WO2012020725A1 - Dérivé hétérocyclique présentant un antagonisme pour le récepteur npy y5 - Google Patents

Dérivé hétérocyclique présentant un antagonisme pour le récepteur npy y5 Download PDF

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WO2012020725A1
WO2012020725A1 PCT/JP2011/068032 JP2011068032W WO2012020725A1 WO 2012020725 A1 WO2012020725 A1 WO 2012020725A1 JP 2011068032 W JP2011068032 W JP 2011068032W WO 2012020725 A1 WO2012020725 A1 WO 2012020725A1
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unsubstituted
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直樹 神山
顕 行正
祐二 西浦
友亮 田村
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塩野義製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • the present invention relates to a novel heterocyclic derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
  • 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 to classify 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”.
  • Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals. In previous reports, NPY has been found to have feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders.
  • Non-Patent Document 5 a pharmaceutical composition having an NPY receptor antagonistic action is a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
  • subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 6).
  • the Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist becomes an anti-obesity drug (see Non-Patent Documents 7 to 9).
  • Patent Documents 1 and 2 and Non-Patent Document 1 include the formula: A benzimidazole derivative having an NPY Y5 receptor antagonistic activity having a group represented by formula (2) at the 2-position is disclosed.
  • Patent Document 3 discloses a benzimidazole derivative having an SCD inhibitory action.
  • the document discloses 6- (cyclopropylsulfonyl) -2- (2′-fluorobiphenyl-4-yl) -1) -1H-benzimidazole (Example 2 of the document).
  • Patent Document 4 discloses a benzimidazole derivative having an anticancer activity.
  • Patent Document 5 discloses a benzimidazole derivative having an ATP-sensitive potassium channel inhibitory action.
  • Patent Document 6 discloses a benzimidazole derivative having a protein kinase inhibitory action.
  • the document includes 2- (4-amino-1- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -N, N-diethyl-1H-benzo [d].
  • Imidazole-5-sulfonamide (Example 59 of that document) is disclosed.
  • Patent Document 7 discloses a benzimidazole derivative having a substituted phenyl-substituted sulfamoyl group at the 5-position, which acts on tyrosine kinase.
  • Patent Documents 8 and 9 disclose benzimidazole derivatives having an unsubstituted sulfamoyl group at the 5-position.
  • Patent Documents 10 to 14 and Non-Patent Documents 2 to 4 disclose benzimidazole derivatives having a methanesulfonyl group at the 5-position.
  • Patent Document 15 discloses a benzimidazole derivative having a benzylsulfamoyl group at the 5-position.
  • Non-Patent Document 2 discloses a benzimidazole derivative having a phenylsulfamoyl group at the 5-position.
  • the nitrogen atom on the benzimidazole ring is substituted with a methyl group.
  • Patent Documents 3 to 15 and Non-Patent Documents 2 to 4 do not describe NPY Y5 receptor antagonistic action.
  • An object of the present invention is to provide a novel heterocyclic derivative having an excellent NPY Y5 receptor antagonistic action.
  • the present inventors have succeeded in synthesizing a novel compound having an excellent NPY Y5 receptor antagonistic action. 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.
  • 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 It may be.
  • X is —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C (—H) —
  • Z is —N ⁇
  • R 2 is cyclopropyl
  • R 11 and R 12 are hydrogen
  • R 4 is phenyl
  • n is 1
  • R 5 is 2-fluorophenyl
  • X is —N (—Et) —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C ( -H)-
  • R 2 is ethyl
  • R 11 is amino
  • R 12 is hydrogen
  • R 4 is piperidin-4-yl
  • n is 1
  • R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl.
  • R 6 is hydrogen or substituted or unsubstituted alkyl, or R 6 together with the adjacent nitrogen atom together with R 2 may form a substituted or unsubstituted heterocycle.
  • the above 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 It may be.
  • X is —N (—Et) —SO 2 —
  • Y 1 is ⁇ C (—H) —
  • Y 3 is ⁇ C (— H) —
  • Z is —N ⁇
  • R 2 is ethyl
  • R 11 is amino
  • R 12 is hydrogen
  • R 4 is piperidin-4-yl
  • n is 1.
  • R 5 is 7H-pyrrolo [2,3-d] -pyrimidin-4-yl.
  • a pharmaceutical composition having an NPY Y5 receptor antagonistic action comprising the compound according to any one of (1) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • 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 It may be.
  • R 4 is a substituted or unsubstituted non-aromatic heterocyclic group, n is 1.
  • a pharmaceutically acceptable salt thereof, or a solvate thereof a pharmaceutical composition having an NPY Y5 receptor antagonistic action.
  • n is 1, and R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted non-aromatic heterocycle
  • 17. The pharmaceutical composition according to the above (16), wherein n is 1, and R 5 is a substituted or unsubstituted non-aromatic heterocyclic group.
  • n is 1, R 5 is cyano, substituted or unsubstituted alkyl or a group represented by the formula: —O—R 10 , and R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl
  • (19) The pharmaceutical composition according to any one of the above (15) to (18), wherein R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • X is —SO 2 — or —N (—R 6 ) —SO 2 —
  • Y 1 is ⁇ C (—R 8 ) —
  • Y 2 is —C (—R 3 ) ⁇
  • (21) For use in prevention and / or treatment of obesity or weight management in obesity for use in combination with the pharmaceutical composition according to any one of (13) to (20) above, which comprises a compound having an anti-obesity action Pharmaceutical composition.
  • a method for preventing and / or treating obesity which comprises administering a compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a method for weight management in obesity comprising administering the compound represented by the formula (I) described in (15) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic action, and is associated with drugs, particularly NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure, sleep disorder and the like.
  • drugs particularly NPY Y5
  • NPY Y5 receptor antagonistic action such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures
  • It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure, sleep disorder and the like.
  • the compound of the present invention since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity.
  • it is very useful as a medicament for the treatment or prevention of diseases in which obesity is a risk factor, such as
  • the present invention relates to a compound of formula (I): (Where X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —, Y 1 is ⁇ C (—R 8 ) — or ⁇ N—, Y 2 is —C (—R 3 ) ⁇ or —N ⁇ , Y 3 is ⁇ C (—R 1 ) — or ⁇ N—, Z is —C (—R 9 ) ⁇ or —N ⁇ , R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsub
  • Formula (I) In the compound represented by the formula (1), when Z is —N ⁇ , it means any of the following structures (Ia) or (Ib). (In the formula, each symbol has the same meaning as the symbol used in the compound represented by formula (I).)
  • X is —SO 2 —, —N (—R 6 ) —SO 2 — or —SO 2 —N (—R 7 ) —.
  • R 6 may be combined with R 2 and the adjacent nitrogen atom to form a substituted or unsubstituted heterocycle
  • R 7 is combined with R 2 and the adjacent nitrogen atom and —SO 2 —.
  • a substituted or unsubstituted heterocyclic ring may be formed.
  • X is preferably —SO 2 —, —N (—R 6 ) —SO 2 —, and more preferably —SO 2 —.
  • R 6 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle.
  • the compound represented by the formula (I) is represented by the following formula (Ic).
  • the “heterocycle” may be aromatic or non-aromatic.
  • a ring atom may contain a nitrogen atom, an oxygen atom, or a sulfur atom.
  • a 3- to 8-membered non-aromatic or aromatic heterocyclic ring is preferable.
  • other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed.
  • the “heterocycle” is preferably a 5- to 7-membered non-aromatic or aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed.
  • the formula: Preferred examples of the group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position. Particularly preferably, Alternatively, these are groups in which a benzene ring or a cyclohexane ring is condensed.
  • the compound represented by formula (I) is represented by the following formula (Id): Indicated by (In the formula, each symbol is as defined above.)
  • the “heterocycle” may contain a nitrogen atom, an oxygen atom, or a sulfur atom in addition to the nitrogen atom and the sulfur atom shown in the above formula as constituent atoms of the ring. Preferably, it is a 3- to 8-membered non-aromatic heterocyclic ring. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed.
  • heterocycle is preferably a 5- to 7-membered non-aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed.
  • group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position.
  • Y 1 is ⁇ C (—R 8 ) — or ⁇ N—. Preferred is ⁇ C (—R 8 ) —, and particularly preferred is ⁇ C (—H) —.
  • Y 3 is ⁇ C (—R 1 ) — or ⁇ N—.
  • Preferred is ⁇ C (—R 1 ) —, and particularly preferred is ⁇ C (—H) —.
  • R 1 , R 3 , R 8 , R 9 , R 11 and R 12 are each independently hydrogen, 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 hetero Aryl, 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 10 ,
  • R 1 , R 3 , R 8 , R 9 , R 11 and R 12 include hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted sulfamoyl, group represented by the formula: —O—R 10 , group represented by the formula: —O—C ( ⁇ O) —R 10 , group represented by the formula: —C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —
  • Particularly preferred substituents for R 1 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 3 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 8 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • Particularly preferred substituents for R 9 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
  • substituents for R 11 are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano, a group represented by the formula: —O—R 10 .
  • Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, methyl, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
  • Preferred substituents for R 12 are hydrogen, hydroxy, halogen, cyano, and a group represented by the formula: —O—R 10 .
  • Further preferred substituents are hydrogen, hydroxy, fluorine, chlorine, cyano, isopropyloxy, trifluoromethyloxy, phenoxy and the like.
  • haloalkyl and haloalkyloxy include a group in which 1 to 5 (preferably 1 to 3) halogens are substituted on the alkyl part of alkyl and alkyloxy.
  • 1 to 5 preferably 1 to 3
  • R 10 is 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 Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
  • R 10 include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted sulfamoyl. Further preferred embodiments include isopropyl, trifluoromethyl, phenyl and the like.
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl.
  • Preferred embodiments of R 2 are substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted cycloalkyl, and particularly preferably substituted or unsubstituted alkyl.
  • a substituted or unsubstituted alkyl having 2 to 10 carbon atoms is preferable, an alkyl having 2 to 4 carbon atoms is particularly preferable, and an alkyl having 3 or 4 carbon atoms is more preferable.
  • methyl, ethyl, propyl, tert-butyl, trifluoromethyl, trifluoromethyl, trifluoropropyl and the like can be mentioned. More preferred are ethyl, propyl, tert-butyl, trifluoroethyl, trifluoropropyl and the like.
  • R 2 is alkyl having 1 or 2 carbon atoms
  • substituted methyl and substituted ethyl are preferable.
  • methyl substituted with 1 to 3 halogens and ethyl substituted with 1 to 3 halogens are preferred.
  • R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 4 are substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, particularly preferably Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group.
  • R 4 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted non-aromatic heterocyclic group, 1 or 2 oxo, thioxo or substituted or unsubstituted imino May be substituted.
  • oxo, thioxo or imino are substituted with carbon atoms or sulfur atoms constituting the ring.
  • a cyclic group having —C ( ⁇ O) —, —S ( ⁇ O) —, —S ( ⁇ O) 2 —, —C ( ⁇ S) —, —C ( ⁇ NH) — in the ring.
  • the imino may have a substituent.
  • R 4 substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted non-aromatic heterocyclic group is R 5
  • any number of substitutable substituents may be present at any substitutable position.
  • substituents 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 or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C ( ⁇ O) —R 10 , formula: — A
  • R 5 is 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 or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R 10 , group represented by formula: —O—C ( ⁇ O) —R 10 , formula: —
  • R 10 has the same meaning as described above.
  • Preferred embodiments of R 5 include cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or An unsubstituted non-aromatic heterocyclic group or a group represented by the formula: —O—R 10 (wherein R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl).
  • 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 aryl or substituted or unsubstituted non-aromatic heterocyclic group is preferable.
  • R 5 is preferably substituted next to the adjacent position of the bond of R 4 (the bond that substitutes for the condensed ring).
  • R 4 when R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted 6-membered monocyclic heteroaryl, R 5 is substituted at the meta position of the bond of the phenyl or 6-membered monocyclic heteroaryl. Is preferred.
  • R 4 is a substituted or unsubstituted non-aromatic heterocyclic group
  • R 5 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Ring system substituents such as heteroaryl, substituted or unsubstituted non-aromatic heterocyclic groups are preferred.
  • R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 5 is in addition to the above ring system substituents, cyano, substituted or unsubstituted alkyl, formula: —O—R 10
  • R 6 and R 7 are hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen.
  • R 6 may be combined with an adjacent nitrogen atom together with R 2 to form a substituted or unsubstituted heterocycle.
  • R 7 may be combined with the adjacent nitrogen atom and —SO 2 — together with R 2 to form a substituted or unsubstituted heterocycle.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • 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 for R 2
  • methyl, ethyl, propyl, isopropyl and tert-butyl are preferable.
  • alkyl having 2 to 10 carbon atoms for R 2 , ethyl, propyl, isopropyl and tert-butyl are preferable.
  • 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 and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups.
  • Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclohexyl and the like.
  • ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms examples include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • non-aromatic carbocycles eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.)
  • non-aromatic heterocycles for example, piperidine ring, piperazine ring, morpholine ring, etc
  • the bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.
  • “Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means.
  • Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
  • cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
  • Examples of the ring condensed with the C3-C8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring).
  • aromatic carbocycles eg, benzene ring, naphthalene ring etc.
  • non-aromatic carbocycles eg cycloalkane ring
  • cyclohexane ring, cyclopentane ring, etc. examples include cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.)) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.)
  • the bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
  • the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.
  • Aryl is a monocyclic or polycyclic aromatic carbocyclic group, and a group obtained by further condensing one or two 3- to 8-membered rings to these monocyclic or polycyclic aromatic carbocyclic groups.
  • Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
  • Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring).
  • the bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
  • the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.
  • aryl in R 4
  • phenyl is preferable.
  • aryl in R 5
  • phenyl is preferable.
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
  • a 5- or 6-membered heteroaryl is particularly preferable.
  • pyrrolyl imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl
  • examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
  • the “polycyclic aromatic heterocyclic group” is particularly preferably a heteroaryl fused with a 5- or 6-membered ring, such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra
  • any ring may have a bond.
  • Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene).
  • a non-aromatic heterocyclic ring for example, a piperidine ring, a piperazine ring, a morpholine ring, etc.
  • the bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
  • heteroaryl groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.
  • heteroaryl in R 4 , pyridyl, pyrazolyl and the like are preferable.
  • Non-aromatic heterocyclic group means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic groups This means a group in which one or two 3- to 8-membered rings are condensed to the formula group. It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
  • ⁇ monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
  • polycyclic non-aromatic heterocyclic group examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • any ring may have a bond.
  • the following groups are also included in the non-aromatic heterocyclic group.
  • non-aromatic heterocyclic group in R 4 , tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, morpholinyl, dihydropyridinyl and the like are preferable.
  • non-aromatic heterocyclic group in R 4 , piperidinyl, morpholino, morpholinyl and the like are preferable.
  • 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”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or Unsubstituted amino, carboxy, 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 10 , represented by the formula: —O—
  • substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, cyano, carboxy and the like.
  • Preferred substituents of “substituted alkyl” include halogen.
  • a preferable substituent of “substituted alkyl having 2 to 10 carbon atoms” includes halogen.
  • Substituted cycloalkyl “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom”
  • Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include 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 unsubstitute
  • Substituted or unsubstituted cycloalkyl “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom Or a substituted or unsubstituted heterocyclic ring formed by R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 — ”can be substituted. Any position may be substituted with oxo, thioxo or substituted or unsubstituted imino.
  • substituted cycloalkyl Preferred “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “R 6 and R 2 together with the adjacent nitrogen atom”
  • Substituents of “substituted heterocycle formed” or “substituted heterocycle formed by combining R 7 and R 2 together with the adjacent nitrogen atom and —SO 2 —” include halogen, alkyl, haloalkyl, Examples include alkyloxy and haloalkyloxy.
  • Preferred substituents of “substituted aryl” include halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy and the like.
  • a preferable substituent of the “substituted non-aromatic heterocyclic group” includes halogen.
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • Formula (Ih) And the pharmaceutically acceptable salt thereof, or a solvate thereof, includes the following (Ih-A) or (Ih-B).
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • Formula (Io) And the pharmaceutically acceptable salts thereof, or the solvates thereof include the following embodiments (Io-A) to (Io-B).
  • R 11 and R 12 are each independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, a group represented by the formula: —O—R 10 , a group represented by the formula: —O—C ( ⁇ O) —R 10 , A group represented by the formula: —C ( ⁇ O) —R 10 , a group represented by the formula:
  • the compounds of the present invention include pharmaceutically acceptable salts of the respective compounds.
  • basic salts include 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, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt and other aliphatic amine salts; N, N-dibenzylethylenediamine, venetamine salt and other aralkylamine salts; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl
  • 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 and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate. In particular, when Z is —N ⁇ , the compound of the present invention can be used as these acid salts.
  • the compounds of the present invention include solvates thereof.
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.
  • the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.).
  • this invention compound has a double bond, when E body and Z body can exist, both are included. Prodrugs of the compounds of the invention are within the scope of the 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 the specific compound is administered in vivo after being administered to a patient with a disease involving NPY Y5. Including compounds that convert to Conventional procedures for selection and formulation of suitable 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 an isotope of hydrogen, carbon or other 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 precursor of which the compound of formula (I) is appropriately halogen-substituted with tritium gas in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. May be included.
  • a suitable catalyst such as Pd / C
  • Suitable methods for preparing other tritium labeled compounds include Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below. (In the formula, each symbol has the same meaning as described above. Hal means halogen.)
  • the compound represented by the formula (III) is produced from the compound represented by the formula (II) via a diazonium salt.
  • the diazonium salt can be produced by reacting the compound represented by the formula (II) with NaNO 2 and HCl.
  • a reaction solvent water, a mixed solvent of water and alcohol (for example, methanol) can be used.
  • the diazonium salt can be reacted with a copper halide (for example, copper bromide, copper chloride, copper iodide, etc.) to produce a compound represented by the formula (III).
  • the reaction can be carried out at 0 ° C. to room temperature. It can also be heated to 40-60 ° C.
  • the compound represented by formula (I) is produced from the compound represented by formula (III).
  • the compound represented by the formula (I) can be produced by reacting a compound having a reactive amino group (—NH—) in the ring with the halogen of the compound represented by the formula (III).
  • the substituent on R 4 may be introduced prior to step 2 or after step 2.
  • As the reaction solvent acetonitrile, tetrahydrofuran, toluene, benzene, 2-propanol, etc.
  • the reaction can also be performed at room temperature. Moreover, you may heat suitably, seeing the progress of reaction. For example, it can be performed by heating to 100 to 120 ° C. in acetonitrile. It can be performed under microwave irradiation.
  • the compound represented by the formula (III) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (II) used in the above step 1 can be produced as follows. (In the formula, X is —SO 2 —, and other symbols are as defined above. Pro represents an amino-protecting group.)
  • the —S— group of the compound represented by the formula (IV) is oxidized to produce the compound represented by the formula (V).
  • the oxidizing agent mCPBA (metachloroperbenzoic acid), KMnO 4 (potassium permanganate), Oxone, NaIO 4 (sodium periodate), NaBO 3 (sodium perborate), hydrogen peroxide, etc. may be used. it can.
  • the reaction solvent dichloromethane, chloroform, acetonitrile, acetone, water and the like can be used. The reaction can be performed at room temperature, or may be appropriately heated while watching the progress of the reaction.
  • the amino protecting group of the compound represented by formula (IV) is removed to produce the compound represented by formula (II).
  • the amino protecting group a methoxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl and the like can be used. What is necessary is just to select deprotection conditions suitably according to a protecting group. For example, the protecting group may be eliminated under alkaline conditions.
  • the compound of formula (VI) is represented by the formula:
  • the compound represented by formula (VII) is produced by reacting the compound represented by formula (II) in the presence of a base and performing amidation.
  • a base As the reaction solvent, dichloromethane, dimethylformamide, tetrahydrofuran, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, acetonitrile and the like can be used.
  • the base triethylamine, pyridine, dimethylaminopyridine, N, N-diisopropylethylamine and the like can be used.
  • HATU (2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium) can be used as a condensing agent.
  • Step 6 the compound represented by the formula (VII) is cyclized to produce the compound represented by the formula (I).
  • the reaction can be carried out at 100 to 150 ° C. using acetic acid, hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, 10-camphorsulfonic acid and the like as the reaction solvent.
  • Steps 5 and 6 are shown as compounds having a group represented by the formula: —X—R 2 , but are similar to steps 5 and 6 using a compound having a group represented by —S—R 2.
  • the reaction may be carried out, followed by oxidation of -S-.
  • the substituent on R 4 may be introduced after Step 5 or 6 or may be introduced prior to Step 5.
  • the compound represented by the formula (VII) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (I) can also be produced by the following steps.
  • X is —SO 2 —, and other symbols have the same meanings as described above, and Hal means halogen.
  • Step 7 the compound represented by the formula (VIII) is reacted with a compound having a reactive amino group (—NH—) in the ring to produce a compound represented by the formula (IX).
  • This step can be performed according to step 2.
  • the reaction can be carried out in the presence of DIEA (N, N-diisopropylethylamine), triethylamine or the like.
  • the reaction can be performed at room temperature or by heating to 150 to 200 ° C.
  • As the reaction solvent IPA (isopropyl alcohol), dioxane, toluene, tetrahydrofuran, ethanol, 1-methylpyrrolidin-2-one, N, N-dimethylformamide and the like can be used.
  • Process 8 In this step, a compound represented by the formula (IX) is reacted with a compound represented by the formula: R 2 SH (wherein R 2 is as defined above) to produce a compound represented by the formula (X).
  • R 2 is as defined above
  • Pd 2 (dba) 3 tris (dibenzylideneacetone) dipalladium (0)
  • Pd (OAc) 2 palladium acetate
  • copper iodide Pd (PPh 3 ) 4 (tetrakistriphenylphosphine palladium, etc.
  • DIEA N, N-diisopropylethylamine
  • DOX dioxane
  • the reaction can be performed at room temperature or by heating to 100 to 120 ° C. This step can be performed under microwave irradiation.
  • R 2 SH wherein R 2 is as defined above
  • R 2 SSR 2 wherein R 2 is as defined above
  • R 2 SH (wherein R 2 is as defined above)
  • R 2 S ( ⁇ O) O—R for example, R is 2-
  • a compound having —S ( ⁇ O) — can be produced using a compound represented by (naphthylmethyl), and then oxidized to produce a compound represented by formula (I).
  • the base n-butyllithium, sec-butyllithium, or tert-butyllithium can be used.
  • —NH— of the condensed ring of the formula (IX) may be protected with an SEM group (2- (trimethylsilyl) ethoxymethyl group). The SEM group can be removed by heating in the presence of TBAF (tetrabutylammonium fluoride).
  • Step 9 the —S— group of the compound represented by the formula (X) is oxidized to produce the compound represented by the formula (I).
  • This step can be performed according to step 3.
  • the substituent on R 4 may be introduced after each of steps 7 to 9, or may be introduced prior to step 7.
  • the compound represented by the formula (X) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • Step 10 Suzuki reaction is performed on the compound represented by the formula (III) using Pd (PPh 3 ) 4 (tetrakis (triphenylphosphine) palladium) and CS 2 CO 3 (cesium carbonate) in the presence of RB (OH) 2. And a step for producing a compound represented by the formula (I).
  • Step 11 the compound represented by the formula (VI) is reacted with CDI (N, N′-carbodiimidazole) to produce the compound represented by the formula (XI).
  • CDI N, N′-carbodiimidazole
  • XI the compound represented by the formula (XI)
  • dimethylformamide, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, dichloromethane, toluene and the like can be used.
  • the reaction can be performed at room temperature, and may be appropriately heated.
  • Step 12 the compound represented by the formula (XI) is reacted with a halogenating agent to produce the compound represented by the formula (III).
  • a halogenating agent phosphorus oxychloride or the like can be used.
  • Step 13 the compound represented by the formula (XII) is reacted with the compound represented by the formula (XIII) to produce the compound represented by the formula (XIV).
  • This step can be performed in the presence of a base.
  • a base NaHMDS (sodium bis (trimethylsilyl) amide) or the like can be used.
  • the amount of the base 1.0 to 1.5 equivalents can be used with respect to the compound represented by (XIII).
  • As the reaction solvent tetrahydrofuran or the like can be used.
  • Step 14 the nitro group of the compound represented by the formula (XIV) is reduced to produce the compound represented by the formula (XV).
  • This step can be performed using a nitro group reduction reaction known in organic chemistry.
  • this step can be performed using Na 2 S 2 O 4 (sodium hydrosulfite) as a reducing agent.
  • Na 2 S 2 O 4 sodium hydrosulfite
  • the solvent methanol, ethanol, tetrahydrofuran, or a mixed solvent of these and water can be used.
  • the reaction can be carried out at room temperature or may be heated to 50-80 ° C.
  • Step 15 A step of producing a compound represented by the formula (XVI) by introducing a group represented by the formula: —C ( ⁇ O) —OR (wherein R is alkyl) into the amino group of the compound represented by the formula (XV). It is.
  • a compound represented by Hal—C ( ⁇ O) —OR can be used.
  • ethyl chlorocarbonate and ethyl chlorocarbonate can be used.
  • This step can be performed in the presence of a base.
  • pyridine, dimethylaminopyridine, triethylamine and the like can be used.
  • As the reaction solvent tetrahydrofuran, N, N-dimethylformamide and the like can be used. This step can be performed at room temperature or may be heated to 50 to 80 ° C.
  • Step 16 the compound represented by the formula (IX) is produced from the compound represented by the formula (XVI).
  • This step can be performed in the presence of TBAF (tetrabutylammonium fluoride). TBAF can be used in an amount of 2 to 3 equivalents based on the compound represented by the formula (XVI).
  • As the reaction solvent tetrahydrofuran, N, N-dimethylformamide and the like can be used.
  • This step can be performed at room temperature or may be heated to 50 to 80 ° C.
  • the compound represented by the formula (IX) thus obtained can be led to the compound represented by the formula (I) through steps 8 and 9. Therefore, the compound represented by the formula (IX) is useful as a synthetic intermediate for the compound represented by the formula (I).
  • the compound represented by the formula (I) thus obtained can be purified by crystallization in various solvents.
  • Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N— Examples thereof include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.
  • the compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndrome. Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP3A4, etc.
  • CYP1A2, CYP2C9, CYP3A4, etc. The inhibitory action against CYP enzymes is weak.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • Low toxicity such as anemia-inducing action.
  • High metabolic stability e. High water solubility.
  • g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention is particularly excellent in the point b).
  • the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and has high Y5 receptor selectivity.
  • NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient.
  • the pharmaceutical composition to be used can be suitably used as a safe medicine.
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.
  • Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • parenteral administration any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipients such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipients include lactose, sucrose, glucose, starch, calcium carbonate, and crystalline cellulose.
  • binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone.
  • disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
  • lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used.
  • solubilizers when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (agents that can be used for weight management in obesity and obesity).
  • agents that can be used for weight management in obesity and obesity agents that can be used for weight management in obesity and obesity.
  • a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like.
  • the pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can.
  • the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.
  • Pancreatic lipase inhibitor Orlistat, cetiristat.
  • Gastrointestinal function regulator 6-chloro-2-phenyl-8,8a-dihydro-indenol [1,2-d] thiazol-3a-ol.
  • Serotonin 2C agonist lorcaserine hydrochloride.
  • Carboxypeptidase inhibitor Formula: A compound represented by GPR119 agonist: Formula: A compound represented by Cannabinoid CB1 receptor antagonist: rimonabant hydrochloride.
  • Neurokinin NK3 receptor antagonist rimonabant hydrochloride.
  • Monoamine uptake inhibitor sibutramine hydrochloride.
  • Selective antagonist of melanin-concentrating hormone MCH receptor (SLC-1): Formula: A compound represented by Stearoyl coenzyme A desaturase-1 inhibitor: Formula: A compound represented by Noradrenaline and dopamine reuptake inhibitors: Tesofensin.
  • a combination of bupropion, a noradrenaline and dopamine reuptake inhibitor, and naltrexone, an opioid receptor antagonist, a combination of fentamine, which has an NE secretion-promoting action, and topiramate, a GABA agonist also contain compounds having an anti-obesity effect Exemplified as a pharmaceutical composition.
  • Tetrahydrofuran (1.5 ml) and a 1 mol / L tetrahydrofuran solution (2.25 ml, 2.25 mmol) of tetrabutylammonium fluoride were added to the resulting residue, and the mixture was slightly stirred at 60 ° C. for 4 hours.
  • the solvent was distilled off under reduced pressure, ethyl acetate was added, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 15 (106.7 mg, yield 40.8%).
  • Second step Compound 25 (969 mg, 5.44 mmol) obtained in the first step was dissolved in THF (5 ml), cooled to 0 ° C., triethylamine (0.904 ml, 6.52 mmol) and mesyl chloride (0.508 ml, 6.52 mmol) were added. The reaction was carried out at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off.
  • N, N-dimethylformamide (5 ml) was added to the resulting residue, and then sodium cyanide (400 mg, 8.16 mmol) and tetrabutylammonium iodide (201 mg, 0.554 mmol) were added.
  • the mixture was reacted at 100 ° C. for 8 hours and cooled to room temperature. Water was added and extracted with ethyl acetate, and the organic layer was washed with water. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain the title compound 26 (346 mg, yield 34%).
  • Example 8 Synthesis of Compound (I-15) First Step N, N-dimethylformamide (5.0 ml), triethylamine (0.570 ml, 4.11 mmol) and 6-chloronicotinic acid (5.0 ml) were added to 4- (propylthio) benzene-1,2-diamine 19 (500 mg, 2.74 mmol) under a nitrogen stream. 432 mg, 2.74 mmol) was added. HATU (1252 mg, 3.29 mmol) was added under ice cooling, and the mixture was vigorously stirred for 1 hour with ice cooling.
  • Example 10 Synthesis of Compound (I-43) Dimethyl sulfoxide (0.4 ml) and acetonitrile (0.4 ml) were added to compound I-9 (8.8 mg, 0.023 mmol) under a nitrogen stream. Selectflour (9.51 mg, 0.026 mmol) was added under ice-cooling, and the mixture was slightly stirred for 1 hour with ice-cooling. Thereafter, the mixture was slightly stirred at room temperature for 1 hour and further stirred at 50 ° C. for 1 hour. Selectflour (9.51 mg, 0.026 mmol, further 19.02 mg, 0.052 mmol) was added, and the reaction was performed at 50 ° C.
  • Example 13 Synthesis of Compound (I-58) First Step Dichloromethane (50 ml) was added to albendazole 53 (5 g, 18.8 mmol), then mCPBA (10.4 ml, 96.0 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes with ice cooling. The reaction solution was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. The solid precipitated at this time was collected by filtration and dried to obtain a sulfone compound.
  • Example 14 Synthesis of Compound (I-59,75) First Step After 2-propanol (15 ml) was added to chloride 57 (3.0 g, 13.0 mmol), 2-phenylmorpholine hydrochloride (2.59 g, 13.0 mmol) and diisopropylethylamine (4.50 ml, 26.0 mmol) were added under ice cooling. added. Microwave was irradiated for 30 minutes under the condition of 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain Compound 58 quantitatively.
  • Second step After adding 1,4-dioxane (10 ml) to compound 58 (1.0 g, 2.79 mmol) obtained in the first step, diisopropylethylamine (1.46 ml, 8.37 mmol), Pd2 (dba) 3 (256 mg, 0.279 mmol), Xantphos (323 mg, 0.558 mmol) and ethanethiol (0.204 ml, 2.79 mmol) were added. Microwave was irradiated for 1 hour at 150 ° C. Thereafter, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate.
  • Example 16 Synthesis of Compound (I-63) After adding 1,4-dioxane (2 ml) and water (0.2 ml) to compound 55 (70 mg, 0.231 mmol), boronic acid (17.6 mg, 0.231 mmol), cesium carbonate (113 mg, 8.37 mmol) and Pd (PPh3) 4 (256 mg, 0.279 mmol) was added. Microwave was irradiated for 20 minutes at 180 ° C. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 64 (60 mg, yield 68%).
  • Example 18 Synthesis of Compound (I-68) First Step NMP (0.25 ml), 2-propanol (0.5 ml) and amine 68 (65 mg, 0, 247 mmol) were added to compound 55 (75 mg, 0.247 mmol) and reacted at 180 ° C. for 1 hour under microwave irradiation. The reaction solution was poured into a 10% aqueous citric acid solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography to obtain an amine adduct (79 mg).
  • Example 19 Synthesis of Compound 72 (I-71) First Step Diamine 5 (1 g, 4.16 mmol) was dissolved in N, N-dimethylformamide (10 ml) and carbonyldiimidazole (743 mg, 4.58 mmol) was added. After reacting overnight at room temperature, the reaction solution was poured into a 2 mol / L aqueous hydrochloric acid solution. After extraction with ethyl acetate, the extract was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the target compound 70 (897 mg, 81% yield).
  • Example 20 Synthesis of Compound (I-72) First Step Reaction was carried out in the same manner as in Step 1 of Example Compound I-2 to give compound 73.
  • Example 23 Synthesis of Compound 86 (I-78) First Step
  • the target product 82 (yield 93.3%) was obtained by the same reaction as in the first step of Example compound (I-1).
  • Second step The target product 83 (yield 93%) was obtained by the same reaction as in the second step of Example compound (I-1).
  • Third step The target compound 84 (79%) was obtained by the same reaction as in the first step of Example compound (I-73).
  • Example 24 Synthesis of Compound (I-76) First Step Compound 84 (22 mg, 0.06 mmol) obtained in the third step of Example compound (I-78) was added to Pd2 (dba) 3 (22 mg, 0.06 mmol), Ru-phos (1.8 mg, 0.0006 mmol), t -Butoxy sodium (17.3 mg, 0.18 mmol) was added with dioxane and amine hydrochloride (10 mg, 0.066 mmol) and reacted under microwave irradiation at 100 ° C. for 30 minutes, 120 ° C. for 30 minutes, and further at 140 ° C. for 30 minutes. .
  • the target product 87 (12.1 mg, 45% yield) was obtained by distilling off the solvent and purifying by column chromatography.
  • Example 25 Synthesis of Compound (I-79) First Step The target compound 89 (44% yield) was obtained by the same reaction as in the 1st and 2nd steps of Example compound (I-74). LCMS; 479.90 (M + H)
  • Example 26 Synthesis of Compound (I-80) First Step After sulfonyl chloride 90 (7 g, 27.3 mmol) was dissolved in THF (70 ml), morpholine (7.14 ml, 82 mmol) was added and stirred at room temperature for 20 minutes. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by column chromatography to give compound 91 (3.72 g, yield 44%).
  • Second step Compound 91 (3.6 g, 11.8 mmol) obtained in the first step was dissolved in acetonitrile (36 ml), and triethylamine (1.96 ml, 14.1 mmol) and benzylamine (2.13 ml, 14.12 mmol) were added. Stir for hours.
  • Examples of combinations of Y 1 , Y 2 , Y 3 , and Z in the compounds of the present invention include the combinations described in Tables 22 and 23 below.
  • R 2 and X in the compounds of the present invention include the combinations described in Tables 24 and 25 below.
  • R 4 in the compound of the present invention examples include the examples described in Table 26 below.
  • (VI) to (XVIII) mean the same groups as those corresponding to R 4 of the compounds represented by formulas (VI) to (XVIII).
  • R 5 in the compound of the present invention examples include combinations described in Table 27 below.
  • R 11 in the compound of the present invention examples include combinations described in Table 28 below.
  • R 12 in the compound of the present invention examples include the combinations described in Table 29 below.
  • Test Example 1 Affinity for Mouse NPY Y5 Receptor
  • a cDNA sequence encoding the mouse NPY Y5 receptor was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol., 8, 466-472).
  • the obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
  • Membrane preparations prepared from CHO cells expressing mouse NPY Y5 receptor were assay buffer together with the compounds of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare).
  • the solution was incubated in a solution (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter.
  • Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)]. The results are shown in Table 30.
  • the compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.
  • Test Example 2 Affinity for human NPY Y5 receptor
  • a cDNA sequence encoding human NPY Y5 receptor was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloning into The obtained expression vector is transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
  • Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare).
  • 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. For example, Compound I-82 had a brain Kp: 0.49.
  • Test Example 4 Evaluation of transferability to mouse brain Oral administration to mice (Jcl; C57BL / 6J, ⁇ , 8weeks) using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) 2 mg / 10 mL / kg) From the plasma and brain concentrations after 3 or 5 hours, the brain transferability (brain / plasma partition coefficient; Kp) can be evaluated.
  • Test Example 5 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was 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 such as high bioavailability and appropriate clearance.
  • Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound according to the present invention was added and incubated for 5 minutes, after which 50 nMNPY and 10 ⁇ M forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC 50 value) of the compound according to the present invention for this NPY action was determined.
  • SIGMA isobutylmethylxanthine
  • Test Example 7 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) membrane preparation and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane preparation were used. The test is performed in the same manner, and the affinity of the compound of the present invention for the NPY Y1 receptor and NPY Y2 receptor is measured. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.
  • Test Example 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the outer occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 25-30 g) to expose the upper skull . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side.
  • a 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and NPY Y5 receptor-specific agonist 1 hour after administration ([CPP 1-7 , NPY 19-23 , Ala 31 , Aib 32 , Gln 34 ] -hPanalytic Polypeptide: manufactured by Tocris Co.) 0.1 nmol was injected from the head opening previously provided using a cannula.
  • the food intake of the mice 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 was administered at a dose of 25 mg / kg, the amount of food intake was significantly suppressed as compared with the case where 0.5% hydroxypropylmethylcellulose was administered.
  • the food intake after 2 hours and 4 hours after injection was 0.28 ⁇ 0.04 g and 0.45 ⁇ 0.09 g, respectively. .
  • the amount of food intake 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.63 ⁇ 0.06 g and 1.22 ⁇ 0.08 g, respectively.
  • the amount of food consumed in the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) in which no NPY Y5 receptor-specific agonist was injected was 0.10 ⁇ 0.07 g, 0.17 ⁇ 0.06 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding suppression rates for the B group 2 hours and 4 hours after the injection in the A group are 65.9% and 74.2%, respectively.
  • Test Example 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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.
  • 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 are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet Compound (I) 15 mg Starch 15mg Lactose 15mg Crystalline cellulose 19mg Polyvinyl alcohol 3mg 30ml distilled water Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 3 Granules Compound (I) 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

Abstract

La présente invention a pour but de trouver un nouveau composé ayant un antagonisme pour le récepteur NPY Y5. Il a été observé qu'un composé représenté par la formule (I) présente un antagonisme pour le récepteur NPY Y5. (I) (Dans la formule, X représente -SO2- ou similaire ; Y1 représente =C(-R8)- ou similaire ; Y2 représente -C(-R3)= ou similaire ; Y3 représente =C(-R1)- ou similaire ; Z représente -N= ou similaire ; R1, R3, R8, R9, R11 et R12 représentent chacun indépendamment hydrogène ou similaire ; R2 représente un groupe alkyle substitué ou non substitué ou similaire ; R4 représente un groupe aryle substitué ou non substitué ou similaire ; et R5 représente un groupe aryle substitué ou non substitué ou similaire ; et n représente 1 ou similaire).
PCT/JP2011/068032 2010-08-10 2011-08-08 Dérivé hétérocyclique présentant un antagonisme pour le récepteur npy y5 WO2012020725A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN106800538A (zh) * 2015-12-03 2017-06-06 四川省人民医院 一种苯并咪唑衍生物及其合成方法
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CN106798740A (zh) * 2015-12-03 2017-06-06 四川省人民医院 一种用于治疗细菌感染的药物
JP2020530005A (ja) * 2017-07-31 2020-10-15 ワシントン・ユニバーシティＷａｓｈｉｎｇｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ Ｂリンパ球活性の調節及び臓器保護のためのピルフェニドン誘導体
US11208407B2 (en) * 2017-08-02 2021-12-28 Merck Sharp & Dohme Corp. Substituted phenyl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
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Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53105529A (en) * 1977-02-22 1978-09-13 Ciba Geigy Ag Novel phenyllbenzimidazolyleefuran
JP2003520273A (ja) * 2000-01-18 2003-07-02 アゴウロン・ファーマスーティカルス・インコーポレーテッド インダゾール化合物、医薬組成物及び細胞増殖を誘発又は阻害する方法
JP2005509633A (ja) * 2001-10-26 2005-04-14 アベンティス・ファーマスーティカルズ・インコーポレイテツド ベンゾイミダゾールおよび類縁体および蛋白キナーゼ阻害剤としてのその使用
WO2005080348A1 (fr) * 2004-02-19 2005-09-01 Banyu Pharmaceutical Co., Ltd. Nouveau dérivé de sulfonamide
JP2005530763A (ja) * 2002-05-13 2005-10-13 アイシーエージェン，インコーポレイティド カリウム・チャネル調節物質としてのビス−ベンズイミダゾール及び関連化合物
WO2006112479A1 (fr) * 2005-04-19 2006-10-26 Kyowa Hakko Kogyo Co., Ltd. Composé hétérocyclique azoté
JP2007511596A (ja) * 2003-11-17 2007-05-10 ファイザー・プロダクツ・インク 癌の治療において有用なピロロピリミジン化合物
JP2007534671A (ja) * 2004-03-02 2007-11-29 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ４−ベンゾイミダゾール−２−イル−ピリダジン−３−オン−誘導体、その製造および医薬におけるその使用
WO2008047831A1 (fr) * 2006-10-17 2008-04-24 Kyowa Hakko Kirin Co., Ltd. Inhibiteurs de JAK
JP2008525417A (ja) * 2004-12-24 2008-07-17 プロシディオン・リミテッド Ｇタンパク質結合受容体作動薬
JP2009507039A (ja) * 2005-09-01 2009-02-19 武田薬品工業株式会社 イミダゾピリジン化合物
WO2009024287A2 (fr) * 2007-08-23 2009-02-26 Sanofi-Aventis Dérivés d'azoloarine, leurs procédés de production, produits pharmaceutiques contenant ces composés et utilisations de ces produits
WO2009039134A1 (fr) * 2007-09-17 2009-03-26 Abbott Laboratories Agents anti-infectieux et leurs utilisations
WO2009039127A1 (fr) * 2007-09-17 2009-03-26 Abbott Laboratories Dérivé d'uracile ou de thymine pour le traitement de l'hépatite c
JP2009516649A (ja) * 2005-10-31 2009-04-23 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害薬
WO2009100130A1 (fr) * 2008-02-04 2009-08-13 Mercury Therapeutics, Inc. Modulateurs de l'ampk
JP2009530381A (ja) * 2006-03-23 2009-08-27 メルク エンド カムパニー インコーポレーテッド グルカゴン受容体アンタゴニスト化合物、この化合物を含む組成物及び使用方法
WO2009129625A1 (fr) * 2008-04-22 2009-10-29 Merck Frosst Canada Ltd. Nouveaux composés hétéroaromatiques substitués en tant qu’inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
JP2010514675A (ja) * 2006-12-21 2010-05-06 アステックス、セラピューティックス、リミテッド プロテインキナーゼ阻害活性を有する置換ピペリジン
JP2010520201A (ja) * 2007-03-02 2010-06-10 シェーリング コーポレイション ベンズイミダゾール誘導体およびその使用方法

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53105529A (en) * 1977-02-22 1978-09-13 Ciba Geigy Ag Novel phenyllbenzimidazolyleefuran
JP2003520273A (ja) * 2000-01-18 2003-07-02 アゴウロン・ファーマスーティカルス・インコーポレーテッド インダゾール化合物、医薬組成物及び細胞増殖を誘発又は阻害する方法
JP2005509633A (ja) * 2001-10-26 2005-04-14 アベンティス・ファーマスーティカルズ・インコーポレイテツド ベンゾイミダゾールおよび類縁体および蛋白キナーゼ阻害剤としてのその使用
JP2005530763A (ja) * 2002-05-13 2005-10-13 アイシーエージェン，インコーポレイティド カリウム・チャネル調節物質としてのビス−ベンズイミダゾール及び関連化合物
JP2007511596A (ja) * 2003-11-17 2007-05-10 ファイザー・プロダクツ・インク 癌の治療において有用なピロロピリミジン化合物
WO2005080348A1 (fr) * 2004-02-19 2005-09-01 Banyu Pharmaceutical Co., Ltd. Nouveau dérivé de sulfonamide
JP2007534671A (ja) * 2004-03-02 2007-11-29 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ４−ベンゾイミダゾール−２−イル−ピリダジン−３−オン−誘導体、その製造および医薬におけるその使用
JP2008525417A (ja) * 2004-12-24 2008-07-17 プロシディオン・リミテッド Ｇタンパク質結合受容体作動薬
WO2006112479A1 (fr) * 2005-04-19 2006-10-26 Kyowa Hakko Kogyo Co., Ltd. Composé hétérocyclique azoté
JP2009507039A (ja) * 2005-09-01 2009-02-19 武田薬品工業株式会社 イミダゾピリジン化合物
JP2009516649A (ja) * 2005-10-31 2009-04-23 メルク エンド カムパニー インコーポレーテッド Ｃｅｔｐ阻害薬
JP2009530381A (ja) * 2006-03-23 2009-08-27 メルク エンド カムパニー インコーポレーテッド グルカゴン受容体アンタゴニスト化合物、この化合物を含む組成物及び使用方法
WO2008047831A1 (fr) * 2006-10-17 2008-04-24 Kyowa Hakko Kirin Co., Ltd. Inhibiteurs de JAK
JP2010514675A (ja) * 2006-12-21 2010-05-06 アステックス、セラピューティックス、リミテッド プロテインキナーゼ阻害活性を有する置換ピペリジン
JP2010520201A (ja) * 2007-03-02 2010-06-10 シェーリング コーポレイション ベンズイミダゾール誘導体およびその使用方法
WO2009024287A2 (fr) * 2007-08-23 2009-02-26 Sanofi-Aventis Dérivés d'azoloarine, leurs procédés de production, produits pharmaceutiques contenant ces composés et utilisations de ces produits
WO2009039134A1 (fr) * 2007-09-17 2009-03-26 Abbott Laboratories Agents anti-infectieux et leurs utilisations
WO2009039127A1 (fr) * 2007-09-17 2009-03-26 Abbott Laboratories Dérivé d'uracile ou de thymine pour le traitement de l'hépatite c
WO2009100130A1 (fr) * 2008-02-04 2009-08-13 Mercury Therapeutics, Inc. Modulateurs de l'ampk
WO2009129625A1 (fr) * 2008-04-22 2009-10-29 Merck Frosst Canada Ltd. Nouveaux composés hétéroaromatiques substitués en tant qu’inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106800538A (zh) * 2015-12-03 2017-06-06 四川省人民医院 一种苯并咪唑衍生物及其合成方法
CN106798739A (zh) * 2015-12-03 2017-06-06 四川省人民医院 一种用于***疾病的药物
CN106798740A (zh) * 2015-12-03 2017-06-06 四川省人民医院 一种用于治疗细菌感染的药物
CN106798740B (zh) * 2015-12-03 2020-05-19 四川省人民医院 一种用于治疗细菌感染的药物
CN106798739B (zh) * 2015-12-03 2020-05-19 四川省人民医院 一种用于***疾病的药物
JP2020530005A (ja) * 2017-07-31 2020-10-15 ワシントン・ユニバーシティＷａｓｈｉｎｇｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ Ｂリンパ球活性の調節及び臓器保護のためのピルフェニドン誘導体
EP3661506A4 (fr) * 2017-07-31 2021-04-21 Washington University Dérivés de la pirfénidone pour la modulation de l'activité des lymphocytes b et la protection des organes
JP7360171B2 (ja) 2017-07-31 2023-10-12 ワシントン・ユニバーシティ Ｂリンパ球活性の調節及び臓器保護のためのピルフェニドン誘導体
US11208407B2 (en) * 2017-08-02 2021-12-28 Merck Sharp & Dohme Corp. Substituted phenyl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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