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WO2012026495A1 - Nouveau dérivé d'hydantoïne et médicament le contenant à titre de principe actif - Google Patents

Nouveau dérivé d'hydantoïne et médicament le contenant à titre de principe actif Download PDF

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WO2012026495A1
WO2012026495A1 PCT/JP2011/069063 JP2011069063W WO2012026495A1 WO 2012026495 A1 WO2012026495 A1 WO 2012026495A1 JP 2011069063 W JP2011069063 W JP 2011069063W WO 2012026495 A1 WO2012026495 A1 WO 2012026495A1
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佐藤　太朗
隆史 小峰
誠 連佛
小林　直樹
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a hydantoin derivative and its addition salt effective as a human AMPK activator for treating lipid metabolism abnormality or diabetes, and a pharmaceutical composition containing these compounds.
  • Non-patent Document 1 As the cause of the disease, visceral fat type obesity, lipid metabolism abnormality, sugar metabolism abnormality or blood pressure abnormality are considered (Non-patent Document 1). Therefore, it is expected that these lifestyle-related diseases can be prevented by improving the energy metabolism abnormality.
  • drugs for controlling blood glucose level and blood lipid concentration are used in combination with pharmacotherapy for diabetic patients with hyperlipidemia and patients with impaired glucose tolerance.
  • drugs for controlling blood glucose levels sulfonylurea drugs, thiazolidine drugs or biguanide drugs are widely used.
  • Non-patent Document 2 AMP-activated protein kinase
  • AMPK is a protein widely present in the living body such as muscle or liver, and its activity increases in a situation where intracellular ATP level decreases, functions as a “metabolic sensor” that promotes metabolism and promotes ATP synthesis. It was known that
  • AMPK is not only regulated by intracellular energy levels, but also by muscle exercise, leptin (Non-patent Document 3), adipocyte-derived hormones such as adiponectin (Non-patent Document 4), etc. It has been considered to be an intracellular mediator of activated and triggered fatty acid oxidation or glucose utilization by them.
  • AMPK affects fatty acid oxidation in mitochondria through activity control on acetyl CoA carboxylase (ACC).
  • AMPK is not only activated in the absence of intracellular energy, but also plays an important role in biological energy metabolism or nutrient metabolism. Therefore, activation of AMPK leads to improvement of abnormal sugar metabolism or abnormal lipid metabolism, and can be said to be an excellent molecular target in the prevention of obesity or the treatment of diabetes.
  • AMPK adipocyte-derived hormone
  • metformin non-patent document 5
  • AICAR aminoimidazole carboxide ribonucleotide
  • adipocyte-derived hormone is metabolically and chemically unstable and cannot be used as a medicine.
  • metformin has a weak AMPK activating action, and side effects such as gastrointestinal disorders or lactic acidosis have been reported, and there is a problem in therapeutic effect or safety.
  • Patent Document 24 discloses a compound represented by the general formula (S) having anticancer activity.
  • the hydantoin derivatives described in the specification are only para-substituted benzylhydantoins, which are completely different from the compounds of the present invention and do not describe any AMPK activation action.
  • R 1 represents an aromatic group or a heterocyclic group
  • X and Y each independently represent an oxygen atom, a sulfur atom, an alkylene, or the like
  • A represents an aromatic group, a heterocyclic monocycle or a heterocyclic group.
  • D represents a phenyl group, a 6-membered ring or a 5-membered heterocyclic group
  • E represents a phenyl group, a pyridyl group or a pyrimidyl group
  • L represents —C (O) —, —S (O) 2.
  • R 4 independently represents a hydrogen atom, an alkyl group or the like.
  • Patent Document 25 discloses a compound represented by the general formula (U) having a factor Xa inhibitory action. However, there is no hydantoin derivative in the compounds described in the specification, and there is no description about the AMPK activation action.
  • D and D ′ represent a hydrogen atom, a cyano group, etc.
  • R 1 represents a hydrogen atom, a halogen atom, etc.
  • R 2 represents a hydrogen atom, ⁇ O, a C 1-4 alkyl group, or the like.
  • R 2 is absent or represents a benzene ring which may be substituted with 0-2 R 10 together with R 2a , R 3 and R 3 ′ are hydrogen, C 1-4 alkyl group, benzyl group, phenyl Z represents a bond or C 1-4 alkylene, A represents a C 3-10 hydrocarbon ring which may be substituted with 0-2 R 6 , and B represents X -Y, CONR 3 R 3 ', etc., X represents -C (O) NR 3- , -NR 3 C (O)-, etc.
  • Y represents 0-2
  • R 6 of C 3-10 substituted group represents such hydrocarbon ring optionally C 3-10 and, R 6 is (CH 2) n OR 3, (CH 2) rR 3 R 3 ' Represents etc., R 10 represents a hydrogen atom, a halogen atom.
  • An object of the present invention is to provide a compound that has a chemical structure different from that of the above-mentioned known compounds, has a strong AMPK activation action, and exhibits an advantageous effect derived from the AMPK activation action in vivo. .
  • the inventors of the present invention have made extensive studies focusing on the specific role of human AMPK in energy metabolism for the purpose of creating a novel structurally effective drug that is highly effective, durable and safe as a type II diabetes drug.
  • the novel benzylhydantoin derivative of the present invention and an addition salt thereof have an excellent human AMPK activating action and exhibit an excellent blood glucose lowering action and lipid lowering action in vivo.
  • R 1 has a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, a C 3 -C 6 cycloalkyl group which may have a substituent, or a substituent.
  • An optionally substituted C 6 -C 10 aryl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent Represents a condensed heterocyclic group which may have X represents C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 2 -C 4 alkynylene or general formula (2), Y represents a single bond, C 1 -C 4 alkylene or general formula (5), Z is a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, or an optionally substituted C 1 to C
  • C 7 -C 12 aralkyl group optionally substituted C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group, optionally substituted good C 1 ⁇ C 6 alkylthio group, an optionally substituted C 6 ⁇ C 10 arylthio group
  • Ring A and Ring B are the same or different, and may be a C 3 to C 6 cycloalkyl group which may have a substituent, a 5- or 6-membered saturated heterocyclic group which may have a substituent, a substituted A C 6 -C 10 aryl group which may have a group, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent, R 2 and R 3 are the same or different and are a hydrogen atom, an optionally substituted C 1
  • T represents a single bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene; U represents a single bond, C 1 -C 4 alkylene or C 2 -C 4 alkenylene;
  • A is a carbonyl group, an oxygen atom, —S (O) p — (p represents an integer selected from 0 to 2), —NR 4 — (R 4 is a hydrogen atom, C 1 which may have a substituent) C 6 alkyl group, optionally substituted C 7 to C 12 aralkyl group, optionally substituted C 6 to C 10 aryl group, optionally substituted C 1 to C 6 aliphatic acyl group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or optionally substituted Represents a good condensed heterocyclic group), —N (R 5
  • L 1 represents a single bond, an oxygen atom or —NR 5 —, and R 5 represents the same meaning as described above]
  • L 2 represents a single bond or an oxygen atom
  • R 5 represents the same meaning as described above.
  • Q 1 represents an oxygen atom
  • —S (O) q — (q represents an integer selected from 0 to 2)
  • —NR 6 — R 6 represents a hydrogen atom, and has a substituent.
  • Q 2 is a single bond, methylene, oxygen atom, —S (O) r — (r represents an integer selected from 0 to 2) or —NR 7 — (R 7 is a hydrogen atom, An optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted C 6 -C 10 aryl group, a substituent A C 1 -C 6 aliphatic acyl group which may have a substituent, a C 1 -C 6 alkylsulfonyl group which may have a substituent, a 5-membered or 6-membered aromatic complex which may have a substituent Represents a condensed heterocyclic group which may have a cyclic group or a substituent, and m and n are the same or different and represent 1 or 2] 2.
  • the hydantoin derivative according to the preceding item 1 wherein X is C 1 -
  • T 1 represents a single bond or C 1 -C 4 alkylene
  • U 1 represents a single bond or C 1 -C 4 alkylene
  • a 1 is an oxygen atom, a sulfur atom, —NR 4a —
  • R 4a is a hydrogen atom, an optionally substituted C 1 to C 6 alkyl group or an optionally substituted C 7 to C 12.
  • An aralkyl group —N (R 5a ) SO 2 —, —SO 2 N (R 5a ) — (R 5a is a C 1 -C 6 alkyl group or substituent optionally having a hydrogen atom or a substituent) Represents a C 7 to C 12 aralkyl group which may have a general formula (3a) or a general formula (4a)]
  • L 1a represents a single bond or —NR 5a —, and R 5a represents the same meaning as described above.
  • R 5a is as defined above.
  • R 5a is as defined above.
  • T 1 represents a single bond or C 1 -C 4 alkylene
  • a 2 represents general formula (3b) or general formula (4a)].
  • R 5a ′ represents a hydrogen atom, a C 1 to C 6 alkyl group which may have a substituent or a C 7 to C 12 aralkyl group which may have a substituent, and R 5a Represents the same meaning as described above]
  • R 5a is as defined above.] 4).
  • Z represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 6 cycloalkyloxy group, Nitro group, cyano group, optionally substituted amino group, optionally substituted C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group A C 1 -C 6 alkylthio group which may have a substituent, a C 6 -C 10 arylthio group which may have a substituent, or a C 7 -C 12 aralkylthio group which may have a substituent. 4.
  • Ring A and Ring B are the same or different and may have a C 3 -C 6 cycloalkyl group which may have a substituent, or C 6 -C which may have a substituent.
  • V 1 , V 2 , V 3 and V 4 are the same or different and each represents a nitrogen atom or C—R 8 (R 8 may have a hydrogen atom, a halogen atom or a substituent. May have a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group which may have a substituent, a C 1 -C 6 alkoxy group which may have a substituent, or a substituent C 3 -C 6 cycloalkyloxy group, hydroxyl group, nitro group, cyano group, hydroxycarbonyl group, C 1 -C 6 alkoxycarbonyl group, amino group which may have a substituent, may have a substituent C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group, optionally substituted C 1 -C 6 alkylthio group, optionally substituted C 6 ⁇ C 10 arylthio group,
  • R 1a has a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, a C 3 -C 6 cycloalkyl group which may have a substituent, or a substituent.
  • X a represents the general formula (2c)
  • Y a represents a single bond, methylene, oxygen atom, sulfur atom or —NR 6a —
  • R 6a represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group
  • Z a is a hydrogen atom, an optionally substituted C 1 to C 6 alkoxy group, an optionally substituted C 3 to C 6 cycloalkyloxy group, or an optionally substituted C 6.
  • Ring A a represents a C 6 -C 10 aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent
  • Ring B a is an optionally substituted C 3 ⁇ C 6 cycloalkyl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent
  • an optionally substituted C 6 ⁇ C 10 represents an aromatic heterocyclic group of the aryl group or 5-membered may have a substituent or 6-membered
  • R 2a and R 3a are the same or different and are a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group or a substituted group.
  • a C 6 -C 10 aryl group which may have a group, or R 2a and R 3a are bonded to each other, together with the carbon atom to which R 2a
  • T 2 represents a single bond or methylene
  • a 3 represents General Formula (3c) or General Formula (4b)]
  • R 5b and R 5b ′ are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent]
  • R 5b represents the same meaning as described above
  • Q 2a represents a single bond, methylene, oxygen atom, sulfur atom, —NR 7a — (R 7a represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent) M and n are the same or different and represent 1 or 2] 8).
  • R 7a represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent
  • M and n are the same or different and represent 1 or 2] 8).
  • R 1b represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a general formula (8);
  • Xb represents general formula (9), general formula (10), or general formula (11),
  • Y b represents an oxygen atom or a sulfur atom,
  • Z b represents a hydrogen atom or a C 1 -C 6 alkoxy group,
  • Ring A b represents a C 6 ⁇ C 10 aryl group or pyridyl group,
  • Ring B b is (1) a C 3 -C 6 cycloalkyl group, (2) a piperidinyl group optionally substituted with a C 1 -C 6 alkyl group, a C 1 -C 6 aliphatic acyl group or a C 2 -C 7 alkoxycarbonyl group, or (3) a halogen atom, C 1 -C A 6 alkyl group, a C 1 -C 6 alkoxy
  • R 9 represents a hydroxyl group, a C 7 to C 12 aralkyloxy group or a 3- to 6-membered cyclic amino group, and v represents an integer of 1 to 6]
  • R 10 represents a hydroxycarbonyl group or a C 8 to C 13 aralkyloxycarbonyl group, and w represents an integer of 1 to 6]
  • R 11 represents a halogen atom, a C 2 -C 7 alkoxycarbonyl group, a cyano group, or an amino group optionally substituted by 1 or 2 C 1 -C 6 alkyl groups, R 1b , R 2b , R 3b and Z b are as defined above. 10.
  • the compound represented by the general formula (1) is (R) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide; (S) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide, 5- (2,4-dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide, 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide, 5- (2,4-dioxoimidazolid
  • a pharmaceutical comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of items 1 to 10 or an hydrate thereof as an active ingredient.
  • An AMPK activator comprising as an active ingredient at least one of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or a hydrate thereof.
  • a lipid lowering agent comprising as an active ingredient at least one of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or a hydrate thereof. 14 11.
  • a prophylactic or therapeutic agent for arteriosclerosis comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above. 15. 11. A prophylactic or therapeutic agent for diabetes comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above. 16. 11. A prophylactic or therapeutic agent for obesity comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above as an active ingredient. 17. 11. A cancer therapeutic agent comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or hydrates thereof as an active ingredient.
  • novel hydantoin derivative and its addition salt of the present invention have an excellent AMPK activating action and an excellent blood glucose lowering action and lipid lowering action in vivo.
  • These compounds of the present invention are effective as a hypoglycemic agent and a lipid-lowering agent, particularly as a blood glucose uptake promoting agent in the liver and a lipid-lowering agent.
  • the compound of the present invention is a hydantoin derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof or a hydrate thereof.
  • R 1 has a hydrogen atom, a C 1 to C 6 alkyl group which may have a substituent, a C 3 to C 6 cycloalkyl group which may have a substituent, and a substituent.
  • R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, or a C 3 -C 6 cycloalkyl group which may have a substituent in order to exhibit an excellent AMPK activation action.
  • a C 7 -C 12 aralkyl group which may have a substituent more preferably a hydrogen atom, a C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group, Particularly preferred is an atom, a C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group.
  • X represents C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 2 -C 4 alkynylene or the following general formula (2).
  • T represents a single bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene;
  • U represents a single bond, C 1 -C 4 alkylene or C 2 -C 4 alkenylene;
  • A is a carbonyl group, an oxygen atom, —S (O) p — (p represents an integer selected from 0 to 2), —NR 4 — (R 4 is a hydrogen atom, C 1 which may have a substituent) C 6 alkyl group, optionally substituted C 7 to C 12 aralkyl group, optionally substituted C 6 to C 10 aryl group, optionally substituted C 1 to C 6 aliphatic acyl group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or optionally substituted Represents a good condensed heterocyclic group), —N (R 5
  • L 1 represents a single bond, an oxygen atom or —NR 5 —, and R 5 represents the same meaning as described above.
  • L 2 represents a single bond or an oxygen atom
  • R 5 represents the same meaning as described above.
  • X preferably represents C 1 -C 4 alkylene or the following general formula (2a) in order to represent an excellent AMPK activation action, and more preferably X is represented by the following general formula (2b). preferable.
  • T 1 represents a single bond or C 1 -C 4 alkylene
  • U 1 represents a single bond or C 1 -C 4 alkylene
  • a 1 is an oxygen atom, a sulfur atom, —NR 4a —
  • R 4a is a hydrogen atom, an optionally substituted C 1 to C 6 alkyl group or an optionally substituted C 7 to C 12.
  • An aralkyl group —N (R 5a ) SO 2 —, —SO 2 N (R 5a ) — (R 5a is a C 1 -C 6 alkyl group or substituent optionally having a hydrogen atom or a substituent) Represents a C 7 to C 12 aralkyl group which may have a general formula (3a) or a general formula (4a).
  • L 1a represents a single bond or —NR 5a —, and R 5a has the same meaning as described above.
  • R 5a represents the same meaning as described above.
  • T 1 represents a single bond or C 1 -C 4 alkylene
  • a 2 represents the following general formula (3b) or the general formula (4a).
  • R 5a ′ represents a hydrogen atom or a C 1 to C 6 alkyl group which may have a substituent or a C 7 to C 12 aralkyl group which may have a substituent
  • R 5a represents It represents the same meaning as described above.
  • Y represents a single bond, C 1 -C 4 alkylene or the general formula (5).
  • Y is particularly preferably an oxygen atom in order to exhibit an excellent AMPK activation action.
  • Q 1 is an oxygen atom
  • —S (O) q — (q represents an integer selected from 0 to 2)
  • —NR 6 — (R 6 is a hydrogen atom, has a substituent) May have a C 1 -C 6 alkyl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted C 6 -C 10 aryl group, and may have a substituent
  • h and j are the same or different and each represents an integer of 0 to 2.
  • Z represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, or a substituent.
  • Z represents a hydrogen atom, a halogen atom, a C 1 to C 6 alkoxy group which may have a substituent, or a C 3 to C 6 cyclo group which may have a substituent in order to exhibit an excellent AMPK activation action.
  • Ring A and Ring B are the same or different, and may be a C 3 to C 6 cycloalkyl group which may have a substituent, a 5-membered or 6-membered which may have a substituent.
  • Ring A and Ring B are the same or different from each other in order to exhibit an excellent AMPK activation action, and may have a C 3 to C 6 cycloalkyl group which may have a substituent, or C which may have a substituent.
  • 6 -C 10 aryl group optionally substituted 5-membered or 6-membered saturated heterocyclic group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or substituted It is preferably a condensed heterocyclic group that may be used.
  • Ring A is a 5-membered or 6-membered saturated heterocyclic group which may have a substituent, a C 6 -C 10 aryl group which may have a substituent, or An optionally substituted 5-membered or 6-membered aromatic heterocyclic group is preferable, a 5-membered or 6-membered saturated heterocyclic group, a C 6 -C 10 aryl group, or a 5-membered or 6-membered aromatic heterocyclic group.
  • a ring group is more preferred, and a C 6 -C 10 aryl group is particularly preferred.
  • Ring A is preferably, for example, the following general formula (7).
  • V 1 , V 2 , V 3 , and V 4 are the same or different, and may be a nitrogen atom or C—R 8 (R 8 may have a hydrogen atom, a halogen atom, or a substituent.
  • Ring B is preferably a C 6 -C 10 aryl group which may have a substituent in order to exhibit an excellent AMPK activation action, and is a halogen atom, a C 1 -C 6 alkyl group or 1 or 2 C atoms.
  • a C 6 -C 10 aryl group that may be substituted with any of the amino groups that may be substituted with 1 to C 6 alkyl groups is more preferred, and may be substituted with 1 to 3 halogen atoms
  • a C 6 -C 10 aryl group is particularly preferred.
  • R 2 and R 3 are the same or different and are a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, or a C 3 -C which may have a substituent.
  • a 6 cycloalkyl group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 7 -C 12 aralkyl group, or R 2 and R 3 are bonded; with bonded carbon atoms of R 2 and R 3 represents the general formula (6).
  • Q 2 represents a single bond, methylene, oxygen atom, —S (O) r — (r represents an integer selected from 0 to 2), —NR 7 — (R 7 represents a hydrogen atom, substituted A C 1 -C 6 alkyl group which may have a group, a C 7 -C 12 aralkyl group which may have a substituent, a C 6 -C 10 aryl group which may have a substituent, a substituent C 1 -C 6 aliphatic acyl group which may have, C 1 -C 6 alkylsulfonyl group which may have a substituent, 5-membered or 6-membered aromatic heterocyclic ring which may have a substituent
  • the compound of the present invention include a hydantoin derivative represented by the following general formula (1a), a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • R 1a has a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and a substituent.
  • X a represents the general formula (2c)
  • Y a represents a single bond, methylene, oxygen atom, sulfur atom or —NR 6a — (R 6a represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group);
  • Z a is a hydrogen atom, an optionally substituted C 1 to C 6 alkoxy group, an optionally substituted C 3 to C 6 cycloalkyloxy group, or an optionally substituted C 6.
  • Ring A a represents a C 6 -C 10 aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent
  • Ring B a is an optionally substituted C 3 ⁇ C 6 cycloalkyl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent
  • an optionally substituted C 6 ⁇ C 10 represents an aromatic heterocyclic group of the aryl group or 5-membered may have a substituent or 6-membered
  • R 2a and R 3a are the same or different and are a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group or a substituted group.
  • T 2 represents a single bond or methylene
  • a 3 represents general formula (3c) or general formula (4b).
  • R 5b and R 5b ′ are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent.
  • R 5b represents the same meaning as described above.
  • Q 2a represents a single bond, a methylene, an oxygen atom, a sulfur atom, —NR 7a — (R 7a represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group).
  • R 7a represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group.
  • m and n are the same or different and represent 1 or 2.
  • the compound of the present invention is preferably a compound represented by the above general formula (1a), more preferably a compound represented by the following general formula (1b), and represented by the following general formula (1c). More preferably, it is a compound.
  • R 1b represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or the general formula (8)
  • Xb represents general formula (9), general formula (10), or general formula (11)
  • Y b represents an oxygen atom or a sulfur atom
  • Z b represents a hydrogen atom or a C 1 -C 6 alkoxy group
  • Ring A b represents a C 6 ⁇ C 10 aryl group or pyridyl group
  • Ring B b is (1) a C 3 -C 6 cycloalkyl group, (2) a piperidinyl group optionally substituted with a C 1 -C 6 alkyl group, a C 1 -C 6 aliphatic acyl group or a C 2 -C 7 alkoxycarbonyl group, or (3) a halogen atom, C 1 -C A 6 alkyl group, a C 1 -C 6 alkoxy group, a C
  • R 9 represents a hydroxyl group, a C 7 to C 12 aralkyloxy group or a 3 to 6-membered cyclic amino group, and v represents an integer of 1 to 6.
  • R 10 represents a hydroxycarbonyl group or a C 8 to C 13 aralkyloxycarbonyl group, and w represents an integer of 1 to 6.
  • R 11 represents a halogen atom, a C 2 -C 7 alkoxycarbonyl group, a cyano group, or an amino group optionally substituted with 1 or 2 C 1 -C 6 alkyl groups, 1b , R 2b , R 3b and Z b are as defined above.
  • the compound represented by the general formula (1) includes (R) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2 from the viewpoint of an excellent AMPK activating action.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1 -C 6 alkyl group examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group. And straight chain or branched hydrocarbon groups having 1 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • C 6 -C 10 aryl group examples include a phenyl group and a naphthyl group.
  • C 7 -C 12 aralkyl group examples include a benzyl group, a naphthylmethyl group, a phenethyl group, and a phenylpropyl group.
  • C 1 -C 6 alkoxy group examples include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butyloxy group, t-butyloxy group, n-pentyloxy group or n-hexyloxy group.
  • C 3 -C 6 cycloalkyloxy group examples include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • Examples of the “C 6 -C 10 aryloxy group” include a phenoxy group and a naphthoxy group.
  • C 7 -C 12 aralkyloxy group examples include a benzyloxy group and a phenethyloxy group.
  • C 2 -C 7 alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a t-butyloxycarbonyl group.
  • Examples of the “C 8 -C 13 aralkyloxycarbonyl group” include a benzyloxycarbonyl group.
  • C 1 -C 6 alkylthio group examples include methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, t-butylthio group, n-pentylthio group, and n-hexylthio group. Can be mentioned.
  • C 6 -C 10 arylthio group examples include a phenylthio group and a naphthylthio group.
  • C 7 -C 12 aralkylthio group examples include a benzylthio group and a phenethylthio group.
  • C 1 -C 6 alkylsulfinyl group examples include a methanesulfinyl group and an ethanesulfinyl group.
  • C 6 -C 10 arylsulfinyl group examples include a benzenesulfinyl group and a naphthylsulfinyl group.
  • C 1 -C 6 alkylsulfonyl group examples include a methanesulfonyl group and an ethanesulfonyl group.
  • C 6 -C 10 arylsulfonyl group examples include a benzenesulfonyl group and a naphthylsulfonyl group.
  • C 1 -C 6 alkylsulfonyloxy group examples include a methanesulfonyloxy group and an ethanesulfonyloxy group.
  • C 6 -C 10 arylsulfonyloxy group examples include a benzenesulfonyloxy group and a naphthylsulfonyloxy group.
  • C 1 -C 6 aliphatic acyl group examples include a formyl group, an acetyl group, and a propanoyl group.
  • Examples of the “C 7 -C 12 aromatic acyl group” include a benzoyl group.
  • the “3- to 6-membered cyclic amino group” is a 3- to 6-membered saturated cyclic group containing one or more nitrogen atoms.
  • Examples of the “3- to 6-membered cyclic amino group” include an aziridyl group, an azetidyl group, a pyrrolidyl group, a piperidyl group, a piperazyl group, a morpholyl group, or a thiomorpholyl group.
  • the “5-membered or 6-membered saturated heterocyclic group” is a 5-membered or 6-membered saturated cyclic group containing one or more nitrogen, oxygen and / or sulfur atoms.
  • Examples of the “5-membered or 6-membered saturated heterocyclic group” include pyrrolidyl group, piperidyl group, piperazyl group, morpholyl group, thiomorpholyl group, tetrahydrofuranyl group, and pyranyl group.
  • the “5-membered or 6-membered aromatic heterocyclic group” is a 5-membered or 6-membered aromatic ring group containing 1 to 3 nitrogen, oxygen and / or sulfur atoms.
  • Examples of the “5-membered or 6-membered aromatic heterocyclic group” include furanyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group , Pyridyl group, pyrimidyl group, pyridazyl group or pyratyl group.
  • “Fused heterocyclic group” means a benzene condensed ring of “5-membered or 6-membered aromatic heterocyclic group” or two fragrances arbitrarily selected from “5-membered or 6-membered aromatic heterocyclic group” A condensed ring group composed of a heterocyclic group.
  • ⁇ fused heterocyclic group '' for example, indolyl group, benzoxazolyl group, benzothiazolyl group, benzofuranyl group, benzothienyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, quinoxalyl group, imidazopyridyl group, Examples include a pyrazolopyridyl group or an imidazopyrimidyl group.
  • C 1 -C 6 alkyl group which may have a substituent “C 3 -C 6 cycloalkyl group which may have a substituent”, “C 6 -C which may have a substituent” 10 aryl group ”,“ optionally substituted C 7 -C 12 aralkyl group ”, optionally substituted C 1 -C 6 alkoxy group”, “optionally substituted C “3 -C 6 cycloalkyloxy group”, “optionally substituted C 6 -C 10 aryloxy group”, “optionally substituted C 7 -C 12 aralkyloxy group”, “substituted” C 2 -C 7 alkoxycarbonyl group which may have a group ”,“ C 8 -C 13 aralkyloxycarbonyl group which may have a substituent ”,“ C 1 -C which may have a substituent ” 6 alkylthio group "," an optionally substituted C 6 ⁇ C 10 arylthio group "," substituted Good C 7
  • Examples of the “substituent” in the condensed heterocyclic group which may have include, for example, a halogen atom, 1 to 3 Optionally substituted with Gen atoms C 1 ⁇ C 6 alkyl group, C 3 ⁇ C 6 cycloalkyl group, one to three optionally substituted with a halogen atom C 1 ⁇ C 6 alkoxy group, C 7 -C 12 aralkyloxy group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfinyl group, C 1 -C 6 alkylsulfonyl group, C 2 -C 7 alkoxycarbonyl group, C 8 -C 13 aralkyloxycarbonyl Group, hydroxyl group, nitro group, amino group optionally substituted by 1 or 2 C 1 -C 6 alkyl groups, 3- to 6-membered cyclic amino group, cyano group, hydroxycarbonyl group, formyl group or aminocarbonyl Group
  • amino group which may have a substituent examples include an amino group which may be substituted with one or two C 1 to C 6 alkyl groups, and examples thereof include an amino group and a methylamino group. Or a dimethylamino group is mentioned.
  • C 1 -C 4 alkylene examples include linear or branched alkylene having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, methylethylene or dimethylmethylene.
  • C 2 -C 4 alkenylene examples include linear or branched alkenylene having 1 to 4 carbon atoms such as vinylene, propenylene or methylethenylene.
  • C 2 -C 4 alkynylene examples include linear or branched alkynylene having 1 to 4 carbon atoms such as ethynylene, propynylene, or 3-methylpropynylene.
  • the compound of the present invention can be converted into a pharmacologically acceptable salt if necessary.
  • pharmacologically acceptable salts include inorganic acid salts such as “hydrochloric acid, hydrobromic acid, sulfuric acid”, “acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, methanesulfonic acid, tosylic acid”.
  • a basic salt with a base such as “sodium salt, potassium salt, calcium salt”.
  • the compound of the present invention and its pharmacologically acceptable salt may be an inner salt, anhydride, hydrate or solvate thereof.
  • the compounds of the present invention include optical isomers based on asymmetric carbon, geometric isomers, stereoisomers, tautomers and the like, and all such isomers and mixtures thereof are of the present invention. It is included in the range.
  • the pharmaceutical of the present invention can be administered by parenteral means such as oral or subcutaneous, intravenous or intramuscular.
  • a pharmacologically acceptable salt thereof or a hydrate thereof as a medicine, it may be in the form of a solid composition, a liquid composition or other composition, and is optimal as necessary. Is selected.
  • the medicament of the present invention can also be produced by blending a pharmacologically acceptable carrier with the compound of the present invention. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers or aqueous or non-aqueous solvents are added, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, powders, solutions, emulsions, suspensions or injections.
  • the compound of the present invention has an excellent AMPK activating action, and exhibits an excellent blood glucose lowering action and lipid lowering action in vivo.
  • the compound of the present invention is useful as an active ingredient of an AMPK activator, lipid lowering agent, arteriosclerosis preventive or therapeutic agent, diabetes preventive or therapeutic agent, obesity preventive or therapeutic agent, or cancer therapeutic agent.
  • the compound represented by the general formula (1) which is the compound of the present invention can be produced by the method shown in Production Method 1 or a combination of known methods.
  • W 1 represents a leaving group
  • R a represents a C 1 -C 6 alkyl group which may have a substituent or a C 7 -C 12 aralkyl group which may have a substituent
  • R 1 , R 2 , R 3 , X, Y, Z, Ring A and Ring B have the same meaning as described above.
  • examples of the leaving group represented by W 1 include a halogen atom, an optionally substituted C 1 to C 6 alkylsulfonyloxy group, a phenylsulfonyloxy group, or a p-tolylsulfonyloxy group. And a C 6 -C 10 arylsulfonyloxy group which may be substituted with a C 1 -C 6 alkyl group.
  • Step 1-A Conversion of the compound represented by the general formula (13) and the compound represented by the general formula (14) to the compound represented by the general formula (15) (Step 1-A) can be carried out by using an appropriate solvent such as methanol.
  • a compound represented by general formula (13) and a compound represented by general formula (14) using a reducing agent such as sodium triacetoxyborohydride in ethanol, dichloromethane, chloroform, acetic acid or a mixture thereof Can be carried out at 0 to 100 ° C. for 5 minutes to 24 hours.
  • Step 1-B Conversion of the compound represented by the general formula (16) and the compound represented by the general formula (17) into the compound represented by the general formula (15) (Step 1-B) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (16) and a compound represented by the general formula (17) at ⁇ 78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.
  • a base such as sodium chloride, triethylamine, diisopropylethylamine or
  • Step 1-C Conversion from the compound represented by the general formula (15) to the compound represented by the general formula (18) (Step 1-C) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane, chloroform or N, N- In dimethylformamide or a mixture thereof, the compound represented by the general formula (15) and an isocyanate such as methyl isocyanate, ethyl isocyanate, phenyl isocyanate, or trimethylsilyl isocyanate are added in the presence of a base such as pyridine or triethylamine as necessary.
  • the reaction can be carried out by reacting at ⁇ 150 ° C. for 5 minutes to 48 hours.
  • R 1 represents a hydrogen atom
  • the compound represented by the general formula (15) in the presence of an acid such as hydrochloric acid or acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane, methanol or ethanol, or a mixture thereof. It can also be carried out by reacting a compound represented by the above with an isocyanate such as sodium isocyanate or potassium isocyanate at 0 to 130 ° C. for 5 minutes to 12 hours.
  • an isocyanate such as sodium isocyanate or potassium isocyanate
  • Step 1-D Conversion of the compound represented by the general formula (18) to the compound represented by the general formula (1) (Step 1-D) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide. Or in a mixed solution thereof, etc., in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine, if necessary.
  • the reaction can be carried out by reacting the compound represented by the general formula (18) at 0 to 130 ° C. for 5 minutes to 12 hours in the presence of an acid such as hydrochloric acid or acetic acid.
  • the compound represented by the general formula (1) which is the compound of the present invention, can also be synthesized by the synthesis method shown in Production Method 2.
  • R 1 , R 2 , R 3 , R a , W 1 , X, Y, Z, Ring A, and Ring B are as defined above.
  • step 2-A Conversion of the compound represented by general formula (13) and the compound represented by general formula (19) into the compound represented by general formula (20) (step 2-A) is the same as step 1-A. It can be done by a method.
  • step 2-B Conversion of the compound represented by the general formula (16) and the compound represented by the general formula (21) into the compound represented by the general formula (20) (step 2-B) is the same as in step 1-B. It can be done by a method.
  • Step 2-C Conversion of the compound represented by the general formula (20) and the compound represented by the general formula (22) to the compound represented by the general formula (23) (Step 2-C) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (20) and a compound represented by the general formula (22) at ⁇ 78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.
  • a base such as sodium chloride, triethylamine, diisopropylethylamine or
  • Step 2-D Conversion from the compound represented by the general formula (23) to the compound represented by the general formula (1) (Step 2-D) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide. , Methanol or ethanol or a mixed solution thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine
  • the reaction can be carried out by reacting the compound represented by the general formula (23) at 0 to 130 ° C. for 5 minutes to 12 hours in the presence of a base.
  • the compound represented by the general formula (1) which is the compound of the present invention can also be synthesized by the synthesis method shown in Production Method 3.
  • R 1 , R 2 , R 3 , W 1 , X, Y, Z, Ring A, and Ring B are as defined above.
  • Step 3-A Conversion of the compound represented by the general formula (24) and the compound represented by the general formula (25) into the compound represented by the general formula (1) (Step 3-A) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, N-methylpyrrolidinone or a mixed solution thereof such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (24) and a compound represented by the general formula (25) at ⁇ 78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.
  • a base such as sodium chloride, triethylamine, diisopropylethylamine or
  • the compound represented by the general formula (1e) can also be synthesized by the synthesis method shown in Production Method 4.
  • R 1d is an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and an optionally substituted C 6- A C 10 aryl group, an optionally substituted C 7 to C 12 aralkyl group, an optionally substituted 5-membered or 6-membered aromatic heterocyclic group, or an optionally substituted condensed group
  • W 2 represents a leaving group or boric acid
  • R 2 , R 3 , X, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • a halogen atom a C 1 -C 6 alkylsulfonyloxy group which may have a substituent, a phenylsulfonyloxy group or a p-tolylsulfonyloxy group such as a lower group.
  • a C 6 -C 10 arylsulfonyloxy group which may be substituted with an alkyl group.
  • W 2 represents a leaving group. In the case of expression, it can be carried out by the same method as in Step 3-A.
  • W 2 represents boric acid, pyridine, triethylamine, 4- (dimethyl) in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide or a mixture thereof.
  • Amino) bases such as pyridine, sodium carbonate or cesium carbonate, metals such as copper acetate, and compounds represented by the general formula (1d) in the presence of a ligand such as pyridine, triethylamine or 2,2-bipyridine if necessary
  • the reaction can be carried out by reacting the compound represented by the formula (26) at 0 to 150 ° C. for 30 minutes to 48 hours.
  • the compound represented by the general formula (1d), of the production method 1 may be produced according to the manufacturing technique when R 1 represents a hydrogen atom.
  • the compound represented by the general formula (1f) can also be synthesized by the synthesis method shown in Production Method 5.
  • a a represents an oxygen atom, a sulfur atom, —NR 4 —
  • PG 1 represents a protecting group
  • Ring B represents the same meaning as described above.
  • the protecting group represented by PG 1 includes an optionally substituted C 1 -C 6 aliphatic acyl group, C 1 -C 6 alkoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyl.
  • examples thereof include a benzyl group which may have a substituent such as a group, a trimethylsilyl group, a silyl group such as tert-butyldimethylsilyl, or a phthalimide group.
  • step 5-A Conversion of the compound represented by the general formula (27) and the compound represented by the general formula (28) to the compound represented by the general formula (1f) (step 5-A) is carried out by using an appropriate solvent such as toluene. , Hexane, tetrahydrofuran, diethyl ether, dichloromethane, N, N-dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide or acetone or a mixture thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride In the presence of a base such as sodium methoxide, potassium tert-butoxide, pyridine, triethylamine or N, N-dimethylaniline, an appropriate iodide salt, such as sodium iodide, potassium iodide or tetrabutyl iodide, is used as necessary. Ammonium or the like is added to form a general formula (27) A compound represented by the general formula (2
  • Step 5-B Conversion from the compound represented by the general formula (27a) to the compound represented by the general formula (29) (Step 5-B) can be carried out without a solvent or an appropriate solvent such as dichloromethane, chloroform, tetrahydrofuran or benzene or these
  • a solvent or an appropriate solvent such as dichloromethane, chloroform, tetrahydrofuran or benzene or these
  • a halogenating agent such as thionyl chloride, phosphorus oxychloride or thionyl bromide. It can be carried out.
  • a suitable sulfonylating agent such as methanesulfonyl chloride or trifluoromethanesulfonic acid in the presence of a base such as triethylamine or pyridine in a suitable solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide or a mixture thereof.
  • a base such as triethylamine or pyridine
  • a suitable solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide or a mixture thereof.
  • the reaction can be carried out by reacting the compound represented by the general formula (27a) at ⁇ 20 to 60 ° C. for 0.5 to 3 hours using an anhydride or the like.
  • a compound represented by the general formula (27a) is obtained by using carbon tetrabromide, carbon tetrachloride or iodine in the presence of triphenylphosphine in a suitable solvent such as dichloromethane, chloroform or tetrahydrofuran or a mixture thereof. It can also be carried out by reacting at ⁇ 20 to 60 ° C. for 0.5 to 3 hours.
  • step 5-C Conversion of the compound represented by the general formula (29) and the compound represented by the general formula (30) into the compound represented by the general formula (1f) (step 5-C) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen In the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (29) and the compound represented by the general formula (30) at ⁇ 78 ° C. to 120 ° C. for 10 minutes to 100 hours. It can be performed by reacting.
  • an appropriate solvent such as toluene. 1,4-dioxane, tetrahydro
  • Step 5-D Conversion from the compound represented by the general formula (31) to the compound represented by the general formula (27) (Step 5-D) can be performed by a known method such as Protecting Groups in Organic Synthesis [John Wiley and Sons (1999). )] And the like.
  • a method using an acid, a base, ultraviolet rays, hydrazine, tetrabutylammonium fluoride, trimethylsilyl iodide, or the like, or a reduction method may be mentioned.
  • the compound represented by the general formula (1g) can also be synthesized by the synthesis method shown in Production Method 6.
  • Ring A 1 may have a C 6 -C 10 aryl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent, or a substituent. It represents a good fused heterocyclic group, and U, Y, Z, R 1d , R 2 , R 3 and Ring B have the same meaning as described above.
  • Step 6-A Conversion of the compound represented by the general formula (27a) and the compound represented by the general formula (30a) into the compound represented by the general formula (1g) (Step 6-A) is carried out by using an appropriate solvent such as toluene.
  • an organophosphorus compound such as triphenylphosphine or tributylphosphine in hexane or tetrahydrofuran or a mixture thereof
  • an electrophilic agent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or dipiperidine azodicarboxylate is used.
  • the reaction can be carried out by reacting the compound represented by (27a) with the compound represented by the general formula (30a) at 0 to 60 ° C. for 3 to 24 hours.
  • it is represented by the general formula (27a) using a phospholane compound such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane in an appropriate solvent such as toluene, benzene, hexane, tetrahydrofuran, or a mixed solution thereof.
  • the reaction can be carried out by reacting the compound and the compound represented by the general formula (30a) at room temperature to 120 ° C. for 1 to 24 hours.
  • the compound represented by the general formula (1h) can also be synthesized by the synthesis method shown in Production Method 7.
  • R a and R b are the same or independently a C 1 to C 6 alkyl group or a C 7 to C 12 aralkyl group which may have a substituent, or R a and R b are together.
  • T a represents a single bond, C 1 -C 3 alkylene or C 2 -C 3 alkenylene
  • R 1 , R 2 , R 3 , R 4 , T, U, Y, Z, Ring A, Ring B are the same as those described above. Represents significance.
  • Step 7-A Conversion of the compound represented by the general formula (27b) and the compound represented by the general formula (32) into the compound represented by the general formula (1h) (Step 7-A) is carried out by using an appropriate solvent such as methanol. , Lithium borohydride, hydrogenation in the presence of acids such as hydrochloric acid, hydrobromic acid or acetic acid, or Lewis acids such as aluminum chloride or zinc chloride in ethanol, dichloromethane or chloroform or a mixture thereof. Using a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, the compound represented by the general formula (27b) and the compound represented by the general formula (32) are heated at 0 to 80 ° C. The reaction can be carried out by reacting for 1 to 24 hours.
  • an appropriate solvent such as methanol.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride
  • Step 7-B The conversion from the compound represented by the general formula (33) and the compound represented by the general formula (30b) to the compound represented by the general formula (1h) (Step 7-B) is the same as in Step 7-A. It can be done by a method.
  • Step 7-C The conversion from the compound represented by the general formula (34) to the compound represented by the general formula (33) (Step 7-C) is described in, for example, Protecting Groups in Organic Synthesis (John Wiley and Sons (1999)). This can be done by deprotection according to the above method.
  • an acid such as hydrochloric acid, sulfuric acid or nitric acid is used.
  • reaction can be carried out by reducing the compound represented by the general formula (34) at 0 to 80 ° C. for 0.5 to 12 hours in the presence of a catalyst in a hydrogen atmosphere at normal pressure to 0.5 MPa.
  • the compound represented by the general formula (1i) can also be synthesized by the synthesis method shown in Production Method 8.
  • R 1 , R 2 , R 3 , R 5 , R a , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • Step 8-A Conversion of the compound represented by the general formula (35) and the compound represented by the general formula (30c) into the compound represented by the general formula (1i) is carried out by using a suitable solvent such as dichloromethane, In chloroform, tetrahydrofuran, diethyl ether or N, N-dimethylformamide or a mixture thereof, a base such as pyridine, triethylamine, N-methylmorpholine or 4- (dimethylamino) pyridine, and if necessary, N-hydroxybenzotriazole, N Dicyclohexylcarbodiimide, 3- (3-dimethylaminopropyl) -1-ethyl in the presence of a reaction aid such as -hydroxysuccinimide or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine Carbodiimide hydrochloride, diethyl cyanophosphate, dipheny Using a condensing agent
  • the compound represented by the general formula (35) may be used in the absence of a solvent or in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, as necessary, with pyridine or triethylamine.
  • a base such as thionyl chloride, thionyl bromide, acetic anhydride or ethyl chlorocarbonate, the compound represented by the general formula (35) is reacted at ⁇ 15 to 50 ° C. for 5 minutes to 6 hours to give a carboxyl group.
  • a reactive derivative group such as acid chloride, acid bromide or acid anhydride
  • a suitable solvent such as toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide or a mixture thereof, pyridine, triethylamine or Represented by the general formula (30c) in the presence of a base such as 4- (dimethylamino) pyridine. That a compound can be carried out by reacting 15 minutes to 12 hours at -78 ⁇ 50 ° C..
  • Step 8-B Conversion from the compound represented by the general formula (36) to the compound represented by the general formula (35) (Step 8-B) can be carried out without a solvent or in a suitable solvent such as water, acetic acid, methanol, ethanol, In dichloromethane, tetrahydrofuran or 1,4-dioxane or a mixture thereof, an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid, or a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate Can be used by hydrolyzing the compound represented by the general formula (36) at 0 to 150 ° C. for 0.5 to 100 hours.
  • a suitable solvent such as water, acetic acid, methanol, ethanol, In dichloromethane, tetrahydrofuran or 1,4-dioxane or a mixture thereof
  • an acid such as trifluoroacetic acid, hydrochloric acid,
  • metals such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide, or rhodium-supported alumina in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide, or a mixture thereof.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide, or a mixture thereof.
  • the reaction can also be carried out by reducing the compound represented by the general formula (36) at 0 to 80 ° C. for 0.5 to 12 hours in the presence of a catalyst in a hydrogen atmosphere at normal pressure to 0.5 MPa.
  • the compound represented by the general formula (1j) can also be synthesized by the synthesis method shown in Production Method 9.
  • R 1 , R 2 , R 3 , R 5 , T, U, Y, Z, Ring A and Ring B have the same meaning as described above.
  • step 9-A The conversion from the general formula (27b) and the general formula (37) to the general formula (1j) (step 9-A) can be performed by the same method as in the step 8-A.
  • the compound represented by the general formula (1k) can also be synthesized by the synthesis method shown in Production Method 10.
  • a b represents an oxygen atom or —NR 5 —
  • R 1 , R 2 , R 3 , R 5 , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • Step 10-A Conversion of the compound represented by the general formula (27c) and the compound represented by the general formula (30c) into the compound represented by the general formula (1k) (Step 10-A) is carried out by using an appropriate solvent such as toluene. , Tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, etc., if necessary, using a carbonyldiimidazole in the presence of a base such as pyridine or triethylamine, and a compound represented by the general formula (27c)
  • the reaction can be carried out by reacting the compound represented by the formula (30c) at 0 to 60 ° C. for 0.5 to 12 hours.
  • Step 10-B the production of the compound represented by the general formula (1k) (Step 10-B) can be carried out using an appropriate solvent, for example, A compound represented by the general formula (27c) and a general formula (38) in the presence of a base such as pyridine or triethylamine in toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, if necessary.
  • the reaction can also be carried out by reacting the compound obtained at 0 to 60 ° C. for 0.5 to 12 hours.
  • Step 10-C production of the compound represented by the general formula (1k) (Step 10-C) has the general formula (35)
  • a suitable solvent such as toluene, benzene, diphenyl ether, tetrahydrofuran, acetonitrile, N, N-dimethylformamide or a mixture thereof, diphenyl phosphate azide and 0 in the presence of a base such as pyridine or triethylamine. It can also be carried out by reacting at ⁇ 120 ° C. for 0.5 to 12 hours and then reacting with the general formula (30c) at 0 to 80 ° C. for 1 to 12 hours.
  • the compound represented by the general formula (1l) can also be synthesized by the synthesis method shown in Production Method 11.
  • R 1 , R 2 , R 3 , R 5 , T, U, Y, Z, Ring A and Ring B have the same meaning as described above.
  • step 11-A Conversion of the compound represented by the general formula (27b) and the compound represented by the general formula (30d) into the compound represented by the general formula (1l) (step 11-A) is the same method as in step 10-A Can be performed.
  • the compounds represented by the general formula (1) which are the compounds of the present invention can also be synthesized by the synthesis method shown in the production method 12.
  • W 3 represents a halogen atom
  • r and t are the same or different and are 0, 1 or 2
  • r + t represents 0, 1 or 2
  • k represents 2, 3 or 4
  • R 1d , R 2 , R 3 , Y, Z, Ring A and Ring B have the same meaning as described above.
  • step 12-A The conversion from the compound represented by the general formula (29a) and the compound represented by the general formula (32a) to the compound represented by the general formula (1m) (step 12-A) is first performed by the general formula (29a).
  • an organic phosphorus compound such as triphenylphosphine or triethyl phosphite is used at ⁇ 78 to 120 ° C.
  • step 12-B Conversion of the compound represented by the general formula (33a) and the compound represented by the general formula (39) into the compound represented by the general formula (1m) (step 12-B) is the same method as in step 12-A Can be performed.
  • Step 12-C Conversion from the compound represented by the general formula (1m) to the compound represented by the general formula (1n) can be carried out by using a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran or N, N -In the presence of a metal catalyst such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide or rhodium-supported alumina in dimethylformamide or a mixed solution thereof, in the hydrogen atmosphere at atmospheric pressure to 0.5 MPa, the general formula (1 m ) Is reduced at 0 to 80 ° C. for 0.5 to 12 hours.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran or N, N -In the presence of a metal catalyst such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide or rhodium-supported a
  • the compound represented by the general formula (1o) can also be synthesized by the synthesis method shown in Production Method 13.
  • R 1d , R 2 , R 3 , W 3 , Y, Z, Ring A, Ring B, r, and t have the same meaning as described above.
  • Step 13-A Conversion of the compound represented by the general formula (29aa) and the compound represented by the general formula (40) into the compound represented by the general formula (1o) is carried out by using an appropriate solvent such as toluene.
  • an appropriate solvent such as toluene.
  • a base such as sodium hydride, n-butyllithium, lithium amide or potassium carbonate, etc. in tetrahydrofuran, diethyl ether, dimethyl sulfoxide, hexamethylphosphoric triamide, or a mixture thereof.
  • the compound represented by the general formula (29aa) and the compound represented by the general formula (40) are converted to -78.
  • the reaction can be carried out by reacting at ⁇ 120 ° C. for 1 to 12 hours.
  • the compound represented by the general formula (16) the compound represented by the general formula (13), the compound represented by the general formula (25), and the compound represented by the general formula (25)
  • the compound represented by the general formula (25a) can be synthesized by the synthesis method shown in Production Method 14.
  • R c represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 7 -C 12 aralkyl group
  • W 1 , X, Y, Z, Ring A and Ring B have the same meaning as described above.
  • Step 14-A Conversion from the compound represented by the general formula (41) to the compound represented by the general formula (25a) is carried out by using an appropriate solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol.
  • a compound represented by the general formula (41) using a reducing agent such as lithium borohydride, borane / dimethyl sulfide complex, lithium aluminum hydride or diisobutylaluminum hydride in ethanol, dichloromethane, or a mixed solution thereof;
  • the reaction can be carried out at 78 to 110 ° C. for 1 to 24 hours.
  • Step 14-B Conversion from the compound represented by the general formula (41) to the compound represented by the general formula (13) is carried out by using an appropriate solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol or dichloromethane, or these. Can be carried out by reacting the compound represented by the general formula (41) at ⁇ 78 to 60 ° C. for 1 to 24 hours using a reducing agent such as diisobutylaluminum hydride.
  • a reducing agent such as diisobutylaluminum hydride.
  • Step 14-C Conversion of the compound represented by the general formula (25a) to the compound represented by the general formula (13) (Step 14-C) is carried out by using an appropriate solvent such as toluene, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide or acetone.
  • an appropriate solvent such as toluene, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide or acetone.
  • the compound represented by the general formula (25a) is reacted with an oxidizing agent such as Jones reagent, PCC, PDC, manganese dioxide or oxalic chloride (Swern oxidation) at ⁇ 78 to 80 ° C. for 1 to 48 hours. Can be performed.
  • Step 14-D Conversion of the compound represented by the general formula (13) to the compound represented by the general formula (25a) is carried out by using a suitable solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol.
  • a compound represented by the general formula (13) is -78 using a reducing agent such as lithium borohydride, sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride in ethanol, dichloromethane or a mixture thereof. It can be carried out by reacting at ⁇ 150 ° C. for 1 to 24 hours.
  • step 14-E The conversion from the compound represented by the general formula (25a) to the compound represented by the general formula (25) (step 14-E) can be performed by the same method as in step 5-B.
  • Step 14-F Conversion of the compound represented by the general formula (25a) to the compound represented by the general formula (16) is carried out by using an appropriate solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl.
  • an appropriate solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl.
  • Electrophilic agent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or dipiperidine azodicarboxylate in the presence of an organic phosphorus compound such as triphenylphosphine or tributylphosphine in formamide, dimethyl sulfoxide or hexamethylphosphoric triamide or a mixture thereof
  • an organic phosphorus compound such as triphenylphosphine or tributylphosphine in formamide, dimethyl sulfoxide or hexamethylphosphoric triamide or a mixture thereof
  • a suitable solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, etc.
  • a suitable solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, etc.
  • a suitable solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, etc.
  • Step 14-G Conversion from the compound represented by the general formula (13) to the compound represented by the general formula (16) (Step 14-G) is carried out by using an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof.
  • an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof.
  • an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof.
  • an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof.
  • an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof.
  • acids such as hydrochloric acid, hydrobromic acid or acetic acid, or Lewis acids such as aluminum chloride or zinc chloride
  • a reducing agent such as sodium borohydride
  • the compound represented by the general formula (13) is reacted with hydroxylamine or
  • Tetrahydrofuran Tetrahydrofuran, ethanol, or a mixture thereof, such as iron, palladium, or zinc
  • an acid such as acetic acid or hydrochloric acid, can be carried out by reacting 1 to 24 hours in a hydrogen stream under 0 ⁇ 80 ° C..
  • an appropriate solvent such as tetrahydrofuran, methanol or ethanol, or a mixture thereof, etc.
  • the reaction can also be carried out by reacting with acid or base at 0 to 80 ° C. for 1 to 24 hours.
  • Step 14-H Conversion of the compound represented by the general formula (25) to the compound represented by the general formula (16) is carried out by using a suitable solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl.
  • a suitable solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl.
  • a suitable solvent such as methanol, ethanol or tetrahydrofuran or a mixture thereof, acid
  • a group or a hydrazine can be carried out by reacting 1 to 24 hours at 0 ⁇ 80 ° C..
  • Step 14-I The conversion from the compound represented by the general formula (42) to the compound represented by the general formula (16) (Step 14-I) is carried out in a suitable solvent such as methanol, ethanol or tetrahydrofuran or a mixture thereof.
  • a suitable solvent such as methanol, ethanol or tetrahydrofuran or a mixture thereof.
  • the reaction is carried out by reacting the compound represented by the general formula (42) with hydrogen at ⁇ 15 to 80 ° C. for 1 to 48 hours in the presence of aqueous ammonia in the presence of a metal catalyst such as palladium carbon, Raney nickel or platinum oxide. Can do.
  • an acid such as aluminum chloride or sulfuric acid or cobalt chloride is added as necessary, and lithium aluminum hydride or borohydride is added.
  • the reaction can be performed by reacting with a reducing agent such as sodium at 0 to 80 ° C. for 1 to 48 hours.
  • R c represents a C 1 to C 6 alkyl group which may have a substituent or a C 7 to C 12 aralkyl group which may have a substituent.
  • Conversion to a compound in which R c represents a hydrogen atom is carried out in the absence of a solvent or in a suitable solvent such as water, acetic acid, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, hydrochloric acid, sulfuric acid or nitric acid.
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the compound represented by the general formula (41) is hydrolyzed at 0 to 100 ° C. for 1 to 48 hours. This can be done by decomposing.
  • Conversion (14-J) from the compound represented by the general formula (43) to the compound represented by the general formula (42) is carried out by using an appropriate solvent such as water, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile.
  • a cyanating agent such as potassium ferricyanide or sodium cyanide
  • the compound represented by the general formula (44) can be synthesized by the synthesis method shown in the production method 15.
  • J a represents a formyl group, a cyano group, and COOR a
  • a a , R a , T, U, W 1 , Y, Z, Ring A, and Ring B have the same meanings as described above.
  • step 15-A Conversion of the compound represented by general formula (45) and the compound represented by general formula (28) into the compound represented by general formula (44) (step 15-A) is the same method as in step 5-A. Can be performed.
  • step 15-B The conversion from the compound represented by the general formula (45a) to the compound represented by the general formula (46) (step 15-B) can be performed by the same method as that for the compound represented by step 5-B.
  • step 15-C Conversion of the compound represented by the general formula (46) and the compound represented by the general formula (30) into the compound represented by the general formula (44) (step 15-C) is the same method as in step 5-C. Can be performed.
  • the compound represented by the general formula (44a) can also be synthesized by the synthesis method shown in Production Method 16.
  • step 16-A The conversion of the compound represented by general formula (30a) and the compound represented by general formula (45a) into the compound represented by general formula (44a) (step 16-A) is the same as step 6-A. It can be done by a method.
  • the compound represented by the general formula (44b) can also be synthesized by the synthesis method shown in Production Method 17.
  • J b represents a cyano group
  • step 17-A The conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (32) into the compound represented by the general formula (44b) (step 17-A) is the same as step 7-A. It can be done by a method.
  • step 17-B The conversion from the compound represented by the general formula (47) and the compound represented by the general formula (30b) to the compound represented by the general formula (44b) (step 17-B) is the same as step 7-A. It can be done by a method.
  • the compound represented by the general formula (44c) can also be synthesized by the synthesis method shown in Production Method 18.
  • J a , R 5 , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • step 18-A Conversion of the compound represented by the general formula (30c) and the compound represented by the general formula (48) into the compound represented by the general formula (44c) (step 18-A) is the same method as in step 8-A. Can be performed.
  • the compound represented by the general formula (44d) can also be synthesized by the synthesis method shown in Production Method 19.
  • J a , R 5 , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • step 19-A Conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (37) into the compound represented by the general formula (44d) (step 19-A) is the same method as in step 8-A. Can be performed.
  • the compound represented by the general formula (44e) can also be synthesized by the synthesis method shown in Production Method 20.
  • J a, R 5, T , U, Y, Z, Ring A, Ring B, the A b represents the same meaning as those described above.
  • step 20-A The conversion of the compound represented by the general formula (30c) and the compound represented by the general formula (45c) into the compound represented by the general formula (44e) (step 20-A) is the same as step 10-A. It can be done by a method.
  • Step 20-B the conversion to the compound represented by 44e) (Step 20-B) can be carried out by the same method as in Step 10-B.
  • Compound represented by the general formula (44e) is in the case A b is a compound which is a -NH-, a compound represented by the general formula (49) and the general formula (30c) generally from the compounds represented by formula Conversion to the compound represented by (44e) (Step 20-C) can be carried out in the same manner as in Step 10-C.
  • the compound represented by the general formula (44f) can also be synthesized by the synthesis method shown in the production method 21.
  • J a , R 5 , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.
  • step 21-A Conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (30d) into the compound represented by the general formula (44f) (step 21-A) is the same method as in step 10-A Can be performed.
  • the compounds represented by the general formula (44) and the general formula (44h) can also be synthesized by the synthesis method shown in the production method 22.
  • J b , W 3 , Y, Z, Ring A, Ring B, r, t, and k have the same meaning as described above.
  • step 22-A The conversion of the compound represented by the general formula (46a) and the compound represented by the general formula (32a) into the compound represented by the general formula (44g) (step 22-A) is the same as step 12-A. It can be done by a method.
  • step 22-B Conversion of the compound represented by the general formula (47a) and the compound represented by the general formula (39) into the compound represented by the general formula (44g) (step 22-B) is the same method as in step 12-A Can be performed.
  • Step 22-C The conversion from the compound represented by the general formula (44g) to the compound represented by the general formula (44h) (Step 22-C) can be performed by the same method as in Step 12-C.
  • the compound represented by the general formula (44i) can also be synthesized by the synthesis method shown in Production Method 23.
  • J a , W 3 , Y, Z, Ring A, Ring B, r, and t have the same meaning as described above.
  • step 23-A The conversion from general formula (46b) and general formula (40) to general formula (44i) (step 23-A) can be performed by the same method as in step 13-A.
  • the compound represented by the general formula (27b) can also be synthesized by the synthesis method shown in the production method 24.
  • R 1 , R 2 , R 3 , R 4 , U, U a and Z have the same meaning as described above.
  • step 24-A The conversion from the compound represented by the general formula (33) and the compound represented by the general formula (50) to the compound represented by the general formula (27b) (step 24-A) is the same as step 7-A. It can be synthesized by the method.
  • the compound represented by the general formula (27e) can also be synthesized by the synthesis method shown in Production Method 25.
  • R 1 , R 2 , R 3 , U, and Z are as defined above.
  • Step 25-A Conversion of the compound represented by the general formula (51) to the compound represented by the general formula (27e) is carried out by using a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or N, N -Performed by reacting a compound represented by the general formula (51) with hydrogen at 0 to 80 ° C for 1 to 24 hours under a metal catalyst such as palladium carbon, Raney nickel or platinum oxide in dimethylformamide or a mixture thereof. be able to.
  • a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or N, N -Performed by reacting a compound represented by the general formula (51) with hydrogen at 0 to 80 ° C for 1 to 24 hours under a metal catalyst such as palladium carbon, Raney nickel or platinum oxide in dimethylformamide or a mixture thereof.
  • a general formula is used using a metal such as reduced iron or zinc in the presence of an acid such as hydrochloric acid or acetic acid. It can also be carried out by reacting the compound represented by (51) at 0 to 150 ° C. for 0.5 to 12 hours.
  • the compounds represented by the general formulas (31), (34), (36) and (51) are included in the compound represented by (56) and are also synthesized by the synthesis method shown in Production Method 26. it can.
  • J c represents PG 1 —A a —U—, R a OOC—U—, O 2 N—U—, R a O (R b O) CH—U a —, and A a , R 1 , R a , R b , R 2 , R 3 , U, U a , W 1 , Z, PG 1 have the same meaning as described above.
  • step 26-A The conversion from the compound represented by the general formula (52) and the compound represented by the general formula (17) to the compound represented by the general formula (53) (step 26-A) is the same as in step 1-B. It can be done by a method.
  • step 26-B Conversion of the compound represented by the general formula (54) and the compound represented by the general formula (14) into the compound represented by the general formula (53) (step 26-B) is the same as in step 1-A. It can be done by a method.
  • step 26-C The conversion from the compound represented by the general formula (53) to the compound represented by the general formula (55) (step 26-C) can be performed by the same method as in step 1-C.
  • step 26-D The conversion from the compound represented by the general formula (55) to the compound represented by the general formula (56) (step 26-D) can be performed by the same method as in step 1-D.
  • step 26-E Conversion of the compound represented by the general formula (52) and the compound represented by the general formula (21) into the general formula (57) (step 26-E) can be performed by the same method as in step 2-B. it can.
  • step 26-F Conversion of the compound represented by the general formula (54) and the compound represented by the general formula (19) into the general formula (57) (step 26-F) can be performed by the same method as in step 2-A. it can.
  • step 26-G The conversion from the compound represented by the general formula (57) to the compound represented by the general formula (58) (step 26-G) can be performed by the same method as in step 2-C.
  • step 26-H The conversion from the compound represented by the general formula (58) to the compound represented by the general formula (56) (step 26-H) can be performed by the same method as in step 2-D.
  • Each optical isomer of the compound represented by the general formula (1) can be synthesized by the above-described production methods 1 to 26 using an optically active raw material compound.
  • An ester derivative or an oxazolidinone derivative can also be synthesized by separating it by fractional crystallization or chromatographic techniques and then hydrolyzing it.
  • Triethylamine (35.3 mL, 253 mmol) and ethyl chloroformate (25.4 mL, 266 mmol) were added to a solution of 5-formyl-2-methoxybenzoic acid (45.6 g, 253 mmol) in N, N-dimethylformamide (500 mL) with stirring under ice cooling. ) And stirred for 10 minutes under the same conditions.
  • [4- (4-fluorophenoxy) phenylmethyl] amine hydrochloride (70.6 g, 278 mmol) was added to the reaction mixture, and the mixture was stirred for 20 minutes under the same conditions.
  • Potassium cyanate (95.4 mg, 1.18 mmol) was added to an acetic acid solution (5 mL) of the compound in the first step (471 mg, 0.98 mmol), stirred at room temperature for 1 hour, and stirred at 100 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated.
  • Examples 2 to 5> According to the method of Example 1, the reaction was carried out using the compound of Reference Example 1 and the corresponding amino acid ester to obtain the compounds shown in the following formula and Table 2.
  • Triethylamine (2.56 mL, 18.3 mmol) and methyl chloroformate (1.21 mL, 15.7 mmol) were added to a tetrahydrofuran solution (66 mL) of the compound of the first step (3.30 g, 13.1 mmol) with stirring under ice cooling. The mixture was stirred for 30 minutes under the same conditions. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated to give the title compound (3.06 g, 75%) as colorless powder crystals.
  • the reaction was carried out using benzyl 3-formylbenzoate (200 mg, 0.83 mmol) and glycinamide hydrochloride (734 mg, 6.64 mmol) to give the title compound 2 (198 mg, 80% ) Was obtained as colorless powdery crystals.
  • the reaction was performed using the compound of the second step (170 mg, 0.47 mmol) to obtain the title compound (107 mg, 92%) as colorless powder crystals.
  • the reaction was performed using the compound of the third step (97.9 mg, 0.39 mmol) to obtain the title compound (73.0 mg, 80%) as colorless powder crystals.
  • Lithium aluminum hydride (2.61 g, 68.8 mmol) was added to a tetrahydrofuran solution (98 mL) of the compound in the first step (8.20 g, 34.4 mmol) under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes.
  • Water (2.61 mL), 15% aqueous sodium hydroxide solution (2.61 mL) and water (7.83 mL) were added to the reaction mixture, and the mixture was stirred for 6 hours.
  • the reaction mixture was filtered through Celite, and the filtrate was concentrated.
  • the compound (8.29 g, 99%) was obtained as pale yellow powdery crystals.
  • Example 8 3- (2,4-Dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 193-195 ° C.
  • Example 10 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenyl] benzamide colorless powdery crystalline melting point: 202-204 ° C.
  • Example 11 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- (4-phenoxyphenylmethyl) benzamide colorless powdery crystalline melting point: 115-117 ° C.
  • Example 12 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-toluyloxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 122-124 ° C.
  • Example 15 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-methoxyphenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 139-140 ° C.
  • Example 16 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide white solid IR (ATR) : 3395.6, 312.11.7, 2946.2, 1763.7, 1712.4, 1693.9, 1634.6, 1597.8, 1510.1 cm ⁇ 1 .
  • Example 17 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenylthio) phenylmethyl] benzamide colorless powdery crystalline melting point: 149-150 ° C.
  • Example 18 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N-[[6- (4-fluorophenoxy) pyridin-3-yl] methyl] benzamide colorless powder crystal IR (ATR ): 3591, 3398, 3162, 3070, 1765, 1712, 1642, 1537, 1505 cm ⁇ 1 .
  • Example 20 4- [4-[[5-[(2,4-Dioxoimidazolidin-1-yl) methyl] -2-methoxybenzamido] methyl] phenoxy] ethyl benzoate colorless powder crystals IR (ATR): 3335. 0, 3137.7, 3065.9, 1769.9, 1710.3, 1598.9, 1499.3, 1469.1, 1425.1, 1308.7, 1279.0, 1246.5, 1163.5, 1098.3, 1015.2, 952.5, 874.4, 843.8, 764.1, 638.5, 596.2, 498.4, 417.1 cm ⁇ 1 .
  • Example 21 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (cyclohexyloxy) phenylmethyl] benzamide white solid IR (ATR): 3341.5, 3121.5, 2932.2, 2856.4, 1796.4, 1710.4, 1623.0, 1546.4 cm ⁇ 1 .
  • Acetic anhydride (0.150 mL) and triethylamine (0.092 mL, 0.663 mmol) were added to a tetrahydrofuran solution (6.64 mL) of the compound of Example 31 (300 mg, 0.613 mmol), and the mixture was stirred at room temperature for 24 hours.
  • the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted 5 times with ethyl acetate.
  • Potassium cyanate (260 mg, 3.21 mmol) was added to an acetic acid solution (7.6 mL) of the compound in the second step (1.21 g, 2.67 mmol), and the mixture was stirred at room temperature for 30 minutes and then at 100 ° C. for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated.
  • ⁇ Test Example 1 De novo lipid synthesis ability inhibiting action> HepG2 cells were cultured in a 12-well plate for 48 hours, replaced with serum-free medium (FCS free / DMEM), and cultured for 16 hours. Subsequently, HepG2 cells were replaced in serum-free medium containing the test compound, [1- 14 C] -labeled acetic acid and unlabeled acetic acid, and further incubated for 3 hours.
  • Table 4 shows the test results.
  • the “inhibitory activity” in the table represents de novo lipid synthesis inhibitory activity when 30 ⁇ M of the test compound was used. Inhibition ratio 81% to 100%: A, inhibition ratio 51% to 80%: B, inhibition ratio 21 % To 50%: C, inhibition ratio 10% to 20%: D
  • the compounds of the present invention showed a strong inhibitory activity on de novo lipid synthesis.
  • AMPK ⁇ and ACC1 phosphorylation promoting action HepG2 cells (6 cm 2 culture dish) cultured in Dulbecco's modified Eagle medium (FCS / DMEM) containing 10% bovine serum and 1% penicillin / streptomycin were cultured in serum-free medium (FCS free / DMEM) for 16 hours. The medium was replaced with a test compound-containing medium and incubated for 3 hours (37 ° C., 5% carbon dioxide). Three hours later, the cell lysate was collected, and the amount of protein was quantified by the Bradford method. Then, phosphorylated AMPK ⁇ (pThr172) and phosphorylated ACC1 (pSer79) were detected by SDS-PAGE and Western blotting.
  • FCS / DMEM Dulbecco's modified Eagle medium
  • FCS free / DMEM serum-free medium
  • EC 50 represents the concentration of the test compound when 50% of the maximum effect of AMPK ⁇ (Thr172) phosphorylation ability by the test compound is shown, EC 50 ⁇ 1 ⁇ M: A, 1 ⁇ M ⁇ EC 50 ⁇ 5 ⁇ M : B, 5 ⁇ M ⁇ EC 50 : C
  • EC 50 represents the concentration of the test compound when showing 50% of the maximum effect of ACC1 (Ser79) phosphorylation ability by the test compound, EC 50 ⁇ 1 ⁇ M: A, 1 ⁇ M ⁇ EC 50 ⁇ 5 ⁇ M. : B, 5 ⁇ M ⁇ EC 50 : C
  • the compounds of the present invention were found to have good AMPK ⁇ phosphorylation promoting action and ACC phosphorylation promoting action.
  • Example 3 Mouse blood glucose and triglyceride lowering action> B6.
  • V-Lep ⁇ ob> / J (ob / ob) male mice were bred from OA-2 diet (CLEA Japan) from 6 weeks of age, and then the test was started from 7 weeks of age.
  • the test compound (30 mg / kg) was suspended in a 0.1% Tween 80 solution and orally administered once a day for 7 days. Seven days later, blood was collected from the tail vein, and blood glucose and triglyceride were measured by an enzymatic method.
  • Table 7 shows the test results.
  • the “decrease rate” in the table is a value obtained by subtracting the average blood glucose level (or average triglyceride level) of the test compound administration group from the average blood glucose level (or average triglyceride level) of the vehicle control group.
  • the compound of the present invention was found to have a good mouse blood glucose lowering action and triglyceride lowering action.
  • novel benzylhydantoin derivative and its addition salt of the present invention have an excellent human AMPK activating action, it is useful as an advantageous effect derived from the AMPK activating action, such as a hypoglycemic agent or a lipid lowering agent.

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Abstract

Cette invention concerne un composé ayant une puissante activité d'activation de l'AMPK et exerçant un effet avantageux provenant de ladite activité d'activation de l'AMPK in vivo. Cette invention concerne un dérivé d'hydantoïne représenté par la formule générale (1), un sel pharmacologiquement acceptable de celui-ci ou un hydrate dudit dérivé ou sel pharmacologiquement acceptable de celui-ci.
PCT/JP2011/069063 2010-08-25 2011-08-24 Nouveau dérivé d'hydantoïne et médicament le contenant à titre de principe actif Ceased WO2012026495A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013172421A1 (fr) 2012-05-17 2013-11-21 杏林製薬株式会社 Procédé de criblage d'un activateur de protéine ampk et activateur de protéine ampk
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof
US12233062B2 (en) 2018-09-26 2025-02-25 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3759121A1 (fr) * 2018-03-01 2021-01-06 Trigemina, Inc. Oxytocine marquée, procédé de production et d'utilisation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5332738A (en) * 1992-09-11 1994-07-26 Ncneilab, Inc. Imidazolidine antipsychotic agents
WO2007005785A1 (fr) * 2005-07-04 2007-01-11 Dr. Reddy's Laboratories Ltd. Derives de thiazole utiles comme activateurs de l'ampk
WO2008006432A1 (fr) * 2006-07-13 2008-01-17 Merck Patent Gmbh Utilisation de dérivés d'imidazole activateurs d'ampk, procédé de préparation de ces composés, et compositions pharmaceutiques pourvues de ceux-ci
WO2008017381A1 (fr) * 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009098000A1 (fr) * 2008-02-07 2009-08-13 Sanofi-Aventis Imidazolidine-2,4-diones substitués par un hétérocycle, procédé de production, médicaments contenant ces composés et leur utilisation
WO2011078370A1 (fr) * 2009-12-25 2011-06-30 杏林製薬株式会社 Nouveau dérivé de l'acide parabanique et médicament le contenant comme principe actif

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5332738A (en) * 1992-09-11 1994-07-26 Ncneilab, Inc. Imidazolidine antipsychotic agents
WO2007005785A1 (fr) * 2005-07-04 2007-01-11 Dr. Reddy's Laboratories Ltd. Derives de thiazole utiles comme activateurs de l'ampk
WO2008006432A1 (fr) * 2006-07-13 2008-01-17 Merck Patent Gmbh Utilisation de dérivés d'imidazole activateurs d'ampk, procédé de préparation de ces composés, et compositions pharmaceutiques pourvues de ceux-ci
WO2008017381A1 (fr) * 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009098000A1 (fr) * 2008-02-07 2009-08-13 Sanofi-Aventis Imidazolidine-2,4-diones substitués par un hétérocycle, procédé de production, médicaments contenant ces composés et leur utilisation
WO2011078370A1 (fr) * 2009-12-25 2011-06-30 杏林製薬株式会社 Nouveau dérivé de l'acide parabanique et médicament le contenant comme principe actif

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
WO2013172421A1 (fr) 2012-05-17 2013-11-21 杏林製薬株式会社 Procédé de criblage d'un activateur de protéine ampk et activateur de protéine ampk
EP2851686A4 (fr) * 2012-05-17 2016-05-18 Kyorin Seiyaku Kk Procédé de criblage d'un activateur de protéine ampk et activateur de protéine ampk
US9863955B2 (en) 2012-05-17 2018-01-09 Kyorin Pharmaceutical Co., Ltd. AMPK activator screening method, and AMPK activator
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US10513499B2 (en) 2014-08-29 2019-12-24 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof
US12233062B2 (en) 2018-09-26 2025-02-25 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors

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