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WO2012036233A1 - Dérivé hétérocyclique condensé ayant une activité antagoniste du récepteur de l'hormone de concentration de la mélanine - Google Patents

Dérivé hétérocyclique condensé ayant une activité antagoniste du récepteur de l'hormone de concentration de la mélanine Download PDF

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WO2012036233A1
WO2012036233A1 PCT/JP2011/071093 JP2011071093W WO2012036233A1 WO 2012036233 A1 WO2012036233 A1 WO 2012036233A1 JP 2011071093 W JP2011071093 W JP 2011071093W WO 2012036233 A1 WO2012036233 A1 WO 2012036233A1
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Inventor
直樹 大森
正英 大段
俊博 和田
輝和 加藤
田中　伸幸
吉田　裕
佐藤　浩樹
孝己 村司
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Shionogi and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
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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
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
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    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
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    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having melanin-concentrating hormone receptor antagonist activity and useful for medicine, particularly for prevention and / or treatment of obesity.
  • Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as the main risk factor for health problems.
  • the body mass index (BMI) is a simple index of the height-weight ratio that is commonly used when classifying an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m 2 ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m 2 or more is “overweight” and 30 kg / m 2 or more is “obese”. On the other hand, the Japanese Obesity Society designates BMI of 25 kg / m 2 or more as “obesity”.
  • MCH Melanin-concentrating hormone
  • MCH knockout mice have a significantly reduced food intake and light body weight compared to normal mice even though normal behavior is normal. From this, MCH receptor antagonists are expected to be excellent anti-obesity agents or appetite suppressants.
  • Patent Documents 1 to 26 and the like describe derivatives having MCH R1 antagonist activity. These compounds differ in structure from the compounds of the present invention.
  • An object of the present invention is to provide a novel compound having excellent melanin-concentrating hormone receptor antagonist activity.
  • the present inventors have succeeded in synthesizing a novel compound having excellent MCH R1 antagonist activity. Moreover, it discovered that this compound showed the strong eating suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.
  • R 1 is halogen, cyano, oxo, substituted or unsubstituted amino, substituted or unsubstituted alkyl, a group represented by the formula: —O—R 7 or a group represented by the formula: —SO 2 —R 7 ;
  • R 7 is substituted or unsubstituted alkyl.
  • At least one R 2 is represented by the formula: —O—R 7 , wherein R 7 is substituted alkyl (the substituent is hydroxy or a substituted or unsubstituted non-aromatic heterocyclic group) ), A pharmaceutically acceptable salt thereof or a solvate thereof.
  • At least one R 2 is represented by the formula: —O—R 7 (wherein R 7 is a substituted non-aromatic heterocyclic group (the substituent is a substituted or unsubstituted non-aromatic heterocyclic group)
  • R 7 is a substituted non-aromatic heterocyclic group (the substituent is a substituted or unsubstituted non-aromatic heterocyclic group)
  • X 1 is O, —Y 1 — is a single bond or —C (R 4 ) ⁇ C (R 4 ) —, R 1 is halogen, cyano, oxo, substituted or unsubstituted amino, substituted or unsubstituted alkyl, a group represented by the formula: —O—R 7 or a group represented by the formula: —SO 2 —R 7 ; Wherein at least one R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, a group represented by the formula: —O—R 7 (wherein R 7 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group), a pharmaceutically acceptable salt thereof, or Their solvates.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (16), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • a compound represented by the formula: The part indicated by And the combination of X 6 , X 7 and X 8 is (X 6 , X 7 , X 8 ) (C (R 5 ), C (R 5 ), C (R 5 )) or (N, N , C (R 5 )), and the compound represented by the formula: —Y 1 —D is alkyl or methyloxy, and the following compounds: Or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • D is the formula: Is a group represented by the formula: The compound shown in the above (1 ′) or (2 ′), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the group represented by is aryl or heteroaryl.
  • (4 ′) D is the formula: Is a group represented by the formula: The group represented by ) Or (2 ′), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (6 ′) D is the formula: Is a group represented by the formula: The compound shown in the above (1 ′) or (2 ′), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the group represented by is cycloalkyl.
  • D is the formula: Wherein p is 1, R 1 is halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, a group represented by the formula: —O—R 7 (R 7 is substituted or unsubstituted alkyl) or a formula: —SO 2- R 7 (wherein R 7 is substituted or unsubstituted alkyl), the compound according to any one of the above (1 ′) to (8 ′), a pharmaceutically acceptable salt thereof, Their solvates.
  • R 2 is represented by the formula: —O—R 7 , wherein R 7 is substituted alkyl (the substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic
  • R 7 is substituted alkyl (the substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic
  • At least one R 2 is represented by the formula: —O—R 7 (wherein R 7 is a substituted non-aromatic heterocyclic group (the substituent is a substituted or unsubstituted non-aromatic heterocyclic group)
  • R 7 is a substituted non-aromatic heterocyclic group (the substituent is a substituted or unsubstituted non-aromatic heterocyclic group)
  • a broken line bonded to X 2 represents the absence of a bond, and X 4 —X 3 —X 2 represents X 4 —O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4) -X 2, (1 ') - (11' compound, a pharmaceutically acceptable salt or solvate thereof according to any one of).
  • X 1 is O, -Y 1 -is a single bond, p is an integer of 1 to 4,
  • Each R 1 independently represents halogen, cyano, oxo, substituted or unsubstituted amino, substituted or unsubstituted alkyl, a group represented by the formula: —O—R 7 , or a formula: —SO 2 —R 7 Group, Wherein at least one R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group or a group represented by the formula: —O—R 7 (wherein R 2 7 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group), the compound according to (15 ′) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising as an active ingredient the compound according to any one of (1') to (21 ') above, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a disease involving MCH R1 which comprises administering the compound according to any one of (1 ′) to (21 ′) above, a pharmaceutically acceptable salt thereof, or a solvate thereof. Treatment or prevention method.
  • the compounds of the present invention have low enzyme inhibitory activity, excellent oral absorption, and excellent melanin-concentrating hormone receptor antagonist activity.
  • the compound of the present invention exhibits MCH R1 antagonistic action, and is a drug, particularly a disease involving MCH R1, such as obesity (malignant mastocytosis, exogenous obesity, hyperinsulin obesity, hyperplasma obesity, pituitary obesity Reduced plasma obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hyposexual obesity, systemic mastocytosis, simple obesity, Such as central obesity), hyperphagia, affective disorder, memory disorder, dementia, hormonal disorder, sexual dysfunction, and the like.
  • obesity malignant mastocytosis, exogenous obesity, hyperinsulin obesity, hyperplasma obesity, pituitary obesity Reduced plasma obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hyposexual obesity, systemic mastocytosis, simple obesity, Such as central obesity
  • the compound of the present invention is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity because the compound of the present invention exhibits an effective feeding inhibitory action.
  • the present invention relates to a compound of formula (I): (Where formula: The part indicated by A structure selected from The dashed line represents the presence or absence of a bond, X 1 is O or S; (I) When the broken line bonded to X 2 represents the absence of a bond, X 2 is N or C (R 3 ), and X 4 -X 3 -X 2 is X 4 -O-C (R 4 ) (R 4 ) -X 2 , X 4 —O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —X 2 , X 4 -C (R 4 ) (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) (R 4 ) -X 2 , X 4 —O—C ( ⁇ O) —X 2 , X 4 —O—C ( ⁇ S) —X 2 , X 4 —N
  • X 1 is O or S. Particularly preferred is O.
  • X 2 is N or C (R 3 )
  • X 4 —X 3 —X 2 is X 4 —O—C (R 4 ) (R 4 ) -X 2 , X 4 —O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —X 2 , X 4 -C (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) -X 2 , X 4 —O—C ( ⁇ O) —X 2 , X 4 —O—C ( ⁇ S) —X 2 , X 4 —N (R 6 ) —C ( ⁇ O) —X 2 , X 4 —N (R 6 ) —C ( ⁇ S) —X 2 , X 4 —N (R 6 ) —C
  • X 2 is N or C (R 3)
  • the dashed line that binds to X 2 represents absence of a bond
  • X 2 is N
  • X 4 -X 3 -X 2 is X 4 -O-C (R 4 ) (R 4) - X 2 , X 4 —O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —X 2 , X 4 —O—C (R 4 ) (R 4 ) —X 2 , X 4 -C (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) -X 2 , This is a case where X 4 —O—C ( ⁇ O) —X 2 or X 4 —N (R 6 ) —C ( ⁇ O) —X 2 .
  • X 2 is N
  • X 4 -X 3 -X 2 is 2 X 4 -O-C (R 4) (R 4)
  • R 4 —O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —X represents the absence of a broken line bond to X 2
  • X 2 is N
  • X 4 -X 3 -X 2 is 2 X 4 -O-C (R 4) (R 4)
  • —Y 1 — represents a single bond, —O—, —S—, —C ( ⁇ O) —N (R 6 ) —, —N (R 6 ) —C ( ⁇ O) —, —C (R 4 ).
  • a single bond, —C (R 4 ) ⁇ C (R 4 ) — or —C (R 4 ) (R 4 ) —O— is preferable.
  • —Y 2 — is a single bond or —C (R 4 ) (R 4 ) —O—.
  • —Y 2 — is a single bond.
  • —Y 2 — is —C (R 4 ) (R 4 ) —O—.
  • a cycloalkyl, aryl or non-aromatic heterocyclic group More preferred is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, tetrahydropyranyl, tetrahydrofuryl, morpholinyl or morpholino. Particularly preferred is cyclopropyl or phenyl.
  • R 1 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 7 , group represented by the formula: —O—C ( ⁇ O) —R 7
  • halogen, cyano, oxo, substituted or unsubstituted amino, substituted or unsubstituted alkyl a group represented by the formula: —O—R 7 or a formula: —SO 2 —R 7 wherein R 7 is Substituted or unsubstituted alkyl).
  • halogen cyano, oxo, substituted or unsubstituted amino (substituent is alkylcarbonyl), substituted or unsubstituted alkyl (substituent is halogen), a group represented by the formula: —O—R 7 (Wherein R 7 is alkyl or haloalkyl) or formula: —SO 2 —R 7 (wherein R 7 is alkyl). Particularly preferred is halogen.
  • P is an integer from 0 to 4.
  • p is 0 or 1.
  • I is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group.
  • Preferred is aryl or heteroaryl. More preferred is phenyl, pyridyl or oxazolyl. Particularly preferred is phenyl.
  • R 2 is halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R 7 , group represented by the formula: —O—C ( ⁇ O) —R 7
  • halogen, substituted or unsubstituted alkyl formula: (wherein, R 7 is unsubstituted alkyl) -O-R 7, a group of the formula: -O-R 7 (wherein, R 7 is Substituted alkyl (the substituent is one or more groups selected from the group consisting of hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted amino)
  • a group represented by the formula: —O—R 7 wherein R 7 is a substituted non-aromatic heteroheterocyclic group (the substituent is a substituted or unsubstituted non-aromatic heterocyclic group) It is an alkyl substituted with a group).
  • R 7 is a substituted alkyl (substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group and substituted or 1 or more groups selected from the group consisting of unsubstituted amino), wherein R 7 alkyl is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic hetero It means a group substituted with one or more groups selected from the group consisting of cyclic groups and substituted or unsubstituted amino.
  • the alkyl may be simultaneously substituted with hydroxy and substituted or unsubstituted cycloalkyl.
  • At least one R 2 is any of the following:
  • “at least one R 2 is any of the following” means that at least one of the substituents of ring B is a group shown below.
  • ring B is further halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azido, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyl
  • (A1) substituted alkyl (the substituent is one or more groups selected from the group consisting of hydroxy; cycloalkyl; pyrrolidyl; cycloalkylcarbonyl and pyrrolidylcarbonyl).
  • (A3) A group represented by the formula: —O—R 7 (wherein R 7 is unsubstituted alkyl).
  • R 7 is substituted or unsubstituted alkyl (the substituent is hydroxy; alkylamino; amino substituted with tetrahydrofuryl; amino substituted with tetrahydrofurylalkyl; Pyrrolidylsulfonylamino; cycloalkylcarbonyl; aminocarbonyl substituted with alkyl and / or tetrahydrofuryl; aminocarbonyl substituted with cycloalkyl; cycloalkyl; alkyl optionally substituted with halogen, oxo, hydroxy, alkylcarbonyl Pyrrolidyl optionally substituted with hydroxy, alkylamino, alkoxycarbonyl, carboxy or alkylsulfonyl; piperidyl optionally substituted with alkyl, halogen; pyrrolyl; pyridyl; morpholino; morpholinyl; A group represented by
  • (A5) A group represented by the formula: —O—R 7 (wherein R 7 is alkylsulfonyl or alkoxycarbonyl).
  • (A6) Formula: —O—R 7 (wherein R 7 is substituted or unsubstituted azetidinyl (the substituent is substituted with carboxy which may be substituted with hydroxy, cycloalkyl, oxetanyl, cyano or alkyl) 1 or more groups selected from the group consisting of cycloalkyl optionally substituted with hydroxy; cycloalkyl optionally substituted with hydroxy; and sulfonyl substituted with piperidyl).
  • a group represented by the formula: —O—R 7 (wherein R 7 is substituted or unsubstituted piperidyl (the substituent is alkyl; alkoxycarbonyl or cycloalkyl)).
  • At least one R 2 is any of the following: A group represented by the formula: —O—R 7 , wherein R 7 is substituted alkyl (the substituent is pyrrolidyl). A group represented by the formula: —O—R 7 , wherein R 7 is substituted azetidinyl (the substituent is alkyl optionally substituted with hydroxy, cycloalkyl, or oxetanyl). Substituted pyrrolidyl (the substituent is amino substituted with alkyl optionally substituted with cycloalkyl; or pyrrolidyl). Substituted diazepanyl (the substituent is alkyl substituted with cycloalkyl).
  • R 7 is substituted or unsubstituted alkyl (substituents are hydroxy; alkylamino; amino substituted with tetrahydrofuryl; amino substituted with tetrahydrofurylalkyl; alkyl and / Or aminocarbonyl substituted with tetrahydrofuryl; aminocarbonyl substituted with cycloalkyl; cycloalkyl; alkyl, alkylcarbonyl, hydroxy, alkylamino, alkoxycarbonyl, carboxy or alkyl optionally substituted with halogen, oxo, hydroxy Pyrrolidyl optionally substituted with sulfonyl; one or more groups selected from the group consisting of alkyl, piperidyl optionally substituted with halogen; pyrrolyl; morpholino; morpholinyl; and piperazinyl substituted with alkyl)
  • R 2 at the para position of the bond has the formula: —O—R 7 (wherein R 7 is substituted alkyl (the substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic) Group or heterocyclic group and one or more groups selected from the group consisting of substituted or unsubstituted amino), or a group represented by the formula: —O—R 7 (wherein R 7 is substituted)
  • a group represented by a non-aromatic heteroheterocyclic group (the substituent is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocyclic group) is preferable.
  • R 2 at the meta position of the bond is preferably a group represented by the formula: —O—R 7 (wherein R 7 is unsubstituted alkyl).
  • R 3 is hydrogen, halogen, hydroxy, mercapto, or substituted or unsubstituted alkyl, a group represented by the formula: —SR 7 , or a group represented by the formula: —O—R 7 . Preferably it is hydrogen.
  • Each R 4 is independently hydrogen, halogen, hydroxy, mercapto, or substituted or unsubstituted alkyl, a group represented by the formula: —SR 7 , or a group represented by the formula: —O—R 7 . Preferably it is hydrogen.
  • R 5 is hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Substituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 7 , group represented by formula: —O—C ( ⁇ O)
  • R 6 is hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen or alkyl.
  • Formula (I-1) (Where X 1 is O or S; C—X 3 —N is C—O—C (R 4 ) (R 4 ) —N, C—O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —N, Or C—O—C ( ⁇ O) —N, X 6 , X 7 and X 8 are each independently C (R 5 ) or N; —Y 1 — is a single bond or —C (R 4 ) ⁇ C (R 4 ) —, formula: The group represented by is aryl or heteroaryl, formula: Is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group, Each R 1 is independently halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl,
  • Preferred examples of the compound represented by the above formula (I-1) include the following.
  • a compound wherein C—X 3 —N is C—O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —N.
  • a compound wherein C—X 3 —N is C—O—CH 2 —CH 2 —N.
  • a compound wherein CX 3 -N is C—O—C (R 4 ) (R 4 ) —N.
  • a compound wherein C—X 3 —N is C—O—CH 2 —N.
  • a compound wherein X 1 is O.
  • a compound in which —Y 1 — is a single bond or —C (R 4 ) ⁇ C (R 4 ) —.
  • R 1 is halogen, cyano, oxo, substituted or unsubstituted amino, substituted or unsubstituted alkyl, a group represented by the formula: —O—R 7 or a group represented by the formula: —SO 2 —R 7 .
  • R 1 is halogen, cyano, oxo, substituted or unsubstituted amino (substituent is alkylcarbonyl), substituted or unsubstituted alkyl (substituent is halogen), a group represented by the formula: —O—R 7 ( A compound in which R 7 is an alkyl or haloalkyl group or a group represented by the formula: —SO 2 —R 7 (wherein R 7 is alkyl). A compound wherein R 1 is halogen.
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group or a group represented by the formula: —O—R 7 (wherein R 2 7 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group).
  • At least one R 2 has the formula: —O—R 7 wherein R 7 is substituted alkyl (the substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic 1 or more groups selected from the group consisting of a group and substituted or unsubstituted amino).
  • R 7 is substituted alkyl (the substituent is hydroxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic 1 or more groups selected from the group consisting of a group and substituted or unsubstituted amino).
  • a compound in which at least one R 2 is a group represented by the formula: —O—R 7 (wherein R 7 is substituted or unsubstituted alkyl (the substituent is amino substituted with a non-aromatic heterocyclic group)) .
  • At least one R 2 is a group represented by the formula:
  • Formula (I-1) In the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof or a solvate thereof, the following embodiments (IA) to (IJ) are exemplified.
  • X 1 is O or S;
  • C—X 3 —N is C—O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —N, C—O—C (R 4 ) (R 4 ) —N or C—O—C ( ⁇ O) —N,
  • X 6 , X 7 and X 8 are each independently C (R 5 ) or N;
  • —Y 1 — is a single bond or —C (R 4 ) (R 4 ) —O—, formula: Is a cycloalkyl or non-aromatic heterocyclic group, formula: Is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group,
  • Each R 1 is independently halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl, substituted or unsubstituted
  • X 1 is O, C—X 3 —N is C—O—C (R 4 ) (R 4 ) —N; X 6 , X 7 and X 8 are each independently C (R 5 ) or N; —Y 1 — is —C (R 4 ) (R 4 ) —O—, formula: Is a cycloalkyl or non-aromatic heterocyclic group, formula: The group represented by is aryl or heteroaryl, Each R 1 is independently halogen, hydroxy or substituted or unsubstituted alkyl; Each R 2 is independently halogen, hydroxy, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 7 ; Each R 4 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy; Each R 5 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or
  • X 1 is O or S;
  • C—X 3 —N is C—O—C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —N, C—O—C (R 4 ) (R 4 ) —N or C—O—C ( ⁇ O) —N,
  • X 6 , X 7 and X 8 are each independently C (R 5 ) or N;
  • the group represented by is aryl or heteroaryl, formula: Is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group,
  • Each R 1 is independently halogen, hydroxy, mercapto, nitro, nitroso, cyano, oxo, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstit
  • X 1 is O, C—X 3 —N is C—O—C (R 4 ) (R 4 ) —N; X 6 , X 7 and X 8 are each independently C (R 5 ) or N; -Y 1 -is a single bond, formula: The group represented by is aryl or heteroaryl, formula: The group represented by is aryl or heteroaryl, Each R 1 is independently halogen, hydroxy or substituted or unsubstituted alkyl; Each R 2 is independently halogen, hydroxy, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 7 ; Each R 4 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy; Each R 5 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy; R 7 is independently substitute
  • the group represented by is aryl or heteroaryl, formula: The group represented by is aryl or heteroaryl, Each R 1 is independently halogen, hydroxy or substituted or unsubstituted alkyl;
  • Each R 2 is independently halogen, hydroxy, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 7 ;
  • Each R 4 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
  • Each R 5 is independently hydrogen, halogen, hydroxy, substituted or unsubstituted
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
  • Alkyl means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like.
  • alkyl in R 2 include methyl, ethyl and the like.
  • alkyl in R 7 include methyl, ethyl, propyl, sec-butyl and the like.
  • Preferable embodiments of “alkyl” in D include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.
  • Alkenyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
  • Alkynyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at an arbitrary position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. A preferred embodiment of “cycloalkyl” in ring B includes cyclohexyl. Preferable embodiments of “cycloalkyl” in ring C include cyclopropyl, cyclobutyl, cyclopentyl and the like. In particular, cyclopropyl, cyclobutyl and the like are preferable, and cyclobulpyl is more preferable.
  • Cycloalkenyl means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring. “Cycloalkenyl” in ring C includes cyclohexenyl.
  • Aryl means a monocyclic or polycyclic aromatic carbocyclic group.
  • phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
  • a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included.
  • indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • a preferable embodiment of “aryl” in ring B includes phenyl.
  • a preferable embodiment of “aryl” in ring C includes phenyl.
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • a group derived from a monocyclic aromatic heterocycle, a group derived from a bicyclic aromatic heterocycle, a group derived from three or more polycyclic aromatic heterocycles are also included.
  • Examples of the group derived from a monocyclic aromatic heterocycle include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl , Thienyl and the like.
  • Examples of the group derived from two aromatic heterocycles include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl Benzoxazolyl, benzoxiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, Examples include pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like.
  • Examples of the group derived from three or more polycyclic aromatic heterocycles include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, dibenzofuryl and the like.
  • any ring may have a bond.
  • Preferable embodiments of “heteroaryl” in ring B include pyridyl, pyrimidyl, oxazolyl and the like.
  • heteroaryl in ring C include pyridyl, pyrimidyl, thienyl, pyrazolyl, quinolyl, indolyl, imidazopyridyl and the like.
  • non-aromatic heterocyclic group is a 4- to 8-membered monocyclic non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N, or a monocyclic ring
  • Non-aromatic heterocyclic groups of the above are aromatic carbocycles (aromatic carbocycles derived from the above “aryl”), aromatic heterocycles (aromatic heterocycles derived from the above “heteroaryl”), monocycles Non-aromatic heterocycle (monocyclic non-aromatic heterocycle derived from “monocyclic non-aromatic heterocyclic group”), condensed non-aromatic fused with cycloalkane (ring derived from “cycloalkyl” above) Means heterocyclic group, specifically indolinyl, dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidin
  • non-aromatic heterocyclic group in ring B include tetrahydrofuryl, piperidyl, piperazyl, dihydropyridyl, morpholino, morpholinyl and the like.
  • Preferable embodiments of the “non-aromatic heterocyclic group” in ring C include oxetanyl, benzodioxanyl, benzmorpholino, benzmorpholinyl, indoline and the like.
  • a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino Also good.
  • substituents of “substituted alkyl”, “substituted alkenyl” or “substituted alkynyl” are halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted cyclohexane.
  • substituents of “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl” or “substituted non-aromatic heterocyclic group” are halogen, hydroxy, mercapto, nitro, nitroso, cyano, Azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted
  • substituents of “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” are hydroxy, cyano, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R, group represented
  • Haloalkyl means a group in which the above “halogen” is bonded to the above “alkyl”.
  • Alkoxy means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.
  • Alkoxycarbonyl means a group in which the oxygen atom of the above “alkoxy” is bonded to a carbonyl group.
  • Alkylcarbonyl and cycloalkylcarbonyl mean groups in which the above “alkyl” and “cycloalkyl” are bonded to a carbonyl group.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • the compound of the present invention contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compounds of the present invention, and each of them is individually produced by a synthesis method and a separation method known per se.
  • a synthesis method and a separation method known per se can be obtained as
  • an optical isomer exists in the compound of the present invention
  • an optical isomer resolved from the compound is also included in the compound of the present invention.
  • the optical isomer can be produced by a method known per se. Specifically, optical isomers are obtained by using optically active synthetic intermediates 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, a chiral column method, a diastereomer method and the like described in detail below are used.
  • 1) Fractional recrystallization method Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
  • an optical isomer separation column chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffers (for example, phosphate buffer), organic Optical isomers are separated by developing a solvent (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as a single or mixed solution.
  • a solvent for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • Diastereomer method A mixture of racemates is made into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography, etc.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound of the present invention when the compound of the present invention has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( ⁇ ) -Menthoxyacetic acid etc.) can be subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Examples of the pharmaceutically acceptable salt include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt and dicyclohexyl.
  • Aliphatic amine salts such as amine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts;
  • Aralkylamine salts such as N, N-dibenzylethylenediamine; Pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc.
  • Heterocyclic aromatic amine salt Heterocyclic aromatic amine salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutyl Quaternary ammonium salts such as Le ammonium salts; arginine salts, basic amino acid salts such as lysine salts.
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include a monosolvate, a disolvate, a monohydrate, a dihydrate and the like. It is done.
  • Prodrugs of the compounds of the present invention are included in the scope of the present invention.
  • Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the compound of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but after administration to a patient with a disease associated with MCH, Contains the compound to be converted. Typical procedures for selection and formulation of appropriate prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).
  • One or more hydrogen, carbon or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon or other isotopes of atoms.
  • the compound represented by the formula (I) includes all radiolabeled compounds of the compound represented by the formula (I).
  • Such “radiolabeled”, “radiolabeled”, etc. of compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. It is.
  • isotopes examples include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine are included, such as 35 S, 18 F, and 36 Cl.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a tritium gas with a precursor in which the compound of formula (I) is appropriately halogenated in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be included.
  • a suitable catalyst for example Pd / C
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Step X1 This step is a step for producing compound (I) by reacting compound (I-X1) with compound (I-X2).
  • the reaction is preferably performed in the presence of a base.
  • a base sodium carbonate or the like can be used.
  • the solvent dimethylformamide or the like can be used.
  • the catalyst PdCl 2 ⁇ dppf ⁇ CH 2 Cl 2 (1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex) or the like can be used.
  • This step is a step of producing the compound (b) by hydrolyzing the compound (a). At this time, it is preferable to use a base.
  • a base sodium hydroxide, lithium hydroxide or the like can be used. Tetrahydrofuran or the like can be used as the solvent.
  • Step A2 This step is a step for producing compound (c) by reacting compound (b) with a compound represented by the formula: NH 2 —Z 2 .
  • the reaction is preferably performed in the presence of a condensing agent and a base.
  • a condensing agent HATU or the like can be used.
  • the base triethylamine or the like can be used.
  • dimethylformamide or the like can be used.
  • Step A3 is a step for producing compound (Ia) by reacting compound (c) with an alkyl halide in a suitable solvent.
  • the reaction is preferably performed in the presence of a base.
  • a base potassium carbonate, cesium carbonate, or the like can be used.
  • the solvent dichloromethane, dimethylformamide or the like can be used.
  • X 4 -X 3 -X 2 is X 4 -C (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) -C (R 4 ) (R 4 ) -X 2
  • R 9 is —C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —C (R 4 ) (R 4 ) —Hal, —C (R 4 ) ⁇ C ( Using a) wherein R 4 ) —C (R 4 ) (R 4 ) —Hal or —C (R 4 ) (R 4 ) —C (R 4 ) ⁇ C (R 4 ) —
  • the above construction method of X 4 -X 3 -X 2 can also be used in the following method.
  • Step B1 This step is a step of producing compound (e) by halogenating compound (d).
  • the reaction is preferably performed in the presence of a halogenating agent.
  • a halogenating agent thionyl chloride or the like can be used.
  • the solvent dimethylformamide or the like can be used.
  • Step B2 In this step, compound (e) is reacted with a compound represented by the formula: NH 2 —Z 2 to produce compound (f).
  • the reaction is preferably performed in the presence of a base.
  • a base triethylamine, N-ethyldiisopropylamine and the like can be used.
  • the solvent tetrahydrofuran, dimethylformamide, or the like can be used.
  • Step B3 This step is a step for producing compound (g) by reacting compound (f) with an alkyl halide in a suitable solvent. It can carry out by the method similar to the said A3 process.
  • Step B4 This step is a step for producing compound (Ib) by reacting compound (g) with a compound represented by the formula: B (OH) 2 —Z 1 .
  • the reaction is preferably performed in the presence of a base.
  • a base sodium carbonate or the like can be used.
  • dimethylformamide or the like can be used.
  • the catalyst PdCl 2 ⁇ dppf ⁇ CH 2 Cl 2 (1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex) or the like can be used.
  • Step C1 This step is a step of producing compound (i) by hydrolyzing compound (h). It can carry out by the method similar to the said A1 process.
  • Step C2 This step is a step of producing compound (j) by reacting compound (i) with a compound represented by the formula: NH 2 —Z 2 . It can carry out by the method similar to the said A2 process.
  • Step C3 This step is a step of producing compound (k) by dealkylating compound (j).
  • a Lewis acid catalyst boron trichloride, boron tribromide, or the like can be used.
  • the solvent dichloromethane or the like can be used.
  • the cyclic amine piperazine, 1-ethylpiperazine or the like can be used.
  • N, N-dimethylformamide, N, N-dimethylacetamide or the like can be used.
  • Step C4 This step is a step for producing compound (l) by reacting compound (k) with an alkyl halide in a suitable solvent. It can carry out by the method similar to the said A3 process.
  • Step C5 This step is a step for producing compound (Ic) by reacting compound (l) with a compound represented by the formula: B (OH) 2 -Z 1 . It can carry out by the method similar to the said B4 process.
  • Method D (Wherein Hal is halogen, R 8 is alkyl, -Z 1 is -Y 1 in formula (I), -ring C- (R 1 ) p , -Z 2 is -Y 2 in formula (I) -Ring B- (R 2 ) q , —O—Z 3 represents X 3 in formula (I), and other symbols are the same as those in the compound represented by formula (I). )
  • Step D1 compound (m) is produced by reacting compound (m) with a compound represented by the formula: NH 2 —Z 2 . It can carry out by the method similar to the said A2 process.
  • Step D2 This step is a step of producing compound (o) by dealkylating compound (n). It can carry out by the method similar to the said C3 process.
  • Step D3 In this step, compound (o) is reacted with a compound represented by the formula: Hal-Z 3 —OH to produce compound (p). It can be carried out by Mitsunobu reaction using triphenylphosphine or the like and diethyl azodicarboxylate (DEAD) or the like. Tetrahydrofuran or the like can be used as the solvent.
  • This step is a step of producing compound (q) by condensing compound (p). At this time, it is preferable to use a base.
  • a base sodium hydride or the like can be used. Tetrahydrofuran or the like can be used as the solvent.
  • This step is a step for producing compound (Id) by reacting compound (q) with a compound represented by the formula: B (OH) 2 —Z 1 . It can carry out by the method similar to the said B4 process.
  • the compound of the present invention Since the compound of the present invention has an excellent MCH R1 antagonistic action, it is useful as a medicament for the prevention or treatment of diseases in which MCH R1 is involved.
  • the compound of the present invention has low toxicity and is excellent in oral absorbability and brain migration. Therefore, a pharmaceutical composition containing the compound of the present invention is used to prevent diseases involving MCH R1 in mammals (eg, rats, mice, guinea pigs, rabbits, sheep, horses, pigs, cows, monkeys, humans, etc.). Or it is safely administered as a medicament for treatment.
  • mammals eg, rats, mice, guinea pigs, rabbits, sheep, horses, pigs, cows, monkeys, humans, etc.
  • examples of diseases involving MCH R1 include obesity (malignant mastocytosis, extrinsic obesity, hyperinsulin obesity, hyperplasma obesity, pituitary obesity, hypoplasmic obesity, hypothyroidism) Obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hyposexual obesity, systemic mastocytosis, simple obesity, central obesity, etc.), hyperphagia Emotional disorder, memory disorder, dementia, hormonal disorder, sexual dysfunction and the like.
  • obesity malignant mastocytosis, extrinsic obesity, hyperinsulin obesity, hyperplasma obesity, pituitary obesity, hypoplasmic obesity, hypothyroidism
  • Obesity hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hyposexual obesity, systemic mastocytosis, simple obesity, central obesity, etc.
  • hyperphagia Emotional disorder memory disorder, dementia, hormonal disorder, sexual dysfunction and the like.
  • the compound of the present invention is used as a medicament for the prevention or treatment of lifestyle-related diseases such as diabetes, diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), arteriosclerosis, knee arthritis, etc. Is also useful. Furthermore, the compound of the present invention is very useful for weight management in obesity, weight loss, and weight maintenance after weight loss.
  • lifestyle-related diseases such as diabetes, diabetic complications (eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), arteriosclerosis, knee arthritis, etc. Is also useful.
  • the compound of the present invention is very useful for weight management in obesity, weight loss, and weight maintenance after weight loss.
  • the compound of the present invention has not only MCH R1 antagonist activity but also usefulness as a pharmaceutical, and has any or all of the following excellent features.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
  • j) Does not cause gastrointestinal disorders for example, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (drugs that can be used for weight management in obesity or obesity).
  • the pharmaceutical composition of the present invention can be used in combination with diet therapy (eg, diabetes diet therapy) and exercise therapy.
  • the pharmaceutical composition containing the compound of the present invention can take a dosage form for oral and parenteral administration. That is, orally administered preparations such as tablets, capsules, granules, powders, syrups, or solutions or suspensions for injection such as intravenous injection, intramuscular injection, subcutaneous injection, inhalants, eye drops, nasal drops, suppositories Or a parenteral preparation such as a preparation for transdermal administration such as an ointment or ointment.
  • preparations can be produced using appropriate carriers, excipients, solvents, bases and the like known to those skilled in the art.
  • the active ingredient and auxiliary ingredients are compressed or molded together.
  • Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (eg, corn starch), fillers (eg, lactose, microcrystalline cellulose, etc.), disintegrants (eg, sodium starch glycolate) Alternatively, a lubricant (for example, magnesium stearate, etc.) is used, etc.
  • Tablets may be appropriately coated.
  • suspending agents For example, methylcellulose etc.
  • emulsifiers eg lecithin etc.
  • preservatives etc.
  • an injectable preparation it may be in the form of a solution, suspension or oily or aqueous emulsion, which is stable in suspension. Or as a liquid or suspending agent when used as an inhaler, or as an eye drop.
  • the dose of the compound of the present invention varies depending on the administration form, patient's symptoms, age, weight, sex, or concomitant drug (if any), and is ultimately left to the judgment of a doctor.
  • 0.01 to 100 mg / kg body weight per day preferably 0.01 to 10 mg, more preferably 0.1 to 10 mg / kg.
  • 0.001 to 100 mg / kg body weight per day Preferably, 0.001-1 mg, more preferably 0.01-1 mg is administered. This may be divided into 1 to 4 doses.
  • the NMR analysis obtained in each example was performed at 300 MHz and measured using d6-DMSO and CDCl 3 .
  • “RT” in the NMR data column represents the retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured as follows.
  • a Shim-pack XR-ODS 50Lx3.0 manufactured by Shimazu was used for the measurement, and acetonitrile / water (0.1% formic acid) at a flow rate of 1.6 ml / min 10:90 to 100: 0/3 min. Measured with a linear gradient of.
  • Step 5 Synthesis of Compound Ia-1
  • Compound 6 35 mg, 0.108 mmol was dissolved in N, N-dimethylformamide, cesium carbonate (105 mg, 0.324 mmol) and compound 7 (28 mg, 27.5 mg, 0. 162 mmol) was added and stirred at 80 ° C. for 3 hours.
  • Water was added to the reaction solution for dilution, followed by extraction with ethyl acetate. The organic layer was washed 3 times with water and dried over anhydrous magnesium sulfate. Purification on an amino-coated thin layer plate gave compound Ia-1 (2.5 mg, 5.5%).
  • Step 1 Synthesis of Compound 10 To a solution of Compound 9 (38.0 g, 273 mmol) and Compound 7 (56.6 g, 333 mmol) in N, N-dimethylformamide (500 mL) was added cesium carbonate (267 g, 820 mmol), and 60 ° C. For 4 hours and then at 80 ° C. for 2 hours with stirring. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layers were combined, washed with water, and back-extracted with 2 mol / L hydrochloric acid (475 mL).
  • Step 2 Synthesis of Compound 11
  • a solution of compound 10 (20.0 g, 80.0 mmol) in ethyl acetate (200 mL) was purged with nitrogen three times, and 10% palladium-carbon catalyst (50% water content, 2.00 g) was added.
  • the mixture was subjected to hydrogen replacement under reduced pressure three times and stirred at room temperature for 3 hours under a hydrogen atmosphere of 1 atm.
  • the catalyst was filtered off with Celite, and the filtrate was concentrated under reduced pressure to obtain Compound 11 (16.6 g, 96%) as a brown oil.
  • Step 3 Synthesis of Compound 13 N, N-dimethylformamide (0.011 mL, 0.138 mmol) and thionyl chloride (1.25 mL) were added to a suspension of Compound 12 (3.00 g, 13.8 mmol) in ethyl acetate (12 mL). , 17.2 mmol) was added and heated under reflux for 1.5 hours. The reaction was cooled to room temperature. The obtained compound 13 was used in the next step as it was in an ethyl acetate solution without purification.
  • Step 4 Synthesis of Compound 14 Triethylamine (5.75 mL, 41.5 mmol) was added to a mixed solution of Compound 11 (3.55 g, 17.2 mmol) in ethyl acetate (15 mL) and tetrahydrofuran (6 mL). Then, an ethyl acetate solution of Compound 13 was added dropwise. The reaction mixture was stirred with heating at room temperature for 10 minutes and at 55 ° C. for 25 minutes, and then N-ethyldiisopropylamine (6.03 mL, 34.5 mmol) and N, N-dimethylformamide (9 mL) were added, and further at 55 ° C. The mixture was heated and stirred for 5 hours.
  • Step 5 Synthesis of Compound 15 A suspension of cesium carbonate (6.11 g, 18.8 mmol) and dibromomethane (1.75 mL, 25.0 mmol) in N, N-dimethylformamide (5 mL) was heated to 100 ° C., A suspension of compound 14, N, N-dimethylformamide (20 mL) was added dropwise, and the mixture was stirred with heating at 100 ° C. for 5 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Step 6 Synthesis of Compound Ib-1-1
  • Compound 16 (37.9 mg, 0.249 mmol), 2 mol / L carbonic acid in a solution of compound 15 (80.0 mg, 0.192 mmol) in N, N-dimethylformamide (2 mL)
  • Aqueous sodium solution (0.383 mL, 0.767 mmol)
  • 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (7.8 mg, 0.010 mmol) were added and the mixture was purged with nitrogen three times.
  • the mixture was stirred at 100 ° C. for 30 minutes.
  • the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water.
  • Step 1 Synthesis of Compound 19
  • Compound 18 (2.0 g, 9.29 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1.9 mol / L borane-dimethyl sulfide complex in tetrahydrofuran solution (9.78 mL, 18.58 mmol). was added under ice-cooling, stirred at room temperature for 4 hours, and allowed to stand overnight.
  • the reaction solution was added to methanol (50 mL), and the solvent was distilled off under reduced pressure.
  • the mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
  • Step 3 Synthesis of Compound 13 N, N-dimethylformamide (40.0 mg, 0.553 mmol) and thionyl chloride (7.89 g) were added to a suspension of Compound 12 (12.0 g, 55.3 mmol) in ethyl acetate (48 mL). , 66.4 mmol) was added and the mixture was heated under reflux for 2 hours, and then the reaction solution was cooled to room temperature. The obtained compound 13 was used in the next step as it was in an ethyl acetate solution without purification.
  • Step 4 Synthesis of Compound 21 Compound N (18.2 g, 77.4 mmol) in tetrahydrofuran (96 mL) and N, N-dimethylformamide (51 mL) in a mixed solution at room temperature with N-ethyldiisopropylamine (29.0 mL, 166 mmol), and an ethyl acetate solution of compound 13 was further added dropwise, followed by heating under reflux for 1.5 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (60 mL) and water (120 mL).
  • Step 5 Synthesis of Compound 22
  • a suspension of cesium carbonate (27.4 g, 84.0 mmol) in N, N-dimethylformamide (200 mL) was heated to 100 ° C., and dibromomethane (5.87 mL, 84.0 mmol) was added.
  • Compound 21 (11.2 g, 28.0 mmol) was added, and the mixture was stirred with heating at 100 ° C. for 3 hr.
  • the reaction solution was cooled to room temperature, diluted with water (200 mL), the precipitated solid was filtered, and washed with water (200 mL) and ethyl acetate (50 mL). The obtained solid was dried under reduced pressure at 60 ° C.
  • Step 6 Synthesis of Compound 24
  • a suspension of Compound 22 (2.00 g, 4.87 mmol) in N, N-dimethylformamide (40 mL) was heated to 100 ° C. to obtain a solution, and Compound 23 (773 mg, 6.34 mmol) was obtained.
  • 2 mol / L aqueous sodium carbonate solution (9.8 mL, 19.5 mmol, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (199 mg, 0.244 mmol) was added at 100 ° C.
  • the reaction solution was cooled to 40 ° C.
  • Step 7 Synthesis of Compound 25
  • the reaction solution was poured into water, diluted with tetrahydrofuran, and adjusted to pH 5 with 2 mol / L aqueous hydrochloric acid.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Step 8 Synthesis of Compound 26
  • Compound 20 (792 mg, 2.84 mmol) was dissolved in dimethylformamide (6 mL), Compound 25 (600 mg, 1.89 mmol), cesium carbonate (1.23 g, 3.78 mmol) were added, Stir at 80 ° C. for 4 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain Compound 26 (940 mg, 89%) as a white solid.
  • Step 9 Synthesis of Compound Ib-2-1
  • Compound 26 (940 mg, 1.88 mmol) was dissolved in chloroform (10 mL), and a 4 mol / L hydrogen chloride / ethyl acetate solution (4.69 mL, 18. 8 mmol) was added and stirred at room temperature for 2 hours.
  • the solvent was distilled off under reduced pressure, and the residual solid was washed with diisopropyl ether and dried under reduced pressure to obtain Compound Ib-2-1 (819 mg, 99%) as a white solid.
  • Step 10 Synthesis of Compound Ib-2-2
  • Compound Ib-2-1 (40 mg, 0.092 mmol) was added to methanol (0.8 mL), acetonitrile (0.8 mL), acetone (27 ⁇ L, 0.368 mmol) and sodium trioxide.
  • Acetoxyborohydride (78 mg, 3.68 mmol) was added and stirred for 3 hours.
  • the residue was purified by silica gel column chromatography (DNH manufactured by Fuji Silysia Chemical Ltd., chloroform-methanol). The eluate was concentrated, and the residue was washed with diisopropyl ether to give compound Ib-2-2 (30 mg, 75%) as a white solid.
  • Step 1 Synthesis of Compound 30
  • Compound 29 (10 g) was dissolved in tetrahydrofuran (100 ml) -methanol (50 ml), 2 mol / L aqueous sodium hydroxide solution (51 ml) was added, and the mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was concentrated, 2 mol / L aqueous hydrochloric acid solution (60 ml) was added to the residue, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water (100 ml ⁇ 2) and then dried over anhydrous sodium sulfate.
  • Step 3 Synthesis of Compound 32
  • Compound 31 (700 mg) was dissolved in dichloromethane (10 ml), 1.0 mmol / mL boron tribromide / dichloromethane solution (8.35 ml) was added, and the mixture was stirred for 1 hour under ice cooling.
  • the reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (20 ml). The organic layer was washed twice with water (50 ml ⁇ 2).
  • Step 4 Synthesis of Compound 33
  • Compound 32 120 mg was dissolved in tetrahydrofuran (10 ml), sodium hydride (44.6 mg) and 1,2-dibromoethane (210 mg) were added, and the mixture was heated and stirred at 80 ° C. for 4 hours. .
  • the reaction mixture was cooled to room temperature, water (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with water (50 ml ⁇ 3) and then dried over anhydrous sodium sulfate.
  • Step 1 Synthesis of Compound 36
  • Compound 30 (26.9 g) was dissolved in N, N-dimethylformamide (400 ml), and HATU (52.4 g), Compound 35 (13.6 g) and triethylamine (44.3 ml) were added in this order. And heated and stirred at 60 ° C. for 2 hours. After cooling to room temperature, water (500 ml) was added, and the precipitated solid was collected by filtration to give compound 36 (36.2 g, 100%).
  • Step 3 Synthesis of Compound 38
  • Compound 37 (5.6 g) was dissolved in tetrahydrofuran (60 ml), 2-chloroethanol (1.79 g) and triphenylphosphine (4.48 g) were added, and then 2.2 mol / l.
  • a diethyl azodicarboxylate / toluene solution (10.1 ml) was added dropwise, and then the mixture was stirred at room temperature for 12 hours.
  • Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed with water (100 ml ⁇ 2) and then dried over anhydrous sodium sulfate.
  • Step 4 Synthesis of Compound 39
  • Compound 38 (4.52 g) was dissolved in tetrahydrofuran (90 ml), sodium hydride (463 mg) was added under ice cooling, and the mixture was stirred with heating at 70 ° C. for 2 hr.
  • the reaction mixture was poured into ice water and extracted with ethyl acetate (90 ml). The organic layer was washed with water (200 ml ⁇ 2) and then dried over anhydrous sodium sulfate.
  • Step 5 Synthesis of Compound 41
  • Compound 39 500 mg
  • Compound 40 556 mg
  • dimethylacetamide (2 ml) dimethylacetamide
  • the mixture was heated and stirred at 170 ° C. for 4 hours under microwave irradiation.
  • water (50 ml) was added and extracted with ethyl acetate (30 ml).
  • the organic layer was washed with water (50 ml ⁇ 2) and dried over anhydrous sodium sulfate.
  • Step 6 Synthesis of Compound 42
  • Compound 41 (314 mg) was dissolved in 4 ml of dioxane, 4 mol / L acetic acid / dioxane (6 ml) was added, and the mixture was stirred at room temperature for 3 hours.
  • the organic layer was washed with water (50 ml ⁇ 3) and then dried over anhydrous sodium sulfate.
  • the organic solvent was distilled off under reduced pressure to obtain Compound 42 (251 mg, 100%).
  • Step 7 Synthesis of Compound 43
  • Step 8 Synthesis of Compound Id-1
  • Compound 43 (95 mg), triphenylphosphine (15.9 mg), palladium acetate (4.52 mg), and compound 44 (37.8 mg) were added to N, N-dimethylformamide (5 ml).
  • 2 mol / L aqueous potassium carbonate solution (302 ul) was added, and the mixture was stirred with heating at 110 ° C. for 0.5 hr.
  • Step 1 Synthesis of Compound 13 To a suspension of Compound 12 (2 g) in ethyl acetate (16 ml) was added ice-cooled thionyl chloride (807 ⁇ l) and N, N-dimethylformamide (7 ⁇ l) at 50 ° C. After stirring for 1 hour, the reaction solution was cooled to room temperature. The obtained compound 13 was used in the next step as it was in an ethyl acetate solution without purification.
  • Step 4 Synthesis of Compound Ie-1
  • Compound 48 (280 mg), Compound 23 (100 mg) and triphenylphosphine (107 mg) were dissolved in N, N-dimethylformamide (10 mL), and a 1 mol / l calcium carbonate aqueous solution (0. 6 ml) and then degassed under a nitrogen stream, palladium acetate (30.6 mg) was added, and the mixture was stirred at 100 ° C. for 2 hours.
  • the reaction mixture was cooled and filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate.
  • Step 5 Synthesis of Compound 50 To a solution of Compound Ie-1 (162 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain Compound 50 (96 mg, 79%) as a white solid. The obtained compound 50 was used in the next step without purification.
  • Step 1 Synthesis of Compound 53
  • ethylene glycol monomethyl ether 40 ml
  • 2 mol / l sodium hydroxide aqueous solution 13.2 ml, 26.3 ml
  • the reaction mixture was cooled to room temperature and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and concentrated.
  • the residue was purified by silica gel chromatography (ethyl acetate-hexane) to obtain Compound 53 (387 mg, 68%) as a yellow solid.
  • LC-MS: 1.63 min, [M + H] 197.1.
  • Step 2 Synthesis of Compound 54
  • Compound 53 400 mg, 1.56 mmol was suspended in water (6 mL), potassium hydroxide (873 mg, 15.6 mmol) was added, and the mixture was heated and stirred at 85 ° C. for 1 hour. .
  • the reaction solution was cooled to room temperature, made weakly acidic by adding 2 mol / l hydrochloric acid, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 54 (407 mg, 95%) as a white solid.
  • Step 3 Synthesis of Compound 56 To a solution of compound 54 (405 mg, 1.47 mmol) in N, N-dimethylformamide (6 ml), compound 55 (543 mg, 2.05 mmol), HATU (725 mg, 1.91 mmol), N, N-diisopropylethylamine (0.512 ml, 2.93 mmol) was sequentially added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 56 (387 mg, 68%) as a yellow solid.
  • Step 5 Synthesis of Compound 58
  • Compound 57 (860 mg, 1.32 mmol) in dichloromethane-methanol (3: 1 v / v) (32 mL) was added to cyclopropanecarboxaldehyde (0.120 ml, 1.59 mmol), sodium triacetoxy.
  • Borohydride (336 mg, 1.59 mmol) was added and stirred at room temperature for 30 minutes.
  • Cyclopropanecarboxaldehyde (0.100 ml, 1.32 mmol) and sodium triacetoxyborohydride (280 mg, 1.32 mmol) were added, and the mixture was further stirred for 30 minutes.
  • reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 58 (387 mg, 68%) as a white solid.
  • Step 6 Synthesis of Compound 59
  • the reaction was warmed to room temperature and stirred for 1 hour, then poured into ice water and neutralized with sodium bicarbonate powder. After extraction with dichloromethane-methanol (9: 1), the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol) to obtain Compound 59 (193 mg, 49%) as a white solid.
  • Step 7 Synthesis of Compound 60 To a solution of Compound 59 (100 mg, 0.216 mmol) in dichloromethane (10 mL), triethylamine (0.045 mL, 0.324 mmol) and methanesulfonyl chloride (0.020 mL, 0.260 mmol) were added under ice cooling. The solution was added dropwise and stirred for 2 hours under ice cooling. Triethylamine (0.015 mL, 0.108 mmol) and methanesulfonyl chloride (0.008 mL, 0.108 mmol) were added, and the mixture was further stirred for 1 hour. The reaction solution was diluted with saturated brine and extracted with dichloromethane.
  • Step 8 Synthesis of Compound 61
  • 60% sodium hydride (5.9 mg, 0.147 mmol) to a solution of compound 60 (79.7 mg, 0.147 mmol) in N, N-dimethylformamide (4 ml) and stir at room temperature for 45 minutes. did. 60% sodium hydride (3.5 mg, 0.147 mmol) was added, and the mixture was further stirred with heating at 50 ° C. for 30 min. The reaction was cooled to room temperature and ice was added. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and concentrated under reduced pressure.
  • Step 9 Synthesis of Compound 62
  • Compound 61 (55.1 mg, 0.124 mmol) in N, N-dimethylformamide (2 ml) solution was added 4-chlorophenylboronic acid (23.3 mg, 0.149 mmol), sodium carbonate aqueous solution (2 mol / l , 0 0.160 ml, 0.320 mmol)) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (3.0 mg, 0.004 mmol), and reduced pressure and nitrogen substitution three times. Stirring was performed at 100 ° C. for 40 minutes.
  • Step 4 Synthesis of Compound 68
  • sodium hydride 47.8 mg, 1.195 mmol
  • the reaction mixture was poured into ice water and extracted with ethyl acetate.
  • the organic layer was washed with water and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (methanol-chloroform) to obtain Compound 68 (319 mg, 77%) as a white powder.
  • Step 5 Synthesis of Compound 69
  • a suspension of Compound 68 (319.4 mg, 0.613 mmol) in ethanol (4 mL) was added pyridinium p-toluenesulfonic acid (46.2 mg, 0.184 mmol), and the mixture was stirred at 70 ° C. for 30 minutes. I did it.
  • the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure. Further, toluene was azeotroped for pyridine removal, and the residue was purified by silica gel chromatography (methanol-chloroform) to obtain Compound 69 (265 mg, 99%) as a white powder.
  • Step 6 Synthesis of Compound 70 To a solution of compound 69 (70.0 mg, 0.160 mmol) in N, N-dimethylformamide (2 ml), 4-chlorophenylboronic acid (30.0 mg, 0.192 mmol), sodium carbonate aqueous solution (2 mol / l, 0.160 ml, 0.320 mmol)) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (6.5 mg, 0.080 mmol), repeated under reduced pressure and nitrogen substitution 3 times The mixture was heated and stirred at 100 ° C. for 30 minutes.
  • Step 1 Synthesis of Compound 72 (R) -1-cyclopropyl-2- (2-methoxy-4-nitrophenoxy) ethanol 71 (20 g, 79. mmol) synthesized by the method described in US2009 / 0298794 was dissolved in dichloromethane (200 ml). ), Imidazole (10.75 g, 158 mmol) and tert-butyldimethylsilyl chloride (15.7 g, 157 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 150 ml of water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 3 Synthesis of Compound 75 6-Chloro-4-methoxynicotinic acid 74 (4.40 g, 23.45 mmol), Compound 73 (7.91 g, 23.44 mmol) were dissolved in N, N-dimethylformamide (40 ml) and triethylamine (9.75 ml) was dissolved. 70.4 mmol) and HATU (11.59 g, 30.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (80 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (140 ml). The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Step 4 Synthesis of Compound 76
  • Compound 75 (10.0 g, 19.72 mmol) was dissolved in N, N-dimethylacetamide (60 ml), 1-ethylpiperazine (3.60 g, 31.6 mmol) was added, and 150 ° C. For 1 hour. Water (80 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (140 ml). The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 76 (7.1 g, yield 73%).
  • Step 5 Synthesis of Compound 77
  • Compound 76 (7.1 g, 14.40 mmol) was dissolved in N, N-dimethylacetamide (50 ml), potassium carbonate (5.97 g, 43.2 mmol) was added, and 110 ° C was added.
  • Dibromomethane (7.51 g, 43.2 mmol) was further added dropwise, and the mixture was stirred at 110 ° C. for 25 hours.
  • Water (80 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (140 ml). The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Step 6 Synthesis of Compound 78
  • Compound 77 (100 mg, 0.198 mmol) was dissolved in toluene (3 ml), tris (dibenzylideneacetone) bispalladium (18.13 mg, 0.02 mmol), 2,2′-bis (diphenylphosphine). Fino) -1,1′-binaphthyl (12.33 mg, 0.02 mmol), sodium t-butoxide (38.13 mg, 0.396 mmol), 2-tetrahydrofuranmethanol (30.3 mg, 0.297 mmol) were added, and nitrogen was added. The mixture was stirred at 100 ° C. for 30 minutes under an air stream.
  • Step 7 Synthesis of Compound 79
  • Compound 78 (42 mg, 0.072 mmol) was dissolved in 1 ml of tetrahydrofuran, 1 mol / l-tetrabutylammonium fluoride (0.072 ml, 0.072 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • Water (20 ml) was poured into the reaction mixture and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Test Example 1 Affinity for MCH1 Receptor
  • a cDNA sequence encoding the human MCH1 receptor (Lakayae et al. Biochim. Biophis. Acta1401, 216) was cloned into the expression vector pcDNA3.1 (+) (trademark, Invitrogen).
  • the obtained expression vector was transfected into host cells and CHO (Chinese HamsterOvery) cells using Lipofectamine reagent (trademark, Invitrogen) according to the instruction manual to obtain stably expressing cells.
  • a cell membrane preparation was prepared from the obtained CHO cells stably expressing MCH1 receptor.
  • the prepared membrane preparation was assayed with 0.5% bovine serum albumin, 10 mM magnesium chloride, 1 mM ethylenediaminetetraacetic acid together with the compound according to the present invention and [ 125 I] S36057 (final concentration about 31 pM, manufactured by PerkinElmer).
  • the reaction was carried out at room temperature for 2 hours in a 25 mM HEPES buffer solution, pH 7.4). After completion of the reaction, suction filtration was performed using a glass filter (GF / C, manufactured by Whatman) treated with 0.5% polyethyleneimine, and a washing solution (25 mM Tris buffer containing 0.1% bovine serum albumin, pH 7.4). ) For 5 times. The radioactivity on the glass filter was measured with a gamma counter.
  • Nonspecific binding was defined as the amount of binding in the presence of 1 ⁇ M MCH (manufactured by Peptide Laboratories), and the inhibitory activity of the compound according to the present invention on MCH1 receptor binding was expressed as 50% inhibitory concentration (IC50).
  • IC50 50% inhibitory concentration
  • Test Example 2 Antagonistic effect on inhibition of intracellular cAMP production by MCH in human MCH1 receptor-expressing CHO cells CHO cells expressing human MCH1 receptor were assayed with an assay buffer (0.1 mM isobutylmethylxanthine (manufactured by Nacalai Tesque), After suspending in 0.2 mM RO20-1724 (Calbiochem), 20 mM HPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4), the compound of the present invention and MCH (final concentration 30 nM) And forskolin (manufactured by Nacalai Tesque, final concentration of 2.5 ⁇ M) were added and reacted at room temperature for 60 minutes.
  • an assay buffer 0.1 mM isobutylmethylxanthine (manufactured by Nacalai Tesque), After suspending in 0.2 mM RO20-1724 (Calbiochem), 20 mM HPES-Hanks buffer containing 0.1% bovine serum albumin, pH
  • the amount of intracellular cAMP was measured using a cAMP HTRF kit (cAMP Dynamic 2, cisbio) according to the instructions.
  • concentration (IC50) at which the compound according to the present invention inhibits the suppressive action of MCH on cAMP production by forskolin stimulation by 50% was calculated as the antagonist activity.
  • Test Example 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ⁇ , 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated. As a result, the compound of the present invention showed good brain migration.
  • Compound Ic-1 and Compound Ib-2-50 had brain Kp: 33.0 and 85.0, respectively.
  • Test Example 4 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life is determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ⁇ , 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated. As a result, the compound of the present invention showed good pharmacokinetics.
  • Test Example 5 Feeding inhibitory action Under somnopentyl (Kyoritsu Pharmaceutical Co., Ltd.) anesthesia, male F344 / Jcl rats (14-16 weeks old, 200-300 g) were incised along the midline from the outer occipital crest to the back of the nose, The upper skull was exposed. Drill an approximately 1mm diameter hole using an electric drill at a position approximately 0.8mm backward from the exposed part bregma toward lambda and about 1.6mm to the left from the midline, and insert a guide cannula (manufactured by Yamashita Seisakusho) It was fixed using a cement (made by Matsukaze).
  • hydroxypropylmethylcellulose manufactured by Shin-Etsu Chemical Co., Ltd.
  • aqueous solution or test substance suspended in this aqueous solution was forcibly administered orally to rats, and about 2 hours after administration, MCH (peptide 5 ⁇ g (manufactured by Research Institute Co., Ltd.) was injected from the guide cannula previously provided using an injection cannula (Yamashita Seisakusho).
  • MCH peptide 5 ⁇ g (manufactured by Research Institute Co., Ltd.) was injected from the guide cannula previously provided using an injection cannula (Yamashita Seisakusho).
  • the food intake of the rats was measured 2 hours and 4 hours after the injection, and the difference in food intake between the 0.5% hydroxypropylmethylcellulose solution administration group and the test substance administration group was investigated.
  • the compound of the present invention when the compound of the present invention was administered at a dose of 3 mg / kg, the amount of food intake was suppressed as compared with the case where 0.5% hydroxypropylmethylcellulose was administered.
  • the food intake after 2 hours and 4 hours after injection was 0.84 ⁇ 0.39 g and 1.00 ⁇ 0. It was 38 g.
  • the amount of food intake after 2 hours and 4 hours after injection of the group (Group B) administered with the compound GW856464 (described in WO2005 / 042541) as a target compound at a dose of 100 mg / kg was 0.97 ⁇ 0.5 g, respectively. It was 35 ⁇ 0.53 g.
  • the amount of food intake 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) was 1.09 ⁇ 0.13 g and 1.43 ⁇ 0.21 g, respectively.
  • the amount of food intake of the 0.5% hydroxypropylmethylcellulose solution administration group (Group D) without MCH injection was 0.36 ⁇ 0.34 g, 0.36 ⁇ 0.34 g, and the values of Group D were A, B When subtracted from Group C and converted, the feeding inhibition rate for Group C after 2 hours and 4 hours after injection in Group A and Group B is 34.5% for Group A, 40.1%, and 16.8 for Group B. %, 7.1%.
  • compound GW856464 is the following compound.
  • Test Example 6 Weight-suppressing action Male C57BL / 6J mice (13-14 weeks old, body weight 26-36 g) whose body weight was increased by feeding a high-fat diet were mixed with 0.5% hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd.) aqueous solution or The test substance suspended in this aqueous solution was orally administered by gavage twice a day for about 3 weeks every day, and daily changes in body weight of the 0.5% hydroxymethylcellulose solution (Vehicle) administration group and the test substance administration group were investigated. . During the compound administration period, feeding with a high fat diet was continued.
  • Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • reaction solution in a 96-well plate 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. As a result, it was shown that the compound of the present invention has a weak inhibitory effect on the CYP enzyme.
  • Test Example 10 Solubility test The solubility of the compound was determined under the condition of addition of 1% DMSO. Prepare a 10 mM compound solution in DMSO, add 6 ⁇ L of the compound solution to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, 0.2 mol / L NaOH test solution 118 mL, water (Added to 1000 mL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water 1/1, and the concentration in the filtrate was measured by HPLC or LC / MS / MS by the absolute calibration curve method. (result) Compound Ib-2-50: 1 ⁇ M Compound Ib-1-49: 12.2 ⁇ M
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (7-BFC) using E. coli-expressed CYP3A4 as an enzyme.
  • 7-benzyloxytrifluoromethylcoumarin (7-BFC) using E. coli-expressed CYP3A4 as an enzyme.
  • HFC 7-hydroxytrifluoromethylcoumarin
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ M or more was designated as (+), and the case where it was 3 ⁇ M or less was designated as ( ⁇ ).
  • Formulation Examples 1 to 10 shown below are merely examples, and are not intended to limit the scope of the invention in any way.
  • the term “active ingredient” means a compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Formulation Example 1 Hard gelatin capsules are made using the following ingredients: Dose (mg / capsule) Active ingredient 250mg Starch (dried) 200mg Magnesium stearate 10mg Total 460mg
  • Formulation Example 2 Tablets are manufactured using the following ingredients. Dose (mg / tablet) Active ingredient 250mg Cellulose (microcrystal) 400mg Silicon dioxide (fume) 10mg Stearic acid 5mg Total 665 mg The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • Formulation Example 3 An aerosol solution containing the following components is prepared. weight(%) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00 The active ingredient and ethanol are mixed and this mixture is added to a portion of propellant 22, cooled to -30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
  • Formulation Example 4 A tablet containing 60 mg of the active ingredient is produced as follows. Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total Active ingredients, starch and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Formulation Example 5 A capsule containing 80 mg of the active ingredient is produced as follows. Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg The active ingredient, starch, cellulose, and magnesium stearate are mixed. 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • Formulation Example 6 A suppository containing 225 mg of the active ingredient is prepared as follows. Active ingredient 225mg Saturated fatty acid glyceride 2000mg Total 2225mg The active ingredient is No. 60 mesh U. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
  • Formulation Example 7 A suspension containing 50 mg of active ingredient is prepared as follows. Active ingredient 50mg Sodium carboxymethylcellulose 50mg Syrup 1.25ml Benzoic acid solution 0.10ml Fragrance q. v. Dye q. v. 5ml in total with purified water The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add a sufficient amount of water to the required volume.
  • Formulation Example 8 The intravenous formulation is produced as follows. Active ingredient 100mg Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • Formulation Example 9 The gel is produced as follows. Active ingredient 100mg Isopropanol 500mg Partially hydrophobized hydroxymethylcellulose 150mg Purified water added for a total of 10,000 mg The active ingredient is dissolved in isopropanol, added to the partially dispersed hydrophobized hydroxymethylcellulose, water is added, and the mixture is uniformly mixed with a stirrer to dissolve all ingredients.
  • Formulation Example 10 The droplet dispersion type ointment is produced as follows. Active ingredient 100mg Benzyl alcohol 400mg Sorbitan sesquistearate 400mg Liquid paraffin 500mg White petrolatum 8600mg Total 10,000mg The active ingredient is dissolved in benzyl alcohol, added to a mixture of sorbitan sesquistearate, liquid paraffin, and white petrolatum, and mixed with a stirrer to prepare.
  • the present compound was found to have low enzyme inhibitory activity, excellent oral absorption, and excellent melanin-concentrating hormone receptor antagonist activity.

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Abstract

L'invention concerne un nouveau composé qui a une activité antagoniste du récepteur R1 de la MCH et est représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci ou un solvate de ceux-ci. (Dans la formule, la partie AA représentée par la formule (1) est BB etc., les lignes en pointillé indiquent si une liaison est présente ou non, X1 représente O ou S, lorsque les lignes en pointillé réunies à X2 indiquent qu'une liaison n'est pas présente, X2 représente N ou C(R3), X4-X3-X2 représente X4-O-C(R4)(R4)-C(R4)(R4)-X2, etc., -Y1- représente une simple liaison, etc., -Y2- représente une simple liaison, etc., chaque R2 représente indépendamment un halogène, etc., R3 représente hydrogène, etc., R4 représente hydrogène, etc., D représente un alkyle, etc., le cycle B représente un cycloalkyle, etc., p est un entier de 0 à 4 et q est un entier de 1 à 4.
PCT/JP2011/071093 2010-09-17 2011-09-15 Dérivé hétérocyclique condensé ayant une activité antagoniste du récepteur de l'hormone de concentration de la mélanine Ceased WO2012036233A1 (fr)

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