CN1039996C - N－取代氮杂双环庚烷衍生物及其用途 - Google Patents
N－取代氮杂双环庚烷衍生物及其用途 Download PDFInfo
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- CN1039996C CN1039996C CN93114691A CN93114691A CN1039996C CN 1039996 C CN1039996 C CN 1039996C CN 93114691 A CN93114691 A CN 93114691A CN 93114691 A CN93114691 A CN 93114691A CN 1039996 C CN1039996 C CN 1039996C
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- China
- Prior art keywords
- azabicyclo
- exo
- heptane
- fluorophenyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- UUAVYXKRUSVCDJ-UHFFFAOYSA-N 1-cycloheptylazepane Chemical class C1CCCCCC1N1CCCCCC1 UUAVYXKRUSVCDJ-UHFFFAOYSA-N 0.000 title description 2
- -1 methylamino- Chemical class 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- NEOIOGUWEUTYIH-UHFFFAOYSA-N 3-azabicyclo[3.2.0]heptane Chemical class C1NCC2CCC21 NEOIOGUWEUTYIH-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 22
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- 230000008018 melting Effects 0.000 description 57
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 229910052753 mercury Inorganic materials 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 5
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- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 5
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- 239000000126 substance Substances 0.000 description 5
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
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- 150000001412 amines Chemical class 0.000 description 4
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 4
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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Abstract
描述了式Ⅰ化合物及它们的制备方法，
其中取代基的定义同说明书。这些新化合物也适用于控制疾病。
Description
本发明涉及新的N-取代氮杂双环庚烷衍生物，其制备方法以及制备药物的用途。
已经知道具有碱性取代基的苯甲酰胺及丙基苯基酮(butyrophenone)衍生物分别具有脑保护及安定作用(US 4605655，EP 410 114，DE1 289 845，EP 400 661，DE 2 941 880，EP 190 472)。
从上述情况看来，除多巴胺及血清亲合性外，σ受体的显著的亲合性也是特别重要的。
现在我们发现了式I的N-取代3-氮杂双环[3.2.0]庚烷衍生物及其与生理上可接受的酸形成的具有药理活性的盐：
其中
R1是未取代或被卤原子、C1-C4烷基、三氟甲基、羟基、C1-C4烷氧基、氨基、单甲氨基、二甲氨基、氰基或硝基单或双取代的苯基、吡啶基、噻吩基或吡咯基，
R2是氢原子或未取代或被卤素、甲氧基、羟基或氨基取代的苯基，
n是数字1、2、3或4
A是氢原子或下列基因之一
R3是氢原子、羟基或未取代或被氟、氯、溴原子取代的苯基，
R4是氢原子，或
R3及R4一起表示氧原子，
R5是氢原子、氟、氯或溴原子或羟基、硝基、C1-C4烷基或甲氧基，及
R6是氢原子或甲基。
式I中的取代基R1至R7以及n，较优选具有下列含义：
R1：未取代的苯基或被氟、氯、甲氧基、三氟甲基、硝基、羟基或氨基取代的苯基
R2：氢
n：2及3
R3：羟基、对氟苯基
R4：氢或与R3一起为氧
R5：氢、氟、氯
R6：氢、甲基
下述化合物是特别优选的：
1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮。
1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，
1-苯基-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]-丁烷-1-酮，
1-苯基-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]-丁烷-1-酮，
1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，
1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，
1-苯基-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇。
1-苯基-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]-丁烷-1-醇，
1，1-双(4-氟苯基-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]-丁烷，
N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氟苯甲酰胺，
N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氟苯甲酰胺，
N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基-4-氟苯甲酰胺，
N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基苯甲酰胺，
N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氟苯甲酰胺，
N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)苯甲酰胺，以及
N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0 ]庚烷-3-基]乙基)-N-甲基苯甲酰胺，
根据本发明，式I化合物可由式II化合物：
Nu-(CH2)n-A (II)
其中A及n定义如前，及Nu为离核性的离去基团，与式III的3-氮杂双环[3.2.0]庚烷衍生物反应：
其中
R1是氢原子或未取代或被卤原子、C1-C4烷基、三氟甲基、羟基、C1-C4烷氧基、氨基、单甲氨基、二甲氨基、氰基或硝基单或双取代的苯基、吡啶基、噻吩或吡咯基，
R2是氢原子或未取代或被卤素、甲氧基、羟基或氨基取代的苯基，
并且必要时，所得化合物与生理上可接受的酸反应形成酸加成盐。
对于Nu而言合适的和优选的离核性离去基团为卤原子，特别是溴或氯。
反应较易在惰性碱的存在下，如三乙胺或碳酸钾，这是为了捕捉
酸，和在惰性溶剂如饱和环醚，特别是四氢呋喃或二烷，或在芳香烃如甲苯或二甲苯中进行。
该反应常规是在20-150℃进行，并且通常在1-10小时内完成；
根据本发明，既可采用常规有机溶剂，优选为低级醇如乙醇，重结晶式I化合物来纯化，也可采用柱色谱纯化。
可通过传统的拆分以简单的方式将外消旋物分成对映异构体，采用光学活性的羧酸，例如酒石酸衍生物，在惰性溶剂，例如低级醇，中进行。
可按常规的方式，将游离的3-氮杂双环[3.2.0]庚烷衍生物转化成其药理上可接受酸的加成盐，优选地是通过将溶液与1当量的相应的酸混合。药理上可接受的酸的实例包括盐酸、磷酸、硫酸、即磺酸、氨基磺酸、马来酸、富马酸、草酸、酒石酸及柠檬酸。
本发明的化合物具有有价值的药理性质。它们可用作安定药(特别)是非典型的)、抗抑制药、镇静药、催眠药、CNS保护或肌肉松弛药。数个所述的效果类型结合出现在同一个本发明化合物中也是可能的。药理学效果可通过体内及体外试验测定而物质特别地可以通过对于受体亚型，例如D1，D2，D3和D4受体，血清1A、1D及2受体，a1及a2受体，组胺1及毒蕈碱受体的亲合性而定性，在某些情况亲合性很高且选择性很好。
采用下述方法对新化合物体内定性
(a)对定向能动性的作用
置于新环境的小鼠显示出一种探察行为，它是由升高的运动活性体现的。该运动活性是将动物(雌性NMRI小鼠)置于笼中后，在光栅(light-barrier cages)笼中测量0-30分钟。
ED50：与服安慰剂对照组相比较降低运动活性50％所用的剂量。
b)阿朴吗啡拮抗作用
雌性小鼠接受1.21mg/Kg阿朴吗啡S.C.，在这个剂量下，阿朴吗啡引起的运动活性，当动物是置于金属丝网笼中时，是由不断攀缘体现的。攀缘按下述分级方法评价(每2分钟共30分钟)：
0：动物四爪着地
1：动物两爪在丝网上
2：动物四爪在丝网上 (正在爬)
这种攀缘行为可通过预服阿朴吗啡被抑制。
ED50与服安慰剂的对照组相比较抑制攀缘行为50％所需要的剂量。
c)L-5-HTP拮抗作用
雌性Sprague-Dawley小鼠接受剂量316mg/Kg i.P.的L-5-HTP。随后动物进入一种激动状态，而前爪搔抓和震颤的表现是在服用L-5-HTP之后，分级评估(0无，1中等，2深度)，在20-60分钟期间内每10分钟一次。服用L-5-HTP之后的平均数是17，实验物质是在服用L-5-HTP前60分钟口服。ED50是平均消减对照级别数50％时的剂量。
所说的方法适于为如抗精神病的物质定性。对L-5-HTP的抑制揭示了血清-拮抗作用，它是一种非典型安定药的作用特征类型。
本发明的化合物在这些试验中显示了很好的作用。
本发明也涉及治疗组合物，除常规的赋形剂及稀释剂外，它包含式I化合物或其药理学上可接受的酸加成盐作为活性组分，还涉及到新化合物控制疾病的用途。
本发明的化合物可以以常规的方式口服或非肠道给药，静脉或肌内注射。剂量取决于病人的年龄、状况和体重以及给药的方式。通常，口服活性组分每天剂量从约1-100mg/Kg体重，而非肠道给药是从0.1-10mg Kg体重。
新化合物可按常规的固体或液体的药物形式给药，例如未包衣或(薄膜)包衣的片剂、胶囊、粉剂、粒剂、栓剂、溶液、软膏、霜剂或喷雾剂。它们可按常规方式制备。为这个目的活性组分可与常规的药物辅剂，如片剂连接剂、填充剂、防腐剂、片剂崩解剂、流体调节剂、增塑剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧剂和/或推进气体一起加工(cf.H.Sucker等：PharmazeutischeTechnologie，Thieme Verlag，Stuttgart，1978)。如此得到的给药形成式通常含1-99％重量活性组分。
需要作为起始物合成新化合物的式II物质是已知的。
式III物质的制备是使式IV的胺
其中R1和R2定义如前，而R7是氢、乙酰基、苄基或三氟乙酰基，进行光化学2+2环加成和在需要时随后除酰基或苄基。
光学反应在惰性溶剂中，优选是丙酮，在20-80℃进行良好。高压汞灯是特别合适的光源。在石英仪器中氮气气氛下，对每mol胺加约1mol盐酸时进行光学环加成是较好的。
在大多数情况，光学环加成反应是高度非对映选择性的，给出对于R1和R2是外构型的双环式III化合物：
通过外消旋拆分，例如采用光活性的酒石酸衍生物，可将两个对映异构体分离得到纯品。
酰基(R7)的消除可按常规的方法通过水解很方便地进行。对于苄基的消除也是类似。
式IV的胺在文献中已有公开，或通过使醛R1-CHO与乙烯基氯化镁反应得到烯丙基醇V
然后与氯化氢进行重排得到烯丙基氯VI
和最后与合适烯丙基胺VII反应
或者使用肉桂醛VIII
与烯丙基胺VII直接进行还原胺化。
下面的实施例说明了本发明：
A)起始物的制备
1.外-6-(对氟苯基)-3-氮杂双环[3.2.0]庚烷将130ml丙酮中的19.4g(102mmol)N-烯丙基-N-[3-(4-氟苯基)烯丙基]胺与130ml 10％浓度的盐酸及600mg米蚩酮混合，并将其在氮气氛下石英容器中用150瓦高压汞灯照射55小时。将反应混合物浓缩，并将残留物在二氯甲烷和水之间分配。用氨水溶液碱化水相，然后用二氯甲烷提取两次。用硫酸钠干燥合并的有机相并将有机相浓缩。产量19.3g(99％)熔点165-166℃。(马来酸盐)
为分离对映体，将15.0g(78.5mmol)外消旋物与31.7g(78.5mmol)(一)-二-邻甲苯酰-L-酒石酸的300ml沸乙醇溶液混合。抽滤冷却搅拌分离出的晶体(13.8g)、用乙醇洗涤，用200ml乙醇加200ml水重结晶。析出碱而得到了(+)对映体(5.5g)[α]D＝+97.0°
(EtOH，C＝0.96g)
过夜后从上述母液结晶出的盐14.2g再用400ml乙醇重结晶(在沸点过滤除不溶物，并浓缩到300ml)。析出碱得到4.0g(-)对映体[α]D＝-96.0°
(EtOH)，C＝0.940)。
通过X-射线结构分析证明了外-苯基构型。
2.外-6-苯基-3-氮杂双环[3.2.0]庚烷
将1600ml丙酮中的50.0g(28.9mmol)N-肉桂基-N-烯丙基胺与300ml 10％浓度的盐酸混合，并将其在氮气气氛下石英仪器中于室温用150瓦高压汞灯照射48小时。将反应混合物浓缩，残留物在二氯甲烷和水之间分配，用氨水溶液调水相呈碱性然后用二氯甲烷萃取二次。用硫酸钠干燥合并的有机相并将有机相浓缩。产量49.0g(98.0％)，粘状油。熔点177-178℃(马来酸盐)。
3.外-6、7-二苯基-3-苄基-3-氮杂双环[3.2.0]庚烷
将2500ml丙酮中的70.0g(206mmol)N，N-二肉桂基苄基胺与0.8g米蚩酮混合，并将其在氮气气氛下硼硅酸盐玻璃仪器中于室温用150瓦的高压汞灯照射25小时。将反应混合物浓缩、残留物在二氯甲烷及水之间分配。用氨水溶液调水相呈碱性，并用二氯甲烷萃取至少二次。用硫酸钠干燥合并的有机层并将有机层浓缩。通过柱色谱(硅胶，洗脱剂甲苯 乙醇98/2)纯化粗产品(65.0g)，得到58.0g(83％)产品，熔点230-232℃(盐酸盐)。
4.外-6，7-二苯基-3-氮杂双环[3.2.0]庚烷
将16.0g(254mmol)甲酸铵及2.0g炭载钯(10％)，加到12.0g(35.4mmol)外-6，7-二苯基-3-苄基-3-氮杂双环[3.2.0]庚烷于300ml正丙醇及16ml水的混合物中，并将混合物回流四小时(放出二氧化碳)。冷却后，吸滤除去催化剂，并用丙醇和二氯甲烷洗涤，再浓缩滤液。残留物在二氯甲烷及水之间分配，用氨水溶液调水相呈碱性，并用二氯甲烷萃取多于两次。用硫酸钠干燥合并的有机相并将有机相浓缩，得到8.1g(92％)产品，熔点140-142℃(马来酸盐)。
5.外-6-苯基-3-苄基-3-氮杂双环[3.2.0]庚烷
将1100ml丙酮中的9.2g(35.0mmol)N-肉桂基-N-烯丙基苄基胺与100mg米蚩酮混合，并将其在氮气气氛下硼硅酸盐玻璃仪器中于室温用150瓦的高压汞灯照射5小时。浓缩反应混合物，采用柱色谱(硅胶，洗脱剂二氯甲烷/甲醇98/2)纯化粗产品(9.4g)，得到3.3g(36％)产物，熔点126-128℃(马来酸盐)。
6. 2，2，2-三氟-1-[外-6-(3-吡啶基)-3-氮杂双环[3.2.0]庚-3-基]-乙酮
将14.0g(51.8mmol)N-烯丙基-N-[3-(3-吡啶基)烯丙基]-2，2，2-三氟乙酰胺溶于140ml丙酮中，并加入30ml 10％浓度的盐酸水溶液，混合物在氮气气氛下在硼硅酸盐玻璃容器中于室温用150瓦高压汞灯照射48小时。然后浓缩反应溶液，溶于150ml水中并用氨水溶液调节PH8-9。用叔丁基甲基醚提取水相两次，并用硫酸钠干燥含并的有机层并将有机层浓缩。采用柱色谱(硅胶，二氯甲烷+2％甲醇)分离残留物，得到6.2g(42％)未变的N-烯丙基-N-[3-(3-吡啶基)烯丙基]2，2，2-三氟乙酰胺及3.7g(26％)2，2，2-三氟-1-[外-6-(3-吡啶基)-3-氮杂双环[3.2.0]庚-3-基]乙酮，为黑色油。
7.外-6-(3-吡啶基)-3-氮杂双环[3.2.0]庚烷
将2.5g氢氧化钾片加到3.7g(13.7mmol)2，2，2-三氟-1-[外-6-(3-吡啶基)-3-氮杂双环[3.2.0]庚-3-基]乙酮的50ml乙醇溶液中，并将溶液于室温搅拌2小时，随后倾入100ml冰水中。用叔丁基甲基醚提取水相三次，用硫酸钠干燥合并的有机层并将有机层浓缩。得到2.3g(96％)黄色油，熔点202-205℃(盐酸盐)。
下面的物质可按类似的方式制备：
8.外-6-(间氟苯基)-3-氮杂双环[3.2.0]庚烷
9.外-6-(邻氟苯基)-3-氮杂双环[3.2.0]庚烷熔点118-120℃(马来酸盐)
10.外-6-(对氯苯基)-3-氮杂双环[3.2.0]庚烷，熔点152-154℃(马来酸盐)
11.外-6-(间氯苯基)-3-氮杂双环[3.2.0]庚烷，熔点130-132℃(马来酸盐)
12.外-6-(对甲氧基苯基)-3-氮杂双环[3.2.0]庚烷
13.外-6-(间甲氧基苯基)-3-氮杂双环[3.2.0]庚烷
14.外-6-(对硝基苯基)-3-氮杂双环[3.2.0]庚烷，熔点158-160℃(马来酸盐)
15.外-6-(间硝基苯基)-3-氮杂双环[3.2.0]庚烷
16.外-6-(对三氟甲基苯基)-3-氮杂双环[3.2.0]庚烷，熔点155-156℃(马来酸盐)
17.外-6-(间三氟甲基苯基)-3-氮杂双环[3.2.0]庚烷，
18.外-6-(3，4-二氯苯基)-3-氮杂双环[3.2.0]庚烷
19.外-6-(3，5-二氯苯基)-3-氮杂双环[3.2.0]庚烷，熔点≥250℃(盐酸盐)
20.外-6-(3，4-二甲基氧苯基)-3-氮杂双环[3.2.0]庚烷
21.外-6-(间羟基苯基)-3-氮杂双环[3.2.0]庚烷
22.外-6-(对羟基苯基)-3-氮杂双环[3.2.0]庚烷
23.外-6-(3，4-二羟基苯基)-3-氮杂双环[3.2.0]庚烷
24.外-6-(对甲基苯基)-3-氮杂双环[3.2.0]庚烷
25.外-6-(间甲基苯基)-3-氮杂双环[3.2.0]庚烷
26.外-6-对叔丁基苯基)-3-氮杂双环[3.2.0]庚烷，熔点＞255℃(盐酸盐)
27.外-6-(间氨基苯基)-3-氮杂双环[3.2.0]庚烷
28.外-6-(对氨基苯基)-3-氮杂双环[3.2.0]庚烷
29.外-6-(对氰基苯基)-3-氮杂双环[3.2.0]庚烷，熔点168-170℃(马来酸盐)
30.外-6-(2-噻吩基)-3-氮杂双环[3.2.0]庚烷，熔点181-182℃(盐酸盐)
31.外-6-(3-噻吩基)-3-氮杂双环[3.2.0]庚烷，熔点143-145℃(盐酸盐)
32.外-6-(5-氯-2-噻吩基)-3-氮杂双环[3.2.0]庚烷，熔点156-157℃(马来酸盐)
33.外-6-(2-吡咯基)-3-氮杂双环[3.2.0]庚烷
34.外-6-(4-吡啶基)-3-氮杂双环[3.2.0]庚烷
35.外-6-(2-吡啶基)-3-氮杂双环[3.2.0]庚烷
B)最终产物的制备
实施例1
1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮×HCl
于130ml二甲苯中的8.65g(50mmol)外-6-苯基-3-氮杂双环[3.2.0]庚烷与10.2ml(60mmol)ω-氯-4-氟丙基苯基酮和11.5g(80mmol)细粉状碳酸钾另外还有0.5g碘化钾混合，并充分搅拌下回流7小时。冷却和在旋转蒸发器中浓缩后，将残留物在氯甲烷和水之间分配。
用二氯甲烷萃取水相两次，然后用水洗涤有机相一次，将有机相用硫酸钠干燥并浓缩。采用柱色谱(硅胶，二氯甲烷/甲醇96/4洗脱)纯化粗产品。将游离碱溶于200ml乙醚中，过滤溶液除去不溶物，并加入含过量醚的盐酸。冷却下滤出固体盐酸化物并用大量乙醚洗涤，得到8.3g(45％)产物，熔点169-171℃。
下面化合物可按类似的方式制备
2. 1-苯基-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点134-136℃(盐酸化物)
3. 1-(4-氟苯基)-4-[外-6，7-二苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点174-176℃(盐酸化物)
4. 1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷，熔点131-133℃(盐酸化物)
5. 1-苯基-2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙烷-1-酮，油
6. 1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷
7. 1-(4-氟苯基)-4-[外-6-间氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
8. 1-(4-氟苯基)-4-[外-6-邻氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点180-182℃(盐酸化物)
9. 1-(4-氟苯基)-4-[外-6-对氯苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
10. 1-(4-氟苯基)-4-[外-6-间氯苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点137-139℃(盐酸化物)
11..1-(4-氟苯基)-4-[外-6-对甲氧基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
12. 1-(4-氟苯基)-4-[外-6-间，对-二氯苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
13. 1-(4-氟苯基)-4-[外-6-间，对-二甲氧基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
实施例14
1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮×HCl
于50ml二甲苯中的4.5g(23.5mmol)的外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷与6.0g(30mmol)ω-氯-4-氟丙基苯基酮及4.2g(30mmol)碳酸钾细粉末和0.5g碘化钾混合，并充分搅拌下回流7小时。冷却和在旋转蒸发器中浓缩后，将残留物在二氯甲烷及水间分配。
然后用二氯甲烷萃取水相两次，随后用水洗涤有机相一次，将在机相用硫酸钠干燥并浓缩。通过柱色谱(硅胶，二氯甲烷/甲醇964洗脱)纯化粗产品(9.4g)。将游离碱溶于150ml乙醚中，过滤溶液去不溶物，然后加入过量的含醚的盐酸。加入10ml丙酮后，冷却下滤出固体盐酸化物并用大量乙醚洗涤，得到4.9g(53％)产物，熔点166-168℃。
下述化合物可按类似的方式制备：
15. 1-苯基-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点141-143℃(马来酸盐)
16. 1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷
17. 1-(4-氟苯基)-4-[外-6-对硝基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点68-70℃(盐酸化物)
18. 1-(4-氟苯基)-4-[外-6-间硝基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
19. 1-(4-氟苯基)-4-[外-6-间三氟甲基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮，熔点158-161℃(盐酸化物)
20. 1-(4-氟苯基)-4-[外-6-对氰基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
21. 1-(4-氟苯基)-4-[外-6-(3-噻吩基)-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
22. 1-(4-氟苯基)-4-[外-6-(3-吡啶基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮
23. 1-(4-氟苯基)-3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙烷-1-酮，熔点151-154℃(盐酸化物)
实施例24
1，1-双(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷×HCl
于80ml二甲苯中的5.0g(26.2mmol)外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷与8.8(28.4mmol)1，1-双(4-氟苯基)-4-氯丁烷，以及7.0g(50.6mmol)碳酸钾细粉和0.3g碘化钾混合，充分搅拌下回流15小时。冷却和在旋转蒸发器中浓缩后，将残留物在水及二氯甲烷中分配。用二氯甲烷萃取水相两次，随后用水洗涤有机相一次，将有机相用硫酸钠干燥并浓缩。采用柱色谱(硅胶，二氯甲烷/甲醇96/4洗脱)纯化粗产品(110g)。将游离碱溶于350ml乙醚，过滤溶液以除去不溶物，随后加入含过量的醚的盐酸。浓缩得到4.9g(40％)产物，熔点49-50℃。
下述化合物可按类似的方式制备：
25. 1，1-双(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷，熔点54-55℃为盐酸化物
实施例26
1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇
将0.6g(16mmol)硼酸钠分批添加到4.6g(13.6mmol)1-(4-氟苯基)-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮的60ml甲醇溶液中。随后在室温搅拌混合物2小时并在旋转蒸发器中浓缩。PH为10时将残留物在二氯甲烷和水之间分配，水相同二氯甲烷萃取多于两次，用水洗涤合并的有机层，将有机层用硫酸钠干燥并浓缩。采用柱色谱(硅胶，用二氯甲烷/甲醇96/4 洗脱)纯化粗产品(4.6g)。将游离碱溶于150ml乙醚中，过滤溶液除去不溶物，并加入过量醚的盐酸。冷却下滤出固体盐酸化物并用大量乙醚洗涤得到3.1g(61％)产物，熔点147-149℃。
下述化合物可按类似的方式制备：
27. 1-(4-氟苯基)-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁-1-醇，熔点128-129℃(盐酸化物)
28. 1-(4-氟苯基)-4-[外-6，7-二苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，熔点228-231℃(盐酸化物)
29. 1-苯基-4-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，熔点128-129℃(盐酸化物)
30. 1-苯基-4-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇
31. 1-(4-氟苯基)-4-[外-6-邻氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，熔点167-168℃(盐酸化物)
32. 1-(4-氯苯基)-4-[外-6-间氯苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，熔点143-145℃(盐酸化物)
33. 1-(4-氟苯基)-4-[外-6-对三氟甲基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇，熔点145-148℃(盐酸化物)
实施例34
1-(4-氟苯基)-4-[外-6-对氨基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇
将66g(17.2mmol)1-(4-氟苯基)-4-[外-6-对硝基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮溶于200ml冰醋酸中，并加入1.7g炭载钯(10％)，在室温1个大气压下氢化混合物4小时。吸滤除去催化剂并浓缩母液，将残留物在二氯甲烷和水之间分配，用浓氨水溶液搅拌使水相呈碱性并用二氯甲烷萃取两次。干燥和浓缩有机相得到5.0g粗产品，采用柱色谱(硅胶，用二氯甲烷/甲醇95/5)纯化得到2.2g(36％)1-(4-氟苯基)-4-[外-6-对氨基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-酮(盐酸化物的熔点136-139℃)及1.4g(23％)1-(4-氟苯基)-4-[外-6-对氨基苯基-3-氮杂双环[3.2.0]庚烷-3-基]丁烷-1-醇(盐酸化物的熔点122-125℃)。
实施例35
N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氟苯甲酰胺
将40ml甲苯中的3.5g(20mmol)外-6-苯基-3-氮杂双环[3.2.0]庚烷与N-3-(氯丙基)-4-氟苯甲酰胺，及4.8g(35mmol)碳酸钾细粉和0.5g碘化钾混合，并在充分搅拌下回流9小时。冷却后，将混合物在旋转蒸发器中浓缩并将残留物在二氯甲烷及水之间分配。然后用二氯甲烷萃取水相两次，随后用硫酸钠干燥有机相并浓缩。采用柱色谱(硅胶，用二氯甲烷/甲醇96/4洗脱)纯化粗产品(8.4g)。将纯化后的游离碱溶解到100ml乙醚和10ml丙酮的混合物中，并且在冰冷却和搅拌下，缓缓滴入1.6g马来酸的丙酮溶液。在氮气中滤出沉淀出的盐，用乙醚洗涤，并在氮气中干燥得到4.9g(70％)作为马来酸盐的吸湿性产物。熔点122-124℃。
下述化合物可按类似的方式制备：
36. N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)苯甲酰胺，熔点70-72℃(盐酸化物)
37. N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)苯甲酰胺
38. N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)苯甲酰胺，熔点89-90℃
39. N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基-4-氟苯甲酰胺，熔点126-128℃(盐酸化物)
40. N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基苯甲酰胺，熔点121-122℃(盐酸化物)
41. N-(2-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基-4-异丙基苯甲酰胺，熔点184-185℃(盐酸化物)
42. N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氯苯甲酰胺
43. N-(2-[外-6-对三氟甲基苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氯苯甲酰胺，熔点112-114℃
44. N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-3-甲氧基苯甲酰胺
45. N-(3-[外-6-苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-3-硝基苯甲酰胺
46. N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氟苯甲酰胺，熔点160-162℃(盐酸化物)。
47. N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)苯甲酰胺，熔点177-178℃(盐酸化物)
48. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氟苯甲酰胺，熔点111-113℃
49. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)苯甲酰胺，熔点94-95℃
50. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基-4-氟苯甲酰胺，熔点170-171℃(盐酸盐)
51. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基苯甲酰胺
52. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-N-甲基-4-异丙基苯甲酰胺，熔点189-190℃(盐酸化物)
53. N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-4-氯苯甲酰胺
54. N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-3-甲氧基苯甲酰胺
55. N-(3-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]丙基)-3-硝基苯甲酰胺
56. N-(2-[外-6-间氯苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-3-氯苯甲酰胺，熔点96-98℃
57. N-(2-[外-6-邻氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氯苯甲酰胺，熔点91-93℃
58. N-(2-[外-6-对氟苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-2-羟基苯甲酰胺，熔点93-95℃(也参考实施例59)
实施例59
N-(2-[外-6-间羟基苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氯苯甲酰胺
将13ml(13mmol)三溴化硼(1M的二氯甲烷溶液)于室温滴加到任70ml二氯甲烷中的4.2g(11mmol)的N-(2-[外-6-间甲氧基苯基-3-氮杂双环[3.2.0]庚烷-3-基]乙基)-4-氯苯甲酰胺中，并将混合物搅拌过夜。冷却后，加入100ml 2N的氢氧化铵溶液，分离出有机相，而水相用二氯甲烷萃取。干燥和浓缩得到4.5g粗产品，采用柱色谱(硅胶，用二氯甲烷/甲醇95/5洗脱)将之纯化得到2.8g(69％)产物，熔点65-68℃。
实施例60
外-3-正丁基-6-苯基-3-氮杂双环[3.2.0]庚烷马来酸盐
于50ml四氢呋喃中的3.5(20mmol)外-6-苯基-3-氮杂双环[3.2.0]庚烷与4.2ml(30mmol)三乙胺及5.4g(40mmol)正丁基溴混合，并在充分搅拌下回流9小时。
冷却后，混合物在旋转蒸发器中浓缩并将残留物在二氯甲烷和水之间分配。
可相用二氯甲烷提取两次，然后用硫酸钠干燥有机相并浓缩。采用柱色谱(硅胶，用二氯甲烷/甲醇96/4洗脱)纯化粗产品(4.2g)。将纯化后的游离碱(3.1g)溶于200ml乙醚中，在冰冷却和搅拌下，将定量的丙酮中的马来酸缓慢滴入。在氮气中吸滤出沉淀出的盐，用乙醚洗涤并在氮气中干燥得到4.4g(64％)马来酸盐，熔点125-126℃
下述化合物可按类似的方式制备：
61.外-3-甲基-6-苯基-3-氮杂双环[3.2.0]庚烷，熔点129-131℃(马来酸盐)
62.外-3-甲基-6-对氟苯基-3-氮杂双环[3.2.0]庚烷
63.外-3-正丙基-6-对氟苯基-3-氮杂双环[3.2.0]庚烷
64.外-3-甲基-6，7-二苯基-3-氮杂双环[3.2.0]庚烷，熔点197-198℃(盐酸化物)
65.外-3-正丙基-6-间羟基苯基-3-氮杂双环[3.2.0]庚烷(参考实施例59)，熔点148-150℃(盐酸化物)
66.外-3-烯丙基-6-间甲氧苯基-3-氮杂双环[3.2.0]庚烷，熔点118-120℃(盐酸化物)
67.外-3-(3，4-二甲氧基苯乙基)-6-苯基-3-氮杂双环[3.2.0]庚烷，熔点207-209℃(盐酸化物)
68.外-3-(3，4-二甲基氧苯乙基)-6-对氟苯基-3-氮杂双环[3.2.0]庚烷，熔点192-193℃(盐酸化物)
69.外-3-(3，4-二羟基苯乙基)-3-氮杂双环[3.2.0]庚烷(类似于实施例59)，熔点202-205℃。
70.外-3-苯乙基-6-对氟苯基-3-氮杂双环[3.2.0]庚烷，熔点128-129℃(马来酸盐)
Claims (2)
1.式I的N-取代3-氮杂双环[3.2.0]庚烷衍生物及其与生理上允许的酸形成的盐：
其中
R1是未取代或被卤原子、C1-C4烷基、三氟甲基、羟基、C1-C4烷氧基、氨基、单甲氨基、二甲氨基、氰基或硝基单或双取代的苯基、吡啶基、噻吩基或吡咯基，
R2是氢原子或未被取代或被卤素、甲氧基、羟基或氨基取代的苯基，
n是数字1、2、3或4
A是氢原子或下列基团之一：
R3是氢原子、羟基或未取代或被氟、氯、溴原子取代的苯基，
R4是氢原子，或
R3及R4一起表示氧原子，
R5是氢原子、氟、氯或溴原子或羟基、硝基、C1-C4烷基或甲氧基，及
R6是氢原子或甲基。
2.如权利要求1所述式I的N-取代3-氮杂双环[32.0]庚烷衍生物用于制备用于治疗中枢神经系统疾病的药物的用途。
Priority Applications (26)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4243287A DE4243287A1 (de) | 1992-06-19 | 1992-12-21 | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| CA002138289A CA2138289C (en) | 1992-06-19 | 1993-06-08 | N-substituted azabicycloheptane derivatives, the preparation and use thereof |
| AU43238/93A AU671130B2 (en) | 1992-06-19 | 1993-06-08 | N-substituted 3-azabicyclo(3.2.0)heptane derivates useful as neuroleptic agents, etc. |
| EP93912910A EP0647231B1 (de) | 1992-06-19 | 1993-06-08 | N-substituierte 3-azabicyclo[3.2.0]heptan-derivate als neuroleptika usw. |
| NZ253121A NZ253121A (en) | 1992-06-19 | 1993-06-08 | N-heterocyclyl(alkyl) substituted 3-azabicyclo-[3.2.0]heptane derivatives and pharmaceutical compositions thereof |
| CZ19943237A CZ288787B6 (cs) | 1992-06-19 | 1993-06-08 | N-Substituovaný azabicyklo[3,2,0]heptanový derivát a jeho použití |
| DE59307217T DE59307217D1 (de) | 1992-06-19 | 1993-06-08 | N-substituierte 3-azabicyclo[3.2.0]heptan-derivate als neuroleptika usw. |
| PCT/EP1993/001438 WO1994000458A1 (de) | 1992-06-19 | 1993-06-08 | N-substituierte 3-azabicyclo[3.2.0]heptanderivate als neuroleptika usw. |
| RU95105435/04A RU2135503C1 (ru) | 1992-06-19 | 1993-06-08 | N-замещенные производные 3-азабицикло (3.2.0)гептана или их соли с физиологически совместимыми кислотами |
| HU9403641A HU218911B (hu) | 1992-06-19 | 1993-06-08 | N-szubsztituált 3-azabiciklo[3.2.O]heptán-származékok, ezeket tartalmazó gyógyászati készítmények és eljárás előállításukra |
| AT93912910T ATE157366T1 (de) | 1992-06-19 | 1993-06-08 | N-substituierte 3-azabicyclo(3.2.0>heptan- derivate als neuroleptika usw. |
| JP51781793A JP3171258B2 (ja) | 1992-06-19 | 1993-06-08 | Ｎ−置換アザビシクロヘプタン−誘導体，その製造および使用 |
| ES93912910T ES2107035T3 (es) | 1992-06-19 | 1993-06-08 | Derivados de 3-azabiciclo(3.2.0)heptano n-substituidos como neurolepticos etc.. |
| SG1996007476A SG44782A1 (en) | 1992-06-19 | 1993-06-08 | N-substituted azabicycloheptane derivatives the preparation and use thereof |
| US08/356,178 US5475105A (en) | 1992-06-19 | 1993-06-08 | N-substituted azabicycloheptane derivatives |
| DK93912910.2T DK0647231T3 (da) | 1992-06-19 | 1993-06-08 | N-substituerede 3-azabicyclo 3.2.0 heptanderivater til anvendelse som bl.a. neuroleptika |
| IL10598993A IL105989A (en) | 1992-06-19 | 1993-06-11 | N-substituted azabicycloheptane derivatives and pharmaceutical compositions containing them |
| ZA934374A ZA934374B (en) | 1992-06-19 | 1993-06-18 | N-substituted azabicycloheptane derivatives the preparation and use thereof |
| CN93109449A CN1042133C (zh) | 1992-06-19 | 1993-06-19 | N－取代的氮杂双环庚烷衍生物及其用途 |
| CN93114691A CN1039996C (zh) | 1992-06-19 | 1993-12-11 | N－取代氮杂双环庚烷衍生物及其用途 |
| TW082110584A TW408126B (en) | 1992-06-19 | 1993-12-14 | N-substituted azabicycloheptane derivatives and use thereof |
| PH47479A PH30466A (en) | 1992-06-19 | 1994-02-14 | N substitutted azabicycloheptane derivatives |
| BG098600A BG62350B2 (bg) | 1992-06-19 | 1994-02-28 | N-заместени производни на 3-азабицикло/3.2.0/хептан като невролептици и други |
| NO944892A NO305176B1 (no) | 1992-06-19 | 1994-12-16 | N-substituerte 3-azabicyklo [3.2.0] heptanderivater og anvendelse derav |
| FI945957A FI108726B (fi) | 1992-06-19 | 1994-12-19 | Menetelmä kaavan (I) mukaisten N-substituoitujen 3-atsabisyklo[3.2.0]heptaanijohdannaisten valmistamiseksi |
| GR970402736T GR3025095T3 (en) | 1992-06-19 | 1997-10-20 | N-substituted 3-azabicyclo 3.2.0]heptane derivates useful as neuroleptic agents, etc. |
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| DE4219974 | 1992-06-19 | ||
| DE4243287A DE4243287A1 (de) | 1992-06-19 | 1992-12-21 | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| CN93114691A CN1039996C (zh) | 1992-06-19 | 1993-12-11 | N－取代氮杂双环庚烷衍生物及其用途 |
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| CN1105358A CN1105358A (zh) | 1995-07-19 |
| CN1039996C true CN1039996C (zh) | 1998-09-30 |
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| CN93114691A Expired - Fee Related CN1039996C (zh) | 1992-06-19 | 1993-12-11 | N－取代氮杂双环庚烷衍生物及其用途 |
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| US (1) | US5475105A (zh) |
| EP (1) | EP0647231B1 (zh) |
| JP (1) | JP3171258B2 (zh) |
| CN (2) | CN1042133C (zh) |
| AT (1) | ATE157366T1 (zh) |
| AU (1) | AU671130B2 (zh) |
| BG (1) | BG62350B2 (zh) |
| CA (1) | CA2138289C (zh) |
| CZ (1) | CZ288787B6 (zh) |
| DE (2) | DE4243287A1 (zh) |
| DK (1) | DK0647231T3 (zh) |
| ES (1) | ES2107035T3 (zh) |
| FI (1) | FI108726B (zh) |
| GR (1) | GR3025095T3 (zh) |
| HU (1) | HU218911B (zh) |
| IL (1) | IL105989A (zh) |
| NO (1) | NO305176B1 (zh) |
| NZ (1) | NZ253121A (zh) |
| PH (1) | PH30466A (zh) |
| RU (1) | RU2135503C1 (zh) |
| SG (1) | SG44782A1 (zh) |
| TW (1) | TW408126B (zh) |
| WO (1) | WO1994000458A1 (zh) |
| ZA (1) | ZA934374B (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE4427648A1 (de) * | 1994-08-04 | 1996-02-08 | Basf Ag | N-Stubstituierte 3-Azabicyclo[3,2,0,]heptan-Derivate, ihre Herstellung und Verwendung |
| DE4338396A1 (de) * | 1993-11-10 | 1995-05-11 | Basf Ag | N-Substituierte Azabicycloalkan-Derivate, ihre Herstellung und Verwendung |
| DE4341402A1 (de) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| DE4341403A1 (de) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituierte 3-Azabicycloalkan-Derivate, ihre Herstellung und Verwendung |
| DE4427647A1 (de) * | 1994-08-04 | 1996-02-08 | Basf Ag | N-substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| US5929080A (en) * | 1997-05-06 | 1999-07-27 | American Cyanamid Company | Method of treating polycystic kidney disease |
| US6323209B1 (en) | 1997-11-06 | 2001-11-27 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
| DE19836404A1 (de) * | 1998-08-12 | 2000-02-17 | Basf Ag | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| US6458821B1 (en) | 1998-08-12 | 2002-10-01 | Abbott Laboratories | N-substituted azabicycloheptane derivatives, production and use thereof |
| DE19836406A1 (de) | 1998-08-12 | 2000-02-17 | Basf Ag | N-Substituierte Azabicycloheptan-Derivate, ihre Herstellung und Verwendung |
| DE19848521A1 (de) * | 1998-10-21 | 2000-04-27 | Basf Ag | Verfahren zur Herstellung von (+)-exo-6-Phenyl-3-azabicyclo-[3.2.0]heptanen |
| DE19960074A1 (de) * | 1999-12-13 | 2001-06-21 | Basf Ag | Neues Salz von Belaperidone und dessen Modifikationen |
| WO2002014295A1 (fr) * | 2000-08-16 | 2002-02-21 | Elena Alexandrovna Izakson | Derives de thiazines de la formule generale (1) manifestant une action antibacterienne et antivirale |
| CA2583333C (en) * | 2004-10-14 | 2013-05-14 | Abbott Gmbh & Co. Kg | Azabicycloheptyl compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
| WO2006096757A2 (en) * | 2005-03-07 | 2006-09-14 | The University Of North Carolina At Chapel Hill | Inhibitors of reca activities for control of antibiotic-resistant bacterial pathogens |
| PL2083811T3 (pl) | 2006-11-22 | 2017-05-31 | Clinical Research Associates, Llc | Sposoby leczenia zespołu downa, zespołu łamliwego chromosomu x oraz autyzmu |
| KR20100046047A (ko) * | 2007-07-27 | 2010-05-04 | 액테리온 파마슈티칼 리미티드 | 2-아자-비시클로[3.3.0]옥탄 유도체 |
| EP3186242B1 (en) * | 2014-08-29 | 2021-10-06 | Tes Pharma S.r.l. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| CN112010851A (zh) * | 2020-06-30 | 2020-12-01 | 浙江美诺华药物化学有限公司 | 一种莫西沙星盐酸盐的制备方法 |
| IL305203A (en) * | 2021-03-17 | 2023-10-01 | Hoffmann La Roche | New histories of thiazolopyrimidines |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3328390A (en) * | 1962-02-27 | 1967-06-27 | Tri Kem Corp | Certain azabicycloalkane compounds |
| US4605655A (en) * | 1984-03-06 | 1986-08-12 | Bristol-Myers Company | Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3155668A (en) * | 1960-04-11 | 1964-11-03 | Sterling Drug Inc | 1-[3-, 2-, and 1-indolyl)-lower-alkyl]-tertiary amines and intermediates therefor |
| US4443451A (en) * | 1981-07-15 | 1984-04-17 | Janssen Pharmaceutica N.V. | Bicyclic pyrimidin-5-one derivatives |
| SU1004389A1 (ru) * | 1981-07-29 | 1983-03-15 | Институт Органической Химии Ан Усср | Способ получени производных тиазоло/3,4-а/пиримидинов |
| US4540318A (en) * | 1982-07-29 | 1985-09-10 | Robert Bosch, Gmbh | Rotary electrical tool with speed control, especially drill |
| DE3228303A1 (de) * | 1982-07-29 | 1984-02-02 | Robert Bosch Gmbh, 7000 Stuttgart | Elektrische motorregelung |
| US4804663A (en) * | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
-
1992
- 1992-12-21 DE DE4243287A patent/DE4243287A1/de not_active Withdrawn
-
1993
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- 1993-06-08 ES ES93912910T patent/ES2107035T3/es not_active Expired - Lifetime
- 1993-06-08 CZ CZ19943237A patent/CZ288787B6/cs not_active IP Right Cessation
- 1993-06-08 DE DE59307217T patent/DE59307217D1/de not_active Expired - Fee Related
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1994
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- 1994-12-16 NO NO944892A patent/NO305176B1/no not_active IP Right Cessation
- 1994-12-19 FI FI945957A patent/FI108726B/fi active
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3328390A (en) * | 1962-02-27 | 1967-06-27 | Tri Kem Corp | Certain azabicycloalkane compounds |
| US4605655A (en) * | 1984-03-06 | 1986-08-12 | Bristol-Myers Company | Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives |
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