WO2004046110A1 - メラニン凝集ホルモン受容体拮抗剤 - Google Patents
メラニン凝集ホルモン受容体拮抗剤 Download PDFInfo
- Publication number
- WO2004046110A1 WO2004046110A1 PCT/JP2003/014534 JP0314534W WO2004046110A1 WO 2004046110 A1 WO2004046110 A1 WO 2004046110A1 JP 0314534 W JP0314534 W JP 0314534W WO 2004046110 A1 WO2004046110 A1 WO 2004046110A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lower alkyl
- phenyl
- methyl
- bis
- optionally substituted
- Prior art date
Links
- 102000029828 Melanin-concentrating hormone receptor Human genes 0.000 title abstract description 10
- 108010047068 Melanin-concentrating hormone receptor Proteins 0.000 title abstract description 10
- 239000005557 antagonist Substances 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 222
- 125000000217 alkyl group Chemical group 0.000 claims description 100
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 66
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 25
- 229940122023 Melanin concentrating hormone receptor antagonist Drugs 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000005647 linker group Chemical group 0.000 claims description 6
- GPTFURBXHJWNHR-UHFFFAOYSA-N protopine Chemical compound C1=C2C(=O)CC3=CC=C4OCOC4=C3CN(C)CCC2=CC2=C1OCO2 GPTFURBXHJWNHR-UHFFFAOYSA-N 0.000 claims description 6
- 229940123502 Hormone receptor antagonist Drugs 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000000883 anti-obesity agent Substances 0.000 claims description 4
- 229940125710 antiobesity agent Drugs 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 229920001577 copolymer Chemical group 0.000 claims description 2
- 239000003689 hormone receptor blocking agent Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 9
- 229920000877 Melamine resin Polymers 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 claims 1
- 230000003248 secreting effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 114
- 229920006395 saturated elastomer Polymers 0.000 abstract description 32
- 239000003814 drug Substances 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- 238000006243 chemical reaction Methods 0.000 description 122
- 239000002904 solvent Substances 0.000 description 112
- 230000002829 reductive effect Effects 0.000 description 103
- 239000000243 solution Substances 0.000 description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 description 88
- 238000001816 cooling Methods 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 238000004519 manufacturing process Methods 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- 238000003756 stirring Methods 0.000 description 61
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 46
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 43
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 33
- 238000010438 heat treatment Methods 0.000 description 33
- 239000007864 aqueous solution Substances 0.000 description 31
- 125000004093 cyano group Chemical group *C#N 0.000 description 29
- 150000002430 hydrocarbons Chemical group 0.000 description 29
- 238000000034 method Methods 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 239000007858 starting material Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000002253 acid Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- 239000007787 solid Substances 0.000 description 27
- 239000000126 substance Substances 0.000 description 27
- 238000012360 testing method Methods 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 23
- 238000001914 filtration Methods 0.000 description 22
- 235000019441 ethanol Nutrition 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 235000011114 ammonium hydroxide Nutrition 0.000 description 17
- 239000012442 inert solvent Substances 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 16
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000012280 lithium aluminium hydride Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 14
- 241000282414 Homo sapiens Species 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000011259 mixed solution Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000003638 chemical reducing agent Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 10
- 239000004472 Lysine Substances 0.000 description 10
- 239000007983 Tris buffer Substances 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 238000009739 binding Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 150000002513 isocyanates Chemical class 0.000 description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 101000581404 Mus musculus Melanin-concentrating hormone receptor 1 Proteins 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 150000007529 inorganic bases Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000010079 rubber tapping Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229920004890 Triton X-100 Polymers 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
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- 239000002184 metal Substances 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 150000003335 secondary amines Chemical class 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 5
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- 101150065749 Churc1 gene Proteins 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 101150106280 Mchr1 gene Proteins 0.000 description 5
- 108700036626 Melanin-concentrating hormone receptor 1 Proteins 0.000 description 5
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 description 5
- 102100038239 Protein Churchill Human genes 0.000 description 5
- 102100037469 Protein DEPP1 Human genes 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 230000037406 food intake Effects 0.000 description 5
- 235000012631 food intake Nutrition 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012948 isocyanate Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 4
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 4
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 4
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 4
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
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- 125000000524 functional group Chemical group 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
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- 238000005259 measurement Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
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- 239000011734 sodium Substances 0.000 description 4
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- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—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
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- A—HUMAN NECESSITIES
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- A61P3/04—Anorexiants; Antiobesity agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a medicament, particularly a melanin-concentrating hormone receptor antagonist containing a nitrogen-containing heterocyclic compound as an active ingredient, more preferably an antiobesity agent, and a novel nitrogen-containing saturated heterocyclic ring useful as the medicament. It relates to a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- Obesity is primarily defined as an increase in adipose tissue weight, and is caused by the breakdown of energy and energy consumption. Modern lifestyles such as overeating and lack of exercise can lead to a positive I Nerki balance. (See, for example, Non-Patent Document 1.) In recent years, obesity is not just a matter of body type, but also a lifestyle habit including diabetes and hyperlipidemia. It has become clear that this is a risk factor for idiopathic diseases (for example, see Non-Patent Document 1).
- MGH Melanin-concentrating hormone
- SLC-1 is expressed in many regions of the brain, including the hippocampus, amygdaloid nucleus, thalamus, middle pons, and hypothalamus of humans and rats (for example, see Non-Patent Documents 6 and 7). .
- the hypothalamus there are distributions in the arcuate nucleus, ventromedial nucleus, dorsal medial nucleus, and solitary nucleus that are involved in feeding and I nervous control, and MGH mediates I nervous homeostasis control A possibility has been suggested (for example, see Non-Patent Document 8).
- the SLC-1 inhibitor suppressed MGH-induced food intake and palatable food intake, and suppressed weight gain due to a high fat diet (see, for example, Non-Patent Documents 9 and 10).
- the mela :: concentrating hormone receptor antagonist is useful as an antiobesity agent.
- melanin-concentrating hormone receptor antagonists compounds having a monocyclic aromatic ring as the main skeleton (Patent Document 1), a compound having a fused polycyclic aromatic ring as a main skeleton (Patent Document 2), a compound having methane having two aromatic rings as a main skeleton (Patent Document 3), and a nitrogen-containing non-aromatic heterocyclic ring.
- a compound having a fused skeleton as a main skeleton (Patent Document 4), a 4-phenylmethylpyridine derivative (Patent Document 5), two carpho'nyls and a ropyrimissin Ring-containing compound (Patent Document 6), phenylami / cal; Tnyl-containing aromatic ring compound (Patent Document 7), N-heteroaryl-N'-hetaryldiurea derivative (Patent Document 8), To a pyramid having an optionally substituted amino / phenyl group.
- Lysine derivatives (Patent Document 10), pyridine derivatives having an acyclic hydrocarbon-substituted phenyl group (Patent Document 11), and quinoline derivatives (Patent Documents 12 and 13) have been reported.
- a compound having a nitrogen-containing saturated heterocycle as a main skeleton is not known as the antagonist.
- the pyridine derivative which is useful for the treatment of urinary incontinence and acquired immunodeficiency syndrome (AIDS) (patent documents 12 and 14), is also a useful substitute for protecting neurons.
- a pyridine derivative having a good ami / phenyl is disclosed (Patent Document 11), but there is no disclosure or suggestion of MCH (or SLG-1) inhibitory activity.
- Non-Patent Document 1 Kopelman P.G. (2000) Nature 404, 635-643
- Non-Patent Document 2 Kawauchi.H. Et al. (1983) Nature 305, 321-323
- Non-Patent Document 3 Nahon.J.L. Et al. (1989) Endocrinology 125, 2056-2065
- Non-Patent Document 5 Sai'to, Y. et al. (1999) Nature 400, 265-269
- Non-Patent Document 6 Kolakowski L.F. et al. (1996) FEBS Lett. 398, 253-258
- Non-patent document 8 Hervieu GJ et al. (2000) Eur.J. Neurosci. 12, 1194-1216
- Non-patent document 9 Takekawa S. et al. (2002) Eur.J. Phramacol. 438, 129-135
- Non-Patent Document 10 Borowski B. et al. (2002) Nature Med. 8, 825-830
- Patent Document 1 International Publication No. 01/21577 c. Unfret Patent Document 1 WO 01/82975 Conflict
- Patent Document 3 International Publication No. 01/21169
- Patent Document 4 WO 01/87834 ⁇ Fretlet
- Patent document 5 WO 02/051809 02 ° fret
- Patent Document 6 WO 02/06245 ⁇ ° Fresh ⁇
- Patent Document 7 WO 02/10146 c. Unfret
- Patent Document 8 WO 02/057233 ⁇ ° Fret
- Patent Document 9 International Publication No. 95/06635
- Patent Document 10 JP 2001-226269 A
- Patent Document 11 European Published Patent No. 1045693
- Patent Document 12 European Published Patent 1052992
- Patent Document 13 WO 03/35624 Han'Fret
- Patent Document 14 International Publication No. 03/45920
- L 1 is an amide bond, a sulfonamide 'bond, the heterocycle having an urea, preferably a monocyclic nitrogen-containing saturated heterocycle, particularly preferably a pyridine bond.
- the present inventors have found that a derivative having ricin or pihellacin as a main skeleton and a pharmaceutically acceptable salt have excellent melanin-aggregating holmon receptor antagonistic activity, and completed the present invention.
- the present invention is as follows.
- R 1 and R 2 are the same or different H; or an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
- ALK 1 and ALK 2 same or different, optionally substituted divalent hydrocarbon groups
- n and n melanin-concentrating hormone receptor antagonists comprising the same or different heterocyclic derivatives represented by 0 or 1) or pharmaceutically acceptable salts thereof as active ingredients.
- Preferred melanin-concentrating hormone receptor antagonists are as follows.
- melanin-concentrating hormone receptor antagonist according to any one of 1 to 3 is a substituted lower Aruke :: Ren even ALK 2 is substituted.
- Linker 5 ⁇ 1 having a nitrogen atom (N) - melanin-concentrating hormone receptor antagonist according to any one of 1 to 4 is.
- R 1a , R 1b , R 1 °, R 1d , and R 1e same or different,
- Lower alkyl optionally substituted with HO, halogen, lower alkyl-NH- or lower alkyl-0-alkyl-NH-;
- Cy 1 a hydrocarbon ring; or a hetero ring
- R 2a , R 2b and R same or different
- GN halogen or a lower alkyl optionally substituted with a heterocycle
- H 2 N H 2 N
- H 2 N lower alkyl-NH- or lower alkyl optionally substituted with (lower alkyl) 2 N-;-(substituted with H 2 N, lower alkyl-NH- or (lower alkyl) 2 N- which may be lower alkyl] 2 N-; (lower alkyl - 0-CO -) (H 2 N, lower alkyl - NH- or (lower alkyl) 2 N - but it may also be substituted with lower alkyl) N-;
- Lower alkyl-NHCO- or lower alkyl-NHCO- which may be substituted with (lower alkyl) 2 N-; (lower alkyl) 2 NGO—;
- Lower alkyl or lower alkyl-heterocycle optionally substituted with 0-GO-; -GO-;
- GN halogen, HO, NH 2, lower alkyl - NH -, or (lower alkyl) lower optionally substituted with 2 N loweralkyl - 0-;
- a heterocycle optionally substituted with lower alkyl Group represented by
- R 13a , R 13b and R 13 ° the same or different H; lower alkyl; HO—CO; lower alkyl-0-; lower alkyl-CO—; or lower alkyl-1 0—CO—,
- Alk 3 lower alkylene
- n1 0; or 1
- R 2a and R 2b may be linked to form a lower alkyleneoxy or hetero ring.
- R 3 H; lower alkyl-CO-NH-; lower alkyl optionally substituted by aryl; formula A group represented by
- R 4 and R 5 same or different
- Halogen lower alkyl optionally substituted with H 2 N, lower alkyl-NH-, or (lower alkyl) 2 N- or aryl; or A group represented by
- L 1a -NR "-CO-NR 12 -; - NR" S0 2 -; -S0 2 NR 11 -; - CONR 11 -; -NR "GO_; or - GO - R" and R 12: the same or different hand,
- R 13 , R 14 and R 15 same or different H; or lower alkyl
- Alk 1a Lower alkylene
- R 6 and R 7 same or different
- R 6 and R 7 together form a lower alkylene.
- R 8a and R 8b same or different; H; lower alkyl; or R 8a and R 8b together
- R 9a , R 9b , R 1 ° a and R 1Q same or different H; lower alkyl; or aryl,
- Cy 2 hydrocarbon ring; or heterocyclic CI ring
- R 9b and Cy 2 are fused together to form a fused ring, R 9a , FT and a saturated carbocyclic ring united with adjacent carbon atoms, or R 9a and R 1Qa are linked together to form To form
- R 1a , R 1b , R 1 . , R 1d , or R 1e is H 2 N or GH 3 CONH, or one of m 2 is 1 and m 3 is 0;
- R 6 ⁇ Pi R 7 is HO, is either mi or m 2 there and in m 3 is 0 at 1; L a force "- G0NR 11 - in and either R 4 and R 5
- one is cycloalkyl the other is (1) H, (2) H 2 N, (3) lower alkyl-CO-NH-, (4) halogen, H 2 N, lower alkyl- ⁇ ⁇ ⁇ ⁇ -, or ( Lower alkyl) 2 N-
- L 1a is - CONR 11 - in the case, but and in and Gy 1 is a hydrocarbon ring 0 R "is (1) H, (2) -G0 2 R 13, -
- NR 14 R 15 , -CONR 14 R 15 or lower alkyl which may be substituted with one aryl, (3) cycloalkyl, or (4) halogen or lower alkyl-NH-GO- Is also a good
- L 1a is - CONR 11 - a, with mi is 0, and R 1a Gy 1 is a hydrocarbon ring, R 1b, R lc, R 1d and R 1e or lower alkyl - 0 - For, R 3 ⁇ 4, Any of R 2b and R 2 ° is a group other than H,
- L 1a is -NR "GO- and Gy 1 is a hetero ring
- m 2 is 1 or 2 and one of R 4 and R 5 is a group other than H;
- Preferred nitrogen-containing saturated heterocyclic derivatives are as follows. 10. The nitrogen-containing saturated heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 9, wherein m 4 is 1.
- a nitrogen-containing saturated heterocyclic derivative selected from the following general formula (IIa), general formula (IIb), general formula (lie) and general formula (lid): A nitrogen-containing saturated heterocyclic derivative or a pharmaceutically acceptable salt thereof.
- Lysin-4-yl) acetamide 2,2-bis (4-fluorophenyl) -N- (1- ⁇ (2E) -3- [4- Yloxy) phenyl] phenyl.- 2-ene-1 -yl ⁇ py.Rishi, 'n-4-yl) acetoami 2,2-bis (4-fluorophenyl) -N- (1 - ⁇ (2E) -3- [2-Fluoro -4- (Pihe. Rishi'n-4-yl) phenyl] Proha. 2--4-yl) acetami to 2- ( ⁇ ⁇ (2E) -3-[4- (3-ace'tin-1-ylf.
- a pharmaceutical composition comprising, as an active ingredient, a nitrogen-containing saturated heterocyclic derivative represented by the general formula (II) described in the above item 9 or a pharmaceutically acceptable salt thereof.
- a method for treating a disease associated with a melanin-concentrating hormone receptor comprising administering an effective amount of a salt to a patient.
- Figure 1 is shows the effect on fasting-induced food intake in the case of the c second shows the effect on fasting-induced food intake in the case of the compound of Example 50 was administered subcutaneously the compound of Example 130 was orally administered.
- FIG. 3 shows the effect of subcutaneous administration of the compound of Example 130 on fasting-induced feeding.
- hydrocarbon group J consisting of carbon and hydrogen of G 1 5
- alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenyl, aryl, alkyl-aryl, aryl-aryl, aryl-alkyl or Alkyl-aryl-alkyl is meant.
- alkyl preferably an alkyl, more preferably 0 bets 6 alkyl. Specifically, methyl, 1 chill, fu. Ropyr, Isov. Ropil, Chill, to.
- Alkenyl means a straight-chain or branched hydrocarbon group having at least one double bond, preferably C 2 ⁇ alkenyl; Specific examples include benzyl, aryl, isopropyl, and hexyl.
- Alkynyl '' means a hydrocarbon group which is linear or branched and has at least one or more triple bonds, and is preferably G 2 _ 1 () alkyl ::, specifically,:!: "Cycloalkyl J means a monocyclic saturated hydrocarbon ring which may have a bridge, and preferably a" cycloalkyl J " a good G 3 _ 8 cycloalkyl j also be specifically Sik in ⁇ off. necked pill, cyclohexylene. pentyl, cyclohexane Kizil, bicyclo off to [2.2.1]. chill or Bijikuro [ 2.2.2] octyl, etc.
- Cycloalkenyl means a monocyclic aliphatic unsaturated hydrocarbon ring which may have a bridge, and is preferably a “cycloalkenyl”. Or G 3 _ 8 cycloalkenyl ”, specifically to cyclo. ⁇ , ⁇ C1 hexenyl, ⁇ ⁇ ⁇ [2.2.1]. Tinyl or bicichro [2.2.2] octenyl.
- Li - and Le meanans an aromatic unsaturated hydrocarbon ring, preferably G 6 _ 14 ⁇ Li - ants Le, specifically, phenyl, naphthyl, 1, 2, 3, 4 -Tetrahuman "dinaphthyl, innyl, anthryl or fluorenyl.
- hydrocarbon ring group is the above-mentioned cycloalkyl, cycloalk ;;: or aryl.
- Heterocyclic group is a 4- to 16-membered monocyclic, bicyclic or tricyclic saturated or unsaturated ring containing 1 to 4 heteroatoms selected from N, S and 0. is there.
- the heterocyclic group may have a bridge.
- Unsaturated rings include aromatic rings (heteroaryl) and non-aromatic rings.
- As a monocyclic compound it is possible to use ace “,” nil, t ° mouth lysine, “nil, pyrazo” lysine, "nil”, “oxanil”, pi ".
- aryl is a bicyclic indolinyl, 3, 4 -Methylene oxyphenyl, 3, 4-1 hex, xy phenyl, fenso, franyl, phenyl, nitro, thiocyan, azo, phenyl, hex, Ril, hen'imita f ril, indolyl, 2,3-hin to mouth, ril,
- the “divalent hydrocarbon group” means a divalent group obtained by removing one arbitrary hydrogen atom from the above hydrocarbon group.
- Alkenylene or 10 alkynylene is mentioned.
- Mashiku is _ 6 alkenylene.
- a linker-J having 1 to 6 linking atoms means an interval in which atoms selected from the group consisting of G, N, S, and 0 may be connected and may be substituted. is - 0 -, - S -, -G0-, -SO-, -S0 2 -, -NR 1M -, - CONR 1M -, -NR 1Q4 G0-, -NR 1M S0 2 -, - S0 2 NR 1Q4 -, -0-G0-, - NR 105 CONR 104 -, -NR 105 S0 2 NR 104 -, - GSNR 1M -, - NR 1M GS -, -GOO-, and - GH 2 G0NR 1M - a.
- R 1Q4 and R 1Q5 are the same or different and (1) H; (2) ⁇ Li - Le, HO - 0G-, alkyl - 0-GO-, R 1Q1 R 1G2 N, H 2 NG0-, alkyl - NHGO- Or (alkyl) 2 an alkyl optionally substituted by NGO-; or (3) acyl (4) a hetero B ring optionally substituted by alkyl.
- R 1M and R 1 , or R 1M and R 1Q5 can be combined with an adjacent nitrogen atom to form an optionally substituted heterocycle.
- I Li Preferably, -NR 1t) 4 G0NR 1 ⁇ ) 5 -, - S0 2 NR 1M -, - NR 1M S0 2 -, - G0NR 104 -, - NR 1M G0- and - GO- der Li, further preferably - NR "G0NR 12 -, - S0 2 NR 11 -, -NR 11 S0 2 -, - G0NR 11 -, and - NR 11 is G0-.
- R "and R 12 are one or different, H; -G0 2 R 13, - NR 14 R 15, - CONR 14 R 15 or ⁇ Li - substituted Le lower alkyl; cycloalkyl; or halogen Or aryl which may be substituted by lower alkyl-NH-CO-.
- “Saturated nitrogen-containing heterocycle J” is the above-mentioned saturated heterocycle having at least one nitrogen atom, and is preferably a 4- to 16-membered nitrogen-containing monocyclic saturated which may have a bridge.
- a terrorist ring More preferably, it is f ' !! To Rishi, Nil and Hi. Rashi,, nil, quinucline “nil, 8-asa, bicyclo
- G H5 hydrocarbon group - GO-, and heterocyclic group - GO- der Li specifically HGO -, Asechiru, 1 ° Ropioniru, to "down" Shikabane I le, Nikochinoiru, Te Le, Pi Mouth risi “dilcarbo” nil or pi.
- Optionally substituted hydrocarbon group “optionally substituted heterocyclic ring”, “optionally substituted aryl” and “optionally substituted hydrocarbon 1
- substituent in the “valent group” include the following group a substituents.
- R 1Q1 R 1Q2 N R 1Q1 and R 1Q2 : same or different and substituted by (i) H, (ii) NH 2 , alkyl-NH- or (alkyl) 2 N- alkyl, even (iii) Ashiru, (iv) alkyl - 0-G0-, or (v) C 6 _ 14 ⁇ Li - Le);
- R 103 -0- R 103: (i) C 6 - 14 ⁇ Li - Le, heterocyclic group, GN or R 101 R 102 N ⁇ optionally substituted by alkyl, (ii) alkyl, ⁇ -ring optionally substituted with acyl or alkyl-0-G0-, or (iii) aryl);
- G w which may be substituted by (15) aryl or (16) aryl.
- “Lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
- the active ingredient of the present invention or the compound of the present invention has a double bond, there are geometric isomers and tautomers.
- the present invention includes a separated form or a mixture of these isomers. Further, depending on the type of the substituent, the compound of the present invention may have an asymmetric carbon atom, and an isomer based on the asymmetric carbon atom may exist.
- the present invention includes a mixture of these optical isomers and an isolated one.
- the present invention also includes a compound obtained by converting the compound of the present invention into a radioisotope.
- the active ingredient of the present invention or the compound of the present invention may form a salt with a base depending on the kind of an acid addition salt or a substituent, and the present invention is not limited as long as such a salt is a pharmaceutically acceptable salt. Is included.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, quinic acid, acetic acid, nt ° on acid, oxalic acid, malonic acid, Acid, fumaric acid, maleic acid, lactic acid, phosphoric acid, tartaric acid, counic acid, methanesulfonic acid, ethanesulfonic acid, P-toluenesulfonic acid, acetic acid, and kuramamic acid Acid addition salts with organic acids; inorganic bases such as sodium, iiium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine, itano-lamine, lysine and ornithine, and ammonium salts.
- the present invention also includes various hydrates and solvates of the active ingredient of the present invention, the compound of the present invention and a pharmaceutically acceptable salt thereof, and further includes a
- the active ingredient of the present invention or the compound of the present invention also includes all compounds that are metabolized and converted in vivo, so-called ⁇ ⁇ V luggage.
- ⁇ g ', rack As a base for forming the ⁇ g ', rack ”of the present invention, Prog. Med., 5, 2157-2161 (1985) and“ Development of Pharmaceuticals ”, Volume 7 (Hirokawa Shoten, 1990) 198 and the like.
- the compounds of the present invention and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents.
- an appropriate protecting group a group that can be easily converted to the functional group
- Such functional groups are, for example, amino groups, hydroxyl groups or carboxyl groups such as "xyl groups”.
- protecting groups are, for example, rprotective Groups in Organ by Greene and Wuts. ic Synthes is (2nd edition)
- the protecting groups described in J can be mentioned, and these may be appropriately selected and used according to the reaction conditions.
- a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group as necessary.
- the active ingredient of the present invention is a known compound, it is commercially available or easily available based on various known documents.
- a typical method for producing the compound of the present invention or an intermediate thereof will be described.
- DMS N, N-methylformamite
- DMS0 S, methylsulfoxide
- TFA Mole furan
- TFA Trifle buckled acetic acid
- Tol Toluene
- EtOAc Acetic acid I Chill
- DGE 1,2-symbol: ⁇ -tan
- TEA tri ⁇ -tilamine
- This reaction is an alkylation reaction.
- the reaction is carried out under cooling or heating with stirring using an equivalent amount or an excess amount of one.
- Bases e.g., carbonic acid; inorganic bases such as permium, sodium carbonate and cesium carbonate, or TEA and organic bases such as "W ° at °!
- Toxic and sodium metal alkoxides such as tert-phthaloxide, or sodium hydride and lithium hydride, etc., additives (tetra-n-phenylthiammonium, potassium iodide, sodium iodide, etc.)
- additives tetra-n-phenylthiammonium, potassium iodide, sodium iodide, etc.
- Solvents which are inert to the above reaction include, for example, methane, DCE, chloroform, ses', n, Tol, xylene, ether, THF, THF, oxane, EtOAc, ethanol, Methanol, 2-Froha, Le, acetonitrile, DMF, N, N-si, 'Methylacetoami, N-methylbiloritol', 'Methylimita', Rishi'none, DMS0, acetone, methylethylketone Or a mixed solvent of a homogeneous system and a heterogeneous system thereof, such as water, etc., which is appropriately selected depending on various reaction conditions.
- Compound (6a) is compound (4a) having a hydroxyl group and compound (5)
- compound (6b) is compound (4b) having a thiol group and compound (5)
- compound (9) is an amine. It can be obtained by combining (7) with compound (8) in the reaction.
- X 1 AQ gene; methanesulfonyl pheasant; or a leaving group such as P-toluenesulfonyloxy;
- R 1Q2a H 2 N, alkyl optionally substituted with alkyl-NH- or (alkyl) 2 N-,
- R 103a lower alkyl optionally substituted with halogen or aryl; or aryl optionally substituted with lower alkyl-CO-NH-,
- This reaction is a reductive Amibahi reaction.
- the reaction can be carried out by reacting a primary or secondary amamine with an aldehyde or a ketone according to a conventional method of reductive oxidation.
- a primary or secondary amamine with an aldehyde or a ketone according to a conventional method of reductive oxidation.
- an imine compound is obtained by stirring a primary or secondary amamine and a corresponding amount of the aldehyde or ketone in a solvent inert to the reaction described in the first production method under cooling or heating.
- a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, sodium borohydride and quinic acid in a solvent inert to the above reaction, and the mixture is cooled or heated.
- the reaction is carried out in the presence of an acid (for example, a Lewis acid such as titanium dioxide / acetic acid, acetic acid, or P-toluenesulfonic acid, etc.) in order for the reaction to proceed smoothly.
- an acid for example, a Lewis acid such as titanium dioxide / acetic acid, acetic acid, or P-toluenesulfonic acid, etc.
- the reducing agent may be added immediately after mixing the primary or primary amine with the alcohol or the ketone, or after a certain time.
- the compound (3a), (12) or (15) of the present invention is reacted with an amine [(1), (7) or (13)] and a corresponding amount of aldehyde t or ketone [(10 ), (11) or (14)].
- ALK 3 a divalent hydrocarbon group which may be substituted with 1 less carbon atom than ALK 2 ;
- R 1Q2b and R 1Q2G same or different H; or 7 alkyl optionally substituted by NH 2 , alkyl-NH- or (alkyl) 2 N-,
- R 1301 and R 1fc2 same or different H; or alkyl
- This reaction is an amidation reaction.
- the reaction can be carried out by reacting a primary or secondary amine with a corresponding amount of a carboxylic acid or a reactive derivative thereof.
- a primary or secondary amine for example, the method described in M. Bodanszky, “Pept i de Chem i stryj (1988, p55-73), Nobuo Izumiya et al. I. Chito”, Synthesis Fundamentals and Experiments J (1985, p89-142). No.
- this reaction is carried out by using a commonly used condensing reagent (Si-pi ⁇ -hexylcarbo-si-imi, 1-1-tyl-3- (3-si-methylami-). ', Immit' or 1, 1 '-force ruho "nil imita" soru -ru (CD I) etc.) ]
- a commonly used condensing reagent Si-pi ⁇ -hexylcarbo-si-imi, 1-1-tyl-3- (3-si-methylami-).
- the carboxylic acid is converted to a reactive derivative such as carboxylic acid / logenide by a chemical reagent such as thionyl chloride, oxalyl chloride Q-lide or phosphorus oxychloride, and then reacted with primary or secondary amine.
- a chemical reagent such as thionyl chloride, oxalyl chloride Q-lide or phosphorus oxychloride
- the reaction may be carried out in an inert solvent as described in the first production method, if necessary, using a base (for example, an organic base such as TEA, thiolamine and pyridine). Or an inorganic base such as sodium carbonate or sodium bicarbonate) with stirring under cooling or heating.
- the compound (18), (21), (23), (26) or (28) of the present invention is carboxylic acid or a reactive derivative thereof [(16), (20), (22) , (24) or (27)] and an amine [(17), (19), (1), (25) or (7)] in the reaction.
- X 2 0H; or a leaving group such as a halogen ', a 1-hydroxy or “hydroxy” tri-l-l-yloxy, methoxy, phenoxy, or an ethyl ”group, or a mixed acid anhydride or symmetric acid Elimination site of anhydride, R 102d -C0-: the aforementioned acyl,
- This production method is a method for producing a urea compound by reacting an isocyanate with a primary or secondary amine.
- This reaction is carried out while using an isocyanate and a primary or secondary amamine in a solvent inert to the reaction described in the first production method or in an equal amount or an excess amount thereof, with cooling or stirring under cooling or heating.
- the isocyanate can be synthesized by Curtius rearrangement to the corresponding acid salt (March, ADVANCED
- the compound (30) of the present invention can be obtained by co-reacting an isocyanate (29) with an amine (19).
- Compound (30a) can be produced by reacting isocyanate (31) obtained in the same manner as described above from compound (16) with compound (17).
- the reaction can also be carried out by treating with a phosgene equivalent such as 1-nil, etc.
- a phosgene equivalent such as 1-nil, etc.
- the reaction is carried out in an inert solvent for the above reaction in an equivalent to excess amount of a base (for example, TEA and sulfur).
- a base for example, TEA and sulfur.
- Compound (17a) or compound (19) is treated with a phosgene equivalent in the presence of an organic base such as thiamine or an inorganic base such as sodium bicarbonate) and then reacted with the other compound. it can.
- chlorocarboxylic acid 4- :: trophenyl or chlorocarboxylic acid phenyl
- the intermediate phenylcarbamate may be once isolated and reacted. (Curtius rearrangement) (ureaization)
- This production method comprises the reaction of an amine represented by the general formula (1), a Wittig reagent or Horner-Emmons reagent represented by the general formula (32) and an artehydride or ketone represented by the general formula (33).
- the reaction is carried out in the presence of an equimolar to excess amount of a base (eg, TEA and organic bases such as Pt ° leuethylamine or inorganic bases such as carbonate, sodium carbonate and cesium carbonate).
- a base eg, TEA and organic bases such as Pt ° leuethylamine or inorganic bases such as carbonate, sodium carbonate and cesium carbonate.
- the compound (32) and the compound (33) are used in the above-mentioned inert solvent in an equal amount or an excess amount of either, while stirring under cooling or heating.
- Reaction in the presence of -phenylammonium or potassium iodide, etc. may be advantageous for the reaction to proceed smoothly.
- the compound (1) and the compound (32) may be reacted first, and the intermediate may be once isolated, and then reacted with the compound (33).
- the compound (32) and the compound (33) may be reacted first, and the intermediate may be once isolated, and then reacted with the compound (1).
- ALK 4 an optionally substituted monovalent hydrocarbon group
- X 3 Wittig reagents such as phosphonium salts and phosphites; or groups used in Horner-Emmons reagents, and so on. 6th manufacturing method
- This production method is a method for producing the present compound (36) from a compound having a leaving group represented by the general formula (35).
- compound (35) is converted from an equimolar amount to an excess amount of a clotting reagent (for example, inorganic acid halides such as phosphorus pentachloride and phosphorus oxychloride, or hydrochloric acid, chlorine, sodium chloride and calcium chloride).
- a clotting reagent for example, inorganic acid halides such as phosphorus pentachloride and phosphorus oxychloride, or hydrochloric acid, chlorine, sodium chloride and calcium chloride.
- X 4 a leaving group such as Br, I, methanesulfonyloxy and P-toluenesulfonyloxy;
- ALK 5 The above alkylene, and so on. )
- the starting compound for producing the compound of the present invention may be a known compound, if desired, according to the reaction described in the above-mentioned production method or a reaction obvious to those skilled in the art ( ⁇ March, ADVANCED ORGA IC CHEMISTRY (John WILEY & SONS (1992))) (For example, acylation, alkylation, ureaization, oxidation, reduction (preferably COMPREHENSIVE ORGANIC SYNTHESIS 8 REDUCTION (Pergamon Press) (1991)), /, lipolysis, and the like).
- the typical production methods for the starting compounds are described below, but are not limited to these production methods.
- R 104A , and R 1 ° 4B H or the same or different and optionally substituted with NH 2 , alkyl-NH- or (alkyl) 2 N-,
- R 1MA and R 1MB can form a hydrocarbon ring group together with the adjacent carbon atoms.
- R 1F and R 2D are divalent hydrocarbon groups, R 103B : aryl which may be substituted by aryl, and so on. )
- the starting compound (77), (80), (82), (85), (88), or (90) is the same as the amide conversion reaction of the third production method or the urea reaction of the fourth production method. It can be synthesized by the method.
- R 1A an optionally substituted hydrocarbon group having 1 fewer carbon atoms than R 1
- X 4 a group which can be converted to a thiol group by a reduction reaction of a cyano group or an ester group, The same applies hereinafter. )
- the starting compound (92) can be synthesized by a reduction reaction of the compound (91).
- compound (91) is cooled in the presence of a reducing agent (for example, lithium aluminum hydride or silicon hydride iso: T-ethylaluminum, etc.) in the reaction-inert solvent described in the first production method. It is preferable to carry out the reaction under stirring from below to under heating.
- a reducing agent for example, lithium aluminum hydride or silicon hydride iso: T-ethylaluminum, etc.
- the starting compound (92), (33) or (96) can be synthesized by the oxidation reaction of the compound (93), (94) or (95).
- the compound (93) '(94) or (95) is converted to the first compound in the presence of an oxidizing agent (eg, chromium trioxide, permanic acid: perium or man dioxide).
- an oxidizing agent eg, chromium trioxide, permanic acid: perium or man dioxide.
- the reaction is carried out in a solvent inert to the reaction described in the method with stirring under cooling or heating.
- Ar-X 5 (97) Ar-Li (98) Ar-CHO (99)
- the starting compound (99) can be synthesized by a formylation reaction of the compound (98).
- compound (98) is prepared by cooling or heating the compound (98) in the presence of a formylating agent (eg, DMF or N-methyl-N-phenylformamide) in an inert solvent described in the first production method. It is preferable to carry out the reaction while stirring.
- a formylating agent eg, DMF or N-methyl-N-phenylformamide
- Compound (98) can be synthesized by the lithiation reaction of the corresponding C1 gene compound (97). This reaction is carried out in the presence of a lithiating agent (for example, ⁇ -methyllithium or lithium) in a solvent inert to the above reaction, with stirring under cooling or heating.
- a lithiating agent for example, ⁇ -methyllithium or lithium
- R 1B and R 1e the same or different, H, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and so on.
- the starting compound (102) can be synthesized by a reduction reaction of the compound (101).
- compound (101) is subjected to catalytic hydrogenation in the presence of a reducing agent (eg, lithium aluminum hydride or borane) or using a catalyst (eg, platinum carbon or platinum oxide). It is preferable to carry out the stirring under cooling or heating with stirring in a solvent inert to the reaction described in the first production method under the conditions c. Further , the compound (101) is reacted with a metal (zinc, iron or soot). The reaction can be carried out in the presence and under acidic conditions (acetic acid, formic acid or hydrochloric acid, etc.) while stirring under cooling or heating.
- a reducing agent eg, lithium aluminum hydride or borane
- a catalyst eg, platinum carbon or platinum oxide
- Compound (101) can be synthesized by the oximation reaction of the corresponding carboxyenyl compound (100).
- This reaction is carried out under stirring with cooling or heating using an equivalent amount or an excess amount of compound (100) and x-toluene-xylamine in a solvent inert to the above-mentioned reaction.
- xylamine 0-alkylaniline xylamine (for example, 0-methylhydroxylxylamine or 0-methylsilvitol, 'B xylamine, etc.) may be used.
- Compound (102) can be synthesized in the same manner as in the reaction.
- the starting compound (102) can be synthesized by a reduction reaction of the compound (104).
- compound (104) is subjected to catalytic hydrogenation in the presence of a reducing agent (eg, lithium aluminum hydride, zinc borohydride, etc.), or using a catalyst (eg, lithium carbon, platinum oxide).
- a reducing agent eg, lithium aluminum hydride, zinc borohydride, etc.
- a catalyst eg, lithium carbon, platinum oxide.
- the reaction is carried out with stirring under cooling or heating, and compound (104) is mixed with triphenylphosphine.
- triphenylphosphine can also be carried out in the presence of water, in a solvent inert to the above reaction, with stirring under cooling or heating.
- Compound (104) can be synthesized by an acylation reaction of compound (103) having a corresponding leaving group.
- compound (103) is stirred under cooling or heating in a solvent inert to the above reaction in the presence of an acylating agent (sodium ash, lithium, lithium oxide, etc.). It is done while.
- an acylating agent sodium ash, lithium, lithium oxide, etc.
- X 6 an electron withdrawing group such as a cyano group and a nitro group
- the starting compound (112) is synthesized by reacting a Wittig reagent or Horner-Emmons reagent represented by the general formula (111) with an aldehyde or ketone represented by the general formula (33). it can.
- excess base e.g. carbonate ⁇ Li 1 beam equal amounts, an inorganic base such as sodium carbonate and cesium carbonate, or TEA and shea "W ° Pt ° Ruechiruamin like organic bases, ii ⁇ 1 ⁇ 4 tert off Compound (1 11) with compound (1 11) in the presence of a metal alkoxy such as "toxite” and sodium tert-butoxy "or sodium hydride
- (33) is carried out in an inert solvent described in the first production method, in an equal amount or in an excess amount of either, while stirring under cooling or heating.
- the starting compound (114) or (118) can be synthesized by subjecting the i-ster compound represented by the general formula (113) or (117) to a known reduction reaction.
- This reaction is carried out in the presence of an equal to excess amount of a reducing agent (for example, lithium aluminum hydride, silicon hydride: T-tyl aluminum, sodium borohydride, etc.) and the Ister compound (113) or (117). ) Is carried out in an inert solvent described in the first production method with stirring under cooling or heating.
- a reducing agent for example, lithium aluminum hydride, silicon hydride: T-tyl aluminum, sodium borohydride, etc.
- the carboxylic acid (115) synthesized from the ester compound (113) by a known deprotection reaction can be converted to an equal to excess amount of a reducing agent (eg, lithium aluminum hydride, hydrogenated isophthalic acid, tilluminium). And / or lanthanum) in the inert solvent described in the first production method with stirring under cooling or heating.
- a reducing agent eg, lithium aluminum hydride, hydrogenated isophthalic acid, tilluminium.
- a reducing agent eg, lithium aluminum hydride, hydrogenated isophthalic acid, tilluminium
- carboxylic acid (115) is converted into a reactive derivative with CDI, chlorocarboxylic acid ester and oxalyl chloride, etc.
- a reducing agent eg, lithium aluminum hydride
- sodium borohydride in an inert solvent described in the first method for producing a derivative under cooling or heating.
- the starting compound (116) can be synthesized by subjecting the carboxylic acid (65) to the above-mentioned reduction reaction and then performing deprotection.
- Alk 7 a divalent hydrocarbon group which may be substituted
- This reaction is carried out by reacting compound (119), (120) or (122) with a halogenating agent (for example, thionyl chloride V, thionyl lomi, inorganic acid halides such as phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride). Or hydrochloric acid such as hydrochloric acid and hydrobromic acid) in a solvent inert to the reaction described in the first production method while cooling and stirring under heating. Done. It may be advantageous to carry out the reaction in the absence of a solvent, in order to make the reaction proceed smoothly.
- a halogenating agent for example, thionyl chloride V, thionyl lomi, inorganic acid halides such as phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
- hydrochloric acid such as hydrochloric acid and hydrobromic acid
- Starting material compound (2) may be substituted for the leaving group X 1 is such G H Q alkylsulfonyl Niruokishi or P- torr I emissions sulfonyl O carboxymethyl such as methanesulfonyl O carboxymethyl of (121) or (103) G 6 - 10 ⁇ Li - compound is Le sulfonyl O alkoxy, the compound (119) can be synthesized by sulfonylation of (120) or (122).
- This reaction is carried out by reacting compound (119), (120) or (122) with the corresponding sulfonyl /, or lysine, with a base (for example, TEA, V-isoallopyr I-tylamine, N-methylmorpholine and pyrisine).
- a base for example, TEA, V-isoallopyr I-tylamine, N-methylmorpholine and pyrisine.
- carbonic acid in the presence of an inorganic base such as sodium, sodium carbonate, cesium carbonate and sodium hydrogencarbonate
- R 1Q3e alkyl, and so on.
- the starting compound (124) can be synthesized by subjecting the carhamate form (123) to a reduction reaction.
- compound (123) is stirred in an inert solvent described in the first production method in the presence of an equal to excess amount of a reducing agent (for example, lithium aluminum hydride or the like) under cooling or heating. Be done.
- a reducing agent for example, lithium aluminum hydride or the like
- the Kalha-Mart body (123) was written by Greene and Wuts in rprotect i e Groups in.
- R 401 (Cyl group; I-tyl group; tert-butyl group; and benzyl group, and the like, and so on.)
- the starting compound (128) can be synthesized by performing an addition reaction between the compound (125) and the ketone compound (126) and then performing deprotection.
- the addition reaction between compound (125) and (126) is carried out by cooling compound (125) in an inert solvent described in the first production method, under cooling or heating, with an equivalent to excess amount of base (for example, n-phenylene). (Til lithium, sodium hydride, lithium hydroxide, etc.), then add an equivalent to excess amount of the carboxy compound (126), and stir under cooling or with stirring.
- base for example, n-phenylene.
- the methanesulfonamido (125) is obtained by converting the amine / group to a sulfonamime described in rprotective Groups in Organic Synthes is (2nd edition) by Greene and Wuts. It can be synthesized by using a protecting method. ,,,,
- the starting compound (130) can be synthesized by a reduction reaction of an amito "compound (129).
- This reaction is carried out in the presence of an equal to excess amount of a reducing agent (for example, lithium aluminum hydride and sifolane) in an inert solvent as described in the first production method.
- a reducing agent for example, lithium aluminum hydride and sifolane
- the stirring is performed under cooling or heating.
- the starting compound (132) can be synthesized by a reduction reaction of the nitrile compound (131).
- the nitrile compound (131) is converted to the first production method in the presence of an equal to excess amount of a reducing agent (eg, lithium aluminum hydride, aluminum hydride and lithium trimethoxyaluminum hydride).
- a reducing agent eg, lithium aluminum hydride, aluminum hydride and lithium trimethoxyaluminum hydride.
- the reaction is carried out in the above-mentioned inert solvent with stirring under cooling or heating.
- a hydrogen atmosphere and in the presence of ammonia in the inert solvent described in the first production method, it is possible to perform catalytic reduction using a metal catalyst such as Raney-nickel under cooling or heating and under normal pressure or pressure. It is also performed.
- 1 B — N (131) R 1 B , ⁇ NH 2 (132) 22nd process
- the starting compound (134) can be synthesized by subjecting a carboxyenyl compound represented by the general formula (33) to a Knoevenagel reaction.
- compound (33) is reacted with an equivalent to excess amount of malonic acid (133) in the presence of a base (for example, ammo :: a and pyridine) in an inactive state as described in the first production method.
- a base for example, ammo :: a and pyridine
- the reaction is carried out in a solvent with stirring under cooling or heating.
- the starting compound (136) can be synthesized by subjecting the alcohol represented by the general formula (135) to a Mitsunobu reaction.
- the compound (135) and the compound (106) are converted into an inert solvent described in the first production method in the presence of an equivalent to excess amount of triphenyl; It is performed while stirring under cooling or heating.
- the starting compound (140) can be synthesized by selective protection and deprotection of the amine represented by the general formula (137).
- the primary amine can be converted to an amine by stirring under cooling or heating in an inert solvent described in the first production method under the same conditions as the compound (137). After protecting with 'retain', treat with equal amount of 'tert-tert' and carboxate to protect the secondary amine as cal /, mart.
- the compound (140) in which the secondary amine is selectively protected can be synthesized by deprotection by hydrolysis of the hydroxyl and hydroxylamine.
- the compound of the present invention or the starting compound thus produced is isolated as a free form or as a salt thereof.
- the salt of the compound can be produced by subjecting the compound of the present invention, which is a free base, to a conventional salt-forming reaction.
- the compound of the present invention or a salt thereof is isolated and purified as a hydrate, a solvate thereof, or a polymorphic substance. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatographic formation.
- optical isomers can be obtained by selecting appropriate raw materials or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a chiral stereoisomer with an optically active acid).
- a stereoisomerically pure isomer can be obtained.
- Rf . Reference example number; Ex .: Example number; Structure: Structural formula; Salt: addition salt; Data: Physicochemical properties (FA: Mass spectrometry value FAB-MS (M + 1)); El: Mass spectrometry the value E Bok MS (+); N: NMR (D S0-d 6, TMS internal standard) characteristic peak of - click ⁇ ppm); NO .: compound No.; Me: methyl; Et: iota chill; Pr: 7 ° Ropyr; i Pr: iso 1 ° pill; Bn: hexyl; Ac: acetyl; Boc: tert-7'-toxylcarboxy "nil; Py: piri, n; Az: ace"thicin; Pyr ro I p rishi, n; P ⁇ pe: to p.
- Reference example 1 Dissolve 26.91 g of [1- (tert-r-toxiccarpho, 'nyl) pyroxyl', n-4-yl] acetic acid in 350 ml of DMF, and add N-ethyl-N'-3-, Add “19.19g” of “Imito” hydrochloride and 14.94g of “Niso” toriol to “Roxy” and stir under ice-cooling for 30 minutes. The reaction mixture was diluted with EtOAc, washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate.
- To 1- (tert-F "Toxical '" Tnyl) -4-methylbi To a mixture of 365 mg of lysine-4-carboic acid, TEAO.25mI and To15mI, add 0.39ml of thiophenephosphoric acid azide, 'do', and at room temperature for 4 hours at 80 ° C. Stir for 3 hours. The reaction mixture was allowed to cool, 0.31 ml of (dimethylmethyl) amine was added at room temperature, and the mixture was stirred at room temperature for 3 hours. 50 ml of EtOAc was added to the reaction mixture, and 25 ml of a 10% aqueous solution of citric acid was added.
- Example 178 the compound of Example 178 was obtained in the same manner as in Reference Example 17.
- Reference Example 31 Go to 4- (4-Cyanofenoxy) pi. After dissolving Rishi, N-1-carbo ', tert-phenyl acid, and tyl 26.99 in To 130 ml, stir at -78 ° C and raise the temperature of the reaction solution to -60 ° C. Omol / l Tol solution) was added dropwise so as not to exceed.-After stirring at 78 ° C for 3 hours, 80 ml of saturated aqueous ammonium chloride solution was added dropwise at the same temperature.
- the reaction mixture was diluted with 500 ml of L-L-I-Tel, and anhydrous magnesium sulfate was added, and the mixture was stirred at room temperature for 16 hours. The insoluble material was removed by filtration. Thereafter, the solvent was distilled off under reduced pressure to obtain 13.14 g of tert-butyl 4- (4-formylph / l / xy) pihenyl-1-carboxylate as a pale brown oil.
- the compound of Reference Example 41 was obtained in the same manner as in Reference Example 40.
- Reference Example 91 and Examples 224 to 322 were obtained in the same manner as in Reference Example 42.
- the compound of Reference Example 50 was synthesized in the same manner as in Reference Example 49.
- the compound of Reference Example 56 was synthesized in the same manner as in Reference Example 55.
- the compound of Reference Example 101 was obtained by using the compound of Reference Example 83 and continuing in the same manner as in Reference Examples 92 and 96.
- (2E) -3- (2-Fluoro-4-methoxyphenyl) acrylic acid 1.1 g of methane in a 40 ml solution of methane: 1 M triodore at -78 ° C under a nitrogen atmosphere 40 ml of a boron chloride chloromethane solution was added, and the mixture was stirred overnight at room temperature.
- the reaction solution was poured into ice water, the precipitate was collected by filtration, washed with water and dichloromethane, and dried under reduced pressure to give colorless crystals of (2E) -3- (2-fluoro-4-human) B.
- Kidif: L-nyl) acrylic acid 1.8 g was obtained.
- reaction solution was added with 1M hydrochloric acid under ice-cooling, stirred for 30 minutes, extracted with EtOAc, and washed with a 1M aqueous sodium hydroxide solution, water and saturated saline. After drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, a colorless amorphous 4- (2- ⁇ (4-fluorophenyl) [4- (hydroxymethyl) W1] amino ⁇ -2-year-old Kiseochil) Go to Pi. There was obtained tert-butyl lysine-1-carboxylate, 570m.
- the compound of Reference Example 138 was synthesized in the same manner as in Reference Example 139.
- Reference Example 141 The compound of Reference Example 141 was synthesized in the same manner as in Reference Example 140.
- Reference example 142 The compound of Reference Example 141 was synthesized in the same manner as in Reference Example 140.
- Reference example 142 The compound of Reference Example 141 was synthesized in the same manner as in Reference Example 140.
- Reference example 142 The compound of Reference Example 141 was synthesized in the same manner as in Reference Example 140.
- Reference example 142 Reference example 142
- Example 2 The compound of Example 2 was obtained in the same manner as in Example 1.
- Example 50 The compounds of Examples 5 to 49 were obtained in the same manner as in Example 4.
- Example 50
- Example 50 The obtained compound was subjected to salt formation in the same salt-forming step as in Example 4 to give N- (s-phenylmethyl) -2- ⁇ 1-[(2E) -3-phenylpropyl chloropropane as a white solid.
- the compound of Examples 51 to 62 was obtained in the same manner as in Example 50. Got.
- Example 102 the compound of Example 102 was obtained in the same manner as in Example 101.
- Example 104 The compounds of Examples 105 to 113 were obtained in the same manner as in Example 104.
- Example 115 The compound of Example 115 was obtained in the same manner as in Example 114.
- Example 1 1 7 2-(H (2E)-3- [3- ('': oxy) phenyl] ⁇ .-2-2 -1- ⁇ ⁇ ⁇ ⁇ ⁇ N N-N -(Ciphenylmethyl) acetamide '212m was dissolved in 5 ml of TFA, 296 mg of hetamethylhexane was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with EtOAc and saturated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (form: methanol).
- Example 118 The obtained compound was subjected to salt formation in the same manner as in Example 4 to give trifumarate, and a colorless solid N- (s-phenylmethyl) -2- 2- ⁇ 1-[ (2E) -3- (3-Hydroxyphenyl) proha-2-ene-1-yl] h.h.Risyn-4-yl ⁇ acetamidofumarate (88 mg) was obtained.
- the compound of Example 118 was obtained in the same manner as in Example 117.
- Example 336 The compound of Example 336 was obtained in the same manner as in Example 335.
- Example 339 The compound of Example 339 was obtained in the same manner as in Example 338.
- the SLG-1 expression vector was constructed using pcDNA3.1sf / Zeo (+), and the SLG-1 expression vector was constructed.
- the nucleotide sequence was confirmed by the ⁇ 377 DNA Sequencer (Applied Biosystems).
- 293 cells were seeded at 1 ⁇ 10 6 cells in a 10 cm culture dish (Asahi Technocras) coated with Typel Col lagen, cultured for 24 hours, and 0.8 g of pcDNA3.1 / Hygro (+) (Invitrogen) ) And 7.2 ⁇ g of pSRE-LUG (Glontech) were transfected using FuGENE6 (Boeringer Mannheim) 40 hours after gene transfer, the seeds were reseeded in a 10 Gm culture dish, and 100 jug / ml of Cells that had been selected with hygromycin (Boehringer Mannheim) and survived to form a corn were recovered to obtain SRE-1 uni erase erase stably transfected cells, which were also subjected to SLG-1 expression.
- HGI H7.4
- JOmM MgGI 2 2mM EGTA, 50 g / ml bacitracin
- 25 1 a test compound 25 1 dissolved in 0.1% BSA solution
- 0.5nM [Phe13, [ 125 l] Tyr19] -MGH was added with 25 I to perform a binding reaction.
- the solution was suction-filtered using a class filter (GF / B), and further washed three times with a washing solution (phosphate buffer ⁇ 7.4, 0.01% Triton-X100).
- MGH binding inhibition rate (%) (Radioactivity when the test substance was added-Radioactivity when the excess was added to the unlabeled ligand) ) / (radioactivity when no a test substance is added -. as radioactivity) x100 when adding excess unlabeled Rika "command of IC 50 values were calculated for analyte from the inhibition rate result, example 50 the compounds were shown to IG M value of 430NNI.
- the human SLC-1 stably expressing cells prepared in Example 356 were transformed into 96 litter cells. 6x10 3 cells were seeded per well and cultured at 37 ° C for 24 hours. After adding the test substance and culturing at 37 ° C for 10 minutes, MGH was added to a final concentration of 40 riNI. At this time, a group to which no test substance was added and a group to which MGH was not stimulated were prepared and used to calculate the SLG-1 activation inhibition rate of the test substance.
- luciferin substrate solution containing cell lysate (12.5 mM Tris HCI (pH 7.8), 1 mM DT, 5% glycerol, 0.5% Triton-X100) (3.8 tnM Tricine. 0.3mM MgG0 3, 0.5mM MgS0 4, 20juM EDTA, 2 ⁇ DT Ding, 0.015% GoenzymeA, 40j «M ATP, 0.01% luciferin) was dissolved by adding 0.99 I per Ueru and reacted.
- Lucifer I was measured using a Rumi / Meter (L3000; TA, Inc., Inatetsukura, Ltd.).
- SLC-1 activation inhibition rate 0 (Luciferase activity when stimulated with MGH in the presence of the test substance-Luciferase activity without stimulation with MGH)
- I When stimulated with MGH in the absence of the test substance
- Lucifer I Hf activity-Lucifer Iase without MGH stimulation x100 IG 50 values were calculated. The results are shown in the table below for representative examples. These compounds had a melanin-concentrating hormone receptor inhibitory effect.
- mouse SLG-1 gene Cloning of mouse and SLC-1 stably expressing cells Full-length GDNA (SEQ ID NO: 9) encoding mouse SLC-1 was obtained by PCR. .
- cDNA from mouse brain was used as a template, and 5′-ggaaagcttgccgccatggatytgGaagcctcgttgc—3 ′ (fat number 7), rehabilitation 1 ⁇ 1 5′-ggactGgagtcaggtgGctttgGtttetgtc-3 ′ (SEQ ID NO: 8)
- PGR is P Turbo DNA
- mice SLC-1 expression vector was similarly transfected into this cell using FuGENE6 (Boeringer Mannheim), and selected with 40 ig / ml zeocin (Invitrogen), and the mouse SLG-1 of the present invention was selected. Stable expression cells were obtained.
- the mouse SLC-1 stably expressing cells prepared in Example 359 were collected, washed, suspended in 0.32 sucrose, and homogenized using a Dounce homogenizer. 1, centrifuge at 300 xg for 10 minutes to enucleate The supernatant was centrifuged again at 12,000 ⁇ g for 15 minutes to obtain a precipitate fraction. This was suspended in 50m Tris.HCI (pH7.4) containing 0.0075% Triton-X100, stirred at 4 ° C for 30 minutes, then centrifuged at 12,000 xg for 15 minutes to obtain a suspension. the precipitate 5 mM Tris once with HCI (pH 7.4), membrane lysis ha ,, Tsufa -.
- test substance 50mM Tris.HGI (pH7.4) , eds MgGI 2, 2mM EGTA, lOKIU / ml aprotiniru 1 ig / ml pepstatin a ), And suspended again in membrane dissolution solution; this was used as a membrane fraction.
- the SLG-1 binding inhibitory activity of the test substance was carried out as follows. To a membrane fraction 501 containing 30 g of protein, 50 mM Tris.HCI (pH 7.4), 10 mM MgCI 2 , 2 mM EGTA, 50 / ml bacitracin, a test substance 25 I dissolved in 0.1% BSA solution were added, and further 0.5 nM [Phe 13 ,
- MCH binding inhibition rate (%) (The test substance and MGH were added. Radioactivity when-unlabeled Portugal ', radioactivity when adding a compound) / (radioactivity without adding a test substance-radioactivity when adding an unlabeled Recant ") x100, The IG 50 value of the test substance was calculated from the inhibition rate, and as a result, the compound of Example 50 exhibited an IG 50 value of 300 n.
- the mouse SLC-1 stably expressing cells prepared in Example 359 were seeded in 96 wells at 9 ⁇ 10 3 cells / well and cultured at 37 ° C. for 24 ′ hours. After adding a test substance and culturing at 37 ° C. for 10 minutes, MGH was added to a final concentration of 50 nM. At this time, a group without addition of the test substance and a group not stimulated with NIGH were prepared and used for calculating the inhibition rate of SLG-1 activation of the test substance.
- luciferin substrate solution containing cell lysate (12.5 mM Tris HGI (pH7.8), ImM DTT, 5% glycerol, 0.5% Triton-X100) ( 3.8 mM Tricine, 0.3 mM MgG03, 0.5 mM MgS04, 20 M EDTA, 24 m DTT, 0.015% GoenzymeA, 40 jM ATP, 0.01% luciferin) were added and dissolved at 150 ⁇ l / well. Next, the activity of Lucif I-Se was measured using Rumi / Meta- (ML3000; TA "Inatec Laho" Lateris "). Was used for the measurement.
- SLG-1 activation inhibition rate (%) (Luciferase-se "activity when test substance and MGH are added -Luciferase I-sease activity when nothing is added) / (Only MGH is added the Rushifu error when - Se "activity - Rushifu I La when nothing was added - cell" as active) x 100, was calculated IG 50 values of the test substance from the inhibition rate. The results are shown in the table below for representative examples. These compounds had a melanin-concentrating hormone receptor inhibitory action.
- mice Male ddy mice (7-9 weeks old, SLG Japan) were used. The animals were bred under standard rearing conditions (light period 7: 30-20: 30, room temperature 23 soil 2 ° C, humidity 55 soil 10%), and were allowed to feed and drink freely. All experiments were performed during the light period.
- mice One week after arrival, they were transferred to individually bred poppy's and acclimatized for one week before conducting experiments.
- the compound or vehicle was administered subcutaneously or orally to mice that had been fasted for 16 hours, fed 1 hour after administration, and the amount of food consumed until 1 hour after feeding was measured.
- the compound is dissolved in physiological saline or distilled water containing 4-12% DMS0 (Kanto Chemical Co., Ltd.) and 4-12% cremophor (Nacalai Tesque, Inc.), or 0.5% methylcellulose (Pure Chemical Co., Ltd.) Suspended in distilled water.
- Example 50 3, 10, 30 mg / kg
- Example 130 1, 3, 10, 10 mg / kg
- Food intake was measured up to 1 hour after feeding.
- these compounds showed a significant antifeedant effect.
- typical compounds of the present invention have a melanin-concentrating hormone receptor antagonistic action and an antifeeding effect. It is useful as a drug for the prevention and treatment of lifestyle-related diseases caused by drugs and obesity.
- the active ingredient of the present invention and the compound of the present invention or a pharmaceutically acceptable salt thereof may be used alone as a medicament, but usually one or more kinds thereof are commonly used in the art as pharmaceutical carriers or excipients. It can be prepared by a commonly used method. Administration is oral (including sublingual administration) using tablets, pills, cases, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eyes, etc.
- parenteral administration such as an ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, and an inhalant may be used.
- solid composition for oral administration tablets, powders or granules are used.
- one or more active ingredients may be combined with at least one inert diluent, such as lactose, man :: tol, triglyceride, nitroxif ' Pill cellulose, microcrystalline cellulose, titanium: mixed with copper, polyvinylpyrrolidone or magnesium metasilicate aluminate, etc.
- the composition is prepared according to a conventional method, using an inert diluent.
- lubricating agents such as 7 stearic acid gene
- disintegrating agents such as calcium cellulose gericolate
- stabilizing agents such as lactose or geltamic acid, and asphalic acid.
- Such a solubilizing agent may be contained.
- Tablets or pills may be coated with sugar, such as sucrose, ceratin, human xylopyrcellose mouth and xylopyrylmethylcell mouth-sphthalate, or a film of gastric or enteric substance, if necessary. May be coated.
- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs and the like, and commonly used inert diluents such as purified Contains water and I-Tanol.
- the liquid composition may contain, in addition to the inert diluent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
- Injections for oral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- Aqueous solutions or suspensions include, for example, distilled water for injection and physiological saline.
- examples of the non-aqueous solution or suspension include propylene glycol and ho.
- Vegetable oils such as oils, alcohols, alcohols or oils such as tartar oils, etc.
- Such compositions may further comprise a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizing agent (eg, lactose) or a solubilizing agent (eg, r-glutamic acid, 7.
- adjuvants such as (acid), which are sterilized, for example, by filtration through a filter retaining silica, blending with a bactericide or irradiation.
- these can be used by preparing a sterile solid composition, dissolving or suspending in sterile water or a sterile injection solvent before use.
- the dose described in 1 is appropriate in the range of about 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg per body weight. It is administered in 2 to 4 divided doses.
- the daily dose is suitably about 0.0001-100 mg / kg per body weight, and is administered once or more than once a day.
- the appropriate daily dose is about 0.0001 to 101 ⁇ / body weight.
- the dose should be administered once or multiple times daily.
- about 0.001 to 100 mg / kg per body weight is administered once or more than once a day.
- the dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like.
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Abstract
Description
Claims
Priority Applications (2)
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JP2004553173A JPWO2004046110A1 (ja) | 2002-11-15 | 2003-11-14 | メラニン凝集ホルモン受容体拮抗剤 |
AU2003284402A AU2003284402A1 (en) | 2002-11-15 | 2003-11-14 | Antagonist to melanin-concentrating hormone receptor |
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JP2002332950 | 2002-11-15 | ||
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