JP2005510487A - メラニン凝集ホルモン受容体１としてのピリミジノン類 - Google Patents

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Publication number

JP2005510487A

JP2005510487A JP2003536216A JP2003536216A JP2005510487A JP 2005510487 A JP2005510487 A JP 2005510487A JP 2003536216 A JP2003536216 A JP 2003536216A JP 2003536216 A JP2003536216 A JP 2003536216A JP 2005510487 A JP2005510487 A JP 2005510487A

Authority

JP

Japan

Prior art keywords

formula

group

compound

alkyl

hydrogen

Prior art date

2001-10-15

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 101000581402 Homo sapiens Melanin-concentrating hormone receptor 1 Proteins 0.000 title description 8
• 102000044674 Melanin-concentrating hormone receptor 1 Human genes 0.000 title description 8
• VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 204
• 238000000034 method Methods 0.000 claims abstract description 56
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 239000012453 solvate Substances 0.000 claims abstract description 16
• 241000124008 Mammalia Species 0.000 claims abstract description 9
• 125000000217 alkyl group Chemical group 0.000 claims description 104
• 239000001257 hydrogen Substances 0.000 claims description 75
• 229910052739 hydrogen Inorganic materials 0.000 claims description 75
• 238000006243 chemical reaction Methods 0.000 claims description 66
• 125000005843 halogen group Chemical group 0.000 claims description 62
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 61
• -1 hydroxy, cyano, acetyl Chemical group 0.000 claims description 59
• 125000003545 alkoxy group Chemical group 0.000 claims description 46
• 150000002431 hydrogen Chemical class 0.000 claims description 41
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
• 125000000623 heterocyclic group Chemical group 0.000 claims description 35
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 125000003118 aryl group Chemical group 0.000 claims description 30
• 229910052717 sulfur Inorganic materials 0.000 claims description 30
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
• 125000001072 heteroaryl group Chemical group 0.000 claims description 27
• 239000002904 solvent Substances 0.000 claims description 26
• 125000004043 oxo group Chemical group O=* 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 24
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 125000003342 alkenyl group Chemical group 0.000 claims description 20
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
• 229910052799 carbon Inorganic materials 0.000 claims description 17
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
• 125000003282 alkyl amino group Chemical group 0.000 claims description 14
• 125000004414 alkyl thio group Chemical group 0.000 claims description 14
• 150000001412 amines Chemical class 0.000 claims description 13
• 239000003054 catalyst Substances 0.000 claims description 13
• 238000004519 manufacturing process Methods 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 229910052763 palladium Inorganic materials 0.000 claims description 12
• 208000008589 Obesity Diseases 0.000 claims description 11
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 11
• 230000002152 alkylating effect Effects 0.000 claims description 11
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 11
• 235000020824 obesity Nutrition 0.000 claims description 11
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
• 125000004122 cyclic group Chemical group 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 8
• 125000001153 fluoro group Chemical group F* 0.000 claims description 8
• 230000008569 process Effects 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 206010012601 diabetes mellitus Diseases 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 239000003638 chemical reducing agent Substances 0.000 claims description 6
• 239000003795 chemical substances by application Substances 0.000 claims description 6
• 229940124597 therapeutic agent Drugs 0.000 claims description 6
• 239000002168 alkylating agent Substances 0.000 claims description 5
• 229940100198 alkylating agent Drugs 0.000 claims description 5
• 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 5
• 125000004385 trihaloalkyl group Chemical group 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 4
• 239000003153 chemical reaction reagent Substances 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 3
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
• 208000019901 Anxiety disease Diseases 0.000 claims description 3
• 201000001320 Atherosclerosis Diseases 0.000 claims description 3
• 206010020772 Hypertension Diseases 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 150000001413 amino acids Chemical class 0.000 claims description 3
• 230000036506 anxiety Effects 0.000 claims description 3
• 239000011593 sulfur Substances 0.000 claims description 3
• 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 2
• 239000007868 Raney catalyst Substances 0.000 claims description 2
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
• 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
• 238000006619 Stille reaction Methods 0.000 claims description 2
• 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
• 239000007822 coupling agent Substances 0.000 claims description 2
• 230000035790 physiological processes and functions Effects 0.000 claims description 2
• 238000006268 reductive amination reaction Methods 0.000 claims description 2
• KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 claims description 2
• 229910000080 stannane Inorganic materials 0.000 claims description 2
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 3
• 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims 1
• ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
• 229910052796 boron Inorganic materials 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 70
• 238000002360 preparation method Methods 0.000 abstract description 22
• 238000009472 formulation Methods 0.000 abstract description 10
• 239000000126 substance Substances 0.000 abstract description 3
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 128
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 88
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
• 239000000047 product Substances 0.000 description 55
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
• 239000000243 solution Substances 0.000 description 48
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• 229910001868 water Inorganic materials 0.000 description 41
• 235000019439 ethyl acetate Nutrition 0.000 description 35
• 239000007787 solid Substances 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
• 235000002639 sodium chloride Nutrition 0.000 description 22
• 239000011541 reaction mixture Substances 0.000 description 20
• 238000002390 rotary evaporation Methods 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 18
• 239000000843 powder Substances 0.000 description 16
• 239000003921 oil Substances 0.000 description 15
• 235000019198 oils Nutrition 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• 239000011734 sodium Substances 0.000 description 13
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 13
• 239000000543 intermediate Substances 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 11
• 239000012267 brine Substances 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
• ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 239000000463 material Substances 0.000 description 9
• 238000010898 silica gel chromatography Methods 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• 0 CC(*)(C=C(C=C1)N)C=C1N(C)C Chemical compound CC(*)(C=C(C=C1)N)C=C1N(C)C 0.000 description 8
• 101800002739 Melanin-concentrating hormone Proteins 0.000 description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
• 239000005557 antagonist Substances 0.000 description 8
• 229910000024 caesium carbonate Inorganic materials 0.000 description 8
• IQFQFNJSTCCSSP-UHFFFAOYSA-N 2-phenyl-1h-thieno[3,2-d]pyrimidin-4-one Chemical compound N1C=2C=CSC=2C(=O)N=C1C1=CC=CC=C1 IQFQFNJSTCCSSP-UHFFFAOYSA-N 0.000 description 7
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
• 239000002609 medium Substances 0.000 description 7
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
• WEKBYHGPOQSONW-UHFFFAOYSA-N 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4-one Chemical compound C1=C(O)C(OC)=CC(N2C(C=3SC(=CC=3N=C2)C=2C=CC(Cl)=CC=2)=O)=C1 WEKBYHGPOQSONW-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
• 239000007864 aqueous solution Substances 0.000 description 6
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
• 125000004432 carbon atom Chemical group C* 0.000 description 6
• 201000010099 disease Diseases 0.000 description 6
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• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
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• 241001465754 Metazoa Species 0.000 description 5
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• MELGGDOYSMRBGA-UHFFFAOYSA-N methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate Chemical compound NC1=C(C(=O)OC)SC(C=2C=CC(Cl)=CC=2)=C1 MELGGDOYSMRBGA-UHFFFAOYSA-N 0.000 description 5
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• VBPMITJBSXBGOI-UHFFFAOYSA-N 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)aniline Chemical compound COC1=CC(N)=CC=C1OCCN1CCCC1 VBPMITJBSXBGOI-UHFFFAOYSA-N 0.000 description 4
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• 229920002472 Starch Polymers 0.000 description 4
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• 150000001409 amidines Chemical group 0.000 description 4
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
• ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 4
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
• 231100000252 nontoxic Toxicity 0.000 description 3
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