CN1265654A - 苯环的2一位被取代的1-(n-苯氨基烷基)-哌嗪衍生物 - Google Patents
苯环的2一位被取代的1-(n-苯氨基烷基)-哌嗪衍生物 Download PDFInfo
- Publication number
- CN1265654A CN1265654A CN98807820A CN98807820A CN1265654A CN 1265654 A CN1265654 A CN 1265654A CN 98807820 A CN98807820 A CN 98807820A CN 98807820 A CN98807820 A CN 98807820A CN 1265654 A CN1265654 A CN 1265654A
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- China
- Prior art keywords
- phenyl
- piperazine
- carbonyl
- methoxy
- aminoethyl
- 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.)
- Granted
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 63
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- 210000001635 urinary tract Anatomy 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- 230000002232 neuromuscular Effects 0.000 claims abstract description 5
- -1 N-oxide compound Chemical class 0.000 claims description 127
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
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- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 7
- 230000004064 dysfunction Effects 0.000 abstract description 6
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 abstract 2
- 125000002950 monocyclic group Chemical group 0.000 abstract 2
- 102000017911 HTR1A Human genes 0.000 abstract 1
- 101150015707 HTR1A gene Proteins 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 176
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 104
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 32
- 239000002904 solvent Substances 0.000 description 31
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 125000004193 piperazinyl group Chemical group 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 230000027939 micturition Effects 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- ZFCOUBUSGHLCDT-UHFFFAOYSA-N 2-(trifluoromethoxy)aniline Chemical compound NC1=CC=CC=C1OC(F)(F)F ZFCOUBUSGHLCDT-UHFFFAOYSA-N 0.000 description 9
- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 9
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
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- 208000008967 Enuresis Diseases 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
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- 239000013078 crystal Substances 0.000 description 7
- BTUIFMCWPFMNRG-UHFFFAOYSA-N furan-3-carbonyl chloride Chemical compound ClC(=O)C=1C=COC=1 BTUIFMCWPFMNRG-UHFFFAOYSA-N 0.000 description 7
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
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- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及式(Ⅰ)的1-(N-苯基氨基烷基)-哌嗪衍生物,(R=H,烷基-CO,环烷基-CO,取代环烷基-CO或单环杂芳基-CO;R1=H或低级烷基;R2=卤素,烷氧基,苯氧基,NO2,CN,乙酰基,NH2,NH(酰基),烷基-SO2NH,烷氧基羰基,NH2CO,(烷基)NHCO,(烷基)2NCO,(酰基)NHCO,CF3或多氟烷氧基;B=苄基或单-或双环芳基或杂芳基,所有基都被任选地取代)与5-HT1A受体结合,并可用来治疗泌尿道下部的神经肌肉功能紊乱。这些化合物用于制备这一疗法的药物,本发明也提及了一些化合物(限定B)。
Description
发明领域
本发明涉及苯环的2-位被取代的1-(N-苯氨基烷基)-哌嗪衍生物,并涉及含所述衍生物的药物组合物,和这类衍生物和药物组合物的应用。
发明背景
在哺乳动物中,排尿动作(排尿)需要膀胱、其内和外括约肌、骨盆底的肌肉组织和对这些肌肉在三个水平上进行的神经控制的综合作用,所述的三个水平控制是膀胱壁或它的括约肌、脊髓的自主中枢和大脑皮层控制下的脑干(桥)中的脑桥排尿中枢(PMC)水平的中枢神经系统控制(De Groat,失禁的神经生物学(Neurobiology of Incontinence)(Ciba基金论坛151:27,1990)。排尿是在来自骶部脊髓的副交感神经自主控制下,由交织的平滑肌纤维构成的逼肌收缩的结果。疼痛、温度和膨胀引起的冲动经感觉神经从膀胱向骶部脊髓传递形成了简单的排空反射。但是,来自膀胱的感觉束也到达PMC,产生的神经冲动通常抑制控制膀胱排空的骶脊髓反射弧。这样,通过对反射弧的皮层抑制的随意抑制,并通过骨盆底的肌肉和外括约肌的松弛便引发正常的排尿。最后,逼肌收缩,开始排空。
人们常常会发生下部泌尿道功能异常,如排尿困难,尿失禁和遗尿。排尿困难包括尿频、夜尿症和尿急,可能是由膀胱炎、前列腺炎或良性的前列腺肥大(BPH)(约70%的老年男性患此症状)引起,或者是由神经疾病引起。尿失禁综合征包括压迫性尿失禁、急迫性尿失禁和溢流性尿失禁。遗尿指在晚上或睡觉期间非随意性的排尿。
在本发明者的研究之前,治疗下部泌尿道的肌肉神经失调涉及给予能直接作用于膀胱肌肉的药物,如黄酮哌酯,一种对PMC(Guarneri等,今日药物(Drugs ofToday)30:91,1994) 也有活性的解痉药(Ruffman,内科研究杂志(J.Int.Med.Res.)16:317,1988)或抗胆碱能化合物,如盐酸奥昔布宁(Andersson,药物(Drugs)35:477,1988)。也常用α1-肾上腺素能受体拮抗剂治疗BPH,但基于不同的作用机理(Lepor,泌尿学(Urology),42:483,1993)。但是,直接抑制骨盆肌肉组织(包括逼肌)的治疗会有不希望的副作用,如不完全排空或调节麻痹、心动过速和口干(Andersson,药物(Drugs),35:477,1988)。因此,希望得到能通过外周或中枢神经系统作用以恢复排尿机理的正常功能的方式来影响骶脊髓反射弧和/或PMC抑制途径的化合物。
GB 2263110揭示了1-(N-苯基-N-环己基羰基-2-氨基乙基)-4-(2-甲氧基苯基)-哌嗪(化合物A),
并报道是5-HT1A的受体拮抗剂。也揭示了该化合物可用来治疗中枢神经系统失调,例如作为治疗焦虑用的抗焦虑药。
下面揭示的本发明化合物由于其苯胺环的2-位处存在的新颖的取代基,故结构不同于化合物A。本发明化合物与GB 2263110揭示的其它不同是在哌嗪环的4-位处的芳环上的取代。这些结构变化既未被GB 2263110揭示,也没有被提出,特别是关于可用来改善泌尿道功能的化合物。这些结构变化得到了在预测对下部泌尿道的活性、特别是抗尿失禁活性的药理试验中比化合物A更有效的化合物。
US 4205173、EP 711757、DE 2405441、US 3472854、Chem.Pharm.Bull.33:1826-1835(1985)和J.Med.Chem.7:721-725(1964)揭示的其它化合物,已被本发明者发现在本发明的方法,如治疗泌尿道疾病中是有用的,所有文献纳入本文,供参考。
发明综述
本发明一方面涉及通式I化合物制备治疗哺乳动物泌尿道下部神经肌肉机能障碍的药物中的应用:其中
R代表氢原子或烷基羰基、环烷基羰基、取代环烷基羰基或单环杂芳基羰基,
R1代表氢原子或低级烷基,
R2代表卤原子或烷氧基、苯氧基、硝基、氰基、酰基、氨基、酰氨基、烷基磺酰基氨基、烷氧基羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰基氨基甲酰基、三氟甲基或多氟烷氧基,和
B代表单-或双环芳基、取代的单或双环芳基、单或双环杂芳基、取代的单或双环杂芳基、苄基或取代苄基。
本发明另一方面提供了通式I(如上所示)化合物,其中:
R代表氢原子或烷基羰基、环烷基羰基、取代环烷基羰基或单环杂芳基羰基,
R1代表氢原子或低级烷基,
R2代表卤原子或烷氧基、苯氧基、硝基、氰基、酰基、氨基、酰氨基、烷基磺酰基氨基、烷氧基羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰基氨基甲酰基、三氟甲基或多氟烷氧基,和
B代表取代的单环芳基、双环芳基、取代的双环芳基、单或双环杂芳基、取代的单或双环杂芳基或取代的苄基,
条件是:
若R和R1代表氢原子,R2代表硝基,则B不代表2-甲氧基苯基、4-氯苯基、4-羟基苯基、3-乙酰基苯基、4-氨磺酰(sulphamoyl)苯基、3,4,5-三甲氧基苯基、2-氯-4-甲基苯基或2-吡啶基;若R和R1都代表氢原子,R2代表氨基甲酰基,则B不代表4-羟基苯基;
若B代表烷氧基取代的芳基,则烷氧基必须在芳环的2-位上;
本发明也包括这些化合物的对映体、非对映异构体、N-氧化物、晶型、水合物和药学上可接受的盐,以及有相同活性类型的这些化合物的代谢物(下面称为“活性代谢物”)。
本发明进一步提供了药物组合物,它包括式I化合物或这类化合物的对映体、非对映异构体、N-氧化物、晶型、水合物或药学上可接受的盐与药学上可接受的稀释剂或载体的混合物。
对于本文中可变的R,烷基羰基包括(C1-C6烷基)-羰基,环烷基羰基包括环己基羰基,取代的环烷基羰基包括被烷基或芳基取代的环己基羰基,单环杂芳基包括含一个或多个杂原子(如氧、氮和硫)的有5-7个环中原子的单环芳基。单环杂芳基羰基与单环杂芳基有相同的定义,但也包括连接到环碳原子的羰基。
对于本文中可变的B,单或双环芳基表示有6-12个碳原子的单或双环芳基(如苯基或萘基)。对于芳基,优选的取代基包括低级烷基、低级烷氧基(如,甲氧基、乙氧基、丙氧基和丁氧基)、低级卤代烷氧基(如,2,2,2-三氟乙氧基)、卤素、氨基、酰基氨基、烷基磺酰基氨基和(低级)烷氨基取代基。
对于可变的B使用的单环杂芳基的定义与上述R的相同,双环杂芳基表示含一个或多个杂原子(如氮、氧、硫)和9-12个环中原子的双环芳基。
对于苄基B,优选的取代基是烷基、烷氧基、卤素、硝基、氰基、酰氨基、氨基、烷氨基、酰基氨基、烷基磺酰基氨基或酰基取代基。
B上优选的取代基是任选取代的单环芳基和双环杂芳基。B上最优选的取代基是烷氧基苯基和含一个氮的双环杂芳基。
R宜代表氢原子或环己基羰基,1-甲基环己基羰基,1-苯基环己基羰基,3-呋喃基羰基,3-噻吩基羰基,4-吡啶基羰基,3-吡啶基羰基或2-吡嗪基羰基。
R1宜代表氢原子或甲基。
R2宜代表碘原子或甲氧基、苯氧基、硝基、氰基、乙酰基、氨基、乙酰氨基、乙酰氧基羰基、氨基甲酰基、乙基氨基甲酰基、二甲基氨基甲酰基、环己基羰基氨基甲酰基、三氟甲基、三氟甲氧基或2-(2,2,2-三氟)乙氧基。
B宜代表2-甲氧基苯基、2,5-二氯苄基或4-吲哚基。
本发明化合物可用来治疗泌尿道下部神经肌肉机能障碍,包括,但不限于排尿困难、尿失禁和遗尿。它们可用来缓解尿急迫症、尿频、失禁、尿滴沥、遗尿、排尿困难、不愿排尿和膀胱排空困难中至少一种的疾病。
本发明化合物可用来阻断5-HT1A血清素能受体,并通过该抑制活性用来治疗哺乳动物,特别是人体由于血清素能失调导致的CNS疾病,如焦虑、抑郁、高血压、睡觉/清醒周期紊乱、摄食行为、性功能和认知障碍。
发明详述
本说明书里所有的专利、专利申请和文献都全文纳入本文供参考。若不一致,以本说明书,包括定义为主。
本发明涵盖包含上述揭示的化合物的药物制剂,本发明也涵盖了用这些制剂治疗泌尿道下部神经肌肉机能障碍,如排尿困难、尿失禁、遗尿等等的方法。排尿困难包括尿频、夜尿、尿急迫症和膀胱排空困难,即在排尿时排出尿的体积未达最佳标准。
失禁综合征包括压迫性失禁、急迫性失禁和溢流性失禁。遗尿指夜晚或睡觉时不随意地排尿。虽然不希望为理论所束缚,但据相信,给予本发明的5-HT1A受体拮抗剂能防止骶反射弧的不希望的活性和/或控制排尿的皮层机理。这样,可以预期,用本发明化合物可治疗很大范围的泌尿道下部肌肉神经功能紊乱。
用于治疗排尿困难的化合物的“有效量”是能导致上述疾病的至少一个症状或参数有可测量的减轻的用量。
用于治疗疾病的有效量可用本技术领域人员公知的经验的方法来确定:如建立给药剂量和给药频率的模型,将一组实验个体或对象与模型里的每个点比较。病人给药的确切剂量根据疾病的状态和严重程度和病人的身体状况而定。通过本技术领域的医生或病人向医生报告的情况来确定任何可测定的症状或参数的改善情况。应当明白,泌尿道疾病任何症状或参数在临床上或统计学上显著的减轻或改善都在本发明的范围里。临床上显著减轻或减善意味着可被病人和/或医生察觉。
例如,一个病人可能同时患有几种排尿困难的症状,如排尿急迫和过频,其中之一或两者都可用本发明的方法来缓解。对于失禁,本发明治疗方法的好处是减少不希望的排尿频率或体积。
本发明化合物可与生理上可接受的载体,如磷酸盐缓冲的盐水或去离子水一起配制成液体剂型。药剂也可含有赋形剂,包括防腐剂和稳定剂,这些都是本技术领域公知的。化合物可配制成固体口服或非口服的剂型单位,如片剂、胶囊剂、粉剂和栓剂,另外可包括赋形剂,不受限制地包括润滑剂、增塑剂、着色剂、吸收增强剂、杀菌剂等等。
给药方式包括口服和肠道给药、静注、肌注、皮下给药、透皮给药、经粘膜给药(包括直肠给药和颊部给药),和吸入途径。优选的是采用口服或透皮给药途径(即,各自通过固体或液体口服制剂或皮肤贴剂)。
给药量的范围是约0.01-25mg/kg/天,优选的是约0.1-10mg/kg/天,最好是约0.2-5mg/kg/天。应当明白,本发明的药物单剂不需要含对治疗疾病有效的整个剂量,而可通过多次给予这类药剂来达到有效量。
在本发明优选的实施方案里,化合物被配制成胶囊剂或片剂,每一胶囊或每片优选地含50-200毫克本发明化合物,患者最好给予总日剂量50~400mg,较佳的是150-250毫克,最好是约200毫克,以缓解尿失禁和可用5-HT1A受体配体治疗的功能紊乱。
下列的方法、表格和实施例用来更详细地阐述本发明较好的实施方案并显示其优点和实用性,它们并非用于限定本发明的范围。
本发明化合物的合成
本发明化合物可用下列反应式,或其变化形式,用易得的起始材料、试剂和本技术领域公知的常规的合成方法来制备。
除非另作说明,反应流程里的化合物和中间体的取代基以与式I相同的方式定义。
流程I显示了合成化合物I的一个方法:
用1,ω-二取代烷烃(Z)使式II邻位取代的苯胺(Y=NH2)烷基化得到产物III。反应在惰性有机溶剂里,宜在极性非质子传递溶剂里,如N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、二噁烷、四氢呋喃(THF)、丙酮、乙腈,或在氯化溶剂里,如二氯甲烷、氯仿、1,2-二氯乙烷,或在质子传递溶剂里,如正丁醇(n-BuOH)里进行。通常在0-+120℃温度下,在诸如三乙胺(Et3N)、二异丙基乙胺等的质子受体存在下,任选地在碘化钾存在下进行该反应。
在式Z的化合物中,X和X1可为Cl,Br,I,芳基或烷基磺酰基氧基,式III中间体用来使合适的哌嗪衍生物IV烷基化以得到式I化合物(其中R=H)。
可在氯化溶剂,如二氯甲烷、氯仿或1,2-二氯乙烷里,或在极性非质子传递溶剂,如DMF、THF、丙酮、乙腈里,或在极性质子传递溶剂,如n-BuOH等里,或在如甲苯、苯、正庚烷等非极性溶剂里,在0-120℃温度下,任选地在质子受体,如Et3N、4-二甲氨基吡啶、碳酸钾、碳酸铯等存在下,也可任选地在碘化钾存在下进行这些烷基化反应。
可这样制备市售不可得到的式IV哌嗪:使合适的B-NH2衍生物(通常通过还原相应的B-NO2衍生物来容易地得到)与双-(2-氯乙基)胺或双-(2-羟乙基)胺在过量氯化氢存在下进行反应。这些反应可在诸如二甲基甲酰胺、二甘醇二甲醚或甲苯的非质子传递溶剂里,在40℃到该溶剂的回流温度,通常在诸如碳酸钾、碳酸铯等碱的存在下,任选地在碘化钾存在下进行。
式V化合物可方便地从X是COO-低级烷基,n是n-1的式V起始制备。常规的还原过程(如,用氢化锂铝或其它络合的金属氢化物)得到了式V中X是CH2OH,n是n-1的相应化合物V,它可接着转化为X是上述离去基团的式V化合物。通过使单取代哌嗪在合适的2-卤代酯上发生亲核取代反应可制备起始酯。
另一种制得化合物V的过程包括用式X-CH(R1)(CH2)n-1CH2-OPrG或X-(CH2)nCH(R1)-X化合物,其中X是离去基团,n的定义同上,PrG是在哌嗪烷基化后可除去的保护基团(如,O-四氢吡喃基),使合适的单取代哌嗪衍生物烷基化。
合成式III中间体的另一个方法是使用结构II(Y=卤素)的起始材料。这些起始材料与式Z化合物反应,其中X和X1各自是NH2和OH。如G.Doleschall等,四面体(Tetrahedron),32,57-64(1976)所述,这些烷基化反应在诸如DMF、甲苯的非质子传递溶剂或诸如n-BuOH等的极性质子传递溶剂里,在+40℃到+140℃温度下,一般使用一当量或过量的式Z试剂(X=NH2)作为质子受体的条件下进行。所得的式III氨基醇(X1=OH)与诸如POCl3,SOCl2或PCl5的氯化剂反应得到中间体,也称为式III(X1=Cl),或与烷基磺酰氯或芳基磺酰氯反应得到相应的磺酸酯。这些反应在诸如氯仿、DMF、吡啶的非质子溶剂里,在+50℃到溶剂的回流温度下进行。
通过用式V中间体,其中B、R1和n的定义同上,X是诸如氯或溴的卤原子,或是诸如甲磺酰氧基或对-甲苯磺酰氧基的离去基团,使式II化合物(Y=NH2)烷基化可得到式I化合物(R=H)。
在没有溶剂或有诸如二氯甲烷、氯仿、DMF、THF、丙酮、乙腈的非质子传递溶剂,或在诸如正丁醇的质子传递溶剂里,于0℃到+160℃的温度下,任意地在诸如Et3N、碳酸钾、碳酸铯、4-二甲氨基吡啶等的质子受体存在下,任意地在碘化钾存在下进行这些反应。
式I中R2是CN的化合物也可通过脱水反应从式I中R2是CONH2的化合物制得。P2O5、PCl5、Ph3P等可用作脱水剂(J.March,高等有机化学,第四版,1041页,Wiley Interscience,1992)。可在诸如二氯甲烷、氯仿、四氯化碳的氯化溶剂,或在诸如DMF、甲苯等的非质子传递溶剂里,在+40℃和溶剂回流温度之间,任意地在诸如Et3N的碱存在下进行脱水反应。
另一种方法是,通过用式II起始材料(Y=Cl,Br,F,I或三氟甲磺酰基氧基)使式V中间体(X=NH2)芳基化制得式I化合物(R=H)。这些反应可用与上述相同的溶剂和条件,通过使用钯络合物催化剂进行(Synlett,329页(1996))。
式I中R2是COalk的化合物可通过酰基化反应从式I中R2是H的化合物合成,所述的酰基化反应用三氯化硼作为路易斯酸,乙腈作为试剂在诸如氯仿、1,2-二氯乙烷、甲苯等的非质子传递溶剂里,在0℃-100℃的温度下进行,然后用HCl在100℃下处理进行酸水解(T.Sugasawa等,Chem.Pharm.Bull.,33,1826-1835(1985))。
式I(R=H)化合物与合适的酰卤R’Hal,其中R’代表烷基羰基、环烷基羰基或单环杂芳基羰基,Hal代表卤原子,酰化得到化合物I(R不是H)。反应在诸如二氯甲烷、氯仿、1,2-二氯乙烷、DMF、丙酮、乙腈、甲苯等的非质子传递溶剂里,在0℃-100℃的温度下,任选地在诸如Et3N、二异丙基乙基胺(DIPEA)、4-二甲氨基吡啶等的质子受体存在下进行。
另外,式I中R的定义同上,但不是氢的化合物(即,其中R2=Br,I,OSO2F或OSO2CF3)可通过与诸如异氰酸三甲基甲硅烷基酯和叔丁基锂(有机化学杂志(J.Org.Chem.)55,3114(1990)),氰化锂和四(三苯基膦)钯(O)(EP 711757),一氧化碳-甲醇和二乙酸钯(在1,3-二苯基膦基丙烷存在下)(有机化学杂志59,6683(1994))的试剂反应来合成式I中R2是CN、CONH2、COCH3或COOCH3的化合物。这类反应可在诸如THF、甲苯、苯、DMSO等的极性和非极性溶剂里进行。
另一种合成式I中R1是H的化合物的方法如下列流程2所示。
流程2式II邻位取代的卤代苯(Y=卤素)被用于芳基化被保护的式VII的氨烷基醛(X=NH2),得到相应的被保护的芳基氨基烷基醛VIII。反应可在诸如吡啶、DMF、甲苯等非质子传递溶剂里,在+40℃和120℃温度下,任意地在诸如Et3N存在下,或使用上述的钯络合物催化剂进行。
制备式VIII中间体的另一个途径包括用式VII被保护的反应性化合物(X=卤素)通过本技术领域公知的常规方法使式II化合物(Y=NH2)烷基化。式VIII化合物是稳定的,它们在下列步骤里临使用之前可用标准方法去保护。
从式VIII化合物去保护得到的式VIII’醛无需分离即可与N-取代的哌嗪IV在还原条件下反应,得到式I化合物(R=R’=H)。这些反应可在诸如甲醇、乙醇的极性溶剂,或在诸如二氯甲烷、氯仿等的氯化溶剂里,用诸如NaBH4和NaBH3CN、NaBH(OAc)3的氢硼化碱金属或用诸如BH3-Py的硼烷络合物,任选地在诸如乙酸的酸性促进剂存在下,于+10℃到100℃的温度下进行。
式I化合物(R=R’=H)可用R’Hal酰基化得到式I中R是烷基羰基的化合物。所述的酰基化反应在流程1最后一个步骤里所述的相同条件下进行。或者,式VIII中间体可用R’Hal按照上述相同的条件进行酰基化,得到式IX化合物。
式IX中间体仅在最后一个步骤里其临使用前用公知方法去保护,得到相应的醛(IX’),它可与合适的式IV的N-取代的哌嗪反应,使用诸如NaBH4,NaBH3CN或NaBH(OAc)3的氢硼化碱金属,任意地在催化量的乙酸或诸如四异丙醇钛的钛催化剂存在下,得到式I化合物。这些反应可在诸如二氯甲烷或氯仿的氯化溶剂,或在诸如甲醇或乙醇的极性非质子传递溶剂里,于+10℃和+100℃温度下进行。
实施例1
1-[N-(2-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
使3.03克2-氯-1-硝基苯、4.52克1-(2-氨乙基)-4-(2-甲氧基苯基)-哌嗪和3.18克无水碳酸钾在30毫升正丁醇里的混合物回流搅拌32小时。冷却后,混合物倒入水中,然后用乙酸乙酯萃取,在无水硫酸钠上干燥有机相。通过蒸发溶剂得到的粗制品经快速色谱(乙酸乙酯∶石油醚4∶6)纯化,蒸发溶剂后得到的残留物溶于二乙醚,搅拌并过滤得到2.2克(31%)标题化合物,熔点117-118℃。
1H-NMR(CDCl3,δ):8.50(bs,1H,NH),8.19(d,1H,苯胺H3),7.45(dd,1H,苯胺,H5),7.08-6.78(m,5H,苯胺H6和甲氧基苯环CHs),6.63(dd,1H,苯胺H4),3.86(s,3H,OCH3),3.40(dt,2H,NHCH2CH2),3.37-3.04(m,4H,哌嗪质子),2.80-2.62(m,6H,NHCH2CH2和哌嗪质子)。
实施例2
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
将环己基甲酰氯(0.98ml)和三乙胺(1.03ml)依次加到含2.1克实施例1制备的化合物和15毫升1,2-二氯乙烷的溶液里。让混合物回流搅拌16小时。最后,冷却,用氯仿稀释,用1N氢氧化钠和水洗涤。有机相用无水硫酸钠干燥,通过蒸发溶剂得到的粗制品经快速色谱(乙酸乙酯∶石油醚1∶1)纯化,用环己烷结晶得到1.79克(65%)标题化合物。熔点:119-121℃。
1H-NMR(CDCl3,δ):8.04(d,1H,硝基苯环H3),7.65-7.47(m,3H,硝基苯环H4,5,6),7.10-6.75(m,4H,甲氧基苯环,CHs),4.15-3.92(m,1H,C(O)NCH(H)CH2),3.83(s,3H,OCH3),3.70-3.50(m,1H,C(O)NCH(H)CH2),3.10-2.80(m,4H,哌嗪质子),2.80-2.40(m,6H,哌嗪质子和C(O)NCH2CH2),2.10-0.75(m,11H,环己基质子)。
通过常规的方法制备实施例2化合物的下列盐:
单盐酸盐,熔点183-187℃(丙酮∶乙醚);
单甲磺酸盐,熔点150-153℃(丙酮);
单甲磺酸盐水合物,熔点136-140℃。
实施例3
1-[N-(2-三氟甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
使2.09克2-三氟甲氧基苯胺和3.15克1-(2-氯乙基)-4-(2-甲氧基苯基)-哌嗪在20毫升正丁醇里的溶液在100℃下搅拌2小时。然后冷却混合物,用水稀释,用2N氢氧化钠碱化,用氯仿萃取,在无水硫酸钠上干燥有机相。蒸发至干,粗制品经快速色谱(乙酸乙酯∶石油醚3∶7)纯化,用乙醇结晶,得到0.55克(12%)标题化合物,熔点69.5-71℃。
1H-NMR(CDCl3,δ):8.02-7.85(br,1H,NH),7.43-7.27(m,2H,苯胺CHs),7.03-6.80(m,4H,甲氧基苯环CHs),6.72(dd,1H,苯胺CH),6.57(t,1H,苯胺CH),3.86(s,3H,OCH3),3.43-3.23(m,2H,NHCH2CH2),3.23-3.03(m,4H,哌嗪质子),2.85-2.60(m,6H,哌嗪质子和NHCH2CH2)。
实施例4
1-[N-(2-三氟甲氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例3制备的1-[N-(2-三氟甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,4-二甲基氨基吡啶代替三乙胺,使混合物加热回流1.5小时外,按照实施例2所述的方法制备标题化合物。粗制品经快速色谱(乙酸乙酯∶石油醚4∶6)纯化,得率44%。
1H-NMR(CDCl3,δ):7.48-7.25(m,4H,三氟甲氧基苯胺环CHs),7.02-6.81(m,4H,甲氧基苯环CHs),4.40-4.20(m,1H,C(O)NCH(H)CH2,3.84(s,3H,OCH3),3,36-3,18(m,1H,C(O)NCH(H)CH2),3.10-2.90(m,4H,哌嗪质子),2.75-2.45(m,6H,哌嗪质子和C(O)NCH2CH2)和2.03-1.80(m,1H,CHC(O)),1.75-0.80(m,10H,环己基质子)。
实施例5
1-[N-(2-苯氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪·3HCl
除用2-苯氧基苯胺代替2-三氟甲氧基苯胺外如实施例3操作,得到粗制的1-[N-(2-苯氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪。它经快速色谱(乙酸乙酯)纯化,将残留物溶于乙醇,使用2N乙醇制氯化氢酸化溶液,接着加入乙醚,过滤后得到45%标题化合物。
熔点184-187℃。
1H-NMR(DMSO-d6,δ):8.70-7.60(m,4H,3+NH和NH),7.32(t,2H,芳族的),7.10-6.85(m,9H,芳族的),6.80(dd,1H,芳族的),6.63(t,1H,芳族的),3.78(s,3H,OCH3),3.65-3.00(m,12H,哌嗪质子和NHCH2CH2)。
实施例6
1-[N-(2-苯氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例5制备的1-[N-(2-苯氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,使混合物回流加热2.5小时外,其它按照实施例4所述的方法制备标题化合物,粗制品经快速色谱纯化(乙酸乙酯∶石油醚7∶3)。得率:32%。
1H-NMR(CDCl3,δ):7.40-7.20(m,4H,芳族的),7.10(t,2H,芳族的),7.05-6.80(m,7H,芳族的),4.21-4.03(m,1H,C(O)NC(H)HCH2),3.83(S,3H,OCH3),3.55-3.40(m,1H,C(O)NC(H)HCH2),3.10-2.93(m,4H,哌嗪质子),2.75-2.50(m,6H,哌嗪质子和C(O)NCH2CH2)和2.25-2.05(m,1H,CHC(O)),1.80-0.80(m,10H,环己基质子)。
实施例7
1-[N-(2-碘苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-碘苯胺代替2-三氟甲氧基苯胺,使混合物在90℃下加热7小时外,其它按照实施例3所述的方法制备标题化合物。粗制品经快速色谱层析纯化(乙酸乙酯∶石油醚1∶4)。得率:37%。
1H-NMR(CDCl3,δ):7.65(dd,1H,苯胺H3),7.20(dd,1H,苯胺H5),7.07-6.80(m,4H,甲氧基苯环CHs),6.55(dd,1H,苯胺H4),6.45(dd,1H,苯胺H6),5.15-5.03(br,1H,NH),3.87(s,3H,OCH3),3.30-3.05(m,6H,哌嗪质子和NHCH2CH2),2.83-2.65(m,6H,哌嗪质子和NHCH2CH2)。
实施例8
1-[N-(2-碘苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例7制备的1-[N-(2-碘苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,使混合物回流加热7小时,其它按照实施例4所述的方法制备标题化合物,得率:73%。
1H-NMR(CDCl3,δ):8.95(dd,1H,碘苯环H3),7.45-7.35(m,2H,碘苯环CHs),7.15-6.80(m,5H,甲氧基苯环CHs和剩余的碘苯环CH),4.53-4.37(m,1H,C(O)NC(H)HCH2),3.84(s,3H,OCH3),3.20-2.95(m,5H,C(O)NC(H)HCH2和哌嗪质子),2.77-2.50(m,7H,C(O)NCH2CH2,哌嗪质子和CHC(O)),1.90-0.80(m,10H,环己基质子)。
实施例9
1-[N-(2-氨基甲酰基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-氨基苯酰胺代替2-三氟甲氧基苯胺外,其它按照实施例3所述的方法制备标题化合物,粗制品经快速色谱纯化(乙酸乙酯),用乙醇结晶。
得率36%。熔点:134-136℃
1H-NMR(CDCl3,δ):8.02-7.85(br,1H,NH),7.41-7.26(m,2H,苯胺H3,5),7.05-6.78(m,4H,甲氧基苯环CHs),6.73(dd,1H,苯胺H6),6.58(t,1H,苯胺H4),5.80-5.45(br,2H,CONH2),3.86(s,3H,OCH3),3.33(t,2H,NHCH2CH2),3.20-3.02(m,4H,哌嗪质子),2.83-2.62(m,6H,NHCH2CH2和哌嗪质子)。
实施例10
1-[N-(2-氰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
使含0.2克实施例9制备的1-[N-(2-氨基甲酰基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪、0.26克三苯基膦、0.08毫升三乙胺、0.5毫升四氯化碳和10毫升1,2-二氯乙烷的混合物回流搅拌3小时。蒸发溶剂后得到的残留物经快速色谱纯化(二氯甲烷∶甲醇98∶2),得到0.14克(74%)标题化合物。
1H-NMR(CDCl3,δ):7.40-7.30(m,2H,苯胺H4,6),7.05-6.80(m,4H,甲氧基苯环CHs),6.70-6.57(m,2H,苯胺H3,5),5.45-5.30(br,1H,NH),3.86(s,3H,OCH3),3.25(q,2H,NHCH2CH2),3.20-3.00(m,4H,哌嗪质子),2.85-2.60(m,6H,NHCH2CH2和哌嗪质子)。
实施例11
1-[N-(2-乙酰基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用苯胺代替2-三氟甲氧基苯胺,且不使用溶剂外,其它按实施例3所述的方法进行。粗制品经快速色谱纯化(石油醚∶乙酸乙酯8∶2),得到1-(N-苯基-2-氨基乙基)-4-(2-甲氧基苯基)-哌嗪。得率:77%。
1H-NMR(CDCl3,δ):7.30-7.10(m,2H,苯胺H2,6),7.10-6.80(m,4H,甲氧基苯环CHs),6.80-6.58(m,3H,苯胺H3,4,5),4.35(br,1H,NH),3.87(s,3H,OCH3),3.30-3.15(m,2H,NHCH2CH2),3.15-2.98(m,4H,哌嗪质子),2.80-2.60(m,6H,NHCH2CH2和哌嗪质子)。
在氮气氛、-3℃搅拌下,将1M三溴化硼在二氯甲烷(2.37毫升)里的溶液滴加入另一个含0.74克上述制备的1-(N-苯基-2-氨基乙基)-4-(2-甲氧基苯基)-哌嗪在10毫升二氯甲烷里的溶液中。接着,在室温下加入0.25毫升乙腈,使混合物在室温下搅拌1小时,再搅拌8小时直到沉淀。在室温下冷却后,用10%碳酸钠水溶液处理混合物,分离的有机相在无水硫酸钠上干燥,蒸发至干。粗制品经快速色谱(二氯甲烷∶甲醇98∶2)纯化,用乙醇结晶残留物,得到0.33克(39%)标题化合物。熔点:92-94℃。
1H-NMR(CDCl3,δ):9.12-8.95(br,1H,NH),7.75(dd,1H,苯胺H3),7.35(dt,1H,苯胺H5),7.05-6.80(m,4H,甲氧基苯环CHs),6.73(dd,1H,苯胺H4),6.58(dt,1H,苯胺H6),3.86(s,3H,OCH3),3.35(q,2H,NHCH2CH2),3.20-3.02(m,4H,哌嗪质子),2.85-2.61(m,6H,NHCH2CH2和哌嗪质子),2.58(s,3H,COCH3)。
实施例12
1-[N-(2-硝基苯基)-2-氨基乙基]-4-(4-吲哚基)-哌嗪
使含0.49克N-(2-氯乙基)-2-硝基苯胺(如Ramage G.R.等在J.Chem.Soc.4406-4409(1952)所述方法制备)、0.55克1-(4-吲哚基)-哌嗪(根据WO95/33743制备)、1毫升三乙胺和3毫升二甲基甲酰胺的混合物在氮气下搅拌加热回流2.5小时。在室温下冷却后,将混合物倒入水中,用二氯甲烷萃取。有机相在无水硫酸钠上干燥,蒸发至干。粗制品经快速色谱(乙酸乙酯∶石油醚3∶7)纯化,得到0.35克(40%)标题化合物。
1H-NMR(CDCl3,δ):8.60-8.45(br,1H,苯胺NH),8.18(dd,1H,苯胺H3),8.20-8.10(br,1H,吲哚NH),7.43(td,1H,苯胺 H5),7.20-7.05(m,3H,吲哚H3,6,7),6.85(dd,1H,苯胺H4),6.70-6.57(m,2H,苯胺H6和吲哚H5),6.50(t,1H,吲哚基H2),3.45(q,2H,NHCH2CH2),3.35-3.25(m,4H,哌嗪质子),3.85-2.70(m,6H,NHCH2CH2和哌嗪质子)。
实施例13
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(4-吲哚基)-哌嗪
除了用实施例12制备的1-[N-(2-硝基苯基)-2-氨基乙基]-4-(4-吲哚基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪,让混合物回流加热5小时外,按实施例4所述的方法制备标题化合物。粗制品经快速色谱(乙酸乙酯∶石油醚7∶3,然后只用乙酸乙酯,最后只用二氯甲烷)纯化,得率:32%。
1H-NMR(CDCl3,δ):8.37-8.20(br,1H,NH),8.05(dd,1H,硝基苯基H3),7.65-7.45(m,3H,硝基苯环H4,5,6),7.20-7.00(m,3H,吲哚H3,6,7),6.55(dd,1H,吲哚H5),6.50(t,1H,引哚H2),4.15-3.95(m,1H,C(O)NC(H)HCH2),3.70-3.55(m,1H,C(O)NC(H)HCH2),3.25-2.95(m,4H,哌嗪质子),2.75-2.45(m,7H,C(O)NCH2CH2,CHC(O),哌嗪质子),2.10-0.80(m,10H,环己基质子)。
实施例14
1-[N-(2-硝基苯基)-2-氨基乙基)-4-(2,5-二氯苄基)-哌嗪
在氮气氛、室温下将2,5-二氯苄基氯(2.01克)加到搅拌着的1.94克1-乙氧基羰基-哌嗪和3.45克无水碳酸钾在20毫升二甲基甲酰胺里的混合物中。在相同温度下搅拌24小时后,将反应混合物倒入水中,用乙酸乙酯萃取,有机相经无水硫酸钠干燥,真空蒸发至干。油状残留物经快速色谱纯化(石油醚∶乙酸乙酯85∶15),得到2克(63%)1-(2,5-二氯苄基)-4-乙氧基羰基-哌嗪。
1H-NMR(CDCl3,δ):7.50(d,1H,芳族的H6),7.27(d,1H,芳族的H3),7.15(dd,1H,芳族的H4),4.13(q,2H,CH3CH2O),3.58(s,2H,苄基CH2),3.55-3.45(m,4H,哌嗪质子),2.50-2.42(m,4H,哌嗪质子),1.26(t,3H,CH3CH2O)。
将上述制备的13克1-(2,5-二氯苄基)-4-乙氧基羰基-哌嗪在35毫升37%盐酸里的溶液回流搅拌40小时。接着,在室温下加入30毫升水和30毫升乙酸乙酯,通过加入35%氢氧化钠将pH调节到11。有机相经无水硫酸钠干燥,真空蒸干。粗制品经快速色谱(氯仿∶甲醇7∶3)纯化得到4.46克(50%)1-(2,5-二氯苄基)-哌嗪。
1H-NMR(CDCl3,δ):7.50(d,1H,芳族的H6),7.26(d,1H,芳族的H3),7.14(dd,1H,芳族的H4),3.55(s,2H,苄基CH2〕,3.00-2.85(m,4H,哌嗪质子),2.55-2.48(m,4H,哌嗪质子),1.76(s,1H,NH)。
用上述制备的1-(2,5-二氯苄基)-哌嗪代替1-(4-吲哚基)-哌嗪,4-二甲基氨基吡啶代替三乙胺,按实施例12的方法制备和纯化标题化合物,反应在120℃下进行8小时。得率:35%。
1H-NMR(CDCl3,δ):8.45(br,1H,NH),8.10(d,1H,苯胺H3),7.45(d,1H,二氯苯环H6),7.38(dd,1H苯胺H5),7.25(d,1H,二氯苯环H3),7.10(dd,1H,二氯苯环H4),6.77(d,1H,苯胺H6),6.55(dd,1H,苯胺H4),3.59(s,2H,苄基CH2),3.35(dt,2H,NHCH2CH2),2.73(t,2H,NHCH2CH2),2.70-2.38(m,8H,哌嗪质子)。
实施例15
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2,5-二氯苄基)-哌嗪
除了用实施例14制备的1-[N-(2-硝基苯基)-2-氨基乙基]-4-(2,5-二氯苄基)-哌嗪代替1-[N-(2-硝基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪,让混合物回流加热12小时外,按实施例2所述的方法制备标题化合物。粗制品经快速色谱(乙酸乙酯∶石油醚4∶6)纯化,得率:22%。
1H-NMR(CDCl3,δ):8.03(dd,1H,硝基苯基H3),7.75-7.40(m,4H,二氯苯环H6和硝基苯环H4,5,6),7.25(d,1H,二氯苯环H3),7.10(dd,1H,二氯苯环H4),4.05-3.90(m,1H,C(O)NC(H)HCH2),3.65-3.50(m,1H,C(O)NC(H)HCH2),3.25(s,2H,苄基CH2),2.70-2.20(m,10H,C(O)NCH2CH2,哌嗪质子),2.00-0.70(m,11H,环己基质子)。
实施例16
1-[N-(2-环己基氨基甲酰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例9制备的1-[N-(2-氨基甲酰基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪,让混合物在2摩尔当量环己基甲酰氯存在下回流加热6小时外,按实施例4所述的方法制备标题化合物。粗制品经快速色谱(二氯甲烷∶甲醇95∶5)纯化,得率:55%。
1H-NMR(DMSO-d6,δ):12.10-11.80(br,1H,NH),8.08(dd,1H,苯基羰基H3),7.88-7.68(m,2H,苯基羰基H5,6),7.47(dt,1H,苯基羰基H4),7.00-6.80(m,4H,甲氧基苯环CHs),4.50-4.33(m,2H,C(O)NCH2CH2),3.75(s,3H,OCH3),3.15-2.85(m,5H,CHC(O)和哌嗪质子),2.80-2.68(m,2H,C(O)NCH2CH2),2.68-2.54(m,4H,哌嗪质子),2.28-2.08(m,1H,CHC(O)),1.97-1.05(m,20H,环己基质子)。
实施例17
1-[N-(2-甲氧基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
使0.93克邻氨基苯甲酸甲酯、2克1-(2-氯乙基)-4-(2-甲氧基苯基)-哌嗪、0.88克乙酸钠和5毫升水的混合物回流加热搅拌24小时。冷却到室温后,用乙酸乙酯萃取混合物。有机相经无水硫酸钠干燥,蒸发至干。残留物经快速色谱(二氯甲烷∶甲醇98∶2)纯化,得到0.41克(18%)标题化合物。
1H-NMR(CDCl3,δ):7.90(dd,1H,苯胺H3),7.90-7.70(br,1H,NH),7.35(td,1H,苯胺H5),7.06-6.80(m,4H,甲氧基苯环CHs),6.70(dd,1H,苯胺H6),6.58(td,1H,苯胺H4),3.87和3.85(2s,6H,COOCH3和OCH3),3.43-3.30(m,2H,NHCH2CH2),3.22-3.05(m,4H,哌嗪质子),2.83-2.67(m,6H,NHCH2CH2和哌嗪质子)。
实施例18
1-[N-(2-甲氧基羰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例17制备的1-[N-(2-甲氧基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪,让混合物回流加热9小时外,按实施例4所述的方法制备标题化合物。粗制品经快速色谱层析(二氯甲烷∶甲醇95∶5)纯化,得率:38%。
1H-NMR(CDCl3,δ):8.03(dd,1H,甲氧基羰基苯环H3),7.57(dt,1H,甲氧基羰基苯环H4),7.45(dt,1H,甲氧基羰基苯环H5),7.37(dd,1H,甲氧基羰基苯环H6),7.03-6.80(m,4H,甲氧基苯环CHs),4.38-4.15(m,1H,C(O)NC(H)HCH2),3.86和3.83(2s,6H,COOCH3和OCH3),3.33-3.15(m,1H,C(O)NC(H)HCH2),3.10-2.93(m,4H,哌嗪质子),2.75-2.50(m,4H,哌嗪质子),2.56(t,2H,C(O)NCH2CH2),2.00-1.83(m,1H,CHC(O)),1.80-0.80(m,10H,环己基质子)。
实施例19
1-[N-(2-二甲基氨基甲酰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用N,N-二甲基-2-氨基苯甲酰胺代替2-三氟甲氧基苯胺外,其它按实施例3所述的方法制备标题化合物。粗制品经快速色谱纯化(乙酸乙酯∶甲醇97∶3)。得率19%。
1H-NMR(CDCl3,δ):7.25(dt,1H,苯胺H5),7.09(dd,1H,苯胺H3),7.06-6.80(m,4H,甲氧基苯环CHs),6.68(dd,1H,苯胺H6),6.66(dt,1H,苯胺H4),5.50-5.10(br,1H,NH),3.86(s,3H,OCH3),3.23(t,2H,NHCH2CH2),3.18-3.08(m,4H,哌嗪质子),3.05(s,6H,N(CH3)2),2.78-2.62(m,6H,NHCH2CH2和哌嗪质子)。
实施例20
1-[N-(2-甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-甲氧基苯胺代替2-三氟甲氧基苯胺,在100℃下加热4小时外,其它按实施例3所述的方法制备和纯化标题化合物,得率50%。
1H-NMR(CDCl3,δ):7.05-6.85(m,5H,甲氧基苯环CHs和苯胺CH),6.85-6.60(m,3H,苯胺CHs),3.87和3.85(2s,6H,OCH3),3.25(t,2H,NHCH2CH2),3.18-3.05(m,4H,哌嗪质子),2.80-2.65(m,6H,NHCH2CH2和哌嗪质子)。
实施例21
1-[N-(2-二甲基氨基甲酰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例19制备的1-[N-(2-二甲基氨基甲酰基-苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)哌嗪,使混合物回流加热5小时外,其它按实施例4所述的方法制备标题化合物,粗制品经快速色谱层析(二氯甲烷∶甲醇93∶7)纯化,得率36%。
1H-NMR(CDCl3,δ):7.50-7.30(m,4H,苯甲酰胺环CHs),7.06-6.80(m,4H,甲氧基苯环CHs),4.85(s,3H,OCH3),4.60-4.40(m,1H,CONCH(H)CH2N),3.67-3.40(m,1H,CONCH(H)CH2N),3.35-2.95(m,4H,哌嗪质子),3.10和2.90(2s,6H,N(CH3)2),2.85-2.45(m,6H,哌嗪质子和CONCH2CH2N),2.10-1.90(m,1H,CHC(O)),1.90-0.80(m,10H,环己基质子)。
实施例22
1-[N-(2-三氟甲基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-三氟甲基苯胺代替2-三氟甲氧基苯胺外,其它按实施例3所述的方法制备标题化合物,粗制品经快速色谱纯化(乙酸乙酯∶石油醚2∶8),得率14%。
1H-NMR(CDCl3,δ):7.50-7.30(m,4H,苯胺CHs),7.10-6.80(m,4H,甲氧基苯环CHs),5.50-5.38(br,1H,NH),3.86(s,3H,OCH3),3.30-3.18(m,2H,NHCH2CH2),3.18-3.05(m,4H,哌嗪质子),2.75(t,2H,NHCH2CH2),2.80-2.63(m,4H,哌嗪质子)。
实施例23
1-[N-(2-甲氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例20制备的1-[N-(2-甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-硝基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)哌嗪,使混合物回流加热6小时外,其它按实施例2所述的方法制备标题化合物,粗制品经快速色谱层析(二氯甲烷∶甲醇9.5∶0.5)纯化。得率59%。
1H-NMR(CDCl3,δ):7.38(dd,1H,甲氧基苯基苯胺H6),7.26(dd,1H,甲氧基苯基胺H4),7.10-6.85(m,6H,甲氧基苯基苯胺H3,H5和甲氧基苯基质子),4.35-4.12(m,1H,CONCH(H)CH2),3.89(s,3H,OCH3),3.86(s,3H,OCH3),3.55-3.33(m,1H,CONCH(H)CH2),3.20-2.98(m,4H,哌嗪质子),2.80-2.50(m,6H,哌嗪质子和CONCH2CH2),2.05(tt,1H,CHC(O)),1.30-0.85(m,10H,环己基质子)。
实施例24
1-[N-(2-乙基氨基甲酰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-乙基氨基甲酰基苯胺代替2-三氟甲氧基苯胺和混合物回流5小时外,其它按实施例3所述的方法制备标题化合物,粗制品经快速色谱纯化(二氯甲烷∶甲醇9.7∶0.3),得率12%。
1H-NMR(CDCl3,δ):7.50(t,1H,CONHEt),7.38-7.23(m,2H,苯胺H4,H6),7.07-6.83(m,4H,甲氧基苯环CHs),6.70(dd,1H,苯胺H3〕,6.60(dd,1H,苯胺H5),6.13-5.90(br,1H,NHCH2CH2),386(s,3H,OCH3),3.53-3.40(m,2H,CONHCH2CH3),3.33(q,2H,NHCH2CH2),3.18-3.02(m,4H,哌嗪质子),2.83-2.63(m,6H,哌嗪质子和NHCH2CH2),1.23(t,3H,CONHCH2CH3)。
实施例25
1-[N-(2-乙基氨基甲酰基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例24制备的1-[N-(2-乙基氨基甲酰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,并使混合物回流12小时,用甲苯代替1,2-二氯乙烷作为溶剂外,其它按实施例2所述的方法制备标题化合物,粗制品经快速色谱纯化(二氯甲烷∶甲醇9.5∶0.5)。得率43%。
1H-NMR(CDCl3,δ):9.30-9.12(br,1H,CONHEt),7.80(dd,1H,苯胺H6),7.45(dd,1H,苯胺H4),7.35(dd,1H,苯胺H5),7.20(dd,1H,苯胺H3),7.05-6.75(m,4H,甲氧基苯环CHs),4.47(dt,1H,CONCH(H)CH2N),3.82(s,3H,OCH3),3.73-3.50(m,1H,CONHCH(H)CH3),3.23-3.10(m,1H,CONHCH(H)CH3),3.03-2.25(m,5H,CONCH(H)CH2N和哌嗪质子),2.65-2.16(m,7H,CONCH2CH2,哌嗪质子和CHC(O)),1.70-0.80(m,10H,环己基质子),1.18(t,3H,CONHCH2CH3)。
实施例26
1-[N-(2-三氟甲基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
在氮气、室温下搅拌2-三氟甲基苯胺(3毫升)、三乙胺(3.5毫升)和二氯甲烷(30毫升)的溶液。滴加3.34毫升环己基甲酰氯。在室温下搅拌2.5小时后,混合物倒入水中,用1N氢氧化钠碱化。有机相经无水硫酸钠干燥,粗制品用乙醇结晶,得到3.82克(59%)1-环己基氨基甲酰基-2-三氟甲基苯。熔点153-154℃。
1H-NMR(CDCl3,δ):8.20(dd,1H,三氟甲基苯环CH),7.60-7.40(m,3H,三氟甲基苯环CHs和NH),7.12(ddd,1H,三氟甲基苯环CH),2.30(tt,1H,CHC(O)),2.10-1.20(m,10H,环己基质子)。
0.2克上述制备的1-环己基氨基甲酰基-2-三氟甲基苯、0.37克1-(2-氯乙基)-4-(2-甲氧基苯基)-哌嗪、0.5毫升50%(w/w)氢氧化钠、0.16克TEBAC和2毫升甲苯的混合物在80℃下搅拌3.5小时。然后再加入0.2克1-环己基氨基甲酰基-2-三氟甲基苯,在80℃下搅拌6小时后倒入水中,用二氯甲烷萃取。有机相经无水硫酸钠干燥,蒸干。残留物经快速色谱(乙酸乙酯∶石油醚3∶7)纯化得到0.12克(17%)标题化合物。
1H-NMR(CDCl3,δ):7.77(dd,1H,三氟甲基苯环CH),7.70-7.45(m,3H,三氟甲基苯环CHs),7.10-6.80(m,4H,甲氧基苯环CHs),4.70-4.50(m,1H,CONCH(H)CH2N),3.85(s,3H,OCH3),3.20-2.90(m,5H,CONCH(H)CH2N和哌嗪质子),2.85-2.45(m,7H,CHC(O),CONCH2CH2N和哌嗪质子),1.90-0.75(m,10H,环己基质子)。
实施例27
1-[N-(2-氨基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
使1.05克实施例2制备的1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪、2毫升水合肼和1克雷氏(Raney)镍在70毫升甲醇里的混合物在50℃下搅拌1.5小时。过滤除去不溶物,蒸干溶液。残留物经乙醇结晶,得到0.69克(71%)标题化合物。熔点:138.5-140℃。
1H-NMR(CDCl3,δ):7.15(dd,1H,氨基苯环CH),7.10-6.80(m,5H,氨基苯环CH和甲氧基苯环CHs),6.80-6.65(m,2H,氨基苯环CHs),4.96(s,2H,NH2),4.96-4.65(m,1H,CONCH(H)CH2N),3.86(s,3H,OCH3),3.20-2.80(m,7H,CONCH(H)CH2N和哌嗪质子),2.45-2.65(m,4H,哌嗪质子),2.10(tt,1H,CH(O)),1.90-0.80(m,10H,环己基质子)。
实施例28
1-[N-(2-乙酰氨基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)哌嗪
将0.04毫升乙酰氯在0.5毫升二氯甲烷中的溶液在室温下加到搅拌着的0.22克实施例27制备的1-[N-(2-氨基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪和0.08毫升三乙胺在5毫升二氯甲烷里的溶液。在相同的温度下搅拌2小时后,蒸发溶剂,残留物经快速色谱(二氯甲烷∶乙腈98∶2)纯化,得到0.12克(50%)标题化合物。
1H-NMR(CDCl3,δ):9.90(s,1H,NH),7.85(dd,1H,乙酰氨基苯环CH),7.40(td,1H,乙酰氨基苯环CH),7.23-7.10(m,2H,乙酰氨基苯环CHs(,7.05-6.80(m,4H,甲氧基苯环CHs),5.00-4.80(m,1H,CONCH(H)CH2N),3.83(s,3H,OCH3),3.20-2.25(m,11H,CONCH(H)CH2N和哌嗪质子),2.15(s,3H,COCH3),2.05-1.85(m,1H,CHC(O)),1.75-0.80(m,10H,环己基质子)。
实施例29
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪N1-氧化物
在5℃下将0.89克83%单过氧邻苯二甲酸镁·0.6H2O在10毫升水里的悬浮液滴加入1.4克实施例2制备的1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪在10毫升氯仿和45毫升甲醇中的溶液里。在室温下放置过夜后,蒸去溶剂。残留物溶于50毫升水,用20%碳酸钠碱化,用氯仿萃取。有机相经无水硫酸钠干燥,蒸干。残留物经快速色谱(氯仿∶2N甲醇制的氨,梯度100∶7到100∶20)纯化,得到0.5克粗制品。用丙酮结晶得到0.35克(24%)标题化合物。熔点:128-132℃。
1H-NMR(CDCl3,δ):8.05(dd,1H,硝基苯环H3),7.70(ddd,1H,硝基苯环H5),7.50(ddd,1H,硝基苯环H4),7.41(dd,1H,硝基苯环H6),7.07-6.76(m,4H,甲氧基苯环CHs),4.40-4.12(m,2H,CONCH2CH2N),3.85(s,3H,OCH3),3.70-3.35(m,6H,CONCH2CH2N和哌嗪质子),3.35-3.07(m,4H,哌嗪质子),2.05-1.80(m,1H,CHC(O)),1.75-0.75(m,10H,环己基质子)。
实施例30
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪N4-氧化物
在实施例29所述的化合物纯化期间分离得到0.23克(16%)标题化合物玻璃状固体。
1H-NMR(CDCl3,δ):8.75(dd,1H,甲氧基苯环H6),8.05(dd,1H,硝基苯环H3),7.71(ddd,1H,硝基苯环H5),7.57(ddd,1H,硝基苯环H4),7.47(dd,1H,硝基苯环H6),7.37(ddd,1H,甲氧基苯环H4(H5)),7.10(ddd,1H,甲氧基苯环H5(H4)),6.98(dd,1H,甲氧基苯环H3),4.72-4.41(m,2H,哌嗪质子),4.03(s,3H,OCH3),3.83(t,2H,CONCH2CH2N),3.35-3.09(m,2H,哌嗪质子),2.98-2.77(m,2H,CONCH2CH2N),2.77-2.30(m,4H,哌嗪质子),2.05-0.83(m,11H,环己基质子)。
实施例31
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪N1,N4-二氧化物
按实施例29所述合成标题化合物,但使用等摩尔单过氧邻苯二甲酸镁和1-[N-(2-硝基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪。用乙腈结晶后的得率43%。熔点:153-157℃。
1H-NMR(CDCl3,δ):8.70(dd,1H,甲氧基苯环H6),8.05(dd,1H,硝基苯环H3),7.70(ddd,1H,硝基苯环H5),7.58(ddd,1H,硝基苯环H4),7.49-7.32(m,2H,硝基苯环H6和甲氧基苯环H4),7.13(ddd,1H,甲氧基苯环H5),7.00(dd,1H,甲氧基苯环H3),5.92-5.67(m,2H,哌嗪质子),4.70-4.45(m,2H,哌嗪质子),4.45-4.05(m,2H,CONCH2CH2N),4.00(s,2H,CONCH2CH2N),3.30-3.08(m,2H,哌嗪质子),3.05-2.85(m,2H,哌嗪质子),2.05-1.78(m,1H,CHC(O)),1.78-0.70(m,10H,环己基质子)。
实施例32
1-[N-(2-硝基苯基)-N-(3-呋喃基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
将0.77克实施例1制备的1-[N-(2-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪一盐酸盐在50毫升甲苯里的悬浮液在回流下搅拌,以除去约20毫升馏出物。冷却到60-70℃后,加入0.9毫升97%二异丙基乙胺(DIPEA),使混合物搅拌15分钟。然后加入0.66克3-呋喃基甲酰氯。使混合物回流下搅拌5小时,冷却到室温,依次用水、1N氢氧化钠和水洗涤,经无水硫酸钠干燥,并蒸干。残留物经快速色谱(乙酸乙酯∶石油醚,梯度1∶1到7∶3)纯化,得到0.67克(75%)标题化合物。
1H-NMR(CDCl3,δ):8.05(dd,1H,硝基苯环H3),7.73-7.58(m,2H,硝基苯环H5和H6),7.58-7.45(m,1H,硝基苯环H4),7.15(bs,1H,呋喃环H2),7.02-6.77(m,5H,呋喃环H5和甲氧基苯环CHs),6.13(bs,1H,呋喃环H4),4.30-4.08(m,1H,CONCH(H)CH2N),3.90-3.70(m,1H,CONCH(H)CH2N),3.83(s,3H,OCH3),3.05-2.80(m,4H,哌嗪质子),2.80-2.62(m,2H,CONCH2CH2N),2.62-2.45(m,4H,哌嗪质子)。
实施例33
1-[N-(2-硝基苯基)-N-(2-呋喃基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述制备标题化合物,但用2-呋喃基甲酰氯代替3-呋喃基甲酰氯。得率77%。
1H-NMR(CDCl3,δ):8.05(dd,1H,硝基苯环H3),7.72-7.45(m,3H,其它硝基苯环CHs),7.20(bs,1H,呋喃环H3),7.05-6.75(m,4H,甲氧基苯环CHs),6.49(bs,1H,呋喃环H4),6.25(bs,1H,呋喃环H5),4.30-4.10(m,1H,CONCH(H)CH2N),3.98-3.75(m,1H,CONCH(H)CH2N),3.83(s,3H,OCH3),3.15-2.85(m,4H,哌嗪质子),2.85-2.65(m,2H,CONCH2CH2N),2.65-2.48(m,4H,哌嗪质子)。
实施例34
1-[N-(2-硝基苯基)-N-(2-噻吩基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述合成标题化合物,但使用2-噻吩基甲酰氯代替3-呋喃基甲酰氯,并回流8小时。得率59%。
1H-NMR(CDCl3,δ):8.03(dd,1H,硝基苯环H3),7.71-7.60(m,2H,硝基苯环H5和H6),7.60-7.45(m,1H,硝基苯环H4),7.27(dd,1H,噻吩环H3(H5)),7.05-6.70(m,6H,噻吩H4及H5(H3)和甲氧基苯环CHs),4.22-4.10(m,1H,CONCH(H)CH2N),3.92-3.71(m,1H,CONCH(H)CH2N),3.80(s,3H,OCH3),3.10-2.80(m,4H,哌嗪质子),2.80-2.65(m,2H,CONCH2CH2N),2.65-2.45(m,4H,哌嗪质子)。
实施例35
1-[N-(2-硝基苯基)-N-(3-噻吩基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述合成标题化合物,但使用3-噻吩基甲酰氯代替3-呋喃基甲酰氯,并回流7小时。得率88%。
1H-NMR(CDCl3,δ):7.93(dd,1H,硝基苯环H3),7.70-7.55(m,2H,硝基苯环H5和H6),7.48-7.35(m,1H,硝基苯环H4),7.25-7.12(dd,1H,噻吩环H2),7.12-7.02(m,1H,噻吩环H5),7.02-6.91(m,1H,噻吩环H4),6.91-6.78(m,4H,甲氧基苯环CHs),4.32-4.10(m,1H,CONCH(H)CH2N),3.90-3.70(m,1H,CONCH(H)CH2N),3.81(s,3H,OCH3),3.05-2.78(m,4H,哌嗪质子),2.78-2.65(m,2H,CONCH2CH2N),2.65-2.45(m,4H,哌嗪质子)。
实施例36
1-[N-(2-硝基苯基)-N-(4-吡啶基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述合成标题化合物,但使用4-吡啶基甲酰氯代替3-呋喃基甲酰氯,并回流14小时。粗制品经快速色谱(氯仿∶2.5N甲醇制氨,梯度100∶1.5到100∶3)纯化。得率39%。
1H-NMR(CDCl3,δ):8.42(dd,2H,吡啶环H2和H6),7.90(dd,1H,硝基苯环H3),7.62-7.45(m,2H,硝基苯环H5和H6),7.45-7.30(m,1H,硝基苯环H4),7.15(dd,2H,吡啶环H3和H5),7.08-6.75(m,4H,甲氧基苯环CHs),4.50-4.20(m,1H,CONCH(H)CH2N),3.90-3.65(m,1H,CONCH(H)CH2N),3.80(s,3H,OCH3),3.15-2.28(m,10H,CONCH2CH2N和哌嗪质子)。
实施例37
1-[N-(2-硝基苯基)-N-(3-吡啶基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述合成标题化合物,但使用3-吡啶基甲酰氯代替3-呋喃基甲酰氯,并回流12小时。粗制品经快速色谱(氯仿∶2.5N甲醇制氨100∶3)纯化。得率46%。
1H-NMR(CDCl3,δ):8.50-8.35(m,2H,吡啶环H2和H6),7.90(dd,1H,硝基苯环H3),7.72(dd,1H,吡啶环H4),7.60-7.50(m,2H,硝基苯环H5和H6),7.43-7.28(m,1H,硝基苯环H4),7.30-7.15(m,1H,吡啶环H5),7.03-6.76(m,4H,甲氧基苯环CHs),4.35-4.15(m,1H,CONCH(H)CH2N),4.00-3.75(m,1H,CONCH(H)CH2N),3.80(s,3H,OCH3),3.10-2.40(m,10H,CONCH2CH2N和哌嗪质子)。
实施例38
1-[N-(2-硝基苯基)-N-(2-吡嗪基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例32所述合成标题化合物,但使用2-吡嗪基甲酰氯代替3-呋喃基甲酰氯,并回流1小时。粗制品经快速色谱(氯仿∶2.5N甲醇制氨,梯度100∶1到100∶3)纯化。得率89%。
1H-NMR(CDCl3,δ):9.08(d,1H,吡嗪环H3),8.40(d,1H,吡嗪环H6),8.07(d,1H,吡嗪环H5),7.97(dd,1H,硝基苯环H3),7.62-7.50(m,2H,硝基苯环H5和H6),7.48-7.31(m,1H,硝基苯环H4),7.05-6.80(m,4H,甲氧基苯环CHs),4.31-4.15(m,1H,CONCH(H)CH2N),4.08-3.92(m,1H,CONCH(H)CH2N),3.82(s,3H,OCH3),3.05-2.40(m,10H,CONCH2CH2N和哌嗪质子)。
实施例39
1-[N-(2-硝基苯基)-N-(1-甲基环己基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
按实施例26第一步操作,但用1-甲基环己基甲碳酰氯[J.Org.Chem.47,3242(1982)]代替环己基甲酰氯,并回流50小时,得到粗制的1-甲基-N-(2-硝基苯基)-环己基羧酰胺。经快速色谱(石油醚∶乙酸乙酯100∶2)纯化。得率90%。
1H-NMR(CDCl3,δ):10.75(s,1H,NH),8.85(dd,1H,硝基苯环H6),8.22(dd,1H,硝基苯环H3),7.62(ddd,1H,硝基苯环H5),7.15(ddd,1H,硝基苯环H4),2.20-1.95(m,2H,环己基质子),1.75-1.35(m,8H,环己基质子),1.25(s,3H,CH3)。
使0.3克上述制备的1-甲基-N-(2-硝基苯基)-环己基羧酰胺,50毫升甲苯和0.26克叔丁醇钾混合物回流搅拌,除去约11毫升馏出物。然后将0.32克1-(2-氯乙基)-4-(2-甲氧基苯基)-哌嗪在10毫升甲苯里的溶液加到混合物中。回流下搅拌16小时后,冷却混合物,用水洗涤。有机层经无水硫酸钠干燥并蒸干。粗制品经快速色谱(石油醚∶乙酸乙酯7∶3)纯化,得到0.51克(43%)标题化合物。
1H-NMR(CDCl3,δ):7.98(dd,1H,硝基苯环H3),7.40(ddd,1H,硝基苯环H5),7.08-6.80(m,6H,硝基苯环H4及H6和甲氧基苯环CHs),4.31-4.10(m,2H,CONCH2CH2),3.85(s,3H,OCH3),3.20-2.98(m,4H,哌嗪质子),2.88-2.62(m,6H,CONCH2CH2和哌嗪质子),1.90-1.70(m,2H,环己基质子),1.53-1.22(m,8H,环己基质子),1.18(s,3H,CH3)。
实施例40
1-[N-(2-硝基苯基)-N-(1-苯基环己基羰基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用1-苯基环己基甲酰氯[J.Am.Chem.Soc.68,2345-7(1946)]代替1-甲基环己基甲酰氯,甲苯代替二氯甲烷,DIPEA代替三乙胺并使反应混合物回流15小时外,其它按实施例39的第一步的方法制备1-苯基-N-(2-硝基苯基)-环己基羧酰胺。粗制品经快速色谱(石油醚∶乙酸乙酯98∶2)纯化。得率91%。
1H-NMR(CDCl3,δ):10.32(s,1H,NH),8.76(dd,1H,硝基苯环H6),8.12(dd,1H,硝基苯环H3),7.64-7.32(m,5H,苯环CHs),7.28(ddd,1H,硝基苯环H5),7.08(ddd,1H,硝基苯环H4),2.54-2.34(m,2H,环己基质子),2.22-2.02(m,2H,环己基质子),1.76-1.28(m,6H,环己基质子)。
除了用1-苯基-N-(2-硝基苯基)-环己基羧酰胺代替1-甲基-N-(2-硝基苯基)-环己基羧酰胺并回流22小时外,其它按实施例39第二步所述的方法制备标题化合物。粗制品经快速色谱(石油醚∶乙酸乙酯,梯度8∶2到7∶3)纯化。得率:37%。
1H-NMR(CDCl3,δ):7.90(dd,1H,硝基苯环H3),7.45-7.10(m,7H,苯环CHs和硝基苯环H5和H6),7.04-6.78(m,5H,硝基苯环H4和甲氧基苯环CHs),4.30-4.12(m,2H,CONCH2CH2),3.82(s,3H,OCH3),3.18-2.93(m,4H,哌嗪质子),2.80-2.50(m,6H,CONCH2CH2和哌嗪质子),2.30-2.10(m,2H,环己基质子),1.92-1.75(m,2H,环己基质子),1.74-1.35(m,6H,环己基质子)。
实施例41
1-[N-[2-(2,2,2-三氟乙氧基)-苯基]-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
除了用2-(2,2,2-三氟乙氧基)苯胺(EP 748800)代替2-三氟甲氧基苯胺,反应混合物回流7小时外,其它按实施例3所述的方法制备标题化合物,粗制品经快速色谱纯化(石油醚∶乙酸乙酯,梯度9∶1到8∶2)。得率38%。
1H-NMR(CDCl3,δ):7.08-6.80(m,5H,甲氧基苯环CHs和三氟乙氧基苯环CH),6.80-6.57(m,3H,三氟乙氧基苯环 CHs),5.11-4.70(m,1H,NH),4.35(q,2H,OCH2CF3),3.85(s,3H,OCH3),3.38-3.19(m,2H,NHCH2CH2),3.19-2.98(m,4H,哌嗪质子),2.88-2.60(m,6H,NHCH2CH2和哌嗪质子)。
实施例42
1-[N-[2-(2,2,2-三氟乙氧基)-苯基]-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪
使0.41克实施例41制备的1-[N-[2-(2,2,2-三氟乙氧基)-苯基]-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪、5.4毫升97%DIPEA和3.9毫升环己基甲酰氯在30毫升甲苯里的混合物在回流下搅拌10小时。冷却到室温后,混合物依次用水、1N氢氧化钠和水洗涤。有机层用无水硫酸钠干燥,并蒸干。粗制品经快速色谱(石油醚∶乙酸乙酯1∶1)纯化,然后用乙醚结晶,得到0.2克(37%)标题化合物。熔点:109.6-112℃。
1H-NMR(CDCl3,δ):7.42-7.22(m,2H,三氟乙氧基苯环CHs),7.15-6.77(m,6H,三氟乙氧基苯环CHs和甲氧基苯环CHs),4.38(q,2H,OCH2CF3),4.22-4.02(m,1H,CONCH(H)CH2N),3.82(s,3H,OCH3),3.58-3.39(m,1H,CONCH(H)CH2N),3.15-2.90(m,4H,哌嗪质子),2.80-2.45(m,6H,CONCH2CH2N和哌嗪质子),2.05-1.88(m,1H,CHC(O)),1.75-0.80(m,10H,环己基质子)。
实施例43
1-[N-(2-氰基苯基)-N-环己基羰基-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪盐酸盐
除了用2-氰基苯胺代替2-三氟甲基苯胺外,其它按实施例26第一步揭示的方法制备N-(2-氰基苯基)-环己基羧酰胺。得率75%。熔点135-137℃。
1H-NMR(CDCl3,δ):8.40(dd,1H,氰基苯环H3),7.70-7.50(m,3H,氰基苯环H5及H6和NH),7.12(ddd,1H,氰基苯环H4),2.30(tt,1H,CHC(O)),2.05-1.10(m,10H,环己基质子)。
除了用上述制备的N-(2-氰基苯基)-环己基羧酰胺代替1-甲基-N-(2-硝基苯基)-环己基羧酰胺,并回流持续1小时外,其它按实施例39第二步所述的方法制备标题化合物。粗制品经快速色谱纯化(二氯甲烷∶甲醇98∶2)。残留物溶于丙酮,加入醚制氯化氢。蒸干溶液,用丙酮∶乙醚结晶得到标题化合物。得率7%。
1H-NMR(DMSO-d6,δ):11.28-11.07(br,1H,NH+),8.05(dd,1H,氰基苯环H6),7.92-7.80(m,2H,氰基苯环CHs),7.72-7.60(m,1H,氰基苯环CH),7.05-6.82(m,4H,甲氧基苯环CHs),4.45-4.30(m,1H,CONCH(H)CH2N),3.92-3.75(m,1H,CONCH(H)CH2N),3.80(s,3H,OCH3),3.70-3.40(m,4H,哌嗪质子),3.40-3.00(m,6H,CONCH2CH2N和哌嗪质子),1,98-1.80(m,1H,CHC(O)),1.80-0.75(m,10H,环己基质子)。
实施例44
1-[N-(2-硝基苯基)-1-氨基-2-丙基]-4-(2-甲氧基苯基)-哌嗪
在氮气下,使1克1-(2-甲氧基苯基)-哌嗪、0.57克2-氯丙酰胺、1毫升DIPEA和5毫升甲苯的混合物回流搅拌3小时。冷却到室温后,混合物倒入水中,用乙酸乙酯萃取。有机层用无水硫酸钠干燥,蒸去溶剂。残留物经快速色谱纯化(二氯甲烷∶2N甲醇制氨95∶5),得到0.88克(63%)2-[4-(2-甲氧基苯基)-1-哌嗪基]-丙酰胺。
1H-NMR(CDCl3,δ):7.25-7.10(br,1H,CONH(H)),7.10-6.80(m,4H,甲氧基苯环CHs),5.75-5.60(br,1H,CONH(H)),3.85(s,3H,OCH3),3.20-3.00(m,5H,哌嗪质子,NCH(CH3)CO),2.85-2.60(m,4H,哌嗪质子),1.30(d,3H,NCH(CH3)CO)。
在氮气和-4℃下将2毫升2M乙硼烷二甲基硫化物在四氢呋喃里的溶液滴加至搅拌着的0.28克上述制备的2-[4-(2-甲氧基苯基)-1-哌嗪基]-丙酰胺在7毫升四氢呋喃里的溶液。使混合物回流6.5小时,然后加入3毫升甲醇。蒸发溶剂,残留物溶于水。用乙酸乙酯萃取,得到的有机相用无水硫酸钠干燥,蒸干。残留物经快速色谱化(二氯甲烷∶2N甲醇制的氨95∶5),得到0.07克(24%)2-[4-(2-甲氧基苯基)-1-哌嗪基]-丙胺。
1H-NMR(CDCl3,δ):7.10-6.80(m,4H,甲氧基苯环CHs),3.85(s,3H,OCH3),3.20-2.90(m,4H,哌嗪质子),2.85-2.50(m,7H,哌嗪质子和NCH(CH3)CH2),2.05-1.85(br,2H,NH2),0.95(d,3H,CH3)。
0.08克使上述制备的2-[4-(2-甲氧基苯基)-1-哌嗪基]-丙胺、0.03毫升2-硝基氟苯、0.3毫升DIPEA和5毫升DMF的混合物在氮气、140℃下搅拌3小时。冷却的混合物用水稀释,用乙醚萃取。有机相用无水硫酸钠干燥,蒸干。残留物经快速色谱(石油醚∶乙酸乙酯8∶2)纯化,得到O.07克(62%)标题化合物。
1H-NMR(CDCl3,δ):8.90-8.70(br,1H,NH),8.15(dd,1H,硝基苯环H3),7.40(ddd,1H,硝基苯环H5),7.15-6.70(m,5H,硝基苯环H6和甲氧基苯环CHs),6.63(ddd,1H,硝基苯环H4),3.85(s,3H,OCH3),3.70-2.60(m,11H,哌嗪质子和NHCH2CH(CH3)),1.10(d,3H,CH3)。
实施例45
1-[N-(2-硝基苯基)-N-环己基羰基-1-氨基-2-丙基]-4-(2-甲氧基苯基)-哌嗪
除了用实施例44制备的1-[N-(2-硝基苯基)-1-氨基-2-丙基]-4-(2-甲氧基苯基)-哌嗪代替1-[N-(2-三氟甲氧基苯基)-2-氨基乙基]-4-(2-甲氧基苯基)-哌嗪,甲苯代替1,2-二氯乙烷,并使混合物加热回流13小时外,其它按实施例4所述的方法制备标题化合物。混合物经快速色谱纯化(石油醚∶乙酸乙酯1∶1)。得率:61%。
1H-NMR(CDCl3,δ):8.05(dd,1H,硝基苯环H3),7.85-7.45(m,3H,硝基苯环H4,H5和H6),7.10-6.75(m,4H,甲氧基苯环CHs),3.85(s,3H,OCH3),3.90-3.75(m,1H,CONCH(H)CH(CH3)),3.65-2.30(m,10H,哌嗪质子和CONHCH(H)CH(CH3)),2.10-1.80(m,1H,CHC(O)),1.80-0.80(m,13H,环己基质子和CH3)。
实施例46
对麻醉大鼠由容积引发的节律性膀胱排空收缩的作用
A.方法:
使用体重在225-275克之间的雌性Sprague Dawley大鼠(Crl:CDo BR,意大利Charles River)。除了实验期间外,动物养在能自由地接近食物和水的地方,并保持在22-24℃、12小时昼夜交替的周期达至少一星期。根据Dray的方法(J.Pharmacol.Mehtods,13:157,1985),和Guarneri(Pharmacol.Res.,27:173,1993)的某些改进,来评估节律性膀胱排空收缩的活性。简言之,皮下注射1.25g/kg(5ml/kg)乌拉坦使大鼠麻醉,然后用充满生理盐水的PE50聚乙烯管通过尿道插入膀胱。插管在外尿道孔处用结扎线固定,并与常规的压力传感器(Statham P23 ID/P23 XL)连接。膀胱内的压力连续地显示在图示记录器上(Battagl ia Rangoni KV 135,带有DC1/TI放大器)。然后通过记录用的插管向膀胱注入体积逐渐增加(通常为0.8-1.5毫升)的温(37℃)盐水,直到发生反射性膀胱排空收缩。为了静脉注射(i.v.)生物活性化合物,充满了生理盐水的PE50聚乙烯管被插入颈静脉。
膀胱内压测量图记录了处理前(基础值)和处理后15分钟里的收缩次数,并评估了这些收缩的平均幅度(峰的平均高度mmHg)。
由于大多数化合物能相当快地开始作用并导致膀胱收缩完全停止,通过测量膀胱静息的持续时间(即,不发生收缩的持续时间)可常规地评价生物活性。也记录了收缩数的减少>基础期间观察值的30%的被试验动物数。
为了比较试验化合物抑制膀胱排空收缩的强度,通过最小二乘方线性回归分析计算了10分钟里使收缩消失所需的等效剂量(ED10分钟)。也使用Bliss方法(BlissC.I.,Quart J.Pharm.Pharmacol.11,192-216,1938)照这样计算了引起处理50%大鼠收缩次数减少大于30%时的外推剂量(ED50,频率)。注射的药物的抑制作用消失后,将收缩峰的高度与在此以前静脉给予对照的赋形剂后记录的峰高相比较。通过Bliss方法(Bliss C.I.,Quart.J.Pharm.Pharmacol.11,192-216,1938)在量子基础上评价试验化合物的强度(ED50:使50%被处理大鼠收缩幅度减少30%的外推剂量)。
B.结果
乌拉但麻醉的大鼠的膀胱快速膨胀引起膀胱一系列节律性的排空收缩,其特征是本技术领域公知的(Maggi等,Brain Res.,380:83,1986;Maggi等,J.Pharmacol.Exp.Ther.,230:500,1984)。这些收缩频率与排尿反射的感觉传入臂和排尿中枢的完整性有关,而它们的幅度是反射的传出臂的性质。在此模型系统里,主要作用于CNS的化合物(如吗啡)阻滞了排空收缩,而作用于逼肌水平的药物,如奥昔布宁,可降低膀胱收缩的幅度。
给予现有技术化合物和本发明化合物后得到的结果如表1所示。
化合物A(现有技术化合物)抑制排空收缩的作用比黄酮哌酯和奥昔布宁更强。该化合物与奥昔布宁相反,不影响收缩幅度,这表明不会削弱膀胱的收缩。
但是,令人惊奇的是,在式I的苯胺环2-位处有取代基(如NO2)的化合物,如实施例2化合物,特别就其ED10分钟值来看,与未取代的化合物A相比,具有明显更高的强度。实施例2化合物象化合物A一样,不影响膀胱的收缩性。对照化合物B和C分别在苯环的3-位和4-位有硝基,它们没有药理活性。
对于R=H的化合物可得到相似的结果(即2-取代衍生物具有较高的强度)。这样,化合物AA、D和E(未取代的,3-取代和4-取代化合物,R=H)明显比实施例1、10和11和18(即2-NO2,2-CN,2-COCH3和2-COOCH3衍生物)差。本发明化合物,特别就其排尿频率指标ED50值来看,明显优于其它化合物。
表1
静注给药后对膀胱节律性排空收缩的作用
数据代表ED10分钟值(使收缩消失10分钟的外推剂量);ED50值(导致50%被处理大鼠收缩数减少>30%的外推剂量)(频率)和ED50值(导致50%被处理大鼠收缩幅度数减少>30%的外推剂量)(幅度)。
化合物 | ED10分钟μg/kg | ED50(频率)μg/kg | ED50(幅度)μg/kg |
化合物A | 650 | 33 | n.a. |
化合物B | >1000 | >1000 | n.a. |
化合物C | >1000 | >1000 | n.a. |
化合物D | >1000 | >1000 | n.a. |
化合物E | >1000 | >1000 | n.a. |
化合物AA | 663 | 244 | n.a. |
实施例1 | 192 | 55 | n.a. |
实施例2 | 60 | 9 | n.a. |
实施例10 | 122 | 28 | n.a. |
实施例11 | 318 | 40 | n.a. |
实施例13 | 266 | 29 | n.a. |
实施例18 | 101 | 17 | n.a. |
实施例20 | 97 | 25 | n.a. |
实施例23 | 93 | 18 | n.a. |
实施例27 | 131 | 13 | n.a. |
黄酮哌酯 | >10000 | 2648 | n.a. |
奥昔布宁 | 7770 | >10000 | 240 |
n.a.=没有活性;不明显降低峰高度。
化合物A
1-(N-苯基-N-环己基羰基-2-氨乙基)-4-(2-甲氧基苯基)-哌嗪
化合物AA
1-(N-苯基-2-氨乙基)-4-(2-甲氧基苯基)-哌嗪
化合物B
1-[N-(3-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
化合物C
1-[N-(4-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
化合物D
1-[N-(3-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
化合物E
1-[N-(4-硝基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪
实施例47
对清醒大鼠膀胱内压测量参数的影响
A.方法:
使用体重为250-350克的雄性Sprague Dawley大鼠(Crl:CDo BR)。除了实验期间外,动物养在能自由地接近食物和水的地方,并在22-24℃保持、12小时昼夜交替的周期达至少一星期。为了对清醒大鼠的尿动力学参数进行定量,用前述方法(Guarneri等,Pharmacol.Res.,24:175,1991)fjtf膀胱内压测量研究。雄性大鼠用戊巴比妥钠(30毫克/千克)和水合氯醛(125mg/kg)腹腔内注射麻醉,仰卧放置。在去毛和清洁的腹壁上作约10毫米长的中线切口。从粘附组织轻轻游离出膀胱,排空,然后通过圆顶处切口将聚乙烯套管(Portex PP30)插入,并用丝线永久缝合。插管通过肩胛后区经皮下通道外置,在此与塑料接管连接以避免从动物排出的危险。为了静脉注射试验化合物,将充满了生理盐水的PE50聚乙烯管插入颈静脉,并于肩胛后区外置。仅在入植后一天使用大鼠。在实验那天,大鼠放在Bollman氏笼中;稳定20分钟后,膀胱插管的游离端通过T形管与压力传感器(Bentley T 800/Marb P 82)和以0.1毫升/分的恒定速率连续输注盐水溶液进入膀胱里蠕动泵(Gilson minipuls 2)连接。输注时的腔内压力信号连续地记录在多种波动描记器上(Battaglia Rangoni KO 380,带有ADC1/T放大器)。
评价两个尿动力学参数:膀胱容量(BVC)和排尿压(MP)。BVC(单位毫升)被定义为逼肌发生收缩(然后排尿)后输注的最小容积。MP(单位mmHg)被定义为排尿期间逼肌收缩引起的最大的膀胱内压。按最初记录的两次膀胱内压测量图的平均值计算基础BVC和MP。在试验中,此时中断输注,给予试验化合物。静脉注射后15分钟对每个动物记录两次膀胱内压,计算两次膀胱内压参数的平均值。成对数据的用Student t-试验评价尿动力学参数差异的统计学意义。
B.结果:
表2显示了试验化合物不同剂量的作用。化合物A增加BVC的作用与黄酮哌酯相似。两个化合物都不损伤膀胱的收缩性,因为没有观察到MP的改变。相反的是,奥昔布宁明显地和剂量依赖地降低MP,对BVC没有作用。实施例2化合物比化合物A和黄酮哌酯的效力更大;静脉注射0.3mg/kg实施例2化合物后观察到BVC明显增加,而这需要给予1.0mg/kg黄酮哌酯或化合物A。实施例2化合物诱导了轻微的(然而明显的)MP下降。但该效果不是剂量依赖性的,且比奥昔布宁诱导的作用明显较低。
表2
在清醒大鼠对膀胱内压的作用
数据代表在静脉注射本发明化合物之前和之后15分钟膀胱容量(BVC;毫升)和排尿压(MP;mmHg)的值±S.E.
化合物 | 剂量微克/kg | BVC处理前 处理后 | 改变% | |
化合物A | 3001000 | 0.81±0.050.78±0.11 | 0.87±0.050.97±0.11** | +7.4+24.4 |
实施例2 | 3001000 | 0.71±0.090.62±0.09 | 0.87±0.10*0.75±0.10** | +22.5+21.0 |
实施例8 | 3001000 | 0.59±0.040.65±0.10 | 0.71±0.05*0.88±0.12** | +21.0+35.0 |
黄酮哌酯 | 3001000 | 0.76±0.110.88±0.15 | 0.87±0.111.11±0.16** | +14.5+26.1 |
奥昔布宁 | 1003001000 | 0.82±0.150.83±0.130.94±0.19 | 0.89±0.180.83±0.121.00±0.18 | +8.5±0.0±6.4 |
化合物 | 剂量微克/kg | MP处理前 处理后 | 改变% | |
化合物A | 3001000 | 90.6±10.490.2±6.5 | 85.6±11.384.1±5.2 | -5.5-6.8 |
实施例2 | 3001000 | 95.4±6.4109.0±12.1 | 80.4±6.5**99.6±11.2* | -15.7-8.6 |
实施例8 | 3001000 | 116.1±17.481.3±9.0 | 98.3±17.2**64.8±10.5* | -15.0-20.0 |
黄酮哌酯 | 3001000 | 89.2±10.790.4±10.7 | 95.0±10.980.1±11.1 | +6.5-11.4 |
奥昔布宁 | 100300 | 95.2±9.282.3±8.7 | 77.4±10.3**50.5±6.3** | -18.7-38/6 |
对成对数据进行的Student t试验,相对于基础值,*=p<0.05,**=p<0.01。
实施例48:放射性受体与5-HT1A和其它不同神经递质结合部位的结合
A.方法:
重组人5HT1A受体:
将为人5-HT1A血清素能受体编码的基因组克隆G-21稳定地转染入人细胞系(HeLa)。HeLa细胞于37℃和5%CO2下在加10%胎牛血清和庆大霉素(100毫克/毫升)的Dulbecco改良的Eagle培养基(DMEM)里呈单层生长。用细胞刮棒使细胞在铺满95%时从生长烧瓶脱落下来,在冰冷的5mM Tris和5mM EDTA缓冲液(pH7.4)里裂解。匀浆以40000×g离心20分钟,粒状沉淀再悬浮于小体积的冰冷的5mM Tris和5mM EDTA缓冲液(pH7.4),马上冷冻并贮存在-70℃下直到使用。实验那天,细胞膜再悬浮于结合缓冲液:50mM Tris HCl(pH7.4),2.5mM MgCl2,10μM巴吉林(pargiline)(Fargin等,Nature 335,358-360,1988)。膜在有或没有竞争性药物存在下与0.2-1nM[3H]8-OH-DPAT培养,最终体积1毫升,在30℃下培养30分钟;非特异性结合在10μM 5-HT存在时测定。通过加入冰冷的Tris-HCl缓冲液来终止培养,经0.2%聚乙烯亚胺预处理的Whatman GF/B或Schleicher & SchuellGF52滤纸迅速过滤。
天然的5-HT2A血清素能受体和α2-肾上腺素受体(来自动物组织)
用大鼠大脑皮层膜进行天然α2肾上腺素能受体(Diop L.等,J.Neurochem.41,710-715,1983)和5-HT2A血清素能受体(Craig A.和Kenneth J.,Life Sci.38,117-127,1986)的结合研究。通过颈椎脱臼处死雄性Sprague Dawley大鼠(200-300克,SD Harlan/Nossan,意大利),切除大脑皮层,马上在液氮里冷冻,贮存在-70℃下直到使用。用Polytron均质器(速度7)使组织在50体积冷的50mMTris-HCl缓冲液pH7.4里均质化(2×20秒)。匀浆在49000×g下离心10分钟,再悬浮于50体积相同的缓冲液,在37℃下培养15分钟,再离心和悬浮两次。最终的粒状沉淀悬浮在100体积含10μM巴吉林和0.1%抗坏血酸(对于α2肾上腺素能受体)的50mM Tris-HCl缓冲液pH7.4里,或在100体积50mM Tris-HCl缓冲液pH7.7里(对于5-HT2A血清素能受体)。在有或没有竞争性药物存在下,最终体积为1毫升,对膜进行培养:用0.5-1.5nM[3H]蛇根木素(rauwolscine)(对于α2肾上腺素能受体)在25℃下培养30分钟,或用0.7-1.3nM[3H]酮色林(ketanserin)(对于5-HT2A受体)在37℃下培养20分钟。在10μM酚妥拉明(α2-肾上腺素能受体)或2μM ketanserin(5-HT2A血清素能受体)存在下测定非特异性结合。通过加入冰冷的50mM Tris-HCl缓冲液来终止培养,并经0.2%聚乙烯亚胺预处理的WhatmanGF/B或Schleicher & Schuell GF52滤纸声速过滤。然后滤纸用冰冷的缓冲液洗涤,用液体闪烁计数器对残留在滤纸上的放射活性进行测量。
B.结果:
分析试验药物对放射性配体特异性结合的抑制,使用非线性曲线拟合程序Allfit(De Lean等,Am.J.Physiol.235,E97-E102,1978)来估计IC50。IC50通过Cheng & Prusoff方程(Cheng,Y.C.;Prusoff,W.H.,Biochem.Pharmacol.22,3099-3108,1973)被转化为亲和常数(Ki)。
表3A的结果显示,化合物A和实施例2化合物对5-HT1A受体都有极高的亲和力,但它们的结合特点是不同的。实施例2化合物比化合物A的选择性高得多,其对5-HT1A受体的选择性比对5-HT2A和α2-肾上腺素受体的高。试验的本发明中所有其它化合物(表3B)对5-HT1A受体的亲和力都很高。
表3A
对5-HT1A受体和其它神经递质结合部位的结合亲和力
数据表示为Ki(nM)。
化合物 | 5-HT1A | 5-HT2A | α2 |
化合物A | 0.10 | 629 | 2625 |
实施例2 | 0.05 | >10000 | >10000 |
实施例8 | 0.36 | 1065 | 2342 |
实施例18 | 0.60 | 1829 | 314 |
表3B
对5-HT1A受体的结合亲和力
数据表达为Ki(nM)
化合物 | 5-HT1A |
实施例3 | 10.28 |
实施例4 | 0.64 |
实施例5 | 14.85 |
实施例6 | 0.45 |
实施例7 | 3.82 |
实施例8 | 0.36 |
实施例10 | 17.23 |
实施例11 | 2.92 |
实施例12 | 4.77 |
实施例13 | 0.50 |
实施例14 | 10.32 |
实施例15 | 6.20 |
实施例16 | 2.90 |
实施例17 | 20.15 |
实施例18 | 0.60 |
实施例20 | 24.62 |
实施例21 | 2.72 |
实施例22 | 18.18 |
实施例23 | 0.14 |
实施例25 | 8.91 |
实施例26 | 2.69 |
实施例27 | 0.57 |
实施例28 | 18.78 |
实施例30 | 7.96 |
实施例32 | 19.36 |
实施例34 | 16.27 |
实施例35 | 8.00 |
实施例38 | 1.02 |
测量突触前和突触后5-HT1A受体拮抗活性
A.方法:
对小鼠被8-OH-DPAT诱导的体温过低的拮抗作用(突触前拮抗作用)
用Moser方法(Moser,Eur.J.Pharmacol.,193:165,1991),但按如下揭示的稍作改变,来评价本发明5-HT1A受体拮抗剂对被8-OH-DPAT诱导的体温过低的拮抗作用。从Charles River(意大利)得到的雄性CD-1小鼠(28-38克)被饲养在控制气候的房间里(室温22±2℃;湿度55±15%),并保持在12小时昼/夜循环、能自由接近食物和水的环境里。在实验那天,小鼠被单个放置在具有相同周围条件的清洁的塑料盒里。通过将温度探子(Termist TM-S,LSI)插入直肠2厘米深来测体温。在静脉注射本发明化合物前马上测量直肠温度。然后对所有的动物给予8-OH-DPAT(0.5mg/kg皮下注射),30分钟后测量体温。对于每个动物,根据处理前的值计算温度改变,且对每个处理组计算平均值。为了评估ID50(定义为阻断皮下注射0.5mg/kg 8-OH-DPAT诱导的体温过低作用50%所需的拮抗剂剂量),使用线性回归议程。
抑制大鼠由8-OH-DPAT诱导的前爪践踏的作用(突触后拮抗作用)
用Tricklebank的方法(Tricklebank等,Eur.J.Pharmacol.,117:15,1985),但按下述作微小的改变,评估5-HT1A受体拮抗剂对由皮下注射8-OH-DPAT诱导的大鼠前爪践踏的抑制作用。
从Charles River(意大利)得到雄性Sprague-Dawley大鼠(150-175克)被饲养在控制气候的房间里并保持在12小时昼/夜循环、能自由接近食物和水的环境里。在实验那天,大鼠被单个放置在清洁的塑料盒里。用利血平1mg/kg皮下注射处理大鼠,在试验前18-24小时耗尽细胞里贮存的去甲肾上腺素。
为评价拮抗活性,在皮下注射1mg/kg 8-OH-DPAT前16分钟静注化合物。用该激动剂处理后3分钟开始观察30秒,以后每15分钟重复观察3分钟。注意由突触后刺激5HT1A受体诱导的前爪践踏症状的出现,其强度用分级打分来表示:0=没有,1=不明确,2=呈现,3=强烈。在一段时间里对每一被处理大鼠的行为计分累加(5个观察时段),以8-10个大鼠的平均值表示。为评估ID50值(定义为阻断由皮下注射1mg/kg 8-OH-DPAT诱导的前爪践踏强度50%所需的拮抗剂剂量),使用线性回归方程。
B.结果:
表4显示了结果。这些结果显示,实施例2化合物具有明显的突触前和突触后5-HT1A受体拮抗活性。相反,化合物A在两个模型里都比实施例2化合物的活性至少小10倍。
表4
突触前和突触后5-HT1A受体的拮抗活性
数据表达为ID50,mg/kg。
化合物 | 突触前5-HT1AID50 | 突触后5-HT1AID50 |
化合物A | 221 | 350 |
实施例2 | 20 | 36 |
实施例13 | - | 82 |
实施例18 | n.a. | 84 |
实施例23 | - | 177 |
Claims (12)
1.一种通式I化合物,或其对映体、N-氧化物、水合物,或这类化合物的药学上可接受的盐:其中
R代表氢原子或烷基羰基、环烷基羰基、取代环烷基羰基或单环杂芳基羰基,
R1代表氢原子或低级烷基,
R2代表卤原子或烷氧基、苯氧基、硝基、氰基、酰基、氨基、酰氨基、烷基磺酰基氨基、烷氧基羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰基氨基甲酰基、三氟甲基或多氟烷氧基,和
B代表取代的单环芳基、双环芳基、取代的双环芳基、单或双环杂芳基、取代的单或双环杂芳基或取代的苄基,
条件是:
若R和R1代表氢原子,R2代表硝基,则B不代表2-甲氧基苯基、4-氯苯基、4-羟基苯基、3-乙酰基苯基、4-氨磺酰苯基、3,4,5-三甲氧基苯基、2-氯-4-甲苯基或2-吡啶基;若R和R1都代表氢原子,R2代表氨基甲酰基,则B不代表4-羟基苯基;
若B代表烷氧基取代的芳基,则烷氧基必须在芳环的2-位上。
2.根据权利要求1所述的化合物,其中B代表2-甲氧基苯基,2,5-二氯苄基或4-吲哚基。
3.根据权利要求1或2所述的化合物,其中R2代表碘原子或甲氧基、苯氧基、硝基、氰基、乙酰基、氨基、乙酰氨基、乙酰氧基羰基、氨基甲酰基、乙基氨基甲酰基、二甲基氨基甲酰基、环己基羰基氨基甲酰基、三氟甲基、三氟甲氧基或2-(2,2,2-三氟)-乙氧基。
4.根据权利要求1-3任一所述的化合物,其中R代表氢原子或环己基羰基、1-甲基环己基羰基、1-苯基环己基羰基、3-呋喃基羰基、3-噻吩基羰基、4-吡啶基羰基、3-吡啶基羰基或2-吡嗪基羰基。
5.根据权利要求1-4任一所述的化合物,其中R1代表氢原子或甲基。
6.任何一种下列所述的化合物,或其对映体、N-氧化物、水合物,或这类化合物的药学上可接受的盐:
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-三氟甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-三氟甲氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-苯氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-苯氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-碘苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-碘苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-氨基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-氰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-乙酰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-2-氨乙基]-4-(4-吲哚基)-哌嗪,
1-[N-(2-硝基苯基)-N-环己烷羰基-2-氨乙基]-4-(4-吲哚基)-哌嗪,
1-[N-(2-硝基苯基)-2-氨乙基]-4-(2,5-二氯苄基)-哌嗪,
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2,5-二氯苄基)-哌嗪,
1-[N-(2-环己基羰基氨基羰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-甲氧基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-甲氧基羰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-二甲基氨基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-甲氧基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-二甲氨基羰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-三氟甲基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-甲氧基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-乙氨基羰基苯基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-乙氨基羰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-三氟甲苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-氨基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-乙酰基氨基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪N1-氧化物,
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪N4-氧化物,
1-[N-(2-硝基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪N1,N4-二氧化物,
1-[N-(2-硝基苯基)-N-(3-呋喃基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(2-呋喃基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(2-噻吩基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(3-噻吩基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(4-吡啶基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(3-吡啶基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(2-吡嗪基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(1-甲基环己基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-N-(1-苯基环己基羰基)-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-[2-(2,2,2-三氟乙氧基)苯基]-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-[2-(2,2,2-三氟乙氧基)苯基]-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-氰基苯基)-N-环己基羰基-2-氨乙基]-4-(2-甲氧基苯基)-哌嗪,
1-[N-(2-硝基苯基)-1-氨基-2-丙基]-4-(2-甲氧基苯基)-哌嗪,和
1-[N-(2-硝基苯基)-N-环己基羰基-1-氨基-2-丙基]-4-(2-甲氧基苯基)-哌嗪。
7.一种药物组合物,它包括如权利要求1-6任一所述的化合物与药学上可接受的稀释剂或载体。
9.根据权利要求8所述的应用,它应用了权利要求1-6任一所述的化合物。
10.根据权利要求8或9所述的应用,它用于制备含药学上可接受的稀释剂或载体的药物。
11.根据权利要求8-10任一所述的应用,它用于制备适合口服给药的药物。
12.根据权利要求11所述的应用,它用于制备含50-400毫克化合物的单剂药物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IT97MI001864A IT1293807B1 (it) | 1997-08-01 | 1997-08-01 | Derivati 1- (n-fenilaminoalchil) piperazinici sostituiti alla posizione 2 dell'anello fenilico |
ITMI97A001864 | 1997-08-01 |
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CN1265654A true CN1265654A (zh) | 2000-09-06 |
CN1127493C CN1127493C (zh) | 2003-11-12 |
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CN98807820A Expired - Fee Related CN1127493C (zh) | 1997-08-01 | 1998-07-31 | 苯环的2-位被取代的1-(n-苯氨基烷基)-哌嗪衍生物 |
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Country | Link |
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US (1) | US6071920A (zh) |
EP (1) | EP1000047B1 (zh) |
JP (1) | JP2001512112A (zh) |
KR (1) | KR20010022509A (zh) |
CN (1) | CN1127493C (zh) |
AT (1) | ATE256671T1 (zh) |
AU (1) | AU737456B2 (zh) |
BR (1) | BR9811482A (zh) |
CA (1) | CA2297095A1 (zh) |
DE (1) | DE69820632D1 (zh) |
HU (1) | HUP0004926A3 (zh) |
IL (1) | IL134089A0 (zh) |
IT (1) | IT1293807B1 (zh) |
NO (1) | NO315232B1 (zh) |
NZ (1) | NZ502804A (zh) |
PL (1) | PL338352A1 (zh) |
RU (1) | RU2199533C2 (zh) |
WO (1) | WO1999006384A1 (zh) |
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CN1984900B (zh) * | 2004-05-12 | 2010-11-10 | 卫材R&D管理有限公司 | 具有哌啶环的吲哚衍生物 |
CN101175751B (zh) * | 2005-05-11 | 2011-03-23 | 卫材R&D管理有限公司 | 具有哌啶环的吲哚衍生物的晶体和其制备方法 |
CN103360342A (zh) * | 2012-04-09 | 2013-10-23 | 江苏恩华药业股份有限公司 | 3-氰基苯胺烷基芳基哌嗪衍生物及在制备药物中的应用 |
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-
1997
- 1997-08-01 IT IT97MI001864A patent/IT1293807B1/it active IP Right Grant
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1998
- 1998-07-31 IL IL13408998A patent/IL134089A0/xx unknown
- 1998-07-31 CN CN98807820A patent/CN1127493C/zh not_active Expired - Fee Related
- 1998-07-31 HU HU0004926A patent/HUP0004926A3/hu unknown
- 1998-07-31 PL PL98338352A patent/PL338352A1/xx unknown
- 1998-07-31 DE DE69820632T patent/DE69820632D1/de not_active Expired - Lifetime
- 1998-07-31 WO PCT/EP1998/004804 patent/WO1999006384A1/en not_active Application Discontinuation
- 1998-07-31 KR KR1020007001096A patent/KR20010022509A/ko not_active Application Discontinuation
- 1998-07-31 EP EP98943815A patent/EP1000047B1/en not_active Expired - Lifetime
- 1998-07-31 CA CA002297095A patent/CA2297095A1/en not_active Abandoned
- 1998-07-31 AT AT98943815T patent/ATE256671T1/de not_active IP Right Cessation
- 1998-07-31 JP JP2000505143A patent/JP2001512112A/ja active Pending
- 1998-07-31 US US09/127,057 patent/US6071920A/en not_active Expired - Fee Related
- 1998-07-31 RU RU2000105266/04A patent/RU2199533C2/ru not_active IP Right Cessation
- 1998-07-31 AU AU91578/98A patent/AU737456B2/en not_active Ceased
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1984900B (zh) * | 2004-05-12 | 2010-11-10 | 卫材R&D管理有限公司 | 具有哌啶环的吲哚衍生物 |
CN101175751B (zh) * | 2005-05-11 | 2011-03-23 | 卫材R&D管理有限公司 | 具有哌啶环的吲哚衍生物的晶体和其制备方法 |
CN103360342A (zh) * | 2012-04-09 | 2013-10-23 | 江苏恩华药业股份有限公司 | 3-氰基苯胺烷基芳基哌嗪衍生物及在制备药物中的应用 |
CN103360342B (zh) * | 2012-04-09 | 2015-12-16 | 江苏恩华药业股份有限公司 | 3-氰基苯胺烷基芳基哌嗪衍生物及在制备药物中的应用 |
Also Published As
Publication number | Publication date |
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IT1293807B1 (it) | 1999-03-10 |
NO20000521L (no) | 2000-02-01 |
NZ502804A (en) | 2001-02-23 |
PL338352A1 (en) | 2000-10-23 |
NO20000521D0 (no) | 2000-02-01 |
JP2001512112A (ja) | 2001-08-21 |
RU2199533C2 (ru) | 2003-02-27 |
ATE256671T1 (de) | 2004-01-15 |
DE69820632D1 (de) | 2004-01-29 |
US6071920A (en) | 2000-06-06 |
EP1000047B1 (en) | 2003-12-17 |
HUP0004926A3 (en) | 2002-01-28 |
EP1000047A1 (en) | 2000-05-17 |
AU9157898A (en) | 1999-02-22 |
CA2297095A1 (en) | 1999-02-11 |
HUP0004926A2 (hu) | 2001-11-28 |
BR9811482A (pt) | 2002-01-22 |
WO1999006384A1 (en) | 1999-02-11 |
AU737456B2 (en) | 2001-08-23 |
CN1127493C (zh) | 2003-11-12 |
KR20010022509A (ko) | 2001-03-15 |
IL134089A0 (en) | 2001-04-30 |
ITMI971864A1 (it) | 1999-02-01 |
NO315232B1 (no) | 2003-08-04 |
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