Classifications

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  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
  • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

• the present invention relates to a melanin-concentrating hormone antagonist useful as an agent for preventing and treating obesity.
• Landscape technology
• Feeding behavior is an indispensable activity for many living things, including humans. Therefore, abnormalities in eating behavior can lead to disorder in normal life activity and often lead to illness.
• obesity has become a social problem with changes in the eating environment.
• Obesity is not only a significant risk factor for lifestyle-related diseases such as diabetes, hypertension, and atherosclerosis, but also can lead to arthritis and pain due to weight gain overloading knees and other joints. Widely known.
• eating disorders such as bulimia caused by genetic or neurotic disorders such as stress.
• MCH melanin-concentrating hormone
• an MCH antagonist can be made, it will be a good appetite suppressant
• a compound having an MCH antagonistic action particularly a non-peptide compound has not yet been known.
• the following compounds are known as amine derivatives.
• R 1 is hydrogen, halogen, Ci-e alkyl, C 3 _ 6 cycloalkyl, COCj- 6 alkyl, - 6 alkoxy, hydroxy, hydroxy (6 Al kill, hydroxy CI- 6 alkoxy, Ashiru, nitro , Trifluoromethyl, cyano, CH ⁇ , SR 9 , S ⁇ R 9 , S0 2 R 9 , SOaNR ⁇ R 11 , CO ⁇ 1 NR ⁇ 0 SO 2 R 11 ⁇ CONR ⁇ R 1 ⁇ CO ⁇ R ⁇ R 11 , CONR 10 (C
• R 2 and R 3 are independently hydrogen, halogen, ⁇ - 6 alkyl, C 3 - 6 Shikuroa alkyl, C 3 - 6 cycloalkenyl, - 6 alkoxy, Ashiru, Ariru, ⁇ Shiruokishi, hydroxy, nitro, Torifuruo Romechiru, Shiano, hydroxy sheet (6 alkyl, C, _ 6 alkyl OC! _ 6 alkyl, CO 2 R 10, CON R ⁇ R 11, N ⁇ R 11 ( here, R 10 and R 11 are independently it is hydrogen or _ 6 alkyl);
• R 4 and R 5 are independently hydrogen or alkyl;
• R 6 is hydrogen, halogen, hydroxy, alkyl or alkoxy;
• R 7 and R 8 are independently hydrogen, ⁇ - 6 containing alkyl, Ararukiru or in combination with the nitrogen atom to which they are to a connexion together, oxygen, one or two hetero atoms selected from nitrogen or sulfur Forming an optionally substituted 5- to 7-membered heterocycle;
• n 1 or 2] or a salt thereof.
• R ⁇ R 2 and R 3 are independently hydrogen, halogen, ⁇ - 6 alkyl, C 3 _ 6 cycloalkyl, C 3 - 6 cycloalkenyl, alkoxy, Ashiru, ⁇ Li Lumpur, Ashiruokishi, hydroxy, nitro , triflumizole Ruo Russia methyl, Shiano, (here, R 9, R 10 and R 11 are independently hydrogen or ⁇ -e alkyl) C0 2 R 9, CONR ⁇ R 11, NR 10 R 1X with Yes;
• R 4 is hydrogen, halogen, hydroxy, 6 alkyl or Ci_ 6 alkoxy
• R 5 and R 6 are independently hydrogen or alkyl
• R 7 and R 8 are independently hydrogen, C ⁇ - 6 alkyl, Ararukiru or colleagues such together with the nitrogen atom bonded connection, oxygen, one or two are selected from nitrogen or sulfur, Forming an optionally substituted 5- to 7-membered heterocycle containing a heteroatom;
• n 1 to 4.
• n 1 or 2;
• JP-A-6-211800 discloses a compound having vasopressin antagonistic activity or oxytocin antagonistic activity.
• R 1 is a hydrogen atom, an octylogen atom, a hydroxyl group, a lower alkanoyloxy group, a lower alkyl group or a lower alkanoyl group as a substituent; an amino lower alkoxy group which may have a group selected from the group consisting of And a lower alkoxy group substituted with a carbonyl group, a lower alkoxy group substituted with a lower alkoxycarbonyl group, or an aminocarbonyl lower alkoxy group which may have a lower alkyl group as a substituent.
• R 4 is a hydrogen atom, group NR 6 R 7 (R 6 and R 7 are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a benzoyl having a halogen atom as a substituent on a phenyl ring. ), A lower alkenyloxy group, a hydroxyl-substituted lower alkyl group, and a group of CO— ANR8R 9 (A represents a lower alkylene group.
• R 8 and R 9 are the same or different and each represents hydrogen. And R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycle with or without a nitrogen or oxygen atom.
• a lower alkyl group may be substituted on the heterocyclic ring), a group 0—R 1Q (R 1G represents an amino acid residue), a lower alkoxycarbonyl-substituted lower alkylidene group , Lower alkoxycarbonyl substitution Lower alkyl group, carboxy-substituted lower alkyl group, group—ACONRHR 12 (A is as defined above.
• R 11 and R 12 are the same or different and are a hydrogen atom, a lower alkyl group which may have a hydroxyl group, a piperidinyl group which may have a phenyl lower alkyl group on a piperidine ring, a carbamoyl-substituted lower alkyl group, Pyridyl-substituted lower alkyl group, pyridyl group, group 1 ANR 39 ; 4 () (A is the same as above.
• R 39 and R 4Q are the same or different and are a lower alkyl group which may have a hydrogen atom or a hydroxyl group.
• R 39 and R 4G may form a 5- or 6-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. May be substituted with a lower alkyl group.
• a pyrazinyl-substituted lower alkyl group which may have a lower alkyl group as a substituent on the pyrazine ring
• a pyrrolyl-substituted lower alkyl group which may have a lower alkyl group
• a pyrrolidinyl-substituted lower alkyl group which may have a lower alkyl group as a substituent on a pyridine ring, or a halogen atom on a phenyl ring.
• R 11 and R 12 may form a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded.
• a lower alkyl group a lower alkoxycarbonyl group, an amino group which may have a group selected from the group consisting of a lower alkyl group and a lower alkanol group as a substituent, a lower alkoxycarbonyl-substituted lower alkyl group, Phenyl group which may have a halogen atom on the phenyl ring, a cyano-substituted lower alkyl group, a lower alkenyl group, an oxylanyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, and a hydroxyl group and a lower alkyl group as substituents
• a lower alkyl group a lower alkyl group, a lower alk
• ACONR 23 24 (A is the same as defined above.
• R 23 and R 24 are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a piperidine ring
• a piperidinyl group or a group which may have a lower alkyl group thereon B- NR23A R24A (wherein B represents a lower alkylene group; R23A and R24A are the same or different and are each a hydrogen atom or a lower alkyl group; R 23A and R 24A together with the nitrogen atom to which they are attached
• a 5- or 6-membered saturated complex ring may be formed with or without a nitrogen atom or an oxygen atom.
• R 23 and R 24 may form a 5- to 7-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom to which they are bonded.
• a lower alkyl group may be substituted on the heterocyclic ring.
• R 27 and R 28 are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylsulfonyl group, or a lower substituent.
• Aminothiocarbonyl group which may have an alkyl group
• R 41 represents a hydrogen atom or a cyano group.
• R 42 represents a lower alkyl group or an amino group which may have a lower alkyl group as a substituent.
• R 27 and R 28 may form a 5- to 10-membered monocyclic or binomial saturated or unsaturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded.
• An oxo group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkynyl group or a lower alkynylamino group may be substituted on the heterocyclic ring.
• the heterocyclic ring may form a saturated heterocyclic ring on which an amino which may have a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkyl group and a lower alkanoyl group.
• an amino which may have a group selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkyl group and a lower alkanoyl group.
• a lower alkylsulfonyl group, a lower alkoxy group, or an aminocarbonyl group which may have a lower alkyl group as a substituent.
• R 5 represents a hydrogen atom or a hydroxyl group.
• R 4 and R 5 may be taken together to form an oxo group.
• R 2 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a halogen atom or a lower alkoxy group.
• R 3 is a group
• R 13 is a halogen atom, a hydroxyl group, a carbamoyl group, a lower alkyl group, a piperazinyl lower alkoxy group having a lower alkanoyl group at the 4-position of the piperazine ring, an imidazolyl-substituted lower alkoxy group, or a lower alkanoyl group on the piperidine ring.
• a substituent on the phenyl ring selected from the group consisting of a halogen atom, a lower alkoxy group, a lower alkyl group, and a nitro group.
• the carbon-carbon bonds at the 4- and 5-positions of the benzoazepine skeleton shall show a single bond or a double bond.
• R 1 represents a hydrogen atom or a halogen atom
• R 4 represents a hydrogen atom
• a group —NR 6 R 7 (the lengths 6 and 17 represent the above-mentioned R other than a benzoyl group having a halogen atom as a substituent on a phenyl ring). 6 and R 7 ), and the group CO-ANR 8 R 9 (A is the same as above.
• R 8 and R 9 are the same or different and represent a hydrogen atom or a lower alkyl group.
• R 13 represents a carpamoyl group, a lower alkayl group having a lower alkenyl group at the 4-position of the piperazine ring, a lower alkoxy group having an imidazolyl-substituted lower alkoxy group, or a lower alkenyl group having an imidazolyl-substituted lower alkoxy group. It must be a pyridinyl lower alkoxy group having a nolamino group, a 1,2,4-triazolyl-substituted lower alkoxy group or a ureido-substituted lower alkoxy group which may have a lower alkyl group. Or a salt thereof.
• the present inventors have conducted intensive studies on compounds having MCH antagonistic activity, and as a result,
• X is a bond or a spacer having 1 to 10 atoms in the main chain
• Y is a spacer having 1 to 6 atoms in the main chain
• Ring A further has an optionally substituted benzene ring
• Ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• R 1 and R 2 are the same or different and each represents a hydrogen atom, or represent an heterocyclic group optionally having an optionally substituted carbon hydrocarbon groups or substituents, R 1 and R 2 are It may form a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom, and R 2 represents a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom and Y. Or a salt thereof, or a melanin-concentrating hormone antagonist;
• R is a cyclic group which may have a substituent
• X is a main chain having 1 to 6 atoms
• R 1 and R 2 are the same or different and are hydrogen atoms Or a hydrocarbon group which may have a substituent
• R 1 and R 2 together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic ring which may have a substituent
• 2 The agent according to the above 1), wherein 2 forms a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom and Y;
• the agent according to the above 1) which is an agent for preventing and treating obesity
• Ar 1 represents a cyclic group which may have a substituent
• X is a bond or a spacer having 1 to 10 atoms in the main chain
• ⁇ is a spacer having 1 to 6 atoms in the main chain
• the ⁇ ring further has an optionally substituted benzene ring
• the ring B 1 is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• R 1 and R 2 are the same or different and each represents a hydrogen atom, or represent an heterocyclic group optionally having an optionally substituted carbon hydrocarbon groups or substituents
• R 1 and R 2 are A nitrogen-containing heterocyclic ring which may have a substituent may be formed together with an adjacent nitrogen atom
• R 2 may be a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom and Y ( (Excluding piperidine).
• the ring B 1 is not azepane or 4,5-dihydroazepine, each of which may further have a substituent, or that Ar 1 has a substituent.
• Y is not CO— (C (R a) H) na — (R a is a hydrogen atom or a hydrocarbon group which may have a substituent, and na represents an integer of 1 to 10) And does not have a bicyclic nitrogen-containing heterocyclic ring substituted with an amino group. ] Or a salt thereof;
• X is a spacer having 1 to 10 atoms in the main chain, and R 1 and R 2 are the same or different and represent a hydrogen atom or a hydrocarbon group which may have a substituent. R 1 and R 2 may form a nitrogen-containing heterocyclic ring which may have a substituent together with an adjacent nitrogen atom, or R 2 may have a substituent together with an adjacent nitrogen atom and Y A compound as described in the above item 5), which forms a good nitrogen-containing heterocycle '(excluding piperidine);
• the aromatic group is formed of two or three selected from a monocyclic or fused polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms and a 5- to 10-membered aromatic heterocycle.
• S Bae one mono represented by X and Y is one 0-; single S -; - CO-; single SO-; -SO 2 -; -N 8 - (R 8 is a hydrogen atom, halogenated which may be C bets 6 Al kill, optionally halogenated C [et alkyl Ichiriki Ruponiru, optionally halogenated represents an C ⁇ 6 alkylsulfonyl); and may have a substituent
• the compound according to the above 5 which is a divalent group composed of 1 to 3 groups selected from divalent C 6 acyclic hydrocarbon groups;
• composition comprising the compound according to 5) or a salt thereof;
• R represents a hydrogen atom, a halogen atom, or a cyclic group which may have a substituent
• 'X is a bond or a spacer having 1 to 10 atoms in the main chain
• Ya is a spacer having 1 to 5 atoms in the main chain
• Ring A further has an optionally substituted benzene ring
• Ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• R b represents a hydrogen atom or a hydrocarbon group which may have a substituent.
• Ya does not have a bicyclic nitrogen-containing heterocyclic ring substituted with an amino group. ] The compound represented by these, or its salt.
• R b is an optionally substituted C 6 - 14 wherein a Ariru 18) SL placement compound
• a pharmaceutical composition comprising the compound according to the above 18) or a salt thereof; 25) a prodrug of the compound according to the above 18);
• L represents a leaving group, and other symbols have the same meanings as described in the above 18), or a salt thereof;
• R represents a hydrogen atom, a halogen atom, or a cyclic group which may have a substituent
• X is a bond or a spacer having 1 to 10 atoms in the main chain
• Ring A further has an optionally substituted benzene ring
• Ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• w 7 is an integer from 0 to 4.
• R 1 and R 2 are the same or different and each represents a hydrogen atom, or represent an heterocyclic group optionally having an optionally substituted carbon hydrocarbon groups or substituents, R 1 and R 2 are A nitrogen-containing heterocyclic ring which may have a substituent may be formed together with an adjacent nitrogen atom. ] Or a salt thereof;
• R is a hydrogen atom, a halogen atom, or an optionally substituted cyclic group
• X is a bond or a main chain having 1 to 10 atoms
• Ring A further has an optionally substituted benzene ring
• Ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• w 2 is an integer from 0 to 5;
• Z represents CH or N
• R c represents a hydrocarbon group which may have a substituent. Or a salt thereof; 31) The compound according to the above 30), wherein Z is CH;
• R c is a good C 6 _ 14 Ariru have a substituent 30) SL placement compound
• a pharmaceutical composition comprising the compound according to the above 30) or a salt thereof; 34) a prodrug of the compound according to the above 30);
• a medicament comprising a combination of the melanin-concentrating hormone antagonist according to 1) and at least one selected from a therapeutic agent for diabetes, a therapeutic agent for hypertension and a therapeutic agent for arteriosclerosis;
• R represents a hydrogen atom, a halogen atom, or a cyclic group which may have a substituent
• X is a bond or a spacer having 1 to 10 atoms in the main chain
• Yb is a spacer having 1 to 6 atoms in the main chain
• Ring A further has an optionally substituted benzene ring
• Ring B is a 5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring which may further have a substituent;
• R 1 and R 2 are the same or different and each represents a hydrogen atom, or represent an heterocyclic group optionally having an optionally substituted carbon hydrocarbon groups or substituents
• R 1 and R 2 are It may form a nitrogen-containing heterocycle (excluding piperidine) which may have a substituent together with an adjacent nitrogen atom
• R 2 may have a substituent together with an adjacent nitrogen atom
• Yb is —CO— (C (R a) H) n- (R a may be a hydrogen atom or a group having a substituent.
• a good hydrocarbon group, n and a each represent an integer of 1 to 10) ]
• a method for preventing or treating obesity in said mammal comprising administering to the mammal an effective amount of the compound represented by the formula (I) or a salt thereof;
• Examples of the “cyclic group” in the “optionally substituted cyclic group” represented by R and Ar 1 include an aromatic group, a non-aromatic cyclic hydrocarbon group, and a non-aromatic heterocyclic group. No.
• aromatic group examples include a monocyclic aromatic group, a condensed aromatic group, a ring-assembled aromatic group, and the like.
• Examples of the monocyclic aromatic group include an I-valent group formed by removing any one hydrogen atom from a monocyclic aromatic ring.
• Examples of the “monocyclic aromatic ring” include a benzene ring and a 5- or 6-membered aromatic heterocyclic ring.
• the “5- or 6-membered aromatic heterocycle” for example, a 5- or 6-membered aromatic containing one or more (eg, 1-3) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom And heterocycles.
• monocyclic aromatic group examples include phenyl, 2- or 3-phenyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl , 2-, 4-mono- or 5-pixazolyl, 1-3- or 4-pyrazolyl, 2-pyrazinyl, 1-1, 4- or 5-pyrimidinyl, 1-, 2- or 3-pyrrolyl, 1-1, 2 —Or 4 ⁇ midazolyl, 3 or 4 pyridazinyl, 3 —isothiazolyl, 3 —isoxazolyl, 1,2,4 —oxaziazolyl 5-yl, 1,2,4— Oxaziazol-3-yl.
• ⁇ condensed aromatic group '' a monovalent group formed by removing any one hydrogen atom from a condensed polycyclic (preferably 2 to 4 ring, more preferably 2 or 3 ring) aromatic ring is mentioned.
• fused polycyclic aromatic ring include a fused polycyclic aromatic hydrocarbon, a fused polycyclic aromatic heterocycle, and the like.
• Examples of the “condensed polycyclic aromatic hydrocarbon” include a condensed polycyclic (2- or 3-cyclic) aromatic hydrocarbon having 9 to 14 carbon atoms (eg, naphthylene, indene, fluorene, anthracene). Etc.).
• fused polycyclic aromatic heterocycle examples include, for example, one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (for example,
• fused polycyclic aromatic heterocycle is more preferably a 10-membered fused polycyclic aromatic heterocycle.
• fused polycyclic aromatic heterocycle examples include benzofuran, benzyl 'midazole, benzoxazole, benzothiazol, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline , Indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, phthalazine, naphthyridine, quinazoline, cinnoline, carbazole, ⁇ -carboline, acridine, phenazine, phthalimide, thioxanthene and the like.
• the "condensed aromatic group” include: 1-naphthyl; 2-naphthyl; 2-, 3-, 4-, 5- or 8-quinolyl; 1, 3-, 4-, 5-, 6- , 7— or 8—isoquinolyl; 1 _, 2—, 3—, 4—, 5—, 6— or 7—indolyl; 1—, 2—, 4— or 5 _ isoindolyl; 1—, 5— or 6-phthalazinyl; 2-, 3- or 5-quinoxalinyl; 2-, 3-, 4-, 5- or 6-benzofurael; 2-, 4-1, 5- or 6-benzothiazolyl; 1-, 2- , 41-, 5- or 6-benzimidazolyl.
• a “ring-assembled aromatic group” is one in which two or more (preferably 2 or 3) aromatic rings are directly connected by a single bond, and the number of rings directly connecting the rings is 1 Less good It means a group obtained by removing one arbitrary hydrogen atom from an aromatic ring assembly.
• aromatic ring assembly examples include monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, etc.) and 5 to 10 members (preferably 5 or 6). Member) An aromatic ring aggregate formed of two or three (preferably two) selected from aromatic heterocycles.
• Preferred examples of the aromatic ring assembly include, for example, benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazol, isothiazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4- 2 or 3 fragrances selected from oxadiazol, 1,2,4-thiadiazole, 1,3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole and benzofuran
• An aromatic ring aggregate consisting of a ring is exemplified.
• ring-assembled aromatic group examples include 2-, 3- or 4-piphenylyl; 3- (1-naphthyl) 1-1,2,4-oxadiazo-1-yl 5-yl; 3- (2 -Naphthyl)-1,2,4-oxoxadiazole 5-yl; 3- (2-benzozofuranyl) -1,2,4-oxosadiazole-5-yl; 3-phenyl-1,2,4 —Oxaziazol-5-ylyl; 3- (2-benzoxazolyl) —1,2,4-oxaziazol-5-yl; 3— (3_indolyl) -1-, 2,4-oxaziazol—5— 3- (2-Indolyl) -1,2,4-oxaziazol-1-yl; 4-phenylthiazole-2-yl; 4- (2-benzofurel) thiazol-2-yl; 4-phenyl-1,3-oxazo-lu-5
• ⁇ aromatic groups '' ⁇ formed from 2 or 3 selected from monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 14 carbon atoms and 5- to 10-membered aromatic heterocycles (Preferably 2-, 3- or 4-biphenyl; 6-phenyl-3-pyridyl, 5-phenyl-1-pyridyl, etc.) j Is preferred.
• non-aromatic cyclic hydrocarbon group for example C 3 _ 8 cycloalkyl, C 3 - 8, such as cycloalkenyl and the like.
• cyclohexyl is preferred especially cyclohexylene.
• non-aromatic heterocyclic group examples include a monocyclic non-aromatic heterocyclic group, a condensed polycyclic non-aromatic heterocyclic group, and the like.
• Examples of the “monocyclic non-aromatic heterocyclic group” include monovalent groups formed by removing any one hydrogen atom from a monocyclic non-aromatic heterocyclic ring.
• the “monocyclic non-aromatic heterocycle” is, for example, a 5- to 8-membered member containing one or more (eg, 1-3) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. And a monocyclic non-aromatic heterocycle.
• tetrahydrothiophene tetrahydrofuran, pyrrolidine, imidazoline, imidazolidine, pyrazoline, villazolidine, tetrahydrothiazol, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, Piperidine, tetrahydropyridine, dihydropyridine, piperazine, morpho Phosphorus, thiomorpholine, tetrahydropyrimidine, tetrahydropyridazine, hexamethyleneimine and the like.
• any one hydrogen atom from a fused polycyclic (preferably 2 to 4 cyclic, more preferably 2 or 3 cyclic) non-aromatic heterocyclic Shows a monovalent group formed by removing atoms.
• the ⁇ condensed polycyclic non-aromatic heterocycle '' includes, for example, one or more (e.g., 1 to 4!) Heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. And a 14-membered, preferably 9- or 10-membered fused polycyclic non-aromatic heterocycle.
• non-aromatic heterocyclic groups “5- to 8-membered monocyclic non-aromatic heterocyclic groups (preferably piperidino; piperazinyl; pyrrolidinyl, etc.)” are preferable.
• the “cyclic group” in the “optionally substituted cyclic group” for R and Ar 1 is preferably an aromatic group, more preferably a monocyclic aromatic group (preferably phenyl, Pyrrolyl) or a ring-assembled aromatic group (preferably biphenyl).
• Examples of the “substituent” in the “optionally substituted cyclic group” represented by R and Ar 1 include oxo, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C et alkylene O carboxymethyl (eg, Mechirenjiokishi, such as ethylene di old alkoxy), nitro, Shiano, optionally halogenated C, _ 6 alkyl, Hydroxy-C 6 alkyl, C 6 14 aryloxy—C 6 alkyl (eg, phenoxymethyl, etc.), — 6 alkyl—C 6 14 aryl C 2 6 alkenyl (eg, methylphenylethenyl) etc.), halogenated C 3 _ 6 optionally Shikuroa alkyl, halogenated which may be C ⁇ 6 alkoxy, optionally halogenated C i _ 6 alkylthio, which may have a substituent Good C 7 _ 19 a
• the “cyclic group” represented by R and Ar 1 may have 1 to 5, preferably 1 to 3, of the above substituents at substitutable positions of the cyclic group. When the number of substituents is two or more, the substituents may be the same or different.
• the ⁇ cyclic group '' represented by R and Ar 1 is a non-aromatic cyclic hydrocarbon group If no is a non-aromatic heterocyclic group, the "cyclic group” may have a substituent group C 6 _ 1 4 Ariru, 5 which may have a substituent group to 10-membered aromatic It may have a heterocyclic group or the like as a substituent.
• the “optionally substituted C 4 aryl” and the “optionally substituted 5- to 10-membered aromatic heterocyclic group” include the following “substituted And the "substituent” in the "5- or 7-membered saturated cyclic amino" which may be mentioned.
• the number of substituents is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• the “optionally halogenated C ⁇ 6 alkyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C 6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.).
• halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
• C 6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
• Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pendufluorethyl, pupill, 3,3,3 -Trifluoropropyl, isopropyl, butyl, 4,4,4-Trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-Trifluoropentyl, hexyl , 6, 6, 6-triflurohexyl and the like.
• the "optionally halogenated and C 3 - 6 cycloalkyl” includes, For example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) to good C 3 _ 6 cycloalkyl optionally having (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene hexyl etc.) and the like.
• 1 to 3 halogen atoms e.g., fluorine, chlorine, bromine, iodine, etc.
• C 3 _ 6 cycloalkyl optionally having (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene hexyl etc.) and the like.
• cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like.
• halogenated C ⁇ 6 alkoxy for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, C ⁇ 6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) which may have bromine, iodine and the like.
• halogen atoms eg, fluorine, chlorine, C ⁇ 6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.
• halogen atoms eg, fluorine, chlorine, C ⁇ 6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) which may have bromine, iodine and the like.
• Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
• C ⁇ 6 alkylthio eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio
• halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
• C 7 1 9 Ararukiru be substituted
• the "C 7 1 9 ⁇ aralkyl” for example, benzyl, phenethyl, Jifuenirumechiru, triphenylmethyl, 1-naphthylmethyl, 2- Examples include naphthylmethyl, 2,2-diphenylethyl, 3_phenylpropyl, 4-phenylbutyl, and 5-phenylpentyl. Among them, benzyl and the like are preferable.
• Examples of the “substituent” in the “optionally substituted 7 to 19 aralkyl” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C ⁇ 3 alkylenedioxy ( examples, Mechirenjiokishi, etc.
• a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
• C ⁇ 3 alkylenedioxy examples, Mechirenjiokishi, etc.
• halogenated which may be C 6 alkyl, optionally C 3 which may be halogenated - 6 cycloalkyl, optionally C 6 alkoxy which may be halogenated, optionally halogenated C [bets 6 alkylthio, hydroxy, amino, mono- C DOO 6 alkylamino (e.g., Mechiruamino, Echiruamino, propyl Ruamino, isopropyl ⁇ Mino, etc.
• Puchiruamino di C Arukirua amino (e.g., Jimechiruamino, Getylamino, dipropylamino, dibutylamino, ethylmethylamino, etc. , Amino - C 6 alkyl (e.g., aminomethyl, Aminoethyl, Aminopuropiru, aminobutyl, etc.), mono- C 6 alkyl-amino C 6 alkyl (e.g., methylaminomethyl, E chill aminomethyl, flop port pills aminomethyl, isopropyl aminoethyl, butylaminoethyl, etc.), di -C ⁇ 6 alkylamino over C ⁇ 6 alkyl (e.g., dimethylaminomethyl, Jefferies chill aminomethyl, dipropylaminomethyl, diisopropylaminoethyl, dibutylaminoethyl, etc.), formyl, force Rupokish
• 6- alkoxy-carbonyl eg, methoxycarbonyl, ethoxycarbonyl, propoxyl-proponyl, tert-butoxycarbonyl, etc.
• mono ( ⁇ -6 alkyl-carbonyl-lumbamoyl eg, methylcarbamoyl, ethylcarbamoyl, etc.
• g C 6 alkyl—force j levamoyl eg, dimethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, etc.
• C ⁇ 6-alkyl-rubbamoyloxy eg, methylcarbamoyloxy, etc.
• di-CJ- 6- alkyl-lumbamoyloxy eg, dimethylcarbamoyloxy, getylcarbamoyloxy, etc.
• hydroxy Examples include alkyl (eg, hydroxyethyl) and the like.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
• halogenated which may be C ⁇ 6 alkyl
• substituent optionally having substituent (s)
• substituent include those exemplified as “substituent” in the above “cyclic group optionally having substituent (s)”.
• Examples of the “optionally halogenated C 6 alkyl-potassium” include 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
• Alkyl-propanols eg, acetyl, propanol, butanol, pentanoyl, hexanoyl, etc.
• Specific examples include, for example, acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanol, butanol, pentanoyl, hexanoyl and the like.
• the “optionally halogenated ci-6 alkylsulfonyl” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
• alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like).
• Specific examples include, for example, methylsulfonyl, difluoromethylsulfonyl, trifluorosulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl Honyl and the like.
• Examples of the “optionally halogenated C; L_ 6 alkyl monovalent lipoxamide” include, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) And C-alkyl monocarpoxamides (eg, acetoamide, propanamide, butanamide, etc.) which may have the following. Specific examples include, for example, acetoamide, trifluoroacetamide, propanamide, butanamide and the like.
• the “C” in the “ 9- aralkyloxy optionally having substituent (s)” 7 - 1 9 The Ararukiruokishi ", for example, Benjiruokishi, Fuenechiruo xylene, diphenyl methyl O alkoxy, triphenylmethyl O alkoxy, 1 one Nafuchirume Chiruokishi, 2-naphthylmethyl O alkoxy, 2, 2-diphenyl E chill O carboxymethyl , 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentoxy, and the like.
• substituents in the “14 aryl rubamoyl” those exemplified as the “substituent” in the aforementioned “optionally substituted C 7 ⁇ 9 aralkyl” can be used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• Examples of the “5- to 7-membered saturated cyclic amino” in the “optionally substituted 5- to 7-membered saturated cyclic amino” include, for example, morpholino, thiomorpholino, piperazine-11-yl, piperidino, And pyrrolidine-11-yl.
• the “5- to 7-membered saturated cyclic amino” may be condensed with a benzene ring.
• substituted 5- to 7-membered saturated cyclic amino for example, oxo, optionally halogenated Ci- 6 alkyl, halogenated which may be C 6 alkyl Ichiriki Ruponiru, optionally halogenated C ⁇ 6 alkylsulfonyl which may have a substituent C 6 _ 1 4 Ariru, optionally substituted C 7 to 19 aralkyl, optionally substituted C 6 _ 14 aryl-carbonyl, optionally substituted 5 to 10-membered aromatic heterocyclic group, hydroxy, 5 Or 8-membered monocyclic non-aromatic heterocyclic group (eg, piberidinyl, piperazinyl, pyrrolidinyl, etc.), sorbamoyl, Hydroxy-C i_ 6 alkyl, C ⁇ 6 alkoxy C ⁇ 6 alkyl
• ⁇ 6 alkylamino eg, dimethylamino, acetylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.
• C i-6 alkyl eg, pyrrolidini Rumechiru etc.
• 6- alkyl eg, 2,6-dimethylphenylaminomethyl and the like
• the number of the substituents is, for example, 1 to 5, preferably 1 to 3.
• each substituent may be the same or different.
• “optionally C ⁇ 6 alkyl which may be halogenated” “optionally substituted c 7 - 19 Ararukiru” as is each of the “optionally substituted cyclic group
• “optionally substituted cyclic group The above-mentioned "substituents" are used.
• the "optionally substituted C 6 - 14 Ariru” is set to "substituent” in the those exemplified as “substituent” of the "C 9 Ararukiru optionally having substituents” Is used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• One Lou force Ruponiru The "location substituent” in the “optionally substituted C 7 _ 1 9 Ararukiru Examples of the “substituent” in “” are used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• Examples of the "5- to 10-membered aromatic heterocyclic group" in the “optionally substituted 5- to 10-membered aromatic heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom.
• Examples of the “substituent” in the “optionally substituted 5- to 10-membered aromatic heterocyclic group” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C 3 alkylene O carboxymethyl (eg, Mechirenjiokishi, etc.
• C et alkyl which may be halogenated
• C 6 _ 1 4 Ariruokishi one C ⁇ 6 alkyl (e.g., such as Fuenokishimechiru), _ 6 Archi Lou C 6 - 1 4 Ariru one C 2 _ 6 alkenyl (e.g., methyl phenylalanine E butenyl), an optionally halogenated C 3 - 6 cycloalkyl, optionally halogenated or 6 alkoxy, halogenated which may be C ⁇ - 6 alkylthio which may have a location substituent C 7 _ 1 9 Ararukiru, hydroxy, optionally substituted C 6 _ 1 4 Ariruokishi, have a substituent C 7 __ 1 9 aralkyloxy, amino, amino-C ⁇ 6 alkyl (eg, aminomethyl, aminoethyl, aminopropyl, aminobutyl, etc.), mono-
• -C 6 alkylamino-C i- 6 alkyl eg, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminoethyl, butylaminoethyl, etc.
• di-C ⁇ ealkylamino-C ⁇ 6 alkyl eg, dimethyl Aminomethyl, acetylaminomethyl, dipropylaminomethyl, diisopropylpyruaminoethyl, dibutylaminoethyl, etc.
• the number of the substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• halogenated which may be C i-6 alkyl
• optionally halogenated optionally C 3 _ 6 cycloalkyl which may be “halogenated C i
• the “5- to 7-membered saturated cyclic amino” is the “substituent” in the “optionally substituted cyclic group” described above. And those exemplified as “5- to 7-membered saturated cyclic amino”.
• the “Ashiru” for example, the formula: A CO- R 3, -CO- OR 3, -CO-NR 3 R 4, one CS- NR 3 R 4, -SO 2 -R 3a, - SO- R 3a, - P0 (- oR 3 ) - oR 4 or - P0 2 - in R 3a
• R 3 is (i) a hydrogen atom, (ii) a may have a substituent hydrocarbon group or, (Iii) a heterocyclic group which may have a substituent;
• R 3a represents (i) a hydrocarbon group which may have a substituent, or (ii) a heterocyclic group which may have a substituent.
• hydrocarbon group for example, chain or cyclic hydrocarbon group (e.g., alkyl Le, alkenyl Alkynyl, cycloalkyl, aryl, aralkyl, arylalkyl, dihydroindene, etc.).
• chain or cyclic hydrocarbon group e.g., alkyl Le, alkenyl Alkynyl, cycloalkyl, aryl, aralkyl, arylalkyl, dihydroindene, etc.
• chain or cyclic hydrocarbon group having 1 to 19 carbon atoms are preferred.
• C Bok 6 alkyl e.g., methyl, Echiru, propyl, Izopuropiru, Petit Le, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, etc.
• C 2 _ 6 alkenyl e.g., Biel, Ariru , Isoprobenyl, 2-butenyl, etc.
• C 2 — 6 alkynyl eg, ethel, propargyl, 2-butenyl, etc.
• C 3 _ 6 cycloalkyl eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
• C 3 — 6 cycloalkyl may be fused to one benzene ring;
• Ararukiru e.g., benzyl, phenethyl, Jifuenirumechiru, preparative riffs enyl methyl, 1-naphthylmethyl, 2-naphthylmethyl, 2, 2-Jifue two Ruechiru, 3-phenylpropyl, 4 one-phenylbutyl, 5-Hue Nilpentyl, etc.
• benzyl, phenethyl, 3-phenylpropyl preferably benzyl, phenethyl, 3-phenylpropyl;
• C 8 - 1 9 ⁇ reel alkenyl e.g., styryl, 3 - phenylene Lou 2- professional pool 2 Eniru etc.
• Hydrocarbon group is preferably a C ⁇ 6 alkyl, c 6 -, etc. 1 4 ⁇ Li Ichiru, c 7 _ 1 9 Ararukiru.
• a halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
• ⁇ _ 3 alkyl Renjiokishi e.g, Mechirenjiokishi, Echirenjiokishi etc.
• nitro Shi ⁇ Bruno
• halogenated which may be C ⁇ 6 alkoxy
• optionally halogenated C 6 alkylthio optionally, hydroxy
• Amino, mono- C 6 alkylamino Roh eg, Mechiruamino, Echiruamino, propyl amino, isopropyl ⁇ Mino, etc. Puchiruamino
• a halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
• ⁇ _ 3 alkyl Renjiokishi eg, Mechirenjiokishi, Echirenjiokishi etc.
• nitro Shi ⁇ Bruno
• halogenated which may be C
• C ⁇ 6 alkyl Ichiriki Rubamoiru (eg, dimethylcarbamoyl, Jechirukarupamo I Le, E chill methylcarbamoyl etc.); an optionally substituted C 6 _ 1 4 Ariru - power Rubamoiru ; to 5 which may have a substituent 6-membered heterocyclic force Rubamoiru; optionally halogenated C i one even though 6 alkylsulfonyl; may have a substituent group C 6 _ 1 4 ⁇ reel sulfonyl ; formylamino; optionally halogenated C alkyl Ichiriki also be Rupokisamido; C 6 alkoxy Ichiriki Rupokisamido (e.g., methoxy Cal poke Sami de, eth Shikarupokisamido, pro epoxy force Rupokisamido, butoxide deer Lupo alkylcarboxamide); C ⁇ 6 alkyl sulfates Honir
• C 6 alkyl-carbonyloxy eg, acetoxy, propanoyloxy, etc.
• optionally substituted C 6 _ 14 aryl-carbonyloxy e.g, C 6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.); optionally substituted C 6 _ 14 aryl-carbonyloxy; c x _ 6 alkoxy-carbonyloxy (eg, methoxycarbonyl) Okishi, Etokishika Ruponiruokishi, propoxy force Ruponiruokishi, butoxy Cal Poni Ruo carboxymethyl, etc.); mono - C i _ 6 alkyl - power Rubamoiruokishi (e.g., methylcarbamoyl old alkoxy, E Ji carbamoyl O carboxymethyl, etc.); G.
• C i _ 6 alkyl one Carbamoyloxy (eg, dimethylcarbamoyloxy, getylcarbamoyloxy, etc.); optionally substituted C 6-i 4 arylene rubamoyloxy; nicotinyloxy.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different. '
• no 5 may have a substituent group to 10-membered aromatic heterocyclic group", "optionally substituted C 6 _ 1 4 ⁇ Li one Lou carbonyl", respectively before Symbol " Those exemplified as the "substituent” in the "5- or 7-membered saturated cyclic amino which may have a substituent” are used.
• Examples of the “5- to 6-membered heterocyclic radical” in the “optionally substituted 5- or 6-membered heterocyclic radical” include, for example, nicotinoyl, isonicotinol, 2-tenol, and 3-tenol , 2-furoyl, 3-furoyl, morpholino-capillonil, piperidinocarponyl, pyrrolidine-11-ylcarbonyl and the like.
• Examples of 6 — j 4 arylsulfonyl J include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.
• 6 — 14 aryl carbonyl includes, for example, benzoyloxy, 11-naphthoyloxy, 2_naphthoyloxy And the like.
• C 6 _ 14 Ariru Ichiriki Rubamoiruokishi of the “optionally C 6 _ 14 may be Ariru Ichiriki Rubamoiruokishi have a substituent", for example, phenylene carbamoyl O carboxymethyl, etc. naphthylcarbamoyl O carboxymethyl and the like .
• substituent for example, phenylene carbamoyl O carboxymethyl, etc. naphthylcarbamoyl O carboxymethyl and the like .
• optionally substituted c 6 _ 14 Ariruokishi - Karuboeru
• the ⁇ heterocyclic group '' in the ⁇ heterocyclic group optionally having substituent (s) '' for R 3 or R 3a is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom 1.
• substituent (s) '' for R 3 or R 3a is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom 1.
• aromatic heterocycle is, for example, a 5- to 14-membered member containing one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, preferably Is a 5- to 10-membered aromatic heterocycle No.
• the “5- to 10-membered non-aromatic heterocycle” for example, 2- or 3-pyrroline, pyrrolidine, 2- or 3-imidazoline, 2-year-old xazoline, oxazolidin, 2- or 3-pyrazoline, pyrazolidine, 2-thiazoline, piperidine, piperazine, hexamethyleneimine, morpholine, thiomorpholine and the like.
• Examples of the “7- to 10-membered bridged heterocyclic ring” include quinuclidine, 7-azabicyclo [2.2.1] heptane and the like.
• heterocyclic group preferably contains one or two, preferably one to four, heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
• Membered (monocyclic or bicyclic) heterocyclic groups Specifically, for example, 2- or 3-Chenyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 2-, 4- or 5-thiazolyl '; 2-, 4- or 5- 1-, 3- or 4-pyrazolyl; 2-pyrazinyl; 2-, 4- or 5-pyrimidinyl; 1, 2- or 3-pyrrolyl; 1-, 2- or 4-imidazolyl; Is 4-pyridazinyl; 3-isothiazolyl; 3-isoxazolyl; 1,2,4-oxaziazol-5-yl; 1,2,4-oxoxadiazolyl 3-yl; 2-, 3-, 4 1, 5- or 8-quinolyl; 1, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl; 1-, 2-, 3-
• the “substituent” in the “heterocyclic group optionally having substituent (s)” is preferable. What was illustrated as is used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• R 4 Represented by R 4 as "( ⁇ _ 6 alkyl” includes, for example, methyl, Echiru, flop port pills, isopropyl, heptyl, isobutyl, sec- butyl, ter t-butyl, pentyl, hexyl and the like to.
• the “nitrogen-containing heterocycle” is preferably piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine and the like.
• the “substituent” in the “nitrogen-containing heterocyclic ring optionally having substituent (s)” is preferable. What was illustrated as a “group” is used.
• the number of the substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• the "Ashiru”. Is Konomashigu is formyl, force Rupokishi force Rubamoiru, halogenation which may be C 6 alkyl Ichiriki Ruponiru (eg, such as Asechiru)
• C alkoxy one carbonyl e.g., methoxycarbonyl, ethoxycarbonyl two Le, propoxy force Ruponiru, tert- butoxide deer Lupo sulfonyl, etc.
• C 6 _ 14 ⁇ Li one Roux carbonyl e.g., Benzoiru, 1 _ Naphthoyl, 2-naphthoyl, etc.
• C 6 _ 14 aryloxycarbonyl eg, phenyloxycarbonyl, 11-naphthyloxycarbonyl, 2-
• Optionally substituted C 7 _i 9 aralkyloxy one-strength rubonyl eg, benzyloxy carbonyl, phenethyloxy carbonyl, etc.
• optionally substituted 5 Or 6-membered heterocyclic carbonyl eg, nicotinol, etc.
• the “optionally halogenated C ⁇ 6 alkyl monopropyl” and the “optionally halogenated C 6 alkylsulfonyl” are respectively the above-mentioned “having a substituent. those exemplified as the "substituent” is used in 19 Ararukiru "- which may C 7 to.
• C 6 _ 14 Ariru Ichiriki Rubamoiru have a substituent
• the one exemplified as “substituent” in the "even cyclic group optionally having substituent (s)” is used.
• Examples of the aforementioned “acylamino” include, for example, an amino substituted with one or two of the aforementioned “acyl”, and are preferably represented by the formula: one NR 5 —C0R 6 , —NR 5 —C00R 6a, —NR 5 — S0 2 R 6 a, -NR 5 - CONR 6 a R 6b, one PO (- oR 5) - oR 6 or -P0 2 -R 6 wherein, R 5 is a hydrogen atom or - 6 alkyl; R 6 is wherein R 3 and as defined; R 6 a is the R 3 a as defined above; R 6 b are mentioned force such as ⁇ Shiruamino represented by the same significance as R 4].
• R 5 Represented by R 5 as "(6 alkyl", those similar to the “(G 6 ⁇ alkyl” represented by R 4 can be mentioned.
• acylamino preferably has formylamino, optionally halogenated C i_ 6 alkyl mono-lupoxamide (eg, methylcarpoxamide, trifluoromethylcarpoxamide, etc.), and a substituent.
• C i_ 6 alkyl mono-lupoxamide eg, methylcarpoxamide, trifluoromethylcarpoxamide, etc.
• C 6 _ 14 Ariru Ichiriki Rupokisamido be (eg, phenylene Rukarupokisamido, 2 Metokishifu E double Luke Lupo alkylcarboxamide, such as 4 Metokishifue two Rukarupokisamido), N- (optionally substituted C 6 - 14 Ariru —N-C 6 aralkylamino (eg, N-4-methoxybenzoyl N-methylamino), optionally substituted C 9 aralkyl-carpoxamide (eg, benzylcarpoxamide), Aromatic heterocyclic monocyclic lipoxamides which may have a substituent (eg, benzothiophene-2-ylcarbo) Oxamide, etc.), and may be octa-logenated (e.g., alkoxy-caproloxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxy) Shikarup
• E chill sulfonyl ⁇ Mino which may have a substituent C 6 _ 14 ⁇ Li one Le sulfonyl ⁇ amino (e.g., 4 - like methoxyphenyl sulfonyl ⁇ Mino) etc. It is.
• each substituent may be the same or different.
• "Asiloxy” includes, for example, the aforementioned “Asil” 1 In substituted Okishi the like, preferably, the formula: - 0- C0R 7, - 0- C00R 7, -0-C0NHR 7, -P0 (OH) -0R 7 or - P0 2 - R 7 wherein And R 7 have the same meaning as R 3 above].
• the "Ashiruokishi” preferably, optionally halogenated and C Bok 6 alkyl Ichiriki Ruponiruokishi (eg, Asetokishi, prop noisy Ruo carboxymethyl, etc.), optionally C 6 _ 14 Ariru have a substituent —Carbonyloxy (eg, benzoyloxy, 4 methoxybenzoyloxy, etc.), optionally halogenated C ⁇ 6 alkoxy monopropylonyloxy (eg, methoxycarbonyloxy, trifluoromethoxycarbonyloxy, Ethoxycarponyloxy, propoxyl-ponyloxy, butoxycarponyloxy, etc., mono- 6- alkyl-lumbamoyloxy (eg, methylcarbamoyloxy, ethylcarba) Moiruokishi etc.), di-C DOO 6 alkyl Ichiriki Rubamoiruokishi (e.g., dimethyl force Rubamoiruokish
• C 6 _ 14 aryl-potassium optionally substituted or “c 6 _ 14 aryl-potassium optionally substituted” may be used.
• substituted those exemplified as the "substituent” in the "optionally substituted c 7 _ 1 9 Ararukiru” and the like.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• the “optionally substituted 5- to 7-membered non-aromatic heterocyclic group” which is the “substituent” in the “optionally substituted cyclic group” represented by R and Ar 1
• the “5- to 7-membered non-aromatic heterocyclic group” for example, 4,5-dihydro-1,3-oxazole-12-yl, 4,5-dihydro-1,3-thiazol-2-yl , 4,5-dihydro-1 ⁇ -2-imidazolyl.
• the “substituent” in the “optionally substituted 5- to 7-membered non-aromatic heterocyclic group” includes the above-mentioned “optionally substituted 5- to 7-membered saturated cyclic amino”. What was illustrated as "substitution group” in is used. .
• “Location substituent" in the "optionally substituted cyclic group” represented by R and Ar 1 is preferably a halogen atom (preferably fluorine, chlorine, bromine, etc.); nitro; C DOO 3 alkyl Renjiokishi (preferably such Mechirenjiokishi); (preferably, methyl, Echiru, flop port pills, triflumizole Ruo Russia methyl, tert- butyl, etc.) halogenation which may be C Bok 6 alkyl; hydroxy one C Bok 6 Al Kill (preferably hydroxymethyl or the like); optionally halogenated C
• cycloalkyl preferably, cyclohexylene hexyl, etc.
• halogenated which may be C ⁇ 6 alkoxy (preferably methoxy, ethoxy, etc.); halogenation which may be C ⁇ 6 alkylthio (preferably Is a methylthio, etc.); hydroxy; optionally substituted C 7 _ 19 aralkyloxy (preferably benzyloxy, 4-methoxybenzyloxy, 3-methoxybenzyloxy, 4-fluorobenzyloxy) , 4-methylthiobenzyloxy, 4-ethylbenzyloxy); optionally substituted C 6 _ 14 aryloxy (preferably phenyloxy); amino; mono-C ⁇ 6 alkylamino (preferably , etc.
• Mechiruamino G. c DOO 6 alkylamino (preferably, etc. Jimechiruamino); substituted Or a 5- to 7-membered saturated cyclic amino (preferably 1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl or the like) which may be condensed with a benzene ring;
• a 5- to 7-membered non-aromatic heterocyclic group preferably 4,5-dihydro-1,3-oxazole-2-yl or the like) which may have: formyl; May C 6
• Ariru Ichiriki Ruponiru (such as preferably Benzoiru); which may have a substituent C 6 _ 1 4 Ariru - Power Rubamoiru (preferably phenylene carbamoyl,
• ⁇ cyclic group '' in the ⁇ cyclic group which may have a substituent '' represented by R and Ar 1 is a non-aromatic cyclic hydrocarbon group or a non-aromatic heterocyclic group, it has a substituent which may be C 6 _ 1 4 Ariru (preferably phenyl) is used as a suitable substituent like.
• “Location substituent” in the "substituted cyclic group which may have a” represented by R and Ar 1 is more preferably a halogen atom (preferably chlorine, etc.), ( ⁇ _ 6 Al Kill (preferably methyl etc.), C i may be substituted in one 6 alkoxy C 7 - 1 9 Ararukiruokishi (preferably such as methoxybenzyl O carboxymethyl) Ru Nadodea.
• R and Ar 1 is preferably a halogen atom (preferably fluorine, chlorine, etc. Bromine); nitro; C _ 3 alkylene O carboxymethyl (such as preferably Mechirenjiokishi); halogenated which may be C ⁇ 6 alkyl (preferably methyl Echiru, propyl, triflumizole Ruo Russia methyl, ter t-butyl, etc.); hydroxy-C ⁇ 6 alkyl (preferably, hydroxypropyl methyl); optionally halogenated C 3 - 6 cycloalkyl (preferably is cyclohexylene hexyl, etc.); halogen of which may be C bets 6 alkoxy (preferably methoxy, etc.
• halogenated which may be C ⁇ 6 alkylthio (preferably, methyl Chio) , hydroxy, optionally substituted C 7 - 1 9
• Ararukiruoki Shi preferably Benjiruokishi, 4- Butoxy benzyl O carboxymethyl, 3-methoxamine Shibenjiruokishi, 4 full O b benzyl O alkoxy, 4-methylthio base Njiru Okishi, 4 E chill benzyl O carboxymethyl, etc.
• an optionally substituted C 6 - 14 aryloxy preferably phenyloxy
• amino mono
• 6 alkylamino (preferably, etc. Mechiruamino); G ( ⁇ - 6 Arukirua Mino (preferably, Jimechiruamino etc.); may have a substituent group, 5 to be condensed with benzene ring 7 membered Saturated cyclic amino (preferably 1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl and the like); a 5- to 7-membered non-aromatic heterocyclic group which may have a substituent (Preferably 4,5-dihydro-1,3-oxazolyl-2-yl and the like); formyl; carboxy; optionally substituted C 6 _ 14 aryl-one-l-ponyl (preferably benzoyl) etc.); an optionally substituted C 6 - 1 4 ⁇ Li one Roux force Rubamoiru (preferably phenyl Karupamoiru, 4 Metokishifue carbamoylmethyl, 3, 4 Jimet
• Ruo b methylcarboxamide Kisamido which may have a substituent C 6 - 1 4 Ariru Ichiriki Rupokisami de (preferably phenylene Rukarupokisamido, 2 Metokishifue two Rukarupokisa bromide, 4 etc.
• R and Ari include those having 1 or 2 substituents selected from oxo and optionally substituted C 6 —i 4 aryl (preferably phenyl). Good piperidino, piperazinyl, pyrrolidinyl and the like.
• halogen atom represented by R examples include fluorine, chlorine, bromine, and iodine. Of these, fluorine is preferred.
• the “space having 1 to 10 atoms in the main chain” represented by X means an interval in which 1 to 10 atoms in the main chain are continuous.
• the number of atoms in the main chain is counted so that the number of atoms in the main chain is minimized.
• the number of atoms of 1,2-cyclopentylene is counted as two, and the number of atoms of 1,3-cyclopentylene is counted as three.
• divalent — e acyclic hydrocarbon group in the “optionally substituted bivalent acyclic hydrocarbon group” include, for example,
• (DC to 6 alkylene eg, —CH 2 —, one (CH 2 ) 2 —, — (CH 2 ) 3 _,-(CH 2 ) 4 one, one (CH 2 ) 5 —, one (CH 2 ) 6 —, one CH (CH 3 ) —, one C (CH 3 ) 2 —, -CH 2 —CH (CH 3 ) —, one (CH (CH 3 )) 2 —,-(CH 2 ) 2 C ( CH 3 ) 2 —,-(CH 2 ) 3 C (CH 3 ) 2 —, etc.);
• C 2 — 6 alkynylene eg — C ⁇ C-, — CH 2 — C ⁇ C—, — C ⁇ C— CH 2 _, — CH 2 — C ⁇ C— CH 2 _CH 2 —, etc.
• the “substituent” in the “optionally substituted divalent C ⁇ 6 acyclic hydrocarbon group” includes, for example, an octogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group , nitro, Shiano, optionally halogenated or -6 alkoxy, optionally halogenation C ⁇ 6 alkylthio, Amiso, mono- C 6 alkyl Ruamino (eg, Mechiruamino, Echiruamino, Puropiruamino, isopropyl Amino.
• an octogen atom eg, fluorine, chlorine, bromine, iodine, etc.
• a hydroxyl group e.g, nitro, Shiano, optionally halogenated or -6 alkoxy, optionally halogenation C ⁇ 6 alkylthio
• Amiso mono- C 6 alkyl Ruamino (eg
• G- 6- alkylamino eg, dimethylamino, getylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.
• G- 6- alkylamino eg, dimethylamino, getylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.
• 'formyl carboxy, carbamoyl, thiocarbamoyl, optionally halogenated C ⁇ 6- alkyl-carbonyl, C ⁇ 6-alkoxy-carbonyl (e.g., methoxycarbonyl) , Ethoxycarponyl, propoxyl-ponyl, tert-butoxycarbonyl), and optionally halogenated C 6 alkylsulfonyl.
• the number of the “substituent” is, for example, 1 to 5, preferably 1 to 3.
• the “substituent” in the “optionally substituted divalent C ⁇ 6 acyclic hydrocarbon group” is preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, etc. It is.
• divalent C 5 _ 8 monocyclic non-aromatic hydrocarbon group for example, C 5 - 8 consequent opening Al force down, with the exception of any two hydrogen atoms from C 5 _ 8 cycloalkenes And divalent groups that can be used.
• divalent groups include, for example, 1,2-cyclopentylene; 1,3-cyclopentylene; 1,2-cyclohexylene; 1,3-cyclohexylene; 1,4-cyclohexylene; 1,2- 1,3-cycloheptylene; 1,4-cycloheptylene; 3-cyclohexene-1,1, -4-ylene; 3-cyclohexene-1,2-ylene; 2,5-cyclohexene Jen-I 1, 4-ylen.
• the “main-chain 1 to 6 atom spacer” represented by Y is, for example, the “main-chain 1 to 10 atom spacer” shown by X in the main chain. Having 1 to 6 atoms.
• the “spacer” represented by X and Y is preferably “a spacer having 1 to 6 atoms in the main chain”, and more preferably 10 ⁇ ; — S —; — CO— ;one SO- .; -SO 2 -; -NR 8 - (R 8 are as defined above); 1 selected from and 2 may have a substituent monovalent C one 6 acyclic 'hydrocarbon group Or a divalent group of three or more.
• spacer having 1 to 6 atoms in the main chain include:
• substituent preferably, a halogen atom, a hydroxyl group, etc. which may have a C Interview _ 6 alkylene (e.g., -CH 2 -, one (CH 2) 2 -, - (CH 2) 3 - , -CH (OH)-(CH 2 —, _ (CH 2 ) 4 —, — (CH 2 ) 5 —, — (CH 2 ) 6 —, one CHCH 3 —, one C (CH 3 ) 2 —, — CH 2 — CH (CH 3 ) —, one CH (CF 3 ) —, one (CH (CH 3 )) 2 —, _ (CF 2 ) 2 —, one (CH 2 ) 2 C (CH 3 ) 2 ,-(CH 2 ) 3 C (CH 3 ) 2 —, etc.);
• a C Interview _ 6 alkylene e.g., -CH 2 -, one (CH 2) 2 -, - (CH 2) 3
• C 2 _ 6 alkynylene eg, one C ⁇ C—, —CH 2 — C ⁇ C—, one C ⁇ C— which may have a substituent (preferably, a halogen atom, a hydroxyl group, etc.) CH 2 —, one (1 2 — (; ⁇ ( ⁇ 01 2 — (11 2 — etc.);
• the main chain having 1 to 10 atomic spacers” represented by X is more preferably 1 (CH 2 ) wl 0 (CH 2 ) w2 —, — C0NR 8 —, — NR s C0—, — (CH 2 ) w3 C0—, — (CH 2 ) w5 NR 8 C0—, —CO—, — (CH 2 ) wl C0 (CH 2 ) w2 — (symbols have the same meanings as above), substituents (Preferably, a halogen atom, a hydroxyl group, or the like) may have a C alkylene (eg, —CH 2 _, — (CH 2 ) 2 —, — (CH 2 ) 3 —, —CH 2 — CH ( CH 3) -, etc.), substituents (preferably, halogen atom, hydroxyl group, etc.) which may have a C 2 - 6 alkenylene (
• the“ main chain having 1 to 5 atom spacers ”represented by Ya is, for example, the“ main chain having 1 to 10 atom atoms represented by X ”. Among them, those having 1 to 5 atoms in the main chain are exemplified.
• Ya is preferably - and the like (CH 2) wl C0 (CH 2) w2 - - ( symbol is as defined above) (for example, preferably one C0 (CH 2) 2).
• the "substituent” which the "benzene ring” represented by ring A and the "5- to 9-membered nitrogen-containing non-aromatic heterocyclic ring” represented by ring B may have the aforementioned R and Ar 1
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• Substituents on rings A and B preferably Okiso, substituents (preferably C alkoxy) optionally having C 6 -, etc. 1 4 Ariru.
• cycloalkyl e.g., cyclopropyl, cyclohexane hexyl, etc.
• C 6 - 1 4 Ariru e.g., phenyl, naphthyl, etc.
• dihydroindene and the like.
• “optionally substituted ( ⁇ -6 alkyl)” is preferable, and “C 6 alkyl” is more preferable.
• ( ⁇ -6alkyl) in “Ci-ealkyl optionally having substituent (s)” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl Tert-butyl, pentyl, hexyl, etc. Among them, methyl, ethyl, propyl and the like are preferable.
• substituents in the “C 6 alkyl optionally having substituent (s)” include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.);
• Optionally halogenated Good C alkoxy eg, methoxy, isopropoxy, etc.
• optionally halogenated C alkylthio eg, methylthio, etc.
• hydroxy amino; mono-alkylamino (eg, methylamino, ethylamino, propylamino, isopropyl) amino, Puchiruamino etc.); di - (hydroxy substituted C i _ 6 alkyl Le) amino (eg, Jimechiruamino, Jechiruamino, dipropylamino, Jie Sopuropiruamino, Jibuchiruamino, E chill methyl ⁇ amino, di ( Hydroxyethyl) amino, etc.); .
• 5- or 6-membered monocyclic Cyclic aromatic heterocyclic amino eg, nitropyridylamino, etc.
• a 5- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by oxo or C 6 alkyl (eg, tetrahydrofuryl, pyrrolidinyl, Okisopi Rorijiniru, Piberijieru, piperidinyl, morpholinyl, etc.
• C i _ 6 alkyl Ichiriki Rubamoiru eg, dimethylcarbamoyl, Jefferies Ji carbamoyl, such as E chill methyl Scarpa moil
• C i _ 6 alkyl sulphonyl formylamino
• C i _ 6 alkyl-carboxamide optionally halogenated C i _ 6 alkyl-carboxamide
• C ⁇ 6 alkoxy-functional lipoxamide eg, methoxycarpoxamide, ethoxycarpoxamide) , propoxy Cal poke Sami de, and butoxy force Rupokisamido
• C preparative 6 alkylsulfonyl ⁇ amino e.g., Mechirusuruhoni Ruamino, such as E chill sulfonyl ⁇ mino
• C i _ 6 alkyl Ichiriki Lupo two Ruoki sheets eg, Asetokishi, prop Noiruokishi
• C i _ 6 alkyl Ichiriki Rubamoiruokishi e.g., dimethyl force Rubamoiruokishi, Jefferies Chi carbamoyl O carboxymethyl, etc.
• an optionally substituted aromatic group halogenated which may be C s _ 19 aryloxy (eg, phenoxy, chlorophenoxy, etc.).
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• halogenated which may be C 3 _ 6 cycloalkyl
• halogeno The optionally substituted C alkoxy j and the “optionally halogenated C 6 alkylthio” include, as the “substituent” in the above “optionally substituted cyclic group”. What was illustrated is used.
• substituents and the "aromatic group 10" in the "aromatic group optionally having substituent (s)" the "cyclic group optionally having substituent (s)” for R
• the exemplified “substituent” and “aromatic group” are used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• the "aromatic group” is preferably phenyl, naphthyl, furyl, pyridyl, 15 imidazolyl, indolyl and the like.
• the “substituent” is preferably —3 alkylenedioxy (eg, methylenedioxy, etc.), optionally halogenated C alkyl (eg, trifluoromethyl, etc.), and may be halogenated ( ⁇ _ 6 alkoxy (e.g., methoxy etc.), and the like halogen atom (e.g., chlorine, etc.).
• heterocyclic group optionally having substituent (s) represented by R 1 and R 2
• those exemplified as the aforementioned R 3 can be used.
• heterocyclic group in the “heterocyclic group optionally having substituent (s)” is preferably a 5- to 10-membered non-aromatic heterocyclic group, more preferably pyrrolidini
• nitrogen-containing heterocycle in the “optionally-substituted arsenic heterocycle” formed by R 1 and R 2 together with the adjacent nitrogen atom
• nitrogen-containing heterocycle in the “optionally-substituted arsenic heterocycle” formed by R 1 and R 2 together with the adjacent nitrogen atom
• a nitrogen-containing heterocyclic ring containing 3 to 10 members (preferably 3 to 8 members) containing a nitrogen atom and may further contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
• ⁇ examples include aziridine, azetidine, morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, hexamethyleneimine, heptamethylenimine, hexahydropyrimidine, 1,4-diazepane, dihydroisoquinolyl And their unsaturated cyclic amines (eg, 1,2,5,6-tetrahydropyridine, 1,4-dazepine, octahydroisoquinoline, etc.).
• unsaturated cyclic amines eg, 1,2,5,6-tetrahydropyridine, 1,4-dazepine, octahydroisoquinoline, etc.
• morpholine, piperidine, piperazine, pyrrolidine and the like are preferable.
• substituents in the “nitrogen-containing heterocyclic ring optionally having substituent (s)
• substituents for example, the “substituent” in the above “optionally substituted 5- to 7-membered saturated cyclic amino” What was illustrated as is used.
• the number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.
• the “substituent” is preferably hydroxy; optionally halogenated C 6 alkyl (eg, methyl, ethyl, etc.); halogen atom, optionally halogenated C 6 alkyl and halogenated and may - 6 alkoxy 1 selected from shea to 3 substituents substituted C 6 _ 1 4 Ariru
• Piberijieru C 8 - 1 9 ⁇ reel alkenyl (e.g., 3 - like phenylene Lou 2- Purobu 2 E sulfonyl); C alkyl Ichiriki Rupokisamido (eg , etc.
• N-C i-6 alkyl one C 6 alkyl Ichiriki Rupokisamido (e.g., (N Di-- 6- alkylamino (eg, dimethylamino, etc.); 5- to 8-membered monocyclic non-aromatic heterocyclic group C i _ 6 alkyl (eg, pyrrolidinylmethyl, etc.) Substituted with one to three C alkyl
• N'i C 6 _ 14 Ariru one amino-C 6 alkyl e.g., 2, 6-dimethyl-phenylalanine ⁇ amino methyl, etc.
• R 1 and R 2 form piperidino, pyrrolidine-1-yl, etc. together with the nitrogen atom adjacent to b.
• the “optionally substituted nitrogen-containing heterocyclic ring” formed by R 1 and R 2 together with the adjacent nitrogen atom is preferably
• Rb is preferably a hydrocarbon group which may have a substituent, and specific examples thereof include, for example, C ⁇ 6 alkyl which may be halogenated (eg, methyl, ethyl, etc.); selected from Gen atom (e.g., fluorine, chlorine, etc.), optionally halogenated C r_ 6 Al kill (e.g., methyl, etc.) and eight halogenated which may be C ⁇ 6 alkoxy (e.g., methoxy, etc.) one to three but it may also have a substituent group C 6 _ 14 Ariru are (e.g., phenyl, naphthyl); hydroxy one C _ 6 7 alkyl;!
• Z is preferably CH.
• examples of the "hydrocarbon group which may have a substituent" represented by Rc include those exemplified as the aforementioned Rb.
• Rc is preferably C 6 which may have a substituent - a 14 Ariru.
• Preferred examples of the compound represented by the formula (I) include compounds represented by the formulas (1), ( ⁇ '), ( ⁇ "), (I"")(I'""), and the like.
• Preferable examples of the compound represented by the formula (1) include the following compounds.
• Preferable examples of the compound represented by the formula ( ⁇ ′) include the following compounds.
• Preferred examples of the compound represented by the formula (I) include the following compounds.
• the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
• Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ -dibenzylethylenediamine And the like.
• salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
• Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, lingic acid, methanesulfonic acid, benzenesulfonic acid , ⁇ -toluenesulfonic acid and the like.
• Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
• Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.
• salts pharmaceutically acceptable salts are preferred.
• the compound (I), (1 '), U “), (I'"), (I "") or (I '”") may be an alkali metal salt (for example, , Sodium salts, potassium salts, etc.), inorganic salts such as alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), and ammonium salts.
• alkali metal salt for example, , Sodium salts, potassium salts, etc.
• inorganic salts such as alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), and ammonium salts.
• Compounds (I), (1,), ( ⁇ ⁇ , (I "0, (I”") and (I”"') are anhydrides
• the compound may have 0.5 to 3 water molecules.
• the compound of the present invention may be an isotope (eg, 3 H, 14 C, 3 5 S, etc.) may be labeled.
• the present invention compounds containing, optical isomers, stereoisomers, positional isomers, if they have free rotamer as they also present compound.
• the optical isomer separated from the compound can be obtained as a single product by a synthesis method and a separation method known per se. Are also included in the compounds of the present invention.
• the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemic mixture according to a conventional method.
• optical resolution method a method known per se, for example, a fractional recrystallization method described below in detail, a chiral column method, a diastereomer method, or the like is used.
• Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1- A method of forming a salt with phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), separating this by a fractional recrystallization method, and, if desired, obtaining a free optical isomer through a neutralization step.
• a method in which a racemate or a salt thereof is applied to an optical isomer separation column (chiral column) for separation For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-0VM (manufactured by Toso Co., Ltd.) or CHIRAL series manufactured by Daicel, and water, various buffers (for example, phosphate buffer) The optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, getylamine, etc.) alone or as a mixed solution.
• an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, getylamine, etc.
• separation is performed using a chiral column such as CP-Chirasil_DeXCB (manufactured by GL Sciences).
• a racemic mixture is formed into a diastereomer mixture by a chemical reaction with an optically active reagent, which is converted into a single substance by ordinary separation means (for example, fractional recrystallization, chromatography, etc.), and then hydrolyzed.
• a method of obtaining optical isomers by separating optically active reagent sites by chemical treatment such as reaction.
• an optically active organic acid for example, MTPA [0!
• a prodrug of compound (1,) or (1 ") is a compound that is converted into compound (1,) or ( ⁇ ') by a reaction with an enzyme or gastric acid under physiological conditions in vivo, that is, a compound that is oxidized enzymatically.
• an enzyme or gastric acid under physiological conditions in vivo, that is, a compound that is oxidized enzymatically.
• a compound, which undergoes hydrolysis, etc. to a compound (I,) or (1") by stomach acid, etc.
• Examples of the prodrug of the compound (1) or (1 ") include a compound in which the amino group of the compound (1) or (1") is acylated, alkylated, or phosphorylated [eg, the compound ( The amino group of (1,) or (1 ") is eicosanoylated, alanylated, pentylaminocarponylated, (5-methyl-2-oxo-1,1,3-dioxolen-14-yl) methoxycarbonylide, Tetrahydrofuranylation, Compounds in which the hydroxyl group of compound (1, 1) or (1 ") has been acylated, alkylated, phosphorylated, or borated , Compounds (1) or (1 ") in which the hydroxyl group is acetylated, palmitoylated, propionated, neilylated, vivaloylated, succinylated, fumarylated, aranylated, dimethylaminomethylcarponylated, etc.)
• the prodrug of the compound (1 ') or (1 ") is described in Hirokawa Shoten, 1990,“ Development of Pharmaceuticals, ”Vol. 7, Molecular Design, pp. 163-198. Even if it changes to compound (1,) or ( ⁇ ') under physiological conditions, Good.
• Compounds (I), (I “0, (I” ") and (I '” ") may also be used as prodrugs.
• the compound of the present invention can be produced by the following [Production method 1] to [Production method 10] or a method analogous thereto. .
• the compound (la) in which X is — (CH 2 ) w 3 C0 (w 3 has the same meaning as described above) is produced, for example, by the following amidation reaction-(amidation reaction)
• the “amidation reaction” includes the following “method using a dehydrating condensing agent” and “method using a reactive derivative of carbonyl compound”. '
• dehydration condensing agent for example, dicyclohexylcarboimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride (WSC) and the like can be mentioned. WSC is particularly preferred.
• DCC dicyclohexylcarboimide
• WSC 1-ethyl-3- (3-dimethylaminopropyl) carboimide hydrochloride
• inert solvent examples include nitrile solvents (preferably acetonitrile), amide solvents (preferably DMF), halogenated hydrocarbon solvents (preferably dichloromethane), ether solvents (preferably dichloromethane). THF) and the like. These may be used as a mixture of two or more at an appropriate ratio.
• hydrides of alkali metals or alkaline earth metals eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.
• Amides of alkali metals or alkaline earth metals eg, lithium amide, na
• Strong bases such as razide, potassium hexamethyldisilazide, etc.), lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide);
• alkali metal or alkaline earth metal hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
• alkali metal or alkaline earth metal carbonate Inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.
• alkali metal or alkaline earth metal hydrogen carbonates eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
• triethylamine, 4-dimethylaminopyridine and the like are preferable.
• the reaction temperature is usually room temperature (0 to 30 ° C, the same applies hereinafter).
• the reaction time is, for example, 10 to 24 hours.
• the reactive derivative of compound (II) is reacted with 1 to 5 equivalents (preferably 1 to 3 equivalents) of compound (III) in an inert solvent. If necessary, the reaction may be carried out in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base.
• acid Puromido mixed acid anhydride (for example, C alkyl Ichiriki carboxylic acid, C 6 _ 1 0 ⁇ Li one Rukarubon acid or acid anhydride with C bets 6 alkyl carbonate), active Esters (eg, esters with optionally substituted phenol, 1-hydroxybenzotriazole or N-hydroxysuccinimide) and the like.
• mixed acid anhydride for example, C alkyl Ichiriki carboxylic acid, C 6 _ 1 0 ⁇ Li one Rukarubon acid or acid anhydride with C bets 6 alkyl carbonate
• active Esters eg, esters with optionally substituted phenol, 1-hydroxybenzotriazole or N-hydroxysuccinimide
• Examples of the “substituent” in the “phenol which may have a substituent” include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, nitrogen, and optionally hydrogenated C It includes 6 alkoxy - 6 alkyl, optionally halogenated good C 1. The number of substituents is, for example, 1 to 5.
• Examples of the “optionally halogenated C 3 _ 6 alkyl” and the “optionally halogenated Ci- 6 alkoxy” include the “substituted or unsubstituted cyclic group” What was illustrated as a "group” is used.
• phenol which may have a substituent include, for example, phenol, phenol phenol, phenol fluorophenol, p-nitrophenol and the like.
• the reactive derivative is preferably an acid halide.
• inert solvent examples include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, water and the like. These may be used by mixing two or more kinds at an appropriate ratio. Above all, preferred are acetonitrile, TH, dichloromethane, chloroform and the like.
• the base is preferably sodium hydride, carbonated sodium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine and the like.
• the reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably room temperature.
• the reaction time is generally 5 minutes to 40 hours, preferably I to 18 hours.
• R_ (CH 2) w 3 - S0 2 0H symbols are as defined above shows a) in represented Ru acid or formula,: R- (CH 2) w 3 - S00H ( sign and the The sulfinic acid represented by the formula (I) is subjected to the same method as in the above “method using a reactive derivative of carbonyl compound”, whereby X in the formula (I) is — (CH 2 ) W 3 S0 2 - or a (CH 2) w3 S0_ (symbol is as defined above) can be prepared compound is.
• Compound (II) can be produced by a method known per se or a method analogous thereto.
• Compound (III) can be prepared by a method known per se, for example, described in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.), 36, 4377 (1988), JP-A-9-506885, JP-A-10-504315, and the like. It can be produced by the method described above or a method analogous thereto.
• compound (III) has the formula
• W represents a protecting group for an amino group, and other symbols have the same meanings as described above].
• the compound is subjected to a deprotection reaction, and w is removed.
• the protecting group of the Amino group represented by W for example, formyl, ( ⁇ _ 6 alkylene Rukaruponiru (eg, Asechiru, propionyl and the like), C I 6 alkoxy one local Poniru (e.g., methoxy Cal Poeru, ethoxy Cal Poni Le, tert - etc.
• Butokishikaru Poniru) Benzoiru C 7 _ 1Q Ararukiru - Karuponiru (eg, such as Benjiruka Ruponiru), C 7 _ 14 Ararukiruokishi Ichiriki Ruponiru (eg, Benjiruokishi carbonyl, 9-O-les methoxy Cal Poni Le etc.), trityl, lid port I le, N, N-dimethylaminomethylene, silyl (eg, trimethylsilyl, Echirushiriru, dimethyl phenylalanine silyl, tert- heptyl dimethylsilyl, tert one Petit Rougier chill silyl, etc.), C 2 - 6 alkenyl (e.g., 1-aryl, etc.) are used.
• C 2 - 6 alkenyl e.g., 1-aryl, etc.
• halogen atoms e.g., fluorine, chlorine, bromine, iodine
• ⁇ _ 6 alkoxy e.g., methoxy, ethoxy, optionally substituted, etc. propoxy, etc.
• double bets port e.g., fluorine, chlorine, bromine, iodine
• the compound (Ilia) is converted into an acid such as a mineral acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, iodic acid, periodic acid, etc.) or an alkali metal hydroxide (eg, water).
• a mineral acid eg, hydrochloric acid, sulfuric acid, hydrobromic acid, iodic acid, periodic acid, etc.
• an alkali metal hydroxide eg, water
• the temperature is preferably maintained at 20 ° C to 140 ° C.
• the amount of the acid or base to be used is generally 1 to 100 equivalents, preferably 1 to 40 equivalents, relative to compound (Ilia).
• the strength of the acid or base is usually 0.1N to 18N, preferably 1N to 12N.
• the reaction time is generally 0.5 hour to 48 hours, preferably 1 hour to 24 hours.
• the deprotection reaction is carried out by converting compound (Ilia) to an organic acid (for example, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, etc.).
• organic acid for example, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, etc.
• it can be carried out by maintaining the mixture at -20 ° C to 200 ° C, preferably at 0 ° C to 100 ° C.
• the amount of the organic acid to be used is 1 to 100 equivalents, preferably 1 to 40 equivalents, relative to compound (Ilia).
• reaction in the deprotection reaction, palladium, palladium-carbon, Raney-nickel, Raney-cobalt, platinum oxide and the like are used as catalysts, for example, in an alcoholic solvent such as ethanol or a solvent such as acetic acid, at normal pressure or as necessary.
• the reaction can also be carried out by subjecting the compound (Ilia) to a catalytic reduction reaction under pressure.
• Compound (Ilia) can be produced by a method known per se or a method analogous thereto.
• Der Ru compound (Illaa) can be produced, for example, according to the following [Reaction formula 11].
• the compound (VIa) is produced by a condensation reaction between the compound (IVa) and the compound (Va).
• Examples of the “leaving group” represented by L include a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C alkylsulfonyloxy
• Arylsulfonyloxy optionally having substituent (s)” include an octylogen atom (eg, chlorine, bromine, iodine, etc.), halogenated etc. good C i-6 alkyl or C _ 6 alkoxy can be mentioned up be.
• the number of substituents is, for example, 1 to 3.
• C 6 ⁇ arylsulfonyloxy optionally having substituent (s) include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthylene sulfonyloxy, and 2-naphthylene Sulfonyloxy and the like.
• the "leaving group” is preferably a halogen atom (eg, chlorine, bromine, iodine, etc.), methanesulfonyloxy, trifluoromethanesulfonyloxy, P-toluenesulfonyloxy and the like.
• This condensation reaction is usually performed in an inert solvent.
• inert solvent examples include alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, water and the like. Is mentioned. These may be used as a mixture of two or more kinds at an appropriate ratio. Of these, preferred are acetonitrile, N, N-dimethylformamide (DMF), acetone, ethanol, pyridine and the like.
• alcohol solvents ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, water and the like. Is mentioned. These may be used as a mixture of two or more kinds at an appropriate ratio. Of these, preferred are acetonitrile, N, N-dimethylformamide (DMF), acetone, ethanol, pyridine and the like.
• DMF N-dimethylformamide
• the amount of compound (Va) to be used is 1 to 100 equivalents relative to compound (IVa). Further, compound (Va) may be used in an amount of the reaction solvent.
• the reaction temperature is about a 2 0 ° C to 2 0 0 ° C
• the c reaction time is preferably from room temperature to 100 ° C, for example about 0.5 hours to 1 day.
• This condensation reaction may be performed in the presence of a base.
• the base is preferably sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and the like.
• the amount of the base to be used is 0.1 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (IVa).
• Compound (IVa) can be produced by a method known per se or a method analogous thereto.
• Compound (IVa) can be produced, for example, by the method described in JP-A-6-166676 or a method analogous thereto.
• Compound (V a) can be produced by a method known per se or a method analogous thereto.
• the compound (VIA) is produced by subjecting the compound (VIa) to a reduction reaction.
• This reduction reaction can be performed using a reducing agent such as sodium borohydride, lithium aluminum hydride, triethylsilane, or the like.
• Reduction reactions include, for example, Reduction with Complex Metal Hydrides; 'Interscience, New York (1956), Chemical Society Reviews (Chem. Soc. Rev.), 5, 23 (1976), Synthesis ( Synthesis), 633 (1974), Journal of the American Chemical Society (J. Am. Chem. Soc.) 91, 2967 (1969), Journal of the Organic Chemistry (J. Org. Chem.), 29 , 121 (1964), Organic Reactions (Org. Reactions), 1, 155 (1942), Angew.
• a reducing agent such as sodium borohydride, lithium aluminum hydride, triethylsilane, or the like.
• step (ac) the compound (Vlla) is subjected to a dehydration reaction to produce a compound (Illaa).
• an acid catalyst eg, sulfuric acid, phosphoric acid, potassium hydrogensulfate, p-toluenesulfonic acid, boron trifluoride ether complex, iodine, etc.
• an activator such as thionyl chloride-pyridine or phosphorus oxychloride-pyridine.
• Compound (IXa) can be produced by a method known per se or a method analogous thereto.
• the compound (IXa) is prepared, for example, from Journal of Chemical Society Perkin Transduction 1 (J. Chem. Soc.,
• R 9 is C alkyl, and the symbol is as defined above.
• R 9 represents “( ⁇ -6 alkyl”, those similar to the "( ⁇ _ 6 ⁇ J Rekiru” represented by R 4 can be mentioned.
• Step (a f) can be carried out using a condensation reaction known per se.
• the condensation reaction can be carried out, for example, by the method described in J. Heterocyclic Chem., 30, 23 (1993), Heterocycles, 22, 195 (1984) or the like. It can be performed according to the method described above.
• Compound (Xa) can be produced by a method known per se or a method analogous thereto.
• the step (ag) includes a reduction reaction known per se (eg, a catalytic reduction reaction using a transition metal catalyst such as Pd / C, a reduction reaction using a metal hydride such as Et 3 SiH, a NaBH (0Ac) 3 etc. (A reduction reaction using a metal hydrogen complex compound).
• the reduction reaction is carried out, for example, according to Journal of the American Chemical Society (J. Am. Chem. Soc), 76, 5014 (1954), and Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.). , 45, 3506 (197.2), etc., or a method analogous thereto.
• the compound (Ilia) wherein Y is — 0_ (CH 2 ) w2 — (where w2 has the same meaning as described above) is prepared according to the following [Reaction formula 2-1]. ) And compound (Xb), for example, by subjecting them to a dehydration reaction under the conditions of the Mitsunobu reaction.
• the dehydration reaction in the step (ba) is described in, for example, Synthesis, 1 (1981), Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.), 49, 510 (1976) and the like.
• the method can be performed according to the method described in or a method analogous thereto.
• Compound (IXb) can be produced by a method known per se or a method analogous thereto.
• Compound (Xb) can be produced by a method known per se or a method analogous thereto.
• the compound (Ilia) in which Y is —C ⁇ — (CH 2 ) W7— CO— (W7 has the same meaning as described above) is obtained according to the following [Reaction Scheme 2 _ 2]
• Compound (IVd) and compound (Va) can be synthesized by subjecting them to the above-mentioned "amidation reaction”.
• Compound (IVd) can be produced by a method known per se or a method analogous thereto.
• inert solvent examples include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and the like. These may be used as a mixture of two or more at an appropriate ratio. Of these, preferred are acetonitrile, dichloromethane, chloroform and the like.
• the base is sodium periodide, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and the like.
• the reaction temperature is usually 20 ° C to 50 ° C, preferably room temperature.
• the reaction time is generally 5 minutes to 40 hours, preferably 1 to 18 hours.
• Compound (I c) in which X in the formula (I) is — (CH 2 ) wl 0 (CH 2 ) w 2 — (the symbols have the same meanings as described above) can be produced, for example, by the following etherification reaction. .
• compound (IVc) is reacted with about 1 to 5 equivalents (preferably 1 to 2 equivalents) of compound (V) in an inert solvent in the presence of a base.
• the base is preferably potassium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine, pyridine and the like.
• the amount of the base to be used is generally about 1 to 5 equivalents relative to compound (V).
• inert solvent examples include alcohol solvents, ether solvents, octogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and water. Is mentioned. These may be used as a mixture of two or more kinds at an appropriate ratio. Above all, acetonitrile, N, Preferred are N-dimethylformamide (DMF), acetone, ethanol, pyridine and the like.
• DMF N-dimethylformamide
• the reaction temperature is about -20 ° C to 100 ° C, preferably room temperature to 80 ° C.
• the reaction time is, for example, about 0.5 hours to 1 day.
• compound (Ic) can be produced using the Mitsunobu reaction.
• compound (V) and 0.5 to 5 equivalents (preferably 1 to 1.5 equivalents) of compound (IVc) are reacted with 0.5 to 5 equivalents (preferably 1 to 1.5 equivalents) of ethyl acetyldicarboxylate.
• the reaction is carried out in the presence of an inert solvent.
• inert solvent examples include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, and sulfoxide solvents. These may be used as a mixture of two or more at an appropriate ratio. Of these, preferred are acetonitrile, dichloromethane, and chloroform.
• the reaction temperature is usually ⁇ 20 ° C. to 50 ° C., preferably room temperature.
• the reaction time is generally 5 minutes to 40 hours, preferably 1 to 18 hours.
• Compound (IVc) can be produced by a method known per se.
• the compound (Id) in which X is — (CH 2 ) w3 NR 8a C0 (CH 2 ) w4 — (the symbols have the same meanings as described above) is produced, for example, by the following amidation reaction . .
• R 8a represents a hydrogen atom or an optionally halogenated C ⁇ 6 alkyl, and other symbols have the same meanings as described above.
• R 8a As the “optionally halogenated C 6 alkyl” represented by R 8a , those exemplified as the aforementioned R 8 can be mentioned.
• Compound (V I) can be produced by a method known per se.
• Compound (VI Id) can be produced by a method known per se. [Production method 5]
• the compound (I e) in which is ((3 ⁇ 4 25 ? «50 ⁇ 83 (01 2 2) w6 (the symbols in the formula have the same meanings as described above)) is, for example, It is produced by the following urea reaction.
• compound (IXe) is reacted with 1 to 5 equivalents (preferably 1 to 1.5 equivalents) of compound (Vllle) in an inert solvent in the presence of a base.
• the base is preferably potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and the like.
• inert solvent examples include alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and water. And the like. These may be used as a mixture of two or more kinds at an appropriate ratio. Of these, preferred are acetonitrile, DMF, acetone, ethanol, pyridine and the like.
• the reaction temperature is generally about 120 ° C to 110 ° C, preferably room temperature to 80 ° C.
• the reaction time is, for example, about 0.5 hours to 1 day.
• Compound (Vllle) can be produced by a method known per se.
• Compound (IXe) can be produced by a method known per se.
• R represents an optionally substituted ring-assembled aromatic group (Ar 2 ′
• Ar 3 ring-assembled aromatic group
• Ar 2 and Ar 3 ′ each represent a monocyclic aromatic group or a condensed aromatic group which may have a substituent;
• L 1 represents hydroxy or C 6 alkyl;
• L 2 represents a halogen ( Preferably chlorine, bromine) or trifluoromethanesulfonyloxy; other symbols are as defined above.
• the aryl coupling reaction is performed according to a method known per se, for example, the method described in Acta. Chemica Scandinavia, pp. 212-1230, 1993, or a method analogous thereto. It can be carried out.
• compound (Xf) is reacted with 1 to 3 equivalents (preferably 1 to 1.5 equivalents) of compound ( ⁇ ) in an inert solvent in the presence of a base and a transition metal catalyst.
• the base As the “base”, those exemplified in the above-mentioned [Production method 1] can be used.
• the base is preferably sodium carbonate, sodium hydrogen carbonate and the like.
• the amount of the “base” to be used is, for example, about 1 to 10 equivalents relative to compound (Xlf). .
• Examples of the “transition metal catalyst” include a palladium catalyst and a nickel catalyst.
• Examples of the “palladium catalyst” include tetrakis (triphenylphosphine) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, palladium-carbon and the like.
• Examples of the “nickel catalyst” include tetrakis (triphenylphosphine) nickel (0).
• the amount of the “transition metal catalyst” to be used is about 0.01 to 1 equivalent, preferably about 0.01 to 0.5 equivalent, relative to compound ( ⁇ ).
• the reaction temperature is from room temperature to 150 ° C, preferably about 80 ° C to 150 ° C.
• the reaction time is, for example, about 1 to 48 hours.
• inert solvent examples include water, alcohol solvents, aromatic solvents and the like. These may be used as a mixture of two or more at an appropriate ratio. Among them, water, ethanol, toluene and the like alone or a mixed solvent of two or more thereof are preferred.
• Compound (Xf) can be produced by a method known per se.
• the condensation reaction in the step (Aa) can be performed, for example, in the same manner as in the step (af).
• the reduction reaction in the step (Ab) may be performed by a method known per se (for example, a catalytic reduction reaction using a transition metal catalyst such as Pd / C, a reduction reaction using a metal hydride such as Et 3 SiH, a NaBH 4 or the like). Reduction reaction using a metal hydrogen complex compound).
• a method known per se for example, a catalytic reduction reaction using a transition metal catalyst such as Pd / C, a reduction reaction using a metal hydride such as Et 3 SiH, a NaBH 4 or the like.
• This reaction can also be performed in two steps.For example, after reducing the double bond under the same conditions as the reduction reaction described in the above step (ag), a metal-hydrogen complex compound such as NaM 4 is used.
• the radical group may be reduced by heating. .
• the dehydration reaction in the step (Ac) can be performed, for example, in the same manner as in the step (ac).
• Compound (1) can be produced by a method known per se.
• Compound (I) can also be produced by subjecting compound (Ila) and compound (III) to a condensation reaction according to the following [Production Method 8].
• the “condensation reaction” can be carried out in the same manner as the condensation reaction in the above step (aa).
• Compound (Ila) can be produced by a method known per se or a method analogous thereto.
• Compound (1 ′) can be produced, for example, by subjecting compound (lib) and compound (Illb) to a condensation reaction according to the following [Production Method 9].
• the “condensation reaction” can be performed in the same manner as in the condensation reaction in the above step (a a).
• Compound (lib) can be produced by a method known per se or a method analogous thereto.
• Compound (Illb) can be produced in the same manner as in the above compound (III).
• Compound (1 ") can be produced, for example, by subjecting compound (Ila) and compound (IIIc) to a condensation reaction according to the following [Production Method 10].
• the “condensation reaction” can be carried out in the same manner as the condensation reaction in the above-mentioned process (a a).
• Compound (I I Ic) can be produced in the same manner as in compound (I I I).
• the “alcohol solvent” include methanol, ethanol, isopropanol, tert-butanol, and the like.
• ether-based solvent examples include jet ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and the like.
• halogenated hydrocarbon solvent examples include dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride.
• aromatic solvent for example, benzene, toluene, xylene, pyridine and the like are used.
• hydrocarbon solvent for example, hexane, pentane, cyclohexane and the like are used.
• amide solvent for example, ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone and the like are used.
• ketone-based solvent for example, acetone, methyl ethyl ketone and the like are used.
• sulfoxide solvent for example, dimethyl sulfoxide (DMS0) and the like are used.
• the functional group in the molecule can be converted to the target functional group by combining chemical reactions known per se. Examples of such chemical reactions include oxidation, reduction, alkylation, and hydrolysis. Reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like.
• a protecting group generally used in peptide chemistry or the like may be introduced into these groups. The desired compound can be obtained by removing the protecting group if necessary after the reaction.
• amino-protecting group the amino-protecting groups exemplified as W above can be used.
• the protecting group of the force Rupokishi for example, C WINCH 6 alkyl (e.g., methyl, E Ji Le, propyl, isopropyl, heptyl, tert- butyl, etc.), C 7 - Araruki Le (e.g., benzyl, etc.), phenyl, trityl , silyl (eg, trimethylsilyl, Toryechirushiriru, dimethyl phenylalanine silyl, tert- heptyl butyldimethylsilyl, etc.
• C WINCH 6 alkyl e.g., methyl, E Ji Le, propyl, isopropyl, heptyl, tert- butyl, etc.
• C 7 - Araruki Le e.g., benzyl, etc.
• phenyl, trityl e.g., silyl (eg, trimethyls
• C 2 - 6 alkenyl e.g., 1-Ariru etc.
• C 2 - 6 alkenyl e.g., 1-Ariru etc.
• These groups may be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), ( ⁇ _ 6 alkoxy (e.g., methoxy, ethoxy, optionally substituted by such professional such as epoxy) or nitro Good.
• ( ⁇ _ 6 alkyl e.g., methyl, E Ji Le, propyl, isopropyl, heptyl, tert- butyl, etc.
• phenyl tri chill
• Ararukiru e.g., benzyl, etc.
• Halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
• C ⁇ 6 alkyl Examples include methyl, Echiru, etc. n- propyl
• C bets 6 alkoxy e.g., methoxy, ethoxy, optionally substituted, etc. propoxy, etc.
• the protective group of carbonyl e.g., cyclic ⁇ Se evening Ichiru (eg, 1,3 Jioki San etc.), acyclic ⁇ Se evening Ichiru (eg, such as di-C Bok 6 alkyl ⁇ Se tar) and the like .
• the above-mentioned method for removing the protecting group is performed according to a method known per se, for example, a method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (198Q). be able to.
• a method known per se for example, a method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (198Q).
• the method used and the reduction method are used.
• the compound of the present invention can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
• the starting compound of the compound of the present invention or a salt thereof can be isolated and purified by the same known means as described above, but is directly used as a starting material in the next step as a reaction mixture without isolation. You may. Since the compound of the present invention has an excellent MCH receptor antagonistic activity, it is useful as a preventive or therapeutic agent for diseases caused by MCH. In addition, the compounds of the present invention have low toxicity, and are excellent in oral absorption and in the brain.
• a melanin-concentrating hormone antagonist containing the compound of the present invention is useful for mammals (for example, rats, mice, guinea pigs, pigs, sheep, sheep, dogs, horses, horses, monkeys, humans, etc.). It is safely administered as an agent for preventing 'therapeutic diseases caused by MCH'.
• the diseases caused by MCH include, for example, obesity [eg, malignant mastocytosis Uiial ig tmas tocytos is), exogenous obesity, exogenous obesity, hyperinsul obesity (hyperinsul inar obes) i ty)., hyperplasmic obesity (hyperpl asmic obes i ty), pituitary obesity (hypophyseal adipos i ty), hypoplasmic obesity (hypoplasmic obesity), hypothyroid obesity (hypothyroid obesity), hypothalamic obesity (symptomaUc obesity), childhood obesity (infantile obesity), upper body obesity (upper body obesity), diet Sex '' obesity (alimentary obesity), hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity, etc. Disorders (hyperphagia), affective disorders, sexual dysfunction and the like. '' obesity
• the compound of the present invention is also useful as a preventive-therapeutic agent for lifestyle-related diseases such as diabetes, diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), arteriosclerosis, and knee arthritis. It is.
• lifestyle-related diseases such as diabetes, diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), arteriosclerosis, and knee arthritis. It is.
• the compound of the present invention is also useful as an antifeedant.
• the MCH antagonist and the pharmaceutical composition of the present invention can be used in combination with diet therapy (eg, diet therapy for diabetes, etc.) and exercise therapy.
• diet therapy eg, diet therapy for diabetes, etc.
• exercise therapy e.g., exercise therapy
• the MCH antagonist and the pharmaceutical composition of the present invention are produced by formulating the compound of the present invention as it is or together with a pharmacologically acceptable carrier according to a means known per se.
• the pharmacologically acceptable carrier includes various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, disintegrants in solid preparations, and solvents in liquid preparations. And solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like.
• additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, and wetting agents can be used, if necessary.
• excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like.
• lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
• binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, and hydroxypropylmethylcell. Loose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.
• disintegrant examples include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, low-substituted hydroxypropylcellulose (L-HPC), and the like.
• solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
• solubilizing agents include polyethylene glycol, propylene glycol, D-manni! Yl, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
• suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalcodium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
• surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalcodium chloride, benzethonium chloride, and glyceryl monostearate
• polyvinyl alcohol examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl
• tonicity agent examples include glucose, D-sorbitol, sodium salt, glycerin, D-mannitol and the like.
• buffers such as phosphate, acetate, carbonate, and citrate.
• Examples of the soothing agent include benzyl alcohol and the like.
• preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
• Antioxidants include, for example, sulfites, ascorbic acid and the like.
• examples of the dosage form of the MCH antagonist and the pharmaceutical composition of the present invention include tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), and liquids.
• Injection eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.
• external preparation eg, nasal administration preparation, transdermal preparation, ointment, etc.
• suppository eg, rectal suppositories, vaginal suppositories, etc.
• sustained release eg, sustained release microcapsules, etc.
• pellets parenteral preparations such as infusions, etc., orally or parenterally (eg, It can be safely administered locally, rectally, or intravenously.
• the content of the compound of the present invention in the MCH antagonist of the present invention, and the content of the compound of the present invention in the pharmaceutical composition of the present invention may be, for example, about 0.1 to about 0.1% of the whole MCH antagonist or the pharmaceutical composition, respectively. 100% by weight. .
• the dose of the MCH antagonist and the pharmaceutical composition of the present invention is appropriately selected depending on the administration subject, administration route, disease and the like.
• the daily dose is about 0% as the active compound of the present invention. It is 1 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 to about 100 mg, and this amount can be administered once or several times a day.
• the MCH antagonist and the pharmaceutical composition of the present invention may be added to the MCH antagonist and the pharmaceutical composition of the present invention for the purpose of, for example, “enhancing the therapeutic effect of obesity” and “reducing the amount of the MCH antagonist used”. Concomitant medications that do not adversely affect can be used.
• concomitant drugs examples include, for example, “diabetic drugs”, “diabetic complication drugs”, “anti-obesity drugs other than MCH antagonists”, “hypertensive drugs”, and “hyperlipidemic drugs”. , “Arthritis treatment drugs”, “Anxiolytics”, “Antidepressants” and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
• agents for treating diabetes include insulin sensitizers, insulin secretagogues, biguanides, insulin, dalcosidase inhibitors, i33 adrenergic receptor agonists and the like.
• insulin sensitizer examples include, for example, peodarisuzone or a salt thereof (preferably hydrochloride), torodarisuzone, rosiglitazone or a salt thereof (preferably maleate), JTT-501, GI-262570. , MCC—555, YM—440, DRF-2593, BM—13—1258, KRP—297, R—19702.
• insulin secretagogues examples include sulfonylurea agents.
• Specific examples of the sulfonylurea agent include, for example, tolptamide, chlorpropamide, tolazamide, acetohexamide, glicloviramide and its ammonium salt, dalibenclamide, daliclazide, glimepiride and the like.
• insulin secretagogues examples include repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608 and the like.
• biguanides examples include metformin, buformin, phenformin and the like.
• insulin examples include animal insulin extracted from the tongue of the pig and bush; semi-synthetic human insulin enzymatically synthesized from the insulin extracted from the tongue of the pig; gene derived from Escherichia coli and yeast. Examples include human insulin that has been engineered.
• insulin insulin zinc containing 0.45 to 0.9 (wZw)% of zinc; zinc chloride, prominamine insulin produced from prominamine sulfate and insulin, and the like are also used. Further, insulin may be a fragment or derivative thereof (eg, INS-1, etc.).
• Insulin includes various types such as ultra-rapid-acting, rapid-acting, biphasic, intermediate, and sustained-acting insulins, which can be appropriately selected depending on the patient's condition.
• dalcosidase inhibitor examples include acarbose, poglipose, miglitol, emiglitol and the like.
• 33 Adrenergic receptor agonists include, for example, AJ-9677, BMS-196085, SB-226552, AZ40140.
• therapeutic agent for diabetes include ergosett, pramlinide, leptin, BAY-27-9955 and the like.
• agents for treating diabetic complications include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors and the like.
• rudose reductase inhibitor examples include tolrestat; epalrestat; imirestat; zenarestat; SNK-860; zopolless ester; AR1-509; AS-321.
• glycation inhibitor examples include pimagedine.
• protein kinase C inhibitors examples include NGF, LY-333531 and the like.
• examples of “drugs for the treatment of diabetic complications” include alprosil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, icosavent ethethyl, memantine, memantine, pimagedrine (ALT-711) and the like. No.
• anti-obesity drugs other than MCH antagonists include, for example, lipase inhibitors, appetite suppressants and the like.
• lipase inhibitor examples include orlistat and the like.
• Appetite suppressants include, for example, mazindol, dexfenfuramine, fluoxetine, sibutramine, piamin and the like.
• anti-obesity drugs other than MCH antagonists include, for example, ribstatin.
• agents for treating hypertension include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists, and the like.
• angiotensin converting enzyme inhibitors examples include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidabril, benazepril, cilazapril, temocapril, trandolapril, and manidipine (hydrochloride).
• Calcium antagonists include, for example, difendipine, amlodipine, Dipin, nicardipine and the like.
• the potassium channel openers for example levcromakalim, L- 27152, AL 0671, ⁇ 5 - 121 , and the like.
• angiotensin II antagonists include oral sultan, candesartan cilexitil, valsartan, irbesartan, CS-866, E4177 and the like.
• agents for treating hyperlipidemia include, for example, HMG-CoA reductase inhibitors, fibrate compounds, and the like.
• HM G—Co A reductase inhibitors include, for example, pravastin, simpastatin, oral pastatin, atorpastatin, flubassin, ripanchil, seribassin, itabassin, ZD—4522 or Salts (eg, sodium salts, etc.).
• fibrate-based compound examples include bezafibrate, clinofibrate, clofibrate, and simfibrate.
• Examples of the "agent for treating arthritis” include ibuprofen.
• Examples of the above-mentioned “anxiolytics” include chlordiazepoxide, diazebam, oxazolam, medazepam, cloxazolam, promazepam, lorazepam, albrazolam, fludiazebam and the like.
• Examples of the above “antidepressant” include fluoxetine, flupoxamine, imibramine, paroxetine, satratraline and the like.
• the administration time of the above-mentioned concomitant drug is not limited, and the MCH antagonist or the pharmaceutical composition and the concomitant drug may be administered to a subject to be administered simultaneously or at an interval.
• the dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
• the administration form of the concomitant drug is not particularly limited as long as the MCH antagonist or the pharmaceutical composition and the concomitant drug are combined at the time of administration.
• Such administration forms include, for example, 1) simultaneous administration of an MCH antagonist or a pharmaceutical composition and a concomitant drug.
• the mixing ratio of the MCH antagonist or the pharmaceutical composition to the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
• room temperature indicates 0 to 30 ° C.
• anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic layer.
• "%" Means weight percent unless otherwise specified. 'The infrared absorption spectrum was measured by a diffuse reflection method using a Fourier transform infrared spectrophotometer.
• FABMS (pos) is a mass spectrum measured by the (+) method in Fast Atom Bombardment Mass Spectrometry.
• MS (APCI) and MS (ESI) are Atmospheric Pressure Chemical Ionization (APCI) or Electron Impact Ionization, respectively.
• DMAP 4-dimethylaminopyridine
• bases and amino acids are indicated by abbreviations, abbreviations based on IUPAC—IUB Commition on Biochemical Nomenclature or related fields are used. This is based on the common abbreviations in the above, examples of which are given below.
• amino acids may have optical isomers, the L-form is indicated unless otherwise specified.
• RNA Messenger liponucleic acid dATP Deoxyadenosine triphosphate dTTP Deoxythymidine triphosphate dGTP Deoxyguanosine triphosphate d CTP Deoxycytidine triphosphate ATP Adenosine triphosphate
• a rg arginine H is histidine
• Trt Trityl
• Fmo c N-9_fluorenylmethoxycarbonyl HOOB t 3, 4-dihide g—3-hydroxy-1 4-oxo-1,2,3-benzotriazine
• sequence numbers in the sequence listing in the specification of the DCC of the present application indicate the following sequences.
• the lipoprobe used to measure the expression level of SLC-lmRNA in each clone of rat SLC-1 expressing CH0 cells is shown.
• [SEQ ID NO: 10] 1 shows a synthetic DNA used for screening cDNA encoding human SLC-1 (S).
• Lipoprobe used to measure the expression level of SLC-lmRNA in each clone of human SLC-1 (S) -expressing CH0 cells and human SLC-1 (L) -expressing CH0 cells
• the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
• To the ether solution of the obtained oil was added 4N hydrogen chloride monoethyl acetate, and the resulting solid was washed with diethyl ether to obtain the title compound (14.8 g) as a hygroscopic colorless powder.
• the title compound was obtained as a viscous oil by sequentially performing the same operation as in Reference Example 1 and Reference Example 2 using triacetyl indoline.
• the title compound was obtained as an oil by sequentially performing the same operations as in Reference Example 1, Reference Example 2, and Reference Example 4 using ethyl 3,4-dihydro-1 (2H) -quinolinecarboxylate. .
• Trifluoroacetic anhydride (47.5 ml, 336 ol) was added dropwise to a solution of 1,2,3,4-tetrahydridoisoquinoline (25 g, 188 bandol) in THF (100 ml) at 0 ° C for 2 hours. After stirring at room temperature, the solvent was distilled off under reduced pressure. The residue was poured into water, extracted with ethyl acetate, washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 43.5 g of 2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline as an oil.

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• 2001
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