CN1268126A - 嘧啶-2,4,6-三酮衍生物、其制备方法以及含有这些化合物的药物产品 - Google Patents
嘧啶-2,4,6-三酮衍生物、其制备方法以及含有这些化合物的药物产品 Download PDFInfo
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- CN1268126A CN1268126A CN98808440A CN98808440A CN1268126A CN 1268126 A CN1268126 A CN 1268126A CN 98808440 A CN98808440 A CN 98808440A CN 98808440 A CN98808440 A CN 98808440A CN 1268126 A CN1268126 A CN 1268126A
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- alkyl
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- aryl
- aralkyl
- heteroaryl
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- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical class O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 title 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 title 1
- -1 hydroxy- Chemical group 0.000 claims abstract description 46
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 239000001301 oxygen Substances 0.000 claims abstract description 12
- 239000005864 Sulphur Substances 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 150000001413 amino acids Chemical class 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000004475 heteroaralkyl group Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 150000001576 beta-amino acids Chemical class 0.000 claims abstract description 5
- 229910052736 halogen Chemical group 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 102000005741 Metalloproteases Human genes 0.000 claims description 6
- 108010006035 Metalloproteases Proteins 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
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- 125000002619 bicyclic group Chemical group 0.000 abstract description 2
- 125000005418 aryl aryl group Chemical group 0.000 abstract 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001371 alpha-amino acids Chemical class 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 125000002950 monocyclic group Chemical group 0.000 abstract 1
- 229930182852 proteinogenic amino acid Natural products 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 8
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 5
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 3
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 3
- 102100028728 Bone morphogenetic protein 1 Human genes 0.000 description 3
- 108090000654 Bone morphogenetic protein 1 Proteins 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 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 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
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- 230000000977 initiatory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- 125000005956 isoquinolyl group Chemical group 0.000 description 3
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- 125000000335 thiazolyl group Chemical group 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- LPBSHGLDBQBSPI-YFKPBYRVSA-N (2s)-2-amino-4,4-dimethylpentanoic acid Chemical compound CC(C)(C)C[C@H](N)C(O)=O LPBSHGLDBQBSPI-YFKPBYRVSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
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- KTQBQWKTAGVKJJ-UHFFFAOYSA-N 2-(2-aminobutan-2-yl)propanedioic acid Chemical compound CCC(C)(N)C(C(O)=O)C(O)=O KTQBQWKTAGVKJJ-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- SVYSPICKAHNPIN-UHFFFAOYSA-N 3-amino-4-hydroxy-3-methylbutanoic acid Chemical compound OCC(N)(C)CC(O)=O SVYSPICKAHNPIN-UHFFFAOYSA-N 0.000 description 2
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- PHXAGOKNORCIIB-RGMNGODLSA-N (2s)-2-amino-2,3-dimethylbutanoic acid;hydrochloride Chemical compound Cl.CC(C)[C@](C)(N)C(O)=O PHXAGOKNORCIIB-RGMNGODLSA-N 0.000 description 1
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- 230000007170 pathology Effects 0.000 description 1
- 125000002958 pentadecyl 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])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 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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- 125000005936 piperidyl group Chemical group 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
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- ZAYJDMWJYCTABM-WHFBIAKZSA-N β-hydroxyleucine Chemical compound CC(C)[C@H](O)[C@H](N)C(O)=O ZAYJDMWJYCTABM-WHFBIAKZSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及通式Ⅰ的物质,其中R1和R2可彼此独立地是H、链烯基或烷基,R3表示基团W-V,其中W表示一个键或直链或支链烷基或链烯基,所述基团可任选地被氧、硫或氮间隔,并且可被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、烷基、芳烷基、芳基或杂芳基取代,并且其中V表示H、单环或双环状的饱和或不饱和的、可以含有1—4个氮、氧或硫原子的环,该环可任地被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、酰氨基、烷基、芳烷基、芳基或杂芳基取代;R4是-N(R13)-C(O)-R5、-N(R13)-C(O)-OR5、-N(R13)-SO2-R5、-N(R13)-C(S)-R5、-N(R13)-C(S)-OR5、-N(R13)-C(O)-CR14R15(-CR16R17)n-C(O)-R5或-N(R13)-CR14R15(-CR16R17)n-C(O)-R18,它们各自通过氮原子与中央嘧啶环连接;n是0或1;R13具有上述R3中所述的含义或者可与R14或R16形成4~7元杂环;并且R5表示烷基、环烷基、芳烷基、芳基或杂芳基,其中这些基团可被羟基、氨基或卤素取代。R14、R15、R16和R17彼此独立地表示氢、形成蛋白的氨基酸的Cα残基、烷基、环烷基、芳基、杂芳基、芳烷基或杂芳烷基;R14和R15或者R16和R17可一起形成3~7元碳环,R18是指OH或N(R6R7),其中R6可以是H、烷基、环烷基、芳烷基、芳基或杂芳基,并且R7与N原子一起表示形成蛋白或非形成蛋白的α-或β-氨基酸或者氨基酸酰胺,另外R6和R7可一起形成可任选含有杂原子例如氧、硫或氮的4~7元环,并且所述基团可任选被烷基、芳烷基、芳基或杂芳基取代。本发明还涉及通式Ⅰ的可药用盐和酯以及这些化合物用于制备药品的用途。
Description
本发明涉及新的嘧啶-2,4,6-三酮衍生物、其制备方法以及含有这些化合物的药物制剂。这些化合物抑制金属蛋白酶,特别是M2和M3族的、M12和M13的虾红素-亚族的蛋白酶。这些蛋白酶族定义在N.D.Rawlings和A.J.Barret,Methods Enzym.(1995)248,183-277。
作为本发明化合物抑制靶,特别优选M12蛋白酶组中的BMP-1。还优选M13族的ECE和NEP以及M2亚族的ACE(肽基二肽酶A)。
金属蛋白酶在许多生理和病理过程中起着主要作用。这些过程的实例是血管紧张素转化酶(ACE)和神经内肽酶(NEP,EC3.4.24.11),它们涉及一系列血压调节肽(例如血管紧张素I和ANF(心钠素))的代谢。ACE催化血管紧张素I转化为高压血管紧张素II的裂解反应。NEP引起扩张肽ANF的降解。内皮素转化酶(ECE)将内源性、失活的big-内皮素裂解为有效的血管收缩剂内皮素I,一种由21个氨基酸组成的肽。这些酶的抑制作用主要对于高血压、心肌机能不全、肾衰和中风的治疗有效。BMP-1(骨形态生成因子1)被认为是一种金属蛋白酶,它在前胶原向胶原纤维的转化中起作用。该酶的抑制剂适于治疗纤维变性硬化病变并可在伤口愈合中有益于结疤的形成(Proc.Natl.Acad.Sci.USA 93,5127(1996);Science Vol.,271,360(1996))。
虽然ACE抑制剂已在治疗上被使用(如,卡托普利、依那普利,(Exp.Opinion Ther.Patents 6,1147(1996)),但临床上可用的、没有有害的副作用和可口服的被用作金属蛋白酶如NEP和ECE的活性物质,迄今还不知道。(文献综述:NEP:Pharmacol.Review 45,87(1993);ECE:Bioorg.Med.Chem.Lett.6,2317(1996))和其中引用的有关膦酰胺酮类抑制剂的参考文献。但BMP-1的低分子量抑制剂仍未可知。
现发现要求保护的新的嘧啶-2,4,6-三酮衍生物是非常有效的金属蛋白酶抑制剂,并具有良好的口服利用度。
其中
R1和R2可彼此独立地是H、链烯基或烷基,
R3表示基团W-V,其中W表示一个键或直链或支链烷基或链烯基,所述基团可任选地被氧、硫或氮间隔,可被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、烷基、芳烷基、芳基或杂芳基取代,V可表示H、单环或双环状的饱和或不饱和的可任选含有1-4个氮、氧或硫原子的环,该环可任选地被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、酰氨基、烷基、芳烷基、芳基或杂芳基取代;
R4可以是基团-N(R13)-C(O)-R5、-N(R13)-C(O)-OR5、-N(R13)-SO2-R5、-N(R13)-C(S)-R5、-N(R13)-C(S)-OR5、-N(R13)-C(O)-CR14R15(-CR16R17)n-C(O)-R5或-N(R13)-CR14R15(-CR16R17)n-C(O)-R18,它们各自通过氮原子与中央嘧啶环连接,
n是0或1,
R13具有上述R3中所述的含义或者任选地与R14或R16形成4~7元杂环,并且
R5表示烷基、环烷基、芳烷基、芳基或杂芳基,其中这些基团可被羟基、氨基或卤素取代;
R14、R15、R16和R17彼此独立地表示氢、形成蛋白的氨基酸的Cα残基、烷基、环烷基、芳基、杂芳基、芳烷基或杂芳烷基;R14和R15或者R16和R17一起可形成3~7元碳环,R18是指OH或N(R6R7),其中
R6是H或可以是烷基、环烷基、芳烷基、芳基或杂芳基,并且
R7与N原子一起表示形成蛋白或非形成蛋白的α-或β-氨基酸或者氨基酸酰胺,并且此外R6和R7可一起形成4~7元环,其任选含有杂原子例如氧、硫或氮,并且可任选被烷基、芳烷基、芳基或杂芳基取代。
R1和R2彼此独立地优选是H或甲基,特别优选是H。
R3优选表示H、烷基、环烷基、芳基、杂芳基、芳烷基或杂芳烷基。尤其优选H或C1-C6烷基。
R4优选是形成蛋白或非形成蛋白的α-或β-氨基酸的残基,它通过氮原子与中央嘧啶环连接,其羧基可以是游离的或与Rx连接的,或者是基团-NH-CO-CHR14-CO-Rx,其中Rx表示羟基、烷氧基或上述的基团-N(R6,R7)。
R13优选是H或烷基。
R14和R16彼此独立地优选是烷基、环烷基或形成蛋白的氨基酸的Cα残基。
R15和R17优选是氢。
n优选是0。
上述提及的优选化合物的组合是十分优选的。
在所有情况下,烷基应是直链或支链C1-C10优选C1-C6烷基链,例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基或己基。
链烯基是指不饱和的具有3-6个碳原子的残基,例如烯丙基、丁-2-烯基、己-2,4-二烯基。
环烷基表示其中CH2基团可被O或NH取代的3~7元环,例如环丙基、环丁基、环戊基、环己基或环庚基,优选环戊基或环己基。
烷氧基是指上述定义的烷基与氧原子结合的基团,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和戊氧基,其中甲氧基、乙氧基、异丙氧基和丁氧基是优选的。
芳基是指优选具有6~10个碳原子的芳香基团,尤其是苯基或萘基,它们各自可与羟基、氨基(可任选地被烷基取代)、烷基或烷氧基连接。杂芳基是由不饱和碳原子和杂原子如氮、氧和硫组成的芳香基团,其中环原子数之和可以为5~10。它们的实例是咪唑基、噻唑基、三唑基、吡啶基、嘧啶基、吡嗪基、吲哚基和嘌呤基。咪唑基、噻唑基、吡啶基或吲哚基是优选的。芳烷基是指其中前面定义的一个烷基与前面定义的一个芳基连接形成的基团,在此优选苄基。杂芳烷基表示前面定义的一个烷基与前面定义的一个烷基的组合。优选吡啶甲基、咪唑甲基和噻唑甲基。如果没有另外的说明,环烷基、芳基和杂芳基可被烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、巯基或硫烷基彼此独立地取代一至三次。
酰基是直链或支链的C2-C10羰烷基,C2-C6酰基是优选的。
如果R6和R7与它们所连的氮原子一起形成一个环,则该环是5元至7元环,优选六元环。哌啶、哌嗪、四氢喹啉和四氢异喹啉、双环(9.4.0)十五烷基和1,2,3,4-四氢苯并(g)异喹啉环是特别优选的。
如果R14和R15或R16和R17形成碳环,则优选是4、5或6元环。
V定义下所述的单环应理解为具有3~8、优选5~7个碳原子的饱和或不饱和的环系,该环系可任选地被杂原子如氮、氧或硫间隔一次或数次,尤其是环戊基、环己基、环庚基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、异噻唑基、异噁唑基、1,2,3-三唑基或1,2,4-三唑基。作为取代基应特别考虑低级烷基、烷氧基和卤素。V定义下所述的双环基优选例如萘基、四氢萘基、十氢萘基、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、吲唑基、羟吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基或嘌呤基,但特别优选的是萘基、喹啉基、异喹啉基、四氢喹啉基、吲哚基或苯并咪唑基。
非形成蛋白的氨基酸的实例是下面列出的:
2-氨基-2-甲基丁烷羧酸、2-氟-β-丙氨酸、β-丙氨酸、2,3-二氨基琥珀酸、β-氨基异丁烷羧酸、异丝氨酸、2-氨基-3-羟基-4-甲基戊烷羧酸、2-氨基-3-甲氧基-丁烷羧酸、二氨基丙酸、2-氨基-2-甲基-3-羟基丙烷羧酸、2-氨基-2-甲基丁烷二羧酸、2-氨基-3-羟基-3-甲基丁烷羧酸、2,3-二氨基丙酸、2-氨基-2-甲基-3-羟基丙烷羧酸、2-氨基-2-甲基丁烷二羧酸、2-氨基-2-甲基-4-戊烯羧酸、2-氨基-3-甲氧基丙烷羧酸、1-氨基-1-环己烷羧酸、1-氨基-1-环戊烷羧酸、1-氨基环丁烷羧酸、1-氨基环丙烷羧酸、2-(2-呋喃基)-甘氨酸、2-氨基-3-氟丁酸、2-氨基异丁酸、3-氯丙氨酸、3-氟正亮氨酸、3-氟缬氨酸、3-氟丙氨酸、3-甲氧基缬氨酸、α-氰基丙氨酸、α-甲基亮氨酸、β-氯丙氨酸、β-氰基丙氨酸、β-羟基亮氨酸、β-羟基天冬氨酸、3-羟基天冬氨酸、2-氨基丁酸、烯丙基甘氨酸、γ-甲基亮氨酸、高丝氨酸、正亮氨酸、正缬氨酸、叔亮氨酸(tert.-leucine)、2,3-二氨基琥珀酸、2-氨基-4-戊烯羧酸、2-氨基庚烷羧酸、2-环丙基-2-甲基甘氨酸、4-硫杂异亮氨酸、别苏氨酸、α-甲基天冬氨酸、α-甲基丝氨酸、β-羟基正缬氨酸、β-甲基天冬氨酸、高半胱氨酸、O-甲基丝氨酸、青霉胺、炔丙基甘氨酸、乙烯基甘氨酸、H-4,5-脱氢-Leu-OH、H-α-Me-Val-OH、H-炔丙基-Gly-OH、H-别-Ile-OH、H-Pra-OH、H-反-4,5-脱氢-Lys-OH、3-羟基天冬氨酸、6-羟基正亮氨酸、别异亮氨酸、烯丙基甘氨酸、α-氨基-N-丁酸、γ-甲基亮氨酸、α,β-二氨基琥珀酸、O-氨基甲酰基丝氨酸、S-甲基半胱氨酸、瓜氨酸、环己基丙氨酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、蛋氨酸亚砜、Ca-甲基丙氨酸、N-甲基甘氨酸(肌氨酸)、萘基丙氨酸、鸟氨酸、1,2,3,4-四氢异喹啉-3-羧酸、高半胱氨酸、4-羟基脯氨酸、5-羟基赖氨酸、氨基丁酸、泛氨酸、葡糖氨酸(glucosaminic acid)、羊毛硫氨酸、aliine、二羟苯基丙氨酸、kanavanin、oletopin、β-赖氨酸、β-丙氨酸。D-氨基酸和L-氨基酸都可以使用。
如果通式I的化合物包含一个或数个不对称碳原子,则通式I的光学活性化合物也是本发明的主题。
通式I的化合物可优选采用熟知的方法制备,其中
a)将通式II的化合物其中R1、R2和R3具有上述含义,而T表示离去基团,例如Hal或OSO2R8,其中Hal是氯、溴或碘,R8是芳基或甲基,与通式III的化合物反应,其中R6和R7具有上述含义,其中的功能基可通过常用的保护基加以保护,还可任选地转化为药理学上可耐受的盐,
或者
或者
c)在R4通过甲酰氨基、氨基甲酰基、硫代氨基甲酰基、脲基、亚磺酰氨基或氨基与中央嘧啶环连接时,可将通式VI的化合物其中R1、R2和R3具有上述含义,与通式VII或VIII化合物反应,
R11-D-Hal (VII)
其中R11表示可任选取代的烷基、环烷基、芳基或杂芳基、D=C(O)、O-C(O)、SO2或价键波折线,卤素=氯、溴或碘并且A表示氧或硫,以及可任选地转化为药理学上可耐受的盐。
通式II的化合物是文献已知的。因此,5位上溴化的2,4,6-嘧啶-三酮可将适当的溴丙二酸的二烷基酯与脲反应进行制备(如,ActaChim.Acad.Sci.Hung.107(2),139(1981))。通过5位被R3取代的2,4,6-嘧啶-三酮与溴(类似于J.pr.Chemie 136,329(1993)或J.Chem.Soc.1931,1870)或磺酰氯(J.Chem.Soc.1938,1622)反应可获得通式II的相应溴代化合物或氯代化合物。
通式III的胺有市售或一般是文献公知的。
通式IV化合物可按照已知方法与脲(式V)反应(参见,例如J.Med.Chem.10,1078(1967)或Helvetica Chim.Acta 34,459(1959)或Pharmacie 38(1),65(1983))。
反应通常在醇,例如甲醇、乙醇或丁醇中,在相应醇钠的存在下于40℃~100℃进行。
通式IV化合物是文献已知的或者可按照文献已知的方法制备。它们可例如用弱酸水解相应的二内酰亚胺醚制备(参见J.Chem.Soc.Chem.Comm.5,400(1990))。其他制备方法是例如,Farmaco Ed.Sci,31(7),478(1976)和Aust.J.Chem.,23(6),1229(1970)中描述的。
通式VI的化合物可按照方法b)通过适当取代的乙酰氨基丙二酸酯进行反应,随后水解掉乙酰基进行制备(参见Can.J.Chem.42(3),605(1964))。
通式VII的酰氯是已知的或可按照熟知的方法由相应的羧酸制备。反应通常使用亚硫酰氯、三溴化磷、五溴化磷、三氯化磷或五氯化磷,在惰性溶剂,如二氯甲烷、乙醚、二氧六环或四氢呋喃中,在0℃~50℃,优选20℃~40℃下进行。
通式VII的氯甲酸酯是文献已知的或者可按照一般已知的方法由相应的醇通过与光气或双光气反应获得。反应在惰性溶剂,如乙醚、二氯甲烷、二氧六环、四氢呋喃或甲苯中,在-20℃~20℃下进行。在使用光气的情况下,反应在有碱,一般是叔胺如三乙胺或吡啶的存在下进行。
通式VII的磺酰氯是已知的,或者可采用与所述方法类似的方法由相应的磺酸与五氯化磷或亚硫酰氯反应制备。反应通常在惰性溶剂例如二甲基甲酰胺中或者在没有溶剂的条件下在20℃~180℃,优选50℃~100℃的温度下进行。
通式VIII的异氰酸酯是已知的或者可按照文献已知的方法制备。因此,可采用类似于Synthesis 1978,760中的方法,将例如通式R11-Hal的相应烷基-卤化物与氰酸钾反应。其他的方法是通式R11-CONH2的酰胺与草酰氯反应,热分解通式R11-CON3的酰基叠氮化物或者通式R11-NH2的胺与光气反应(类似于Ann.Chem.562,110)。
通式VII的羧酸卤化物、磺酸卤化物或氯甲酸酯与通式VI的胺的反应通常在溶剂,例如二氯甲烷、二甲基甲酰胺或吡啶中,添加辅助的碱,例如三乙胺或4-二甲氨基吡啶在-10℃~50℃,优选在室温下进行。
通式I的化合物可包含一个或数个手性中心,因此可以外消旋体或光学活性形式存在。外消旋体可按照已知方法拆分为对映体。可通过结晶分离的非对映体盐优选由外消旋体混合物与光学活性的酸如D-酒石酸或L-酒石酸、苦杏仁酸、苹果酸、乳酸或樟脑磺酸或与光学活性的胺如D-苯乙胺或L-苯乙胺、麻黄碱、奎尼丁或金鸡尼丁反应形成。
强碱盐(alkali salt)、铵盐、乙酸胺或盐酸盐被用作药理学上可耐受的盐,它们可采用常规方式制备,例如通过将化合物用无机或有机碱或者无机酸,例如氢氧化钠、氢氧化钾、氨水、胺(例如,三乙胺)或盐酸滴定进行制备。盐通常采用水/丙酮沉淀法进行纯化。
本发明的式I新物质及其盐可经肠或非胃肠以液体或固体形式服用。所有常见的给药形式均可考虑采用,例如片剂、胶囊、糖衣丸、糖浆、溶液、悬浮液等。优选使用水作为注射媒介,注射媒介还含有常用的添加剂,如稳定性、增溶剂和缓冲剂。
这类添加剂是例如,酒石酸盐缓冲剂和柠檬酸盐缓冲剂、乙醇、配位剂(如乙二胺四乙酸及其无毒盐)、用于调节粘度的高分子聚合物(如,液体聚氧乙烯)。注射液的液体载体须是无菌的,优选分装在安瓿中。固体载体是,例如淀粉、乳糖、甘露醇、甲基纤维素、滑石、高分散性硅酸、高分子脂肪酸(例如,硬脂酸)、明胶、琼脂、磷酸钙、硬脂酸镁、动物和植物脂肪、固体高分子聚合物(例如,聚乙二醇);适宜的口服制剂可任选地含有芳香剂和甜味剂。
剂量取决于各种因素,例如应用方式、人种、年龄和/或个体状况。每日给药剂量为约10~1000mg/人,优选100~500mg/人,可单次或分为数次给药。
除实施例中列出的化合物和权利要求所述所有取代基含义的组合构成的化合物外,可按照上述方法制备的下列巴比土酸衍生物也在本发明的优选范围内:
1.N-(5-苄基-2,4,6-三氧代-六氢嘧啶-5-基)-丙二酸
2.N-(5-苄基-2,4,6-三氧代-六氢嘧啶-5-基)-丙二酸甲酯
3.N-(5-苄基-2,4,6-三氧代-六氢嘧啶-5-基)-N’-甲基-丙二酰胺
4.3-(2,4,6-三氧代-六氢嘧啶-5-基氨基)-丙酸
5.3-(1H-吲哚-3-基)-2-(2,4,6-三氧代-六氢嘧啶-5-基氨基)-丙酸
6.3-(4-羟基-苯基)-2-{[1-(2,4,6-三氧代-六氢嘧啶-5-基氨基)-环丁烷羰基]-氨基}-丙酸
7.1-(2,4,6-三氧代-六氢嘧啶-5-基)-吡咯烷-2-羧酸
实施例1
N-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基)-丙二酸酰胺甲酯
将2g 5-氨基-5-苯基-2,4,6-三氧代嘧啶溶于20ml乙腈中并与1.5ml N-甲基-吗啉混合。在搅拌和用冰冷却的同时,滴加1.03ml丙二酸单甲酯酰氯,将该悬浮液在室温搅拌2小时。吸滤出沉淀,用乙腈、水洗涤,并再次用乙腈洗涤,干燥。获得1.97g(68%)标题化合物。
TLC Rf=0.1(硅胶,异己烷/丙酮/冰醋酸7∶3∶0.1)
MS 319m/e
实施例2
N-甲基-N’-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基)-丙二酰胺
将160mg实施例1获得的化合物与7m1饱和甲基胺的甲醇溶液混合。短时间后,开始结晶。2小时后将该悬浮液蒸发,残余物用乙醚研制,吸滤并干燥。获得149mg(93%)标题化合物。
TLC Rf=0.3(硅胶,二氯甲烷/甲醇9∶1)
MS 318m/e
实施例3
3,3-二甲基-2-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基氨基甲酰基)-丁酸乙酯
如果用叔丁基丙二酸单乙酯酰氯替代实施例1中的丙二酸单甲酯酰氨,则以94%的收率获得标题化合物。
TLC Rf=0.62(硅胶,二氯甲烷/甲醇9∶1)
MS 389m/e
实施例4
3,3-二甲基-2-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基氨基甲酰基)-丁酸
将1g实施例3获得的产物溶于乙醇中并与0.5g氢氧化钾在1ml水中的溶液混合。在室温2天后,将反应混合物蒸发,残余物与冰水和乙酸乙酯混合后,用2N盐酸酸化到pH3。将乙酸乙酯相干燥并蒸发。获得0.7g(75%)标题化合物。
TLC Rf=0.5(硅胶,二氯甲烷/甲醇/水9∶1∶1)
MS 361m/e
实施例5
测定IC50值的ACE-荧光分析
文献:Amos Carmel和Arieh Yaron,Eur.J.Biochem.787,265-273(1978)。分子内消除(quenched)荧光三肽作为血管紧张素I转化酶和细菌二肽基羧基肽酶的萤光底物。
酶:从兔肺中获得的血管紧张素转化酶(EC.3.4.15.1),Fluka(3.3U/μg)
底物:Abz-Gly-Phe(NO2)-Pro,M-1100 Bachem C23H29N5O7,MW=483.4
分析缓冲液:0.05M Tris-HCl
0.01M NaCl
pH 8.0
激发:360nm(激发狭缝:8nm)
发射:410nm(发射狭缝:10nm)
温度:36℃
底物储备溶液:0.4nM分析缓冲液
酶储备溶液:50μl/ml分析缓冲液
抑制剂储备溶液:在分析缓冲液中稀释的1mM在DMSO中的溶液
测量杯:50μl底物(得到20μM)
100μl酶
0~100μl抑制剂储备溶液(0~100μM)
加至1ml
将底物、抑制剂和缓冲液一起加到加热的测量杯中,加入酶引发酶反应。按时间扫描监测荧光随时间(200秒)的增加。由增加来测定各自的引发率。
可如下测定IC50值:
V=V0/(1+[I]/IC50)V=引发率V0=没有抑制剂的引发率[I]=抑制剂浓度表1:药理数据
化合物 | IC50 |
实施例4 | 159μM |
Claims (6)
其中
R1和R2可彼此独立地是H、链烯基或烷基,
R3表示基团W-V,其中W表示一个键或直链或支链烷基或链烯基,所述基团可任选地被氧、硫或氮间隔,可被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、烷基、芳烷基、芳基或杂芳基取代,V可表示H、单环或双环状的饱和或不饱和的可任选含有1-4个氮、氧或硫原子的环,该环可任选地被羟基、氨基、巯基、烷氧基、氧代、羧基、酰基、酰氨基、烷基、芳烷基、芳基或杂芳基取代;
R4可以是基团-N(R13)-C(O)-R5、-N(R13)-C(O)-OR5、-N(R13)-SO2-R5、-N(R13)-C(S)-R5、-N(R13)-C(S)-OR5、-N(R13)-C(O)-CR14R15(-CR16R17)n-C(O)-R5或-N(R13)-CR14R15(-CR16R17)n-C(O)-R18,它们各自通过氮原子与中央嘧啶环连接,
n是0或1,
R13具有上述R3中所述的含义或者任选地与R14或R16形成4~7元杂环,并且
R5表示烷基、环烷基、芳烷基、芳基或杂芳基,其中这些基团可被羟基、氨基或卤素取代;
R14、R15、R16和R17彼此独立地表示氢、形成蛋白的氨基酸的Cα残基、烷基、环烷基、芳基、杂芳基、芳烷基或杂芳烷基;R14和R15一起或者R16和R17一起可形成3~7元碳环,
R18是指OH或N(R6R7),其中
R6是H或可以是烷基、环烷基、芳烷基、芳基或杂芳基,并且
R7代表与N原子一起表示形成蛋白或非形成蛋白的α-或β-氨基酸或者氨基酸酰胺的基团,另外R6和R7可一起形成4~7元环,其可任选含有杂原子例如氧、硫或氮,并且任选地可被烷基、芳烷基、芳基或杂芳基取代。
2、权利要求1的式I化合物,其中R1和R2彼此独立地是氢或甲基。
3、权利要求1或2的式I化合物,其中R3表示H、烷基、环烷基、芳基、杂芳基、芳烷基或杂芳烷基。
4、权利要求1~3任一项的式I化合物,其中R4优选是形成蛋白的或非形成蛋白的α-或β-氨基酸残基,它通过氮原子与中央嘧啶环连接,其羧基可以是游离的或与Rx连接,或者是基团-NH-CO-CHR13-CO-Rx,其中Rx表示羟基、烷氧基或上述的基团-N(R6,R7)。
5、药物制剂,含有至少一种权利要求1~4任一项的式I化合物与常规载体和辅助物质。
6、权利要求1~4任一项的式I化合物用于制备抑制M2和M3族的、M12和M13的虾红素-亚族的金属蛋白酶的药物制剂的用途。
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DE19726427.1 | 1997-06-23 | ||
DE19726427A DE19726427A1 (de) | 1997-06-23 | 1997-06-23 | Pyrimidin-2,4,6-trion-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
Publications (1)
Publication Number | Publication Date |
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CN1268126A true CN1268126A (zh) | 2000-09-27 |
Family
ID=7833267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN98808440A Pending CN1268126A (zh) | 1997-06-23 | 1998-06-19 | 嘧啶-2,4,6-三酮衍生物、其制备方法以及含有这些化合物的药物产品 |
Country Status (13)
Country | Link |
---|---|
US (1) | US6242455B1 (zh) |
EP (1) | EP0991626A2 (zh) |
JP (1) | JP2002504917A (zh) |
KR (1) | KR20010014152A (zh) |
CN (1) | CN1268126A (zh) |
AR (1) | AR013119A1 (zh) |
AU (1) | AU8627898A (zh) |
BR (1) | BR9810286A (zh) |
CA (1) | CA2294113A1 (zh) |
DE (1) | DE19726427A1 (zh) |
TR (1) | TR199903213T2 (zh) |
WO (1) | WO1998058915A2 (zh) |
ZA (1) | ZA985406B (zh) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19548624A1 (de) * | 1995-12-23 | 1997-06-26 | Boehringer Mannheim Gmbh | Neue Barbitursäure-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
HRP990246A2 (en) * | 1998-08-07 | 2000-06-30 | Du Pont Pharm Co | Succinoylamino benzodiazepines as inhibitors of a beta protein production |
NZ525513A (en) | 1998-08-07 | 2004-09-24 | Pont Pharmaceuticals Du | Succinoylamino lactams as inhibitors of Abeta protein production |
EP1313426A4 (en) | 1998-12-24 | 2003-05-28 | Bristol Myers Squibb Pharma Co | SUCCINOYLAMINOBENZODIAZEPINE AS INHIBITORS OF A-BETA PROTEIN PRODUCTION |
US6265578B1 (en) * | 1999-02-12 | 2001-07-24 | Hoffmann-La Roche Inc. | Pyrimidine-2,4,6-triones |
US6960576B2 (en) | 1999-09-13 | 2005-11-01 | Bristol-Myers Squibb Pharma Company | Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production |
US6503902B2 (en) | 1999-09-13 | 2003-01-07 | Bristol-Myers Squibb Pharma Company | Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production |
AU7997600A (en) | 1999-10-08 | 2001-04-23 | Du Pont Pharmaceuticals Company | Amino lactam sulfonamides as inhibitors of abeta protein production |
EP1261610A2 (en) | 2000-02-17 | 2002-12-04 | Bristol-Myers Squibb Pharma Company | Succinoylamino carbocycles and heterocycles as inhibitors of a-beta protein production |
US6495540B2 (en) | 2000-03-28 | 2002-12-17 | Bristol - Myers Squibb Pharma Company | Lactams as inhibitors of A-β protein production |
BR0110051A (pt) | 2000-04-03 | 2004-12-07 | Bristol Myers Squibb Pharma Co | Composto, uso do composto, composição farmacêutica e método de tratamento do mal de alzheimer |
US6759404B2 (en) * | 2000-04-03 | 2004-07-06 | Richard E. Olson | Cyclic malonamides as inhibitors of aβ protein production |
CA2404273A1 (en) | 2000-04-11 | 2001-10-18 | Bristol-Myers Squibb Pharma Company | Substituted lactams as inhibitors of a.beta. protein production |
WO2001092235A1 (en) | 2000-06-01 | 2001-12-06 | Bristol-Myers Squibb Pharma Company | LACTAMS SUBSTITUTED BY CYCLIC SUCCINATES AS INHIBITORS OF Aβ PROTEIN PRODUCTION |
EP1332136A2 (en) | 2000-10-26 | 2003-08-06 | Pfizer Products Inc. | Pyrimidine-2,4,6-trione metalloproteinase inhibitors |
SE0100902D0 (sv) | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
US6716845B2 (en) * | 2001-03-30 | 2004-04-06 | Hoffmann-La Roche Inc. | Barbituric acid derivatives |
AU2002346729A1 (en) * | 2001-12-20 | 2003-07-09 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-$g(a) converting enzyme (tace) and/or matrix metalloproteinases |
AU2002357312A1 (en) * | 2001-12-20 | 2003-07-09 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-alpha converting enzyme (tace) and/or matrix metalloproteinases |
AU2003220401A1 (en) | 2002-03-18 | 2003-10-08 | Bristol-Myers Squibb Company | Uracil derivatives as inhibitors of tnf-alpha converting enzyme (tace) and matrix metalloproteinases |
RU2402329C2 (ru) * | 2004-04-01 | 2010-10-27 | Юниверсите Де-Льеж | Применение триоксопиримидина для лечения и предупреждения воспалительных заболеваний бронхов |
RU2411043C2 (ru) * | 2004-04-01 | 2011-02-10 | Юниверсите Де Льеж | Фармацевтические композиции пиримидин-2,4,6-трионов |
KR101155335B1 (ko) * | 2005-01-07 | 2012-06-11 | 엘지전자 주식회사 | 이동통신 단말기의 멀티미디어 메시지 동작방법 |
EA031654B1 (ru) | 2014-01-10 | 2019-02-28 | Глэксосмитклайн Интеллекчуал Проперти (No.2) Лимитед | Гидроксиформамидные производные и их применение |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2222375A1 (en) * | 1973-03-20 | 1974-10-18 | Ugine Kuhlmann | 5-Substd guanidino barbituric acids - intermediates prepd from a cyanamide and a uramil |
EP0058637A1 (de) * | 1981-02-12 | 1982-08-25 | Ciba-Geigy Ag | Stabile Präparation eines Behandlungsmittels für textile Substrate |
EP0640594A1 (en) | 1993-08-23 | 1995-03-01 | Fujirebio Inc. | Hydantoin derivative as metalloprotease inhibitor |
US5606512A (en) * | 1994-07-27 | 1997-02-25 | The Dow Chemical Company | Determining the biodegradability of iminodiacetic acid derivatives |
EP0796257B1 (en) * | 1994-12-09 | 1999-08-18 | Roche Diagnostics GmbH | Malonic acid based matrix metalloproteinase inhibitors |
DE19548624A1 (de) * | 1995-12-23 | 1997-06-26 | Boehringer Mannheim Gmbh | Neue Barbitursäure-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
-
1997
- 1997-06-23 DE DE19726427A patent/DE19726427A1/de not_active Withdrawn
-
1998
- 1998-06-19 BR BR9810286-9A patent/BR9810286A/pt not_active IP Right Cessation
- 1998-06-19 AU AU86278/98A patent/AU8627898A/en not_active Abandoned
- 1998-06-19 EP EP98937509A patent/EP0991626A2/de not_active Withdrawn
- 1998-06-19 TR TR1999/03213T patent/TR199903213T2/xx unknown
- 1998-06-19 WO PCT/EP1998/003740 patent/WO1998058915A2/de not_active Application Discontinuation
- 1998-06-19 CA CA002294113A patent/CA2294113A1/en not_active Abandoned
- 1998-06-19 KR KR1019997012220A patent/KR20010014152A/ko not_active Application Discontinuation
- 1998-06-19 US US09/445,460 patent/US6242455B1/en not_active Expired - Fee Related
- 1998-06-19 JP JP50377799A patent/JP2002504917A/ja not_active Ceased
- 1998-06-19 CN CN98808440A patent/CN1268126A/zh active Pending
- 1998-06-22 ZA ZA9805406A patent/ZA985406B/xx unknown
- 1998-06-23 AR ARP980103001A patent/AR013119A1/es unknown
Also Published As
Publication number | Publication date |
---|---|
DE19726427A1 (de) | 1998-12-24 |
AU8627898A (en) | 1999-01-04 |
ZA985406B (en) | 1999-12-22 |
JP2002504917A (ja) | 2002-02-12 |
AR013119A1 (es) | 2000-12-13 |
WO1998058915A3 (de) | 1999-05-14 |
EP0991626A2 (de) | 2000-04-12 |
BR9810286A (pt) | 2000-09-12 |
US6242455B1 (en) | 2001-06-05 |
KR20010014152A (ko) | 2001-02-26 |
TR199903213T2 (xx) | 2000-06-21 |
WO1998058915A2 (de) | 1998-12-30 |
CA2294113A1 (en) | 1998-12-30 |
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