CN1376157A - 三唑并嘌呤衍生物、含有该衍生物的药物组合物和腺苷a3受体亲和剂 - Google Patents
三唑并嘌呤衍生物、含有该衍生物的药物组合物和腺苷a3受体亲和剂 Download PDFInfo
- Publication number
- CN1376157A CN1376157A CN00813431A CN00813431A CN1376157A CN 1376157 A CN1376157 A CN 1376157A CN 00813431 A CN00813431 A CN 00813431A CN 00813431 A CN00813431 A CN 00813431A CN 1376157 A CN1376157 A CN 1376157A
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- Prior art keywords
- alkyl group
- low alkyl
- phenyl
- methyl
- ethyl
- Prior art date
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- 102000008161 Adenosine A3 Receptor Human genes 0.000 title claims abstract description 16
- 108010060261 Adenosine A3 Receptor Proteins 0.000 title claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 title claims description 22
- 239000000203 mixture Substances 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 title abstract description 6
- 229940079593 drug Drugs 0.000 title abstract description 4
- -1 Phenyl Chemical group 0.000 claims description 193
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
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- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical group CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 claims description 2
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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 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 229910000077 silane Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- UOHUDFHWFDUDID-UHFFFAOYSA-N [Cl].C[SiH](C)C Chemical compound [Cl].C[SiH](C)C UOHUDFHWFDUDID-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
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- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- LDYMCRRFCMRFKB-MOROJQBDSA-N (2s,3s,4r,5r)-5-[6-[(4-aminophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=CC(N)=CC=3)=C2N=C1 LDYMCRRFCMRFKB-MOROJQBDSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
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- 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 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
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Abstract
通式(1)表示的三唑并嘌呤衍生物,该化合物具有腺苷A3受体亲和性,在医药组合物中含有。式中R1和R2的定义如说明书中记载。
Description
技术领域
本发明涉及具有腺苷A3受体亲和性的新型三唑并嘌呤衍生物,含有该衍生物的药物组合物和腺苷A3受体亲和剂。
背景技术
在J.Heterocyclic Chem.,31,1171(1994)中公开了2-芳基-8-氟苄基-1,2,4-三唑并[5,1-i]嘌呤作为腺苷A2的受体拮抗剂有用。
本发明的目的在于提供对腺苷A3受体具有亲和性的新型化合物。
发明的公开
式中,R1表示低级烷氧基低级烷基,低级烷基亚硫酰基低级烷基,低级烷基磺酰基低级烷基,低级烷氧基羰基低级烷基,羧基低级烷基,环烷基,卤素取代低级烷基,膦酰基低级烷基,低级烷基膦酰基低级烷基,二低级烷基膦酰基低级烷基,低级烷酰氧基低级烷基,羟基低级烷基,二低级烷基氨基低级烷基,苯基低级烷氧基低级烷基或低级烷基硫代低级烷基;R2苯基,该苯基可以具有1-3个选自低级烷基,低级烷氧基,卤素原子,卤素取代低级烷基和苯基中的取代基。
本发明的三唑并嘌呤衍生物是文献中未记载的新化合物。
本发明优选R1表示低级烷氧基低级烷基,低级烷基硫代低级烷基,低级烷基亚硫酰基低级烷基,低级烷基磺酰基低级烷基或羧基低级烷基。
更优选R1是甲氧基甲基,乙氧基甲基,2-甲氧基乙基,2-甲基亚硫酰基乙基,2-乙基磺酰基乙基,2-羧基乙基,3-羧基丙基,4-羧基丁基或2-甲基硫代乙基。
更优选R2是苯基,4-联苯基,4-正丙氧基苯基,4-叔丁基苯基,4-氯苯基,4-三氟甲基苯基,或3,4,5-三甲氧基苯基。
本发明的三唑并嘌呤对腺苷A3受体具有优良的亲和性,作为与腺苷A3受体结合的化合物,期待在降血压剂、抗过敏剂、抗炎剂、缺血性疾病治疗剂、白血病治疗剂、止痒剂、去痰剂、镇咳剂、哮喘治疗剂、镇痛剂等方面的应用。
本发明还提供药物组合物,含有上述的三唑并嘌呤衍生物和制剂上允许的载体。
具体而言,本发明提供腺苷A3受体亲和剂,含有上述的三唑并嘌呤衍生物作为有效成分。
实施发明的最佳方案
本发明中,所说的低级烷基例如有甲基、乙基、丙基、丁基、异丁基、叔丁基、戊基、己基、异丙基、异戊基、新戊基、1-乙基丙基等碳原子数1-6的直链或支链低级烷基。
低级烷氧基如甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等碳原子数1-6的直链或支链烷氧基。
低级烷氧基低级烷基如甲氧基甲基、乙氧基甲基、丙氧基甲基、丁氧基甲基、叔丁氧基甲基、戊氧基甲基、己氧基甲基、1-甲氧基乙基、2-甲氧基乙基、3-甲氧基丙基、4-甲氧基丁基、5-甲氧基戊基、6-甲氧基己基、2-乙氧基乙基、3-丙氧基丙基等烷氧基部分和烷基部分的碳原子数总共为1-6的低级烷氧基低级烷基。
低级烷基亚硫酰基低级烷基如甲基亚硫酰基甲基、乙基亚硫酰基甲基、丙基亚硫酰基甲基、丁基亚硫酰基甲基、叔丁基亚硫酰基甲基、戊基亚硫酰基甲基、己基亚硫酰基甲基、1-甲基亚硫酰基乙基、2-甲基亚硫酰基乙基、3-甲基亚硫酰基丙基、4-甲基亚硫酰基丁基、5-甲基亚硫酰基戊基、6-甲基亚硫酰基己基等烷基部分的碳原子数为1-6的低级烷基亚硫酰基低级烷基。
低级烷基磺酰基低级烷基如甲基磺酰基甲基、乙基磺酰基甲基、丙基磺酰基甲基、丁基磺酰基甲基、叔丁基磺酰基甲基、戊基磺酰基甲基、己基磺酰基甲基、1-甲基磺酰基乙基、2-甲基磺酰基乙基、3-甲基磺酰基丙基、4-甲基磺酰基丁基、5-甲基磺酰基戊基、6-甲基磺酰基己基等烷基部分的碳原子数为1-6的低级烷基磺酰基低级烷基。
低级烷氧基羰基低级烷基,如甲氧基羰基甲基、乙氧基羰基甲基、丙氧基羰基甲基、丁氧基羰基甲基、戊氧基羰基甲基、己氧基羰基甲基、1-甲氧基羰基乙基、2-甲氧基羰基乙基、3-甲氧基羰基丙基、4-甲氧基羰基丁基、5-甲氧基羰基戊基、6-甲氧基羰基己基、2-乙氧基羰基乙基、3-乙氧基羰基丙基、4-乙氧基羰基丁基等烷氧基部分和烷基部分的碳原子数总共为1-6的低级烷氧基羰基低级烷基。
羧基低级烷基如羧基甲基、1-羧基乙基、2-羧基乙基、3-羧基丙基、4-羧基丁基、5-羧基戊基、6-羧基己基等烷基部分的碳原子数1-6的羧基低级烷基。
低级烷基硫代低级烷基如甲基硫代甲基、乙基硫代甲基、丙基硫代甲基、丁基硫代甲基、叔丁基硫代甲基、戊基硫代甲基、己基硫代甲基、1-甲基硫代乙基、2-甲基硫代乙基、3-甲基硫代丙基、4-甲基硫代丁基、5-甲基硫代戊基、6-甲基硫代己基、2-乙基硫代乙基、3-丙基硫代丙基等烷基部分的碳原子数为1-6的低级烷基硫代低级烷基。
卤素取代低级烷基如三氟甲基、五氟乙基、七氟丙基、九氟丁基、十一氟戊基、十三氟己基等烷基部分的碳原子数为1-6的全氟低级烷基。
环烷基如环丙基、环丁基、环戊基、环己基、环庚基、环辛基等碳原子数3-8的环烷基。
膦酰基低级烷基如膦酰基甲基、1-膦酰基乙基、2-膦酰基乙基、3-膦酰基丙基、4-膦酰基丁基、5-膦酰基戊基、6-膦酰基己基等烷基部分的碳原子数为1-6的膦酰基低级烷基。
低级烷基膦酰基低级烷基如甲基膦酰基甲基、乙基膦酰基甲基、丙基膦酰基甲基、丁基膦酰基甲基、戊基膦酰基甲基、己基膦酰基甲基、2-乙基膦酰基乙基、1-乙基膦酰基乙基、3-乙基膦酰基丙基、4-乙基膦酰基丁基、5-乙基膦酰基戊基、6-乙基膦酰基己基等烷基部分的碳原子数为1-6的低级烷基膦酰基低级烷基。
二低级烷基膦酰基低级烷基如二甲基膦酰基甲基、二乙基膦酰基甲基、二丙基膦酰基甲基、二丁基膦酰基甲基、二戊基膦酰基甲基、二己基膦酰基甲基、乙基甲基膦酰基甲基、2-二乙基膦酰基乙基、1-二乙基膦酰基乙基、3-二乙基膦酰基丙基、4-二乙基膦酰基丁基、5-二乙基膦酰基戊基、6-二乙基膦酰基己基等烷基部分的碳原子数为1-6的二低级烷基膦酰基低级烷基。
低级烷酰氧基低级烷基如乙酰氧基甲基、丙酰氧基甲基、丁酰氧基甲基、戊酰氧基甲基、己酰氧基甲基、庚酰氧基甲基、1-乙酰氧基乙基、2-乙酰氧基乙基、3-乙酰氧基丙基、4-乙酰氧基丁基、5-乙酰氧基戊基、6-乙酰氧基己基等烷酰基部分和烷基部分的碳原子数总共为1-6的低级烷酰氧基低级烷基。
羟基低级烷基如羟基甲基、2-羟基乙基、1-羟基乙基、3-羟基丙基、4-羟基丁基、5-羟基戊基、6-羟基己基等烷基部分的碳原子数为1-6的羟基低级烷基。
二低级烷基氨基低级烷基如二甲基氨基甲基、二乙基氨基甲基、二丙基氨基甲基、二丁基氨基甲基、二戊基氨基甲基、二己基氨基甲基、乙基甲基氨基甲基、2-二甲基氨基乙基、1-二甲基氨基乙基、3-二甲基氨基丙基、4-二甲基氨基丁基、5-二甲基氨基戊基、6-二甲基氨基己基等烷基部分的碳原子数为1-6的二低级烷基氨基低级烷基。
苯基低级烷氧基低级烷基如苄氧基甲基、2-苯基乙氧基甲基、3-苯基丙氧基甲基、4-苯基丁氧基甲基、5-苯基戊氧基甲基、6-苯基己氧基甲基、1-苄氧基乙基、2-苄氧基乙基、3-苄氧基丙基、4-苄氧基丁基、5-苄氧基戊基、6-苄氧基己基等烷氧基部分和烷基部分的碳原子数总计为1-6的苯基低级烷氧基低级烷基。
作为可以具有从低级烷基、低级烷氧基、卤素原子、卤素取代低级烷基和苯基中选择的取代基的苯基,除苯基之外,例如有2-甲基苯基、3-甲基苯基、4-甲基苯基、4-乙基苯基、4-丙基苯基、4-异丙基苯基、4-丁基苯基、4-叔丁基苯基、4-戊基苯基、4-己基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、3,4-二乙基苯基、3,4-二丙基苯基、3,4-二丁基苯基、3,4-二戊基苯基、3,4-二己基苯基、3,4,5-三甲基苯基、2,3,4-三甲基苯基、2,3,5-三甲基苯基、2,3,6-三甲基苯基、2,4,6-三甲基苯基、2,4,5-三甲基苯基、3,4,5-三乙基苯基、3,4,5-三丙基苯基、3,4,5-三丁基苯基、3,4,5-三戊基苯基、3,4,5-三己基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-丁氧基苯基、4-戊氧基苯基、4-己氧基苯基、2,3-二甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、2,6-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、3,4-二乙氧基苯基、3,4-二丙氧基苯基、3,4-二丁氧基苯基、3,4-二戊氧基苯基、3,4-二己氧基苯基、3,4,5-三甲氧基苯基、2,3,4-三甲氧基苯基、2,3,5-三甲氧基苯基、2,3,6-三甲氧基苯基、2,4,6-三甲氧基苯基、2,4,5-三甲氧基苯基、3,4,5-三乙氧基苯基、3,4,5-三丙氧基苯基、3,4,5-三丁氧基苯基、3,4,5-三戊氧基苯基、3,4,5-三己氧基苯基、4-甲氧基-3-甲基苯基、4-甲氧基-2-甲基苯基、3-甲氧基-2-甲基苯基、4-甲氧基-3,5-二甲基苯基、4-联苯基、3-联苯基、2-联苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、4-五氟乙基苯基、4-七氟丙基苯基、4-九氟丁基苯基、4-十一氟戊基苯基、4-十三氟己基苯基、2,4-二(三氟甲基)苯基、3,5-二(三氟甲基)苯基、2,4,6-三(三氟甲基)苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-氟苯基、4-溴苯基、4-碘苯基、2,4-二氯苯基、3,4-二氯苯基、3,5-二氯苯基、2,4,6-三氯苯基等。上述的低级烷基、低级烷氧基、卤素取代低级烷基都是碳原子数1-6的基团。本发明化合物(1)例如可以由以下的反应工序式1-6制造。〖反应工序式-1〗
式中,R1A表示低级烷氧基低级烷基、低级烷氧基羰基低级烷基、环烷基、卤素取代低级烷基、二低级烷基膦酰基低级烷基、低级烷酰氧基低级烷基、二低级烷基氨基低级烷基、苯基低级烷氧基低级烷基或低级烷基硫代低级烷基,R2与上述相同,Y和Z分别表示相同或不同的低级烷基。
将式(2)表示的化合物与式(3)表示的原酸酯衍生物反应,得到式(4)表示的亚氨基酯衍生物。该反应在无溶剂或惰性溶剂中,加入相对于化合物(2)为等摩尔或过剩量的原酸酯衍生物(3),在50℃-回流温度下加热约10分钟-5小时。上述惰性溶剂可以使用如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、甲醇、二苯基醚、二甲苯、二甘醇二甲醚等。
生成的亚氨基酯衍生物(4)不经精制直接使用,或用常法精制后与式(5)的酰基肼衍生物反应,得到化合物(6)。该反应是在惰性溶剂中,加入相对于亚氨基酯衍生物(4)为等摩尔量或稍过剩量的酰基肼衍生物(5),根据需要添加催化剂量的1,8-二氮杂双环[5.4.0]-7-十一碳烯,在50℃-回流温度下加热约1-50小时。作为惰性溶剂,可以使用与上述相同的溶剂。根据需要还可以在上述加热反应后添加氢氧化钠水溶液、氢氧化钾水溶液等成为碱性,在0℃-室温下追加10分钟-50小时的处理反应。
然后,在盐酸、硫酸等无机酸水溶液中回流5分钟-50小时,使化合物(6)转换成胺化合物(7)。
然后将胺化合物(7)酰基化。该酰基化例如在吡啶、二甲基吡啶、三甲胺、4-(N,N-二甲基氨基)吡啶等胺类惰性溶剂中,将胺化合物(7)与羧酸氯化物(8)反应。该反应中,羧酸氯化物(8)使用1-过剩当量,反应在0℃-回流温度下进行10分钟-3小时左右完成。该酰基化反应,因为有时存在多个酰基被取代的化合物,所以要根据需要将生成物在甲醇或乙醇等惰性溶剂中与催化剂量的无水碳酸钾或无水碳酸钠等碱一起回流10分钟-2小时左右,将混在物转换成目的的单酰基化合物(9)。
然后将上述得到的单酰基化合物(9)利用环化反应变换成本发明的化合物(1A)。该环化反应是在惰性溶剂中,在碱存在下,使单酰基化合物(9)与卤化三烷基硅烷反应。
此处使用的惰性溶剂例如有苯、甲苯、二甲苯、石油醚等芳香族或脂肪族烃类,二甲醚、四氢呋喃等醚类,二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等卤代烃类,乙腈等脂肪族腈等。碱例如有三乙胺、二异丙基乙基胺、N,N-二乙基苯胺、N-甲基吗啉、吡啶、4-(N,N-二甲基氨基)吡啶等叔胺。卤化三烷基硅烷例如有氯三甲基硅烷、氯三乙基硅烷、氯乙基二甲基硅烷、氯二甲基丙基硅烷、氯丁基二甲基硅烷、氯三丙基硅烷、三丁基氯硅烷、氯乙基甲基丙基硅烷等氯三烷基硅烷。
卤化三烷基硅烷和碱的用量没有特别限制,一般相对于单酰基化合物(9)为1-过剩当量,优选3-20当量。环化反应通常在0-100℃下反应0.5-100小时左右完成。
式中,R1B表示低级烷氧基羰基低级烷基,R1C表示羧基低级烷基,R2与上述相同。
如上述反应工序式-2所示,本发明化合物(1B)利用水解反应转变成本发明化合物(1C)。该反应是在甲醇、乙醇等惰性溶剂中与氢氧化钠水溶液、氢氧化钾水溶液等碱进行反应来完成。碱的使用量相对于化合物(1-B)为1-稍过剩当量,反应在0℃-室温附近的温度下反应0.5-10小时左右完成。
反应工序式-3
式中,R1D表示低级烷基硫代低级烷基,R1E表示低级烷基亚硫酰基低级烷基或低级烷基磺酰基低级烷基,R2与上述相同。
如上述反应工序式-3所示,本发明化合物(1D)通过氧化反应转变成本发明化合物(1E)。该氧化反应,在乙酸中使用作为氧化剂的过氧化氢,或在二氯甲烷、四氯化碳等惰性溶剂中,使用作为氧化剂的间氯过苯甲酸、过碘酸钠等实施。如果想将上述氧化反应停留在亚硫酰基化合物时,上述氧化剂的用量相对于原料化合物为1-稍过剩当量,在0℃-室温左右的温度下反应15分钟-10小时左右。如果想将氧化反应进行到磺酰基化合物时,上述氧化剂的用量相对于原料化合物为2当量-过剩量,再根据需要添加钨酸钠等催化剂,在0℃-回流温度下反应15分钟-10小时左右。
式中,R1F表示二低级烷基膦酰基低级烷基,R1G表示低级烷基膦酰基低级烷基,R2与上述相同。
利用反应工序式-4,使化合物(1F)与氯化锂、溴化锂、碘化锂等卤化锂反应,在后处理阶段利用盐酸、硫酸等无机酸水溶液处理,得到目的化合物(1G)。反应在乙腈、DMF等惰性溶剂中使用过剩量的卤化锂在室温-溶剂的回流温度下反应5-24小时。
由反应工序式-5,将化合物(1F)与氯三甲基硅烷、氯三乙基硅烷等卤化三烷基硅烷反应,在后处理阶段,用盐酸、硫酸等无机酸水溶液处理,得到目的化合物(1H)。该反应在乙腈、丙腈等惰性溶剂中在碘化钠、碘化钾等碱金属碘化物的存在下实施。相对于化合物(1F)的卤化三烷基硅烷和碱金属碘化物盐的用量分别为2倍摩尔以上,反应在室温-溶剂的回流温度下进行2-12小时。
式中,R1J表示低级烷酰氧基低级烷基,R1K表示羟基低级烷基,R2表示与上述相同。
由反应工序式-6,化合物(1J)通过水解转变成目的化合物(1K)。该水解反应与上述反应工序式-2的水解反应的条件相同。
上述各反应工序式表示的各工序中的目的化合物,可以用通常的分离手段容易地分离精制。作为这种分离手段,例如有吸附色谱法、制备薄层色谱法、重结晶、溶剂萃取等。
式中,R1和R2与上述相同。
本发明化合物(1)可以形成医药上允许的酸加成盐,这些盐也包括在本发明化合物中。能形成酸加成盐的酸例如有盐酸、氢溴酸、硫酸等无机酸,草酸、富马酸、马来酸、酒石酸、柠檬酸、对甲苯磺酸等有机酸。酸加成盐的形成按常法进行。
本发明化合物(1)按常法形成如钠盐、钾盐等碱金属盐,钙盐、镁盐等碱土金属盐,铜盐等,这些盐也包括在本发明内。
本发明化合物(1)可以与适当的无毒性制剂载体一起以一般的医药制剂的形态使用。作为上述制剂载体,根据制剂的使用形态适当选择常用的充填剂、增量剂、粘合剂、付湿剂、崩解剂、表面活性剂、润滑剂等稀释剂或赋形剂等,根据得到的制剂的给药单位形态适当选择。
本发明化合物(1)使用的医药制剂的给药单位形态,可以根据治疗目的选择各种形态,代表性的有片剂、丸剂、散剂、液剂、悬浮剂、乳剂、颗粒剂、胶囊剂、栓剂、注射剂(液剂、悬浮剂)、软膏剂等。
成形为片剂形态时,制剂载体例如有乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钠、高岭土、结晶纤维素、硅酸、磷酸钾等赋形剂;水、乙醇、丙醇、单糖浆、葡萄糖液、淀粉液、明胶溶液、羧甲基纤维素、羟丙基纤维素、甲基纤维素、聚乙烯吡咯烷酮等粘合剂;羧甲基纤维素钠、羧甲基纤维素钙、低取代度羟丙基纤维素、干燥淀粉、藻酸钠、琼脂粉末、昆布多糖末、碳酸氢钠、碳酸钙等崩解剂;聚氧乙烯山梨糖醇酐脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯等表面活性剂;白糖、硬脂酸、可可黄油、氢化油等崩解抑制剂;季铵盐、月桂基硫酸钠等吸收促进剂;甘油、淀粉等保湿剂;淀粉、乳糖、高岭土、膨润土胶态硅酸等吸附剂;精制滑石粉、硬脂酸盐、硼酸粉末、聚乙二醇等润滑剂等。
片剂还可以是经过包衣的片剂,如糖衣片、明胶包衣片、肠溶衣片、薄膜包衣片、双层片、多层片。
成形为丸剂时,可以使用制剂载体如葡萄糖、乳糖、淀粉、可可脂、硬化植物油、高岭土、滑石粉等赋形剂;阿拉伯胶粉末、西黄耆胶、明胶、乙醇等粘合剂;昆布多糖、琼脂等崩解剂等。
成形为栓剂时,可以使用制剂载体如聚乙二醇、可可脂、高级醇、高级醇的酯类、明胶、半合成甘油酯等。
胶囊剂是按常法将本发明化合物(1)与上述例示的各种制剂载体混合后充填到硬质明胶胶囊、软胶囊等中。
调制成液剂、乳剂、悬浮剂等注射剂时,优选进行杀菌且调整为与血液等张力。调制成注射剂时,可以使用稀释剂如水、乙醇、鲸蜡醇、丙二醇、乙氧基化异硬质酰醇、聚氧化异硬质酰醇、聚氧乙烯山梨糖醇酐脂肪酸酯类等。为调整为等张性的溶液,可以含有充分量的食盐、葡萄糖、甘油等,也可以添加通常的溶解辅助剂、缓冲剂、无痛化剂等。
在上述医药制剂中可以根据需要含有着色剂、保存剂、香料、风味剂、甜味剂等或其它医药品。
调制成糊剂、霜剂、凝胶等软膏剂时,可以使用稀释剂如白凡士林、石蜡、甘油、纤维素衍生物、聚乙二醇、硅、膨润土等。
上述医药制剂中含有的本发明化合物(1)的量,无特别限制,可以在广范围内选择,通常优选在医药制剂中含有约1-85重量%左右。
对上述医药制剂的给药方法无特别限制,可以根据制剂形态、患者年龄、性别或其它条件、疾病程度等来适当决定。如片剂、丸剂、液剂、悬浮剂、乳剂、颗粒剂、胶囊剂可以口服给药,注射剂可单独或与葡萄糖、氨基酸等通常的补液混合后静脉内给药,还可根据需要单独给药或肌肉内、皮内、皮下或腹腔内给药,栓剂是直肠内给药。
上述医药制剂的给药量,根据用法、患者年龄、性别或其它条件、疾病的程度等来适当决定,通常本发明化合物(1)的每天的给药量为每公斤体重约0.5-20mg,优选1-10mg。每天分为1-4次给药。
产业上的利用可能性
本发明的三唑并嘌呤衍生物因为具有腺苷A3受体亲和性,所以期待在降血压剂、抗过敏剂、抗炎剂、缺血性疾病治疗剂、白血病治疗剂、止痒剂、去痰剂、缜咳剂、哮喘治疗剂、镇痛剂等方面的应用。
实施例
以下给出实施例和参考例来详细说明本发明化合物。
参考例1
5-甲基-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将4-氨基-5-氰基咪唑5g悬浮于10mlDMF中,加入原乙酸甲酯10ml,在90℃下搅拌30分钟。将反应液在减压下浓缩,残渣用乙酸乙酯稀释,滤取析出的结晶4.2g。浓缩母液,残渣用硅胶柱色谱法精制(洗脱液:乙酸乙酯),再用乙酸乙酯-正己烷重结晶,与上述结晶4.2g合并,得到N-(5-氰基咪唑-4-基)乙酰亚氨酸甲酯的结晶7.1g(熔点:147-149℃)。
上述得到的N-(5-氰基咪唑-4-基)乙酰亚氨酸甲酯4.0g和N-苯甲酰基肼3.65g溶解于40mlDMF中,在80℃下搅拌1小时,然后在150℃下搅拌15小时。然后将反应液放冷至室温,滴加10%氢氧化钠水溶液13ml,调整pH为9-10,室温下搅拌1小时。反应结束后,依次加入10%盐酸和水,使pH为3,滤取析出的结晶,用热乙醇洗涤,得到目的化合物的结晶5.5g。
(熔点:285℃以上)
参考例2-7
与参考例1同样制备下列各化合物。
参考例2
5-甲基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:248-251℃)
参考例3
8-(4-联苯基)-5-甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
参考例4
5-甲基-8-(4-正丙氧基苯基)-1H-1, 2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
参考例5
8-(4-叔丁基苯基)-5-甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
参考例6
8-(4-氯苯基)-5-甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
参考例7
5-甲基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例1
8-(4-联苯基)-5-乙氧基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将参考例3得到的化合物5.0g加入浓盐酸15ml的水35ml和乙醇25ml溶液中,加热回流24小时。将反应液冷却至室温,加入25%氨水,将pH调节至8,滤取析出的结晶,将其用硅胶柱色谱法精制(洗脱液为氯仿∶甲醇=30∶1,之后为10∶1),得到3-(4-氨基咪唑-5-基)-5-(4-联苯基)-1,2,4-三唑的结晶2.8g(熔点230℃以上(分解))。
另一方面,在乙氧基乙酸0.6g的二氯甲烷10ml溶液中加入氯化亚硫酰0.4ml,加热回流1小时。冷却该溶液,在0℃下滴加到上述得到的结晶0.5g的4ml吡啶溶液中,0℃下搅拌30分钟,然后在室温下搅拌1小时,之后加热回流1小时。减压浓缩反应液,残渣溶于乙醇40ml,加热回流15分钟。将反应液冷却至室温,滤取析出的结晶,依次用乙醇和热80%乙醇洗涤,得到5-(4-联苯基)-3-[4-(N-乙氧基乙酰基氨基)咪唑-5-基]-1,2,4-三唑的结晶0.51g(熔点:280℃)。
然后将得到的结晶0.45g悬浮于二氯甲烷5ml中,加入二异丙基乙基胺2ml和氯三甲基硅烷0.74ml,加热回流72小时。将反应液冷却至室温,用氯仿稀释,加入盐酸中和。滤取析出的结晶,用热50%乙醇洗涤,风干,得到目的化合物的结晶0.34g。
(熔点:280℃以上)
实施例2-30
与实施例1同样,制备下列各化合物。
实施例2
8-(4-联苯基)-5-甲氧基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例3
8-(4-联苯基)-5-(2-甲氧基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:245-246℃)
实施例4
8-(4-联苯基)-5-(2-甲基硫代乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:249-251℃)
实施例5
5-乙氧基甲基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:254-255.5℃)
实施例6
5-甲氧基甲基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例7
5-(2-甲氧基乙基)-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤(水和物;水分量=3.09%(w/w))
(熔点:192-194℃)
实施例8
5-乙氧基甲基-8-(4-正丙氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:262-263℃)
实施例9
5-乙氧基甲基-8-(4-正丙氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例10
5-(2-乙氧基乙基)-8-(4-正丙氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:231.5-232.5℃)
实施例11
5-乙氧基甲基-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:247-249℃)
实施例12
5-甲氧基甲基-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例13
5-(2-甲氧基乙基)-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤(水和物;水分量=2.73%(w/w))
(熔点:217.5-218.5℃)
实施例14
8-(4-叔丁基苯基)-5-乙氧基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:243-244℃)
实施例15
8-(4-叔丁基苯基)-5-甲氧基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例16
8-(4-叔丁基苯基)-5-(2-甲氧基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:237-239℃)
实施例17
8-(4-叔丁基苯基)-5-(2-甲基硫代乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:229-231℃)
实施例18
5-(3-甲氧基羰基丙基)-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:228-230℃)
实施例19
5-(2-甲基硫代乙基)-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:233-234℃)
实施例20
8-(4-联苯基)-5-(2-乙氧基羰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:241.5-244℃)
实施例21
8-(4-联苯基)-5-(3-甲氧基羰基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:243-245.5℃)
实施例22
8-(4-联苯基)-5-(4-乙氧基羰基丁基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:241-243℃)
实施例23
8-(4-叔丁基苯基)-5-(3-甲氧基羰基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:169-172.5℃)
实施例24
5-甲氧基甲基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例25
5-乙氧基甲基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例26
5-(2-甲氧基乙基)-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:256℃以上;分解)
实施例27
5-(2-甲基硫代乙基)-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:255℃以上;分解)
实施例28
8-(4-氯苯基)-5-(2-甲氧基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:278℃以上;分解)
实施例29
8-(4-氯苯基)-5-(2-甲基硫代乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:257℃以上;分解)
实施例30
8-(4-氯苯基)-5-(3-甲氧基羰基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:261-262.5℃)
实施例31
5-(3-羧基丙基)-8-苯基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例18得到的化合物0.5g悬浮于乙醇5ml中,向其中加入10氢氧化钠水溶液1.78ml,室温下搅拌2小时。将反应液用水40ml稀释,加入盐酸调节为酸性。滤取析出的结晶,用水和热乙醇依次洗涤后,干燥,得目的化合物的结晶0.35g。
(熔点:280℃以上)
实施例32-36
与实施例31同样,由实施例20-23和30的化合物分别制备对应的下列化合物。
实施例32
8-(4-联苯基)-5-(2-羧基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例33
8-(4-联苯基)-5-(3-羧基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例34
8-(4-联苯基)-5-(4-羧基丁基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例35
8-(4-叔丁基苯基)-5-(3-羧基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例36
5-(3-羧基丙基)-8-(4-氯苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例37
8-(4-联苯基)-5-(2-甲基亚硫酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例4得到的化合物0.15g悬浮于醋酸1.5ml中,向其中加入30%过氧化氢水50μl,室温下搅拌20分钟。在反应液中加入3ml水,滤取析出的结晶,依次用水和乙醇-水洗涤后,干燥,得目的化合物结晶0.14g。
(熔点:188℃以上;分解)
实施例38-40
与实施例37同样,由实施例29、17和27的化合物分别制备对应的下列化合物。
实施例38
8-(4-氯苯基)-5-(2-甲基亚硫酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:218℃以上;分解)
实施例39
8-(4-叔丁基苯基)-5-(2-甲基亚硫酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:162℃以上;分解)
实施例40
5-(2-甲基亚硫酰基乙基)-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:203℃以上;分解)
实施例41
8-(4-联苯基)-5-(2-甲基磺酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例4得到的化合物0.25g悬浮于乙酸5ml中,向其中加入30%过氧化氢水0.16ml,室温下搅拌15分钟,然后在55℃下搅拌16小时。反应后,滤取析出的结晶,依次用水和热乙醇-水洗涤后,干燥,得目的化合物的结晶0.28g。
(熔点:280℃以上)
实施例42-44
与实施例41同样,由实施例29、17、27的化合物分别制备对应的下列各化合物。
实施例42
8-(4-氯苯基)-5-(2-甲基磺酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:244℃以上;分解)
实施例43
8-(4-叔丁基苯基)-5-(2-甲基磺酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:201℃以上;分解)
实施例44
5-(2-甲基磺酰基乙基)-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:261℃以上;分解)
实施例45-59
与实施例1同样制备下列各化合物。
实施例45
8-(4-联苯基)-5-环己基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例46
8-(4-联苯基)-5-环戊基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例47
8-(4-联苯基)-5-三氟甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:280℃以上)
实施例48
8-(4-联苯基)-5-甲基硫代甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:284-286℃)
实施例49
8-(4-联苯基)-5-乙基硫代甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:264-266℃)
实施例50
8-(4-联苯基)-5-二乙基膦酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:188-192℃)
实施例51
8-(4-联苯基)-5-(2-二乙基膦酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:110℃以上)
实施例52
8-(4-联苯基)-5-乙酰氧基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:233-235℃)
实施例53
8-(4-叔丁基苯基)-5-二乙基膦酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:162-166℃)
实施例54
8-(4-联苯基)-5-二甲基氨基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:284-286℃;分解)
实施例55
8-(4-联苯基)-5-(3-二甲基氨基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:227-230℃;分解)
实施例56
5-(3-苄氧基丙基)-8-(4-联苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:237-238℃)
实施例57
5-(4-苄氧基丁基)-8-(4-联苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:205-207℃)
实施例58
5-二乙基膦酰基甲基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:196-198℃)
实施例59
8-(4-联苯基)-5-(3-二乙基膦酰基丙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:175-178℃)
实施例60-61
与实施例37同样由实施例48、49的化合物分别制备对应的下列各化合物。
实施例60
8-(4-联苯基)-5-甲基亚硫酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:246℃以上;分解)
实施例61
8-(4-联苯基)-5-(2-甲基亚硫酰基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:234℃以上;分解)
实施例62
8-(4-联苯基)-5-羟基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例52的化合物进行与实施例31同样的反应处理,得到目的化合物。
(熔点:280℃以上)
实施例63
8-(4-叔丁基苯基)-5-乙基膦酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例59的化合物0.20g与溴化锂0.47g悬浮于乙腈4ml中,在60℃下搅拌72小时。将反应混合物在室温放冷后,滤取析出的结晶,用乙腈10ml洗涤2次。得到的结晶溶解于50%乙醇10ml中,室温搅拌下,在该溶液中加入1N盐酸水溶液0.45ml。室温下搅拌10分钟后,滤取析出的结晶,用乙醇-水重结晶,得到目的化合物的结晶0.12g。
(熔点:254-256℃)
实施例64和65
与实施例63同样,由实施例58及实施例50的化合物分别制备对应的下列各化合物。
实施例64
5-乙基膦酰基甲基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:268-270℃)
实施例65
8-(4-联苯基)-5-乙基膦酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤
(熔点:274-277℃)
实施例66
8-(4-叔丁基苯基)-5-膦酰基甲基-1H-1,2,4-三唑并[5,1-i]嘌呤的制备
将实施例53的化合物0.20g和碘化钠0.20g悬浮于乙腈4ml中,室温下在该悬浮液中缓慢滴加氯三甲基硅烷0.17ml。室温下搅拌3小时,然后在50℃下搅拌20小时后,在反应混合液中加入10ml水,加热回流10分钟。冷却至室温,滤取析出的结晶,用热乙醇洗涤,得到目的化合物的结晶0.10g。
(熔点:270℃以上;分解)
上述各实施例化合物的1H-NMR光谱数据(δ:ppm)如下所述。测定溶剂用二甲亚砜-d6,内标用四甲基硅烷。·实施例11.30(3H,t,J=6.9),3.85(2H,q,J=6.9),5.20(2H,s),7.4-7.7(3H,m),7.84(2H,d,J=8.2),7.95(2H,d,J=8.2),8.42(2H,d,J=8.2),8.56(1H,s).·实施例23.54(3H,s),5.11(2H,s),7.4-7.6(3H,m),7.79(2H,d,J=7.2),7.91(2H,d,J=8.4), 8.38(2H,d,J=8.4),8.50(1H,s).·实施例33.38(3H,s),3.70(2H,t,J=6.4),4.08(2H,t,J=6.4),7.4-7.7(3H,m),7.84(2H,d,J=7.9),7.95(2H,d,J=8.2),8.42(2H,d,J=8.2),8.51(1H,s).·实施例42.20(3H,s),3.15(2H,t,J=7.2),3.69(2H,t,J=7.2),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.2),8.37(2H,d,J=8.2),8.46(1H,s).·实施例51.24(3H,t,J=6.9),3.77(3H,s),3.78(2H,q,J=6.9),3.93(6H,s),5.14(2H,s),7.56(2H,s),8.49(1H,s).·实施例63.53(3H,s),3.76(3H,s),3.93(6H,s),5.10(2H,s),7.56(2H,s),8.49(1H,s).·实施例73.31(3H,s),3.64(2H,t,J=6.4),3.77(3H,s),3.93(6H,s),4.01(2H,t,J=6.4),7.56(2H,s),8.44(1H,s).·实施例81.01(3H,t,J=7.4),1.22(3H,t,J=6.9)1.7-1.9(2H,m),3.76(2H,q,J=6.9),4.03(2H,t,J=6.9),5.11(2H,s),7.12(2H,d,J=8.9),8.20(2H,d,J=8.9),8.47(1H,s).·实施例91.01(3H,t,J=7.4),1.7-1.9(2H,m),3.52(3H,s),4.03(2H,t,J=6.4),5.07(2H,s),7.12(2H,d,J=8.9),8.20(2H,d,J=8.9),8.48(1H,s). ·实施例101.10(3H,t,J=7.4),1.8-2.0(2H,m),3.39(3H,s),3.69(2H,t,J=6.4),4.0-4.2(4H,m),7.20(2H,d,J=8.9),8.28(2H,d,J=8.9),8.51(1H,s).·实施例111.23(3H,t,J=6.9),3.77(2H,q,J=6.9),5.13(2H,s),7.5-7.6(3H,m),8.2-8.3(2H,m),8.49(1H,s).·实施例123.53(3H,s),5.10(2H,s),7.5-7.6(3H,m),8.2-8.3(2H,m),8.50(1H,s).·实施例133.31(3H,s),3.64(2H,t,J=6.4),4.01(2H,t,J=6.4),7.5-7.6(3H,m),8.2-8.3(2H,m),8.45(1H,s),13.6-14.1(1H,brs).·实施例141.22(3H,t,J=7.4),1.35(9H,s),3.77(2H,q,J=7.4),5.12(2H,s),7.61(2H,d,J=8.4),8.21(2H,d,J=8.4),8.49(1H,s).·实施例151.42(9H,s),3.60(3H,s),5.16(2H,s),7.67(2H,d,J=8.4),8.29(2H,d,J=8.4),8.56(1H,s).·实施例161.35(9H,s),3.30(3H,s),3.63(2H,t,J=6.4),4.00(2H,t,J=6.4),7.60(2H,d,J=8.4),8.21(2H,d,J=8.4),8.44(1H,s),13.6-14.1(1H,brs).·实施例171.35(9H,s),2.18(3H,s),3.13(2H,t,J=7.4),3.67(2H,t,J=7.4),7.60(2H,d,J= 8.4),8.21(2H,d,J=8.4),8.45(1H,s),13.7-14.0(1H,brs).·实施例182.2-2.4(2H,m),2.65(2H,t,J=7.4),3.49(2H,t,J=7.4),3.65(3H,s),7.6-7.7(3H,m),8.3-8.4(2H,m),8.51(1H,s).·实施例192.20(3H,s),3.13(2H,t,J=7.4),3.67(2H,t,J=7.4),3.76(3H,s),3.92(6H,s),7.56(2H,s),8.45(1H,s).·实施例201.26(3H,t,J=7.4),3.14(2H,t,J=6.9),3.74(2H,t,J=6.9),4.17(2H,q,J=7.4),7.5-7.7(3H,m),7.87(2H,d,J=7.9),7.98(2H,d,J=8.4),8.46(2H,d,J=8.4),8.52(1H,s).·实施例212.2-2.3(2H,m),2.57(2H,t,J=6.9),3.42(2H,t,J=7.4),3.58(3H,s),7.4-7.6(3H,m),7.78(2H,d,J=6.9),7.89(2H,d,J=8.4),8.36(2H,d,J=8.4),8.44(1H,s).·实施例221.24(3H,t,J=6.9),1.7-1.9(2H,m),2.0-2.2(2H,m),2.49(2H,t,J=7.4),3.46(2H,t,J=7.4),4.12(2H,q,J=6.9),7.4-7.6(3H,m),7.85(2H,d,J=6.9),7.96(2H,d,J=8.4),8.44(2H,d,J=8.4),8.51(1H,s).·实施例231.43(9H,s),2.2-2.4(2H,m),2.64(2H,t,J=7.4),3.48(2H,t,J=7.4),3.65(3H,s),7.68(2H,d,J=8.4),8.29(2H,d,J=8.4),8.50(1H,s).·实施例24 3.54(3H,s),5.11(2H,s),7.96(2H,d,J=8.4),8.48(2H,d,J=8.4),8.52(1H,s).·实施例251.23(3H,t,J=6.9),3.77(2H,q,J=6.9),5.14(2H,s),7.96(2H,d,J=8.4),8.49(2H,d,J=8.4),8.51(1H,s).·实施例263.31(3H,s),3.64(2H,t,J=6.4),4.01(2H,t,J=6.4),7.95(2H,d,J=8.4),8.47(1H,s),8.48(2H,d,J=8.4).·实施例272.19(3H,s),3.14(2H,t,J=7.4),3.68(2H,t,J=7.4),7.95(2H,d,J=8.4),8.47(1H,s),8.49(2H,d,J=8.4).·实施例283.31(3H,s),3.62(2H,t,J=6.4),4.00(2H,t,J=6.4),7.64(2H,d,J=8.4),8.27(2H,d,J=8.4),8.45(1H,s).·实施例292.18(3H,s),3.13(2H,t,J=7.4),3.66(2H,t,J=7.4),7.64(2H,d,J=8.4),8.28(2H,d,J=8.4),8.46(1H,s).·实施例302.1-2.3(2H,m),2.56(2H,t,J=7.4),3.39(2H,t,J=7.4),7.64(2H,d,J=8.9),8.27(2H,d,J=8.9),8.43(1H,s).·实施例312.1-2.3(2H,m),2.47(2H,t,J=6.9),3.41(2H,t,J=7.4),7.5-7.6(3H,m),8.2-8.3(2H,m),8.43(1H,s). ·实施例323.07(2H,t,J=6.9),3.70(2H,t,J=6.9),7.4-7.6(3H,m),7.86(2H,d,J=7.4),7.97(2H,d,J=8.4),8.45(2H,d,J=8.4),8.52(1H,s).·实施例332.1-2.3(2H,m),2.48(2H,t,J=6.9),3.42(2H,t,J=6.8),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.89(2H,d,J=8.4),8.37(2H,d,J=8.4),8.44(1H,s).·实施例341.6-1.8(2H,m),1.9-2.1(2H,m),2.34(2H,t,J=7.4),3.39(2H,t,J=7.9),7.4-7.6(3H,m),7.78(2H,d,J=7.9),7.89(2H,d,J=8.4),8.37(2H,d,J=8.4),8.43(1H,s).·实施例351.35(9H,s),2.1-2.3(2H,m),2.47(2H,t,J=6.9),3.40(2H,t,J=7.4),7.60(2H,d,J=8.4),8.21(2H,d,J=8.4),8.43(1H,s).·实施例362.1-2.3(2H,m),2.46(2H,t,J=6.9),3.40(2H,d,J=7.4),7.64(2H,d,J=8.4),8.28(2H,d,J=8.4),8.43(1H,s).·实施例372.70(3H,s),3.2-3.6(2H,m),3.79(2H,t,J=6.9),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.4),8.38(2H,d,J=8.4),8.47(1H,s).·实施例382.69(3H,s),3.2-3.6(2H,m),3.76(2H,t,J=7.4),7.64(2H,d,J=8.4),8.29(2H,d,J=8.4),8.46(1H,s) ·实施例391.35(9H,s),2.69(3H,s),3.2-3.6(2H,m),3.77(2H,t,J=7.4),7.60(2H,d,J=8.4),8.22(2H,d,J=8.4),8.45(1H,s).·实施例402.70(3H,s),3.2-3.6(2H,m),3.78(2H,t,J=7.9),7.95(2H,d,J=8.4),8.48(1H,s),8.49(2H,d,J=8.4).·实施例413.18(3H,s),3.86(4H,s),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.4),8.39(2H,d,J=8.4),8.48(1H,s).·实施例423.16(3H,s),3.83(4H,s),7.65(2H,d,J=8.4),8.31(2H,d,J=8.4),8.48(1H,s).·实施例431.35(9H,s),3.17(3H,s),3.84(3H,s),7.61(2H,d,J=8.4),8.23(2H,d,J=8.4),8.47(1H,s).·实施例443.17(3H,s),3.85(4H,s),7.96(2H,d,J=8.4),8.49(1H,s),8.51(2H,d,J=8.4).·实施例451.3-2.0(8H,m),2.1-2.3(2H,m),3.7-3.8(1H,m),7.4-7.6(3H,m),7.79(2H,d,J=7.4),7.91(2H,d,J=8.4),8.38(2H,d,J=8.4),8.45(1H,s).·实施例461.7-1.9(4H,m),2.0-2.1(2H,m),2.2-2.3(2H,m),4.15(1H,quint,J=7.9),7.4-7.6(3H,m),7.78(2H,d,J=7.9),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.43(1H,s), 13.6-14.1(1H,brs).·实施例477.4-7.6(3H,m),7.79(2H,d,J=6.9),7.93(2H,d,J=8.4),8.38(2H,d,J=8.4),8.73(1H,s).·实施例482.26(3H,s),4.38(2H,s),7.4-7.6(3H,m),7.78(2H,d,J=6.9),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.49(1H,s).·实施例491.27(3H,t,J=7.4),2.72(2H,q,J=7.4),4.41(2H,s),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.4),8.36(2H,d,J=8.4),8.49(1H,s).·实施例501.19(6H,t,J=6.9),4.0-4.2(6H,m),7.4-7.6(3H,m),7.79(2H,d,J=7.2),7.91(2H,d,J=8.4),8.38(2H,d,J=8.4),8.50(1H,s).·实施例511.24(6H,t,J=6.9),2.4-2.5(2H,m),3.5-3.6(2H,m),4.0-4.1(4H,m),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.47(1H,s).·实施例522.22(3H,s),5.76(2H,s),7.4-7.6(3H,m),7.78(2H,d,J=7.2),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.52(1H,s).·实施例531.18(6H,t,J=7.4),1.35(9H,s),4.0-4.2(6H,m),7.62(2H,d,J=8.7),8.22(2H,d,J=8.7),8.48(1H,s). ·实施例542.43(6H,s),4.20(2H,s),7.4-7.6(3H,m),7.78(2H,d,J=7.2),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.48(1H,s).·实施例552.0-2.2(2H,m),2.18(6H,s),2.43(2H,t,J=6.9),3.39(2H,t,J=7.2),7.4-7.6(3H,m),7.78(2H,d,J=8.2),7.89(2H,d,J=8.4),8.36(2H,d,J=8.4),8.42(1H,s).·实施例562.2-2.3(2H,m),3.48(2H,t,J=7.2),3.65(2H,t,J=6.2),4.48(2H,s),7.2-7.6(8H,m),7.78(2H,d,J=7.2),7.89(2H,d,J=8.4),8.37(2H,d,J=8.4),8.43(1H,s).·实施例571.7-1.8(2H,m),1.9-2.2(2H,m),3.41(2H,t,J=7.4),3.54(2H,t,J=6.2),4.47(2H,s),7.2-7.6(8H,m),7.78(2H,d,J=8.2),7.88(2H,d,J=8.4),8.36(2H,d,J=8.4),8.43(1H,s).·实施例581.18(6H,t,J=6.9),4.0-4.2(6H,m),7.98(2H,d,J=8.4),8.50(2H,d,J=8.4),8.51(1H,s).·实施例591.24(6H,t,J=6.9),1.9-2.1(2H,m),2.1-2.3(2H,m),3.50(2H,t,J=7.4),3.94.1(4H,m),7.4-7.6(3H,m),7.78(2H,d,J=7.4),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.44(1H,s).·实施例602.88(3H,s),4.84(1H,d,J=13.4),5.00(1H,d,J=13.4),7.4-7.6(3H,m),7.79(2H,d, J=7.4),7.91(2H,d,J=8.4),8.39(2H,d,J=8.4),8.53(1H,s).·实施例611.33(3H,t,J=7.4),2.9-3.2(2H,m),4.78(1H,d,J=13.4),4.97(1H,d,J=13.4),7.4-7.6(3H,m),7.79(2H,d,J=7.9),7.91(2H,d,J=8.4),8.38(2H,d,J=8.4),8.53(1H,s).·实施例625.13(2H,s),5.79(1H,brs),7.4-7.6(3H,m),7.79(2H,d,J=8.2),7.90(2H,d,J=8.2),8.38(2H,d,J=8.2),8.48(1H,s).·实施例631.16(3H,t,J=7.2),1.35(9H,s),3.9-4.1(4H,m),7.61(2H,d,J=8.2),8.22(2H,d,J=8.2),8.46(1H,s).·实施例641.16(3H,t,J=6.9),3.9-4.1(4H,m),7.97(2H,d,J=8.4),8.49(1H,s),8.50(2H,d,J=8.4).·实施例651.18(3H,t,J=6.9),3.9-4.2(4H,m),7.4-7.6(3H,m),7.78(2H,d,J=7.9),7.90(2H,d,J=8.4),8.37(2H,d,J=8.4),8.48(1H,s).·实施例661.38(9H,s),3.8-4.1(2H,m),7.60(2H,d,J=8.4),8.21(2H,d,J=8.4),8.45(1H,brs).
试验例
三唑并嘌呤衍生物(1)的腺苷A3受体结合能试验
按照Molecular Pharmacology,45,978(1994)中记载的方法,进行腺苷A3受体结合能试验。
将编码腺苷A3受体的质粒转换的人肾脏内皮细胞HEK-293的细胞膜,在pH7.7的Tris-盐酸缓冲液中按常法分离,将其用125I标记的N6-(4-氨基苄基)-9-[5-(甲基羰基)-β-D-呋喃核糖基]腺嘌呤(AB-MECA)处理,调制成结合该化合物的细胞膜。
然后培养该细胞膜和供试化合物,测定游离出来的[125I]AB-MECA的量。由供试化合物的各浓度的测定值,求出50%的[125I]AB-MECA游离时的供试化合物浓度IC50。
按照Archives of Pharmacology,336,204(1987)和The Journalof Pharmacology and Experemental Therapeutics,251(3),888(1989)中记载的方法测定供试化合物的腺苷A2受体结合能,作为IC50评价。测定结果如下表所示。
表1
制剂例1片剂的调制按以下处方调制以实施例3得到的化合物8-(4-联苯基)-5-(2-甲氧基乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤为有效成分的,每片含300mg有效成分的片剂(2000片)。
实施例序号 | 受体结合能(IC50)(nM) | |
腺苷A2 | 腺苷A3 | |
3 | 1×104以上 | 0.9 |
4 | 1×104以上 | 1.1 |
5 | 1×104以上 | 24 |
6 | 1×104以上 | 104 |
7 | 1×104以上 | 27 |
10 | 2821 | 0.9 |
11 | 827 | 1.6 |
12 | 792 | 2.2 |
13 | 1110 | 0.9 |
16 | 1×104以上 | 2.1 |
17 | 1×104以上 | 27 |
19 | 2544 | 5.6 |
26 | 1×104以上 | 2.4 |
27 | 3842 | 13 |
28 | 1097 | 0.9 |
29 | 670 | 1.1 |
32 | 1×104以上 | 14.5 |
33 | 1×104以上 | 8.7 |
34 | 1×104以上 | 9.1 |
37 | 1×104以上 | 5.6 |
41 | 1×104以上 | 2.6 |
实施例3得到的化合物 600g
乳糖(日本药典收载品) 67g
玉米淀粉 33g
羧甲基纤维素钙(日本药典收载品) 25g
甲基纤维素(日本药典收载品) 12g
硬脂酸镁(日本药典收载品) 3g
按上述处方,充分混合实施例3得到的化合物、乳糖、玉米淀粉和羧甲基纤维素钙,用甲基纤维素水溶液将混合物颗粒化,过24目筛,将其与硬脂酸镁混合,压成片,得目的片剂。
制剂例2
胶囊剂的调制
按以下处方调制以实施例4得到的化合物8-(4-联苯基)-5-(2-甲基硫代乙基)-1H-1,2,4-三唑并[5,1-i]嘌呤为有效成分的,每胶囊含200mg有效成分的硬质明胶胶囊剂(2000个)。
实施例4得到的化合物 400g
结晶纤维素(日本药典收载品) 60g
玉米淀粉(日本药典收载品) 34g
滑石粉(日本药典收载品) 4g
硬脂酸镁(日本药典收载品) 2g
按上述处方,将各成分研成细粉末,混合成均匀的混合物,充填至具有所希望尺寸的口服用明胶胶囊中,得目的胶囊剂。
Claims (10)
1、通式(1)表示的三唑并嘌呤衍生物,
式中,R1表示低级烷氧基低级烷基,低级烷基亚硫酰基低级烷基,低级烷基磺酰基低级烷基,低级烷氧基羰基低级烷基,羧基低级烷基,环烷基,卤素取代低级烷基,膦酰基低级烷基,低级烷基膦酰基低级烷基,二低级烷基膦酰基低级烷基,低级烷酰氧基低级烷基,羟基低级烷基,二低级烷基氨基低级烷基,苯基低级烷氧基低级烷基或低级烷基硫代低级烷基;R2苯基,该苯基可以具有1-3个选自低级烷基,低级烷氧基,卤素原子,卤素取代低级烷基和苯基中的取代基。
2、权利要求1记载的三唑并嘌呤衍生物,其中R1表示低级烷氧基低级烷基,低级烷基亚硫酰基低级烷基,低级烷基磺酰基低级烷基,羧基低级烷基或低级烷基硫代低级烷基。
3、权利要求1或2记载的三唑并嘌呤衍生物,其中R1是甲氧基甲基,乙氧基甲基,2-甲氧基乙基,2-甲基亚硫酰基乙基,2-乙基磺酰基乙基,2-羧基乙基,3-羧基丙基,4-羧基丁基或2-甲基硫代乙基。
4、权利要求1-3任一项记载的三唑并嘌呤衍生物,其中R2是苯基,4-联苯基,4-正丙氧基苯基,4-叔丁基苯基,4-氯苯基,4-三氟甲基苯基,或3,4,5-三甲氧基苯基。
5、权利要求2记载的三唑并嘌呤衍生物,其中R1是低级烷氧基低级烷基或低级烷基硫代低级烷基,R2是联苯基。
6、权利要求5记载的三唑并嘌呤衍生物,其中R1是2-甲氧基乙基或2-甲基硫代甲基,R2是4-联苯基。
7、药物组合物,含有权利要求1-6中任一项记载的三唑并嘌呤衍生物和制剂上允许的载体。
8、腺苷A3受体亲和剂,含有权利要求1-6任一项记载的三唑并嘌呤衍生物作为有效成分。
9、腺苷A3受体阻断或刺激方法,特征在于给以有效量的权利要求1-6任一项记载的三唑并嘌呤衍生物。
10、权利要求1-6记载的三唑并嘌呤衍生物用于阻断或刺激腺苷A3受体。
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- 2000-09-22 KR KR1020027002550A patent/KR20020046285A/ko active IP Right Grant
- 2000-09-22 AT AT00961172T patent/ATE265459T1/de not_active IP Right Cessation
- 2000-09-22 CN CNB008134316A patent/CN1207298C/zh not_active Expired - Fee Related
- 2000-09-22 DE DE60010311T patent/DE60010311T2/de not_active Expired - Fee Related
- 2000-09-22 CA CA002385865A patent/CA2385865A1/en not_active Abandoned
- 2000-09-22 WO PCT/JP2000/006487 patent/WO2001023391A1/ja active IP Right Grant
- 2000-09-22 JP JP2001526543A patent/JP4077198B2/ja not_active Expired - Fee Related
- 2000-09-22 US US10/089,244 patent/US6686343B1/en not_active Expired - Fee Related
- 2000-09-22 EP EP00961172A patent/EP1227098B1/en not_active Expired - Lifetime
- 2000-09-22 AU AU73196/00A patent/AU768520B2/en not_active Ceased
- 2000-09-28 TW TW089120065A patent/TW523517B/zh not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
WO2001023391A1 (fr) | 2001-04-05 |
TW523517B (en) | 2003-03-11 |
ATE265459T1 (de) | 2004-05-15 |
CN1207298C (zh) | 2005-06-22 |
EP1227098A1 (en) | 2002-07-31 |
JP4077198B2 (ja) | 2008-04-16 |
EP1227098A4 (en) | 2003-04-09 |
AU768520B2 (en) | 2003-12-18 |
KR20020046285A (ko) | 2002-06-20 |
US6686343B1 (en) | 2004-02-03 |
DE60010311D1 (de) | 2004-06-03 |
EP1227098B1 (en) | 2004-04-28 |
DE60010311T2 (de) | 2005-05-12 |
AU7319600A (en) | 2001-04-30 |
CA2385865A1 (en) | 2001-04-05 |
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