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WO2012070114A1 - Dérivé sulfamide ayant un antagonisme du récepteur npy y5 - Google Patents

Dérivé sulfamide ayant un antagonisme du récepteur npy y5 Download PDF

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Publication number
WO2012070114A1
WO2012070114A1 PCT/JP2010/070876 JP2010070876W WO2012070114A1 WO 2012070114 A1 WO2012070114 A1 WO 2012070114A1 JP 2010070876 W JP2010070876 W JP 2010070876W WO 2012070114 A1 WO2012070114 A1 WO 2012070114A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
aromatic heterocycle
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Japanese (ja)
Inventor
隆行 奥野
直樹 神山
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to PCT/JP2010/070876 priority Critical patent/WO2012070114A1/fr
Publication of WO2012070114A1 publication Critical patent/WO2012070114A1/fr
Anticipated expiration legal-status Critical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • 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
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Definitions

  • the present invention relates to a novel sulfamide derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.
  • 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.
  • NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress 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.
  • central nervous system diseases such as Alzheimer's dementia and Parkinson's disease.
  • NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders.
  • metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action may be a prophylactic or therapeutic agent for various diseases involving the NPY receptor as described above.
  • Non-Patent Document 2 subtypes of Y1, Y2, Y3, Y4, Y5 and Y6 have been discovered so far (see Non-Patent Document 2).
  • 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 3 to 5).
  • Patent Document 1 describes a benzimidazole derivative and an imidazopyridine derivative having a sulfonyl group having an NPY Y5 receptor antagonistic action. Further, amine derivatives having a sulfonyl group having an NPY Y5 receptor antagonistic action are described in Patent Documents 2, 3 and the like. In addition, Patent Documents 4 and 5 describe that amide derivatives having a sulfonyl group have NPY Y5 antagonistic activity. Patent Document 14 describes that a pyrazole derivative has NPY Y5 antagonistic activity. These compounds differ in structure from the compounds of the present invention. Further, a compound having a structure different from that of the compound of the present invention but having NPY Y5 antagonistic activity is disclosed in Patent Document 6 and the like.
  • An object of the present invention is to provide a novel sulfamide 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 body weight suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, X is an aromatic hetero
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, R 1 and R 2 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R 1 and R 5 together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, X is an aromatic heterocycle or a non-aromatic heterocycle,
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, (2) (5) The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is hydrogen or substituted or unsubstituted alkyl;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, its pharmaceutical Top acceptable salts or solvates thereof.
  • R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, The pharmaceutically acceptable salt or solvate thereof.
  • R 3 is each independently substituted or unsubstituted phenyl.
  • Treatment of a disease involving NPY Y5, comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof, or Prevention method.
  • (16) The use of the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5. use.
  • the pharmaceutical composition according to the above (13) which is a medicament for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.
  • Obesity-related diseases include bulimia, hypertension, impaired glucose tolerance, diabetes, metabolic syndrome, lipid metabolism abnormality, arteriosclerosis, hyperuricemia, gout, fatty liver, proteinuria, endometrial cancer, breast cancer, prostate (18)
  • Prevention or treatment of obesity or obesity-related diseases comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a method for treating or preventing a disease involving NPY Y5, which is used for weight management in obesity comprising administering a drug used for management.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic activity, and is associated with drugs, especially 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 or sleep disorder.
  • drugs especially NPY Y5 receptor antagonistic activity, and is associated with drugs, especially 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 or sleep disorder.
  • 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 treating or preventing diseases in which obesity is a risk factor, such as diabetes,
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
  • Alkyl means a linear 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.
  • Alkenyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at an arbitrary 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 linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • Cycloalkenyl means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic or polycyclic aromatic carbocyclic group.
  • phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
  • a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included.
  • indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.
  • “Aromatic heterocycle” means an aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic aromatic heterocycles. “Monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene.
  • a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
  • the “polycyclic aromatic heterocycle” refers to the above “monocyclic aromatic heterocycle”, an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (the above “cycloalkane”).
  • a ring derived from “alkyl” or a ring fused with a cycloalkene (ring derived from “cycloalkenyl” above).
  • the “nitrogen-containing aromatic heterocycle” means a monocyclic or polycyclic aromatic heterocycle having at least one nitrogen atom in the ring.
  • Examples of the “monocyclic nitrogen-containing aromatic heterocycle” include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, and thiazole. , Thiadiazole and the like.
  • Examples of the ⁇ polycyclic nitrogen-containing aromatic heterocycle '' include, for example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benziso
  • Two-ring nitrogen-containing compounds such as oxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine
  • Aromatic heterocycles 3-ring nitrogen-containing aromatic heterocycles such as carbazole, acridine, phenothiazine, phenoxazine and the like
  • Heteroaryl means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • the group includes a group derived from the above “monocyclic aromatic heterocycle” and a group derived from the above “polycyclic aromatic heterocycle”.
  • Examples of the ⁇ monocyclic aromatic heterocyclic group '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, Thienyl and the like can be mentioned.
  • polycyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl , Benzoxazolyl, benzoxiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra Bicyclic aromatic heterocyclic groups such as dinopyridazinyl, oxazolopyridyl, thiazolopy
  • Non-aromatic heterocycle means a non-aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic non-aromatic heterocycles. “Monocyclic non-aromatic heterocycle” means a 4- to 8-membered monocyclic non-aromatic ring having one or more hetero atoms arbitrarily selected from O, S and N in the ring.
  • Examples include thiazole, oxazolidine, thiazolidine and the like. In particular, a 5-membered or 6-membered monocyclic non-aromatic heterocycle is preferable.
  • Polycyclic non-aromatic heterocycle refers to the above “monocyclic non-aromatic heterocycle”, aromatic carbocycle (ring derived from the above “aryl”), aromatic heterocycle, monocyclic A non-aromatic heterocycle, a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed.
  • aromatic carbocycle ring derived from the above “aryl”
  • aromatic heterocycle monocyclic
  • a cycloalkane ring derived from the above “cycloalkyl”
  • a cycloalkene ring derived from the “cycloalkenyl
  • the “nitrogen-containing non-aromatic heterocycle” means a monocyclic or polycyclic non-aromatic heterocycle having at least one nitrogen atom in the ring.
  • Monocyclic nitrogen-containing non-aromatic heterocycle '' includes, for example, azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrothiazole, tetrahydro Examples include isothiazole, oxazolidine, thiazolidine and the like.
  • Examples of the “polycyclic nitrogen-containing non-aromatic heterocycle” include indoline, isoindoline, dihydrobenzothiadiazole and the like.
  • Heterocyclyl means a non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring.
  • a monocyclic non-aromatic heterocyclic group (a group derived from the above “monocyclic non-aromatic heterocyclic ring”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic heterocyclic group”); Group derived from “aromatic heterocycle”.
  • ⁇ 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. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
  • Alkoxy means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.
  • Haloalkyl and haloalkoxy mean a group in which the “halogen” is bonded to the “alkyl” and “alkoxy”.
  • Aryloxy means a group in which the above “aryl” is bonded to an oxygen atom. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy, indanyloxy, indenyloxy, biphenylyloxy, acenaphthyloxy, tetrahydronaphthyloxy, fluorenyloxy and the like.
  • alkenyloxy means a group bonded to an oxygen atom.
  • Alkylthio “alkenylthio”, “cycloalkylthio”, “cycloalkenylthio”, “arylthio”, “heteroarylthio” and “heterocyclylthio” are the above-mentioned “alkyl”, “alkenyl”, “cycloalkyl” ”,“ Cycloalkenyl ”,“ aryl ”,“ heteroaryl ”and“ heterocyclyl ”mean a group bonded to a sulfur atom.
  • Alkoxycarbonyl means a group in which the oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group .
  • Alkylcarbonyl “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl” and “heterocyclylcarbonyl” are the above “alkyl”, “alkenyl”.
  • Cycloalkyl “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a carbonyl group.
  • Alkylsulfonyl “alkenylsulfonyl”, “cycloalkylsulfonyl”, “cycloalkenylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl” and “heterocyclylsulfonyl” are the above “alkyl”, “alkenyl”.
  • Cycloalkyl “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.
  • the bond of the divalent group may be bonded to the same or different atom.
  • the divalent group may be bonded so as to form a bicyclo ring or a spiro ring as well as a case where the bond of the divalent group is bonded to an adjacent atom. Any position may be substituted with one or more groups selected from these.
  • substituted or unsubstituted cycloalkyl eg, cyclohexyl
  • alkylene eg, —CH 2 —CH 2 —
  • substituent of “substituted or unsubstituted aryl” is a group represented by the formula: —N (R 7 )-(alkylene) -O—, the following groups are exemplified.
  • substituent is another divalent group, it may be substituted in the same manner as described above.
  • “Acyl” means (1) a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, (2) cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms and (3) arylcarbonyl having 7 to 11 carbon atoms are included.
  • Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
  • acyloxy means a group in which the above “acyl” is bonded to an oxygen atom.
  • the compounds of the present invention all have NPY Y5 receptor antagonistic action, but particularly preferred compounds include the following compounds in the formula (I).
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or A compound that is unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
  • R 1 and R 2 are each independently hydrogen; alkyl; alkyl substituted with halogen or cyano; alkoxy;
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • R 1 is hydrogen or substituted or unsubstituted alkyl; A compound wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • R 1 is hydrogen; alkyl; or alkyl substituted with cyano; A compound wherein R 2 is alkyl; alkyl substituted with halogen or cyano; alkoxy; cycloalkyl; aryl.
  • a compound in which R 1 and R 2 together with the adjacent nitrogen atom form piperidine, oxo substituted oxazolidine or morpholine.
  • R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxaziny
  • R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or substituted or unsubstituted indazolyl (each substituted group is halogen, cyano, nitro, nitroso, azide, oxo
  • R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl (the substituents are each selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy and haloalkoxy A compound which is the above group).
  • a compound in which R 3 is substituted or unsubstituted phenyl or pyridyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).
  • R 3 is substituted or unsubstituted phenyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).
  • R 4 is halogen, cyano, nitro, nitroso, azide, oxo, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy, Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or un
  • R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryloxy.
  • R 4 is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy (the substituents are halogen, cyano, nitro, Nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, mercapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, And one or more groups selected from sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl and
  • R 4 is halogen, cyano or substituted or unsubstituted alkyl.
  • R 4 is halogen, cyano, or substituted or unsubstituted alkyl (the substituents are one or more groups selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, and haloalkoxy, respectively) Compound).
  • R 4 is halogen, cyano, or alkyl.
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • a compound wherein R 5 is hydrogen or alkyl having 1 to 3 carbon atoms.
  • a compound wherein R 5 is hydrogen.
  • a compound wherein m is 1 or 2.
  • a compound wherein m is 1.
  • a compound wherein n is 0-2.
  • a compound wherein n is 0 or 1.
  • R is halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • p is an integer of 0-2.
  • a compound wherein X is an aromatic heterocycle or a non-aromatic heterocycle.
  • a compound in which X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole.
  • a compound wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrazole, pyrrole or benzimidazole.
  • a compound wherein X is pyrazole.
  • a compound in which X is a group selected from the following. (The bond from cyclohexane, (R 3 ) m, and (R 4 ) n may be bonded to any substitutable atom on the ring.)
  • a group represented by (X ′ is an aromatic heterocycle or non-aromatic heterocycle having a bond to the cyclohexane ring adjacent to the nitrogen atom in the ring.) The compound which is group shown by these.
  • the compound represented by the formula (I) is formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) And / or the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) Means a compound represented by Particularly preferably, formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) It is a compound shown by these.
  • the compound of the present invention is capable of producing each compound and includes pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.
  • the compound of the present invention includes its solvate.
  • Preferable examples include hydrates and alcohol hydrates.
  • the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when E body and Z body may exist, both are included.
  • the prodrug of the compound of the present invention is included in the scope of the compound of the present invention.
  • Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the “compound” of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but is administered to a patient with a disease involving NPY Y5 in vivo. Including compounds that convert to The usual procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs ed (ed. H. Bundgaard, Elsevier, 1985).
  • the compound represented by formula (I) which is the compound of the present invention can be synthesized, for example, by the following method.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSO 2 Hal to obtain a compound represented by formula (I).
  • the compound represented by the formula (III-2) is reacted with a compound represented by the formula: R 5 Hal to obtain a compound represented by the formula (I).
  • the above reaction can be performed using a base.
  • pyridine triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
  • the above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
  • the above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
  • the compound of the present invention can be synthesized as follows. (In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)
  • Compound (III-1) is reacted with a compound represented by the formula: R 1 (R 2 ) NSOHal to obtain compound (III-3). Further, the obtained compound (III-3) is oxidized to obtain a compound represented by the formula (I).
  • the step of using the compound represented by the formula: R 1 (R 2 ) NSOHal can be performed in the presence of a base.
  • a base pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • the above reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof.
  • the oxidation step can be performed using an oxidizing agent.
  • oxidizing agent examples include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.
  • the above reaction may be carried out while protecting R 3 and R 4 on X, and may be deprotected after the reaction.
  • the compound (X-4), which is an intermediate of the compound of the present invention can be synthesized using the synthesis method shown below.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Process A The compound (X-1) having the substituent R 5 corresponding to the target compound and the compound represented by the formula: R 1 (R 2 ) NSO 2 Hal are treated with a base in an appropriate solvent to give the compound (X-2) Get.
  • the reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof
  • a solvent or the like can be used.
  • it is dichloromethane.
  • These solvents may be appropriately selected and used in combination with a base.
  • triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-1).
  • Process B Compound (X-2) is treated with a base in a suitable solvent to give compound (X-3). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
  • tetrahydrofuran dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Tetrahydrofuran and / or ethanol are preferred. These solvents may be appropriately selected and used in combination with a base.
  • Process C Compound (X-3) is treated with a halogenating agent in a suitable solvent and reacted at 0 ° C. to 50 ° C.
  • halogenating agent examples include oxalyl chloride, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxychloride and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a halogenating agent relative to compound (X-3). Further, dimethylformamide may be added as a catalyst.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a halogenating agent.
  • an active ester may be obtained instead of the acid halide using acetic anhydride, methanesulfonyl chloride, or ethyl chlorocarbonate, and used in the next step D.
  • Process D The acid halide or active ester obtained in Step C and ethyl acetate are reacted in a suitable solvent in the presence of Lewis acid and N-alkylimidazole at ⁇ 100 ° C. to 0 ° C. for several minutes to several hours. Addition yields compound (X-4).
  • titanium tetrachloride As the Lewis acid, titanium tetrachloride, tin tetrachloride, aluminum trichloride, boron trifluoride ether complex, boron trichloride, trimethylsilyl trifluoromethanesulfonate (TMSOTf), zinc dichloride, or the like can be used. Titanium tetrachloride is preferable.
  • N-alkylimidazole N-methylimidazole, N-ethylimidazole and the like can be used. N-methylimidazole is preferable.
  • N, N′-diisopropylethylamine, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • N, N′-diisopropylethylamine is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preference is given to methylene chloride and / or ethyl acetate. These solvents may be appropriately selected and used in combination with a base.
  • the compound of the present invention can be synthesized from compound (X-4) using the synthesis method shown below.
  • Hal is halogen
  • R 6 is a group derivable to R 3 , R 4 or R 3 or R 4.
  • Each other symbol has the same meaning as each symbol in the compound represented by the formula (I). .
  • Process E Compound (X-4) is reacted with hydrazine (eg, hydrazine monohydrate) in a suitable solvent to give compound (X-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
  • a compound represented by the formula: NH 2 NHR 6 can also be used.
  • R 6 can be introduced into the hydrazine ring simultaneously with the hydroxy group.
  • Process F By a conventional method, the compound represented by the formula (I) can be obtained by attaching the substituents R 3 and R 4 corresponding to the target compound using the compound (X-5).
  • Process G The compound (X-4) and the compound represented by the formula: Hal-C ( ⁇ O) —R 6 are treated with a base in an appropriate solvent to obtain a compound (X-6). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof
  • a solvent or the like can be used.
  • it is dichloromethane.
  • triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, metallic sodium and the like can be used.
  • Pyridine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-4).
  • the step can also be performed in the presence of an activator.
  • the activator magnesium chloride, magnesium bromide, magnesium iodide and the like can be used. Preferably, it is magnesium chloride. It is preferable to use 1 to 5 equivalents of an activator with respect to compound (X-4).
  • Process H Compound (X-6) is treated with a base in a suitable solvent to give compound (X-7). The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • Solvents include dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, A mixed solvent thereof or the like can be used. Preferred is dimethyl sulfoxide. These solvents may be appropriately selected and used in combination with a base.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
  • Step A the amino group of the compound (X-1) having the substituent R 5 corresponding to the target compound is protected by a conventional method, and the formula: (In the formula, B is a protecting group, and other symbols are the same as the symbols in the compound represented by formula (I).)
  • Compound (Xa-1) represented by the above can be obtained and Step B to Step I can also be carried out.
  • the protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl and the like. Preferably, it is benzyloxycarbonyl.
  • step I deprotection is carried out by a conventional method, and the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) To obtain a compound (Xa-2) represented by the formula:
  • Compound (Xa-2) can be treated with a base represented by the formula: R 1 (R 2 ) —N—SO 2 -Hal in a suitable solvent with a base to obtain a compound represented by formula (I). .
  • the reaction conditions are the same as in step A.
  • compound (IV-4) which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.
  • Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Acetonitrile, water, a mixed solvent thereof or the like can be used.
  • Preferred is dimethylformamide.
  • Step b Compound (IV-2) and sulfonyl halide are reacted in a suitable solvent in the presence of a base to obtain compound (IV-3).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • sulfonyl halide p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the like can be used.
  • base triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (IV-2).
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof and the like can be used.
  • it is methylene chloride.
  • These solvents may be appropriately selected and used in combination with a base.
  • DABCO (1,4-Diazabicyclo [2,2,2 ] octane), HCl, H 2 SO 4, acetic acid, CF 3 COOH, toluenesulfonic acid, p- toluenesulfonic acid and the like. DABCO is preferable.
  • Process c Compound (IV-3) is treated with a base in a suitable solvent to give compound (IV-4). The reaction may be performed at ⁇ 50 ° C. to 50 ° C. for several minutes to several hours.
  • the base n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, hydrazine, propanethiol lithium salt and the like can be used.
  • Strong bases are preferred, such as n-butyllithium.
  • the solvent methylene chloride, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, acetone and the like can be used. Tetrahydrofuran and / or hexane are preferable.
  • These solvents may be appropriately selected and used in combination with a base.
  • the compound of the present invention can be synthesized as follows. (In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).) Step d N-bromosuccinimide is added to compound (V-1) in a suitable solvent to give compound (V-2). The reaction may be performed at ⁇ 50 ° C. to room temperature for several minutes to several hours.
  • Process e Compound (V-3) is obtained by adding ethyl halogenocarbonate to compound (V-2) in a suitable solvent. The reaction may be performed at 0 ° C. to 100 ° C.
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, dichloromethane, toluene, benzene, pyridine, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, Acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used, but the present invention can also be performed without a solvent. Tetrahydrofuran and / or pyridine are preferable. The reaction may be performed in the presence of a base. As the base, pyridine, N-methylmorpholine, dimethylaniline and the like can be used.
  • Process f Compound (V-3) and compound (IV-4) are reacted in a suitable solvent in the presence of a base to obtain compound (V-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base triethylamine, DBU, sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred are triethylamine, potassium carbonate and the like.
  • Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Propanol, acetonitrile, water, a mixed solvent thereof or the like can be used.
  • Preferred is dimethylformamide.
  • catalysts examples include Pd (PPh3) 4 (tetrakistriphenylphosphine palladium), PdCl2 (PPh3) 2 (dichlorobistriphenylphosphine palladium), Pd (DBA) (bisdibenzylideneacetone palladium), copper iodide, DABCO and the like. It is done. Preferred is dichlorobistriphenylphosphine palladium and / or copper iodide.
  • Process g Compound (V-4) is treated with a base in a suitable solvent to give compound (I-3). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Tetrabutylammonium fluoride Use as bases tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrazine, propanethiol lithium salt, etc. Can do. Tetrabutylammonium fluoride is preferred.
  • Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, etc.
  • a mixed solvent or the like can be used.
  • Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.
  • lithium diisopropylamine lithium tetramethylpiperidide, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, methyllithium, or the like can be used.
  • Lithium diisopropylamine is preferable.
  • the solvent tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.
  • Step i Compound (VI-2) is treated with a base in a suitable solvent to give compound (VI-3).
  • the reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours.
  • the base barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferably, it is ethanol. These solvents may be appropriately selected and used in combination with a base.
  • Step j Compound (VI-4) is obtained by treating compound (VI-3) with a base in a suitable solvent and reacting with diphenylphosphoric acid azide. The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base diisopropylamine, triethylamine, dimethylaminopyridine and the like can be used. Triethylamine is preferable.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, chloroform, dioxane, acetone, acetonitrile, butanol, a mixed solvent thereof or the like can be used. T-butanol is preferable.
  • These solvents may be appropriately selected and used in combination with a base.
  • Process k Compound (VI-4) and compound (IV-4) are reacted in an appropriate solvent in the presence of a base to obtain compound (VI-5). The reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours. The reaction conditions are the same as in step f.
  • Process l Compound (VI-5) is treated with a base in a suitable solvent to give compound (I-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • As the base 1,8-diazabicyclo [5,4,0] -7-undecene, tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, metal alkoxide and the like can be used. 1,8-diazabicyclo [5,4,0] -7-undecene is preferred.
  • solvent tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. is there. Methanol and / or water are preferred. These solvents may be appropriately selected and used in combination with a base. In the compounds (VI-1), (VI-2), (VI-3), (VI-4), and (VI-5) in steps h to l, compounds having different nitrogen atom positions and numbers are used. Thus, the compound represented by the formula (I) in which X is various aromatic heterocycles can be synthesized.
  • the compound of the present invention can be synthesized as follows.
  • Y represents R 3 , R 4 or hydrogen in formula (I).
  • Other symbols are the same as those in the compound represented by formula (I).
  • Process m A compound (VII-1) having a substituent R 1 , R 2 , or R 5 corresponding to the target compound (the synthesis method is described in WO2001 / 037826) is treated with a dehydrating agent in an appropriate solvent, and 0 ° C. to 50 ° C. The reaction mixture is reacted for several minutes to several hours to convert it into an acid halide, and further, N, O-dimethylhydroxyamine hydrochloride is added, and in a suitable solvent at 0 ° C.
  • compound (VII-2) examples include oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, acetic anhydride, methanesulfonyl chloride, ethyl chlorocarbonate and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a dehydrating agent relative to compound (VII-1). Further, dimethylformamide may be added as a catalyst.
  • triethylamine As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, potassium carbonate, sodium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a base.
  • the compound represented by compound (VII-2) is treated with a methylating reagent in an appropriate solvent to obtain compound (VII-3).
  • the reaction may be performed at ⁇ 80 ° C. to 100 ° C. for several minutes to several hours.
  • methylating reagent methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, or methyllithium can be used.
  • Preferred are methylmagnesium bromide and methylmagnesium chloride. It is preferable to use 1 to 5 equivalents of a Grignard reagent relative to compound (VII-2).
  • tetrahydrofuran diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used.
  • Tetrahydrofuran and / or diethyl ether are preferred.
  • These solvents may be appropriately selected and used in combination with a methylating reagent.
  • Process o Compound (VII-3) and an aldehyde having a substituent R 3 corresponding to the target compound are treated with a base in an appropriate solvent to obtain compound (VII-4).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • the base triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, butyllithium, LDA, sodium methoxide and the like can be used.
  • Sodium hydroxide is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, methanol, Ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.
  • Process p Compound (VII-4) and nitromethane are treated with a base in an appropriate solvent to obtain compound (VII-5).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • As the base tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, diethylamine, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • Preferred is diethylamine.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, Those mixed solvents can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.
  • Process q Compound (VII-5) is treated with a base at 0 ° C. to 100 ° C. for several minutes to several hours in a suitable solvent, further treated with methanol at 0 ° C. to 65 ° C. for several minutes to several hours, and then treated with acid.
  • compound (VII-6) is obtained.
  • the base diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • it is potassium hydroxide.
  • As the acid concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used.
  • it is concentrated sulfuric acid.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, Ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methanol and / or tetrahydrofuran are preferred. These solvents may be appropriately selected and used in combination with a base or an acid.
  • Process r Compound (VII-6) is reacted with ammonium acetate in a suitable solvent to give compound (I-5).
  • the reaction may be performed at room temperature to 150 ° C. for several minutes to several hours.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, diisopropyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, acetic acid Ethyl, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used.
  • it is acetic acid.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, and mixtures thereof
  • a solvent or the like can be used. Acetonitrile is preferred.
  • Process t Compound (VIII-3) is obtained by reacting compound (VIII-2) with hexamethylenetetramine in a suitable solvent. The reaction may be performed at room temperature to 100 ° C.
  • Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, those A mixed solvent or the like can be used. Preferably, it is chloroform.
  • Step u Compound (VIII-3) is reacted with an acid in an appropriate solvent to give compound (VIII-4).
  • the reaction may be performed at room temperature to 100 ° C. for several minutes to several hours.
  • As the acid concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Concentrated hydrochloric acid is preferred.
  • Process v Compound (VIII-5) is obtained by reacting compound (VII-1) having substituents R 1 , R 2 and R 5 corresponding to the target compound and compound (VIII-4). The reaction conditions are the same as in step m above.
  • Process w Compound (I-6) can be obtained by subjecting compound (VIII-5) to the same method as in step r above.
  • the compound of the present invention can be synthesized as follows.
  • Y represents R 3 , R 4 or hydrogen in formula (I).
  • Each other symbol has the same meaning as each symbol in the compound represented by formula (I).
  • Process x Compound (IX-1) having substituents R 3 and R 4 corresponding to the target compound is reacted with halogenomethyl in a suitable solvent to obtain a compound represented by compound (IX-2).
  • the reaction may be performed at 0 ° C. to 100 ° C. for several minutes to several hours.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Acetonitrile is preferred.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable.
  • Step z Compound (VI-7) is obtained by treating compound (X-3) and compound (X-2) with a base in a suitable solvent. The reaction may be performed at 50 ° C. to 150 ° C. for several minutes to several hours.
  • a base diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, propanethiol lithium salt and the like can be used. Triethylamine is preferable.
  • Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.
  • a compound in which R 1 and R 5 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle can also be synthesized as follows. (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).
  • the benzene ring in the formula may have a substituent, or another ring instead of the benzene ring. It may be.)
  • Compound (I-1) is reacted with H 2 NSO 2 NH 2 in the presence of a base to give compound (I-8).
  • a base pyridine or the like can be used.
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • R 5 is hydrogen.
  • Other symbols are as defined in the compound represented by formula (I).)
  • R 5 is hydrogen or substituted or unsubstituted alkyl.
  • the other symbols have the same meanings as those in the compound represented by formula (I).
  • R 5 is hydrogen.
  • R 5 is hydrogen or substituted or unsubstituted alkyl and R 8 is substituted or unsubstituted alkyl.
  • R 5 is hydrogen and R 8 is methyl, ethyl, isopropyl or tert -Butyl, and other symbols are the same as the symbols in the compound represented by formula (I).
  • R 5 is hydrogen or substituted or unsubstituted alkyl. Preferably, R 5 is hydrogen.
  • Other symbols are as defined in the compound represented by formula (I).) A compound represented by formula (I).
  • the compounds of the present invention are effective for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders 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, hyperlipidemia, 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.
  • i) Does not cause reproductive toxicity (eg, teratogenicity).
  • j) Does not cause gastrointestinal disorders for example, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and 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, the possibility of inducing side effects based on peripheral vasoconstriction is low, and a pharmaceutical composition containing the compound of the present invention as an active ingredient can be preferably used as a safe medicine. It is considered possible.
  • 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, crystalline cellulose and the like.
  • 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.
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used as a suppository base.
  • 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).
  • the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with known diet therapy, drug therapy, exercise and the like.
  • the following methods are also within the scope of the present invention.
  • a pharmaceutically acceptable salt thereof or a solvate thereof a drug used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity is administered.
  • a method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity Drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity to patients undergoing prevention or treatment by administration of the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof
  • a method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity which comprises administering
  • Examples of drugs used for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity include compounds having anorectic effect (selective serotonin reuptake inhibitors such as fenfluramine and fluoxetine; mazindol, etc.), nutrients
  • a compound having an inhibitory action on digestion and absorption compounds having an inhibitory action on sugar absorption ( ⁇ -glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin and KGT-1075);
  • Example 1 First Step of Synthesis of Compound Ia-1 Methylene chloride (50 ml) was added to compound 1 (10 g, 48.1 mmol), and then dimethylsulfamoyl chloride (10.4 ml, 96.0 mmol) and triethylamine (26.7 ml, 193 mmol) were added under ice-cooling. The mixture was stirred for 4 hours with cooling. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 2.
  • Second step Compound 2 was dissolved in ethanol (15 ml) and tetrahydrofuran (30 ml), sodium hydroxide (2.89 g, 72.2 mmol) dissolved in 10 ml of water was added, and the mixture was stirred at room temperature for 5 hours. After part of the organic solvent was distilled off under reduced pressure, the reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with chloroform. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 3 quantitatively.
  • N-methylimidazole (4.09 ml, 51.3 mmol) in methylene chloride (50 ml) -ethyl acetate (6.70 mL, 68.4 mmol) was added a solution of acid chloride (42.7 mmol) in methylene chloride (50 ml) at -60 ° C.
  • titanium tetrachloride (15.6 ml, 141 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes.
  • N, N′-diisopropylethylamine (26.9 ml, 154 mmol) was added to the reaction mixture, and the mixture was stirred at ⁇ 40 ° C.
  • Example 2 Synthesis of Compound Ia-9 and Compound IIa-3 First Step Acetonitrile (40 ml) and water (20 ml) were added to compound 1 (10 g, 48.1 mmol), and then benzyloxycarbonyl chloride (8.25 ml, 57.8 mmol) and triethylamine (26.7 ml, 193 mmol) under ice-cooling. And stirred for 4 hours with ice cooling. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate.
  • Second step Compound 8 (14.7 g, 48.1 mmol) was dissolved in ethanol (60 ml) and tetrahydrofuran (30 ml), 2N aqueous sodium hydroxide solution (120 ml, 240 mmol) was added, and the mixture was stirred at room temperature for 4 hr.
  • the reaction solution was poured into dilute hydrochloric acid, acidified, extracted with chloroform, the organic layer was washed with water, and further washed with saturated brine. At this time, some of the target product was precipitated as crystals, and they were collected by filtration.
  • the organic layer of the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain crystals.
  • N-methylimidazole (1.04 ml, 13.0 mmol) in methylene chloride (50 ml) -ethyl acetate (1.69 mL, 17.3 mmol) is added a solution of acid chloride (10.8 mmol) in methylene chloride (50 ml) at -60 ° C.
  • titanium tetrachloride (3.94 ml, 35.7 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes.
  • N, N′-diisopropylethylamine (6.80 ml, 38.9 mmol) was added to the reaction mixture, and the mixture was stirred at ⁇ 40 ° C.
  • Acetonitrile (20 ml) was added to 2-chloroethanol (0.374 ml, 5.58 mmol), then chlorosulfonyl isocyanate (0.484 ml, 5.58 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min. Active species were obtained.
  • Acetonitrile (100 ml) was added to compound 13 (1.50 g, 5.07 mmol), then N-methylmorpholine (2.79 ml, 25.4 mmol) was added under ice cooling, and the reaction activity prepared above at the same temperature. Seeds were dripped.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R 1 and R 2 may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring.
  • Second step (R 1 and R 2 are as defined above.)
  • Compound 17 (1 eq), zinc powder (0.2 eq), zinc cyanide (0.6 eq) are dissolved in dimethylacetamide, Pd (P t Bu 3 ) 2 (0.1 eq) is added under a nitrogen stream, and the mixture is stirred at 95 ° C. for several hours. To do.
  • the reaction mixture is then poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography to obtain the desired product 18.
  • These compounds 16 to 18 are also compounds of the present invention.
  • Test Example 1-1 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)].
  • IC 50 value 50% inhibitory concentration 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 1.
  • 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 1-2 Affinity for Human NPY Y5 Receptor
  • a cDNA sequence encoding the human NPY Y5 receptor was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466- 472).
  • 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). Incubate in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filter 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 is determined with a gamma counter.
  • Non-specific binding is 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 is determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
  • Test Example 2 Rat and Mouse Brain Migration Evaluation Using the cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966), rat (Crl; CD (SD), ⁇ , 8weeks) 30 minutes after intravenous administration (0.5 mg / mL / kg), for mice (Jcl; C57BL / 6J, J, 8weeks), plasma and brain 3 hours or 5 hours after oral administration (2 mg / 10 mL / kg) From the concentration, brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
  • Test Example 3 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.
  • Test Example 4 cAMP Production Inhibitory Action in CHO Cells After CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), the compounds 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
  • NPY Y5 Receptor Selectivity Test Example 1-2 and Y1-expressing cell (human neuroblastoma, SK-N-MC) membrane sample and Y2-expressing cell (human neuroblastoma, SMS-KAN) membrane sample 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 the 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 6 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external 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.
  • mice The food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated.
  • the compound of the present invention when administered at a dose of 12.5 mg / kg, the amount of food intake was significantly suppressed compared to the case where 0.5% hydroxypropylmethylcellulose was administered.
  • the food intake after 2 hours and 4 hours after injection was 0.28 ⁇ 0.05 g and 0.57 ⁇ 0.08 g, respectively. Met.
  • the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.62 ⁇ 0.06 g and 1.37 ⁇ 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 ⁇ 0.03 g, 0.13 ⁇ 0.02 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 at 2 hours and 4 hours after the injection in the A group are 65.1% and 64.1%, respectively.
  • Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • reaction solution in a 96-well plate 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • 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.
  • the compound of the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound of the present invention is used as a medicament for the prevention or treatment of eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure, sleep disorders, etc. Very useful. In addition, 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. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.
  • obesity is a risk factor

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Abstract

La présente invention concerne, comme nouveau composé ayant un antagonisme du récepteur NPY Y5, un composé représenté par la formule (I), un sel ou un solvate pharmaceutiquement acceptable de celui-ci. Dans la formule (I) : R1 et R2 représentent chacun indépendamment hydrogène, un alkyle substitué ou non substitué, ou similaire, ou R1 et R2 peuvent former, avec l'atome d'azote adjacent, un hétérocycle aromatique contenant de l'azote, substitué ou non substitué, ou un hétérocycle non aromatique contenant de l'azote, substitué ou non substitué ; X représente un hétérocycle aromatique ou un hétérocycle non aromatique ; les R3 représentent chacun indépendamment aryle substitué ou non substitué, hétéroaryle substitué ou non substitué ou hétérocyclyle substitué ou non substitué ; les R4 représentent chacun indépendamment halogène, cyano ou similaire ; R5 représente hydrogène, alkyle substitué ou non substitué, etc. ; m est un entier de 0-2 ; n est un entier de 0-5 : les R représentent chacun indépendamment halogène, oxo ou similaire ; et p est un entier de 0-2.
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