JP4630820B2 - 4−アミノ−7,8−ジヒドロプテリジン類、これらを含む医薬組成物、および一酸化窒素レベル上昇によってもたらされる疾病の治療に対するそれらの使用 - Google Patents
4−アミノ−7,8−ジヒドロプテリジン類、これらを含む医薬組成物、および一酸化窒素レベル上昇によってもたらされる疾病の治療に対するそれらの使用 Download PDFInfo
- Publication number
- JP4630820B2 JP4630820B2 JP2005512684A JP2005512684A JP4630820B2 JP 4630820 B2 JP4630820 B2 JP 4630820B2 JP 2005512684 A JP2005512684 A JP 2005512684A JP 2005512684 A JP2005512684 A JP 2005512684A JP 4630820 B2 JP4630820 B2 JP 4630820B2
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- Prior art keywords
- alkyl
- hydrogen
- radicals
- aryl
- amino
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- 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.)
- Expired - Lifetime
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title description 50
- 201000010099 disease Diseases 0.000 title description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 8
- 238000011282 treatment Methods 0.000 title description 7
- OFOBCDMFTWNACR-UHFFFAOYSA-N 7,8-dihydropteridin-4-amine Chemical class N1CC=NC2=C1N=CN=C2N OFOBCDMFTWNACR-UHFFFAOYSA-N 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- -1 1,2-dihydroxypropyl Chemical group 0.000 claims description 76
- 150000001875 compounds Chemical class 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 150000002483 hydrogen compounds Chemical class 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 125000003118 aryl group Chemical group 0.000 description 23
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 22
- 125000000217 alkyl group Chemical group 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- 150000003254 radicals Chemical class 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 14
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 150000005840 aryl radicals Chemical class 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 11
- 150000002367 halogens Chemical class 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 6
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002877 alkyl aryl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- UTTPUMOOQSNOHH-UHFFFAOYSA-N 2-amino-6-chloro-5-nitro-1h-pyrimidin-4-one Chemical compound NC1=NC(=O)C([N+]([O-])=O)=C(Cl)N1 UTTPUMOOQSNOHH-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229940127557 pharmaceutical product Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 150000003195 pteridines Chemical class 0.000 description 4
- 150000003230 pyrimidines Chemical class 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UUEDCZUDIRXZHY-UHFFFAOYSA-N 2-[(2,6-diamino-5-nitropyrimidin-4-yl)-methylamino]-1-phenylethanone Chemical compound N=1C(N)=NC(N)=C([N+]([O-])=O)C=1N(C)CC(=O)C1=CC=CC=C1 UUEDCZUDIRXZHY-UHFFFAOYSA-N 0.000 description 3
- IDAICLIJTRXNER-UHFFFAOYSA-N 5,6,7,8-tetrahydropteridine Chemical class C1=NC=C2NCCNC2=N1 IDAICLIJTRXNER-UHFFFAOYSA-N 0.000 description 3
- PRDGFSDICDDIFG-UHFFFAOYSA-N 7,8-dihydropteridine Chemical compound C1=NC=C2N=CCNC2=N1 PRDGFSDICDDIFG-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 3
- LHQIJBMDNUYRAM-UHFFFAOYSA-N L-erythro-Biopterin Natural products N1=C(N)NC(=O)C2=NC(C(O)C(O)C)=CN=C21 LHQIJBMDNUYRAM-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical class N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 3
- LZTWMDUXAADMLF-UHFFFAOYSA-N 2-(methylamino)-1-phenylethanone;hydrochloride Chemical compound Cl.CNCC(=O)C1=CC=CC=C1 LZTWMDUXAADMLF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 2
- PLYTVAFAKDFFKM-UHFFFAOYSA-N 3,4-dimethylmorpholine Chemical compound CC1COCCN1C PLYTVAFAKDFFKM-UHFFFAOYSA-N 0.000 description 2
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- CQVRSNVYTNWGII-UHFFFAOYSA-N 8-methyl-6-phenyl-7h-pteridine-2,4-diamine Chemical compound N=1C2=C(N)N=C(N)N=C2N(C)CC=1C1=CC=CC=C1 CQVRSNVYTNWGII-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- LHQIJBMDNUYRAM-DZSWIPIPSA-N L-erythro-biopterin Chemical compound N1=C(N)NC(=O)C2=NC([C@@H](O)[C@@H](O)C)=CN=C21 LHQIJBMDNUYRAM-DZSWIPIPSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- 150000001298 alcohols Chemical class 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
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- FSEUPUDHEBLWJY-HWKANZROSA-N diacetylmonoxime Chemical compound CC(=O)C(\C)=N\O FSEUPUDHEBLWJY-HWKANZROSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
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Description
R1は、水素、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1-C3)-アルキルアリール、またはアリールアルキルであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは1つ以上の置換基によって、好ましくは置換基R6によって置換され得るものであり、
R2は、R1とは独立して、水素、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1-C3)-アルキルアリール、またはアリールアルキルであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは1つ以上の置換基、好ましくは置換基R6によって置換され得るか、または、
R1およびR2が、これらを有する窒素原子と共に3〜8員環を形成してもよく、これは場合によりN、O、Sの群からの0、1または2個のさらなるヘテロ原子を含んでもよく、これは場合により1つ以上のラジカル、好ましくはR6ラジカルによって置換され、
R4は、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、または(C1-C20)-アルキルアリール、好ましくは(C1-C3)-アルキルアリール、アリールアルキル、-CO-O-アルキル、好ましくは-CO-O-(C1-C5)-アルキル、-CO-O-アリール、-CO-アルキル、好ましくは-CO-(C1-C5)-アルキル、または-CO-アリールであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは1つ以上の置換基、特に置換基R7によって置換され得るものであり、
R6は、-F、-Cl、-Br、-I、-OH、-O-(C1-C10)-アルキル、-O-フェニル、-O-CO-(C1-C10)-アルキル、-O-CO-アリール、-NR8R9、オキソ、フェニル、-CO-(C1-C5)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C5)-アルキル、-CO-O-アリール、-S(O)n-(C1-C5)-アルキル、または-SO2-NR8R9であり、
R7は、R6とは独立して、R6を意味するものの1つを有し、
R8は、水素または(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルであり、
R9は、水素、(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルまたはアリール、好ましくはフェニルであり、
R11は、水素、(C1-C20)-アルキル、好ましくは(C1-C5)-アルキル、アリール、-CO-アルキル、-CO-アリールであり、ここで有機ラジカル、好ましくはアルキルおよび/またはアリールラジカルは1つ以上の置換基、好ましくは置換基R6によって置換され得るものであり、
R12は、水素、(C1-C10)-アルキル、好ましくは(C1-C5)-アルキル、アリール、-O-(C1-C10)-アルキル、-O-フェニル、-O-CO-(C1-C10)-アルキル、-O-CO-アリール、-NR8R9、フェニル、-CO-(C1-C10)-アルキル、好ましくは-CO-(C1-C10)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C10)-アルキル、好ましくは-CO-O-(C1-C10)-アルキル、-CO-O-アリール、-Fまたは-Clであり、
R13は、R12とは独立して、R12を意味するものの1つを有し、
アリールは、好ましくはフェニル、ナフチル、またはヘテロアリールであり、各々は置換されなくてもされてもよく、例えば、ハロゲン、(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルまたはフェニル、-OH、-O-(C1-C20)-アルキル、好ましくは-O-(C1-C5)-アルキル、(C1-C20)-アルキレンジオキシ、好ましくは(C1-C2)-アルキレンジオキシ、-NR8R9、-NO2、-CO-(C1-C5)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C5)-アルキル、-S(O)n-(C1-C5)-アルキル、-SO2-NR8R9の群からの1つ以上の同一または異なる置換基により置換され得るものであり、
ヘテロアリールは、不飽和5〜7員複素環であり、これはO、N、Sの群から1つ以上のヘテロ原子を含み、
nは、0、1または2であり、
これらのすべての立体異性体および互変異性体、ならびにあらゆる割合でのこれらの混合物、そしてこれらの生理学的に許容される塩、水和物、およびエステルにおいてである。
R1は、好ましくは水素、1つ以上の置換基R6により置換され得る(C2-C4)-アルキル、または(C1-C2)-アルキルアリールであり、そしてR1は特に好ましくは水素であり、
R2は、好ましくは水素、1つ以上の置換基R6により置換され得る(C2-C4)-アルキル、または(C1-C2)-アルキルアリールであり、そしてR2は特に好ましくは水素、シクロヘキシルメチル、またはシクロヘキシルエチルである。
R12は、好ましくは水素、メチル、またはエチルであり、
R13は、好ましくは水素、メチル、またはエチルである。
R1は、水素であり、
R2は、水素、(C1-C20)-アルキル、またはシクロアルキルアルキルであり、
R4は、フェニル、(C1-C20)-アルキルフェニル、または(C12-C20)-アルキルであり、これは場合により-OH、アルキルオキシ、またはハロゲンで置換され、ここで、
R11、R12およびR13が互いに独立して、水素またはメチルのいずれかである。
R1が、シクロアルキル、シクロアルキルアルキル、または(C1-C10)-アルキルであり、
R2が、水素であり、
R4が、1,2-ジヒドロキシプロピルであり、そして
R11、R12およびR13が互いに独立して、水素またはメチルのいずれかであるような化合物に代表される。
R1は、水素であり、
R2は、水素、(C1-C20)-アルキル、またはシクロアルキルアルキルであり、
R4は、フェニル、(C1-C20)-アルキルフェニル、または(C1-C20)-アルキルであり、これは場合により-OH、(C1-C20)-アルキルオキシ、またはハロゲンで置換され、
R11は、(C1-C5)-アルキル、好ましくはメチルまたはエチルであり、これは場合により置換され、そして、
R12およびR13は互いに独立して、水素または(C1-C5)-アルキル、好ましくはメチルまたはエチルのいずれかであり、これは場合により置換される。
R1が、シクロヘキシルであり、場合により(C1-C5)-アルキルまたは(C1-C5)-O-アルキルで置換され、
R2が、水素であり、
R4が、1,2-ジヒドロキシプロピルであり、そして
R12およびR13が互いに独立して、水素またはメチルのいずれかであるような化合物である。
R1は、水素、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1-C3)-アルキルアリールまたはアリールアルキルであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは、1つ以上の置換基、好ましくは置換基R6によって置換され得るものであり、
R2は、R1とは独立して、水素、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、アルキルアリール、好ましくは(C1-C3)-アルキルアリールまたはアリールアルキルであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは、1つ以上の置換基、好ましくは置換基R6によって置換され得るか、または
R1およびR2が、これらを有する窒素原子と共に3〜8員環を形成してもよく、これは場合によりN、O、Sの群からの0、1または2個のさらなるヘテロ原子を含んでもよく、これは場合により1つ以上のラジカル、好ましくはR6ラジカルによって置換され、
R4は、(C1-C20)-アルキル、(C1-C20)-アルケニル、(C1-C20)-アルキニル、好ましくは(C1-C10)-アルキル、シクロアルキル、シクロアルケニル、好ましくは(C3-C8)-シクロアルキル、シクロアルキルアルキル、アリール、またはアルキルアリール、好ましくは(C1-C3)-アルキルアリール、アリールアルキル、-CO-O-アルキル、好ましくは-CO-O-(C1-C5)-アルキル、-CO-O-アリール、-CO-アルキル、好ましくは-CO-(C1-C5)-アルキルまたは-CO-アリールであり、ここで有機ラジカル、好ましくはアルキルおよびアリールラジカルは、1つ以上の置換基、特に置換基R7によって置換され得るものであり、
R6は、-F、-Cl、-Br、-I、-OH、-O-(C1-C10)-アルキル、-O-フェニル、-O-CO-(C1-C10)-アルキル、-O-CO-アリール、-NR8R9、オキソ、フェニル、-CO-(C1-C5)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C5)-アルキル、-CO-O-アリール、-S(O)n-(C1-C5)-アルキル、-SO2-NR8R9であり、
R7は、R6とは独立して、R6を意味するものの1つを有し、
R8は、水素または(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルであり、
R9は、水素、(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルまたはアリール、好ましくはフェニルであり、
R11は、水素、(C1-C20)-アルキル、(C1-C20)-アルキルアリール、好ましくは(C1-C5)-アルキル、アリール、アリールアルキル、-CO-アルキル、-CO-アリールであり、ここで有機ラジカル、好ましくはアルキルおよび/またはアリールラジカルは、1つ以上の置換基、好ましくは置換基R6によって置換され得るものであり、
R12は、水素、(C1-C5)-アルキル、アリール、-O-(C1-C10)-アルキル、-O-フェニル、-O-CO-(C1-C10)-アルキル、-O-CO-アリール、-NR8R9、フェニル、-CO-(C1-C5)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C5)-アルキル、-CO-O-アリール、-Fまたは-Clであり、
R13は、R12とは独立して、R12を意味するものの1つを有し、
アリールは、好ましくはフェニル、ナフチル、またはヘテロアリールであり、各々は置換されなくてもされてもよく、例えば、ハロゲン、(C1-C20)-アルキル、好ましくは(C1-C5)-アルキルまたはフェニル、-OH、-O-(C1-C20)-アルキル、好ましくは-O-(C1-C5)-アルキル、(C1-C20)-アルキレンジオキシ、好ましくは(C1-C2)-アルキレンジオキシ、-NR8R9、-NO2、-CO-(C1-C5)-アルキル、-CF3、-CN、-CONR8R9、-COOH、-CO-O-(C1-C5)-アルキル、-S(O)n-(C1-C5)-アルキル、-SO2-NR8R9の群からの1つ以上の同一または異なる置換基により置換され得るものであり、
ヘテロアリールは、不飽和5〜7員環複素環であり、これはO、N、Sの群から1つ以上のヘテロ原子を含み、
nは、0、1または2であり、
これらのすべての立体異性体および互変異性体、ならびにあらゆる割合でのこれらの混合物、そしてこれらの生理学的に許容される塩、水和物、およびエステルにおいてであり、ただし、式(Ia)の化合物が除外されるものとし、
R1は、好ましくは水素、1つ以上の置換基R6により置換され得る(C2-C4)-アルキル、または(C1-C2)-アルキルアリールであり、そしてR1は特に好ましくは水素であり、
R2は、好ましくは水素、1つ以上の置換基R6により置換され得る(C2-C4)-アルキル、または(C1-C2)-アルキルアリールであり、そしてR2は特に好ましくは水素またはシクロヘキシルメチルであり、
さらに、R1およびR2は好ましくは、これらを有する窒素原子と共に5〜7員環を形成し、これは好ましくはN、O、Sの群からの他のヘテロ原子を含まないかまたは1つだけ含む。このタイプの環で特に非常に好ましいものは、ピロリジン、ピペリジン、モルホリン、ジメチルモルホリン、チオモルホリン、またはN-(C1-C2)-アルキルピペラジンであり、これらの環はまた、これら自身が、例えば-OH、-O-(C1-C3)-アルキル、-NR8R9、または-COOHによって置換され得る。
R12は、好ましくは水素、メチル、またはエチルであり
R13は、好ましくは水素、メチル、またはエチルである。
1.1. 2,4-ジアミノ-8-メチル-6-フェニル-7,8-ジヒドロプテリジンの調製
N8原子にアルキル置換を有する本発明のプテリジン化合物についての例示としての、2,4-ジアミノ-8-メチル-6-フェニル-7,8-ジヒドロプテリジンは、以下のプロトコルに従って合成され得る。
第1のステップにおいて、2-アミノ-4-クロロ-6-N-シクロヘキシルメチルアミノ-5-ニトロピリミジンは、2-アミノ-4-クロロ-6-ヒドロキシ-5-ニトロピリミジンから出発して、Hanaya Tら, Pteridines(1995)Vol. 6 pp. 1-7に記載される光延反応を用いて調製され得る(実施例2.2bもまた参照せよ)。
2.1 in vivoにおける安定性の判定
化合物4-N-シクロヘキシルメチルアミノ-5,6,7,8-テトラヒドロビオプテリン(化合物A)、2-アミノ-4-ピペリジノ-6-フェニル-(R,S)-5,6,7,8-テトラヒドロプテリジン(化合物B)、および2-アミノ-4-ジ-n-プロピルアミノ-6-(4-メトキシフェニル)-(R,S)-5,6,7,8-テトラヒドロプテリジン(化合物C)を、オスのSprague-Dawleyラットに静脈注射した(1〜10 mg/kg)。静脈血サンプルは注射後8時間まで採取し、そして注射したテトラヒドロ化合物およびそれらに相当するジヒドロ誘導体(in vivoにおいて自然に生成する)について、LC-MS/MSによって解析した。テトラヒドロ化合物が5分未満の半減期で酸化される一方、相当するジヒドロ化合物は有意に緩慢な速度で血流から除去された(表1を参照せよ)。
a)2-アミノ-4-ピペリジノ-6-フェニル-(R,S)-5,6,7,8-テトラヒドロプテリジン(化合物B)および2-アミノ-4-ジ-n-プロピルアミノ-6-(4-メトキシフェニル)-(R,S)-5,6,7,8-テトラヒドロプテリジン(化合物C)の合成
2-アミノ-4-ピペリジノ-6-フェニル-(R,S)-5,6,7,8-テトラヒドロプテリジンおよび2-アミノ-4-ジ-n-プロピルアミノ-6-(4-メトキシフェニル)-(R,S)-5,6,7,8-テトラヒドロプテリジンは、Matterら, Journal of Medical Chemistry, 2002, 45, 14, 2923-2941ページまたはWO 01/21619に記載されるように調製した。
1. トリ-N 2 ,1’,2’-O-アセチル-L-ビオプテリンの合成
ピリジン(40 ml)および無水酢酸(20 ml)中に溶解したビオプテリン(1 g、4.21 mmol)を100℃に加熱した。3時間後、TLCによる判定で出発材料が消失し、混合液から溶媒を蒸発させて乾燥させ、残渣物をシリカゲルクロマトグラフィーにかけ、ジクロロメタン(DCM)〜DCM:MeOH(95:5)を用いて溶出した。生成物トリ-N2,1’,2’-O-アセチル-L-ビオプテリンは、茶色の泡状物質として定量的な収量(1.5 g)で得られた。生成物を、NMRおよび質量分析によって解析した。
トリフェニルホスフィン(1.2 g、5.4 mmol)および2-フェニルエタノール(0.65 g、5.4 mmol)を、1,4-ジオキサン(7 ml)中のトリ-N2,1,2’-O-アセチル-L-ビオプテリン(1.5 g、4.21 mmol)の溶液に、順に添加した。この混合液に、ジイソプロピルアゾジカルボキシラート(1.05 ml、5.4 mmol)を滴下して添加し、そしてこの反応混合液を室温で18時間攪拌した。蒸発乾燥、およびAcOEt(1:2)の次にAcOEtで溶出するシリカゲルカラムクロマトグラフィーにより、予想される生成物がトリフェニルホスフィン酸化物と共に得られた。
次に、ステップ2で得られた反応混合物を、1,4-ジオキサン(20 ml)中のシクロヘキシルメチルアミン(2.2 ml、16.8 mmol)と共に、還流下で2時間加熱した。この反応液の量を蒸発乾燥によって50%減らし、そして次に濃アンモニア(32%)(30 ml)を添加した。その後、混合液を18時間攪拌した。反応混合液を蒸発乾燥させ、そしてシリカゲルクロマトグラフィーにかけて、ジクロロメタン(DCM):MeOH(9:1)〜DCM:MeOH:NH4OH(90:10:1)を用いて溶出して、予想される生成物を黄色固体として得た(0.9 g、収率64%)。生成物を、NMRおよび質量分析によって解析した。
トリフルオロ酢酸(15 ml、TFA)中に溶解した4-N-シクロヘキシルメチルアミノ-4-デオキシ-L-ビオプテリン(1.1 g、3.3 mmol)を、事前に金属白金に水素化しておいたTFA(10 ml)中のPtO2(0.18 g)の懸濁液に添加した。この反応混合液を3時間水素化し、セライトを通して濾過し、そして蒸発乾燥した。残渣物をHCl(メタノール中1.25 M)(20 ml)中に溶解し、そして一晩攪拌した。溶媒を蒸発させて乾燥させ、そしてAcOEtを用いて粉砕することにより、予想される生成物が濾過によって緑色粉末として生じる(1.3 g、収率97%)。生成物を、NMR、質量分析および元素分析によって解析した。
NO放出の阻害
一般式(I)の化合物によるNO放出の阻害は、KnippおよびVasak(Analytical Biochemistry 286, 257-264 (2000))の研究に基づいた活性アッセイによって測定され得る。精製されたNO合成酵素(NOS)についてのこのアッセイにおいて、NO生成中に得られる副産物L-シトルリンを定量的に測定する。これは、試薬ジアセチルモノオキシムとチオセミカルバジドとを用いたシトルリンのカルバミド基との間の発色反応を利用することで実施される。この反応の後、呈色した生成物を540 nmでの吸光度を測定することにより、直接的に定量することが可能である。
Claims (3)
- 請求項1に記載の化合物であって、ここで
R 4 は、フェニルであり、
R 11 は、メチルである、化合物。 - 請求項1に記載の化合物であって、ここで
R 1 およびR 2 は水素であり、
R 4 は1,2-ジヒドロキシプロピルであり、そして
R 11 はメチルまたはエチルである、化合物。
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PCT/EP2003/014970 WO2005063752A1 (en) | 2003-12-30 | 2003-12-30 | 4-amino-7,8-dihydropteridines, pharmaceutical compositions containing them and their use for the treatment of diseases which are caused by an increased nitric oxide level |
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EP (1) | EP1699793A1 (ja) |
JP (1) | JP4630820B2 (ja) |
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WO2008003149A2 (en) * | 2006-07-06 | 2008-01-10 | Gilead Sciences , Inc. | Substituted pteridines for the treatment and prevention of viral infections |
US10144736B2 (en) * | 2006-07-20 | 2018-12-04 | Gilead Sciences, Inc. | Substituted pteridines useful for the treatment and prevention of viral infections |
CN102633799B (zh) | 2012-04-10 | 2014-06-25 | 凯莱英医药集团(天津)股份有限公司 | 一种从消旋体中间体拆分路线合成二盐酸沙丙蝶呤的方法 |
CN102627644B (zh) | 2012-04-10 | 2014-04-16 | 凯莱英医药集团(天津)股份有限公司 | 一种通过直接手性合成方法制备二盐酸沙丙蝶呤的方法 |
CN107108615B (zh) | 2015-03-04 | 2020-11-20 | 吉利德科学公司 | Toll样受体调节性4,6-二氨基-吡啶并[3,2-D]嘧啶化合物 |
EP3507276B1 (en) | 2016-09-02 | 2021-11-03 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
US10640499B2 (en) | 2016-09-02 | 2020-05-05 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
TW202212339A (zh) | 2019-04-17 | 2022-04-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
TW202210480A (zh) | 2019-04-17 | 2022-03-16 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
TW202115056A (zh) | 2019-06-28 | 2021-04-16 | 美商基利科學股份有限公司 | 類鐸受體調節劑化合物的製備方法 |
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US3242178A (en) * | 1963-08-20 | 1966-03-22 | Burroughs Wellcome Co | 2, 4-diamino-6-hydroxymethyl-7, 8-dihydropteridine |
FR2523019B1 (fr) * | 1982-03-15 | 1985-11-08 | Commissariat Energie Atomique | Buse de sablage a jet plat et contenant des particules solides abrasives, et procede de mise en oeuvre d'une buse de sablage pour la decontamination radioactive |
US4746659A (en) * | 1985-12-30 | 1988-05-24 | Sri International | Diastereomers of 10-alkyl-10-deazaminopterins and process for preparing the same |
GB8929076D0 (en) | 1989-12-22 | 1990-02-28 | Scras | Treatment of shock by blocking agents of edrf effect or formation |
GB9127376D0 (en) | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
DE4418097A1 (de) * | 1994-05-24 | 1995-11-30 | Cassella Ag | Verwendung von Tetrahydropteridin-Derivaten als Hemmstoffe der NO-Synthase |
US5922713A (en) * | 1997-06-26 | 1999-07-13 | Werner; Ernst | Inhibition of nitric oxide synthase |
DE59703603D1 (de) * | 1997-10-06 | 2001-06-28 | Ernst Werner | Pteridinderivate als NO Synthase-Hemmer |
JP2002533464A (ja) | 1998-12-28 | 2002-10-08 | カー・イュー・ルーベン・リサーチ・アンド・ディベロップメント | プテリジン誘導体の免疫抑制作用 |
DE19944767A1 (de) * | 1999-09-17 | 2001-03-29 | Vasopharm Biotech Gmbh & Co Kg | N-substituierte 4-Aminopteridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
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AU2003290127A1 (en) | 2005-07-21 |
JP2007525407A (ja) | 2007-09-06 |
EP1699793A1 (en) | 2006-09-13 |
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