WO2002053548A1 - Derives de la benzothiazepine - Google Patents

Derives de la benzothiazepine Download PDF

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Publication number
WO2002053548A1
WO2002053548A1 PCT/JP2001/011267 JP0111267W WO02053548A1 WO 2002053548 A1 WO2002053548 A1 WO 2002053548A1 JP 0111267 W JP0111267 W JP 0111267W WO 02053548 A1 WO02053548 A1 WO 02053548A1
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group
alkyl
alkoxy
amino
rubamoyl
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PCT/JP2001/011267
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English (en)
Japanese (ja)
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Toshio Nagase
Yoshiyuki Sato
Junichi Eiki
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Banyu Pharmaceutical Co.,Ltd.
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Publication of WO2002053548A1 publication Critical patent/WO2002053548A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • A61P3/08—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

Definitions

  • the present invention is clearly useful in the field of medicine. More specifically, since the benzothiazepine derivative of the compound of the present invention has an activity of exhibiting a high blood GLP-1 concentration, it is useful as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes or an antiobesity agent. is there. Background technology
  • the blood sugar level of a healthy person is constantly controlled by the action of insulin. Diabetes refers to a chronic hyperglycemic state in which this control is ineffective and a disease caused by it.
  • diabetes treatment The basis of diabetes treatment is to correct hyperglycemia, i.e., to return blood glucose levels to normal levels.In recent years, however, it has been particularly important in recent years to prevent a rapid rise in blood glucose after eating without affecting fasting blood glucose. It has been recognized that it is extremely important in terms of treatment to control the amount of the drug.
  • the first is a group of drugs called insulin-releasing drugs typified by sulfonylprea drugs, which promote insulin secretion directly from the brain and lower blood sugar levels.
  • the second is a drug that has recently been launched, called an insulin sensitizer, that lowers blood glucose by promoting glucose uptake in peripheral tissues without directly promoting insulin release. is there.
  • the third monoglucosidase inhibitor is a drug that controls the rapid rise in blood glucose by delaying the digestion and absorption of carbohydrates in the gastrointestinal tract and suppressing the temporary rise in blood glucose after meals. is there. .
  • GLP-1 glucagon-like peptide-1
  • L cells which are endocrine cells present in the small intestinal intestinal epithelium due to intensification, etc., and acts on ⁇ cells present in the islets of Langerhans to promote the secretion of insulin to lower blood sugar.
  • GLP_1 insulin secretion by GLP_1 depends on blood glucose level.Insulin secretion by GLP-1 is not observed in normoglycemia, and it is reported that insulin secretion is enhanced only in hyperglycemia.
  • GLP-1 not only enhances insulin secretion but also enhances insulin biosynthesis (Endocri no lgygy, 130, 159, 1992) and promotes the proliferation of] 3 cells (Diabeto 1 ogia, Vol. 42, p. 856, 1999), which is an essential factor for maintaining 8 cells.
  • GLP-1 gastrointestinal motility inhibitory effect
  • Metatab. D is pos., 27, p. 637 , 1999 (hereinafter referred to as Reference I), Curr. Opin. Cardiova sc., Renal Instst Drugs, 1, p. 276, 1999 (hereinafter referred to as Reference J). ), J. Lipid Res., 40, p. 2158, 1999 (hereinafter referred to as Reference K), Anal. Biochem., 282, p. 94, 2000 (hereinafter referred to as Reference L). ), International Publication No. WOO 0Z38725 (hereinafter referred to as Reference M), International Publication No. WO00 / 38726 (hereinafter referred to as Reference N), and International Publication No.
  • WO00 / 38727 (hereinafter referred to as Reference 0). ), International Publication Number WO00 / 3 No. 8728 (hereinafter referred to as Reference P), International Publication No. WO 00/38729 (hereinafter referred to as Reference Q), and International Publication No. WO00 / 55355 (hereinafter referred to as Reference R). ing.
  • references A to R describe compounds having a 1,4-benzothiazepine skeleton.
  • the 1,4-benzothiazepine 1,1-dioxoside skeleton is common to the compounds of References A to R, the 3-position substituent on the skeleton is a monosubstituted compound.
  • References A to R are hypolipidemic compounds caused by the inhibitory action of bile acid uptake, and have the same industrial application fields as the present invention, but are completely different from the uses of the present invention. This is an unrelated application. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.
  • Reference S discloses a 1,4-benzothiazepine skeleton and its oxidized and reduced forms, specifically, 1,4-benzen. Scaffolds such as 4,5-dihydro, 4,5-dihydro, N-oxidized, and 4,5-year-old oxaziridine derivatives of the zothiazepine skeleton are described.
  • the compounds of the present invention have a 1,4-benzothiazepine skeleton in common with the compound of Reference J
  • the 4-benzodiazepine skeleton has a 4-dihydro form, a 4-dihydroform, an N-oxidized form, and a 4,5-year-old compound.
  • Oxaziridines are compounds with completely different structures outside the scope of the present invention.
  • the use of Reference S is a compound having a muscle relaxant and anticonvulsant activity and has the same industrial field of application, but is completely unrelated to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.
  • Reference T discloses a three-ring fused ring containing a 1,4-benzothiazepine skeleton, pyrrole [1,2-d]-. Compounds having a 1,4-benzothiazepine skeleton have been described.
  • Reference T is a condensed tricyclic ring, and is a compound having a completely different structure outside the scope of the present invention.
  • the use of Reference T is a compound having a locomotor activity-suppressing action, and although it has the same industrial field of application, it has no relation to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.
  • Reference U discloses a cheno [3,2-f] _1,4,1-benzothiazepine containing a 1,4-benzothiazepine skeleton. Compounds having a skeleton are described.
  • Reference U is a compound in which the substituent at the 5-position on the skeleton has hydrogen, a straight-chain C 5 alkyl group or a C 3 -C 7 cyclic alkyl group, and the compound of the present invention has a substituent.
  • the compound has a completely different structure in that it may have an aromatic ring or a heterocyclic ring. Although it has the same industrial field of application as a drug for suppressing intraocular pressure rise and for treating glaucoma, it is a use that has no relation to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.
  • antidiabetic drugs such as sulfonylprea drugs, insulin resistance Drugs such as sex-improving agents and mono-dalcosidase inhibitors are widely used in the clinic, but have the following problems, and they cannot be said to be sufficient drugs.
  • sulfonylurea agents have a slow onset of action and a long duration of action, making it difficult to develop a synergistic effect during postprandial hyperglycemia, and also lower fasting blood sugar and are often life-threatening Such severe hypoglycemic attacks can be caused.
  • Insulin sensitizers often have side effects on the liver and require careful use under strict control. It may also cause edema and other side effects. In addition, side effects such as bloating and diarrhea have become a problem with Hi-Dalcosidase inhibitors.
  • An object of the present invention is to provide a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, an anti-obesity drug, and the like, since they exhibit an activity of exhibiting a high blood GLP-1 concentration.
  • the present inventors have intensively studied for the purpose of creating a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an anti-obesity agent capable of controlling blood glucose level depending on the blood glucose level. ]
  • 1 and R 2 are the same or different and each represents a hydrogen atom, a C—C ⁇ alkyl group,
  • R 3 is a hydrogen atom, a C, —C 6 alkyl group (excluding an n-butyl group), R 4 is a hydrogen atom, a hydroxyl group, a C 3 alkyl group,
  • R 5 is a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a carboxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group Group, formylamino group, cyclic saturated or unsaturated C 3 -C 9 aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N -Aralkyl groups: rubamoyl group, aryl group, N-arylamino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyl
  • C i one C 6 alkoxy group, one C 6 alkylthio group, Nyu- - C 6 alkylamino group, N-CI- C 6 alkyl force Rubamoiru group, N-Ci-C 6 alkyl
  • a carbon atom which may have a substituent selected from the group consisting of thiocarbamoyl groups; Kowamoto, 1 to tricyclic C 7-C 15 carbon ring group or a 5- or 6-membered heterocyclic group or a nitrogen atom, a heteroatom 1 ring system selected from the group consisting of SansoHara bar and a sulfur atom 1 to 5 mono- to 3-cyclic heteroaromatic groups (excluding 5- or 6-membered heterocyclic groups),
  • Ar represents a hydrogen atom, an azide group, an amino group, a rubamoyl group, a rubamoylamino group, a rubamoyloxy group, a lipoxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, cyclic saturated or unsaturated C 3 -C 9 aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N -Aralkyl groups: rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group,
  • Alkyl rubamoyl groups N, N-di-I. Alkyl Scarpa model I le group, N- C 2 - C 6 alkenyl carbamoylmethyl group, N, N- di C 2 -. C 6 alkenyl carbamoylmethyl group, N- amino ( ⁇ primary alkyl force Rubamoiru group, N- one C 6 Alkoxy G 10 Alkyl Lubamoyl group, NC x -C 6 Alkoxy Luponyl C! -1 C.
  • Alkyl Lubamoyl group N-C "C 6 Alkoxy Lubamoyl group C 10 Alkyl Lubamoyl group, NC i -Ce alkoxycarbonylamino ( ⁇ — Ce alkoxycarbonyl group, 1 C 6 alkylthio group, NC i 1 C 6 alkylsulfamoyl group, N, N-di C — C 6 alkylsulfamoyl group, C!
  • C 6 alkyl force Rubamoiru group has a NC-Ce. alkylthio force Rubamoiru substituents selected from the group ing from the base which may be a carbon aromatic ring group, 1 to 3 rings of the C 7 - C 15 carbon ring group or 5 young Or a 6-membered heterocyclic group, or a 2- or 3-cyclic fused heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur , And 5 or 6 membered heterocyclic groups are excluded.), And n is an integer of 0 to 2.] It has been found that the compound represented by the formula (1) achieves a high blood GLP-1 concentration in vivo. Completed the invention.
  • the present invention relates to benzothiazepine derivatives and uses thereof, and these inventions are novel ones not described in the literature. Next, various symbols and terms described in this specification will be described.
  • the C er C 3 alkyl group such as methyl group, Echiru group, a propyl group can be mentioned, et al are, inter alia methyl, and the like Echiru group.
  • a C 6 alkyl group includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, a hexyl group, and an isohexyl group.
  • isopropyl group, isobutyl group, sec-butyl group, neopentyl group, isohexyl group and the like are preferable.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, among which a fluorine atom, a chlorine atom and an iodine atom are preferred, and a fluorine atom and a chlorine atom are more preferred.
  • the cyclic saturated or unsaturated C 3 -C 9 aliphatic group includes a cyclic alkyl group or alkenyl group having 3 to 9 carbon atoms, among which a cyclic alkyl group having 3 to 6 carbon atoms. Or an alkenyl group, and more preferably a cyclic alkyl group having 3 to 6 carbon atoms.
  • cyclic alkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclononyl group.
  • a tyl group and a cyclohexyl group are preferred.
  • Examples of the cyclic alkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclohexenyl group, and a cyclononenyl group.
  • a cyclopropenyl group, a cyclobutenyl group and the like are exemplified.
  • Group, cyclopentenyl group, cyclohexenyl group and the like are exemplified.
  • the aralkyl group means an aralkylyl group having 7 to 15 carbon atoms, specifically, for example, a benzyl group, a monomethylbenzyl group, a phenethyl group, a 3-phenylpropyl group, a 1-naphthylmethyl group. , 2-naphthylmethyl group, ⁇ -methyl (1-naphthyl) methyl group, a-methyl (2-naphthyl) methyl group, ⁇ -ethyl (1naphthyl) methyl group, Q!
  • the N-aralkylamino group means a group in which the above-mentioned aralkyl group is substituted on the amino group, and specifically, for example, N-benzylamino group, N- (1-methylbenzyl) amino group, N-phenethylamino group, N- (3-Phenylpropyl) amino group, N— (1-naphthylmethyl) amino group, N— (2-naphthylmethyl) amino group, N— [Hi-methyl (1-naphthyl) methyl] amino group, N— [1-methyl (2-naphthyl) methyl] amino group, N— [1-ethyl (1-naphthyl) methyl] amino group, N — [— ethyl (2-naphthyl) methyl] amino group, diphenylmethyl amino group, Examples include an N- (dinaphthylmethyl) amino group, and among them, an N-benzylamin
  • the ⁇ , ⁇ -aralkylamino group means a group obtained by substituting the above aralkyl group for an amino group, and specifically, for example, ⁇ , ⁇ -dibenzylamino group, ⁇ , ⁇ -di (monomethyl) group.
  • An aralkyloxy group means a group in which an oxygen atom is substituted by the above aralkyl group.
  • the aralkylcarbonyl group means a group in which the aralkyl group is substituted on the carbonyl group, specifically, for example, a benzylcarbonyl group, a monomethylbenzylcarbonyl group, a phenethylcarbonyl group, Phenylpropyl carbonyl group, 1-naphthylmethyl carbonyl group, 2-naphthylmethyl carbonyl group, mono-methyl (1-naphthyl) methyl carbonyl group, ⁇ -methyl (2-naphthyl) methyl carbonyl group, a-ethyl (1-naphthyl) ) Methylcarbonyl group, methylethyl (2-naphthyl) methylcarbonyl group, diphenylmethylcarbonyl group, dinaphthylmethylcarbonyl group, etc., among which benzylcarbonyl group, 1-methylbenzylcarbonyl group,
  • the N-aralkyl molybamoyl group means a group obtained by substituting the above-mentioned aralkyl group with a molybmoyl group, and specifically includes, for example, N-benzylcarbamoyl group, N- (monomethylbenzyl) molybmoyl group, Netyl carbamoyl group, N— (3-phenylphenyl) dirubamoyl group, N— (1-naphthylmethyl) dirubamoyl group, N— (2-naphthylmethyl) dirubamoyl group, N- ( ⁇ -methyl (1 Naphthyl) methyl) dirubamoyl group, N— (Hi-methyl (2-naphthyl) methyl) dirubamoyl group, N— (1-ethyl (1-naphthyl) methyl) dirubamoyl group, N- ( ⁇ -ethyl) 2-naph
  • the aryl group means an aryl group having 6 to 15 carbon atoms, for example, a naphthyl group, a phenyl group and the like, among which a phenyl group and the like are preferable.
  • arylamino means a group obtained by substituting the above-mentioned aryl group with an amino group, specifically, for example, a phenylamino group, a ⁇ (1-naphthyl) amino group, an ⁇ — (2— Naphthyl) amino group and the like, among which a ⁇ -phenylamino group and the like are preferable.
  • the ⁇ , ⁇ -diarylamino group means a group obtained by disubstituting the above aryl group with an amino group.
  • the aryloxy group means a group in which an oxygen atom is substituted by the above aryl group, and specific examples include a phenoxy group and a naphthyloxy group. Among them, a phenoxy group and the like are preferable.
  • the arylsulfonyl group means a group in which the above-mentioned aryl group is substituted on the sulfonyl group, specifically, for example, a phenylsulfonyl group, a naphthylsulfonyl group and the like. Groups and the like are preferred.
  • the arylsulfonyloxy group means a group in which a sulfonyloxy group is substituted with the above-mentioned aryl group, and specifically, for example, phenylsulfonyloxy group, naphthylsulfonyloxy group and the like. Among them, a phenylsulfonyloxy group and the like are preferable.
  • the N-arylsulfonylamino group means a group in which the above-mentioned arylsulfonyl group is N_substituted for an amino group, specifically, for example, an N-phenylsulfonylamino group, (1_naphthylsulfonyl) amino group, N- (2-naphthylsulfonyl) amino group and the like are preferable, and among them, N-phenylsulfonylamino group and N- (2-naphthylsulfonyl) amino group are preferable.
  • N- ⁇ Li one Le sulfonyl ⁇ amino d-C 6 alkylamino group, d-C 6 alkyl groups having on the Symbol of ⁇ Li one Le sulfonyl ⁇ amino group to Amino group means a N- substituted group Specifically, for example, N-phenylsulfonylaminomethylamino group, N- (1-phenylsulfonylaminoethyl) amino group, N— (2-phenylsulfonylaminoethyl) amino group, N-naphthylsulfonylamino Methylamino group, N- (1-naphthylsulfonylaminoethyl) amino group, N- (2-naphthylsulfonylaminoethyl) amino group and the like, among which N-phenylsulfonylaminomethylamino group, N- (2 —Phen
  • the C 6 alkoxy Cal Poni group, a group of the above N- ⁇ Li one Le sulfonyl ⁇ amino group is substituted with one C 6 alkoxy Cal Poni Le group was meaning taste, specifically, for example N- phenylalanine sulfonylamino methoxy Cal Poni Le Group, N-naphthylsulfonylaminomethoxycarbonyl group, 1- (N-phenylsulfonylamino) ethoxycarbonyl group, 2- (N-phenylsulfonylamino) ethoxycarbonyl group, etc., among which N-phenylsulfonylaminomethoate Xycarbonyl group, N-naphthylsulfony
  • the arylsulfamoyl group means a sulfamoyl group substituted with the above aryl group, and specifically includes, for example, a phenylsulfamoyl group, a naphthylsulfamoyl group and the like, and among them, a phenylsulfamoyl group and the like. preferable.
  • the arylsulfamoyloxy group means a sulfamoyloxy group substituted with the above aryl group, specifically, for example, phenylsulfamoyloxy group, naphthylsulfayl group Moyloxy groups and the like can be mentioned, among which phenylsulfamoyloxy groups and the like are preferable.
  • the arylsulfamoyl C 11 -C] _ 0 alkyl rubamoyl group means a group in which the above arylsulfamoyl is substituted with a d-C 10 alkyl rubamoyl group, and specifically, for example, phenylsulfamoyl Moylmethylcarbamoyl group, naphthyls And a phenylsulfamoylmethylcarbamoyl group.
  • Li one Rusurufamoiru ( ⁇ - The C 6 alkoxy Cal Poni group, means a group above ⁇ Li one Rusurufamoiru has been substituted with d-C 6 alkoxy Cal Poni group, concrete in, for example Hue acylsulfamoyl methoxy Cal Poni Le group And a naphthylsulfamoylmethoxycarbonyl group, among which a phenylsulfamoylmethoxycarbonyl group and the like are preferable.
  • the N-arylcarbamoyl group means a group in which the above aryl group is N-substituted with a carbamoyl group, and specifically includes, for example, a phenylcarbamoyl group, a naphthylcarbamoyl group and the like. And the like.
  • An aroyl group means a group in which a carbonyl group is substituted with the above-mentioned aryl group, and specific examples thereof include a benzoyl group and a naphthylcarboel group, and among them, a benzoyl group and the like are preferable.
  • the alkoxy group means a group in which the above-mentioned aroyl group is substituted by an oxygen atom, and specifically includes, for example, a benzoyloxy group, a naphthylcarponyloxy group and the like, and among them, a benzoyloxy group and the like are preferable.
  • the N— (N-aroylamino) d _C 10 alkyl rubamoyl group means a group obtained by substituting a rubamoyl group with the above-mentioned N-aroylamino C 11 -Ci 0 alkyl group.
  • N- (N-benzoylaminomethyl) rubamoyl group N- (1- (N-benzoylamino) ethyl) rubamoyl group, N— (2- (N-benzoyl) aminoethyl) rubamoyl group, N— (N-naphthylcarbonylaminomethyl) rubamoyl group, N— (1- (N-naphthylcarbonylamino) ethyl) rubamoyl group, N— (2- (N-naphthylcarbonylamino) ethyl) rubamoyl group Among them, an N- (N-benzoylaminomethyl) carbamoyl group and an N- (2- (N-benzoylamino) ethyl) rubamoyl group are preferable.
  • the N-aroylamino d-Ce alkoxycarbonyl group means a group in which the above-mentioned N-aroylamino d-C 6 alkyl group is substituted for an oxycarbonyl group, and specifically, for example, an N-benzoylaminomethoxycarbonyl group , 1- (N-benzoylamino) ethoxycarbonyl group, 2_ (N-benzoylamino) ethoxycarbonyl group, N-naphthylcarbonylaminomethoxycarbonyl group, 1- (N-naphthylcarbonylamino) ethoxycarbonyl group, 2- (N-naphthylcarbonylamino) ethoxycarbonyl group and the like, among which an N-benzoylaminomethoxycarbonyl group and a 2_ (N-benzoylamino) ethoxycarbonyl group are preferable.
  • the C 2 -C 6 alkanol group means a carbonyl group substituted with an alkyl group having 1 to 5 carbon atoms, and specifically includes, for example, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, and a valeryl group.
  • acetyl group, propionyl group, pivaloyl group and the like are preferable.
  • the C 2 —C 6 alkenyl group refers to a group in which the above-mentioned C 2 -C 6 alkynyl group is substituted for a hydroxyl group, specifically, for example, an acetyloxy group, a propionyloxy group, a butyryloxy group, Examples include an isoptyryloxy group, a valeryloxy group, an isovaleryloxy group, a pivaloyloxy group, and a pentanoyloxy group. Of these, an acetyloxy group, a propionyloxy group, and a vivaloyloxy group are preferable.
  • the N—C 2 —C 6 alkanoylamino group refers to a group in which the above C 2 —C 6 alkanoyl group is substituted for an amino group, and specifically, for example, an N—acetylamino group, Mouth pionylamino, N-butyrylamino, N-isobutyrylamino, N-valerylamino, N-isovalerylamino, N-bivaloylamino, N-pentanoylamino, etc.
  • N, N - The C 6 alkanoyloxy noisy Rua amino group, the Amino group of the C 2 - - di -C 2 C 6 Arukanoiru group means two substituted groups, and specific examples N, N-Jiasechi A lumino group, an N, N-dipropionylamino group, an N, N-dibutyrylamino group, N, N-diisobutyrylamino group, N, N-divalerylamino group, N, N-diisovalerylamino group, N, N-dipiparylylamino group, N, N-dipentanoylamino group, N-acetyl-N- A propionylamino group, an N-acetyl-N-butylylamino group, an N-acetyl-N-piparylylamino group and the like, among which N, N-diacetylamino, N, N-dipropion
  • the N-Ci-C 6 alkylamino group means a group in which an amino group is substituted with an alkyl group having 1 to 6 carbon atoms, specifically, for example, N-methylamino group, N-ethylamino group, N- To propylamino group, N-isopropylamino group, N-butylamino group, N-isobutylamino group, N-sec-butylamino group, N-tert-butylamino group, N-pentylamino group, N-neopentylamino group, N- Xylamino group, N-isohexylamino group and the like.
  • N-methylamino group, N-ethylamino group, N-propylamino group, N-isopropylamino group, N-butylamino group, N-isobutylamino group, — Tert-butylamino group and the like are preferable.
  • the N, N-di-d-C 6 alkylamino group means a diamino-substituted alkyl group having 1 to 6 carbon atoms, specifically, for example, N, N-dimethylamino group, N, N-diethylamino, N, N-dipropylamino, N, N-diisopropylamino, N, N-dibutylamino, N, N-ditert-butylamino, N, N-dipentylamino, N, N-dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-tert-butyl-N-methylamino group, N-ethyl N-isopropylamino group and the like, among which N, N-dimethylamino group, N, N-diethylamino
  • N—Ci—C 10 alkyl rubamoyl group means that the rubamoyl group does not have 1 carbon atom And a group substituted by 10 alkyl groups, specifically, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, Butylcarbamoyl, N-isobutyl carbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl, N-neopentylcarbamoyl, N-hexylcarbamoyl, N-iso A xylcarbamoyl group, an N-octylcarbamoyl group, an N-decylcarbamoyl group, and the like.
  • an N-methyl rubamoyl group an N-ethyl carbamoyl group, an N-propyl carbamoyl group, an N-isopropyl carbamoyl group, N-isobutylcarbamoyl group, N-sec-butyl carbamoyl group, N-tert-butyl Rubamoiru group, N- old Kuchiruka Rubamoiru group, N- dodecylcarbamoyl group and the like.
  • the N, N-di-C i-C ioalkyl rubamoyl group refers to a group obtained by disubstituting a carbamoyl group with an alkyl group having 1 to 10 carbon atoms.
  • N - C 2 - A C 6 alkenyl carbamoylmethyl group, having 2 to carbon Karupamoiru based means a group alkenyl group substituted consisting six, specifically for example, N- vinyl carbamoyl group, N- Ariru force Rubamoyl group, N- (1-probenyl) carbamoyl group, N-isoprobenylcarbamoyl group, N- (2-butenyl) carbamoyl group, N-isobutenylcarbamoyl group, N— (2-pentenyl) Cal Bamoyl group, N- (2-hexenyl) carpamoyl group, N- (2-heptenyl) -powered rubamoyl group, N- (2-octenyl) -powered rubamoyl group, etc., among which N-vinylcarbamoyl group, Preferred are an N-arylcarpamoyl group, an N- (1
  • the N, N-di-C 2 -C 6 alkenylcarbamoyl group refers to a disubstituted alkamoyl group having 2 to 6 carbon atoms in a carbamoyl group.
  • N- The Amino Ci one C 1 0 alkyl force Rubamoiru group, 1 -C force Rubamoiru based means a group aminoalkyl group consisting of 1 0-substituted, specifically, example if N- amino-methylcarbamoyl N-aminoethylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminomethylethylcarbamoyl group, N-aminobutylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminopentylcarbamoyl group, N— Examples include an aminohexylcarbamoyl group, and among them, an N-aminomethylcarbamoyl group, an N-aminoethylcarbamoyl group, an N-aminopropylcarbamoy
  • N—d—C 6 alkoxy d—C 10 alkyl rubamoyl group refers to a group in which an alkoxy group having 1 to 10 carbon atoms is N-substituted to the above-mentioned C 1 -C 1 0 alkyl rubamoyl group.
  • N-methoxymethylcarbamoyl, N-methoxyethylcarbamoyl, N-methoxypropylcarbamoyl, N-methoxybutylcarbamoyl, N-ethoxypentylcarbamoyl And N-butoxyhexylcarbamoyl group among which N-methoxymethylcarbamoyl group, N-methoxyethylcarbamoyl group, N-methoxypropylcarbamoyl group, N-methoxybutylcarbamoyl group and the like are preferable.
  • N - a Ci o alkyl force Rubamoiru 1 -C based to an alkoxycarbonyl group composed of six N- substituted group - C i - Ce alkoxy Cal The Poni Le Ci _ C 1 0 alkyl force Rubamoiru group, the above d
  • C ioalkylcarbamoyl group means a C 1 C] L 0 alkyl group having an alkoxycarbonylamino group having 1 to 6 carbon atoms in addition to an N-alkylcarbamoyl group.
  • Means a substituted group specifically, for example, N-methoxycarbonylaminomethylcarbamoyl group, N-methoxycarbonylaminoethylcarbamoyl group, N-methoxycarbonylaminopropyl carbamoyl group, N-methoxycarbonylaminobutylcarbamoyl Group, N-ethoxycarbonylaminopentylcarbamoyl group, N-butoxycarbonylaminohexylcarbamoyl group, N-tert-butoxycarbonylaminoethylcarbamoyl group, etc., among which N-methoxycarbonylaminomethylcarbamoyl Group, N-methoxycarbonylaminoethylcal Moil group, N- methoxy Cal Poni Rua amino propyl force Rubamoiru group, N- methoxycarbonylamino butylcarbamoyl group, N- tert-butoxy-
  • the C 6 alkoxy force Ruponiru group, 1 -C on Ci one C 6 alkoxy Cal Poni Le group consisting of six alkoxy It means a N-substituted cycarponylamino group, specifically, for example, N-methoxycarbonylaminomethoxycarbonyl group, N-methoxycarbonylaminoethoxycarbonyl group, N-methoxycarbonylaminopropoxycarbonyl group N-methoxycarbonylaminobutoxycarbonyl group, N-ethoxycarbonylaminopentyloxycarbonyl group, N-butoxycarbonylaminohexyloxycarbonyl group, N-tert-butoxycarbonylaminoethoxycarbonyl group, etc.
  • N-methoxycarbonylaminomethoxycarbonyl group N-methoxycarbonylaminoethoxycarbonyl group, N-methoxycarbonylaminopropoxycarbonyl group, N-methoxycarbonylaminobutoxycarbonyl group, N-tert-butoxy Cal Poni Le aminoethoxy Cal Poni Le group and the like.
  • the d-Cealkylthio group means a group in which a sulfur atom is substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group Group, isobutylthio group, sec monobutylthio group, tert-butylthio group, pentylthio group, neopentylthio group, hexylthio group, isohexylthio group, etc., among which methylthio group, ethylthio group, propylthio group, isopropylthio group, A butylthio group, a tert-butylthio group and the like are preferred.
  • the N-d-Ce alkylsulfamoyl group means a group in which a sulfamoyl group is substituted by an alkyl group having 1 or 6 carbon atoms, specifically, for example, an N-methylsulfamoyl group, an N-ethyls group.
  • N, N-Gee d—C 6 alkylsulfamoyl group means It means a group in which an alkyl group having 1 to 6 carbon atoms is disubstituted.
  • the Ci one C 6 alkyl sulfide El group, 1 -C sulfinyl alkyl group composed of six is meant substituted group, specifically, for example Mechirusurufi two group, E chill sulfide El, propyl sulfinyl Group, isopropylsulfinyl group, butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, neopentylsulfinyl group, hexylsulfinyl group, isohexylsulfinyl group, etc.
  • a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, a tert-butylsulfinyl group and the like are preferable.
  • d—C 6 alkylsulfonyl group means a group in which a sulfonyl group is substituted by an alkyl group having 1 to 6 carbon atoms, specifically, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropyl A sulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, a neopentylsulfonyl group, a hexylsulfonyl group, and an isohexylsulfonyl group.
  • the C i -Ce alkoxy group means a group in which an oxygen atom is substituted by an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group Group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, hexoxy group, isohexyloxy group, etc., among which methoxy group, ethoxy group, propoxy group, isopropoxy group Group, butoxy group, isobutoxy group, tert-butoxy group and the like are preferable.
  • the d—C 6 alkoxycarbonyl group means a group in which a carbonyl group is substituted with an alkoxy group having 1 to 5 carbon atoms, specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group.
  • a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group and the like are preferable.
  • the amino d-C 6 alkoxycarbonyl group means a group in which a carbonyl group is substituted with an aminoalkoxy group having 1 to 6 carbon atoms, specifically, for example, an aminomethoxycarbonyl group, an aminoethoxycarbonyl group, Aminopropoxy carbonyl, 2-amino-2-methylpropoxy carbonyl, 2-aminomethyl ethoxycarbonyl, aminobutoxy carbonyl, 2-amino propoxy Luponyl, aminopentyloxy carbonyl, amino Xyloxycarbonyl group and the like, among which aminomethoxycarbonyl group, aminoethoxycarbonyl group, aminopropoxycarbonyl group, 2-aminomethylethoxycarbonyl group, 2-amino-2-methylpropoxycarbonyl group, etc. Is preferred.
  • 6- cycloalkylamino group refers to a group in which a cyclic alkyl group having 3 to 6 carbon atoms is N-substituted on an amino group, and specifically, for example, an N-cyclopropylpyramino group , N-cyclobutylamino group, N-cyclopentylamino group, N-cyclohexylamino group and the like, among which N-cyclopropylamino group , N- cyclopentyl Rua amino group, N- cycloheteroalkyl Kishiruamino group and the Shi-liked ⁇ N, N- di C 3 - and Ji 6 cycloalkylamino group, an annular in Amino group consisting six number 3 of stone carbon It means a group in which an alkyl group is disubstituted, and specifically, for example, N, N-dicyclopropylamino group, N, N-dicyclobutyla
  • Cycloalkyl O alkoxy group, C 3 -C oxygen atom 6 becomes ring-shaped alkyl group means a group obtained by substituting, for example, N- cyclopropoxy group, N- sheet Kurobutokishi group, Examples thereof include an N-cyclopentyloxy group and an N-cyclohexyloxy group, among which an N-cyclopropoxy group, an N-cyclopentyloxy group, an N-cyclohexyloxy group and the like are preferable.
  • the N, N-di-C 3 -C 6 cycloalkyl forcerubamoyl group means a group in which a forcerubamoyl group is disubstituted with a cyclic alkyl group having 3 to 6 carbon atoms.
  • N-dicyclopropyl rubamoyl group N, N-dicyclobutyl carbamoyl group, N, N-dicyclopentylcarbamoyl group, N, N-dicyclohexylcarbamoyl group, N-cyclobutyl-N-cyclopropyl rubamoyl group, N-cyclopentyl -N-cyclopropyl rubamoyl group, N-cyclohexyl N-cyclopropyl rubamoyl group, etc., among which N, N-dicyclopropyl rubamoyl group, N, N-dicyclobutylcarbamoyl group, N, N —Dicyclopentylcarbamoyl group and the like are preferable.
  • the 5- or 6-membered heterocyclic group includes, for example, an isoxazolyl group, an isothiazolyl group, an imidazolyl group, an oxazolyl group, an oxaziazolyl group, a thiazolyl group, a thiaziazolyl group, a chenyl group, a triazinyl group, a triazolyl group, a pyridyl group, a pyrazyl group, Pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, virazyl group, furyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, tetrahydrofuranyl group, pyrazolidinyl group, pyrazolinyl group, piperidinyl group, piperidinyl group Group, pyrrolidinyl group,
  • isooxazolyl group isothiazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, chenyl group, pyridyl group, pyrazyl group Piraji group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, pyranyl group, furyl group, tetrahydrofuranyl group, morpholino group and the like are preferable.
  • a mono- to tri-cyclic heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur is, for example, an acridinyl group, an isoquinolyl group, an isoindolyl group , Indazolyl group, indolyl group, indolizinyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolizinyl group, quinolyl group, coumalonyl group, chromenyl group, fenanslidinyl group, fenansloryl Nyl group, dibenzofuranyl group, dibenzothiophenyl group, cinnolinyl group, thonaphthenyl group, naphthyridinyl group, phenazinyl group, phenaxazinyl group, phenothiazinyl group, phthalazin
  • the alkyl group is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group. Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, etc., among which methyl group, ethyl group Group, propyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group and the like.
  • the alkenyl group includes, for example, vinyl group, aryl group, 1-propenyl group, isopropenyl group, 2-butenyl group, isobutenyl group, 2-pentenyl group, 2-hexenyl group, 2-heptenyl group And 2-octenyl group, among which vinyl group, aryl group, 1-propenyl group and the like are preferable.
  • the alkynyl group includes, for example, ethynyl group, 1-propenyl group, 1-butenyl group, 11-pentenyl group, 1-hexynyl group, 11-heptynyl group, 1-octynyl group and the like. And a 1-propynyl group.
  • the N-Ci-Cjo alkyl rubamoyl group means a carbamoyl group substituted with an alkyl group having 1 to 10 carbon atoms, specifically, for example, an N-methylcarbamoyl group, —Ethylcarbamoyl group, N _propylcarbamoyl group, N-isopropylcalilevamoyl group, N-butylcarbamoyl group, N_isobutylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group, N-pentylcarbamoyl group, N-neopentylcarbamoyl group, N-hexylcarbamoyl group, N-isohexylcarbamoyl group, N-butylcarbamoyl group, N-decylcarbamoyl group, etc., among which
  • N—C “CJ 0 alkylthioalkavamoyl group means a group in which a thiocarbamoyl group is N-substituted with an alkyl group having 1 to 10 carbon atoms, and specifically, for example, an N-methylthioalkavamoyl group N-ethylthiolrubamoyl group, N-propylthiolrubamoyl group, N-isopropylthiolrubamoyl group, N-butyltylylrubamoyl group, NTsobutylthiolrubamoyl group, N-sec-butylbutylcarbamoyl group, N-tert —Butylthiocarpamoyl group, N—Pentylchi Carbamoyl group, N-neopentylthiolrubamoyl group, N-hexylthiolrubamoyl group, N-isohe
  • the monocyclic to tricyclic C 7 -C 15 carbon aromatic ring group excludes the above aryl group, and includes, for example, an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, a norpolnyl group, a phenanthryl group and the like. Among them, an anthryl group and a phenanthryl group are preferred.
  • R 1 and R 2 are the same or different and each represent, for example, a hydrogen atom or a -alkyl group, and among them, a hydrogen atom is preferable.
  • R 3 represents, for example, a hydrogen atom or a ⁇ - ⁇ alkyl group (excluding n-butyl group), and among them, a C 2 -C 6 alkyl group (excluding n-butyl group) is preferable. Particularly, for example, a C 3 -C 5 branched alkyl group is suitable.
  • R 4 represents, for example, a hydrogen atom, a hydroxyl group or a 1 C 3 alkyl group, among which a hydrogen atom and a —C 3 alkyl group are preferable, and a hydrogen atom is particularly preferable.
  • R 5 is, for example, a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, Formyl group, formylamino group, cyclic saturated or unsaturated C 3 -C 9 aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkyl Kilcarponyl group, N-aralkyl rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfony
  • Alkylsulfamoyl group, arylsulfamoyl. i one C 6 alkoxycarbonyl group, N- Arirukaru Bamoiru group, Aroiru group, Arokishi group, N- Aroiru group, N- (N-Aroirua Mino) C ⁇ Co alkyl force Rubamoiru group, N- Aroiruamino (: ⁇ one C 6 Alkoxycarbonyl group, C 2 —C 6 alkanoyl group, C 2 —C 6 alkanoyloxy group, N—C 2 _C 6 alkanoylamino group, N, N—di—C 2 _C 6 alkanoylamino group, N—Ci—C 6 alkylamino group, N, N—diCi—C 6 alkylamino group, N——C 1Q alkyl rubamoyl group, N, N—di — ( ⁇ - ⁇ alkircalcarbamoyl group, N,
  • C i alkyl L-bamoyl group N — ⁇ -C 6 alkoxycarbonyl C 1 () alkyl rubamoyl group, N—1 C 6 alkoxy ruponylamino Ci—C i Q alkyl rubamoyl group, N _C i—C 6 alkoxy rupponylamino d—C 6 alkoxy carbonyl, Ci— Ce alkylthio group, N eleven C 6 alkylsulfamoyl group, N, N-di-C - Ce alkylsulfamoyl Moil group, C - C 6 alkylsulfinyl group, CI- C 6 alkylsulfonyl group, Ct-C 6 alkoxy group, an alkoxycarbonyl Cal Poni group, an amino one (6 ⁇ Le Koki deer Lupo sulfonyl group, N-C 3 - C 6 cycloalkyl amino group, N, N-
  • a linear or branched, saturated or unsaturated C A C 9 aliphatic group which may be substituted with a mono- to tricyclic heteroaromatic ring group having 5 C 6 alkoxy group, C—C 6 alkylthio group, A carbon aromatic ring group which may have a substituent selected from the group consisting of N-Ci-Ce alkylamino group, NC x -C 6 alkyl rubamoyl group, and N-Ci-C 6 alkylthio rubamoyl group , 1 to 3 cyclic C 7 — C] L 5 carbon aromatic ring groups or 5 or 6 membered heterocyclic groups or a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms per ring system
  • a 5- to 6-membered heteroaromatic group (excluding a 5- or 6-membered heterocyclic group) having 5 to 5 carbon atoms, and among them, a carbon-aromatic ring group is a phenyl group or a naphth
  • the C 7 -C 15 carbon aromatic ring group is an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, a phenanthryl group, and the 5- or 6-membered heterocyclic group is an isoxazolyl group, an isothiazolyl group, an imidazolyl group, an oxazozolyl group.
  • a naphthyl group, and a substituent of the optionally substituted carbon aromatic ring group may be a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carboxy group, a cyano group, a nitro group, Rogen atom, hydroxy group, aralkyl group, N-aralkylamino group, aralkyloxy group, aralkylcarponyl group, N-aralkyl rubamoyl group, aryl group, aryloxy group, arylsulfonyl group, arylsulfonyl Okishi group, ⁇ reel sulfamoyl group, Aroiru group, Arokishi group, N- Aroiru group, C 2 one C 6 Arukanoiru groups, C 2 - C 6 alkanoyloxy noisy Ruo alkoxy group, N- C 2 - C 6 alkanol Iruamino group An N-Cj-Ce
  • Alkyl carbamoyl group N—C 2 —C 6 alkenylcarbamoyl group, N, N—di C 2 —C 6 alkenylcarbamoyl group, N—amino C 1 CJ 0 Alkyl rubamoyl group, N—C — Ce alkoxy ( : C 10 alkyl alkyl group, NC x -C 6 alkoxycarbonyl C!
  • alkylcarbamoyl group C — C 6 alkylsulfinyl group, C — C 6 alkoxy group, C 1 -C 6 alkoxycarbonyl Group, amino Ci—C 6 alkoxycarbonyl group, N—C 3 — ( 6 cycloalkylamino group, (: 3 _ ( 6 cycloalkyloxy group, isoxoazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, Nyl, pyridyl, pyrazinyl, pyrimigel, pyridazinyl, furyl, tetrahydrofuranyl, morpholino, isoquinolyl, iso Ndoriru group, ethylenedioxy O carboxymethyl-phenylalanine group, quinazolinyl group, quinoxalinyl group, quinolyl group, a dibenzofuranyl El group, dibenzothiophen
  • Ar is, for example, a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, Formyl group, formylamino group, cyclic saturated or unsaturated C 3 -C 9 aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkyl Kill carbonyl group, N-aralkyl rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy
  • Alkyl Rubamoyl group N, N—Gee Ci—. Alkyl force Rubamoiru group, N- C 2 - C 6 alkenyl carbamoylmethyl group, N, N- di C 2 - C 6 alkenyl carbamoylmethyl group, N- amino ( ⁇ one C 1Q alkyl force Rubamoiru group, N one CI- C 6 alkoxy 1.
  • Alkyl group Lbamoyl group, N—C i-C 6 alkoxyl force L-ponylamino C, _ C 6 alkoxycarbonyl group, C 6 alkylthio group, N-C! -C 6 alkylsulfamoyl group, N, N-G C-C 6 alkylsulfamoyl group, C 1 -C 6 alkylsulfinyl group, C i — C 6 alkylsulfonyl group,
  • the carbon aromatic ring group is preferably a phenyl group or a naphthyl group.
  • Alkylcarbamoyl group C i one C 6 alkylsulfinyl group, (1 -0 6 Arukokishi groups, C one C 6 alkoxy Cal Poni group, an amino C i one C 6 alkoxycarbonyl alkylsulfonyl group, N-C 3 - C 6 cycloalkyl Alkylamino group, C 3 — (: 6 cycloalkyloxy group, dioxoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, cetyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, furyl group, tetrahydrofura Nyl, morpholino, isoquinolyl, isoindolyl, ethylenedioxyphenyl, quinazolinyl, quinoxalinyl, quinolyl, dibenzofurany
  • oxazolyl group, thiazolyl group, thienyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, and furyl group, and a heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as one ring 1 to 5 mono- to 3-cyclic heteroaromatic groups (excluding 5- or 6-membered heterocyclic groups) per group include isoquinolyl, isoindolyl, ethylenedioxyphenyl, quinazolinyl, quinoxalinyl, and dibenzofuran.
  • a zoxazolyl group, a benzothiazolyl group, a benzofuranyl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group is more preferred.
  • n represents an integer of 0 to 2, and 0 or 2 is preferable, and 2 is more preferable.
  • suitable compounds include, for example, 1009, 1011, 1
  • the compound represented by the general formula [I] can be produced by the following production methods AH. Manufacturing method A
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out by using a base in a dehydrated inert organic solvent in the presence of a suitable additive.
  • the compound represented by the general formula [II] can be obtained by reacting the solvent at a temperature of from 0 ° C to the boiling point of the solvent, preferably from 17 to 30 ° C, for from 0.5 to 96 hours, preferably from 12 to 24 hours. Then, a solution of arylnitrile represented by the general formula [III] in an inert solvent is added dropwise at a temperature of 100 ° C. to the boiling point of the solvent, preferably ⁇ 78 to 3O: 0.5.
  • the reaction is carried out for up to 96 hours, preferably 12 to 24 hours.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include hexane, cyclohexane, pentane, ether, 1,4-dioxane , Tetrahydrofuran, tetrahydropyran and the like. Among them, ether, tetrahydrofuran, cyclohexane and the like are preferable.
  • Additives used in the reaction include N, N, N ', N' And TMEDA, hexamethylphosphoramine HMPA, lithium chloride and the like. Among them, ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethylethylenediamine is preferable.
  • Examples of the base used in the reaction include ⁇ -butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, methyllithium and the like. Among them, n-butyllithium and sec-butyllithium are preferable. is there.
  • the amount of the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions.
  • 1 to 10 equivalents, preferably 1.5 to 2 equivalents, of arylyl nitrile represented by the above general formula [III] is used.
  • RR 2 is a hydrogen atom or a C 3 alkyl group
  • R 3 is a hydrogen atom or a C 1 C 6 alkyl group (however, excluding n-butyl group)].
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions.
  • the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [IV].
  • the compound represented by the above general formula [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane.
  • methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 with respect to the compound represented by the above general formula [IV]. 1.2—Use 2 equivalents of aziridin represented by the above general formula [V].
  • R 1 R 2 , R 3 , 1 ⁇ 5 and 8 has the above-mentioned meaning] in a suitable solvent such as 2,6-lutidine.
  • Azeotropic distillation optionally in the presence of an acid, or heating to reflux in the presence of a desiccant, for example, molecular sieves.
  • a desiccant for example, molecular sieves.
  • R 1 R 2 , R 3 , R 5 and Ar have the above-mentioned meanings].
  • the reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, and in an appropriate solvent such as 2,6-lutidine.
  • the reaction is completed by refluxing for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable acid such as hydrochloric acid.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, etc. From the viewpoint of securing a suitable reaction temperature, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are particularly preferable.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid; for example, Lewis such as trifluoroboric acid, titanium tetrachloride, and zinc chloride.
  • inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid
  • Lewis such as trifluoroboric acid, titanium tetrachloride, and zinc chloride.
  • Acids for example, sulfonic acids such as P-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; and organic acids such as formic acid, trifluoroacetic acid, and acetic acid, and among them, hydrochloric acid, acetic acid, and P-toluenesulfonic acid
  • sulfonic acids such as P-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid
  • organic acids such as formic acid, trifluoroacetic acid, and acetic acid, and among them, hydrochloric acid, acetic acid, and P-toluenesulfonic acid
  • Preferred examples of the desiccant used in the reaction include molecular sieves, magnesium sulfate, and sodium sulfate. Among them, molecular sieves are preferred.
  • the amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually, 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VI] is used.
  • the acid and the desiccant may be used alone or in appropriate combination of two or more.
  • R 1 R 2 , R 3 , R 5 and Ar have the meaning described above, in an appropriate organic solvent with an oxidizing agent to give a compound of the general formula [VIII ]
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out in a suitable organic acid solvent such as trifluoroacetic acid, for example, a suitable oxidizing agent such as hydrogen peroxide.
  • a suitable organic acid solvent such as trifluoroacetic acid
  • a suitable oxidizing agent such as hydrogen peroxide.
  • the reaction is completed by stirring for 5 to 96 hours, preferably 12 to 24 hours, in the presence of
  • stirring in a suitable inert organic solvent such as, for example, methylene chloride
  • a suitable oxidizing agent such as, for example, methacrylic acid mouth perbenzoic acid
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include methylene chloride, methylene chloride, 1,2-dichloroethane, and trichloroethane.
  • Preferred are methylene, chloroform, 1,2-dichloroethane, trichloroethane, toluene, xylene and the like.
  • Examples of the acid solvent used in the reaction include organic acids such as formic acid, trifluoroacetic acid and acetic acid, among which trifluoroacetic acid is preferred.
  • the oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • hydrogen peroxide, peracetic acid, trifluoroperacetic acid, methachloroperbenzoic acid, oxone examples thereof include chromic acid and permanganese sun.
  • hydrogen peroxide, metachloroperbenzoic acid, and the like are preferable.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VII]. 1.2 Use 2 to 2 equivalents of oxidizing agent.
  • R 1 , R 2 , R 3 , 5 and 8 have the above-mentioned meanings] in a suitable organic solvent such as tetrahydrofuran (THF).
  • a suitable organic solvent such as tetrahydrofuran (THF).
  • Reduction using a reducing agent or catalytic hydrogenation using a catalyst such as 10% palladium on carbon, or reaction with zinc chloride in the presence of an acid catalyst such as hydrochloric acid The general formula [I]
  • the reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction can be carried out in a suitable organic acid solvent such as THF, for example, using a suitable reducing agent such as porane.
  • the reaction is completed by stirring for up to 96 hours, preferably 12 to 24 hours.
  • a suitable organic solvent such as methyl alcohol in the presence of a suitable palladium catalyst such as 10% palladium on carbon for 5 to 96 hours, preferably 12 to 24 hours
  • the reaction is complete.
  • the reaction is completed by appropriately stirring with a metal or a metal salt for 5 to 96 hours, preferably 12 to 24 hours in an acid or alkali solution.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane.
  • Carbon chloride acetic acid, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc., among which methylene chloride, Preferred are chloroform, 1,2-dichloroethane, trichloroethane, toluene, xylene and the like.
  • Examples of the reducing agent used in the reaction include lithium borohydride, sodium borohydride, sodium cyanotrihydroborate, porane methyl sulfide complex, porane THF complex, and lithium aluminum hydride. Among them, a porane methylsulfide complex and a porane THF complex are preferable.
  • the amount of the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VIII]. Use 2 to 2 equivalents of reducing agent.
  • Catalysts used in the catalytic hydrogenation reaction include, for example, palladium activated carbon, Raney nickel, platinum oxide, etc., and among them, 10% palladium activated carbon is preferred.
  • Metal used in the reaction is, for example, zinc, aluminum, iridium. , Chromium, titanium, tin, cerium, iron, copper, vanadium, magnesium, etc., of which zinc and magnesium are preferred.
  • the product represented by the above general formula [I] can be obtained by purifying the product by a conventional method.
  • the compound represented by the general formula [I] or a salt thereof can be isolated and purified from the reaction solution by a known separation means such as solvent extraction, recrystallization, and chromatography.
  • R represents an alkyl group such as a methyl group
  • R 5 and Ar have the above-mentioned meanings] by heating the compound represented by the formula [XI]
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but usually the reaction is carried out in a suitable organic acid solvent such as N, N-dimethylformamide, for example, sodium hydride.
  • a suitable organic acid solvent such as N, N-dimethylformamide, for example, sodium hydride.
  • the reaction is completed by reacting the mixture with a suitable base at 0 ° C. to the boiling point of the solvent, preferably 0 to 150, 0.5 to 96 hours, preferably 12 to 24 hours. Then, for example, in an inert organic solvent or neat, from 0 ° C. to the boiling point of the solvent, preferably 100 to 300 ° C., 0.1 to 96 hours, preferably 0.5 to 2 hours.
  • the reaction is completed by stirring for an hour.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, but specific examples thereof include, for example, Shiridani methylene, chloroform, 1,2-dichloroethane, trichloroethane, Carbon tetrachloride, N, N-dimethylformamide, acetonitrile, acetone, benzene, toluene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc., among which N, N-dimethylformamide, toluene, xylene, acetone , Ether, tetrahydrofuran and the like are preferred.
  • Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpiperidine, N, N-dimethylaniline, Tertiary aliphatics such as 1, 8-diazabicyclo [5.4.0] pendant force _7-en (DBU), 1,5-azabicyclo [4.3.0] nona5 -en (DBN)
  • Amines for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal alkoxides such as potassium tert-butylate, sodium ethylate, and sodium methylate; for example, potassium hydroxide, sodium hydroxide, and the like Alkali metal hydroxides; for example, alkali metal carbonates such as carbonated lime; and the like, among which triethylamine, N, N-diisopropylethylamine, Sodium
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 relative to the compound represented by the above general formula [IX].
  • inert solvent used in the rearrangement reaction for example, toluene, xylene, diphenyl ether, dipara-tolyl ether and the like can be mentioned, and among them, diphenyl ether is preferable.
  • the compound represented by the general formula [XI] is hydrolyzed with a base such as sodium hydroxide in a suitable organic solvent, or with a reducing agent such as lithium aluminum hydride in a non-polar solvent such as THF.
  • a base such as sodium hydroxide in a suitable organic solvent
  • a reducing agent such as lithium aluminum hydride in a non-polar solvent such as THF.
  • the compound represented by the above general formula [IV] can be prepared by reduction.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, benzene examples thereof include silene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, and tetrahydropyran.
  • methyl alcohol, ethyl alcohol, ether, 1,4-dioxane, and tetrahydrofuran are preferable.
  • Examples of the base used in the reaction include alkali metal alkoxides such as potassium tert-butylate, sodium ethylate and sodium methylate; for example, alkali metal hydroxides such as lithium hydroxide and sodium hydroxide.
  • alkali metal carbonates such as potassium carbonate and the like, among which potassium tert-butylate, sodium ethylate, sodium methylate, potassium hydroxide and sodium hydroxide are preferred.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include hexane, cyclohexane, pentane, ether, 1,4-dioxane And tetrahydrofuran, tetrahydropyran and the like, among which ether, tetrahydrofuran, cyclohexane and the like are preferable.
  • Lithium aluminum hydride is suitable as the reducing agent used in the reaction.
  • the compound represented by the above general formula [IV] thus obtained is prepared in the same manner as in Step 2-5 of Production Method A.
  • the compound represented by the above general formula [I] can be obtained by reacting
  • Ar has the above-mentioned meaning
  • salicylic acid an aryl compound represented by R 5 —H (where R 5 has the above-mentioned meaning); It can be synthesized by a Friedel-Crafts reaction using lumimium.
  • Ar has the above-mentioned meaning] by converting an aryl halide compound and metallic magnesium into a suitable ether-based dehydrating solvent such as, for example, ethyl ether, tetrahydrofuran, etc., at a low temperature.
  • a suitable ether-based dehydrating solvent such as, for example, ethyl ether, tetrahydrofuran, etc.
  • the Grignard reagent prepared by reacting at the boiling point of the solvent is reacted with the above-mentioned dehydrated inert organic solvent at a low to room temperature in the above-mentioned dehydrated inert organic solvent, and the resulting product is subsequently dissolved in a suitable solvent such as dichloromethane.
  • a suitable solvent such as dichloromethane.
  • it can be produced by reacting with an oxidizing agent such as manganese dioxide.
  • R 2 and 1 3 are as defined above] is reacted with a compound represented by then formula by the resulting amino group apply a protecting group suitable Amino group [XV]
  • PG 1 represents a protecting group for an amino group
  • R 1 R 2 , R Ar and PG have the above-mentioned meanings.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XIV] and the above general formula
  • the compound [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane.
  • methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.
  • the amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting material and the reaction conditions. Usually, 1.2 to 10 equivalents, preferably 1 Use 2 to 2 equivalents of the aziridine represented by the above general formula [V].
  • Examples of the protective group for the carbonyl group include lower alkyl groups such as methyl group, ethyl group and tert-butyl group, and aralkyl groups such as benzyl group and p-methoxybenzyl group. , An ethyl group, a tert-butyl group, a benzyl group and the like.
  • Examples of the protecting group for the amino group include benzyl, p-nitrobenzyl and the like.
  • An aralkyl group for example, an acyl group such as a formyl group or an acetyl group; a lower alkoxy group such as an ethoxycarbonyl group, an aryloxycarbonyl group, or a tert-butoxycarbonyl group; for example, a benzyloxycarbonyl group, p-nitro Aralkyloxycarbonyl groups such as benzyloxycarbonyl group, triphenylmethyl group, paramethoxyphenyldiphenylmethyl group, diphenylphosphonyl group, and benzenesulfenyl group; among them, aryloxycarbonyl group Tert-butoxycarbonyl, benzyloxycarbonyl, triphenylmethyl and the like are preferred.
  • the removal of the protecting group of the hydroxyl group depends on the type and stability of the compound, but the method described in the literature [Protective Groups 'In' Organic Synthesis (Organic Synthesis), TW Greene, John John & Sons (1981)] or a method analogous thereto, for example, solvolysis using an acid or base, chemical reduction using a metal hydride complex, or the like. It can be carried out by corrosion reduction using a palladium carbon catalyst, Raney nickel catalyst or the like.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually, the reaction is carried out by reacting the deprotected carboxylic acid with N, 1-dimethylhydroxylamine in a dehydrated inert organic solvent. , In the presence of a base, a condensation aid and Z or a condensing agent as appropriate — from 100 ° C. to the boiling point of the solvent, preferably from 0 to 30 ° C., from 0.5 to 96 hours, preferably from 3 to 24 hours. Let it.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, and trichloroethane. , N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, acetic anhydride, methyl alcohol, ethyl alcohol, benzene, xylene, water, acetic acid, toluene, 1,4-dioxane, tetrahydrofuran and the like.
  • Bases used in the reaction include, for example, trimethylamine, triethyl ⁇ / ami, N, N-diisopropylethylamine, N-methylmorpholine, N-methylvinyl lysine, N-methylpiperidine, N, N-dimethyl Anilin, 1,8-diazabicyclo [5.4.0] pendant 7-ene (DBU), 1,5-azabicyclo [4.3.0] nona-5-ene (DBN), etc.
  • Tertiary aliphatic amines for example, aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline; metal salts such as potassium metal, sodium metal, and lithium metal; Metal hydrides such as sodium hydride and hydrogen hydride; alkyl metal hydrides such as butyl lithium; potassium lithium-tert-butylate, sodium ethylate Alkali metal alkoxides such as sodium methylate and the like; alkali metal hydroxides such as hydroxylated sodium hydroxide and sodium hydroxide; alkali metal alkoxides such as carbonated lithium and the like.
  • Tertiary aliphatic amines and the like are preferred, and in particular, triethylamine, N, N-diisopropylethylamine and the like are more preferred.
  • condensation auxiliary used in the reaction examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-15-norpolene-2,3-dicarboximide, and 3-hydroxy-3 , 4-dihydro-4-oxo-1,2,3-benzotriazol and the like. Among them, N-hydroxybenzotriazole and the like are preferable.
  • Examples of the condensing agent used in the reaction include thionyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, and N, N'-capillonyldiimidazole , Diphenylphosphoryl chloride, diphenylphosphoryl azide, N, N, disuccinimidyl carbone, N, N'-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride, ethyl ethyl chloroformate, isoptyl chloroformate, benzotriazo-1-lyloxysheetris (dimethylamino) phosphonium hexafluorophosphate, and the like, among which N, N-dicyclohexylcarposimide, 1-ethyl-3- ( 3-dimethylaminopropyl) carposi
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but is usually 1 to 50 equivalents, preferably 1 to 2 equivalents of N, di-dimethylhydroxyl hydroxylase relative to the carboxylic acid.
  • Min 1 to 50 equivalents, preferably 3 to 5 equivalents of base, 1 to 50 equivalents, preferably 1 to 5 equivalents of condensation aid and / or 1 to 50 equivalents, preferably 1 to 5 equivalents
  • the base, the condensation aid, and the condensing agent can be used alone or in appropriate combination of two or more.
  • RR 2 , R 3 , Ar, PG 1 and Me have the above-mentioned meaning
  • a halogenated aryl compound and metal magnesium to a suitable ether-based compound such as, for example, methyl ether, tetrahydrofuran, etc.
  • a general formula [XVI I] is obtained by reacting in a dehydrated inert organic solvent at a low temperature to room temperature with a Grignard reagent prepared by reacting at a low temperature to the boiling point of the solvent in a dehydrated solvent.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in an inert organic solvent that has been dehydrated by reacting the compound represented by the above general formula [XVI] with the Grignard reagent.
  • the reaction is carried out at a temperature of 100 to the boiling point of the solvent, preferably -78 to 30 ⁇ , for 0.5 to 96 hours, preferably for 12 to 24 hours.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but is usually 2 to 10 equivalents, preferably 2 to 10 equivalents to the compound represented by the above general formula [XVI]. Use 3 equivalents of Grignard reagent.
  • the removal of the protecting group depends on the type and stability of the compound, but the method described in the literature [Protective Groups in Organic Synthesis, T.W. Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using an acid or a base, chemical reduction using a metal hydride complex, or the like. Alternatively, it can be carried out by catalytic reduction using a palladium carbon catalyst, a Raney nickel catalyst or the like.
  • the compound represented by the above general formula [VI] can be synthesized by subsequently reacting the compound represented by the above general formula [VI] by the method of Step 3-5 of Production method A. . Manufacturing method D
  • L 1 represents a leaving group such as halogen, and R 5 and Ar have the above-mentioned meanings] can be synthesized by a known method.
  • R 5 is The compound can be synthesized by reacting with an aryl compound represented by the following formula) by, for example, a Friedel-Crafts reaction using aluminum chloride.
  • the reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in a suitable organic acid solvent such as N, N-dimethylformamide, for example, potassium carbonate.
  • the reaction is completed by reacting with a suitable base at o: from the boiling point of the solvent, preferably 50 to 120 ° C, for 0.5 to 96 hours, preferably 2 to 12 hours.
  • any organic solvent that does not adversely affect the reaction can be used.
  • Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpiperidine, N, N-dimethylaniline, Tertiary fats such as 1,8-diazabicyclo [5.4.0] pendant 7-ene (DBU) and 1,5-azabicyclo [4.3.0] noner 5-ene (DBN)
  • Aliphatic amines for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal alkoxides such as potassium tert-butylate, sodium ethylate, sodium methylate; potassium hydroxide, 7jc oxidation Alkali metal hydroxides such as sodium; for example, alkali metal carbonates such as carbon dioxide, etc., among which triethylamine, N, N-diisopropylethyl Amin, sodium hydride, potassium
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 1.2 to 20 equivalents, preferably 1 to 20 equivalents to the compound represented by the above general formula [XIX]. 1. Use 2 to 5 equivalents of the compound represented by the general formula [XX].
  • the compound represented by the above general formula [XV II] is synthesized into the compound represented by the above general formula [I] by the method of the fourth step of the production method C and the third to fifth steps of the production method A. can do.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XXI] and the above general compound.
  • the compound represented by the formula [V] is dissolved at room temperature in 0.
  • the reaction is performed for 5 to 96 hours, preferably 3 to 24 hours.
  • any organic solvent that does not adversely affect the reaction can be used.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but usually, the amount of the compound represented by the above general formula [XXI] is 1.
  • R 5 has the meaning described above, and azeotropic distillation in a suitable solvent such as 2,6-lutidine in the presence of an appropriate acid, or for example, By heating to reflux in the presence of a desiccant such as Ura sieves, the general formula [XXIV]
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, for example, using a suitable agent such as 2,6-lutidine.
  • the reaction is completed by refluxing in a solvent, for example for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable acid such as hydrochloric acid.
  • any organic solvent that does not adversely affect the reaction can be used.
  • specific examples include, but are not limited to, methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, N, N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, and methyl alcohol.
  • pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferred.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid; for example, Lewis acids such as trifluoroboric acid, titanium tetrachloride, and zinc chloride; !) Sulfonic acids such as mono-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and hydrochloric acid, acetic acid, and p-toluenesulfonic acid are preferable.
  • inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid
  • Lewis acids such as trifluoroboric acid, titanium tetrachloride, and zinc chloride
  • Sulfonic acids such as mono-tolu
  • the desiccant used in the reaction includes, for example, molecular sieves, magnesium sulfate, sodium sulfate, etc. Among them, the molecular sieves are preferable. Although it can be increased or decreased as appropriate, it is usually 1.2 to 10 equivalents to the compound represented by the above general formula [XXII]. Preferably 1.2 to 2 equivalents of the aldehyde represented by the above general formula [XXIII], 1.2 to 10 equivalents, preferably 1.2 to 2 equivalents of the desiccant, 1 to 50 equivalents Preferably, 3 to 5 equivalents of acid are used. The acid and the desiccant may be used alone or in combination of two or more.
  • R 1 , R 2 , R 3 , R 5 , Ar, and L 2 have the above-mentioned meanings.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out in a dehydrated inert organic solvent using a suitable base in the presence of an appropriate additive at a temperature of 100 ° C.
  • an appropriate additive at a temperature of 100 ° C.
  • To the boiling point of the solvent preferably 1 to 78 to 30 ° (: 0.5 to 96 hours, preferably 12 to 24 hours to complete the intramolecular ring closure reaction.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include hexane, cyclohexane, pentane, ether, and 1,4-dioxane.
  • tetrahydrofuran, tetrahydropyran and the like, and particularly, for example, ether, tetrahydrofuran, cyclohexane and the like are preferable.
  • additives used in the reaction include ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetramethylethylenediamine TMEDA, hexamethylphosphoramine HMPA, lithium salt, and the like.
  • ', ⁇ '-Tetramethylethylenediamine is preferred.
  • Examples of the base used in the reaction include ⁇ -butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, methyllithium and the like. Among them, n-butyllithium and sec-butyllithium are preferred. is there.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions. However, usually, the amount of the reagent represented by the above general formula [XXIV] is 2%. ⁇ 10 equivalents, preferably 2-3 equivalents of base are used.
  • the obtained compound represented by the general formula [XXV] can be synthesized by the method of the fourth step of the production method A to produce the compound represented by the general formula [I].
  • Manufacturing method F
  • R 1 R 2 and R 3 have the above-mentioned meanings in a polar solvent such as lutidine, and the compound represented by the general formula [XXVI I]
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XXVI] and the compound represented by the above general formula.
  • the compound represented by [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.
  • any organic solvent that does not adversely affect the reaction can be used.
  • specific examples include, but are not limited to, methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, carbon tetrachloride, N, N-dimethylformamide, ethyl acetate, methyl acetate, and acetate nitrite.
  • Ryl methyl alcohol, ethyl alcohol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, etc., among which methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N —Dimethylformamide, toluene, xylene and the like are preferred.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [XXV II]. 1. Use 2 to 2 equivalents of the aziridine represented by the above general formula [V].
  • the reagent used in the oxidation reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out, for example, in a suitable solvent with a suitable oxidizing agent such as manganese dioxide at room temperature for 5 to 96 hours.
  • the reaction is completed for a period of time, preferably 12 to 24 hours.
  • the oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, but specific examples thereof include manganese dioxide, chromic acid, t-butyl chromate, lead tetraacetate, and tetroxide. Ruthenium, selenium dioxide, halogen, oodosil compounds, oxygen, organic peroxides, silver peroxosulfate, nitric oxide, dimethyl sulfoxide, o-chloranil, silver oxide, etc., among which manganese dioxide, chromic acid, selenium dioxide And dimethyl sulfoxide.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually preferably from 0.22 to 50 equivalents, preferably from the compound represented by the above general formula [VII]. Use 1.2 to 2 equivalents of oxidizing agent.
  • the reagent used in the ring closure reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, for example, 2,6-lutidine.
  • the reaction is completed by refluxing in a suitable solvent, for example in the presence of a suitable acid such as hydrochloric acid for 5 to 96 hours, preferably 12 to 24 hours.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, pyridine , Lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran and the like.
  • pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid and perchloric acid; for example, Lewis acids such as trifluoroboric acid, titanium tetrachloride, zinc chloride and the like. Sulfonic acids such as p-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and hydrochloric acid, acetic acid, and p-toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid and perchloric acid
  • Lewis acids such as trifluoroboric acid, titanium tetrachloride, zinc chloride and the like.
  • Sulfonic acids such as p-tolu
  • Suitable desiccants used in the reaction include, for example, molecular sieves, magnesium sulfate, and sodium sulfate, with molecular sieves being preferred.
  • the amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually 1.2 to 10 equivalents to the compound represented by the above general formula [XXVIII].
  • 1.2 to 2 equivalents of desiccant, 1 to 50 equivalents, preferably 3 to 5 equivalents of acid are used.
  • the acid and the desiccant may be used alone or in appropriate combination of two or more.
  • R 1 R 2 , R 3 and Ar have the above-mentioned meanings] and a compound obtained by activating a halogenated aryl compound with a metal such as magnesium, lithium, copper or zinc. Is reacted in a suitable ether-based dehydrating solvent at a low temperature to the boiling point of the solvent to obtain the general formula [XXV]
  • This production method is a method for producing a compound represented by the general formula [I] wherein R 4 is 1 C 3 alkyl.
  • R 4 represents one C 3 alkyl and L 3 represents a leaving group such as halogen] by reacting an alkyl octride represented by the general formula [XXX I]
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out by reacting the compound represented by the above general formula [VII] with the alkyl halide represented by the above general formula [XX].
  • the reaction is completed by heating to reflux in an inert organic solvent for 5 to 96 hours, preferably 12 to 24 hours.
  • the organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, and the like. Of these, acetonitrile, toluene, xylene and the like are preferred.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but is usually 1 to 50 equivalents, preferably 10 to 10 equivalents to the compound represented by the above general formula [VII]. Use 50 equivalents of the compound represented by the above general formula [XXX].
  • This production method is a method for producing a compound represented by the general formula [I] wherein R 4 is a hydroxyl group.
  • the reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in a suitable inert organic solvent such as methylene chloride, for example,
  • the reaction is completed by stirring at room temperature for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable oxidizing agent.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, and trichloroethane. , Carbon tetrachloride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran and the like. Preferred are methylene, chloroform, 1,2-dichloroethane, trichloroethane, ethyl acetate and the like.
  • the oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • hydrogen peroxide, peracetic acid, trifluoroperacetic acid, methachloroperbenzoic acid, oxone examples thereof include chromic acid and permanganese sun.
  • hydrogen peroxide, metachloroperbenzoic acid, and the like are particularly preferable.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1.2 to 10 equivalents to the compound represented by the above general formula [XXV]. Use 1.2 to 2 equivalents of oxidizing agent.
  • the compound of Compound Example 116 was used as a representative compound, and the effect on GLP-1 concentration in plasma after administration of the compound was examined. .
  • Control group 111 610 mg / kg group Based on the above results, 30 minutes after administration, plasma GLP_1 was significantly higher in the plasma of the group to which 1 Omg / kg of the compound was administered compared to the control group. Was. From these results, it was shown that the compound of the present invention has an activity capable of exhibiting a high blood GLP-1 concentration in rats.
  • the compound of the present invention is useful as a therapeutic agent for diabetes mellitus, a preventive for chronic complications of diabetes or an antiobesity drug, since it exhibits an activity of exhibiting a high blood GLP-1 concentration.
  • the compound of the general formula [I] of the present invention can be used as a medicament containing the same as an active ingredient, particularly as an agent for treating diabetes, an agent for preventing chronic complications of diabetes or an antiobesity agent.
  • the compound of the present invention in a therapeutic agent, a preventive agent for chronic complications of diabetes or an anti-obesity agent means a pharmaceutically acceptable conventional one,
  • RR 2 , R 3 , R 4 , R 5 , Ar and n have the above-mentioned meanings.
  • Compounds represented by, E ester or a pharmaceutically acceptable salt in the force Rupokishiru group on R 5 or A r, salts in hydroxyl groups on R 5 or A r, or at the amino group on R 5 or A r Salts are included.
  • Examples of the salt in the carboxyl group or the hydroxy group include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.
  • Examples of the acid addition salt for the amino group include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate and perchlorate; for example, acetate, propionate and lactic acid Organic salts such as salt, maleate, fumarate, tartrate, malate, citrate, and ascorbate; for example, methanesulfonate, isethionate, benzenesulfonate, toluenesulfonate, etc.
  • Sulfonic acid salts for example, acidic amino acid salts such as aspartate and glutamate.
  • the compound of the present invention when used as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an antiobesity agent, it can also be used as a pharmaceutically acceptable salt thereof.
  • Typical examples of the pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium.
  • the method for producing a pharmaceutically acceptable salt of the compound of the present invention can be carried out by appropriately combining methods usually used in the field of synthetic organic chemistry. Specific examples include neutralization titration of a free solution of the compound of the present invention with an alkaline solution.
  • compositions of the present invention for treating diabetes, preventing chronic complications of diabetes or treating obesity Various forms can be selected as the dosage form for use as a tablet, for example, oral preparations such as tablets, capsules, powders, granules, and liquid preparations, and sterilized liquid parenteral preparations such as solutions and suspensions. Is mentioned.
  • Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives.
  • the additive include sugars such as lactose and glucose; starches such as corn, wheat and rice; fatty acids such as stearic acid; inorganic salts such as sodium metasilicate, magnesium aluminate and anhydrous calcium phosphate; Synthetic polymers such as polyvinylpyrrolidone and polyalkylene glycol; fatty acids such as calcium stearate and magnesium stearate; alcohols such as stearyl alcohol and benzyl alcohol; methyl cellulose, carboxymethyl cellulose, and ethyl cellulose And synthetic cellulose derivatives such as hydroxypropylmethylcellulose, and other commonly used additives, such as water, gelatin, talc, vegetable oil, and gum arabic.
  • These tablets, capsules, granules, powders and other solid preparations can generally contain 0.1 to 100% by weight, preferably 5 to 100% by weight, of the active ingredient.
  • appropriate additives normally used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc. It can be manufactured as a form.
  • Particularly suitable solvents for parenteral administration include, for example, distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous dextrose, ethanol, and liquid for intravenous injection (for example, quinic acid). , Sodium citrate, etc.), an electrolyte solution (for example, intravenous drip, intravenous injection) and the like, or a mixed solution thereof.
  • Liquid preparations such as suspensions or syrups for oral administration may contain 0.5 to 10% by weight of active ingredients.
  • the practically preferred dosage of the compounds of the present invention may be adjusted as appropriate depending on the type of compound used, the type of composition formulated, the frequency of application and the particular site to be treated and the condition of the patient. .
  • the daily dose per adult per day is 0.1 to 100 mg for oral administration and 100 mg / day for parenteral administration. It is 0.01 to 50 Omg.
  • the frequency of administration varies depending on the administration method and symptoms, but it can be administered once or in 2 to 5 doses.
  • the thin-layer chromatograph of the example has a plate of Si 1 i c ag e 160 F
  • the silica gel for the column is Wakoge 1 TM C-300 (Wako Pure Chemical Industries), and the silica gel for the reversed-phase column is LC-SORB TM S PB-ODS (Chemco) or Y
  • the solution was boiled for 90 minutes, cooled to room temperature, and acidified to pH ⁇ 2 with concentrated hydrochloric acid.
  • the acidic solution was extracted with dichloromethane, and the combined extracts were dried and concentrated to give a red oil.
  • This oil was treated with a 1 M aqueous sodium hydroxide solution, extracted with dichloromethane, the water tank was separated, and treated with concentrated hydrochloric acid to obtain an oil.
  • the oil was extracted into dichloromethane, the extracts were combined, dried and concentrated under reduced pressure to give the desired orange-red oily product phenyl (2-sulfanylphenyl) methanone (36.4 g, 17 Ommo). 1) was obtained (80% yield).
  • Step 1 The compound obtained in Step 1 (0.3 ml) was combined with the product of Step 2 (300 mg, 1.
  • step 3 To a solution of the product of step 3 (180 mg, 0.64 Ommo 1) in trifluoroacetic acid (3.0 ml) was added 30% aqueous hydrogen peroxide (1.0 ml) at a temperature of about 0. After the addition was completed, the mixture was stirred at room temperature overnight, treated with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. And concentrated under reduced pressure. The residue and 4-hydrogen chloride 1,4-dioxane solution (3.0 ml) were mixed, and zinc powder (200 mg, 3.06 mmol 1) was gradually added.
  • Diastereomer a (A r: Ph; R 1 : H; R 2 : H; 3 : i-Pr; R 4 : H
  • Diastereomer b (Ar: Ph j R ⁇ H .- R 'r H j R 3 : i -P r; R 4 : H
  • Diastereomer a (Ar i Ph j R ⁇ H j R ⁇ H i R 3 : i- 1 Pr; R 4 : H
  • Diastereomer b (Ar i P j R ⁇ H j R ⁇ H i R 3 : i-P r; 4 : H

Abstract

L'invention concerne des composés de formule générale (I), dans laquelle R1 et R2 sont chacun hydrogène ou alkyle C¿1-3 ; R?3 est hydrogène ou alkyle C¿1-6? (excepté n-butyle) ; R?4¿ représente hydrogène, hydroxyle ou alkyle C¿1-3 ; R?5 désigne un groupe aliphatique cyclique C¿3-6? saturé ou insaturé, ou bien un groupe aliphatique C1-9 saturé ou insaturé, linéaire ou ramifié ; Ar désigne un groupe aliphatique cyclique C3-9 saturé ou insaturé, ou bien un groupe aliphatique C1-9 saturé ou insaturé, linéaire ou ramifié ; n est un nombre entier entre 0 et 2. Ces composés contribuent à l'élévation de la concentration de GLP-1 dans le sang et sont donc utiles comme agents de lutte contre le diabète et de prévention de complications chroniques dues au diabète, comme agents contre l'obésité, etc.
PCT/JP2001/011267 2000-12-27 2001-12-21 Derives de la benzothiazepine WO2002053548A1 (fr)

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