WO2011096462A1 - Composé hétérocyclique ayant une activité antagoniste du récepteur npy y5 - Google Patents

Composé hétérocyclique ayant une activité antagoniste du récepteur npy y5 Download PDF

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WO2011096462A1
WO2011096462A1 PCT/JP2011/052215 JP2011052215W WO2011096462A1 WO 2011096462 A1 WO2011096462 A1 WO 2011096462A1 JP 2011052215 W JP2011052215 W JP 2011052215W WO 2011096462 A1 WO2011096462 A1 WO 2011096462A1
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substituted
compound
unsubstituted
pharmaceutically acceptable
acceptable salt
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隆行 奥野
直樹 神山
恭平 林
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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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel heterocyclic compound 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 preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
  • Non-Patent Document 2 subtypes 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 Documents 1 to 3 describe amine derivatives having an NPY Y5 receptor antagonistic action.
  • Patent Documents 4 to 6 describe derivatives having a sulfamide side chain having NPY Y5 receptor antagonistic activity. These compounds differ in structure from the compounds of the present invention.
  • An object of the present invention is to provide a novel heterocyclic compound 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.
  • R 1 , R 2 and R 3 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 form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring together with the adjacent nitrogen atom, or R 2 and R 3 together may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle; X is S
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero
  • R 7 is halogen.
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, X is S (O) 2 or C (O); R 4 and R 5 are hydrogen, or R 4 and R 5 together may form oxo, R 6 is hydrogen; m is 0, Y is S or O; Each R 7 is independently halogen; n is an integer of 0 to 2, the compound according to any one of (1) to (9), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (15), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • (21) Formula: Or a pharmaceutically acceptable salt or solvate thereof.
  • (22) A pharmaceutical composition comprising the compound according to (21), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (24) A method for treating or preventing a disease involving NPY Y5, comprising administering the compound according to (21), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (25) Use of the compound according to (21), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
  • a pharmaceutical composition comprising the compound according to (33), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to (39), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (45) Formula: Or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition comprising the compound according to (45), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to (51), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (57) Formula: Or a pharmaceutically acceptable salt or solvate thereof.
  • (58) A pharmaceutical composition comprising the compound according to (57), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (60) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (57), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (61) Use of the compound according to (57), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving NPY Y5.
  • (62) The compound according to (57), a pharmaceutically acceptable salt or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.
  • a pharmaceutical composition comprising the compound according to (63), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (69) Formula: Or a pharmaceutically acceptable salt or solvate thereof.
  • (70) A pharmaceutical composition comprising the compound according to (69), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (72) A method for treating or preventing a disease involving NPY Y5, which comprises administering the compound according to (69), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Formula (75) Or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition comprising the compound according to (75), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to (81), 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
  • Each atom in the compound of the present invention may be an isotope.
  • hydrogen may be any of the hydrogen isotopes, ie light hydrogen (H), deuterium (D) and tritium (T).
  • 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 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.
  • 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.
  • 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 thereof 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.
  • polycyclic aromatic heterocycle means that the above “monocyclic aromatic heterocycle” is an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (above “cyclohexane”). A ring derived from “alkyl” or a ring fused with 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, Examples include thienyl and the like.
  • 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.
  • the “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-mentioned “monocyclic non-aromatic heterocycle”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic group”); A group derived from an “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.
  • Substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl” or “substituted or unsubstituted alkoxy” include halogen, cyano, nitro, nitroso, azide Acyl, acyloxy, imino, hydroxy, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, Heterocyclyloxy, Mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthi
  • Substituted or unsubstituted cycloalkyl “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted heterocyclyl”,
  • substituent of “substituted or unsubstituted nitrogen-containing aromatic heterocycle” or “substituted or unsubstituted nitrogen-containing nonaromatic heterocycle” include alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, nitroso, Azide, acyl, acyloxy, imino, hydroxy, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyl,
  • “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.
  • 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.
  • Haloalkyl and haloalkoxy mean a group in which the “halogen” is bonded to the “alkyl” and “alkoxy”.
  • alkenyloxy "alkynyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “heteroaryloxy” and “heterocyclyloxy” are the above “alkenyl”, “alkynyl”, “cycloalkyl” , “Cycloalkenyl”, “heteroaryl” and “heterocyclyl” mean a group bonded to an oxygen atom.
  • 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.
  • 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 “alkenyloxycarbonyl”, “cycloalkyloxycarbonyl”, “cycloalkenyloxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl” and “heterocyclyloxycarbonyl” It means a group in which an oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group. .
  • alkenylcarbonyl alkenylcarbonyl
  • cycloalkylcarbonyl cycloalkenylcarbonyl
  • arylcarbonyl cycloalkenylcarbonyl
  • heteroarylcarbonyl arylcarbonyl
  • heterocyclylcarbonyl a group bonded to a carbonyl group.
  • Alkylsulfonyl alkenylsulfonyl
  • cycloalkylsulfonyl cycloalkenylsulfonyl
  • arylsulfonyl arylsulfonyl
  • heteroarylsulfonyl and “heterocyclylsulfonyl” are the above “alkyl”, “alkenyl” , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.
  • 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 alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or A compound that is unsubstituted heteroaryl.
  • substituent for R 1 and R 2 include one or more groups selected from cyano, alkoxy, halogen, and hydroxy.
  • R1, R2-2 The compound wherein R 1 and R 2 are each independently substituted or unsubstituted alkyl.
  • the substituent for R 1 and R 2 include one or more groups selected from cyano, alkoxy, halogen, and hydroxy.
  • R1, R2-3) A compound wherein R 1 is substituted or unsubstituted alkyl and R 2 is substituted or unsubstituted cycloalkyl.
  • R 1 is preferably unsubstituted alkyl, and R 2 is preferably unsubstituted cycloalkyl.
  • R1, R2-4 A compound wherein R 1 is substituted or unsubstituted alkyl and R 2 is substituted or unsubstituted alkoxy.
  • R 1 is preferably unsubstituted alkyl, and R 2 is preferably unsubstituted alkoxy.
  • R1, R2-5) A compound in which R 1 and R 2 together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.
  • the nitrogen-containing non-aromatic heterocycle include morpholine, piperidine, pyrrolidine, oxazolidine and the like.
  • the substituent of the nitrogen-containing non-aromatic heterocycle include one or more groups selected from halogen, alkyl and oxo. For example, the following compounds are mentioned.
  • R1, R2-6) A compound wherein R 1 is hydrogen and R 2 is substituted or unsubstituted alkyl. Examples of the substituent for R 2 include halogen.
  • R1, R2--7 A compound wherein R 1 is hydrogen and R 2 is substituted or unsubstituted cycloalkyl. R 2 is preferably unsubstituted cycloalkyl.
  • R1, R2-8) A compound wherein R 1 is hydrogen and R 2 is substituted or unsubstituted alkoxy. R 2 is preferably unsubstituted alkoxy.
  • R1, R2-9) A compound wherein R 1 is hydrogen and R 2 is substituted or unsubstituted aryl. Examples of the substituent for R 2 include halogen.
  • R1, R2-10) A heteroaryl compound in which R 1 is hydrogen and R 2 is substituted or unsubstituted. R 2 is preferably unsubstituted pyrimidine.
  • R1, R2-11) A compound wherein R 1 and R 2 are hydrogen.
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A compound which is cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • substituent include one or more groups selected from phenyl, cyano and halogen.
  • R 3 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl.
  • substituent include one or more groups selected from phenyl, cyano and halogen.
  • R3-3 The compound in which R 3 is hydrogen; alkyl optionally substituted with phenyl; cycloalkyl optionally substituted with cyano; aryl optionally substituted with halogen or cyano; or heteroaryl.
  • R 2 and R 3 may be combined to form a substituted or unsubstituted nitrogen-containing aromatic heterocycle.
  • R 1 has the same meaning as the symbol in the compound represented by formula (I)).
  • X is S (O), S (O) 2 or C (O).
  • R 4 and R 5 are each independently hydrogen or substituted or unsubstituted alkyl. Or, R 4 and R 5 together may form an oxo.
  • R 6 is hydrogen or substituted or unsubstituted alkyl.
  • Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • m is an integer of 0-2.
  • Y is S or O.
  • Each R 7 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkoxy. Particularly preferred is halogen.
  • n is an integer of 0-2.
  • 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 thereof 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 both E body and Z body may exist, both are included.
  • Prodrugs of the compounds of the present invention are included in the scope of the present invention.
  • Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the compound of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but the above-mentioned specific compound is administered in vivo after administration to a patient with a disease involving NPY Y5.
  • Including compounds that convert to Normal procedures for selection and formulation of appropriate prodrug derivatives are described, for example, in Design of Prodrugs (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.
  • Method A In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and R is alkyl.
  • Process A The substituent R 6 is introduced into the compound (a).
  • compound (b) can be obtained by reacting R 6 -Hal (Hal is halogen) in the presence of a base.
  • a base As the solvent, tetrahydrofuran, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature.
  • the base triethylamine, pyridine, dimethylaminopyridine and the like can be used. Note that, in the compound represented by the formula (I), the compound in which R 6 is hydrogen does not perform this step.
  • Process B Compound (b) is represented by the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).) A group represented by is introduced.
  • the compound (c) can be obtained by reacting the group represented by the above in the presence of a base.
  • a base methanol, ethanol, isopropanol, dimethylformamide, or the like can be used.
  • the reaction can be carried out at room temperature or under heating.
  • the sealing can be carried out using a microwave reactor.
  • N N-diisopropylethylamine or the like can be used.
  • Process C Compound (c) is reduced to obtain compound (d).
  • the reducing agent lithium aluminum hydride or the like can be used. Tetrahydrofuran or the like can be used as the solvent.
  • the reaction can be carried out at room temperature.
  • Process D Compound (d) is azidated to give compound (e).
  • compound (d) is reacted with mesyl chloride using triethylamine as a base to induce compound (d) to mesylate.
  • chloroform or the like can be used as a solvent for the mesylation.
  • the compound obtained can be reacted with sodium azide and azidated in dimethylformamide or the like at room temperature or under heating to obtain compound (e).
  • Process E Compound (e) is reduced to obtain compound (f). It can be carried out by catalytic reduction.
  • the catalyst 10% palladium carbon or the like can be used.
  • solvent ethanol or the like can be used.
  • Process F Compound (f) is converted to formula (II): (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.) Is reacted with compound (IA) to give compound (IA).
  • compound represented by the formula (II) various sulfonyl chlorides, acyl chlorides and the like can be used.
  • the solvent use tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof or the like.
  • the reaction can be carried out at room temperature or under heating. It is preferably carried out in the presence of a base.
  • pyridine triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
  • a compound in which R 3 , R 4 and R 5 are hydrogen does not perform the subsequent step G, and the compound (IA) becomes the final target compound.
  • the compound in which the substituents R 4 and R 5 are other than hydrogen is subjected to a process of introducing the substituents R 4 and R 5 into the compound (IA) by an appropriate method. Obtainable.
  • the oxidation step can be performed using an oxidizing agent.
  • the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, sodium tungstate, and the like.
  • compound (d) is represented by formula (III): (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
  • a compound (IA) can also be obtained by reacting the compound represented by formula (I). For example, mesyl chloride is reacted with compound (d) using triethylamine, pyridine or the like as a base to induce compound (d) to mesylate. As the solvent for the mesylation, chloroform, methylene chloride or the like can be used. The obtained compound is reacted with a compound represented by the formula (III) to obtain a compound (IA).
  • potassium tert-butoxide sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium pentoxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like can be used.
  • Solvents include methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazo Lidinone, ethyl acetate, propyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, a mixed solvent thereof and the like can be used.
  • the above reaction may be carried out while protecting one hydrogen of NH 2 in the compound represented by the formula (III), followed by deprotection after the reaction. Further, the compound (d) and the compound represented by the formula (III) are reacted in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD), or azodicarboxylic acid diethyl ester (DEAD) to obtain a compound (IA) You can also get About the compound shown by Formula (III), you may deprotect after the said reaction using the protector (for example, Boc protector).
  • the protector for example, Boc protector
  • a protecting group is introduced into the compound (b).
  • the protecting group the protecting groups described in Protective Groups in Organic Synthesis (by Theodora W. Greene) and the like can be widely used.
  • Amino protecting groups that can be removed under acidic conditions are preferred. Examples thereof include benzyloxycarbonyl group and tert-butyloxycarbonyl group.
  • compound (h) can be obtained by reacting ProHal (Hal is halogen, Pro is a protecting group), Pro-O-Pro (Pro is a protecting group) in the presence of a base.
  • the solvent tetrahydrofuran, dimethylformamide, or the like can be used. The reaction can be carried out at room temperature.
  • Process I Compound (h) is reduced to obtain compound (i).
  • the reducing agent lithium aluminum hydride or the like can be used. Tetrahydrofuran or the like can be used as the solvent. The reaction can be carried out at room temperature.
  • Process J Compound (i) is azidated to give compound (j).
  • compound (i) is converted to mesylate by reacting mesyl chloride with triethylamine as a base.
  • chloroform can be used as a solvent for the mesylation.
  • the obtained compound is reacted with sodium azide, and azidated in dimethylformamide or the like at room temperature or under heating to obtain compound (j).
  • Process K Compound (j) is reduced to obtain compound (k).
  • Compound (j) is obtained by reducing compound (j) with triphenylphosphine and water.
  • the reaction can be carried out under warming. Tetrahydrofuran or the like can be used as the solvent.
  • it can be carried out by catalytic reduction.
  • 10% palladium carbon or the like can be used as the catalyst.
  • As the solvent ethanol or the like can be used. Which reduction method is used can be appropriately selected depending on the protecting group to be used.
  • the solvent use tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof or the like.
  • the reaction can be carried out at room temperature or under heating. It is preferably carried out in the presence of a base.
  • pyridine triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like
  • 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, sodium tungstate, and the like.
  • Process M The protecting group of compound (m) is removed.
  • the removal of the protecting group can be used by selecting various conditions depending on the protecting group.
  • the tert-butyloxycarbonyl group can be removed with an acid.
  • the benzyloxycarbonyl group can be removed by catalytic reduction or the like.
  • Process N Compound (n) is represented by the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
  • a group represented by is introduced.
  • the formula: (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Hal is halogen.) Is reacted in the presence of a base to give compound (IB).
  • the solvent methanol, ethanol, isopropanol, dimethylformamide, or the like can be used.
  • the reaction can be carried out at room temperature or under heating.
  • the sealing can be carried out using a microwave reactor.
  • N, N-diisopropylethylamine or the like can be used.
  • the compound represented by the formula (I) the compound in which the substituents R 4 and R 5 are other than hydrogen is subjected to a step of introducing the substituents R 4 and R 5 into the compound (IB) by an appropriate method. Obtainable.
  • a compound in which R 2 and R 3 are combined to 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.) Process O Compound (o) is reacted with H 2 NSO 2 NH 2 in the presence of a base to obtain compound (IC). As the base, pyridine or the like can be used.
  • Process P 2-Chloroethanol and chlorosulfonyl isocyanate are reacted, and the reaction solution is reacted with compound (f) to obtain compound (ID).
  • a base for example, 1-methylmorpholine or the like can be used.
  • the solvent acetonitrile or the like can be used.
  • Process Q Compound (ID) is reacted with an amine of the formula: NH (R 1 ) (R 2 ) to obtain compound (IA). This step can be performed in the presence of a base and TMSOTf (trimethylsilyl triflate). Examples of the base include triethylamine, pyridine and the like.
  • the step of introducing the substituents R 4 and R 5 into the compound (IA) by an appropriate method Can be obtained through
  • Process R Compound (d) is oxidized to give compound (q).
  • the oxidizing agent for example, 2-iodoxybenzoic acid (IBX) can be used.
  • the solvent dimethyl sulfoxide or the like can be used.
  • Process S Compound (r) is obtained by reacting compound (q) with a compound represented by the formula: R 3 —NH 2 . This step can be performed in the presence of a reducing agent.
  • reducing agent sodium triacetoxyborohydride or the like can be used.
  • the solvent methylene chloride or the like can be used.
  • Process T Chlorosulfonyl isocyanate and t-butanol are reacted, and the reaction solution is reacted with compound (r) to obtain compound (s).
  • a base for example, triethylamine or the like can be used.
  • methylene chloride or the like can be used.
  • Process U Compound (IE) may be obtained by reacting compound (s) with the formula: R 1 —OH in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD) or azodicarboxylic acid diethyl ester (DEAD). it can.
  • DIAD azodicarboxylic acid diisopropyl ester
  • DEAD azodicarboxylic acid diethyl ester
  • Tetrahydrofuran or the like can be used as the solvent.
  • the substituents R 2 , R 4 and R 5 are other than hydrogen, the substituents R 2 , R 4 and R It can be obtained through the step of introducing R 5 .
  • Process V Compound (c) is hydrolyzed to obtain compound (t).
  • a base for example, sodium hydroxide or the like can be used. Tetrahydrofuran or the like can be used as the solvent.
  • Process W Compound (t) is converted to formula (IV): (In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I), and Pro is a protecting group.) The compound shown by these is made to react, and a compound (u) is obtained.
  • a condensing agent As the condensing agent, HATU or the like can be used.
  • Process X Compound (IF) is obtained by deprotecting compound (u) under strongly acidic conditions.
  • As the strong acid trifluoroacetic acid or the like can be used.
  • As the solvent methylene chloride or the like can be used.
  • the compound represented by the formula (I) the compound in which R 1 and R 2 are hydrogen does not perform the subsequent step Y, and the compound (IF) becomes the final target compound.
  • the oxidation step can be performed using an oxidizing agent.
  • the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, sodium tungstate, and the like.
  • Process Y Compound (IF) is reacted with the formula: R 1 —OH in the presence of triphenylphosphine, azodicarboxylic acid diisopropyl ester (DIAD) or azodicarboxylic acid diethyl ester (DEAD) to obtain compound (IG).
  • DIAD azodicarboxylic acid diisopropyl ester
  • DEAD azodicarboxylic acid diethyl ester
  • Tetrahydrofuran or the like can be used as the solvent.
  • a compound in which the substituent R 2 is other than hydrogen can be obtained through a step of introducing the substituent R 2 into the compound (IG)
  • 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, dyslipidemia, arteriosclerosis, and acute coronary syndrome. Furthermore, the compound of the present invention has not only NPY Y5 receptor antagonistic activity but also usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP3A4, etc.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • Low toxicity such as anemia-inducing action.
  • 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, 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 (drugs that can be used for weight management in obesity or obesity).
  • 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.
  • Example 1 First Step of Synthesis of Compound Id-1
  • Compound 1 (5 g, 52.0 mmol) was dissolved in DME (30 ml), piperidine (3.91 ml, 46.8 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 6 hours. After the solvent was distilled off under reduced pressure, the obtained solid was washed with chloroform-hexane (1: 1, 5 mL) to obtain Compound 2 (7.05 g, 90%).
  • Second step Compound 3 (1 g, 3.78 mmol) was dissolved in methylene chloride (10 mL), and then triethylamine (1.05 mL, 7.57 mmol) was added with stirring at room temperature, followed by mesyl chloride (0.324 mL, 4.16 mmol). added. After stirring at room temperature for 5 hours, water was added and extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The product was used in the next reaction without purification.
  • the obtained mesylate (300 mg, 0.876 mmol), the compound 2 (158 mg, 1.051 mmol) obtained in the first step, and cesium carbonate (428 mg, 1.314 mmol) were mixed in DMF (8 mL) solvent at 100 ° C. for 4 hours. Heated. Thereafter, Compound 2 (158 mg, 1.051 mmol) and cesium carbonate (428 mg, 1.314 mmol) were added again, and the mixture was heated at 75 ° C. for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain compound Id-1 (115 mg, 33%).
  • Second step Compound 10 (3 g, 11.35 mmol), compound 9 (3.58 g, 17.03 mmol) and triphenylphosphine (3.57 g, 13.62 mmol) were dissolved in methylene chloride (40 mL), and DIAD (2. 79 mL, 13.62 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, and disappearance of compound 10 as a raw material was confirmed by LC / MS.
  • Third step To the reaction solution of the second step, trifluoroacetic acid (15.72 mL, 204 mmol) was added at room temperature and stirred overnight.
  • Example 4 First Step of Synthesis of Compound Ie-2 IBX (5.00 g, 16.77 mmol) was dissolved in dimethyl sulfoxide (10 mL), a solution of compound 3 (3.00 g, 11.35 mmol) in dimethyl sulfoxide (9.0 mL) was added, and the mixture was stirred at room temperature for 24 hours. Insoluble matters in the reaction solution were removed by filtration through celite, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 5 First Step of Synthesis of Compounds Ij-1 and Ie-3
  • Compound 17 (10.2 g, 33.4 mmol) was stirred in tetrahydrofuran (100 ml), 2N aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 3 hours.
  • a 2N aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 3.5.
  • the precipitated crystals were collected by filtration and dried under reduced pressure to obtain Compound 18 (7190 mg, yield 77%).
  • Second step Compound 18 (500 mg, 1.797 mmol) was dissolved in dimethylformamide (3 ml), HATU (820 mg, 2.156 mmol) and triethylamine (0.548 ml, 3.95 mmol) were added, and the mixture was stirred at room temperature for 1 minute.
  • Compound 9 (453 mg, 2.156 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature.
  • Triethylamine (0.548 ml, 3.95 mmol) was added, and the mixture was further stirred at room temperature for 3 hours, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate.
  • 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 to obtain NPY Y5 receptor stably expressing cells.
  • Membrane preparation prepared from CHO cells expressing mouse NPY Y5 receptor was assay buffer together with the compound according to the present invention and 30,000 cpm [ 125 I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). The mixture was incubated 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 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 human NPY Y5 receptor was expressed in 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 is 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 2-2 Mouse Brain Migration Evaluation Using the cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966) Brain transferability (brain / plasma partition coefficient; Kp) is evaluated from plasma and brain concentrations 3 hours or 5 hours after administration (2 mg / 10 mL / kg).
  • 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 Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane samples 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 6 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 an anesthetized mouse and an NPY Y5 receptor-specific agonist 1 hour after administration.
  • 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 12.5 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 0.27 ⁇ 0.02 g and 0.50 ⁇ 0.09 g, respectively. there were.
  • the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.69 ⁇ 0.06 g and 1.30 ⁇ 0.12 g, respectively.
  • the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) to which no NPY Y5 receptor-specific agonist was injected was 0.12 ⁇ 0.02 g, 0.25 ⁇ 0.03 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding inhibition rates for the B group at 2 hours and 4 hours after the injection in the A group are 74.2% and 75.3%, 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 microsome 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 collected with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • 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 results are shown below.
  • Compound Ia-2 5 types> 20 ⁇ M Compound Ia-11: 5 species> 20 ⁇ M Compound Ia-13: 5 species> 20 ⁇ M Compound Ib-1: 4 types> 20 ⁇ M, 3A4 10 ⁇ M Compound Ic-1: 5 species> 20 ⁇ M Compound Id-1: 5 species> 20 ⁇ M Compound Ie-4: 5 species> 20 ⁇ M Compound Ie-7: 5 species> 20 ⁇ M Compound Ie-10: 5 species> 20 ⁇ M Compound Ie-19: 5 species> 20 ⁇ M Compound If-1: 5 types> 20 ⁇ M Compound Ig-2: 5 species> 20 ⁇ M Compound Ii-1: 5 species> 20 ⁇ M Compound Ij-8: 5 species> 20 ⁇ M
  • 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 the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.

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Abstract

L'invention concerne un composé représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, ou un solvate de ceux-ci comme nouveau composé ayant une activité antagoniste du récepteur NPY Y5. Dans la formule (I), R1, R2 et R3 représentent chacun indépendamment hydrogène, alkyle substitué ou non substitué, aryle substitué ou non substitué, ou similaires, ou R1 ou R2 peuvent être combinés conjointement avec l'arôme d'azote adjacent pour former un hétérocycle aromatique contenant de l'azote, substitué ou non substitué, ou similaire ; X représente S(O), S(O)2 ou C(O) ; R4 et R5 représentent chacun indépendamment hydrogène ou alkyle substitué ou non substitué, ou R4 et R5 peuvent être combinés pour former un groupe oxo ; R6 représente hydrogène ou alkyle substitué ou non substitué ; les R représentent chacun indépendamment halogène, oxo, alkyle substitué ou non substitué, ou similaires ; m représente un entier de 0 à 2 ; Y représente S ou O ; les R7 représentent chacun indépendamment halogène ou similaire ; et n représente un entier de 0 à 2.
PCT/JP2011/052215 2010-02-04 2011-02-03 Composé hétérocyclique ayant une activité antagoniste du récepteur npy y5 WO2011096462A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002543067A (ja) * 1999-04-22 2002-12-17 シナプティック・ファーマスーティカル・コーポレーション 選択的なｎｐｙ（ｙ５）のアンタゴニスト
JP2003503486A (ja) * 1999-06-30 2003-01-28 シナプティック・ファーマスーティカル・コーポレーション 選択的ｎｐｙ（ｙ５）アンタゴニスト
WO2009054434A1 (fr) * 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002543067A (ja) * 1999-04-22 2002-12-17 シナプティック・ファーマスーティカル・コーポレーション 選択的なｎｐｙ（ｙ５）のアンタゴニスト
JP2003503486A (ja) * 1999-06-30 2003-01-28 シナプティック・ファーマスーティカル・コーポレーション 選択的ｎｐｙ（ｙ５）アンタゴニスト
WO2009054434A1 (fr) * 2007-10-25 2009-04-30 Shionogi & Co., Ltd. Dérivé d'amine présentant une activité antagoniste du récepteur npy y5 et son utilisation

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Title
MCNALLY, J.J. ET AL.: "N-Acylated alpha-(3- pyridylmethyl)-beta-aminotetralin antagonists of the human neuropeptide Y Y5 receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 10, no. 15, 2000, pages 1641 - 1643, XP004213213 *
RUEEGER, H. ET AL.: "Discovery and SAR of potent, orally available and brain-penetrable 5,6- dihydro-4H-3-thia-l-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 10, 2004, pages 2451 - 2457, XP004841219 *

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