TWI433676B - 迅速解離之多巴胺2受器拮抗劑 - Google Patents
迅速解離之多巴胺2受器拮抗劑 Download PDFInfo
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- TWI433676B TWI433676B TW096146645A TW96146645A TWI433676B TW I433676 B TWI433676 B TW I433676B TW 096146645 A TW096146645 A TW 096146645A TW 96146645 A TW96146645 A TW 96146645A TW I433676 B TWI433676 B TW I433676B
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- disorder
- compound
- piperidin
- benzyl
- carbonitrile
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P25/22—Anxiolytics
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
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Description
本發明乃有關為迅速解離多巴胺2受器拮抗劑之6-(哌啶-4-基胺基)嗒-3-腈化合物,及含彼等化合物作為活性成分之醫藥組成物。彼等化合物藉由發揮無運動神經副作用之抗精神病效力而於治療或預防中樞神經系統疾病(例如精神分裂症)用藥上尋得用途。
J.Med.Chem.(1999),42(4),730-741揭示作為乙醯膽鹼酯酶抑制劑之6-苯基-N
-[1-(苯基甲基)-4-哌啶基]-3-嗒胺及類似化合物。
Farmaco,Vol.35,no.11,1980第951-964頁揭示具有多巴胺活性之經取代之N
-[4-哌啶基]-2-胺基嘧啶化合物,亦即多數所揭示化合物係多巴胺D2受器之促效劑。由於所測試化合物無一者拮抗由隨後劑量阿朴嗎啡(apomorphine)誘發之刻板行為,因此彼等被視為缺乏多巴胺受器封阻性質。本發明化合物不同處為存在嗒而非嘧啶基團,並意外地發現彼等對多巴胺D2受器具有拮抗作用。
精神分裂症係影響全世界大約1%人口之嚴重及慢性之心理疾病。臨床症狀於生命相當早期即很明顯,通常在青少年時期或成年初期即浮現。精神分裂症之症狀一般分為被述為正向者,包括妄想、錯覺與思想混亂;及被述為負向者,包括社會退縮、情感冷漠、言語貧乏及無法體驗愉悅。此外,精神分裂症病患受認知不足之苦,例如注意力及記憶力減弱。此疾病之病因仍未知,惟異常之神經傳導素作用被假設係構成精神分裂症症狀之基礎。多巴胺假說為最常被慮及者;它提出多巴胺傳達作用之過度活性係於精神分裂症病患觀察到的正向症狀之原由。此假說乃基於觀察到多巴胺增強藥物(例如安非他命或古柯鹼)可能誘發精神病,及基於存在抗精神病藥物臨床劑量與其封阻多巴胺D2受器的效力間之相互關係。市售之所有抗精神病藥物均傳介其藉由封阻多巴胺D2受器對抗正向症狀之治療功效。除了臨床功效之外,抗精神病藥物之主要副作用,例如錐體外徑症狀(EPS)與遲發性運動困難,似乎亦與多巴胺拮抗作用相關。使用典型或第一代抗精神病藥物(例如,氟哌啶醇),最常出現彼等令人衰弱之副作用。使用非典型或第二代抗精神病藥物(例如,利培酮(risperidone)、奧氮平(olanzapine))則彼等副作用較不顯著;使用被視為原型非典型抗精神病藥物之氯氮平(clozapine),則彼等副作用甚至差不多不存在。於被提出用於解釋使用非典型抗精神病藥物所觀察到的EPS之較低發生率之諸多不同理論中,
過去十五年期間,最引人注意者為多受器假說。該假說係始於一項受器結合研究,該研究證實許多非典型抗精神病藥物除了多巴胺D2受器外,亦與各種其他神經傳導素受器互相作用,特別是與血清素5-HT2受器作用,而典型抗精神病藥物如氟哌啶醇則較為選擇性地與D2受器結合。此理論近年來已受到挑戰,因為所有主要非典型抗精神病藥物於臨床適當劑量下完全佔用血清素5-HT2受器,惟卻不同地誘發運動神經副作用。替代於多受器假說,Kapur與Seeman(“Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics:A new hypothesis”,Am.J.Psychiatry 2001,158:3 p.360-369)已提出,由自多巴胺D2受器解離之速率,可區分非典型抗精神病藥物與典型抗精神病藥物。迅速自D2受器解離將使抗精神病藥物更通融生理上之多巴胺傳送,容許於無運動神經副作用下之抗精神病藥物效應。慮及氯氮平與喹硫平(quetiapine)時,此假說特別有說服力。此二藥物具有最迅速之與多巴胺D2受器之解離率,及帶有最低之於人體中誘發EPS之風險。相反地,典型抗精神病藥物伴隨高EPS罹患率,係最慢解離之多巴胺D2受器拮抗劑。因此,根據自D2受器之解離速率鑑定新藥物似為提供新穎非典型抗精神病藥物之有效策略。附加之目標為結合迅速解離性質及對多巴胺D2受器之選擇性。當前非典型抗精神病藥物之多受器性質被視為係其他副作用(例如體重增加及糖尿病)之起因。尋找選擇性D2拮抗劑有一段時間為被忽略
之方法,惟申請人等相信,於臨床上使用較具選擇性之化合物可能減少與目前非典型抗精神病藥物相關的代謝失調症之發生。
本發明之目的在於提供為迅速解離之多巴胺2受器拮抗劑之新穎化合物,其具有前文說明的有利藥理性質,特別是運動神經副作用減少,及與其他受器之相互作用適度或可忽略,導使形成代謝失調症之風險減少。
此目的藉由本發明之根據式(I)之新穎化合物、其醫藥上可接受之鹽與溶劑合物、及其立體異構物型而達成:
式中R為氫或C1-6
烷基;R1
為苯基;被各自獨立地選自包括氫、鹵基、氰基、C1-4
烷基、C1-4
烷氧基、全氟C1-4
烷基、與三氟甲氧基之組群之1、2或3個取代基取代之苯基;噻吩基;被選自包括鹵基與C1-4
烷基之組群之1或2個取代基取代之噻吩基;C1-4
烷基;被羥基、C3-8
環烷基或C5-7
環烯基取代之C1-4
烷基;C3-8
環烷基;或C5-7
環烯基;R2
為氫或C1-6
烷基;R3
與R4
各自獨立地為氫、C1-4
烷基或鹵基,或R3
與R4
一起形成含有至少一個氧、氮或硫原子之5、6或7
員碳環或5、6或7員雜環。
根據本發明之化合物係迅速解離之D2
受器拮抗劑,一種非歸因於J.Med.Chem.(1999),42(4),730-741之任何6-苯基-N
-[4-哌啶基]-3-嗒胺衍生物,抑或Farmaco,Vol.35,no.11,1980,第951-964頁之任何經取代之N
-[4-哌啶基]-2-胺基嘧啶化合物之活性。此性質使得根據本發明之化合物尤其適於作為藥劑用以治療或預防下述疾病:精神分裂症、類精神分裂症、情感性精神分裂症、妄想症、短期精神病、共享型精神病、一般醫學狀況造成之精神病、物質誘發之精神病、未另列名之精神病;伴隨癡呆之精神病;重鬱症、輕鬱症、經前煩憂症、未另列名之憂鬱症、I型躁鬱症、II型躁鬱症、循環性精神病、未另列名之躁鬱症、一般醫學狀況造成之情緒性疾病、物質誘發之情緒性疾病、未另列名之情緒性疾病;廣泛性焦慮症、強迫症、恐慌症、急性壓力症、創傷後壓力症;智能障礙;廣泛性發展障礙;注意力缺乏症、注意力缺乏/過動症、破壞性行為症;偏執狂型人格異常、類精神分裂型人格異常、精神分裂型人格異常;抽動症、妥瑞氏症;物質依賴;物質濫用;物質戒斷;拔毛症。
熟習此項技藝者可根據下文實驗部分提供之實驗數據進行化合物之選擇。化合物之任何選擇均包含於本發明範圍之內。
第一組化合物乃有關式(I)化合物中R、R3
與R4
為氫者。
第二組化合物乃有關式(I)化合物中R2
為氫或甲基者。
第三組化合物乃有關式(I)化合物中R1
為3,5-二氟苯基、3,4,5-三氟苯基、3-三氟甲基苯基、3-氟-5-三氟甲基苯基或3-氟-4-甲基苯基者。
式(I)化合物為,例如,6-[1-(3,4-二氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E1)、6-[1-(4-氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E2)、6-[1-(4-氯-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E3)、6-[1-(3-氟-4-甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E4)、6-[1-(3-氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E5)、6-[1-(4-甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E6)、6-[1-(4-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E7)、6-[1-(3-氟-4-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E8)、6-[1-(4-氟-3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E9)、6-[1-(4-甲基-3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E10)、6-[1-(3,5-雙-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E11)、6-[1-(2-氟-5-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E12)、6-[1-(3-氯-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E13)、
6-[1-(3-氯-4-三氟甲氧基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E14)、6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E15)、6-[1-(3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E16)、6-[1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E17)、6-[1-(3,4,5-三氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E18)、6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-4,5-二甲基-嗒-3-甲腈(E19)、6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-4-甲基-嗒-3-甲腈(E20)、與6-(1-苄基-哌啶-4-基)-嗒-3-甲腈(D2)。
於本申請案全文中,「C1-4
烷基」一詞於單獨使用及組合使用(例如「C1-4
烷氧基」、「全氟C1-4
烷基」、「二C1-4
烷基胺基」)時,包含例如甲基、乙基、丙基、丁基、1-甲基丙基、1,1-二甲基乙基;「C1-6
烷基」包含甲基、乙基、丙基、丁基、1-甲基丙基、1,1-二甲基乙基、成基與己基;「全氟C1-4
烷基」包含例如三氟甲基、五氟乙基、七氟丙基與九氟丁基;C3-8
環烷基包含環丙基、環丁基、環成基、環己基、環庚基與環辛基;C5-7
環烯基包含環成烯基、環己烯基與環庚烯基。鹵基一詞包含氟、氯、溴與碘基。
醫藥上可接受之加成鹽係界定為包括根據式(I)之化合物可形成之具治療活性之無毒酸加成鹽型。該等鹽可藉
由以適當酸處理鹼型之根據式(I)之化合物而製得;其中適當酸為例如無機酸如氫鹵酸特別是鹽酸或氫溴酸、硫酸、硝酸與磷酸;有機酸,例如,乙酸、羥基乙酸、丙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、順丁烯二酸、杏仁酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、環己基胺磺酸、水楊酸、對胺基水楊酸及雙羥萘酸。相反地,該等鹽型可藉由以適當鹼處理轉化為游離型。
溶劑合物一詞係指式(I)化合物可形成之水合物及醇合物。
前文所用「立體化學異構物型」一詞界定式(I)化合物可具有的所有可能異構物形式。除非另行提及或指示,否則化合物之化學稱號代表所有可能立體化學異構型之混合物,該混合物含有基礎分子結構之所有非鏡像異構物與鏡像異構物。詳言之,立體發生中心可具有R-或S-組態;二價環狀(部分)飽和基團上之諸取代基可具有順式-或反式-組態。包含雙鍵之化合物於該雙鍵處可具有E-或Z-立體化學性。式(I)化合物之立體化學異構物型涵蓋於本發明範圍之內。
如下文所述程序製備之式(I)化合物可呈鏡像異構物之消旋混合物型予以合成,再依據技藝已知之解析程序彼此分離。式(I)之消旋化合物可利用以適當對掌酸處理,轉化為對應之非鏡像異構物鹽型。接著,將該非鏡像異構物鹽型,例如,藉由選擇或分級結晶法分離,利用鹼使其釋
出鏡像異構物。分離式(I)化合物之鏡像異構物型之替代方法包括使用對掌靜止相之液相層析法。該等純立體化學異構物型亦可衍生自對應之純立體化學異構物型之適當起始物質,只要反應之發生具立體專一性即可。較佳為,若需要專一性立體異構物,則可利用具立體專一性之製備方法合成該化合物;彼等方法係有利地使用純鏡像異構物型之起始物質。
為了尋找對正向症狀具活性及具有增進之安全性質(低EPS發生率且無代謝失調症)之抗精神病化合物,申請人等已針對與多巴胺D2受器選擇性互相作用及迅速自此受器解離之諸化合物進行篩檢。首先,使用[3
H]螺旋丁苯(spiperone)及人類D2L受器細胞膜於結合試驗中針對諸化合物對D2之親和性進行篩檢。顯示IC50
小於10 μM之化合物於自JoseeE.Leysen and Walter Gommeren,Journal of Receptor Research,1984,4(7),817-845發表的方法改造之間接試驗中進行測試,以評估其解離速率。
經選定之化合物E15、E16、E17與E18進一步於一組50個以上一般連接G蛋白之受器(CEREP)中進行篩檢,發現彼等具有清潔性質(clean profile),對所測試之受器親和性低。
多數化合物已進一步於活體內模式例如「於大鼠中由阿朴嗎啡誘發的震顫試驗之抑制作用」中進行皮下及經口
投與測試,發現有些化合物具經口投與之生物利用性及活性。
鑑於式(I)化合物之前述藥理學性質,因而彼等適於作為藥劑用途,特別是作為抗精神病藥物之用。詳言之,彼等化合物適於作為藥劑用以治療或預防下述疾病:精神分裂症、類精神分裂症、情感性精神分裂症、妄想症、短期精神病、共享型精神病、一般醫學狀況造成之精神病、物質誘發之精神病、未另列名之精神病;伴隨癡呆之精神病;重鬱症、輕鬱症、經前煩憂症、未另列名之憂鬱症、I型躁鬱症、II型躁鬱症、循環性精神病、未另列名之躁鬱症、一般醫學狀況造成之情緒性疾病、物質誘發之情緒性疾病、未另列名之情緒性疾病;廣泛性焦慮症、強迫症、恐慌症、急性壓力症、創傷後壓力症;智能障礙;廣泛性發展障礙;注意力缺乏症、注意力缺乏/過動症、破壞性行為症;偏執狂型人格異常、類精神分裂型人格異常、精神分裂型人格異常;抽動症、妥瑞氏症;物質依賴;物質濫用;物質戒斷;拔毛症。
為了有效進行罹患前段述及疾病病患之治療,式(I)化合物可與其他治療精神異常之化合物一起投與。因此,於精神分裂症之情形下,可以負向及認知症狀為目標。
本發明亦提供罹患該等疾病的溫血動物之治療方法,該方法包括全身性投與有效處理上述疾病之治療用量之式(I)化合物。
本發明進一步提供預防任何前述疾病發生於容易罹患
該等疾病的溫血動物之方法,該方法包括全身性投與有效預防上述疾病之治療用量之式(I)化合物。
本發明亦有關使用如上文界定之式(I)化合物製造醫藥劑之用途,特別是抗精神病醫藥劑,詳言之為治療或預防下述疾病之藥劑:精神分裂症、類精神分裂症、情感性精神分裂症、妄想症、短期精神病、共享型精神病、一般醫學狀況造成之精神病、物質誘發之精神病、未另列名之精神病;伴隨癡呆之精神病;重鬱症、輕鬱症、經前煩憂症、未另列名之憂鬱症、I型躁鬱症、II型躁鬱症、循環性精神病、未另列名之躁鬱症、一般醫學狀況造成之情緒性疾病、物質誘發之情緒性疾病、未另列名之情緒性疾病;廣泛性焦慮症、強迫症、恐慌症、急性壓力症、創傷後壓力症;智能障礙;廣泛性發展障礙;注意力缺乏症、注意力缺乏/過動症、破壞性行為症;偏執狂型人格異常、類精神分裂型人格異常、精神分裂型人格異常;抽動症、妥瑞氏症;物質依賴;物質濫用;物質戒斷;拔毛症。
熟習治療及預防該等疾病技藝者可從下文呈現之測試結果決定治療有效之日劑量。治療有效之日劑量可為約0.01毫克/公斤至約10毫克/公斤體重,較佳為約0.05毫克/公斤至約1毫克/公斤體重。
本發明亦有關一種醫藥組成物,其含有醫藥上可接受之載劑,及作為活性成分之治療有效量之根據式(I)之化合物。
視投與途徑而定,醫藥組成物含有0.05%至99%重量
比之活性成分,及1%至99.95%重量比之醫藥上可接受之載劑。
為了容易投與,主題化合物可調配為供投與目的之各種醫藥形式。根據本發明之化合物,特別是根據式(I)之化合物、其醫藥上可接受之酸或鹼加成鹽、其立體化學異構物型、其N
-氧化物型及其前驅藥物、或其任何子群或組合物,可調配為供投與目的之各種醫藥形式。可引用之適當組成物為一般全身性投與藥物用之所有組成物。製備本發明醫藥組成物時,可將有效量之作為活性成分之特定化合物(視需要呈加成鹽型)與醫藥上可接受之載劑密切摻合,該載劑視投與所需製劑形式而定,可有多種形式。彼等醫藥組成物係符合所需地呈適用於特別是經口、直腸、經皮膚、或利用非經腸注射或吸入投與之單位劑量型。舉例而言,於製備呈口服劑量型之組成物時,任何常用醫藥介質均可使用,例如,於口服液體製劑例如懸浮液、糖漿、酏劑、乳液及溶液情形下之水、二醇類、油類、醇類等;或於粉劑、丸劑、膠囊及錠劑情形下之固體載劑例如澱粉、糖類、高嶺土、稀釋劑、潤滑劑、黏合劑、崩解劑等。錠劑及膠囊由於容易投與而為最有利之口服單位劑量型,此時,明顯地係使用固體醫藥載劑。非經腸組成物之載劑通常包括至少大部分之無菌水,惟亦可包含其他組成以,例如,幫助溶解。注射用溶液,舉例而言,可使用包括食鹽溶液、葡萄糖溶液或鹽液與葡萄糖溶液混合物之載劑而製備。含有式(I)化合物之注射用溶液可於供延緩作用之油中
調配。供此目的之適當油類為,例如,花生油、芝麻油、棉籽油、玉米油、大豆油、長鏈脂肪酸之合成甘油酯類及彼等與其他油類之混合物。也可製備注射用懸浮液,此時,可使用適當的液體載劑、懸浮劑等。亦包括於使用前才轉化為液體型製劑之固體型製劑。於適用於經皮膚投與之組成物中,其載劑視需要含有滲透增進劑及/或適當潤濕劑,視需要以微小比例與任何性質之適當添加劑組合,此添加劑對皮膚不會引起明顯有害之作用。該等添加劑可促進對皮膚之投與及/或可能有助於所需組成物之製備。彼等組成物可呈各種方式投與,例如,呈皮膚貼片、點劑、或軟膏。式(I)化合物之酸或鹼加成鹽由於相較於對應鹼或酸型之水溶性較高,因此較適用於製備水性組成物。
由於容易投與及劑量之均一性,前述醫藥組成物以調配為劑量單位型尤其有利。本文所用之劑量單位型係指呈單位劑量之物理分立單位,各單位含有經計算與所需醫藥載劑結合下,可產生所需治療效果的預定量活性成分。此等劑量單位型之實例為錠劑(包含剝痕或包衣錠劑)、膠囊、丸劑、粉包、雙層扁片、栓劑、注射溶液或懸浮液等,及其分離倍數。
由於根據本發明化合物係強效之可經口投與之化合物,因此以包含該等化合物供經口投與之醫藥組成物尤其有利。
為了提升式(I)化合物於醫藥組成物中之溶解性及/或安定性,以使用α-、β-或γ-環糊精類或其衍生物,特別是
羥烷基經取代之環糊精類,例如2-羥丙基-β-環糊精,較為有利。共溶劑例如醇類亦可增進根據本發明化合物於醫藥組成物中之溶解性及/或安定性。
式(I)化合物,
式中R、R1
、R2
、R3
與R4
如前文所界定者,係藉由使具下式(II)之化合物,
式中R2
、R3
與R4
如前文所界定,與式R1
-C(=O)-R(III-a)化合物(式中R與R1
如前文所界定),於適當還原劑例如三乙醯氧基硼氫化鈉、適當酸觸媒例如乙酸存在下,在適當反應惰性溶劑例如1,2-二氯乙烷中反應予以製備。
式(I)化合物中,R、R1
、R2
、R3
與R4
如前文所界定者,亦可藉由使式(II)化合物(其中R2
、R3
與R4
如前文所界定)與式R1
-CHX-R(III-b)(式中R與R1
如前文所界定,X代表鹵基或適當釋離基),於適當鹼例如二異丙基乙胺存在下,
在適當惰性反應溶劑例如乙腈中,於合宜溫度(典型地為微波照射下,於120℃加熱)反應予以製備。
式(II)化合物,其中R2
、R3
與R4
如前文所界定者,係藉由使式(IV)之氯嗒衍生物
式中R2、R3
與R4
如前文所界定,P代表適當保護基例如苄基,與氰化物鹽例如氰化鋅,於鈀觸媒例如肆(三苯膦)鈀存在下,在適當惰性溶劑例如N
,N
-二甲基甲醯胺中,於適當反應條件下(典型地為微波照射下,於120℃加熱)反應,隨後脫除保護基P(例如,脫除苄基時,於適當條件下,舉例而言,與氯甲酸酯1-氯乙酯,於適當鹼例如二異丙基乙胺存在下,在適當惰性反應溶劑例如二氯甲烷中反應)予以製備。
式(IV)化合物,其中R2
、R3
與R4
如前文所界定及P代表適當保護基者,係藉由使具下式(V)之化合物,
式中R2
如前文所界定及P代表適當保護基例如苄基,與具下式(VI)之化合物
式中R3
與R4
如前文所界定,於適當觸媒例如碘化鉀存在下,在適當反應條件下(例如熔融)反應予以製備。
式(VI)化合物係市售可得或可利用類似WO 99/36407中敘述之彼等程序製備。
式(I)化合物中,R、R1
、R2
、R3
與R4
如前文所界定者,亦可使具下式(VII)之3-氯嗒
式中R3
與R4
如前文所界定,與具下式(VIII)之哌啶衍生物
式中R、R1
與R2
如前文所界定,於適當鹼例如二異丙基乙胺存在下,在適當溶劑,諸如反應惰性溶劑,例如乙腈中,於高溫下反應予以製備。
式(VIII)化合物,其中R與R1
如前文所界定及R2
=H者,係藉由使哌啶-4-基胺基甲酸第三丁酯(IX)
與式R1
-CHX-R(III-b)化合物(式中R與R1
如前文所界定,X代表鹵基或適當釋離基),於適當鹼例如二異丙基乙胺存在下,在適當惰性反應溶劑例如二氯甲烷中反應,隨後利用以酸例如三氟乙酸處理,將式(X)中間產物中之第三丁氧羰基脫保護,得到式(VIII)中R2
=H之化合物予以製備。
式(VIII)中R與R1
如前文所界定及R2
=H之化合物亦可藉由使哌啶-4-基胺基甲酸第三丁酯(IX)與式R1
-C(=O)-R(III-a)化合物(式中R與R1
如前文所界定),於適當還原劑例如三乙醯氧基硼氫化鈉、適當酸觸媒例如乙酸存在下,在適當惰性反應溶劑例如1,2-二氯乙烷中反應,隨後利用以酸例如三氟乙酸處理,將式(X)中間產物中之第三丁氧羰基脫保護,得到式(VIII)中R2
=H之化合物予以製備。
式(VIII)化合物中,R2
≠H者,可藉由使具下式(XI)之化合物
式R與R1
如前文所界定,與式R2
-NH2
(XII)之胺,於適當還原劑例如氫、適當觸媒例如披鈀碳存在下,於適當惰性反應溶劑例如乙醇中反應予以製備。
式(XI)化合物中,R與R1
如前文所界定者,係藉由使4,4-伸乙二氧基哌啶(XIII)
與式R1
-C(=O)-R(III-a)化合物(式中R與R1
如前文所界定),於適當還原劑例如三乙醯氧基硼氫化鈉、適當酸觸媒例如乙酸存在下,於適當惰性反應溶劑例如1,2-二氯乙烷中反應,隨後利用以酸例如鹽酸處理,使具下式(XIV)之中間產物脫保護予以製備
式中R與R1
如前文所界定。
式(VII)化合物中,R3
與R4
如前文所界定者,係藉由使具下式(XV)之3-氯-6-碘-嗒
與氰化物鹽例如氰化鋅或銅,於鈀觸媒例如肆(三苯膦)鈀存在下,於惰性溶劑例如N
,N
-二甲基甲醯胺或乙腈中,適當反應條件下(典型地為微波照射下,於160℃加熱)反應予以製備。
實例(E1-E20)係使用所述溶洗液於矽膠上利用管柱層析法或於Hyperprep RP 18 BDS(Shandon)(8微米,200毫米,250克)管柱上利用逆相製備性HPLC進行最後純化步驟。使用三個移動相(移動相A:90% 0.5%乙酸銨+10%乙腈;移動相B;甲醇;移動相C:乙腈)進行梯度溶洗,開始時為流速40毫升/分鐘之75% A與25% B(相同條件下維持0.5分鐘,隨後於0.01分鐘內流速增加至80毫升/分鐘),至50% B與50% C溶洗41分鐘,至100% C溶洗20分鐘,及維持彼等條件4分鐘。
於Bruker DPX 360、DPX 400或Bruker AV-500分光計上記錄1
H光譜。化學位移以相對於四甲基矽烷之ppm
表示。
說明1
(1-苄基-哌啶-4-基)-(6-氯-嗒-3-基)-胺(D1)
於120℃,攪拌4-胺基-1-苄基哌啶(4克,21毫莫耳)與3,6-二氯-嗒(1.56克,10.5毫莫耳)之混合物1小時,然後添加正丁醇(10毫升),此反應混合物再於120℃攪拌1小時。添加水及二氯甲烷後,分離有機層,乾燥(Na2
SO4
),過濾,真空蒸發溶劑。殘留物以乙腈結晶化,過濾分離所得固體,乾燥,獲得D1
(1.3克,41%)C16
H19
ClN4
計算值302;實測值303(MH+
);熔點:208.2-209.3℃。
1
H NMR(360 MHz,DMSO-d 6
)δ 1.36-1.54(m,2 H),1.94(d,J
=10.98 Hz,2 H),2.08(t,J
=10.79 Hz,2 H),2.78(d,J
=11.71 Hz,2 H),3.47(s,2 H),3.69-3.84 (m,1 H),6.88(d,J
=9.15 Hz,1 H),7.03(d,J
=7.32 Hz,1 H),7.22-7.28(m,1 H),7.28-7.34(m,4 H),7.34(d,J
=9.51 Hz,1 H)。
說明2
6-(1-苄基-哌啶-4-基胺基)-嗒-3-甲腈(D2)
微波(Milestone微波爐)照射下,於160℃加熱(1-苄基-哌啶-4-基)-(6-氯-嗒-3-基)-胺(D1)(3克,9.9毫莫耳)、氰化鋅(2.09克,17.8毫莫耳)與肆(三苯膦)鈀(0)(2.74克,2.3毫莫耳)於N
,N
-二甲基甲醯胺(30毫升)中之混合物30分鐘。然後真空蒸發溶劑,添加碳酸鉀水溶液(10%)與乙酸乙酯。分離有機相,乾燥(Na2
SO4
),過濾,真空蒸發溶劑。殘留物利用管柱層析法(矽膠;0至1.5%氨之甲醇溶液(7M)/二氯甲烷),然後利用HPLC進行純化,獲得呈固體之D2
(1.06克,36%)。C17
H19
N5
計算值293;實測值294(MH+
)。
1
H NMR(500 MHz,DMSO-d 6
)δ 1.42-1.57(m,2 H),1.92(d,J
=10.40 Hz,2 H),2.09(t,J
=10.84 Hz,2 H),2.79(d,J
=11.27 Hz,2 H),3.48(s,2 H),3.92(br.s.,1 H),6.87(d,J
==8.96 Hz,1 H),7.21-7.27(m,2 H),7.27-7.37(m,3 H),7.68(d,J
=9.54 Hz,1 H),7.77(br.s.,1 H)。
說明3
6-(哌啶-4-基胺基)-嗒-3-甲腈(D3)
於0℃,逐滴添加氯甲酸1-氯乙酯(2.9克,20毫莫耳)至6-(1-苄基-哌啶-4-基)-嗒-3-甲腈(D2)(1.5克,5.1毫莫耳)與二異丙基乙胺(2.6克,20毫莫耳)之二氯甲烷(50毫升)攪拌混合物中。此反應混合物於室溫攪拌2小時,然後真空蒸發溶劑。添加甲醇(50毫升)於殘留物中,迴流加熱此混合物2小時。真空蒸發溶劑,殘留物利用管柱層析法純化(矽膠;5-12%氨之甲醇溶液(7M)/二氯甲烷)。收集所需溶離份,真空蒸發溶劑,獲得呈固體之D3
(0.9克,90%)。C10
H13
N5
計算值203;實測值204(MH+
)。
1
H NMR(360 MHz,DMSO-d 6
)δ 1.67-1.86(m,2 H),2.10(dd,J
=13.72,3.48 Hz,2 H),3.03(td,J
=12.81,2.93 Hz,2 H),3.32(tt,J
=13.17,3.66 Hz,2 H),4.24(br.s.,1 H),7.00(d,J
=9.51 Hz,1 H),7.75(d,J
=9.15 Hz,1 H),8.33(br.s.,1 H),8.23(d,J
=6.95 Hz,1 H)。
說明4
6-氯-嗒-3-甲腈(D4)
微波(Milestone微波爐)照射下,於160℃,攪拌3-氯-6-碘-嗒(CAS 135034-10-5,5.5克,22.9毫莫耳;Goodman,A.J.;Stanforth,S.P.;Tarbit,B.Tetrahedron
(1999),55(52),15067-15070)與氰化銅(4克,44.7毫莫耳)於乙腈(30毫升)中之混合物30分鐘。然後將混合物傾入二氯甲烷(200毫升)中,通過矽藻土過濾,真空蒸發溶劑。然後利用管柱層析法純化殘留物(矽膠;二氯甲烷/庚烷1:1至7:3),獲得呈固體之D4
(2.84克,89%)。
1
H NMR(400 MHz,CDCl3
)δ 7.65 (d,J=8.8 Hz,1H),7.75(d,J=8.8 Hz,1H)。
說明5
1-(3,5-二氟-苄基)-哌啶-4-基胺(D5)
於室溫攪拌哌啶-4-基胺基甲酸第三丁酯(5克,24.9毫莫耳)、3,5-二氟苄基溴(2.9毫升,22.7毫莫耳)與二異丙基乙胺(5.9毫升,34.03毫莫耳)於二氯甲烷(50毫升)中之混合物2小時。其後,添加三氟乙酸(32毫升),此反應混合物進一步攪拌2小時。真空蒸發溶劑,添加碳酸鈉飽和溶液。此混合物以二氯甲烷萃取,乾燥(Na2
SO4
)經分離之有機層,過濾,真空蒸發溶劑,獲得呈固體之D5
(4.5克,90%)。C12
H16
F2
N2
計算值226;實測值227(MH+
)。
說明6
1-(3-三氟甲基-苄基)-哌啶-4-基胺(D6)
於室溫攪拌哌啶-4-基胺基甲酸第三丁酯(2.5克,12.4毫莫耳)、3-(三氟甲基)苄基溴(1.7毫升,11.3毫莫耳)與二異丙基乙胺(2.9毫升,16.9毫莫耳)於二氯甲烷(25毫升)中之混合物2小時。其後,添加三氟乙酸(32毫升),此反應混合物進一步攪拌2小時。真空蒸發溶劑,添加碳酸鈉飽和溶液。此混合物以二氯甲烷萃取,乾燥經分離之有機層(Na2
SO4
),過濾,真空蒸發溶劑。殘留物利用管柱層析法純化(矽膠;5-10%氨之甲醇溶液(7 M)/二氯甲烷),獲得呈固體之D6
(1.9克,60%)。C13
H17
F3
N2
計算值258;實測值259(MH+
)。
說明7
1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺(D7)
於室溫攪拌哌啶-4-基胺基甲酸第三丁酯(4克,20毫莫耳)、3-氟-5-(三氟甲基)苄基溴(4.6克,18.1毫莫耳)與二異丙基乙胺(4.7毫升,27.1毫莫耳)於二氯甲烷(25毫升)
中之混合物2小時。其後,添加三氟乙酸(32毫升),此反應混合物進一步攪拌2小時。真空蒸發溶劑,添加碳酸鈉飽和溶液。此混合物以二氯甲烷萃取,乾燥(Na2
SO4
)經分離之有機層,過濾,真空蒸發溶劑,獲得呈固體之D7
(4克,80%)。C13
H16
F4
N2
計算值276;實測值277(MH+
)。
說明8
1-(3,4,5-三氟-苄基)-哌啶-4-基胺(D8)
於室溫攪拌哌啶-4-基胺基甲酸第三丁酯(2.5克,12.4毫莫耳)、3,4,5-三氟苄基溴(2.5克,11.3毫莫耳)與二異丙基乙胺(2.9毫升,16.9毫莫耳)於二氯甲烷(25毫升)中之混合物2小時。其後,添加三氟乙酸(15.6毫升),進一步攪拌此反應2小時。真空蒸發溶劑,添加碳酸鈉飽和溶液。此混合物以二氯甲烷萃取,乾燥(Na2
SO4
)經分離之有機層,過濾,真空蒸發溶劑,獲得呈固體之D8
(2.9克,96%)。C12
H15
F3
N2
計算值244;實測值245(MH+
)。
說明9
3,6-二氯-4,5-二甲基-嗒(D9)
微波(Biotage微波爐)照射下,於160℃,攪拌6-羥基-4,5-二甲基-2H-嗒-3-酮(2.56克,18毫莫耳)(以類似WO 99/36407中敘述之程序製備)、氯氧化磷(8毫升)與二異丙基乙胺(4毫升)之混合物20分鐘。然後部分真空蒸發溶劑,將殘留物質傾入至冷水、飽和碳酸氫鈉與二氯甲烷之混合物中。然後以碳酸氫鈉少量多次鹼化該混合物,至CO2
不再逸出為止。分離有機層,乾燥(Na2
SO4
),過濾,真空蒸發溶劑。殘留物利用管柱層析法純化(二氯甲烷/庚烷1/1至10/0),獲得呈固體之D9(1.7克,53%)。C6
H6
Cl2
N2
計算值176;實測值177(MH+
)。
說明10
3-氯-6-碘-4,5-二甲基-嗒(D10)
微波照射下,於120℃,攪拌D9(0.2克,1.13毫莫耳)、碘化鈉(0.420克,2.8毫莫耳)與氫碘酸(57重量%水溶液,2毫升)之混合物10分鐘。將混合物傾入至碳酸鈉飽和水溶液、Na2
S2
O3
、水與二氯甲烷中。分離有機相,於棉布上過濾,真空蒸發溶劑。殘留物利用管柱層析法純化(二氯甲烷/庚烷1:1至8:2),獲得呈固體之D10
(0.235克,77%)。C6
H6
ClIN2
計算值268;實測值269(MH+
)。
說明11
6-氯-4,5-二甲基-嗒-3-甲腈(D11)
微波照射下,於160℃,攪拌D10(0.225克,0.84毫莫耳)、氰化銅(0.15克,1.67毫莫耳)於乙腈(2毫升)中之混合物20分鐘。然後添加二氯甲烷,於矽藻土上過濾此混合物。真空蒸發溶劑,殘留物利用管柱層析法純化(矽膠;二氯甲烷/庚烷1:1至7:3),獲得呈固體之D11
(0.120克,85%)。C7
H6
ClN3
計算值167;實測值166(MH+
)。
實例7
6-[1-(4-三氯甲基-苄基)-哌啶-4-基胺基}-嗒-3-甲腈(E7)
於6-(哌啶-4-基胺基)-嗒-3-甲腈(D3)(0.15克,0.7毫莫耳)與α,α,α-三氟-對甲苯醛(0.15毫升,1.1毫莫耳)之二氯甲烷(2毫升)混合物中,添加三乙醯氧基硼氫化鈉(0.232克,1.1毫莫耳)與乙酸(0.041毫升)。然後於室溫攪拌此反應混合物18小時。接著添加碳酸氫鈉飽和溶液,分離有機層,乾燥(Na2
SO4
),過濾,真空蒸發溶劑。殘留物利用HPLC進行純化。收集所需溶離份,真空蒸發溶劑,
獲得呈固體之E7
(0.101克,38%)。C18
H18
F3
N5
計算值361;實測值362(MH+
);熔點:243.1℃。
1
H NMR(500 MHz,CDCl3
)δ 1.56-1.65 (m,2 H),2.09(d,J
=11.85 Hz,2 H),2.22(t,J
=10.55 Hz,2 H),2.85(d,J
=11.85 Hz,2H),3.58(s,2 H),3.93(br.s.,1 H),5.14(br.s.,1 H),6.60(d,J
=9.25 Hz,1H),7.40(d,J
=9.25 Hz,1 H),7.45(d,J
=7.80 Hz,2 H),7.58(d,J
=8.09 Hz,2 H)。
實例13
6-[1-(3-氯-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E13)
微波(Biotage微波爐)照射下,於120℃,攪拌6-(哌啶-4-基胺基)-嗒-3-甲腈(D3)(0.150克,0.74毫莫耳)、3-氯苄基溴(0.102毫升,0.78莫耳)與二異丙基乙胺(0.196毫升,1.11莫耳)於乙腈(2毫升)中之混合物5分鐘。然後以二氯甲烷稀釋此反應混合物,並以碳酸鈉飽和溶液萃取。分離有機層,乾燥(Na2
SO4
),過濾,真空蒸發溶劑。然後利用管柱層析法純化殘留物(矽膠;0-2.5%氨之甲醇溶液(7 M)/二氯甲烷)。收集所需溶離份,真空蒸發,殘留物以二異丙醚研製,獲得呈白色固體之E13
(0.095克,39%)。C17
H18
ClN5
計算值327;實測值328(MH+
);熔點:
151℃。
1
H NMR(400 MHz,CDCl3
)δ 1.52-1.70(m,2 H)2.08(d,J
=12.02 Hz,2 H),2.19(t,J
=11.30 Hz,2 H), 2.85(d,J
=11.82 Hz,2 H),3.50(s,2 H),3.91 (br.s.,1 H),5.23(br.s.,1 H),6.62(d,J
=9.33 Hz,1 H),7.17-7.21(m,1 H),7.21-7.28(m,2 H),7.34(br.s.,1 H),7.41(d,J
=9.33 Hz,1 H)。
實例15 6-[1-(3,5-二氯-苄基)-哌啶-4-基胺基]-嗒-3
-甲腈(E15)
微波(Milestone微波爐)照射下,於120℃,攪拌6-氯-嗒-3-甲腈(D4)(1.74克,12.46毫莫耳)、1-(3,5-二氟-苄基)-哌啶-4-基胺(D5)(2.35克,10.386毫莫耳)與二異丙基乙胺(2.71毫升,15.58毫莫耳)於乙腈(30毫升)中之混合物40分鐘。然後添加二氯甲烷、水與碳酸鈉飽和溶液。其有機層於棉布上進行過濾,真空蒸發,殘留物利用管柱層析法純化(矽膠;0-1.5%氨之甲醇溶液(7 M)/二氯甲烷)。收集所需溶離份,真空蒸發。使殘留物於庚烷中產生沉澱,獲得呈固體之E15
(2.065克,60%)。C17
H17
F2
N5
計算值329;實測值330(MH+
);熔點:187.9℃。
1
H NMR(500 MHz,CDCl3
)δ 1.55-1.69(m,2 H),2.10(d,J
=11.85 Hz,2 H),2.21(t,J
=11.42 Hz, 2 H),2.85(d,J
=11.85 Hz,2 H),3.50(s,2 H),3.94(br.s.,1 H),5.22(br.s.,1 H),6.62(d,J
=9.54 Hz,1 H),6.69(tt,J
=8.92,2.20 Hz,1 H),6.83-6.93(m,2 H),7.41(d,J
=9.25 Hz,1 H)。
實例16
6-[1-(3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E16)
微波(Biotage微波爐)照射下,於120℃,攪拌6-氯-嗒-3-甲腈(D4)(0.130克,0.931毫莫耳)、1-(3-三氟甲基-苄基)-哌啶-4-基胺(D6)(0.241克,0.931毫莫耳)與二異丙基乙胺(0.243毫升,1.4毫莫耳)於乙腈(3毫升)中之混合物30分鐘。添加二氯甲烷與水,然後以碳酸鈉飽和溶液洗滌該混合物。其有機層於棉布上進行過濾,真空蒸發溶劑。殘留物利用管柱層析法純化(矽膠;0-2%氨之甲醇溶液(7M)/二氯甲烷),獲得呈固體之E16
(0.215克,64%)。C18
H18
F3N5
計算值361;實測值362(MH+
);熔點:170.3℃。
1
H NMR(400 MHz,CDCl3
)δ 1.61(qd,J
=11.20,3.52 Hz,2 H),2.09(d,J
=12.44 Hz,2 H),2.22(td,J
=11.20,2.07 Hz,2 H),2.86(d,J
=12.02 Hz,2 H),3.58(s,2 H),3.93(br.s.,1 H),5.18(br.s.,1 H),6.61(d,J
=9.33 Hz,1 H),7.41(d,J
=9.33 Hz,1 H),7.45(d,J
=7.67 Hz,1 H),7.49-7.55(m,2 H),7.60(br.s.,1 H)。
實例17
6-[1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E17)
微波(Biotage微波爐)照射下,於120℃,攪拌6-氯-嗒-3-甲腈(D4)(1.39克,9.95毫莫耳)、1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺(D7)(2.5克,9.04毫莫耳)與二異丙基乙胺(2.63毫升,14.92毫莫耳)於乙腈(2毫升)中之混合物30分鐘。然後以二氯甲烷(50毫升)稀釋混合物,並以碳酸鈉飽和溶液萃取。分離有機層,乾燥(Na2
SO4
),過濾,真空蒸發,殘留物利用管柱層析法純化(矽膠;0-2.5%氨之甲醇溶液(7M)/二氯甲烷)。收集所需溶離份,真空蒸發。殘留物以二異丙醚使產生沉澱,獲得呈固體之E17
(2.76克,73%)。C18
H17
F4
N5
計算值379;實測值380(MH+
);熔點:151.4℃。
1
H NMR(500 MHz,CDCl3
)δ 1.56-1.70(m,2 H),2.11(d,J
=11.85 Hz,2 H),2.24(t,J
=11.27 Hz,2 H),2.85(d,J
=11.56 Hz,2 H),3.56(s,2 H),3.96(br.s.,1 H),5.24(br.
s.,1 H),6.63(d,J
=9.25 Hz,1 H),7.22(d,J
=8.38 Hz,1 H),7.28(d,J
=9.25 Hz,1 H),7.39(s,1 H),7.42(d,J
=9.25 Hz,1 H)。
實例18
6-[1-(3,4,5-三氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E18)
微波(Milestone微波爐)照射下,於120℃,攪拌6-氯-嗒-3-甲腈(D4)(1.32克,9.46毫莫耳)、1-(3,4,5-三氟-苄基)-哌啶-4-基胺(D8)(2.10克,8.6毫莫耳)與二異丙基乙胺(2.25毫升,12.9毫莫耳)於乙腈(12毫升)中之混合物20分鐘。然後添加二氯甲烷、水與碳酸鈉飽和溶液。其有機層於棉布上進行過濾,真空蒸發,殘留物利用管柱層析法純化(矽膠;0-2%氨之甲醇溶液(7M)/二氯甲烷)。收集所需溶離份,真空蒸發。殘留物以二異丙醚使產生沉澱,獲得呈固體之E18
(2.210克,74%)。C17
H16
F3
N5
計算值347;實測值348(MH+
);熔點:185℃。
1
H NMR(500 MHz,CDCl3
)δ 1.52-1.69(m,2 H),2.10(d,J
=12.14 Hz,2 H),2.21(t,J
=10.69 Hz,2 H),2.83 (d,J
=11.85 Hz,2 H),3.44(s,2 H),3.95(br.s.,1 H),5.17(br.s.,1 H),6.62(d,J
=9.25 Hz,1 H),6.89-7.07(m,2 H),7.41
(d,J
=9.25 Hz,1 H)。
實例19
6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-4,5-二甲基-嗒-3-甲腈(E19)
微波(Biotage微波爐)照射下,於180℃,攪拌6-氯-4,5-二甲基-嗒-3-甲腈(D11)(0.120克,0.72毫莫耳)、1-(3,5-二氟-苄基)-哌啶-4-基胺(D5)(0.194克,0.86毫莫耳)與二異丙基乙胺(0.188毫升,1.08毫莫耳)於乙腈中之混合物20分鐘,然後於180℃再攪拌30分鐘。接著添加二氯甲烷、水與碳酸鈉飽和溶液。分離有機相,於棉布上過濾,真空蒸發。殘留物利用管柱層析法純化(矽膠;0-1%氨之甲醇溶液(7M)/二氯甲烷)。收集所需溶離份,真空蒸發溶劑,獲得呈固體之E19
(0.108克,42%)。C19
H21
F2
N5
計算值357;實測值358(MH+
)。
1
H NMR(400 MHz,CDCl3
)δ 1.57(qd,J
=11.58,3.63 Hz,2 H),2.07(s,3 H),2.15(d,J
=12.65 Hz,2 H),2.18-2.27(m,2 H),2.41(s,3 H),2.85(d,J
=11.82 Hz,2 H),3.49(s,2 H),4.23-4.39(m,1 H),4.46(d,J
=7.46 Hz,1 H),6.69(tt,J
=8.91,2.28 Hz,1 H),6.82-6.95(m,2 H)。
一些化合物之熔點係於開口毛細管中,以Mettler FP62裝置測定。測量熔點時,使用3或10℃/分鐘之溫度梯度。最高溫度為300℃。自數字顯示器讀取熔點,其取得帶有通常與此分析方法相關之實驗上之不確定因素。
下述附加實例(E1-E6、E8-E12與E14)係利用類似實例E7及E13敘述之程序,以D3及對應之醛類或烷化劑製備。
下述實例(E20)係利用類似實例E19敘述之程序劑製備。
若干化合物之質量係使用LCMS(液相色層分析質譜法)進行記錄。茲將所述方法敘述於下文:HPLC係使用得自Agilent Technologie之由帶有排氣器之幫浦(四溶媒或二溶媒梯度)、自動取樣器、管柱恒溫器、光電二極陣列檢測器(DAD)及下述各個方法中詳述的管柱構成之HP 1100進行測定。管柱之流液被切分至MS分光計;MS檢測器安裝著電噴灑電離源;使用氮氣作為噴霧氣體;來源溫度維持於140℃。數據之獲取係使用MassLynx-Openlynx軟體進行。逆相HPLC於得自Advanced Chromatography Technologies之ACE-C18管柱(3.0微米,4.6 x 30毫米)上進行,流速1.5毫升/分鐘,溫度40℃。
所用梯度條件為:6.5分鐘內由80% A(0.5克/升乙酸銨溶液)、10% B(乙腈)、10% C(甲醇)至50% B與50% C,7分鐘時至100% B,7.5分鐘時平衡至初始條件至9.0分鐘止;注入量為5微升。高解析質譜光譜(Time of Flight,TOF)僅自正電離模式獲取,係於0.5秒內自100掃瞄至750,停留時間為0.1秒。正電離模式之毛細管針電壓為2.5 kV,錐電壓為20 V。使用Leucine-Enkephaline作為封鎖質量(lock mass)校正之標準物質。
下述化學名稱參照實例編號:6-[1-(3,4-二氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E1)、6-[1-(4-氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E2)、6-[1-(4-氯-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E3)、6-[1-(3-氟-4-甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E4)、6-[1-(3-氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E5)、6-[1-(4-甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E6)、6-[1-(4-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E7)、
6-[1-(3-氟-4-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E8)、6-[1-(4-氟-3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E9)、6-[1-(4-甲基-3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E10)、6-[1-(3,5-雙-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E11)、6-[1-(2-氟-5-三氟甲基--苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E12)、6-[1-(3-氯-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E13)、6-[1-(3-氯-4-三氟甲氧基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E14)、6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E15)、6-[1-(3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E16)、6-[1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E17)、6-[1-(3,4,5-三氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈(E18)、6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-4,5-二甲基-嗒-3-甲腈(E19)及6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-4-甲基-嗒-3-甲腈(E20)。
將經人類多巴胺D2L
受器轉染之CHO細胞之冰凍膜解凍,使用ULtra-TurraxT25均質器簡單地均質化,然後以含有NaCl、CaCl2
、MgCl2
、KCl(分別為50、120、2、1、與5 mM,以HCl調至pH 7.7)之Tris-HCl試驗緩衝液稀釋至經最適化以供專一性及非專一性結合之適當蛋白質濃度。放射配位體[3
H]螺旋丁苯(NEN,比活性~70 Ci/毫莫耳)以試驗緩衝液稀釋至濃度為2奈莫耳/升。然後使製備好之放射配位體(50微升)與50微升10% DMSO對照組[Butaclamol(最終濃度10-6
莫耳/升)]或參與之化合物以及400微升製備好之膜溶液一起培育(30分鐘,37℃)。以通過Packard Filtermate收取器過濾於GF/B Unifilterplates 上,再以冰冷Tris-HCl緩衝液(50 mM;pH 7.7;6 x 0.5毫升)洗滌後表示膜結合之活性。待濾器乾燥後,添加閃爍液,於Topcount閃爍計數器上進行計數。使用S-Plus軟體(Insightful)計算專一性結合及競爭性結合曲線。
顯示IC50
小於10 μM之化合物於自Josee E.Leysen and Walter Gommeren,Journal of Receptor Research,1984,4(7),817-845發表的方法改造之間接試驗中進行測試,以評估其解離速率。先使濃度4倍於其IC50
之化合物與容積2毫升之人類D2L受器細胞膜於25℃培育一小時,然後在抽吸下,使用40槽多分器(multividor),在玻璃纖維濾器上過濾。隨後立即釋放真空。將含有1 nM[3
H]螺旋丁苯之0.4毫升先行加溫之緩衝液(25℃)添加於濾器上5分鐘。開始抽真空以終止培育,隨即以2 x 5毫升冰冷緩衝液清洗。於液相閃爍分光計中測定與濾器結合之放射活性。檢測原理係基於假設化合物愈快與D2受器解離,則[3
H]螺旋丁苯愈快與D2受器結合。舉例而言,當D2受器與濃度1850 nM(4 x IC50
)之氯氮平一起培育時,於濾器上培育5分鐘後之[3
H]螺旋丁苯結合作用相當於其總結合量(於不存在藥物下測定)之60-70%;與其他抗精神病藥物一起培育時,[3
H]螺旋丁苯結合作用為20至50%不等。由於各回合過濾中均涵蓋氯氮平,因此測試化合物之解離若與氯氮平一樣快或比氯氮平快,則視其為迅速解離之D2拮抗劑。到目前為止,所有經測試之化合物均具有較氯氮平迅速之解離速率,亦即>50%。
投與Wiga Wistar公大鼠(180-280克)測試化合物(sc:皮下;po:經口;每劑量n=3;劑量=0.16、0.63與2.5毫克/公斤)或溶劑,接著於30分鐘時以阿朴嗎啡(1.0毫克/公斤,i.v.)攻毒。以多系列經溶劑預處理之大鼠所得對照組數據產生之分佈為基礎,根據全有或全無準則,評估測試化合物對行為變化之影響。
注射阿朴嗎啡後,於第一小時期間,每隔5分鐘評分
記錄由阿朴嗎啡(1.0毫克/公斤,i.v.)誘發之震顫、刻板症(強迫性地嗅、舔、咀嚼)。該評分系為:(3)明顯、(2)中度、(1)輕微、及(0)不存在。藥物引發之對震顫之抑制作用準則:記分為3者少於6隻[0.16%偽陽性(false positives);n=2966]、記分≧2者少於6隻(0.0%偽陽性)或記分≧1者少於7隻(0.0%偽陽性)。下表提供3隻測試大鼠中有3隻符合藥物引發之震顫抑制作用準則之一者時之最低活性劑量。
Claims (10)
- 一種具下式(I)之化合物
- 根據申請專利範圍第1項之化合物,其中R、R3 與R4 為氫。
- 根據申請專利範圍第1項之化合物,其中R2 為氫或甲基。
- 根據申請專利範圍第1項之化合物,其中R1 為3,5-二氟苯基、3,4,5-三氟苯基、3-三氟甲基苯基、3-氟-5-三氟甲基苯基或3-氟-4-甲基苯基。
- 根據申請專利範圍第1項之化合物,其中該化合物係選自下述組群:6-[1-(3,5-二氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈、 6-[1-(3-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈、6-[1-(3-氟-5-三氟甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈、6-[1-(3,4,5-三氟-苄基)-哌啶-4-基胺基]-嗒-3-甲腈、及6-[1-(3-氟-4-甲基-苄基)-哌啶-4-基胺基]-嗒-3-甲腈。
- 一種醫藥組成物,其包含治療上有效量之如申請專利範圍第1項界定之化合物。
- 如申請專利範圍第1項界定之化合物,係作為藥劑用途。
- 如申請專利範圍第7項界定之化合物,係作為抗精病藥物用途。
- 如申請專利範圍第7項界定之化合物,係作為藥劑用途以治療或預防下述疾病:精神分裂症、類精神分裂症、情感性精神分裂症、妄想症、短期精神病、共享型精神病、一般醫學狀況造成之精神病、物質誘發之精神病、未另列名之精神病;伴隨癡呆之精神病;重鬱症、輕鬱症、經前煩憂症、未另列名之憂鬱症、I型躁鬱症、II型躁鬱症、循環性精神病、未另列名之躁鬱症、一般醫學狀況造成之情緒性疾病、物質誘發之情緒性疾病、未另列名之情緒性疾病;廣泛性焦慮症、強迫症、恐慌症、急性壓力症、創傷後壓力症;智能障礙;廣泛性發展障礙;注意力缺乏症、注意力缺乏/過動症、破壞性行為症;偏執狂型人格異常、類精神分裂型人格異常、精神分裂型人格異常;抽動症、妥端氏症;物質依賴;物質濫用; 物質戒斷;拔毛症。
- 一種製備式(I)化合物之方法,
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