CN1053438C - 苯并二氮杂䓬－2－酮衍生物,其制备方法和含它们的药物组合物 - Google Patents
苯并二氮杂䓬－2－酮衍生物,其制备方法和含它们的药物组合物 Download PDFInfo
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- CN1053438C CN1053438C CN95101504A CN95101504A CN1053438C CN 1053438 C CN1053438 C CN 1053438C CN 95101504 A CN95101504 A CN 95101504A CN 95101504 A CN95101504 A CN 95101504A CN 1053438 C CN1053438 C CN 1053438C
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- compound
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- alkyl
- benzodiazepine
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- 238000002360 preparation method Methods 0.000 title claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 238000000034 method Methods 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 229940049706 benzodiazepine Drugs 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 19
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- NDNQCTVYOKEYIV-UHFFFAOYSA-N 1h-1,2-benzodiazepin-3-amine Chemical compound C1=CC(N)=NNC2=CC=CC=C21 NDNQCTVYOKEYIV-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 150000002923 oximes Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 4
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- QPILZZVXGUNELN-UHFFFAOYSA-M sodium;4-amino-5-hydroxynaphthalene-2,7-disulfonate;hydron Chemical compound [Na+].OS(=O)(=O)C1=CC(O)=C2C(N)=CC(S([O-])(=O)=O)=CC2=C1 QPILZZVXGUNELN-UHFFFAOYSA-M 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
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- -1 γ-An Jidingsuan Chemical compound 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
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- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical compound NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及式（Ⅰ）的化合物，其中Ｒ<sub>Ⅰ</sub>，R<sub>Ⅱ</sub>，X<sub>1</sub>，X<sub>2</sub>，X<sub>3</sub>和X<sub>4</sub>如权利要求１中所定义。
Description
本发明涉及3-酰氨基-5-苯基-1，4-苯并二氮杂-2-酮衍生物和其盐，它们的制备方法和含它们的药物组合物。
本发明的组合物因其新的结构和新的药理性质而不同于其它1，4-苯并二氮杂衍生物。这些化合物是苯并二氮杂5位上的苯基被至少三取代的1，4-苯并二氮杂卓衍生物。
该特殊结构使本发明产品具有出人意料且非常优良的药理性质。具体讲，本发明化合物对缩胆囊肽受体具有亲和力；更具体讲，本发明主题在胰淀粉酶试验中显示出是缩胆囊肽(CCK)受体的新的激动剂。
CCK是一种广泛分布于脑，尤其是在皮质，纹状体，海马，大脑前盖，隔膜和下丘脑的肽。
CCK也在外周通过小肠分泌，其作用主要是通过刺激泡囊收缩，增加胆汁份泌，控制胰酶分泌及对胃收缩和肠蠕动作用而显示的。在一些情况下，它可对动脉压有作用且也可影响免疫系统。
在一些中枢神经元中，CCK是与多巴胺共存的。其在包括乙酰胆碱，γ-氨基丁酸，5-羟色胺，鸦片制剂，生长激素抑制，素物质p和离子通道的机理中起重要作用。
服用CCK可引起生理变化：上睑下垂，低温，高血糖和倔强症，及一些行为上的变化：不爱运动，进取心下降，缺少痛觉，对学习知识的影响，性行为和对饮食时的饱满感的变化。
因此，CCK受体激动剂，尤其CCKA受体激动剂可用作治疗饮食，肥胖，糖尿病，情绪，性行为和记忆方面疾病的药物，及治疗精神分裂症，精神病，帕金森氏疾病和各种胃肠道方面疾病的药物(Prug of the Future，1992，17，No.3，197-206)。
目前所记载的所有对CCKA受体有良好亲和性的1，4-苯并二氮杂都是拮抗剂。
可与CCK受体和促胃酸激素酰位的化合物在文献中是已知的，例如见专利申请WO-93/20099。
作为例子可提到的有：Devazepide或L-365260，，它们的通式是：
在肽本质或结构上明显不同于本发明化合物的CCK受体激动剂记载于文献中。例如具有这些性质的一些产品记载于EP-A-0,383,690，WO/90/06937和E-A-0,376,849。
本发明化合物和其无机或有机酸加成盐及其立体异构体对应于下式
其中RI代表(i)氢；
(ii)C1-4烷基；
(ii)基团-CH2-CHOH-(CH2)m-Z，其中m为0或1，Z代表C1-4烷基；C3-8环烷基；由C1-4烷基，C1-4烷氧基或卤素选择性取代的芳基；或Z代表由C1-4烷基，C1-4烷氧基或卤素选择性取代的饱和或不饱和杂环；或(iv)RI代表基团-(CH2)nCOR0，其中n代表1-3，R0代表OR2或NR2R3，R2和R3可相同或不同，代表H或C1-4烷基或R2和R3与所连的氮原子一起形成饱和或不饱和杂环；RII代表(i)含氮芳香杂环，RIIa选自喹啉，异喹啉，苯并咪唑和吲哚，后者可在其氮原子被基团W选择性取代，其中W代表基团CO-C1-4烷基；或基团(CH2)nCOR0，其中n和R0如对RI定义，或(ii)下式基团
其中Y代表卤原子或C1-3烷基或C1-3烷氧基；X1，X2和X3是相同或不同的，且代表C1-3烷基，C1-3烷氧基，卤原子或三氟甲基；X4代表氢或与X1，X2或X3相同。
术语烷基意指含1-4个碳原子的直链或支链烷基。
术语饱和或不饱和杂环意指芳香或非芳香杂环，它们选自呋喃，噻吩，吡咯，咪唑，吡咯烷，哌啶，哌嗪，吡啶和吗啉。
具体的一组本发明化合物是由这样的通式I化合物组成的，其中X1在苯基2位，X2在苯基4位，X3在苯基6位和X4在苯基3或5位。
在这些化合物中，优选至少三个取代基X1，X2，X3或X4代表C1-2烷基或C1-2烷氧基，尤其是选择芳环的2位，4位，6位为甲基或甲氧基的那些化合物，更具体讲，R2优选为取代或未取代的吲哚基。
每一组优选的化合物是由这样的化合物组成的，其中两个取代基X1，X2，X3和X4分别代表2-C1-3烷氧基和6-C1-3烷氧基。
当X1，X2或X3为卤原子时，优选为氯原子，但也可为氟，溴或碘原子。
本发明所有化合物都具有不对称中心，因此它们也可以光学异构体形式存在。本发明因此也包括分离的或混合物的这些异构体。
与无机或有机酸所成加成盐可是与下面这些酸所成的盐：盐酸，氢溴酸，硝酸，硫酸，磷酸，乙酸，甲酸，丙酸，苯甲酸，马来酸，富马酸，琥珀酸，酒石酸，柠檬酸，草酸，乙醛酸，天冬氨酸，烷基磺酸如甲磺酸或乙磺酸，芳基磺酸，如苯磺酸或对甲苯磺酸，和芳基羧酸。
可提到的具体本发明产物是相应上述式(I)的衍生物，其与无机或有机酸的加成盐，其特征在于：在所述式(I)中，取代基RII代表式RIIa基团：
其中W，X1，X2，X3和X4如上定义。
在本发明优选的化合物中，可提到下面化合物：
N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧代-1H-1，4-苯并二氮杂-3-基〕-1H-2-吲哚甲酰胺；
〔N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧代-1H-1，4-苯并二氮杂-3-基〕-2-氨基羰基-1H-吲哚-1-基〕乙酸；
{N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧代-1H-1，4-苯并二氮杂-3-基〕-2-氨基羰基吲哚-1-基}乙酸甲酯；
右旋N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧代-1H-1，4-苯并二氮杂-3-基〕-1H-吲哚-2-甲酰胺；
N-〔2，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-2-氧代-1H-1，4-苯并二氮杂-3-基〕-1H-2-吲哚甲酰胺。
本发明化合物可按下面反应路线1制备：
反应路线1
当RII代表含氮杂环RIIa时，式(I)化合物可知下制备：在通常酰化胺功能基的条件下，将式(II)3-氨基-5-(取代的)苯基-1-甲基-1，4-苯并二氮杂-2-酮与酸RIIaCOOH(其中活性基团RIIa已选择性保护)，或活化形式的酸偶联，活化形式的酸如酰卤，酸酐或活化的酯可从肽合成中常用的反应物得到。
当功能基已被保护时，可在适当时候进行脱保护反应，如必要，可在偶联后进行脱保护。
一些酸RIIaCOOH是已知的，甚至是可买到的；其它的可用制备类似酸的已知方法，尤其是EP-A-432,040所述方法来制备。
当RII代表基团RIIb时
其中Y如对(I)的定义，相应的脲(I)可由氨基苯并二氮杂(II)与下式取代的异氰酸苯酯反应制备，其中Y如上定义。这些异氰酸酯衍生物是可买到的或可由已知方法制备。
式II 3-氨基-1，4-苯并二氮杂-2-酮和下面的合成中间体(V)，(VI)和(VII)是新的且代表了本发明另一方面。
根据本发明另一方面，本发明涉及制备式(I)化合物的方法，其特征在于：下式的取代的苯衍生物
其中X1，X2，X3和X4如对(I)中的定义，与下式靛红酸酐
其中RI如对(I)中定义，反应，得到下式二苯基酮衍生物其中X1，X2，X3和X4和RI如对(I)中定义，然后该化合物与下式卤代酮
Hal-CH2COCl其中Hal优选代表溴或氯原子，反应，所得化合物然后在例如氨存在下环化，得到下式苯并二氮杂其中X1，X2，X3和X4和RI如对(I)中定义，但需说明的是，如RI为C2-4烷基，化合物(VI)也可通过用AlKI(其中AlK代表C2-4烷基)将酰胺(RI＝H的VI)烷基化而制备，在式(VI)化合物的肟是通过叔丁醇钾与亚硝酸异戊酯(CH3)2CH-CH2-CH2-ONO反应制备的之后，得到下式苯并二氮杂，其中RI，
X1，X2，X3和X4如对(I)的定义，随后通过在催化剂如钌/活性碳存在下用氢对该肟进行还原，得到下式氨基苯并二氮杂-2-酮，
其中X1，X2，X3和X4和RI如对(I)定义，然后将其与酸RIIaCOOH或其一种活化形式(其中RIIa如对(I)所定义)反应，或与下式异氰酸苯酯反应，
其中Y如对(I)定义，得到本发明化合物(I)或其一种盐。
中间式(II)，(V)，(VI)和(VII)是构成本发明一部分的新化合物。式II化合物的立体异构体和加成盐也是本发明一部分。
3-氨基苯并二氮杂-2-酮(II)可按已知的及文献中记载的方法制备，例如根据专利申请WO/9307130，通过催化氢化或在酸性条件下用适宜金属还原肟(VII)制备(II)。适宜的氢化催化剂包括贵金属催化剂，如可结合到活性碳上的钌或铑。该反应优选在适宜有机溶剂如醇，如甲醇，于温度60-70℃，优选于60℃进行。用金属进行的适宜还原反应包括在适宜溶剂如乙酸中，在大约40-50℃，使用锌和三氟乙酸。
肟(VII)可按例如M.G.Bock等人，J.Org.Chem，1987，523232-3239所述，在碱如碱金属醇盐，例如叔丁醇钾存在下，通过还原亚硝酸异戊酯来制备。
苯并二氮杂(VI)可按M.G.Bock等人，J.Org.Chem.1987，52，3232-3239所述，通过卤代酮Hal-CH2-COCl与式(V)二苯基酮(也可按Bock等人所述制得)之间的环化反应来制备。二苯基酮(V)是通过偶联式(IV)靛红酸酐(RI代表氢或甲基)来制备的。
当RI为C2-4烷基时，式(VI)的苯并二氮杂可按EP-167，919所述，通过在碱金属氢化物如氢化钠存在下，在有机溶剂如二甲基甲酰胺中，用烷基化剂AlkX，其中Alk代表C2-4烷基，X代表卤素，优选碘，烷基化酰胺(VI，R＝H)来制备。
3-氨基苯并二氮杂-2-酮(II)也可应用或采用WO 93/07130，EP-167,919，EP-540,,039或B.E.Evans在J.Med.Chem，1988，31，2235中所述方法来制备。
制备3-氨基苯并二氮杂-2-酮的其它方法，尤其是5位苯基被四取代的可采用M.G.Bock等人在J.Org.Chem，1987，52，3232中所述方法。二苯基酮的制备可采用J.R.Lewis等人在Tetrahedron，1981，37，209中所述方法，通过用芳基锂试剂还原2-甲基-1，3-苯并噁嗪-4-酮来制备。
式(I)光学纯化合物的制备可采用M.G.Bock等人在J.Org.Chem，1987，52，3232-3239中所述方法并按下面反应路线2进行制备：
反应路线2 
根据本发明另一方面，本发明主题还包括含化合物(I)的药物。
这些化合物已在体外用来进行对CCKA受体的亲和性测量研究。
该亲和性位于0.5-100nM之间，其对CCKA受体选择性超过对CCKB受体的选择性，例如实施例1化合物的选择性可达到系数10,000。
本发明其它化合物(实施例6和7的化合物)对CCKB受体的亲和性与对CCKA受体的亲和性是相同的或更大。
对CCKA受体的激动作用研究是通过如下测量所产生的淀粉酶分泌而说明的。胰腺泡细胞是通过酶消化(胶原酶)禁食18小时的大鼠胰腺而得到的。按Jensen等人；在J.Biol.Chem，1982，257(10)，5554所述方法，将等份样品(每份485/ul)在不同浓度的激动剂存在下于37℃培养30分钟。该培养通过15秒离心停止。将上清液保存在冰浴中以便按Leska等人，Chin.，Chim.，Acta，1969，26，437的技术(phadbas试剂)测量淀粉酶含量。待测的化合物溶在二甲基亚砜中，然后置于培养缓冲液中。
本发明化合物是作为CCK-受体激动剂使用的，其EC50(诱导由CCK本身得到的最大反应的50％的产物浓度)数量级是毫微摩尔)。
按D.Gully等人，在European J.Pharmacol.，1993，232，13-19中所述步骤，在体外模型中发明的激动剂作用在禁食小鼠的体内胆汁排空模型上得到了确认。这些化合物在处死小鼠前1小时口服。摘除胆囊，然后称重，结果用mg/kg体重表示，例如实施例10化合物的ED50为0.3mg/kg。
因此，作为CCK受体激动剂的式(I)化合物可用于制备用于治疗下列不适或疾病的药物：饮食，肥胖，糖尿病，情绪疾病，性和记忆行为方面疾病，精神病，尤其是精神分裂症，帕金森氏症和各种胃肠道疾病。
式(I)化合物几乎无毒；其毒性与它们用作治疗上述不适和疾病的药物是相适合的。
式(I)化合物可组合到用于给药于包括人类的哺乳动物的药物组合物中，以治疗上述疾病。
根据治疗对象和所定症状而变化的剂量范围为0.05-100mg/天/口服/成人。本发明的主题还包括药物组合物，其包括一种上述化合物作为活性成份。这些组合物可通过消化道或非肠道给药。
当本发明药物组合物用于口服、舌下、皮下、肌内、静脉、经皮、局部或直肠给药时，活性成份可与常规药物载体混合成单位给药剂量形式给药于动物和人类。适宜的单位给药剂型包括口服剂型如片剂，明胶胶囊，粉剂，粒剂和口服液或悬浮液，舌下和颊给药剂型，皮下，肌内，静脉，鼻内或眼内给药剂型和直肠给药剂型。
当固体组合物被制备成片剂时，主活性成份与药用赋形剂如明胶，淀粉，乳糖，硬脂酸镁，滑石，阿拉伯胶等混合。片剂可用庶糖或其它适宜材料包衣，或将其进行处理以便其具有延长的或延迟的活性，从而其可连续释放预定量的活性成份。
明胶胶囊制剂可通过将活性成份与稀释剂混合，然后把所得混合物倾入到软或硬明胶胶囊中而制得。
喷雾剂或酏剂可含有与甜味剂，优选不带颜色的甜味剂，作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯及调味剂和适宜染料结合的活性成份。
水分散性粉剂或粒剂可含有有效成分并混有分散剂、润湿剂，或悬浮剂，如聚乙烯吡咯烷酮，以及混有甜味剂或调味剂。
对于直肠给药，可制成栓剂，其是用在直肠温度下可熔化的粘合剂，例如可可油或聚乙二醇制备而成。
对于非肠道、鼻内或眼内给药，可使用含有可药用的分散剂和/或润湿剂，例如聚乙二醇或丁二醇的水悬液，等渗盐溶液或无菌注射液。
也可将有效成分配制成微胶囊形式，其可选择性地含有一种或多种载剂或添加剂。
该组合物可以含有0.05-100mg有效成分的单位剂量形式存在。
在下文中，描述了本发明的实施例，以及某些合成中间体的制备方法。所示的熔点，m.p.是用毛细管测得的，以摄氏度表示。
下列实施例用来说明本发明，而不对本发明构成任何限制。
制备例I
(2，6-二甲氧基-4-甲基苯基)-(2-甲氨基苯基)酮(化合物1)
在-20℃左右的温度下，将129ml 1.6M丁基锂的己烷溶液加入到30g在3，5-二甲氧基甲苯于400ml四氢呋喃的溶液中。加毕，使反应混合物升温至0℃，然后搅拌1小时。将其冷却到-20℃并逐份加入36.67gN-甲基N-羧氨基苯甲酸酐。使混合物恢复到室温并搅拌2小时，随后加入500ml水并用乙酸乙酯萃取。有机相用水洗涤、用硫酸钠干燥并在真空下蒸发。用硅胶色谱法纯化残余物，洗脱剂：甲苯/乙酸乙酯9/1。在真空下浓缩纯产物部分，残余物用异丙醚结晶，过滤并干燥。得到熔点为215℃的米色结晶；产率＝78％。
下列化合物也可以同样的方式制备：
(2，4，6-三甲氧基苯基)(2-甲氨基苯基)酮；
m.p.＝190℃；产率＝86％(化合物2)。
(2，4，6-三甲氧基-4-甲基苯基)(2-甲氨基苯基)酮；m.p.＝141℃；产率＝81％(化合物3)。
制备例II
N-〔2-)(2，6-二甲氧基-4-甲基苯甲酰)苯基〕-N-甲基溴乙酰胺(化合物4)
向冷却至-10℃的10g(2，6-二甲氧基-4-甲基苯基)(2-甲氨基苯基)酮于100ml二氯甲烷和20ml水的混合物中，滴加6.34g溴乙酰氯的20ml二氯甲烷溶液。使反应混合物恢复到室温，然后强力搅拌2小时。发生沉降后使相分离，有机相用水洗、用硫酸钠干燥，然后蒸发至干，得到熔点为121℃的米色结晶；产率＝99％。
下列化合物也可以同样的方式制得：
N-〔2-(2，4，6-三甲氧基苯甲酰)苯基〕-N-甲基溴乙酰胺；m.p.＝118℃；产率＝92％(化合物5)。
N-(2-(2，3，6-三甲氧基-4-甲基苯甲酰)苯基〕-N-甲基溴乙酰胺；油状物，产率＝100％(化合物6)。
制备例III
1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮(化合物7)。
将14g N-〔2-(2，6-二甲氧基-4-甲基苯甲酰基)苯基〕-N-甲基溴乙酰胺溶于300ml冷却至-10℃的甲醇中并通入氨气2小时。然后加热加流反应混合物3小时，随后蒸发至干。然后将残余物浸溶于二氯甲烷中，然后用水洗有机相、用硫酸钠干燥、最后蒸发至干。用硅胶柱色谱法纯化残余物，洗脱剂：二氯甲烷/甲醇95/5。
浓缩纯产物部分，得到熔点为200℃的白色结晶；产率＝89％。
下列化合物以同样的方式制备：
1，3-二氢-5-(2，4，6-三甲氧基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，m.p.＝161℃；产率＝89％(化合物8)，和
1，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，m.p.＝180℃，产率＝84％(化合物9)。
制备例IV
1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-3-羟亚氨基-1-甲基-1，4-苯并二氮杂-2-酮(化合物10)
在冷却至-20℃的条件下，向9g 1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮于300ml甲苯的悬浮液中逐份加入7.8g叔丁醇钾，然后在35分钟内使温度缓慢升至0℃，使混合物冷却至-20℃并滴加3.9g亚硝酸异戊酯的50ml甲苯溶液。然后在0℃下搅拌反应混合物90分钟，随后将反应混合物倾入水中，用乙酸调节pH至4，用乙酸乙酯萃取，用水洗有机相，用硫酸钠干燥并蒸发至干。用异丙醚结晶残余物，过滤并干燥，得到熔点为150℃的米色结晶；产率-76％。
以同样的方式制备下列化合物
1，3-二氢-5-(2，4，6-三甲氧基苯基)-1-甲基-1.4-苯并二氮杂-2-酮，m.p.＝155℃；产率＝80％(化合物11)
1，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，m.p.＝144℃；产率＝83％(化合物12)。
制备例V
3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮(化合物13)
将6.4g 1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-3-羟亚氨基-1-甲基-1，4-苯并二氮杂-2-酮置于含有180ml甲醇和1.32g 5％钌/C的高压釜中，将其加热至60℃并在6巴的氢气压力下氢化22小时，随后使反应混合物冷却，过滤催化剂，最后蒸发至干。将残余物浸溶于丙酮中并通过成盐作用(形成其草酸盐中间体)纯化产物。得到熔点为170℃的预期产物的草酸盐的米色结晶；产率＝80％。
以同样的方式制备下列化合物：
3-氨基-1，3-二氢-5-(2，4，6-三甲氧基苯基)-1-甲基-1，4-苯并二氮杂-2-酮草酸盐，m.p.＝155℃；产率＝83％(化合物14)，和
3-氨基-1，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，以油状物的形式得到；产率＝75％(化合物15)。
式(II)化合物的非对映异构体的分离
制备例VI
步骤1
在1.42g BOC-D-苯丙氨酸存在下，将1.73g 3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮溶于30ml二甲基甲酰胺中，随后冷却至5℃，加入1.07ml三乙胺，然后加入2.4gBOP，使反应混合物恢复至室温并搅拌过夜。然后将其倾入水中并用乙酸乙酯萃取。有机相用水洗，相沉降后分离出来，用Na2SO4干燥，过滤并在真空下浓缩。以定量的产率得到2-叔丁氧羰基氨基-N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-3-苯基丙酰胺，将其直接用于下一步骤(化合物16)。
步骤2
将上面得到的4.6g 2-叔丁氧羰基氨基-N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-3-苯基丙酰胺溶于30ml乙酸乙酯中，使混合物冷却至0℃，然后滴加30ml 5N盐酸的乙酸乙酯溶液。
加毕，使溶液恢复到室温并搅拌3小时。将反应混合物倾入乙醚中，过滤分离生成的沉淀，然后用乙醚洗涤并干燥，得到白色结晶状2-氨基-N-〔2，3--二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-3-苯基丙酰胺，产率为90％；m.p.＝165℃(化合物17)。
步骤3
通过制备性HPLC分离上一步中得到的非对映异构体。在PROCHROM LC 50仪器上以轴流式压循法进行非对映异构体的分离。所用的固定相是孔隙度100A的KROMASIL反相。用65％(水+1％三氟乙酸)和35％(乙腈/水/90/10，含有0.8％三氟乙酸)以等效方式进行洗脱，流速为120ml/分钟，在200nm处进行UV检测。用3.7g得自上一步的外消旋混合物，在冻干和碱化之后，得到泡沫状的两种立体异构体的每一种，分离产率为45％。
制备例VII
3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-l-甲基-l，4-苯并二氮杂-2-酮的右旋和左旋对映体的合成
采用常规的Edman降解法(P.Edman，Acta CHem；Scand.，1950，4，283)，以两步从以上分离的两种非对映异构体得到两种对映体。
右旋对映体的合成
步骤1(化合物18)
将720mg在制备例VI的步骤3中得到的非对映异构体溶于10ml二氯甲烷并加入220mg异硫代氰酸苯酯。将混合物加热回流1小时，随后在真空下蒸发反应混合物并用异丙醚结晶残余物。得到熔点为140℃的结晶；产率＝95％。
步骤2
将860mg上一步中得到的硫脲衍生物溶于20ml乙酸乙酯中，冷却至5℃左右，并滴加10ml 5N盐酸的乙酸乙酯溶液。使反应混合物恢复到室温并搅拌2小时，随后蒸发并进行硅胶柱色谱(洗脱剂∶二氯甲烷/甲醇/水/乙酸90/10/1/1)。在真空下蒸发纯产物部分，随后蒸发、碱化残余物，得到熔点为139℃的结晶；产率＝89％。〔α〕D 20＝+140(c＝0.2，在CH3OH中)。
左旋对映体(化合物19)的合成
通过使用对另一种非对映异构体的Edman降解法，用相似的方法得到左旋对映体。得到熔点为139℃的结晶；产率＝85％；〔α〕D 20＝-146(c＝0.2，在CH3OH中)。
实施例1
X3＝4-CH3；X4＝H
将0.47ml吡啶溶于10ml的二氯甲烷，冷却至-5℃，滴加0.68ml亚硫酰氯，在相同的温度下搅拌混合物20分钟，然后在搅拌30分钟的条件下逐份加入208mg吲哚-2-羧酸。逐份加入400mg 3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-苯基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，然后使反应混合物恢复到室温并搅拌16小时。将水加入到反应混合物中，滤出生成的沉淀并干燥，得到N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-1H-2-吲哚甲酰胺的白色结晶，熔点为310℃(分解)；产率＝79％。
实施例2
X3＝4-OCH3；X4＝H
按照实施例1的方法，使用3-氨基-1，3-二氢-5-(2，4，6-三甲氧基苯基)-1-甲基-1，4-苯并二氮杂-2-酮，得到N-〔2，3-二氢-5-(2，4，6-三甲氧基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-1H-2-吲哚甲酰胺；m.p.＝297℃；产率＝87％。
实施例3
X3＝4-CH3；X4＝H
向冷却至5℃的0.37g 3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮于10ml二甲基甲酰胺的溶液中，加入0.28g 1-甲氧基羰基甲基-1H-吲哚-2-羧酸，578mgBOP和0.303ml三乙胺。将反应混合物在室温下搅拌过夜，然后倒入水中并用乙酸乙酯萃取。有机相用水洗，用硫酸镁干燥并蒸发至干。得到的结晶用异丙醚和异丙醇的混合物重结晶。得到{N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-2-氨基羰基吲哚-1-基}乙酸甲酯，m.p.＝242℃；产率＝77％。
实施例4
X3＝4-CH3；X4＝H
将220mg N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基-2-氨基羰基-1H-吲哚-1-基〕乙酸甲酯溶于10ml甲醇并滴加1ml 1N氢氧化钠，随后在室温下搅拌过夜。将混合物浸溶于水中并用乙醚萃取。用硫酸氢钾将含水相酸化至pH3，用二氯甲烷萃取，用硫酸钠干燥并蒸发至干。得到的{N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-2-氮基羰基-1H-吲哚-1-基}乙酸用异丙醚结晶，得到的熔点为138℃的白色结晶；产率＝75％。
实施例5
X3＝4-CH3；X4＝H
向56mg 3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮的10ml二氯甲烷溶液中加入0.022ml异氰酸2-氯苯酯，然后将反应混合物在室温下搅拌过夜。将其在真空下蒸发并用异丙醚结晶残余物，得到3-(2-氯苯基脲基)-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮；m.p.＝260℃；产率＝91％。
实施例6
X3＝4-CH3；X4＝H
使用如上的3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮与异氰酸3-甲基苯酯如上进行缩合，得到1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-3-(3-甲基苯基脲基)-1，4-苯并二氮杂-2-酮；m.p.＝260℃；产率＝94％。
实施例7
X3＝6-OCH3；X4＝H
使3-氨基-1，3-二氢-1-甲基-5-(2，4，6-三甲氧基苯基)-1，4-苯并二氮杂-2-酮与异氰酸3-甲基苯酯缩合，得到1，3-二氢-1-甲基-3-(3-甲基苯基脲基)-5-(2，4，6-三甲氧基苯基)-1，4-苯并二氮杂-2-酮；m.p.＝240℃，产率＝94％。
实施例8
X3＝6OCH3；X4＝H
按照实施例7的方法，使用异氰酸2-甲基苯酯，得到1，3-二氢-1-甲基-3-(2-甲基苯基脲基)-5-(2，4，6-三甲氧基苯基)-1，4-苯并二氮杂-2-酮；m.p.＝250℃；产率＝92％。
实施例9
X3＝6-OCH3；X4＝H
左旋对映体
向冷却至5℃的0.38g 3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮的左旋对映体于10ml二甲基甲酰胺的溶液中加入0.52g BOP和0.19g吲哚-2-羧酸，随后加入0.23ml三乙胺。将反应混合物在室温下搅拌过夜，然后倒入水中，用乙酸乙酯萃取，用硫酸钠干燥并蒸发至干。通过硅胶柱色谱法纯化产物(洗脱剂：二氯甲烷/甲醇95/5)。将纯产物部分蒸发至干并用异丙醚结晶残余物。得到(-)-N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲
基-2-氧-1H-1，4-苯并二氮杂-3-基〕-1H-吲哚-2-甲酰胺的白色结晶；m.p.＝135℃；产率＝81％；〔α〕D 20＝-408(c＝0.35，在1NHCl/CH3OH-50/50中)。
实施例10X3＝6-OCH3；X4＝H
右旋对映体
按照制备另一种对映体(实施例9)的完全相同的方法，从3-氨基-1，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮的右旋对映体开始，得到此化合物。得到右旋(+)-N-〔2，3-二氢-5-(2，6-二甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-1H-吲哚-2-甲酰胺，m.p.＝135℃；产率＝78％；〔α〕D 20＝+412(c＝0.32，在1NHCl/CH3OH-50/50中)。
实施例11
X3＝6-OCH3；X4＝4-CH3
按照实施例3的方法，从3-氨基-1，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-1，4-苯并二氮杂-2-酮和吲哚-2-羧酸开始，得到N-〔2，3-二氢-5-(2，3，6-三甲氧基-4-甲基苯基)-1-甲基-2-氧-1H-1，4-苯并二氮杂-3-基〕-1H-吲哚-2-甲酰胺的结晶，m.p.＝290℃；产率＝68％。
Claims (11)
1.式(I)的化合物，其立体异构体及其加成盐：
其是RI代表(i)氢；(ii)C1-4烷基；(iii)基团-CH2-CHOH-(CH2)m-Z，其中m为0或1，Z代表C1-4烷基；C3-8环烷基；由C1-4烷基，C1-4烷氧基或卤素选择性取代的芳基；或Z代表由C1-4烷基，C1-4烷氧基或卤素选择性取代的选自呋喃，噻吩，吡咯，咪唑，吡咯烷，哌啶，哌嗪，吡啶和吗啉的饱和或不饱和杂环；或RI代表(iv)基团-(CH2)nCOR0，其中n代表1-3，R0代表OR2或NR2R3，R2和R3可相同或不同，代表H或C1-4烷基或R2和R3与所连的氮原子一起形成选自吡咯，咪唑，吡咯烷，哌啶，哌嗪，吡啶和吗啉的饱和或不饱和杂环；RII代表(i)选自喹啉，异喹啉，苯并咪唑和吲哚的RIIa，吲哚核可在其氮原子被基团W选择性取代，其中W代表基团CO-C1-4烷基；或基团(CH2)nCOR0，其中n和R0如对RI定义，或(ii)下式基团其中Y代表卤原子或C1-3烷基或C1-3烷氧基；X1，X2和X3是相同或不同的，且代表C1-3烷基，C1-3烷氧基，卤原子或三氟甲基；X4代表氢或与X1，X2或X3相同。
2.根据权利要求1的式(I)化合物及其盐，其中RII代表RIIa，RIIa代表被选择性取代的吲哚，并且其中W，RI，X1，X2，X3和X4如式(I)中所定义。
3.根据权利要求1的式(I)化合物及其盐，其中RII代表RIIa，并且其中Y，RI，X1，X2，X3和X4如式(I)中所定义。
4.根据权利要求1的式(I)化合物，其中X1在苯基的2位上，X2在苯基4位上，X3在苯基的6位上，X4在苯基的3位或5位上。
5.根据权利要求1的式(I)化合物及其盐，其中X1代表2-(C1-C3)烷氧基，X2代表6-(C1-C3)烷氧基，X3，X4，RI和RII如式(I)中所定义。
6.根据权利要求1的式(I)化合物，其中取代基X1，X2，X3和X4中至少三个代表(C1-C2)烷基或(C1-C2)烷氧基。
7.根据权利要求1-4任一项的式(I)化合物，该化合物以光学纯形式存在。
8.权利要求1的式(I)化合物的制备方法，其特征在于下式的取代的苯衍生物
其中X1，X2，X3和X4如对(I)中的定义，与下式靛红酸酐其中RI如对(I)中定义，反应，得到下式二苯基酮其中X1，X2，X3，X4和RI如对(I)中定义，然后该化合物与下式卤代酮
Hal-CH2COCl其中Hal优选代表溴或氯原子，反应，然后使所得化合物环化，得到下式苯并二氮杂其中X1，X2，X3和X4和RI如对(I)中定义，但需说明的是，如RI为C2-4烷基，化合物(VI)也可通过用其中AlK代表C2-4烷基的AlKI将RI＝H酰胺的VI烷基化而制备，在式(VI)化合物的肟是通过叔丁醇钾与亚硝酸异戊酯(CH3)2CH-CH2-CH2-ONO反应制备的之后，得到下式苯并二氮杂，其中RI，X1，X2，X3和X4如对(I)的定义，随后通过在催化剂如钌/活性碳存在下用氢对该肟进行还原，得到下式氨基苯并二氮杂-2-酮，其中X1，X2，X3和X4和RI如对(I)定义，然后将其与其中RIIa如对(I)所定义的酸RIIaCOOH或其一种活化形式反应，或与下式异氰酸苯酯反应。
其中Y如对(I)定义，得到本发明化合物(I)或其一种盐。
9.药物组合物，其含有作为有效成分的权利要求1-5任一的一种化合物或其可药用盐。
10.框据权利要求9的药物组合物，该组合物以单位剂型存在。
11.根据权利要求9的药物组合物，其特征在于它含有0.05-1O0mg有效成分及至少一种药用赋形剂。
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| Application Number | Priority Date | Filing Date | Title |
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| FR9401642A FR2716194B1 (fr) | 1994-02-14 | 1994-02-14 | Dérivés de 3-acylamino-5-phényl-1,4-benzodiazépin-2-one polysubstitués, leur procédé de préparation et les compositions pharmaceutiques les contenant. |
| FR9408665 | 1994-07-12 | ||
| FR9401642 | 1994-07-12 | ||
| FR9408665A FR2716195B1 (fr) | 1994-02-14 | 1994-07-12 | Dérivés de 3-acylamino-5-phényl-1,4-benzodiazépin-2-one polysubstitués, leur procédé de préparation et les compositions pharmaceutiques les contenant. |
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| CN1126207A CN1126207A (zh) | 1996-07-10 |
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| EP (1) | EP0667344A1 (zh) |
| JP (1) | JPH07300467A (zh) |
| KR (1) | KR950032145A (zh) |
| CN (1) | CN1053438C (zh) |
| AU (1) | AU692202B2 (zh) |
| CA (1) | CA2142411A1 (zh) |
| FI (1) | FI950625A (zh) |
| FR (1) | FR2716195B1 (zh) |
| HU (1) | HUT70050A (zh) |
| IL (1) | IL112589A (zh) |
| NO (1) | NO307784B1 (zh) |
| NZ (1) | NZ270478A (zh) |
| PL (1) | PL179904B1 (zh) |
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| US6635632B1 (en) | 1996-12-23 | 2003-10-21 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6683075B1 (en) | 1996-12-23 | 2004-01-27 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use |
| US6528505B1 (en) | 1998-06-22 | 2003-03-04 | Elan Pharmaceuticals, Inc. | Cyclic amino acid compounds pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6552013B1 (en) | 1998-06-22 | 2003-04-22 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6569851B1 (en) | 1998-06-22 | 2003-05-27 | Elan Pharmaceutials, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6509331B1 (en) | 1998-06-22 | 2003-01-21 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6958330B1 (en) | 1998-06-22 | 2005-10-25 | Elan Pharmaceuticals, Inc. | Polycyclic α-amino-ε-caprolactams and related compounds |
| US6774125B2 (en) | 1998-06-22 | 2004-08-10 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| GB9920872D0 (en) | 1999-09-04 | 1999-11-10 | Glaxo Group Ltd | Benzophenones as inhibitors of reverse transcriptase |
| GB0011092D0 (en) * | 2000-05-08 | 2000-06-28 | Black James Foundation | Gastrin and cholecystokinin receptor ligands (III) |
| US20040167146A1 (en) * | 2002-01-22 | 2004-08-26 | Karen Jackson | Method of treatment |
| US6713470B2 (en) * | 2002-01-22 | 2004-03-30 | Ml Laboratories Plc | Method of treatment |
| US20040043990A1 (en) * | 2002-04-09 | 2004-03-04 | Karen Jackson | Method of treatment |
| GB0221923D0 (en) * | 2002-09-20 | 2002-10-30 | Arrow Therapeutics Ltd | Chemical compounds |
| EA012387B1 (ru) * | 2002-09-20 | 2009-10-30 | Эрроу Терапьютикс Лимитед | Производные бензодиазепина, содержащие их продукт и фармацевтическая композиция и их применение |
| JP2007529261A (ja) * | 2004-03-18 | 2007-10-25 | コンティピ リミテッド | 女性骨盤臓器脱出症治療装置 |
| CN1950374A (zh) * | 2004-05-25 | 2007-04-18 | 辉瑞产品公司 | 四氮杂苯并[e]甘菊环衍生物及其类似物 |
| WO2010067233A1 (en) | 2008-12-08 | 2010-06-17 | Pfizer Inc. | 1,2,4 triazolo [4, 3 -a] [1,5] benzodiazepin-5 (6h) -ones as agonists of the cholecystokinin-1 receptor (cck-ir) |
| CN102924448B (zh) * | 2012-09-19 | 2015-02-25 | 渤海大学 | 生物碱cryptolepine类似物吲哚并喹啉酸化合物及制备方法 |
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| EP0167919A2 (en) * | 1984-06-26 | 1986-01-15 | Merck & Co. Inc. | Benzodiazepine derivatives and pharmaceutical compositions containing them |
| EP0376849A1 (fr) * | 1988-12-29 | 1990-07-04 | Roussel-Uclaf | Nouveaux dérivés de la 2,4-dioxo 2,3,4,5-tétrahydro 1H-1,5-benzodiazépine, leur procédé et les intermédiaires de préparation, leur application comme médicaments et les compositions les renfermant |
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- 1995-02-10 AU AU11668/95A patent/AU692202B2/en not_active Ceased
- 1995-02-13 EP EP95400293A patent/EP0667344A1/fr not_active Withdrawn
- 1995-02-13 FI FI950625A patent/FI950625A/fi unknown
- 1995-02-13 CN CN95101504A patent/CN1053438C/zh not_active Expired - Fee Related
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- 1995-02-13 JP JP7023848A patent/JPH07300467A/ja not_active Withdrawn
- 1995-02-13 HU HU9500434A patent/HUT70050A/hu unknown
- 1995-02-13 KR KR1019950002560A patent/KR950032145A/ko not_active Application Discontinuation
- 1995-02-13 CA CA002142411A patent/CA2142411A1/en not_active Abandoned
- 1995-02-14 US US08/390,770 patent/US5719143A/en not_active Expired - Fee Related
- 1995-02-14 PL PL95307255A patent/PL179904B1/pl unknown
- 1995-02-16 TW TW084101431A patent/TW427982B/zh active
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| EP0167919A2 (en) * | 1984-06-26 | 1986-01-15 | Merck & Co. Inc. | Benzodiazepine derivatives and pharmaceutical compositions containing them |
| EP0376849A1 (fr) * | 1988-12-29 | 1990-07-04 | Roussel-Uclaf | Nouveaux dérivés de la 2,4-dioxo 2,3,4,5-tétrahydro 1H-1,5-benzodiazépine, leur procédé et les intermédiaires de préparation, leur application comme médicaments et les compositions les renfermant |
Also Published As
| Publication number | Publication date |
|---|---|
| FI950625A0 (fi) | 1995-02-13 |
| PL179904B1 (pl) | 2000-11-30 |
| NO950537D0 (no) | 1995-02-13 |
| NO950537L (no) | 1995-08-15 |
| FR2716195A1 (fr) | 1995-08-18 |
| CA2142411A1 (en) | 1995-08-15 |
| FI950625A (fi) | 1995-08-15 |
| CN1126207A (zh) | 1996-07-10 |
| EP0667344A1 (fr) | 1995-08-16 |
| US5798353A (en) | 1998-08-25 |
| NZ270478A (en) | 1996-12-20 |
| TW427982B (en) | 2001-04-01 |
| KR950032145A (ko) | 1995-12-20 |
| IL112589A0 (en) | 1995-05-26 |
| NO307784B1 (no) | 2000-05-29 |
| HU9500434D0 (en) | 1995-03-28 |
| IL112589A (en) | 2000-06-01 |
| FR2716195B1 (fr) | 1996-06-21 |
| AU692202B2 (en) | 1998-06-04 |
| PL307255A1 (en) | 1995-08-21 |
| AU1166895A (en) | 1995-08-24 |
| HUT70050A (en) | 1995-09-28 |
| US5719143A (en) | 1998-02-17 |
| JPH07300467A (ja) | 1995-11-14 |
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