CN1449397A - 具有抗惊厥作用的2,5－二氢吡唑并[3,4－d]嘧啶－4－酮及其制备方法 - Google Patents
具有抗惊厥作用的2,5－二氢吡唑并[3,4－d]嘧啶－4－酮及其制备方法 Download PDFInfo
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- pyrimidin
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- pyrazolo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
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- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
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- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 229940073608 benzyl chloride Drugs 0.000 claims description 17
- -1 5-(4-pyridylmethyl)-2,5-dihydro-pyrazolo [3,4-d] pyrimidin-4-one 5-benzyl-2-methyl-2,5-dihydro-pyrazolo [3,4-d] pyrimidin-4-one Chemical compound 0.000 claims description 12
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- LZESYJSTDCRAGF-UHFFFAOYSA-N 2-methyl-5-(pyridin-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N=1N(C)C=C(C2=O)C=1N=CN2CC1=CC=NC=C1 LZESYJSTDCRAGF-UHFFFAOYSA-N 0.000 claims description 2
- MUHJBDDCEXIXHK-UHFFFAOYSA-N 5-[[2-(trifluoromethyl)phenyl]methyl]-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound FC(F)(F)C1=CC=CC=C1CN1C(=O)C2=CNN=C2N=C1 MUHJBDDCEXIXHK-UHFFFAOYSA-N 0.000 claims description 2
- FQXKRMCCAZDGMY-UHFFFAOYSA-N 5-benzyl-1h-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=NC=2NN=CC=2C(=O)N1CC1=CC=CC=C1 FQXKRMCCAZDGMY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
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- 239000011630 iodine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 4
- 230000001037 epileptic effect Effects 0.000 claims 2
- 206010015037 epilepsy Diseases 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 9
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- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
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- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
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- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
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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
- C07D487/02—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 two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及在5－位含有芳(烷基)和在2－位含有氢或芳(烷基)的2，5－二氢吡唑并[3，4－d]嘧啶－4－酮及其互变异构体，其制备方法，及其作为药物、尤其是用于治疗不同类型癫痫的药物的应用。
Description
技术领域
本发明涉及在5-位含有芳(烷基)基团和在2-位含有氢或芳(烷基)基团的2，5-二氢吡唑并[3，4-d]嘧啶-4-酮及其互变异构体，其制备方法，及其作为药物、特别是用于治疗不同形式癫痫的药物的应用。由于结构与腺嘌呤类似，所以吡唑并[3，4-d]嘧啶是在药理方面令人关注的化合物。
现有技术
迄今为止，只有5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮和5-苯乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮被描述过[Sochneva，E.O.；Solov′eva，N.P.；Granik，V.G.，Khim.Geterotsikl.Soedin.1978，(12)，1671-6；Granik，V.G.；Sochneva，E.O.；Solov′eva，N.P.；Shvarts，G.Ya.；Syubaev，R.D.；Mashkovskii，M.D.，Khim.-Farm.Zh.1980，14(6)，36-40]。试验了这些化合物的抗炎活性；没有提及或提出抗惊厥活性。
在吡唑环中具有另外的取代基的5-芳基甲基(Arylmetyl)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮是未知的。
一方面，已知的抗惊厥剂具有产生不利的副作用例如神经毒性和特异反应的缺点，另一方面，它们对一些形式的癫痫没有活性。
因此，本发明是基于这样的目的，即获得具有有利的药理性质的化合物，这样的化合物具有抗惊厥活性，并且可用作药物、特别是用于治疗癫痫的药物。
发明描述
依据本发明，这些新化合物是通式1所示的2，5-二氢吡唑并[3，4-d]嘧啶-4-酮或其互变异构体
其中R＝CH2-苯基，其中所述苯基可被下列基团单取代或多取代：卤素，直链或支链的、任选被卤素单取代或多取代的C1-C3-烷基，直链或支链C1-C3-烷氧基，苯基NO2CN；CH2-吡啶基；R1＝H；C1-C4-烷基；苯基；CH2-苯基，其中所述苯基可任选被卤素取代；CH2-吡啶基；四氢呋喃基甲基；R2＝H、甲基；其中R代表CH2-苯基，且R1代表氢的化合物不包括在内。
可提及的通式1化合物的实例是：5-(2-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氟苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4-二氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲氧基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4，6-三甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-苄基-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲氧基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-三氟甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-苯基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-硝基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4-二氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-碘苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氰基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4，6-三甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-吡啶基甲基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮2，5-二(2-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-吡啶-2-基甲基-2，5-二氢-吡唑[3，4-d]嘧啶-4-酮5-(2-氯苄基)-2-四氢呋喃-2-基甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯苄基)-6-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-6-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2，6-二甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2，6-二甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮
制备式1化合物及其互变异构体的方法是用已知的3-氨基吡唑-4-甲酸酯(通式2化合物)或3-氨基吡唑-4-甲酰胺(通式3化合物)作为原料[P.Schmidt，J.Druey；Helv.Chim.Acta 1956，39，986-991；K.Eichenberger，P.Schmidt，M.Wilhelm，J.Druey；Helv.Chim.Acta 1959，42，349-359；.J.K.Chakrabarti，T.M.Hotten，I.A.Pullar，N.C.Nicholas，J.Med.Chem.1989，32(12)，2573-2582]，
其中R1＝H、C1-C4-烷基；苯基；CH2-苯基，其中所述苯基可任选被卤素取代；CH2-吡啶基、四氢呋喃基甲基；且Et代表烷基。
一方面，在较高温度下使用甲酰胺(R2＝H)或乙酰胺(R2＝甲基)将通式2或通式3化合物环合，或者，使用原甲酸酯和/或甲酸/乙酸酐混合物(R2＝H)或使用原乙酸酯和/或乙酸酐(R2＝甲基)将通式3化合物环合，然后与其中R具有所述含义的R-卤化物反应，以生成通式
1化合物(方法B)。
另一方面，将通式3化合物与二甲基甲酰胺缩二甲醇(Dimethylformamiddimethylacetal)(R2＝H)或二甲基乙酰胺缩二甲醇(Dimethylacetamiddimethylacetal)(R2＝甲基)反应，并将由此获得的产物与其中R具有所述含义的R-胺反应，以生成通式1化合物(方法A)。
象已描述的化合物5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮一样，本发明化合物或其可药用盐适于制备药物组合物。药物组合物或药物可含有一种或多种本发明化合物。可使用常规药物载体和助剂来制备药物组合物。药物可例如非胃肠道给药(例如静脉内、肌内、皮下给药)或口服给药。
给药剂型可通过在药物实践中通常已知的且常用的方法制得。
象已描述的化合物5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮一样，本发明化合物具有强的抗惊厥作用。抗惊厥活性
依据国际通常标准(Pharmac.Weekblad，Sc.Ed.
14，132(1992)和Antiepileptic Drugs，Third.Ed.，Raven Press，New York 1989)，对小鼠腹膜内给药后，测试本发明化合物的体内抗惊厥作用(表1)。表1：所选的2，5-二氢吡唑并[3，4-d]嘧啶-4-酮的抗惊厥作用
表1的注解：1)依据在表2中实施例的化合物的编号2)辛醇/水分配系数3)小鼠i.p.：MES＝最大电休克，PTZ＝s.c.戊四氮4)mg/kg5)受保护的动物的％
| 化合物1) | log P2) | 测试3) | 剂量4) | 作用5) |
| 1 | 1.14 | MESPTZ | 30100 | 10080 |
| 2 | 1.34 | MESPTZ | 100100 | 33- |
| 3 | 0.62 | MESPTZ | 100300 | 3360 |
| 4 | 1.96 | MESPTZ | 100300 | 10040 |
| 5 | 0.28 | MESPTZ | 30300 | 100- |
| 6 | 1.36 | MESPTZ | 100300 | 67100 |
| 8 | 0.78 | MESPTZ | 100100 | 6720 |
| 13 | 0.72 | MESPTZ | 100300 | 100- |
| 14 | 1.76 | MESPTZ | 30100 | 10080 |
| 17 | 0.92 | MESPTZ | 100300 | 100100 |
| 19 | 1.56 | MESPTZ | 100300 | 100- |
| 21 | 0.67 | MESPTZ | 30100 | 10080 |
| 37 | 1.43 | MESPTZ | 100300 | 8020 |
| 43 | 1.88 | MESPTZ | 300300 | 10033 |
| 58 | 2.59 | MESPTZ | 300300 | -- |
| 60 | 1.67 | MESPTZ | 100300 | 67- |
| 5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮 | 0.47 | MESPTZ | 3030 | 100100 |
| 比较物质 | ||||
| 卡马西平 | MESPTZ | 100100 | 1000 | |
| 丙戊酸盐 | MESPTZ | 100100 | 030 | |
对于口服作用获得了类似结果。
例如，对于化合物1(5-(2-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮)，在大鼠中，对于最大电休克，测定的ED50(p.o.)为18mg/kg，对于神经毒性，NT50＞500mg/kg。该化合物在使用荷包牡丹碱和木防己苦毒素作为惊厥诱导因素的惊厥模型中也具有活性。化合物14(5-(2-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮)同样是强的抗惊厥剂，具有大的治疗宽度(ED50(大鼠p.o.)＝9mg/kg，NT50＞300mg/kg)。化合物21具有类似药理性质(ED50(大鼠p.o.)＝3mg/kg，NT50＞300mg/kg)。
实施例
下述实施例是为了进一步举例说明本发明，而不是限制本发明。制备表2所示式1化合物和其互变异构体的一般方法(方法A)
将50mmol 3-氨基吡唑-4-甲酰胺与二甲基甲酰胺缩二甲醇(R2＝H)或二甲基乙酰胺缩二甲醇(R2＝甲基)于较高温度下、优选90-130℃，在/或不在有机溶剂中反应。12-40小时后，将过量溶剂和试剂完全除去。向残余物中加入其中R具有所述含义的50mmol R-胺，以及如果适当的话，惰性有机溶剂，优选二甲苯、氯苯等。将该反应混合物在较高温度下、优选100-180℃反应。10-35小时后，除去溶剂，通过从有机溶剂，优选DMF、乙醇、甲醇或丙酮中重结晶，或通过色谱法纯化，获得了式1化合物。制备表2所示式1化合物及其互变异构体的一般方法(方法B)步骤1
将50mmol 3-氨基-吡唑-4-甲酸酯/甲酰胺在甲酰胺(R1＝H)或乙酰胺(R2＝甲基)中于较高温度下(100-200℃)反应3-15小时。反应完全后，通过过滤分离出产物(吡唑并嘧啶)，或者除去溶剂后通过色谱法收集产物。
或者，将50mmol 3-氨基吡唑-4-甲酰胺与原甲酸酯和/或与甲酸/乙酸酐混合物(R2＝H)或者与原乙酸酯和/或与乙酸酐(R2＝甲基)在较高温度下、优选80-120℃反应10-50小时。反应完全后，通过过滤分离出产物(吡唑并嘧啶)，或者除去溶剂后通过色谱法收集产物。步骤2
将20mmol吡唑并嘧啶溶解在DMF中，用无机碱，优选碳酸钠、碳酸钾或碳酸钙，和碘化钠/碘化钾处理，并与其中R具有所述含义的25-40mmol R-卤化物在较高温度下、优选50-140℃反应。5-40小时后，将该反应混合物过滤，通过过滤分离出式1化合物，或者除去溶剂后通过色谱法收集式1化合物。将由此获得的粗产物从有机溶剂，优选DMF、乙醇、甲醇或丙酮中重结晶。或者，可通过色谱法进行纯化。表2：吡唑并[3，4-d]嘧啶
1)所用的缩写：Me＝CH3，Et＝C2H5，Pro＝C3H7，i-Pro＝i-C3H7，Bu＝C4H9，Ph＝C6H5，Bn＝-CH2-C6H5，Py＝C5H4N，THF＝C4H8O。
| 化合物 | R1) | R1 1) | R2 1) | 产率(％) | 熔点(℃) | 方法 |
| 1 | 2-Cl-Bn | H | H | 38 | 186-187 | A |
| 2 | 4-Cl-Bn | H | H | 41 | 246-247 | A |
| 3 | 4-F-Bn | H | H | 84 | 260-261 | A |
| 4 | 2，4-Cl2-Bn | H | H | 63 | 236-237 | A |
| 5 | 2，6-F2-Bn | H | H | 15 | 214-216 | A |
| 6 | 2-Me-Bn | H | H | 46 | 221-222 | A |
| 7 | 2-MeO-Bn | H | H | 18 | 188-189 | A |
| 8 | 2-CF3-Bn | H | H | 29 | 168-171 | A |
| 9 | 2，4，6-Me3-Bn | H | H | 34 | 199-200 | A |
| 10 | 2-Py-CH2- | H | H | 45 | 224-225 | A |
| 11 | 3-Py-CH2- | H | H | 39 | 200-201 | A |
| 12 | 4-Py-CH2- | H | H | 47 | 220-221 | A |
| 13 | Bn | Me | H | 28 | 202-204 | B |
| 14 | 2-Me-Bn | Me | H | 28 | 185-186 | A |
| 15 | 3-Me-Bn | Me | H | 5 | 114-117 | A |
| 16 | 4-Me-Bn | Me | H | 34 | 224-226 | A |
| 17 | 2-MeO-Bn | Me | H | 31 | 160-162 | B |
| 18 | 2-Cl-Bn | Me | H | 25 | 205-206 | A |
| 19 | 3-Cl-Bn | Me | H | 15 | 169-170 | A |
| 20 | 2-CF3-Bn | Me | H | 23 | 215-217 | A |
| 21 | 2，6-F2-Bn | Me | H | 13 | 226-228 | A |
| 22 | 4-CF3-Bn | Me | H | 56 | 211-212 | B |
| 23 | 2-Cl-6-F-Bn | Me | H | 49 | 216-218 | B |
| 24 | 2-Ph-Bn | Me | H | 59 | 189-191 | B |
| 25 | 2，6-Cl2-Bn | Me | H | 51 | 200-202 | B |
| 26 | 2-NO2-Bn | Me | H | 24 | 220-222 | B |
| 27 | 4-Cl-Bn | Me | H | 62 | 209-210 | B |
| 28 | 2，4-Cl2-Bn | Me | H | 60 | 218-219 | B |
| 29 | 2-I-Bn | Me | H | 16 | 187-190 | B |
| 30 | 2-CN-Bn | Me | H | 21 | 198-199 | B |
| 31 | 4-F-Bn | Me | H | 62 | 216-217 | B |
| 32 | 2，4，6-Me3-Bn | Me | H | 45 | 182-184 | B |
| 33 | 2-Py-CH2- | Me | H | 53 | 203-205 | B |
| 34 | 4-Py-CH2- | Me | H | 48 | 192-195 | B |
| 35 | 2-Cl-6-F-Bn | Et | H | 61 | 207-209 | B |
| 36 | 4-Me-Bn | Et | H | 57 | 178-179 | B |
| 37 | 2，6-F2-Bn | Et | H | 63 | 185-187 | B |
| 38 | 2-Py-CH2- | Et | H | 71 | 190-191 | B |
| 39 | 2-Cl-6-F-Bn | Pro | H | 73 | 163-165 | B |
| 40 | 4-Me-Bn | Pro | H | 6865 | 157-158 | B |
| 41 | 2，6-F2-Gn | Pro | H | 167-168 | B | |
| 42 | 2-Py-CH2- | Pro | H | 72 | 179-181 | B |
| 43 | 2-Cl-6-F-Bn | i-Pro | H | 66 | 159-161 | B |
| 44 | 4-Me-Bn | i-Pro | H | 78 | 145-147 | B |
| 45 | 2，6-F2-Bn | i-Pro | H | 74 | 156-157 | B |
| 46 | 2-Py-CH2- | i-Pro | H | 63 | 163-164 | B |
| 47 | 2-Cl-6-F-Bn | Bu | H | 45 | 156-157 | B |
| 48 | 4-Me-Bn | Bu | H | 51 | 146-147 | B |
| 49 | 2，6-F2-Bn | Bu | H | 62 | 151-152 | B |
| 50 | 2-Cl-6-F-Bn | Ph | H | 67 | 195-197 | B |
| 51 | 4-Me-Bn | Ph | H | 71 | 182-183 | B |
| 52 | 2，6-F2-Bn | Ph | H | 65 | 189-191 | B |
| 53 | 2-Py-CH2- | Ph | H | 75 | 199-201 | B |
| 54 | 2-Cl-6-F-Bn | Bn | H | 48 | 176-177 | B |
| 55 | 4-Me-Bn | Bn | H | 54 | 167-169 | B |
| 56 | 2，6-F2-Bn | Bn | H | 58 | 173-174 | B |
| 57 | 2-Py-CH2- | Bn | H | 44 | 182-184 | B |
| 58 | 2-Cl-Bn | 2-Cl-Bn | H | 42 | 167-168 | B |
| 59 | 2，6-F2-Bn | 2-Py-CH2- | H | 49 | 174-175 | B |
| 60 | 2-Cl-Bn | 2-THF-CH2- | H | 39 | 128-130 | A |
| 61 | 2-Cl-Bn | H | Me | 24 | 222-224 | A |
| 62 | 2，6-F2-Bn | H | Me | 18 | 235-236 | A |
| 63 | 2-CF3-Bn | Me | Me | 47 | 192-193 | B |
| 64 | 2，6-F2-Bn | Me | Me | 54 | 201-202 | B |
Claims (11)
1.通式1所示的新化合物或其互变异构体其中R＝CH2-苯基，其中所述苯基可被下列基团单取代或多取代：卤素，直链或支链的、任选被卤素单取代或多取代的C1-C3-烷基，直链或支链C1-C3-烷氧基，苯基NO2CN；CH2-吡啶基；R1＝H；C1-C4-烷基；苯基；CH2-苯基，其中所述苯基可任选被卤素取代；CH2-吡啶基；四氢呋喃基甲基；R2＝H、甲基；其中R代表CH2-苯基，且R1代表氢的化合物不包括在内。
2.通式1的化合物5-(2-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氟苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4-二氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲氧基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4，6-三甲基苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-吡啶基甲基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-苄基-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-甲氧基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(3-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-三氟甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-苯基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-硝基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4-二氯苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-碘苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氰基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-氟苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，4，6-三甲基苄基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-吡啶基甲基)-2-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-乙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-异丙基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-丁基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-苯基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯-6-氟苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(4-甲基苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-吡啶基甲基)-2-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮2，5-二(2-氯苄基)-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2-吡啶-2-基甲基-2，5-二氢-吡唑[3，4-d]嘧啶-4-酮5-(2-氯苄基)-2-四氢呋喃-2-基甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-氯苄基)-6-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-6-甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2-三氟甲基苄基)-2，6-二甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮5-(2，6-二氟苄基)-2，6-二甲基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮。
3.制备通式1所示2，5-二氢吡唑并[3，4-d]嘧啶-4-酮的方法，其特征在于将通式3化合物与二甲基甲酰胺缩二甲醇或者与二甲基乙酰胺缩二甲醇反应，然后用其中R具有所述含义的R-胺环合(方法A)。
4.制备通式1所示2，5-二氢吡唑并[3，4-d]嘧啶-4-酮的方法，其特征在于用甲酰胺或乙酰胺将其中Et代表烷基的通式2化合物或通式3的化合物环合，并然后与其中R具有所述含义的R-卤化物反应(方法B)。
5.权利要求4的方法，其特征在于对于通式3化合物的环合，使用原甲酸酯和/或甲酸/乙酸酐混合物或原乙酸酯和/或乙酸酐。
6.药物组合物，其特征在于含有一种或多种权利要求1的式1所示2，5-二氢吡唑并[3，4-d]嘧啶-4-酮或其可药用盐作为活性化合物和一种或多种生理可接受的助剂和/或载体和如果适当的话稀释剂。
7.药物组合物，其特征在于含有一种或多种权利要求2的2，5-二氢吡唑并[3，4-d]嘧啶-4-酮或其可药用盐作为活性化合物和一种或多种生理可接受的助剂和/或载体和如果适当的话稀释剂。
8.药物组合物，其特征在于包含5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮或其可药用盐作为活性化合物和一种或多种生理可接受的助剂和/或载体和如果适当的话稀释剂。
9.药物组合物，其特征在于包含5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮和一种或多种权利要求1或权利要求2的2，5-二氢吡唑并[3，4-d]嘧啶-4-酮或其可药用盐作为活性化合物和一种或多种生理可接受的助剂和/或载体和如果适当的话稀释剂。
10.式1所示2，5-二氢吡唑并[3，4-d]嘧啶-4-酮在制备用于治疗不同形式的癫痫疾病的药物中的应用。
11.5-苄基-2，5-二氢吡唑并[3，4-d]嘧啶-4-酮在制备用于治疗不同形式的癫痫疾病的药物中的应用。
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| DE10042092A1 (de) | 2002-03-07 |
| BR0113517A (pt) | 2003-07-29 |
| RU2003108258A (ru) | 2005-01-27 |
| HRP20030226A2 (en) | 2003-06-30 |
| EP1311510A1 (de) | 2003-05-21 |
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