Hz)
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-3-(ピリミジン-2-イルスルホニル)ベンズアミド
参考例16で得られた化合物および5-シクロプロピル-1H-ピラゾール-3-アミンを原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.71-0.80(2H,m),0.92-1.01(2H,m),1.85-1.96(1H,m),6.38(1H,s),7.52(1H,t,J=4.9Hz),7.70(1H,t,J=7.8Hz),8.22(1H,d,J=7.8Hz),8.27(1H,d,J=7.8Hz),8.62(1H,s),8.91(2H,d,J=4.9Hz),11.12(1H,s).
N-(4-イソプロポキシフェニル)-3-(ピラジン-2-イルスルホニル)ベンズアミド
参考例17で得られた化合物および4-イソプロポキシアニリンを原料として用い、実施例116(工程1)に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=5.9Hz),4.48-4.59(1H,m),6.91(2H,d,J=8.8Hz),7.52(2H,d,J=8.8Hz),7.72(1H,t,J=7.8Hz),7.89(1H,s),8.21-8.26(2H,m),8.49(1H,s),8.63-8.66(1H,m),8.80(1H,d,J=2.4Hz),9.43(1H,d,J=1.5Hz)
N-(4-イソプロポキシフェニル)-3-(1H-1,2,4-トリアゾール-3-イルスルホニル)ベンズアミド
参考例18で得られた化合物および1H-1,2,4-トリアゾール-3-チオールを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.25(6H,d,J=6.1Hz),4.51-4.62(1H,m),6.91(2H,d,J=8.8Hz),7.62(2H,d,J=8.8Hz),7.82(1H,t,J=8.0Hz),8.12-8.18(1H,m),8.28-8.34(1H,m),8.49(1H,s),8.84(1H,s),10.43(1H,s)
N-(4-イソプロポキシフェニル)-3-(1H-ピラゾール-4-イルスルホニル)ベンズアミド
参考例14で得られた化合物及び4-ヨード-1H-ピラゾールを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(DMSO-d6)δ:1.25(6H,d,J=6.1Hz),4.50-4.64(1H,m),6.91(2H,d,J=9.0Hz),7.62(2H,d,J=9.0Hz),7.75(1H,t,J=7.8Hz),8.02(1H,s),8.09-8.13(1H,m),8.19(1H,dt,J=7.8,1.3Hz),8.43(1H,t,J=1.6Hz),8.58(1H,s),10.36(1H,s),13.82(1H,s)
3-(シクロヘキシルスルホニル)-N-(4-イソプロポキシフェニル)ベンズアミド
参考例19で得られた化合物および4-イソプロポキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.04-1.30(3H,m),1.34(6H,d,J=5.9Hz),1.36-1.48(2H,m),1.63-1.72(1H,m),1.80-1.92(2H,m),1.98-2.12(2H,m),2.87-3.02(1H,m),4.47-4.61(1H,m),6.91(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.70(1H,t,J=7.8Hz),7.94(1H,s),8.01(1H,d,J=7.8Hz),8.21(1H,d,J=7.8Hz),8.27(1H,s)
3-(シクロヘキシルスルホニル)-N-(2-メトキシフェニル)ベンズアミド
参考例19で得られた化合物および2-メトキシアニリンを原料として用い、実施例73に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.07-1.32(3H,m),1.37-1.51(2H,m),1.63-1.73(1H,m),1.83-1.93(2H,m),2.03-2.13(2H,m),2.96(1H,tt,J=12.2,3.4Hz),3.94(3H,s),6.95(1H,dd,J=8.0,1.5Hz),7.04(1H,td,J=7.8,1.5Hz),7.13(1H,td,J=7.8,1.8Hz),7.72(1H,t,J=7.8Hz),8.05(1H,dt,J=8.0,1.5Hz),8.19(1H,dt,J=7.8,1.5Hz),8.34(1H,t,J=1.5Hz),8.48(1H,dd,J=7.8,1.5Hz),8.54(1H,s)
3-(シクロヘキシルスルホニル)-N-(4-メトキシフェニル)ベンズアミド
3-ヨード-N-(4-メトキシフェニル)ベンズアミドおよびシクロヘキサンチオールを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.05-1.29(3H,m),1.33-1.49(2H,m),1.64-1.72(1H,m),1.81-1.91(2H,m),1.99-2.11(2H,m),2.90-3.00(1H,m),3.83(3H,s),6.93(2H,d,J=9.0Hz),7.57(2H,d,J=9.0Hz),7.70(1H,t,J=7.8Hz),8.01(1H,d,J=7.8Hz),8.01-8.07(1H,m),8.22(1H,d,J=8.0Hz),8.28(1H,s)
3-(シクロヘキシルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
(工程1)3-(シクロヘキシルスルホニル)-N-[3-(シクロヘキシルスルホニル)ベンゾイル]-N-(3-メトキシピリジン-2-イル)ベンズアミドの合成
参考例19で得られた化合物(100mg)をクロロホルム(2.0mL)に溶解し、2-アミノ-3-メトキシピリジン(46mg)、トリエチルアミン(0.156mL)、25%2-クロロ-1,3-ジメチルイミダゾリニウムクロリドジクロロメタン溶液(0.200mL)を順次加え、室温にて30分間攪拌した。反応液を濃縮後、逆相HPLC(0.1%TFAアセトニトリル:H2O)=10%-95%、グラジェント)で精製し、目的化合物(44mg、19%)を白色結晶として得た。
(工程2)3-(シクロヘキシルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
工程1で得られた化合物(25mg)をメタノール(2.0mL)に溶解し、2M水酸化ナトリウム水溶液(0.20mL)を加えた後、室温にて4時間攪拌した。酢酸エチルを加え、水、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去し、表題化合物(15mg、100%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.06-1.34(3H,m),1.36-1.50(2H,m),1.61-1.74(1H,m),1.82-1.92(2H,m),2.01-2.11(2H,m),2.89-3.00(1H,m),3.94(3H,s),7.13(1H,dd,J=8.0,4.9Hz),7.24(1H,dd,J=8.2,1.3Hz),7.72(1H,t,J=7.8Hz),8.05(1H,dt,J=7.8,1.5Hz),8.12(1H,d,J=4.9Hz),8.25(1H,d,J=7.8Hz),8.32(1H,s),8.48(1H,s)
3-(ブチルスルホニル)-N-(3-メトキシピリジン-2-イル)ベンズアミド
参考例20で得られた化合物およびブタン-1-チオールを原料として用い、参考例8(工程1)および実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:0.94(3H,t,J=7.3Hz),1.41-1.52(2H,m),1.62-1.71(2H,m),2.98(2H,t,J=7.4Hz),3.93(3H,s),7.08(1H,dd,J=8.3,4.9Hz),7.20(1H,dd,J=8.0,1.5Hz),7.39(1H,t,J=7.6Hz),7.45-7.50(1H,m),7.66(1H,dt,J=7.6,1.3Hz),7.85(1H,t,J=1.7Hz),8.13(1H,dd,J=4.9,1.5Hz),8.45(1H,s)
2-メトキシ-N-(4-メトキシフェニル)-5-(ピペリジン-1-イルスルホニル)ベンズアミド
2-メトキシ-5-(ピペリジン-1-イルスルホニル)安息香酸および4-メトキシアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.46(2H,m),1.57-1.68(4H,m),2.96-3.06(4H,m),3.82(3H,s),4.14(3H,s),6.91(2H,d,J=8.9Hz),7.14(1H,d,J=8.8Hz),7.57(2H,d,J=8.9Hz),7.87-7.89(1H,m),8.62-8.63(1H,m),9.45(1H,s)
N-(4-イソプロピルフェニル)-2-メトキシ-5-(ピペリジン-1-イルスルホニル)ベンズアミド
2-メトキシ-5-(ピペリジン-1-イルスルホニル)安息香酸および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25(6H,d,J=6.8Hz),1.39-1.46(2H,m),1.62-1.72(4H,m),2.89-2.98(1H,m),3.00-3.07(4H,m),4.13(3H,s),7.14(1H,d,J=8.8Hz),7.23(2H,d,J=8.5Hz),7.58(2H,d,J=8.5Hz),7.88(1H,dd,J=8.8,2.4Hz),8.63(1H,d,J=2.4Hz),9.49(1H,s)
2-ヒドロキシ-N-(4-イソプロポキシフェニル)-5-(ピペリジン-1-イルスルホニル)ベンズアミド
2-ヒドロキシ-5-(ピペリジン-1-イルスルホニル)安息香酸(470mg)にクロロベンゼン(2.0mL)を加え攪拌しているところに、三塩化りん(0.072mL)を加え、130℃にて1時間攪拌した。4-イソプロピルアニリン(249mg)を加え、130℃にて16時間攪拌した。溶媒を減圧留去した後、酢酸エチルを加え、水、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、目的物(515mg、75%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.35(6H,d,J=6.1Hz),1.38-1.47(2H,m),1.53-1.65(4H,m),2.98(4H,t,J=5.4Hz),4.50-4.61(1H,m),6.93(2H,d,J=8.8Hz),7.13(1H,d,J=8.8Hz),7.51(2H,d,J=8.8Hz),7.76(1H,dd,J=8.8,2.0Hz),8.11(1H,d,J=2.2Hz),8.49(1H,s),12.91(1H,s)
2-エトキシ-N-(4-イソプロポキシフェニル)-5-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例151で得られた化合物(30mg)をDMF(0.50mL)に溶解し、炭酸カリウム(30mg)、ヨードエタン(0.030mL)を順次加え、室温にて18時間攪拌した。逆相HPLC(0.1%TFAアセトニトリル:H2O)=10%-95%、グラジェント)で精製し、表題化合物(25mg、78%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.1Hz),1.37-1.45(2H,m),1.60-1.73(7H,m),3.01(4H,t,J=5.5Hz),4.36(2H,q,J=7.0Hz),4.48-4.60(1H,m),6.90(2H,d,J=9.0Hz),7.11(1H,d,J=8.5Hz),7.56(2H,d,J=9.0Hz),7.87(1H,dd,J=8.5,2.4Hz),8.66(1H,d,J=2.4Hz),9.76(1H,s)
2-(シアノメトキシ)-N-(4-イソプロポキシフェニル)-5-(ピペリジン-1-イルスルホニル)ベンズアミド
実施例151で得られた化合物およびブロモアセトニトリルを原料として用い、実施例152に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.1Hz),1.38-1.48(2H,m),1.60-1.71(4H,m),3.00(4H,t,J=5.5Hz),4.48-4.60(1H,m),5.06(2H,s),6.90(2H,d,J=9.0Hz),7.13(1H,d,J=8.8Hz),7.55(2H,d,J=9.0Hz),7.81(1H,dd,J=8.8,2.4Hz),8.39(1H,d,J=2.2Hz),8.74(1H,s)
[2-{[(4-イソプロポキシフェニル)アミノ]カルボニル}-4-(ピペリジン-1-イルスルホニル)フェノキシ]酢酸
実施例151で得られた化合物(100mg)をDMF(2.0mL)に溶解し、炭酸カリウム(50mg)、tert-ブチルブロモアセテート(0.047mL)を順次加え、室温にて21時間攪拌した。反応液に酢酸エチルを加え、水、飽和食塩水にて順次洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、無色油状化合物(125mg)を得た。得られた化合物(100mg)にトリフルオロ酢酸(2.0mL)を加え、室温にて3時間攪拌した。溶媒を減圧留去することにより、表題化合物(100mg、100%)を無色固体として得た。
1H-NMR(DMSO-d6)δ:1.25(6H,d,J=5.9Hz),1.30-1.39(2H,m),1.49-1.60(4H,m),2.88(4H,t,J=5.2Hz),4.51-4.64(1H,m),5.03(2H,s),6.91(2H,d,J=9.0Hz),7.40(1H,d,J=8.8Hz),7.72(2H,d,J=9.0Hz),7.85(1H,dd,J=8.8,2.4Hz),8.16-8.20(1H,m),10.44(1H,s)
N-(4-イソプロピルフェニル)-4-メトキシ-3-(ピペリジン-1-イルスルホニル)ベンズアミド
4-メトキシ-3-(ピペリジン-1-イルスルホニル)安息香酸および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25(6H,d,J=6.8Hz),1.46-1.71(6H,m),2.86-2.95(1H,m),3.17-3.25(4H,m),3.95(3H,s),7.05(1H,d,J=8.8Hz),7.23(2H,d,J=8.8Hz),7.58(2H,d,J=8.8Hz),8.10(1H,s),8.14(1H,dd,J=8.8,2.4Hz),8.31(1H,d,J=2.4Hz)
2-メトキシ-N-(3-メトキシピリジン-2-イル)-5-(ピペリジン-1-イルスルホニル)ベンズアミド
2-メトキシ-5-(ピペリジン-1-イルスルホニル)安息香酸および3-メトキシピリジン-2-アミンを原料として用い、実施例92に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.37-1.46(2H,m),1.58-1.69(4H,m),2.98-3.03(4H,m),3.97(3H,s),4.14(3H,s),7.09(1H,dd,J=7.8,4.9Hz),7.15(1H,d,J=8.8Hz),7.22(1H,d,J=7.8Hz),7.89(1H,dd,J=8.8,2.4Hz),8.16(1H,d,J=4.9Hz),8.68(1H,d,J=2.4Hz)
N-(4-イソプロピルフェニル)-6-(フェニルスルホニル)ピリジン-2-カルボキサミド
(工程1)6-クロロ-N-(4-イソプロピルフェニル)ピリジン-2-カルボキサミドの合成
6-クロロピリジン-2-カルボン酸および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により目的化合物を得た。
(工程2)N-(4-イソプロピルフェニル)-6-(フェニルチオ)ピリジン-2-カルボキサミドの合成
工程1で得られた化合物(500mg)のNMP(4.0mL)溶液に、ベンゼンチオール(221mg)および炭酸セシウム(889mg)を順次加え、200℃にて1時間攪拌した。放冷後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液にて3回洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、目的物(639mg、100%)を白色固体として得た。
(工程3)N-(4-イソプロピルフェニル)-6-(フェニルスルホニル)ピリジン-2-カルボキサミドの合成
工程2で得られた化合物(100mg)のクロロホルム(3.0mL)溶液に、m-クロロ過安息香酸(99.0mg)を加え、室温にて3時間攪拌した。反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液にて3回洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(NHバイオタージカラム、酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、表題化合物(47.0mg、86%)を白色固体として得た。
1H-NMR(CDCl3)δ:1.26(6H,d,J=6.8Hz),2.87-2.98(1H,m),7.23-7.28(2H,m),7.55-7.59(2H,m),7.59-7.65(2H,m),7.67-7.73(1H,m),8.10-8.13(2H,m),8.17(1H,t,J=7.8Hz),8.35(1H,dd,J=7.8,1.5Hz),8.43(1H,dd,J=7.8,1.0Hz),9.40(1H,s)
N-(4-イソプロピルフェニル)-5-(フェニルスルホニル)ニコチンアミド
(工程1)5-ブロモ-N-(4-イロプロピルフェニル)ニコチンアミドの合成
5-ブロモニコチン酸および4-イソプロピルアニリンを原料として用い、実施例92に準じた方法により目的化合物を得た。
(工程2)N-(4-イソプロピルフェニル)-5-(フェニルチオ)ニコチンアミドの合成
工程1で得られた化合物およびベンゼンチオールを原料として用い、参考例8(工程1)に準じた方法により目的化合物を得た。
(工程3)N-(4-イソプロピルフェニル)-5-(フェニルスルホニル)ニコチンアミドの合成
工程2で得られた化合物を原料として用い、実施例112に準じた方法により表題化合物を得た。
1H-NMR(CDCl3)δ:1.25(6H,d,J=6.5Hz),2.85-3.00(1H,m),7.20-7.30(3H,m),7.50-7.68(3H,m),7.97(2H,d,J=7.0Hz),8.19(1H,s),8.66(1H,s),9.22(1H,s),9.26(1H,s)
4-イソプロポキシ-N-[3-(ピペリジン-1-イルスルホニル)ベンジル]ベンズアミド
参考例22で得られた化合物(200mg)をDMF(2.0mL)に溶解し、アジ化ナトリウム(200mg)を加え、室温にて22時間攪拌した。酢酸エチルを加えた後、水、飽和食塩水にて順次洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、無色油状化合物(205mg)を得た。得られた無色油状化合物(200mg)を、メタノール(4.0mL)に溶解し、10%パラジウム炭素(60mg)を加えた後、水素雰囲気下、室温にて23時間攪拌した。反応液をセライトろ過し、溶媒を減圧留去することにより無色油状化合物(181mg)を得た。得られた無色油状化合物(181mg)および4-イソプロポキシ安息香酸(128mg)を用い、実施例92に準じた方法により目的化合物(172mg、57%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.36(6H,d,J=6.3Hz),1.37-1.46(2H,m),1.55-1.68(4H,m),2.97(4H,t,J=5.4Hz),4.57-4.67(1H,m),4.71(2H,d,J=6.3Hz),6.52(1H,brs),6.90(2H,d,J=8.8Hz),7.46-7.53(1H,m),7.59(1H,d,J=8.3Hz),7.63-7.71(2H,m),7.75(2H,d,J=8.8Hz)
N-(4-イソプロポキシフェニル)-2-[3-(ピペリジン-1-イルスルホニル)フェニル]アセトアミド
参考例23で得られた化合物(100mg)に30%硫酸水溶液(3.0mL)を加え、80℃にて4日間攪拌した。0℃にて、5M水酸化ナトリウム水溶液を用いpH=10にした後、5M塩酸を用いpH=3にし、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去することにより無色油状化合物(101mg)を得た。得られた無色油状化合物(100mg)及び4-イソプロポキシアニリン(53mg)を用い、実施例92に準じた方法により目的化合物(124mg、79%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.30(6H,d,J=6.3Hz),1.34-1.48(2H,m),1.59-1.69(4H,m),3.00(4H,t,J=5.4Hz),3.76(2H,s),4.43-4.54(1H,m),6.82(2H,d,J=8.8Hz),7.07-7.21(1H,m),7.33(2H,d,J=8.8Hz),7.50-7.57(1H,m),7.61(1H,d,J=7.8Hz),7.69(1H,d,J=7.8Hz),7.72(1H,s)
4-イソプロポキシ-N-{2-[3-(ピペリジン-1-イルスルホニル)フェニル]エチル}ベンズアミド
参考例23で得られた化合物(100mg)をメタノール(2.0mL)に溶解し、塩酸-メタノール溶液(0.50mL)及び10%パラジウム炭素(50mg)を加えた後、水素雰囲気下、室温にて22時間攪拌した。反応液をセライトろ過し、溶媒を減圧留去することにより黄色油状化合物(120mg)を得た。得られた黄色油状化合物(120mg)及び4-イソプロポキシ安息香酸(68mg)を用い、実施例92に準じた方法により表題化合物(111mg、68%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.34(6H,d,J=6.3Hz),1.35-1.44(2H,m),1.55-1.69(4H,m),2.94(4H,t,J=5.6Hz),3.02(2H,t,J=7.1Hz),3.68-3.78(2H,m),4.54-4.67(1H,m),6.10(1H,brs),6.88(2H,d,J=8.8Hz),7.45-7.50(2H,m),7.58-7.69(4H,m)
N-(4-イソプロポキシフェニル)-3-[3-(ピペリジン-1-イルスルホニル)フェニル]プロパンアミド
(工程1)3-(ピペリジン-1-イルスルホニル)ベンズアルデヒドの合成
参考例21で得られた化合物(1.00g)をアセトン(10mL)に溶解し、二酸化マンガン(500mg)を加え、55℃にて5日間攪拌した。放冷後、反応液をセライトろ過し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、目的化合物(572mg、58%)を無色固体として得た。
(工程2)エチル(2E)-3-[3-(ピペリジン-1-イルスルホニル)フェニル]アクリレートの合成
トリエチルホスホノアセテート(398mg)をTHF(3.0mL)に溶解し、0℃にて水素化ナトリウム(62mg)を加え、0℃にて10分間攪拌した。工程1で得られた化合物(300mg)をTHF(3.0mL)に溶解したものを加え、室温にて90分間攪拌した。水を加えた後、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、目的化合物(380mg、99%)を無色固体として得た。
(工程3)(2E)-3-[3-(ピペリジン-1-イルスルホニル)フェニル]アクリル酸の合成
工程2で得られた化合物(380mg)をメタノール(6.0mL)に溶解し、2M水酸化ナトリウム水溶液(1.10mL)を加えた後、室温にて1日間攪拌した。0℃にて、2M塩酸を用いpH=3にし、水を加えた後、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去し、目的化合物(339mg、98%)を無色固体として得た。
(工程4)(2E)-N-(4-イソプロポキシフェニル)-3-[3-(ピペリジン-1-イルスルホニル)フェニル]アクリルアミドの合成
工程3で得られた化合物(150mg)及び4-イソプロポキシアニリン(77mg)を実施例92に準じた方法により目的化合物(193mg、89%)を無色固体として得た。
(工程5)N-(4-イソプロポキシフェニル)-3-[3-(ピペリジン-1-イルスルホニル)フェニル]プロパンアミドの合成
工程4で得られた化合物(64mg)をメタノール(2.0mL)に溶解し、10%パラジウム炭素(30mg)を加えた後、水素雰囲気下、室温にて21時間攪拌した。反応液をセライトろ過し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、表題化合物(55mg、86%)を無色固体として得た。
1H-NMR(CDCl3)δ:1.31(6H,d,J=6.1Hz),1.32-1.40(2H,m),1.53-1.62(4H,m),2.66(2H,t,J=7.4Hz),2.93(4H,t,J=5.5Hz),3.13(2H,t,J=7.4Hz),4.42-4.55(1H,m),6.82(2H,d,J=9.0Hz),7.17(1H,s),7.34(2H,d,J=9.0Hz),7.41-7.51(2H,m),7.59(1H,dt,J=7.4,1.6Hz),7.62(1H,s)
3-{[(4-イソプロポキシフェニル)アミノ]カルボニル}ベンゼンスルホニルクロリド
4-イソプロポキシアニリン(3.17g)のトルエン(50mL)溶液に、3-(クロロスルホニル)ベンゾイルクロリド(5.00g)を加え、室温にて一終夜攪拌した。反応中の固体をろ別後、ろ液を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製した後、得られた化合物にジイソプロピルエーテルを加え懸濁させた後、固体をろ取し、表題化合物(2.27g、35%)を淡青色固体として得た。
3-{[(4-イソプロピルフェニル)アミノ]カルボニル}ベンゼンスルホニルクロリド
4-イソプロピルアニリン、3-(クロロスルホニル)ベンゾイルクロリドを原料として用い、参考例1に準じた方法により表題化合物を得た。
3-{[(2-メトキシフェニル)アミノ]カルボニル}ベンゼンスルホニルクロリド
2-メトキシアニリン、3-(クロロスルホニル)ベンゾイルクロリドを原料として用い、参考例1に準じた方法により表題化合物を得た。
3-{[(4-メトキシフェニル)アミノ]カルボニル}ベンゼンスルホニルクロリド
4-メトキシアニリン、3-(クロロスルホニル)ベンゾイルクロリドを原料として用い、参考例1に準じた方法により表題化合物を得た。
3,3’-{[(3-メトキシピリジン-2-イル)イミノ]ジカルボニル}ジベンゼンスルホニルクロリド
3-(クロロスルホニル)ベンゾイルクロリド(3.00g)のトルエン(50mL)溶液に、3-メトキシピリジン-2-アミン(780mg)を加え、室温にて一終夜攪拌した。反応液に酢酸エチルを加え、水にて2回、飽和食塩水にて1回洗浄し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、表題化合物(608mg、18%)を白色固体として得た。
3,3’-{[(5-イソプロポキシピリジン-2-イル)イミノ]ジカルボニル}ジベンゼンスルホニルクロリド
2-アミノ-5-イソプロポキシピリジン及び3-(クロロスルホニル)ベンゾイルクロリドを用い、参考例5に準じた方法により表題化合物を得た。
tert-ブチル5-{[3-(クロロスルホニル)ベンゾイル]アミノ}-3-イソプロポキシ-1H-ピラゾール-1-カルボキシレート
(工程1)
tert-ブチル5-アミノ-3-イソプロポキシ-1H-ピラゾール-1-カルボキシレートの合成
参考例9(工程1)で得られた化合物(5.35g)をジクロロメタン(100mL)に溶解し、5M水酸化ナトリウム水溶液(30mL)、ジ-tert-ブチルジカーボネート(8.68g)を加え、室温にて3日間攪拌した。反応液を酢酸エチルにて抽出し、有機層を水、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、目的化合物(6.28g、69%)を淡黄色固体として得た。
(工程2)tert-ブチル5-{[3-(クロロスルホニル)ベンゾイル]アミノ}-3-イソプロポキシ-1H-ピラゾール-1-カルボキシレートの合成
工程1で得られた化合物およびm-クロロスルホニルベンゾイルクロライドを用い、参考例1に準じた方法により表題化合物を得た。
3-(ピリジン-2-イルスルホニル)安息香酸
(工程1)3-(ピリジン-2-イルチオ)安息香酸の合成
2-ヨードピリジン(7.31g)、3-メルカプト安息香酸(5.0g)、N,N-ジイソプロピルエチルアミン(11.30mL)のジオキサン(150mL)溶液にXantphos(3.75g)及びPd2(dba)3(2.97g)を順次加え、窒素雰囲気下、100℃にて一終夜攪拌した。放冷後、反応溶液を減圧留去した後、残渣に酢酸エチルを加え、飽和塩化アンモニウム水溶液にて3回洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)で精製し、目的物(4.95g、66%)を褐色固体として得た。
(工程2)3-(ピリジン-2-イルチオ)安息香酸メチルエステルの合成
工程1で得られた化合物(4.95g)のメタノール(100mL)溶液に塩化チオニル(2.34mL)を滴下し、60℃にて3時間攪拌した。放冷後、反応溶液を減圧留去した後、残渣に酢酸エチルを加えた。水にて2回洗浄後、飽和食塩水にて洗浄し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-80%、グラジェント)で精製し、目的物(3.64g、69%)を無色油状物質として得た。
(工程3)3-(ピリジン-2-イルスルホニル)安息香酸メチルエステルの合成
工程2で得られた化合物(3.64g)のアセトン(50mL)-蒸留水(50mL)の混合溶液に、酢酸(4.25mL)と過マンガン酸カリウム(7.04g)を加え、室温にて一終夜攪拌した。反応液に亜硫酸ナトリウム水溶液を加え、1時間攪拌した後、反応溶液をあらかた減圧濃縮した。残渣にクロロホルムと飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて3度抽出した。有機層を集め、硫酸マグネシウムにて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)にて精製し、目的物(3.44g、84%)を白色固体として得た。
(工程4)3-(ピリジン-2-イルスルホニル)安息香酸の合成
工程3で得られた化合物(3.44g)のメタノール(50mL)溶液に、5M水酸化ナトリウム水溶液(12.4mL)を加えた後、室温にて一終夜攪拌した。反応液を5M塩酸にて中和した後、溶媒を減圧留去した。残渣にメタノールを加え、攪拌させた後、固体をろ別後、溶媒を減圧留去し表題化合物(2.83g、87%)を白色固体として得た。
5-イソプロポキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミン
(工程1)5-イソプロポキシ-1H-ピラゾール-3-アミンの合成
3-アミノ-5-ヒドロキシピラゾールアミン(25g)の2-プロパノール(250mL)溶液に、メタンスルホン酸(25mL)を加え、120℃にて2日間攪拌した。反応液を放冷後、溶媒を減圧留去した。残渣に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルにて抽出し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去し、目的物(5.35g、15%)を淡褐色固体として得た。
(工程2)5-イソプロポキシ-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-ピラゾール-3-アミンの合成
工程1で得られた化合物(4.84g)のDMF(100mL)溶液に、氷冷下、水素化ナトリウム(1.44g)を加え、氷冷下、2時間攪拌した。反応液を-18℃に冷却後、塩化2-(トリメチルシリル)エトキシメチル(6.38mL)を滴下した。-18℃にて2時間攪拌した後、室温まで昇温させ、さらに1時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルにて抽出し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-40%グラジェント、その後、メタノール/クロロホルム=0%-20%、グラジェント)で精製し、表題化合物(2.28g、25%)を淡黄色油状物質として得た。
2-フルオロ-4-(メトキシメトキシ)アニリン
2-フルオロ-4-(メトキシメトキシ)-1-ニトロベンゼン(3.86g)のエタノール(100mL)溶液に、触媒として10%パラジウム-炭素(390mg)を加え、水素雰囲気下、室温にて一終夜撹拌した。触媒をろ過後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)にて精製し、表題化合物(2.40g,73%)を茶色油状物質として得た。
N-(2-フルオロ-4-ヒドロキシフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
(工程1)N-[2-フルオロ-4-(メトキシメトキシ)フェニル]-3-(ピリジン-2-イルスルホニル)ベンズアミドの合成
参考例8で得られた化合物および参考例10で得られた化合物を原料として用い、実施例116(工程1)に準じた方法により目的物を得た。
(工程2)N-(2-フルオロ-4-ヒドロキシフェニル)-3-(ピリジン-2-イルスルホニル)ベンズアミドの合成
工程1で得られた化合物(1.58g)のTHF(40mL)溶液に、5M塩酸を加えた後、60℃にて5時間攪拌した。放冷後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムで乾燥し、乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)で精製し、表題化合物(800mg、57%)を白色固体として得た。
6-ブロモ-5-(メトキシメトキシ)ピリジン-2-アミン
(工程1)2-ブロモ-3-(メトキシメトキシ)-6-ニトロピリジンの合成
2-ブロモ-6-ニトロピリジン-3-オール(1.0g)のアセトン(30mL)溶液に、氷冷下、クロロメチルメチルエーテル(1.04mL)および炭酸カリウム(3.16g)を順次加え、室温にて一終夜攪拌した。反応液を減圧下濃縮した後、残渣に酢酸エチルを加え、水、飽和食塩水にて洗浄した。有機層を硫酸ナトリウムにて乾燥後、ろ過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)にて精製し、目的物(1.16g,97%)を褐色固体として得た。
(工程2)6-ブロモ-5-(メトキシメトキシ)ピリジン-2-アミンの合成
工程1で得られた化合物(482mg)のエタノール(20mL)溶液に、飽和塩化アンモニウム水溶液(2.0mL)および鉄粉(4.0g)を加え、加熱還流下12時間攪拌した。放冷後、反応液に水を加えた後、酢酸エチルにて抽出した。有機層を硫酸ナトリウムにて乾燥後、ろ過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=0%-20%、グラジェント)にて精製し、表題化合物(294mg,69%)を褐色固体として得た。
N-(6-ブロモ-5-ヒドロキシピリジン-2-イル)-3-(ピリジン-2-イルスルホニル)ベンズアミド
参考例8で得られた化合物および参考例12で得られた6-ブロモ-5-(メトキシメトキシ)ピリジン-2-アミンを原料として用い、実施例116(工程1)に準じた方法により表題化合物物を得た。
N-(4-イソプロポキシフェニル)-3-メルカプトベンズアミド
4-イソプロポキシアニリン、3-メルカプト安息香酸を原料として用い、実施例92に準じた方法により表題化合物を得た。
3-[(4-フルオロフェニル)スルホニル]安息香酸
(工程1)3-[(4-フルオロフェニル)チオ]安息香酸の合成
4-フルオロベンゼンチオール(3.10g)、3-ヨード安息香酸(5.00g)のN-メチルピロリジノン(100mL)溶液に、酸化銅(II)(4.01g)および炭酸セシウム(19.7g)を順次加え、160℃にて一終夜攪拌した。放冷後、反応溶液内の固体をろ別した。ろ液に1M塩酸を加えた後、酢酸エチルにて3回抽出し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をクロロホルム-ヘキサンの混合溶媒に懸濁させた後、固体をろ取し目的物(4.08g、82%)を白色固体として得た。
(工程2)3-[(4-フルオロフェニル)スルホニル]安息香酸の合成
工程1で得られた化合物(1.00g)のアセトニトリル(46mL)溶液に、硫酸マンガン五水和物(20.0mg)を加えた後、30%過酸化水素水(34mL)-0.2M炭酸水素ナトリウム水溶液の混合溶液を滴下し、室温にて一終夜攪拌した。反応液に0.1M塩酸を加えた後、酢酸エチルにて2回抽出した。有機層を集め、硫酸ナトリウムにて乾燥し、減圧濃縮した。得られた残渣をクロロホルム-ヘキサンの混合溶媒に懸濁させた後、固体をろ取し表題化合物(921mg、82%)を白色固体として得た。
3-(ピリミジン-2-イルスルホニル)安息香酸
2-ブロモピリミジン、3-メルカプト安息香酸を原料として用い、参考例8に準じた方法により表題化合物を得た。
3-(ピラジン-2-イルスルホニル)安息香酸
2-ヨードピラジン、3-メルカプト安息香酸を原料として用い、参考例8に準じた方法により表題化合物を得た。
3-ヨード-N-(4-イソプロポキシフェニル)ベンズアミド
3-ヨード安息香酸及び4-イソプロポキシアニリンを原料として用い、実施例92に準じた方法により表題化合物を得た。
3-(シクロヘキシルスルホニル)安息香酸
(工程1)3-(シクロヘキシルチオ)安息香酸エチルエステルの合成
3-ヨード安息香酸エチルエステル(5.00g)、をジオキサン(100mL)に溶解し、シクロヘキサンチオール(2.32mL)、N,N-ジイソプロピルエチルアミン(6.29mL)、Xantphos(2.09g)およびPd2(dba)3(1.66g)を順次加え、窒素雰囲気下、100℃にて7時間攪拌した。放冷後、酢酸エチルを加え、水、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-25%、グラジェント)で精製し、目的化合物(5.11g)をオレンジ色油状物として得た。
(工程2)3-(シクロヘキシルスルホニル)安息香酸エチルエステルの合成
工程1で得られた化合物(5.11g)をクロロホルム(100mL)に溶解し、0℃にてm-クロロ過安息香酸(15.0g)を加え、0℃にて2時間攪拌した。反応液に10%チオ硫酸ナトリウム水溶液を加えた後、10%炭酸カリウム水溶液を加え、酢酸エチルにて抽出した。有機層を10%炭酸カリウム水溶液、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、目的物(5.30g、99%)を淡黄色油状物として得た。
(工程3)3-(シクロヘキシルスルホニル)安息香酸の合成
工程2で得られた化合物(5.30g)をメタノール(80mL)に溶解し、2M水酸化ナトリウム水溶液(17.9mL)を加えた後、室温にて5時間攪拌した。2M塩酸を加えおよそpH=2にした後、メタノールを減圧下留去した。残渣を酢酸エチルにて抽出し、有機層を飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣にジエチルエーテルを加え懸濁させた後、固体をろ取する事により、表題化合物(3.78g、79%)を無色固体として得た。
3-ヨード-N-(3-メトキシピリジン-2-イル)ベンズアミド
2-アミノ-3-メトキシピリジン(1.50g)をTHF(20mL)に溶解し、0℃にてトリエチルアミン(3.37mL)、3-ヨードベンゾイルクロライド(3.23g)を加え、室温にて30分間攪拌した。トリエチルアミン(3.37mL)、3-ヨードベンゾイルクロライド(3.23g)を再び加え、室温にて18間攪拌した。反応液にクロロホルムを加えた後、飽和炭酸水素ナトリウム水溶液にて洗浄し、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣に酢酸エチル(約50mL)を加え懸濁させた後、固体をろ取し、無色固体(5.96g)を得た。得られた個体(2.00g)にメタノール(50mL)、2M炭酸水素ナトリウム水溶液(3.42mL)を加え、室温にて18間攪拌した。メタノールを減圧下留去した後、酢酸エチルを加え、水、飽和食塩水にて順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、表題化合物(1.15g、80%)をオレンジ色油状物として得た。
[3-(ピペリジン-1-イルスルホニル)フェニル]メタノール
3-(ピぺリジン-1-イルスルホニル)安息香酸(7.00g)をTHF(70mL)に溶解し、0℃にてN,N’-カルボジイミダゾール(6.32g)を加えた後、0℃にて4時間攪拌した。反応液に水素化ホウ素ナトリウム(1.97g)を水(10mL)に溶解させたものを滴下し、その後0℃にて1時間攪拌した。水を加えた後、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-100%、グラジェント)で精製し、表題化合物(7.01g、100%)を無色油状物として得た。
1-{[3-(クロロメチル)フェニル]スルホニル}ピペリジン
DMF(5.0mL)にオキシ塩化りん(1.00mL)を加え、80℃にて30分間攪拌した。参考例21で得られた[3-(ピペリジン-1-イルスルホニル)フェニル]メタノール(2.00g)をDMF(5.0mL)に溶解したものを加え、80℃にて30分間攪拌した。0℃にて飽和炭酸ナトリウム水溶液を加えた後、酢酸エチルにて抽出した。有機層を水、飽和食塩水にて順次洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、表題化合物(1.26g、59%)を無色固体として得た。
[3-(ピペリジン-1-イルスルホニル)フェニル]アセトニトリル
参考例22で得られた化合物(500mg)をDMF(5.0mL)に溶解し、テトラエチルアンモニウムシアニド(500mg)を加え、室温にて18時間攪拌した。酢酸エチルを加えた後、水、飽和食塩水にて順次洗浄後、硫酸ナトリウムで乾燥した。乾燥剤をろ別後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン=0%-50%、グラジェント)で精製し、表題化合物(342mg、71%)を無色固体として得た。
被検化合物をジメチルスルホキシド(DMSO)に10mMとなるように溶解し、更にDMSOで希釈し、評価濃度の1000倍濃縮溶液を作製した。LCE酵素活性阻害試験はMoon(J.Biol.Chem.,276巻,45358-45366頁(2001年))らの方法を改良して行った。すなわち、希釈した被検化合物を96ウェルアッセイプレート(Corning、96ウェルアッセイブロック)へ1ウェルあたり1.0μL添加した後、50μLのリン酸緩衝溶液(100mM リン酸カリウム緩衝溶液(pH6.5))、25μLの基質溶液(100mM リン酸カリウム緩衝溶液(pH6.5)、4.0μM rotenone、80μM 脂肪酸不含ウシ血清アルブミン、160μM パルミトイルCoA、80μM マロニルCoA、3.5μM[14C]-マロニルCoA(1.92GBq/mmol、Amersham製))を各ウェルに加え、更に25μLの酵素溶液(100mM リン酸カリウム緩衝溶液(pH6.5)、100μg/mL ヒトLCE)を添加してプレート上部をシールで密閉し、37℃で90分間穏やかに振盪攪拌しながらインキュベーションした。その後、各ウェルに100μLの5M 塩酸を添加して室温で5分間アッセイプレートを攪拌して酵素反応を停止させるとともにアシルCoAを加水分解した。その後、各ウェルの酵素反応溶液をあらかじめ水を通液させておいた96ウェルGF/Cフィルタープレート(PerkinElmer ユニフィルター96GF/C)の各ウェルに吸着させ、各ウェルを水で洗浄し非吸着のマロニルCoAを除去した後、50℃で60分間GF/Cフィルタープレートを乾燥させた。その後、各ウェルに30μLのシンチレーター(PerkinElmer マイクロシンチ0)を加えてプレート上部をシールし、固定された[14C]の放射活性をマイクロプレートシンチレーションカウンター(PerkinElmer トップカウント)で測定し酵素活性とした。被検化合物によるヒトLCEの酵素阻害活性は被検化合物を含まないDMSO添加のウェルにおける放射活性をコントロールとして算出した。本発明化合物の活性を本アッセイを用いて調べたところ、それらの化合物はヒトLCEの活性を阻害した。結果を表1に示す。
Claims (11)
- 式(I)
Wは、C1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル又は-N(R1)(R2)を表し、
R1及びR2は、各々独立して、水素原子、C1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表すか、又はR1及びR2が一緒になって、それらが結合する窒素原子とともに含窒素複素環を形成し、
前記アルキル、シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル又は含窒素複素環は、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される置換基で置換されていてもよく、
Xは、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、該基は、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される置換基で置換されていてもよく、
Yは、式(II-1)、式(II-2)、式(II-3)又は式(II-4)を表し、
ここで、式(II-1)から式(II-4)における任意の水素原子は、C1-6アルキル、ハロC1-6アルキル又はC3-8シクロアルキルで置換されていてもよく、
Zは、水素原子、ヒドロキシ、シアノ、カルボキシル、スルホ、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、ハロC1-6アルコキシ、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシC1-6アルキル、アミノ(該アミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、カルバモイル(該カルバモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、スルファニル(該スルファニルは、C1-6アルキル、アリール若しくはヘテロアリールで1置換されていてもよい)、C1-6アルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、C1-6アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、スルファモイル(該スルファモイルは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルキルスルホニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、C1-6アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、C1-6アルコキシカルボニル、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、カルバモイルアミノ(該カルバモイルアミノは、C1-6アルキル、アリール若しくはヘテロアリールで1乃至2置換されていてもよい)、C1-6アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、ヘテロアリールオキシカルボニルアミノ、C1-6アルキルカルボニルアミノ、アリールカルボニルアミノ、ヘテロアリールカルボニルアミノ、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、アラルキルオキシ及びヘテロアラルキルオキシからなる群から選択される基を表し、そして
A1、A2、A3及びA4は、各々独立して、CH又はNを表し、但し、A1、A2、A3及びA4のうち少なくとも3つはCHである]
で表される化合物又は薬学的に許容されるその塩を有効成分とする長鎖脂肪酸伸長酵素(LCE)阻害剤。 - Wがアリール又はヘテロアリールである、請求項1に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- Wが-N(R1)(R2)であり、R1及びR2は、各々独立して、水素原子、C1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキルを表すか、又はR1及びR2が一緒になって、それらが結合する窒素原子とともに含窒素複素環を形成する、請求項1に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- R1及びR2が、各々独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルを表す、請求項3に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- R1及びR2が一緒になって、それらが結合する窒素原子とともに5-7員の単環式含窒素複素環を形成する、請求項3に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- R1及びR2が一緒になって、それらが結合する窒素原子とともに5-7員の2環式含窒素複素環を形成する、請求項3に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- Zが、水素原子である、請求項1~6のいずれかの請求項に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- Yが、式(II-2)又は式(II-3)で表される、請求項1~7のいずれかの請求項に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- Yが、式(II-1)であり、Xが、アリール又はヘテロアリールである、請求項1~7のいずれかの請求項に記載の長鎖脂肪酸伸長酵素(LCE)阻害剤。
- Xが、式(X-1)、式(X-2)又は式(X-3)
R3aは、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、
R3bは、水素原子、ハロゲン、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル又はヘテロアラルキルを表し、但し、R3a-O-は、炭素原子上に結合しており、
R4は、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、C1-6アルコキシ、ハロC1-6アルコキシ、アリールオキシ又はヘテロアリールオキシを表し、
R5は、イソプロピル又はイソプロピルオキシを表し、
R6は、水素原子又はC1-6アルキルを表し、
R7は、水素原子、C1-6アルキル、ハロC1-6アルキル、C3-8シクロアルキル、アリール、ヘテロアリール、アラルキル、ヘテロアラルキル、C1-6アルコキシ、ハロC1-6アルコキシ、アリールオキシ、ヘテロアリールオキシ、ヘテロアラルキルオキシ、C1-6アルキルチオ、C1-6アルキルスルファニル、C1-6アルキルスルホニル、アリールチオ、アリールスルファニル又はアリールスルホニルを表し、
- 長鎖脂肪酸伸長酵素に関連する疾患の治療のために治療活性物質として使用される、請求項1~10のいずれかの請求項に記載の阻害剤。
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Also Published As
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CA2722075C (en) | 2015-11-24 |
AU2009239116B2 (en) | 2013-05-30 |
ES2527589T3 (es) | 2015-01-27 |
EP2280001B1 (en) | 2014-10-15 |
CA2722075A1 (en) | 2009-10-29 |
US20110009622A1 (en) | 2011-01-13 |
EP2280001A4 (en) | 2012-01-18 |
CN104352492A (zh) | 2015-02-18 |
CN104352492B (zh) | 2017-12-05 |
CN102015638A (zh) | 2011-04-13 |
EP2280001A1 (en) | 2011-02-02 |
AU2009239116A1 (en) | 2009-10-29 |
JPWO2009131065A1 (ja) | 2011-08-18 |
JP5501226B2 (ja) | 2014-05-21 |
US8420823B2 (en) | 2013-04-16 |
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