CN115025086A - 双环杂芳基衍生物及其制备与用途 - Google Patents
双环杂芳基衍生物及其制备与用途 Download PDFInfo
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- CN115025086A CN115025086A CN202210514104.9A CN202210514104A CN115025086A CN 115025086 A CN115025086 A CN 115025086A CN 202210514104 A CN202210514104 A CN 202210514104A CN 115025086 A CN115025086 A CN 115025086A
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- selenazol
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Abstract
提供了式(A)的化合物,即双环杂芳基衍生物,以及其制备与用途,和包含这些化合物的药物组合物以及其作为谷氨酸传递功能失调的调节剂的用途,其中式(A)的化合物中的变量的限定如说明书中所述。还提供了该化合物或药物组合物用于治疗或预防人类的一些神经及精神病症和疾病以及癌症的用途。
Description
本申请为2017年03月30日提交的申请号为201780088998.7且发明名称为“双环杂芳基衍生物及其制备与用途”的专利申请的分案申请。
技术领域
本发明涉及医药技术领域,特别涉及一些化合物、其制备与用途,以及包含该化合物的药物组合物。如示例性的,本发明涉及一些双环杂芳基衍生物、其制备方法以及相应的药物组合物。本发明的化合物和/或药物组合物能潜在地用于制备用于预防、治疗、改善患者的某些病症或疾病(其特别包括神经或精神病症或疾病以及癌症)的药物。相信本发明的化合物和/或药物组合物尤其是经由调节(例如阻断)谷氨酸传递功能失调的作用来发挥其治疗益处。
背景技术
根据临床发现及其相关临床前模型的证据,谷氨酸传递功能失调在多种疾病病理学中扮演重要的角色(例如于3/7/2017检索的概要:https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4693272/pdf/biomolecules-05-03112.pdf)。在这些疾病的进展中,谷氨酸的释放和/或吸收的潜在机制明显涉及由通过各自的细胞膜离子通道的异常细胞间离子流动而引起的其细胞间的传递。如下文所示,经由公开的药物(无论是直接地或经由诱导一连串介入路径)对这些通道的调节(例如阻断)可以缓解该疾病的进展。
许多神经和精神疾病涉及由异常的Na和/或Ca活化的K(亦称为KCa2、SK)离子通道引起的谷氨酸传递功能失调例如A.Doble,The Role of Excitotoxicity inNeurodegenerative Disease:Implications for Therapy,Pharmacol.Ther.Vol.81(3),pp.163–221和J.Lam,et.al.The Therapeutic Potential of Small-Conductance KCa2Channels in Neurodegenerative and Psychiatric Diseases,Expert Opin TherTargets Vol.17(10),pp.1203–1220)。这类神经变性疾病包括肌萎缩侧索硬化症(ALS)、例如是神经病变的慢性疼痛、多发性硬化症(MS)、运动失调、帕金森氏症、亨廷顿舞蹈症、妥瑞氏症、癫痫、肌张力不全症、X染色体脆折症以及由创伤性脑/脊髓损伤或脑缺血引起的病症。精神疾病包括抑郁症、焦虑症、躁郁症、精神分裂症、强迫症、自闭症、青光眼诱发的视神经病以及酒精/药物成瘾。认知功能障碍包括但不限于痴呆(血管和阿兹海默症)和注意力缺陷/多动症(ADHD)。不幸的是,当上述疾病/病症进展时,它们在晚期会抵抗目前批准的药物治疗或在早期开始药物治疗后变为具有抗药性。例如,在重度抑郁症中(例如于3/7/2017检索的https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762009/pdf/nihms- 113976.pdf),大量患者群体 (10-55%,取决于所访问的数据库)具有/产生‘治疗抗药性’(参见例如于3/7/2017检索的 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609854/pdf/DRT2015-842817.pdf和PMH14 http://www.valueinhealthjournal.com/ article/S1098-3015(14)03177-5/pdf的摘要)。在癫痫中,相当一部分患者(20-30%)对目前批准的药物具有/产生抗药性(例如:于3/7/2017检索的https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC5068473/pdf/ndt-12-2605.pdf)。癫痫是一种据估计影响全球超过5000万人的复杂的神经系统疾病,其特征是由于神经元过度兴奋以及超同步神经放电引起的反复发作的自发性癫痫发作。尽管可获得超过20种抗癫痫药物(AED),但30%的癫痫患者仍然继续经受癫痫发作或遭受不良的药物副作用,例如嗜睡、行为改变、肝损伤或致畸(参阅例如于3/7/2017检索的https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC5114206/pdf/40268_2016_Article_148.pdf中引用的多篇参考文献)。
此外,涉及肿瘤细胞的Na受体通道的谷氨酸吸收被认为会增强癌症的转移(例如M.B.A. Djamgoz,Persistent Current Blockers of Voltage-Gated Sodium Channels:AClinical Opportunity for Controlling Metastatic Disease,Recent Pat AnticancerDrug Discov.Vol.8(1),pp.66-84以及 T.Koltai,Voltage-gated sodium channel as atarget for metastatic risk reduction with re-purposed drugs,F1000 ResearchVol.4,p.297)。在患有转移性黑色素瘤患者的第二期临床试验中和之后使用利鲁唑(Riluzole)治疗(对于利鲁唑,目前市场批准仅用于治疗ALS,参阅于3/7/2017 检索的https://en.m.wikipedia.org/wiki/Riluzole;于3/7/2017检索的2017年1月陈述以利鲁唑治疗包含ALS的疾病的第2-4期临床疗效试验:https://clinicaltrials.gov/ct2/ results?term=riluzole&type=Intr&rslt=&recr=&age_v=&gndr=&cond=&intr= riluzole&titles=&outc=&spons=&lead=&id=&state1=&cntry1=&state2=& cntry2=&state3=&cntry3=&locn=&phase=1&phase=2&phase=3&rcv_s=&rcv_e=& lup_s=&lup_e=)。在临床试验中,尽管RECIST(实体瘤疗效评价标准)等级没有整体改善,但转移初步稳定在42%。为进一步提高利鲁唑治疗转移性黑色素瘤的疗效,提出与其他抗癌药物的结合治疗(于 3/7/2017检索的http://meetinglibrary.asco.org/content/ 83734-102)。
因此,迫切需要治疗这些「‘抗药性’患者的新药,无论是作为单一治疗还是整合到结合方案中(例如some combinations of existing drugs to treat epilepsy:N.Matsumura,Isobolographic analysis of the mechanisms of action ofanticonvulsants from a combination effect,European Journal of Pharmacology,Vol.741,pp.237-246)。
本申请中公开的化合物和药物配方在为上述治疗适应症提供实现调节谷氨酸传递功能失调所需的解决方案方面是有效的。
发明内容
以下仅为本发明的一些方面的概述,但不限于此。本说明书中的所有参考文献的全部内容通过引用并入本文。当本说明书的公开与引文不同时,以本说明书的公开为准。本发明提供经由钠通道及KCa2通道调节谷氨酸传递功能失调的化合物及药物组合物,本发明包含一些双环杂芳基衍生物、其制备方法及相对应的药物组合物。本发明的化合物和/或药物组合物能够潜在地用于制备用于预防、治疗、改善患者的某些病症或疾病(其特别包括神经或精神病症或疾病以及癌症)的药物。
本发明的一个方面为提供式(A)的化合物或其药学上可接受的盐:
其中
X为NH、O、S或Se;
W1或W2为CH或N,条件为W1和W2不同时为N;
R1和R2为相同或不同,并且独立地选自由以下所组成的基团组:
氢和
GRa,其中G为不存在、-C(O)-或–C(O)O-且Ra为具有1至4个碳原子的饱和直链或支链烷基,或具有3至6个碳原子的饱和环烷基,条件为R1和R2不同时为GRa,其中G 存在;
Yq为选自由氢、氘、SF5、CF3、OCF3、SCF3、S(O)CF3、S(O)2CF3、CN、SCN、S(O)CH3、 S(O)2CH3、NO2所组成的基团组,且其中q为1或2;条件为当q为2时,Y1和Y2可以相同或不同,且Y1和Y2不同时为氢、或不同时为氘、或不分别为氢和氘;
并且
当W1和W2为CH时,式(A)的化合物不为以下化合物之一:
其中R1或R2如上述定义;且
当W1或W2为N时,式(A)的化合物不为以下化合物之一:
其中R1或R2为如上述定义。
在另一方面,本发明涉及多种药物组合物,每种药物组合物包含有效量的至少一种式(A) 的化合物或式(A)的化合物的药学上可接受的盐。依据本发明的药物组合物可进一步包含至少一种药学上可接受的赋形剂、载体、佐剂、溶剂、载剂或其组合。
在另一方面,本发明涉及一种治疗特别是患有由谷氨酸传递功能失调介导的神经或精神疾病或病症或癌症医学症状的受试者的方法,包含向需要该治疗的受试者给药有效量的至少一种式(A)的化合物或式(A)的化合物的药学上可接受的盐,或包含向需要该治疗的受试者给药有效量的包含有效量的至少一种式(A)的化合物或式(A)的化合物的药学上可接受的盐的药物组合物。
本发明的一方面涉及式(A)的化合物用于制备在治疗、预防、抑制或消除神经和精神病症或疾病中使用的药物的用途,该药物还包含治疗有效量的一种或多种任选的辅助活性成分,该辅助活性成分包含抗精神障碍类疾病药、非典型抗精神障碍类疾病药、抗癫痫药、抗帕金森氏症药、抗肌萎缩性侧索硬化症药、抗疼痛药、抗多发性硬化症药、脊髓损伤药或其组合,选自由利鲁唑(riluzole)、阿米替林(amitriptyline)、地昔帕明(desipramine)、米氮平(mirtazapine)、安非他酮(bupropion)、瑞波西汀(reboxetine)、氟西汀(fluoxetine)、曲唑酮(trazodone)、舍曲林 (sertraline)、度洛西汀(duloxetine)、氟伏沙明(fluvoxamine)、米那普仑(milnacipran)、左旋米那普仑(levomilnacipran)、去甲文拉法辛(desvenlafaxine)、维拉佐酮(vilazodone)、文拉法辛 (venlafaxine)、达泊西汀(dapoxetine)、奈法唑酮(nefazodone)、非莫西汀(femoxetine)、氯米帕明(clomipramine)、西酞普兰(citalopram)、依他普仑(escitalopram)、帕罗西汀(paroxetine)、碳酸锂(lithium carbonate)、丁螺环酮(buspirone)、奥氮平(olanzapine)、喹硫平(quetiapine)、利培酮(risperidone)、齐拉西酮(ziprasidone)、阿立哌唑(aripiprazole)、哌罗匹隆(perospirone)、氯氮平(clozapine)、莫达非尼(modafinil)、美卡拉明(mecamylamine)、卡麦角林(cabergoline)、金刚烷(adamantane)、丙咪嗪(imipramine)、普拉克索(pramipexole)、甲状腺素(thyroxine)、右美沙芬(dextromethorphan)、奎尼丁(quinidine)、纳曲酮(naltrexone)、塞米多芬(samidorphan)、丁丙诺啡(buprenorphine)、褪黑激素(melatonin)、阿普唑仑(alprazolam)、匹泮哌隆(pipamperone)、维替匹坦(vestipitant)、奋乃静(perphenazine)、咪达唑仑(midazolam)、三唑仑(triazolam)、艾司唑仑(estazolam)、地西泮(diazepam)、氟西泮(flurazepam)、硝西泮(nitrazepam)、氯硝西泮 (clonazepam)、替马西泮(temazepam)、氟硝西泮(flunitrazepam)、奥沙西泮(oxazepam)、唑吡坦(zolpidem)、扎来普隆(zaleplon)、佐匹克隆(zopiclone)、右佐匹克隆(eszopiclone)、茚地普隆(indiplon)、噻加宾(tiagabine)、加波沙朵(gaboxadol)、氯米帕明(clomipramine)、多塞平 (doxepin)、水合氯醛(chloral hydrate)、氟哌啶醇(haloperidol)、氯丙嗪(chlorpromazine)、卡马西平(carbamazepine)、异丙嗪(promethazine)、劳拉西泮(lorazepam)、羟嗪(hydroxyzine)、阿司匹林(aspirin)、苯海拉明(diphenhydramine)、氯苯那敏(chlorpheniramine)、恋多眠(lendormin)、雷美尔通(ramelteon)、他司美琼(tasimelteon)、阿戈美拉汀(agomelatine)、米安色林(mianserin)、非莫西汀(femoxetine)、大麻隆(nabilone)、多塞平(doxepin)、加巴喷丁(gabapentin)、利眠宁(chlordiazepoxide)、苏沃雷生(suvorexant)、血藏固本(Xuezang Guben)或其组合所组成的群组。
本发明的一方面涉及式(A)的化合物用于制备在治疗、预防、抑制或消除癌症中使用的药物的用途,该药物还包含治疗有效量的一种或多种任选的辅助活性成分,该辅助活性成分包括化疗药剂,该化疗药剂选自由以下所组成的群组:细胞毒性药剂、顺铂(cisplatin)、阿霉素(doxorubicin)、泰素帝(taxotere)、他克唑(taxol)、依托泊苷(etoposide)、伊立替康(irinotecan)、开普拓(camptostar)、托泊替康(topotecan)、紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)、埃博霉素(epothilones)、他莫昔芬(tamoxifen)、5-氟尿嘧啶(5-fluorouracil)、甲氨蝶呤(methoxtrexate)、替莫唑胺(temozolomide)、环磷酰胺(cyclophosphamide)、SCH 66336、替吡法尼 (tipifarnib)(Zarnestra)、R115777、L778,123、BMS 214662、易瑞沙(Iressa)、特罗凯 (Tarceva)、C225、格列卫(GLEEVEC)、intron、佩乐能(Peg-Intron)、芳香化酶(aromatase)组合物、阿糖胞苷(ara-C)、阿霉素(adriamycin)、爱忆欣(ercept)、吉西他滨(gemcitabine)、乌拉莫司汀(Uracil mustard)、氮芥(Chlormethine)、异环磷酰胺(Ifosfamide)、美法仑(Melphalan)、苯丁酸氮芥(Chlorambucil)、哌泊溴烷(Pipobroman)、三亚乙基蜜胺 (Triethylenemelamine)、三亚乙基硫代磷胺(Triethylenethiophosphoramine)、白消安(Busulfan)、卡莫司汀(Carmustine)、洛莫司汀(Lomustine)、链佐星(Streptozocin)、达卡巴嗪(Dacarbazine)、氟尿苷(Floxuridine)、阿糖胞苷(Cytarabine)、6-巯嘌呤(6-Mercaptopurine)、6-硫鸟嘌呤 (6-Thioguanine)、磷酸氟达拉滨(Fludarabine phosphate)、奥沙利铂(oxaliplatin)、亚叶酸 (leucovirin)、奥沙利铂(oxaliplatin)(ELOXATIN)、喷司他丁(Pentostatine)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、博来霉素(Bleomycin)、更生霉素(Dactinomycin)、道诺霉素(Daunorubicin)、表柔比星(Epirubicin)、伊达比星(Idarubicin)、光辉霉素TM(MithramycinTM)、脱氧助间型霉素(Deoxycoformycin)、丝裂霉素-C(Mitomycin-C)、 L-门冬酰胺酶(L-Asparaginase)、替尼泊苷17α-炔雌醇(Teniposide17α-Ethinylestradiol)、己烯雌酚(Diethylstilbestrol)、睾酮(Testosterone)、泼尼松(Prednisone)、氟甲睾酮(Fluoxymesterone)、丙酸屈他雄酮(Dromostanolonepropionate)、睾内酯(Testolactone)、醋酸甲地孕酮(Megestrol acetate)、甲基泼尼松龙(Methylprednisolone)、甲基睾固酮(Methyltestosterone)、泼尼松龙 (Prednisolone)、曲安奈德(Triamcinolone)、氯烯雌醚(Chlorotrianisene)、羟孕酮(Hydroxyprogesterone)、氨鲁米特(Aminoglutethimide)、雌莫司汀(Estramustine)、醋酸甲羟孕酮(Medroxyprogesteroneacetate)、亮丙瑞林(Leuprolide)、氟他胺(Flutamide)、托瑞米芬 (Toremifene)、戈舍瑞林(goserelin)、卡铂(Carboplatin)、羟基脲(Hydroxyurea)、安吖啶 (Amsacrine)、丙卡巴肼(Procarbazine)、密妥坦(Mitotane)、米托蒽醌(Mitoxantrone)、左旋咪唑(Levamisole)、诺维本(Navelbene)、阿那曲唑(Anastrazole)、来曲唑(Letrazole)、卡培他滨 (Capecitabine)、雷洛昔芬(Reloxafine)、屈洛昔芬(Droloxafine)、六甲三聚氰胺 (Hexamethylmelamine)、安维汀(Avastin)、贺癌平(herceptin)、百克沙(Bexxar)、万珂(Velcade)、替伊莫单抗(Zevalin)、三氧化二砷(Trisenox)、截瘤达(Xeloda)、长春瑞滨(Vinorelbine)、卟吩姆钠(Porfimer)、艾比特思(Erbitux)、脂质体(Liposomal)、赛替派(Thiotepa)、六甲蜜胺 (Altretamine)、美法仑(Melphalan)、曲妥珠单抗(Trastuzumab)、氟维司群(Fulvestrant)、依西美坦(Exemestane)、异环磷酰胺(Ifosfomide)、利妥昔单抗(Rituximab)、坎帕斯(Campath)、亚叶酸(leucovorin)、和地塞米松(dexamethasone)、比卡鲁胺(bicalutamide)、卡铂(carboplatin)、苯丁酸氮芥(chlorambucil)、来曲唑(letrozole)、甲地孕酮(megestrol)和戊柔比星(valrubicin)或其组合。
本发明的另一方面涉及式(A)的化合物用于制备经由调节患者的谷氨酸传递而治疗、预防、抑制或消除所述患者的病症或疾病或医学症状的药物的用途,其中所述病症或疾病或医学症状选自由以下所组成的群组:神经胶质瘤、乳癌、黑色素瘤;肌萎缩侧索硬化症(ALS)、慢性神经病疼痛、多发性硬化症、运动失调、帕金森氏症、亨廷顿舞蹈症、妥瑞氏症、癫痫、肌张力不全症、X染色体脆折症、由创伤性脑/脊髓损伤引起的病症、由脑缺血引起的病症;抑郁症、焦虑症、躁郁症、精神分裂症、强迫症、自闭症、酒精/药物成瘾;血管和阿兹海默痴呆症、青光眼诱发的视神经病和注意力缺陷/多动症(ADHD)。
在本发明的又一方面,该式(A)的化合物及其药学上可接受的盐类用作谷氨酸传递的调节剂。因此,本发明涉及一种用于调节受试者谷氨酸传递的方法,包含将该受试者暴露于有效量的至少一种式(A)的化合物或式(A)的化合物的药学上可接受的盐。
在又一方面,本发明涉及制备式(A)的化合物及其药学上可接受的盐类的方法。
在本发明的化合物、药物组合物以及方法的一些实施例中,式(A)的化合物为选自以下在具体实施方式部分中详细描述或列举的那些种类的化合物、或为该化合物的药学上可接受的盐。
在另一优选的实施例中,本发明涉及制备多种药物组合物的方法,每种药物组合物包含有效量的至少一种式(A)的化合物或式(A)的化合物的药学上可接受的盐。依据本发明的药物组合物可进一步包含至少一种药学上可接受的赋形剂、载体、佐剂、溶剂、载剂或其组合。
如果配制为固定剂量,该组合产物采用本文所述的(或本领域技术人员已知的)剂量范围内的本发明化合物和剂量范围内的其他药物活性药剂或治疗剂。例如,已发现CDC2抑制剂奥罗莫星(olomucine)与已知的细胞毒性药剂药剂协同作用诱导细胞凋亡(J.CellSci.,(1995)108,2897)。当组合配制不适合时,本发明的化合物亦可与已知的抗癌或细胞毒性药剂依序地给药。在任何组合治疗中,本发明不受给药顺序的限制;式(A)的化合物可在已知抗癌或细胞毒性药剂给药之前或之后给药。例如,细胞周期蛋白依赖性激酶抑制剂夫拉平度(flavopiridol)的细胞毒活性受抗癌药剂给药顺序的影响(Cancer Research,(1997)57,3375)。该技术在本领域技术人员以及主治医师的技术范围内。
任何前述方法可经由流体(例如水)、髓袢利尿剂、一种或多种化疗或抗肿瘤药剂(例如亚叶酸(商品名也称为若克瘤,leucovorin)和氟尿嘧啶(商品名也称为服乐癌,fluorouracil))、以及辅助化疗药剂(例如惠尔血添(filgrastim)和红细胞生成素(erythropoietin))、或任何前述的组合的给药来增强。
另一实施例为通过向需要其的受试者(如人)给药本发明的药物调配物来向该受试者给药本发明的化合物的方法。
另一实施例为通过将至少一种药学上可接受的本发明的化合物和任选地一种或多种药学上可接受的添加剂或赋形剂混合来制备本发明的药物调配物的方法。
为了从本发明所述的化合物制备药物组合物,惰性的、药学上可接受的载体可为固体或液体。固体型式的制剂包含粉剂、片剂、可分散的颗粒剂、胶囊、珠剂、扁囊剂以及栓剂。粉剂及片剂可包括约5至约95百分比的活性成分。适宜的固体载体为本技术领域中已知,如碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、粉剂、扁囊剂以及胶囊可用作适宜口服给药的固体剂型。药学上可接受的载体以及制备各种组合物的方法的示例可在A.Gennaro(ed.), Remington's Pharmaceutical Sciences,18th Edition,(1990),Mack PublishingCo.,Easton,Pa.中发现。
液体型式的制剂包含溶液、悬浮液以及乳液。作为示例可提及用于肠胃外注射的水或水 -丙二醇溶液或添加甜味剂和遮光剂(opacifier)用于口服溶液、悬浮液和乳液。液体型式的制备亦可包含用于鼻内给药的溶液。
适宜用于吸入的气雾剂制剂可包含溶液和粉末型式的固体,其可与药学上可接受的载体组合,例如惰性压缩气体,如氮气。
亦包含固体型式制剂,其用于在使用前不久转化为用于口服或肠胃外给药的液体型式制剂。该液体型式包含液体、悬浮液和乳液。
本发明的化合物亦可经皮递送。该经皮组合物可以采用乳膏剂、洗剂、气雾剂和/或乳液的型式,并且可包含在本技术领域中通常用于该目的的基质或储存型式的经皮贴剂中。
本发明的化合物亦可皮下递送。
该化合物优选为口服或静脉内给药。
优选地,该药物制剂为单位剂型。在这种型式中,制剂会被细分成含有适量(如达到所需目的的有效量)的活性成分的大小适宜的单位剂量。
根据具体应用,在制剂的单位剂量中活性化合物的量可从约1mg变化或调整至约1000mg,优选为从约1mg变化或调整至约500mg,更佳为从约1mg变化或调整至约250mg,还更佳为从约1mg变化或调整至约50mg。
使用的实际剂量可依据患者的需求以及受治疗症状的严重性来变化。对特定情况确定适当的给药方案在本技术领域的范围内。为求方便起见,可根据需要将每日总剂量分成多个部分并在一天内分次给药。本发明的化合物及其药学上可接受的盐的给药量及给药频率将根据主治医师结合患者的年龄、症状和大小以及受治疗病状的严重程度等因素的判断来调节。用于口服给药的典型推荐的每日给药方案可在约1mg/天至约200mg/天的范围内,优选在10mg/ 天至100mg/天的范围内,以1至2个分剂量服用。
本文所公开的任何实施例可与其他实施例结合,只要它们彼此之间不矛盾,即使这些实施例是在本发明的不同方面之下描述的。此外,只要它们彼此之间不矛盾,一实施例中的任何技术特征可应用于其他实施例中的相对应的技术特征,即使这些实施例是在本发明的不同方面之下描述的。
前述仅概述了本文所公开的某些方面,并且本质上不是限制性的。本发明的这些方面和其他方面以及其他实施例、特征和优点将从以下详细描述和通过本发明的实施变得明显。
附图说明
经由参考所附方案和附图进行的以下描述,本公开的实施例的这些和其它方面和优点将变得明显且更易于理解,其中:
图1A和图1B显示化合物I对hNav1.2/1.7通道的抑制效果。
图2显示在SNL大鼠中化合物I的抗异常性疼痛效果。
图3显示在大鼠中化合物I的药物动力学参数。
具体实施方式
为求简洁起见,本说明书中所引用的包含专利和专利申请的出版物的公开在此通过引用全部并入本文。
在本文中使用的大部分化学名称是使用IUPAC命名法产生的。一些化学名称是使用本技术领域已知的不同命名法或替代名称或商业名称产生的。在名称和结构之间存在冲突的情况下,以结构为准。
定义及一般术语
现在将参考本发明的一些实施例来详细描述本发明,其示例伴随结构式和化学式来说明。本发明旨在涵盖可能包含在如权利要求书所限定的本发明的范围内的所有替代、修改和等同物。本领域技术人员会识别出许多类似于或等同于本文所描述的方法和材料,这些方法和材料可以应用于本发明的实践中。本发明绝非限于本文所描述的方法和材料。如果一个或多个所并入的文献、专利和相似的材料不同于本申请或与本申请相抵触,其中包括但不限于术语的定义、术语的用法、描述的技术等,则以本申请为准。
可进一步理解的是,为清楚起见在分开的实施例的上下文中描述的本发明的一些特征也可在单一实施例中组合提供。相反地,为简洁起见在单一实施例的上下文中描述的本发明的各种特征亦可单独地或在任何适宜的次组合中提供。
除非另有定义,否则本文所使用的所有技术及科学术语具有与本发明所属技术领域的技术人员所通常理解的相同含义。本文所提及的所有专利和出版物在此通过参考全部并入。
如本文所述,除非另有说明,否则应适用以下定义。为了本发明的目的,化学元素依据元素周期表,CAS版本和Handbook of Chemistry and Physics,第75版,1994来确定。另外,有机化学的一般原则在“Organic Chemistry”,Thomas Sorrell,UniversityScience Books, Sausalito:1999、和Michael B.Smith和Jerry March的“March’sAdvanced Organic Chemistry”, John Wiley&Sons,New York:2007中描述,其所有内容通过引用并入本文。
如上述以及在整个本公开中所使用的,除非另有说明,以下术语应理解为具有以下含义。如果缺少定义,则以本技术领域的技术人员已知习用的定义为准。如果本文提供的定义与任何引用的出版物中提供的定义冲突或不同,则以本文提供的定义为准。
如本文中使用,术语“包括”、“含有”以及“包含”以其开放式、非限制性的含义使用。
如本文中使用,单数形式“一个”、“一种”以及“该”包括复数形式,除非上下文另有明确规定。
为了提供更简洁的描述,本文给出的一些量的表达不符合术语“约”。应了解的是,无论术语“约”明确使用与否,本文给出的每个量是指实际给定值,也可以是指基于本技术领域的常规技术合理推断的该给定值的近似值,包括由于实验和/或测量条件所导致的该给定值的当量值和近似值。当产率以百分比形式给出时,该产率指的是给出产率的实体的质量相对于可在特定化学计量条件下获得的同一实体的最大量。除非另有不同的指示,否则以百分比形式给出的浓度是指质量比。
化学定义
如本文中使用,“烷基”是指具有1至12个碳原子的饱和的、直链或支链烃基。代表性的烷基基团包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2- 甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1- 戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、 3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等,以及较长的烷基基团,如庚基、辛基等。如本文中使用的,“低级烷基”是指具有1 至6个碳原子的烷基。
如本文中使用的术语“烷基氨基”是指本文所定义的氨基基团,其中氨基基团的一个氢原子被如本文所定义的烷基基团取代。氨基烷基基团可以由以下通式-NH-烷基定义。该通式包含以下通式的基团:-NH-C1-C10烷基和-NH-C1-C6烷基。氨基烷基基团的示例包含,但不限于氨基甲基、氨基乙基、氨基丙基、氨基丁基。
如本文中使用的术语“二烷基氨基”是指本文所定义的氨基基团,其中氨基基团的两个氢原子被如本文所定义的烷基基团取代。二氨基烷基基团可以由以下通式-NH-(烷基)2定义,其中烷基基团可为相同或不同,且可选自本文所定义的烷基,例如C1-C10烷基或C1-C6烷基。
如本文中使用的术语“烷氧基”包含-O-(烷基),其中烷基如上述定义。
如本文中使用,“烷氧基烷基”表示-(亚烷基(alkylenyl))-O-(烷基),其中每个“烷基”独立地为上述定义的烷基。
如本文中使用的术语“氨基”是指-NH2基团。
“芳基”表示单-、双-、或三环芳香族基团,其中基团的所有环均为芳香族的。对于双- 或三环体系,各个芳香环彼此稠合。芳基基团的示例包含但不限于苯基、萘和蒽。
如本文中使用的“芳氧基”系指-O-(芳基)基团,其中芳基如上述定义。
如本文中使用的“芳基烷基”是指-(亚烷基)-(芳基)基团,其中亚烷基和芳基如上述定义。芳基烷基的非限制性示例包含低级烷基基团。适宜的芳基烷基基团的非限制性示例包含苄基、2-苯乙基和萘基甲基。
如本文中使用的“芳基烷氧基”是指-O-(亚烷基)-芳基基团,其中亚烷基和芳基如上述定义。
如本文中使用的术语“氰基”表示具有经由三键与氮原子连接的碳原子的取代基。
术语“氰基烷基”是指如上所定义的烷基,其中烷基基团的氢原子被氰基(-CN)取代。氰基烷基基团的烷基部分提供与分子其余部分的连接点。
如本文中使用的术语“氘”表示氢的具有一个质子和一个中子的稳定同位素。
如本文中使用的术语“卤素”是指氟、氯、溴或碘。术语“卤代”表示氯代、氟代、溴代或碘代。
术语“卤代烷基”表示如上述定义的烷基基团,其中烷基基团的一个或多个,例如一个、二个或三个氢原子被卤素原子取代,例如氟代、溴代或氯代,特别是氟代。卤代烷基的示例包含但不限于单氟代-、二氟代-或三氟代-甲基、-乙基或-丙基,例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基、二氟甲基或三氟甲基、或溴乙基或氯乙基。类似地,术语“氟代烷基”表示被一个或多个,例如一个、二个或三个氟原子取代的如上述定义的烷基。
如本文中使用的术语“卤代烷氧基”表示-O-(卤代烷基)基团,其中卤代烷基如上述定义。卤代烷氧基基团的示例为溴乙氧基、氯乙氧基、三氟甲氧基和2,2,2-三氟乙氧基。
术语“羟基”表示-OH基团。
术语“羟烷基”表示被至少一个羟基基团(例如一个、二个或三个羟基基团)取代的烷基。羟烷基基团的烷基部分提供与分子其余部分的连接点。羟烷基基团的示例包含,但不限于羟甲基、羟乙基、1-羟丙基、2-羟异丙基、1,4-二羟丁基等。
术语“含氧(oxo)”表示=O基团且可连接至碳原子或硫原子。术语“N-氧化物”表示氮原子的氧化形式。
如本文中使用,术语“环烷基”表示具有3至12个环碳原子的饱和或部分饱和的单环、稠合多环、桥接多环、或螺环(spiro)多环的碳环。环烷基基团的非限制性种类为饱和或部分饱和的具有三至六个碳原子的单环碳环。环烷基基团的说明性示例包含,但不限于以下部分:
术语“环烷氧基”是指-O-(环烷基)基团。
如本文所使用,术语“杂芳基”是指具有3至15个选自碳、氧、氮、硒和硫的环原子的单环、或稠合多环、芳香族杂环。适宜的杂芳基基团不包括必须带电荷为芳香族的环体系,例如吡喃鎓。一些适宜的5-元杂芳环(作为单环杂芳基或作为多环杂芳基的一部分)具有一个氧、硫或氮原子,或者一个氮加上一个氧或硫,或者2、3或4个氮原子。一些适宜的6-元杂芳环(作为单环杂芳基或作为多环杂芳基的一部分)具有1、2或3个氮原子。杂芳基基团的示例包含,但不限于吡啶基、咪唑基、咪唑并吡啶基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基(cinnolinyl)、吲唑基、吲哚嗪基、酞嗪基(phthalazinyl)、哒嗪基(pyridazinyl)、三嗪基、异吲哚基、喋啶基(pteridinyl)、嘌呤基、噁二唑基、三唑基、噻二唑基、呋咱基、苯并呋咱基、苯并苯硫基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。
术语“双环杂芳基”是指如上述定义的杂芳基,其具有两个组成芳环,其中两个环彼此稠合且至少一个环为上述定义的杂芳基。双环杂芳基包含含有1、2、3或4个杂原子环成员的双环杂芳基基团且是未经取代的或被一个或多个选自由氨基和卤素所组成的基团组的取代基取代;且其中所述杂芳基的一个或多个N环成员任选地为N-氧化物。双环杂芳基亦包含 8-、9-或10-元双环杂芳基基团。双环杂芳基亦包含8-、9-或10-元双环杂芳基基团,其具有 1、2、3或4个杂原子环成员且其是未经取代的或被一个或多个选自由氨基和卤素所组成的基团组的取代基取代;且其中所述杂芳基的一个或多个N环成员任选地为N-氧化物。关于本发明的双环杂芳基的说明性示例包含,但不限于:
本领域技术人员将理解上述所列或说明的杂芳基和环烷基基团的种类不是穷举的,且还可选择在这些定义的术语范围内的其他种类。
如本文所述,本文所公开的化合物可任意地被一个或多个取代基取代,或如本发明的特定类别、子类别、及种类所示例的。
如本文所使用,术语“取代”表示特定基团或部分具有一个或多个适宜的取代基。如本文所使用,术语“未取代”表示特定基团不具有取代基。如本文所使用,术语“任选取代”是指特定基团未被取代或被特定数量的取代基取代。在使用术语“取代”描述结构体系时,该取代表示发生在体系的任何化合价允许的位置处。
如本文所使用,“一个或多个取代基”的表达用语表示能够发生在体系上任何化合价允许的位置处的一个至最大可能数目的取代。在一些实施例中,一个或多个取代基表示1、2、3、 4或5个取代基。在其他的实施例中,一个或多个取代基表示1、2或3个取代基。
本文用不饱和化合价表示的任何原子假设为具有足够数目的氢原子以满足原子的化合价。
当任何变体(如烷基、亚烷基、杂芳基、R1、R2或Ra)出现在本文所提供的任何化学式或描述中的超过一个位置处时,该变体每次出现时的定义独立于其在每次其他出现时的定义。
本文使用的数值范围旨在包含连续的整数。例如,表示为“从0至4”或“0-4”的范围包含 0、1、2、3和4,而表示为“10-20%”的范围包含10%、11%、12%、13%、14%、15%、16%、 17%、18%、19%和20%。同样地,数值范围还旨在包含连续的小数整数。例如,表示为“1-2%”的范围包含1.0%、1.1%、1.2%、1.3%、1.4%、1.5%、1.6%、1.7%、1.8%、1.9%和2.0%。
当显示多功能部分时,与核心的连接点用线或连字符表示。例如,芳氧基-表示其中氧原子是与核心分子连接的点而芳基与氧原子相连的部分。
其他定义
如本文所使用,术语“受试者”涵盖哺乳类动物和非哺乳类动物。哺乳类动物的示例包含,但不限于哺乳类纲的任何成员:人类;非人灵长类动物,例如黑猩猩、以及其他类人猿和猴子种类;农畜,例如牛、马、羊、山羊、猪;家畜,例如兔子、狗和猫;以及包括啮齿动物的实验室动物,例如大鼠、小鼠和豚鼠等。非哺乳类动物的示例包括,但不限于鸟类、鱼类等。在本发明的一个实施例中,哺乳动物为人。
“患者”包含人类和动物。
术语“抑制剂”是指阻断或以其他方式干扰特定生物活性的分子,例如化合物、药物、酵激活剂或激素。
术语“调节剂”是指增加或降低,或以其他方式影响给定蛋白质、受体及/或离子通道的活性的分子,例如本发明的化合物。
术语“有效量”或“治疗有效量”是指足够量的药剂以提供所需的生物性结果。该结果可以是降低和/或缓解疾病或医学症状的病征、病状或病因,或生物体系的任何其他所需的改变。例如,用于治疗用途的“有效量”为在疾病状态、病状或医学症状方面提供临床上相关变化所需的化合物的量或包含该化合物的组合物的量。在任何个体情况中适当的“有效”量可由本领域的普通技术人员使用常规实验确定。因此,“有效量”的表达用语通常表示活性物质具有治疗所需效果的量。
如本文所使用,术语“治疗(treat)”或“治疗(treatment)”包含“预防性”和“治愈性”治疗。“预防性”治疗是指推迟疾病、疾病的病状、或医学症状的发展,抑制可能出现的病状,或降低疾病或病状发展或复发的风险。“治愈性”治疗包含降低现有疾病、病状或症状的严重性或抑制现有疾病、病状或症状的恶化。因此,治疗包含改善现有疾病病状或预防现有疾病病状的恶化、预防出现其他病状、改善或预防病状的潜在代谢病因、抑制病症或疾病,例如阻止病症或疾病的发展、缓解病症或疾病、使病症或疾病消退、缓解疾病或病症引起的症状、或终止疾病或病症的病状。
如本文所使用,术语“给药(administration of)”和“给药(administering)”化合物应理解为是指提供本发明的化合物、包含本发明的化合物或化合物的前药的药物组合物给所需个体。可理解的是,非限制性领域的技术人员可以用有效量的本发明的化合物治疗目前患有神经和精神病症的患者或预防性地治疗患有该病症的患者。
如本文所使用的术语“组合物”旨在包含含有特定含量的特定成分的产物,以及由特定含量的特定成分的组合直接地或间接地产生的任何产物。与药物组合物有关的该术语旨在包含含有活性成分和组成载体的惰性成分的产物,以及由任何两种或更多种成分的组合、复合或聚集直接或间接形成的任何产物、或由例如会引起一种或多种成分解离的其他类型的反应或交互作用所直接或间接产生的任何产物。因此,本发明的药物组合物包含由本发明的化合物混合药学上可接受的载体所形成的任何组合物。
其他化学描述
本文给出的任何化学式旨在表示具有该结构式以及某些变体或型式所描述的结构的化合物。例如,本文给出的任何化学式的化合物可以具有不对称或手性中心,因此以不同的立体异构型式存在。通式化合物的所有立体异构体(包括光学异构体、对映异构体和非对映异构体)以及其混合物被认为落入该化学式的范围内。此外,某些结构可以以几何异构体(即顺式和反式异构体)、互变异构体或阻转异构体的型式存在。所有这些异构体型式及其混合物在本文中都被认为是本发明的一部分。因此,本文给出的任何化学式旨在表示外消旋体 (racemate)、一种或多种对映异构体型式、一种或多种非对映异构体型式、一种或多种互变异构体或阻转异构体型式、及其混合物。
“立体异构体”是指具有相同化学组成,但原子或基团在空间中的排列不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺式/反式)异构体、阻转异构体等。
“手性”是指具有镜像配偶体(mirror image partner)的非重叠性质的分子,而术语“非手性”是指可以与其镜像配偶体重叠的分子。
“对映异构体”是指化合物的两种立体异构体,它们是彼此的不可重叠的镜像。
“非对映异构体”是指具有两个或更多个手性中心且其分子不是彼此的镜像的立体异构体。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质或生物活性。非对映异构体的混合物可以在如电泳和色谱分析(例如HPLC)的高分辨分析过程中被分离。
本文使用的立体化学定义及规定通常遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;和Eliel,E.and Wilen,S., "Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。
许多有机化合物以光学活性型式存在,即它们具有旋转偏振光的平面的能力。在描述光学活性化合物时,前缀D和L、或R和S用于表示分子关于其手性中心的绝对构型。前缀d 和l或者(+)和(-)用于表示化合物对平面偏振光旋转的符号,带有(-)或l表示该化合物是左旋的。带有前缀(+)或d的化合物是右旋的。特定的立体异构体可以被称为对映异构体,并且该立体异构体的混合物被称为对映体异构混合物。对映异构体的50:50混合物被称为外消旋混合物或外消旋体,其可以发生在化学反应或过程中没有立体选择性或立体定向性的情况下。
本文公开的化合物的任何不对称原子(例如碳或类似物)可以是富含外消旋的或对映异构体的,例如(R)-、(S)-或(R,S)-构型。在一些实施例中,每种不对称原子在(R)-或(S)-构型中具有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少 80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量、或至少99%对映异构体过量。
依据起始材料和过程的选择,取决于不对称碳原子的数目,化合物可以以可能的立体异构体之一或作为其混合物(例如外消旋体和非对映异构体混合物)的型式存在。光学活性(R)- 和(S)-异构体可以使用手性合成子或手性试剂来制备,或使用习用的技术解决。如果化合物含有双键,则取代基可以是E或Z构型。如果化合物含有二取代的环烷基,则环烷基取代基相对于相同环烷基框架的另一个取代基可以具有顺式或反式构型。
任何得到的立体异构体混合物可基于组分的物理化学差异通过例如色谱分析和/或分级结晶来分离成纯的或大体上纯的几何异构体、对映异构体、非对映异构体。经由本领域技术人员已知的方法,例如经由分离其非对映异构体的盐,可以将任何所得终产物或中间体的外消旋体分解成光学对映体。外消旋产物亦可以经由手性色谱分析分解,例如使用手性吸附剂的高效液相色谱(HPLC)。优选的对映异构体亦可经由不对称合成来制备。参阅例如Jacques, et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012); Eliel,E.L.Stereochemistry of CarbonCompounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents andOptical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press, Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
经由本领域技术人员熟知的方法,例如经由色谱分析和/或分级结晶,可以将非对映异构体混合物基于其物理化学差异分离成它们各自的非对映异构体。对映异构体可以通过以下方法进行分离:将对映异构体混合物经由与适当的光学活性化合物(如手性助剂,例如手性醇或Mosher酰氯、或形成非对映异构体的盐的混合物)反应而转化成非对映异构体混合物,将非对映异构体进行分离并将各个非对映异构体转化(例如水解或脱盐)成相对应的纯的对映异构体。对映异构体亦可经由使用手性HPLC柱来分离。
本发明的化合物可以形成药学上可接受的盐,其亦在本发明的范围内。“药学上可接受的盐”是指式I的化合物的游离酸或碱的盐,其为无毒的、生理上可耐受的、可与配制的药物组合物兼容,并且适合配制和/或向受试者给药。除非另有说明,否则本文提及化合物应理解为包括提及所述化合物的药学上可接受的盐。
化合物的盐包括与无机酸和/或有机酸形成的酸性盐,以及与无机碱和/或有机碱形成的碱性盐。此外,在给定的化合物同时含有碱性部分(例如但不限于吡啶或咪唑)和酸性部分(例如但不限于羧酸)的情况下,本领域技术人员将理解该化合物可以以两性离子存在(“内盐”);该盐包括在本文所用的术语“盐”的范围内。本发明化合物的盐可以例如经由化合物与一定量的适宜的酸或碱(例如等量)在介质(例如盐在其中发生沉淀的介质)中或者在水性介质中反应,随后冻干来制备。
示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、重硫酸盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡醣醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐(methanesulfonate)(“甲磺酸盐(mesylate)”)、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐以及双羟萘酸盐(即1,1’-亚甲基-双(2-羟基-3-萘甲盐))。药学上可接受的盐可涉及包含另一种分子,该分子例如是乙酸根离子、琥珀酸根离子或其他反离子。该反离子可为使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电荷的原子。其中多个带电原子是药学上可接受的盐的一部分的示例可以具有多个反离子。因此,药学上可接受的盐可以具有一个或多个带电荷的原子和/或一个或多个反离子。
示例性的酸加成盐包括乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、硝酸盐、草酸盐、磷酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(也称为甲苯磺酸盐(tosylate))以及类似物。
示例性的碱性盐包括铵盐,例如钠盐、锂盐及钾盐的碱金属盐,例如钙盐及镁盐的碱土金属盐,与有机碱(例如有机胺)例如二环己胺、叔丁基胺形成的盐,以及与氨基酸(例如精氨酸、赖氨酸以及类似物)形成的盐。碱性含氮基团可以用试剂来进行季铵化,该试剂例如为低级烷基卤化物(例如甲基、乙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸盐(例如二甲基、二乙基和二丁基硫酸盐)、长链卤化物(例如癸基、月桂基及硬脂酰的氯化物、溴化物和碘化物)、芳烷基卤化物(例如苄基和苯乙基溴化物)等。
此外,讨论了通常认为适合用于由药物化合物形成药学上有用的盐的酸和碱,例如通过 P.Stahl et al,Camille G.(eds.)Handbook of PharmaceuticalSalts.Properties,Selection and Use. (2002)Zurich:Wiley-VCH;S.Berge et al,Journal of Pharmaceutical Sciences(1977)66(1)1-19; P.Gould,International J.ofPharmaceutics(1986)33 201-217;Anderson et al,The Practice of MedicinalChemistry(1996),Academic Press,New York;以及橘皮书(Food&Drug Administration,MD,可从FDA获得)。该些公开经由引用并入本文。
此外,本文所述的任何化合物也旨在是指此类化合物的任何未溶剂化型式、或水合物、溶剂化物、或多晶型物及其混合物,即使这些型式未明确列出。“溶剂化物”是指本发明化合物与一种或多种溶剂分子的物理结合。这种物理结合涉及不同程度的离子键和共价键结合,包括氢键结合。在某些情况下,例如当一种或多种溶剂分子结合在结晶固体的晶格中时,能够分离溶剂化物。“溶剂化物”包括溶液相和可分离的溶剂化物。适宜的溶剂化物包括与药学上可接受的溶剂如水、乙醇以及类似物形成的那些溶剂化物。在一些实施例中,溶剂是水且溶剂化物是水合物。
本发明的一种或多种化合物可以任选地转化为溶剂化物。制备溶剂化物的方法通常是已知的。因此,例如,M.Caira et al.,J.Pharmaceutical Sci.,93(3),601-611(2004)描述了抗真菌剂氟康唑在乙酸乙酯中以及从水中制备溶剂化物。E.C.van Tonder et al,AAPS PharmSciTech.,5(1),article 12(2004)和A.L.Bingham et al,Chem.Commun.,603-604(2001)描述了溶剂化物、半溶剂化物(hemisolvate)、水合物等的类似制备。典型的非限制性的方法涉及在高于环境温度下将本发明化合物溶解于适量溶剂(有机溶剂或水或其混合物)中,并以足以形成晶体的速率冷却溶液,然后经由标准方法分离晶体。分析技术,例如红外光谱,显示溶剂(或水)以溶剂化物(或水合物)存在于晶体中。
本发明还涉及式(A)的化合物的药物活性代谢物,以及该代谢物在本发明方法中的用途。“药物活性代谢物”是指式(A)的化合物或其盐在体内代谢产生的药理学活性产物。化合物的活性代谢物可以使用本技术领域已知或可用的习用技术来确定。参阅如Bertolini et al.,J. Med.Chem.1997,40,2011-2016;Shan et al.,J.Pharm.Sci.1997,86(7),765-767;Bagshawe, Drug Dev.Res.1995,34,220-230;Bodor,Adv.Drug Res.1984,13,255-331;Bundgaard,Design of Prodrugs(Elsevier Press,1985);以及Larsen,Design and Application of Prodrugs,Drug Design and Development(Krogsgaard-Larsen et al.,eds.,Harwood Academic Publishers,1991)。
本文提供的任何化学式亦旨在表示化合物的未标记型式和同位素标记型式。除了一个或多个原子被具有所选择的原子量或质量数的原子替换外,同位素标记的化合物具有由本文提供的化学式所描绘的结构。可并入本发明的化合物中的同位素的实施例包括氢、碳、氮、氧、磷、氟、氯和碘的同位素,例如分别为2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、36Cl、和125I。该同位素标记的化合物可用于代谢研究(例如利用14C)、反应动力学研究(利用例如2H或3H)、包括药物或基质组织分布分析的检测或成像技术(例如正电子放射断层造影术(PET)或单光子发射计算机断层成像术(SPECT))或可用于患者的放射治疗。特别是,18F或11C标记的化合物可以特别适合于PET或SPECT研究。此外,用较重的同位素例如氘(即2H)取代可提供由更大的代谢稳定性而产生的一些治疗优势,例如增加体内的半衰期或减少剂量需求。同位素标记的本发明化合物通常可以经由进行以下描述的方案或实施例和制备方法中所公开的步骤,以及用容易获得的同位素标记的试剂取代非同位素标记的试剂来制备。
就本文所述的化合物而言,术语“盐”、“溶剂化物”、“多晶型物”及类似物的使用旨在同等地适用于本发明化合物的对映异构体、立体异构体、旋转异构体、互变异构体、阻转异构体和外消旋体的盐、溶剂化物和多晶型型式。
本发明化合物的描述
本发明涉及特定的分子及其药学上可接受的盐类或异构体。该发明进一步涉及用于调节谷氨酸传递功能失调的分子及其药学上可接受的盐类、溶剂化物、酯或异构体。
本发明涉及如本文所述的化合物及其药学上可接受的盐类、溶剂化物、酯或异构体,以及包含如本文所述的一种或多种化合物及其药学上可接受的盐类或异构体的药物组合物。本发明的一方面是提供用于调节哺乳类动物中谷氨酸传递的化合物、组合物、试剂盒和解毒剂,其具有式(A)的化合物或其药学上可接受的盐:
其中
X为NH、O、S或Se;
W1或W2为CH或N,条件为W1和W2不同时为N;
R1和R2为相同或不同,且各自独立地选自由以下所组成的基团组:
氢和
GRa,其中G不存在、或为-C(O)-或–C(O)O-且Ra为具有一至四个碳原子的饱和直链或支链烷基,或具有三至六个碳原子的饱和环烷基,条件为R1和R2不同时为GRa,其中 G存在;
Yq选自由氢、氘、SF5、CF3、OCF3、SCF3、S(O)CF3、S(O)2CF3、CN、SCN、S(O)CH3、 S(O)2CH3、NO2所组成的基团组,且其中q为1或2;条件为当q为2时,Y1和Y2能够相同或不同,且Y1和Y2不同时为氢、或不同时为氘、或不分别为氢和氘;
并且
当W1和W2为CH时,式(A)的化合物不为以下化合物之一:
其中R1或R2如上述定义;以及
当W1或W2为N时,式(A)的化合物不为以下化合物之一:
其中R1或R2如上述定义。
在一些实施例中,在具有通式(A)的化合物中,X为NH或O或S或Se。在其他实施例中,W1或W2为N,条件为W1和W2不同时为N。在其他实施例中,W1或W2为CH。在其他实施例中,该核心双环杂芳基选自由以下所组成的基团组:
在其他实施例中,在具有通式(A)的化合物中,Yq选自由氢、氘、SF5、CF3、OCF3、SCF3、S(O)CF3、S(O)2CF3、CN、SCN、S(O)CH3、S(O)2CH3、NO2所组成的基团组,其中q为1 或2;但条件为当q为2时,Y1和Y2能够相同或不同,且Y1和Y2不同时为氢、或不同时为氘、或不分别为氢和氘。
在一些实施例中,在具有通式(A)的化合物中,R1和R2相同或不同,且各自独立地选自由以下所组成的基团组:氢和GRa,其中G不存在、或为-C(O)-或-C(O)O-且Ra为具有一至四个碳原子的饱和直链或支链烷基,或具有三至六个碳原子的饱和环烷基,条件为R1和R2不同时为GRa,其中G存在。
在一些实施例中,在具有通式(A)的化合物中,R1或R2为GRa,其中G不存在且Ra为具有一至四个碳原子的直链或支链烷基,且选自由以下所组成的基团组:-CH3、-CH2CH3、 -CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH2CH(CH3)2和-C(CH3)3。
在一些实施例中,在具有通式(A)的化合物中,R1或R2为GRa,其中G不存在且Ra为具有三至六个碳原子的环烷基,且选自由以下所组成的基团组:
任选地,Ra被C1-C4烷基取代。
在一些实施例中,在具有通式(A)的化合物中,R1和R2其中之一为GRa,其中G为–C(O)- 且Ra为具有一至四个碳原子的饱和直链或支链烷基、或具有三至六个碳原子的饱和环烷基,且选自由以下所组成的基团组:
任选地,Ra被C1-C4烷基取代。
在一些实施例中,在具有式(A)的化合物中,R1和R2其中之一为GRa,其中G为–C(O)O- 且Ra为具有一至四个碳原子的饱和直链或支链烷基、或具有三至六个碳原子的饱和环烷基,且选自由以下所组成的基团组:
任选地,Ra被C1-C4烷基取代。
在其他实施例中,在具有通式(A)的化合物中,R1和R2其中之一为GRa,其中Ra选自由具有一至四个碳原子的饱和直链或支链烷基、和具有三至六个碳原子的饱和环烷基所组成的基团组,其中所述碳原子中的一个或多个任选地为不对称原子。
本发明的实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为N, Y1为SF5,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为N,Y1和Y2为SF5,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为O,Y1为SF5,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为O,Y1和Y2为SF5,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为S,Y1为SF5,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为S,Y1和Y2为SF5,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为Se,Y1为SF5,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为Se,Y1和Y2为SF5,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1和W2为CH,X为Se,Y1选自由CF3、OCF3、SCF3、S(O)CF3、S(O)2CF3、CN、SCN、S(O)CH3、S(O)2CH3和NO2所组成的基团组,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1或W2为N,X选自由N、O、S和Se组成的基团组,Y1为SF5,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1或W2为N,X选自由N、O、S和Se所组成的基团组,Y1为CF3,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1或W2为N,X选自由N、O、S和Se所组成的基团组,Y1为OCF3,Y2为H或D,且R1和R2如上述定义。
本发明的另一实施例提供一种化合物,其中各个部分独立选择,W1或W2为N,X选自由N、O、S和Se所组成的基团组,Y1选自由SCF3、S(O)CF3、S(O)2CF3、CN、SCN、S(O)CH3、 S(O)2CH3和NO2所组成的基团组,Y2为H或D,且R1和R2如上述定义。
在一些实施例中,式(A)的化合物进一步由以下组成的化合物群组及其药学上可接受的盐来说明:
本发明的一个方面涉及本文公开的化合物。
本发明的一个方面涉及为或能够为谷氨酸传递功能失调的调节剂的化合物。
本发明的一个方面涉及谷氨酸传递功能失调的调节剂用于制备用于治疗、预防、抑制或消除肿瘤的药物的用途。
本发明的一个方面涉及谷氨酸传递功能失调的调节剂用于制备经由调节患者的谷氨酸传递功能失调以用于治疗、预防、抑制或消除所述患者的病症或疾病或医学症状的药物的用途,其中所述病症或疾病或医学症状选自由神经胶质瘤、乳癌、黑色素瘤;肌萎缩侧索硬化症(ALS)、慢性神经病疼痛、多发性硬化症、运动失调、帕金森氏症、亨廷顿舞蹈症、妥瑞氏症、癫痫、肌张力不全症、X染色体脆折症、由创伤性脑/脊髓损伤引起病症、由脑缺血引起的病症;抑郁症、焦虑症、躁郁症、精神分裂症、强迫症、自闭症、酒精/药物成瘾;血管和阿兹海默氏痴呆症、青光眼诱发的视神经病和注意力缺陷/多动症(ADHD)。
本发明还描述了一种或多种合成本发明的化合物的方法。
本发明还描述了一种或多种本发明的化合物的用途。
本发明还描述了本发明的化合物与辅助药剂一起使用的一种或多种用途,例如与肿瘤坏死因子(TNF)、粒细胞集落刺激因子(GCSF)或其他化疗药剂一起使用的用途。
本发明还描述了制备包含本发明的化合物的各种药物组合物的一种或多种方法。
本发明还描述了本发明的各种药物组合物用于制备经由调节患者的谷氨酸传递功能失调以用于治疗、预防、抑制或消除所述患者的病症或疾病或医学症状的药物的一种或多种用途。
本发明的化合物的药物组合物以及制剂和给药
本发明提供一种包含本发明的化合物(如示例的化合物)的药物组合物。根据本发明的具体示例,该药物组合物可进一步包含药学上可接受的赋形剂、载体、佐剂、溶剂和其组合。
本发明提供一种治疗、预防或改善疾病或病症的方法,包含给药安全且有效量的含有本发明的化合物和一种或多种治疗活性药剂的药物的组合。其中,药物的组合包含一种或多种用于治疗神经和精神病症以及中枢神经系统疾病的其他药物。
用于治疗神经和精神病症以及中枢神经系统疾病的其他药物包含,但不限于抗精神障碍类疾病药、非典型抗精神障碍类疾病药、抗癫痫药、抗帕金森氏症药、抗肌萎缩性侧索硬化症药、抗疼痛药或其任何组合。
本文公开的药物组合物的化合物的量是指可以有效检测到能调节生物学样本和患者中谷氨酸传递功能失调的量。可以在治疗持续时间内以给药途径将活性成分给药至需要该治疗的受试者,给药计量为提供最佳药物功效的剂量,所述药物功效不限于期望的治疗效果。依据疾病的性质和严重程度、患者的体重、患者随后所遵循的特殊饮食、同时用药和本领域技术人员将认识到的其他因素,剂量将随患者不同而异。依据具体应用,单位制剂剂量中的活性化合物的量可以在约1mg至约1000mg、优选约1mg至约500mg、更优选约1mg至约 250mg、还更优选约1mg至约50mg的范围内变化或调节。
实际使用的剂量可依据患者的需求和受治疗症状的严重程度而变化。对特定情况确定适宜的给药方案在本领域的技术范围内。为方便起见,可以根据需要将每日总剂量分成多个部分并在一天内分次给药。本发明的化合物和/或其药学上可接受的盐的给药量和给药频率将依据主治医师结合患者的年龄、症状和大小以及所治疗病状的严重程度等因素的判断来调整。用于口服给药的典型推荐的每日给药方案可以在约1mg/天至约200mg/天的范围内、优选在10mg/天至100mg/天的范围内,其可以以单剂量或多剂量给药。在另一实施例中,每个患者每天给药约1mg至50mg。
还应理解的是,本发明的一些化合物可以以游离型式存在用于治疗,或在适宜的情况下作为其药学上可接受的衍生物或前药。药学上可接受的衍生物包括药学上可接受的盐、酯、该酯的盐、或当给药至需要其的患者后能直接或间接地提供本文所述的化合物或其治疗有效的代谢物或残留物的任何其他加合物或衍生物。
本发明的药物组合物可以以散装形式制备和包装,其中可以取安全且有效量的本文所公开的式(A)的化合物,然后用粉末或糖浆给药患者。通常,每日向患者给药的剂量水平在 0.0001至10mg/kg体重之间以获得对谷氨酸传递功能失调的有效调节。可选地,本发明的药物组合物可以以单位剂型制备和包装,其中每个物理上独立的单位含有安全且有效量的本文公开的式(A)的化合物。当以单位剂型制备时,本发明的药物组合物通常含有约0.5mg至1g、或1mg至700mg、或5mg至100mg、或更优选地25mg至60mg本发明的化合物。
当本发明的药物组合物除了本发明的化合物外还含有一种或多种其它活性成分时,本发明的化合物与第二活性成分的重量比可以变化并且取决于每种成分的有效剂量。因此,例如,当本发明的化合物与另一种药剂组合时,本发明的化合物与其他药剂的重量比通常在约 1000:1至约1:1000,例如约200:1至1:200的范围内。本发明的化合物与其他活性成分的组合通常也在上述范围内,但在每种情况下,应使用组合中每种活性成分的有效剂量。
如本文所用的“药学上可接受的赋形剂”是指涉及赋予药物组合物型式或一致性的药学上可接受的材料、组合物或媒剂(vehicle)。当混合时,每种赋形剂需要与药物组合物的其他成分兼容,否则当给药至患者时,相互作用会实质上降低本发明化合物的功效并导致药学上不可接受的组合物的产生。另外,每种赋形剂当然需要具有足够高的纯度以使其为药学上可接受的。
适宜的药学上可接受的赋形剂将依据所选择的特定剂型而变化。另外,可以根据其在组合物中可能发挥的特定功能来选择适宜的药学上可接受的赋形剂。例如,可以选择某些药学上可接受的赋形剂,因为它们具有有助于生产统一剂型的能力。可以选择某些药学上可接受的赋形剂,因为它们具有有助于生产稳定剂型的能力。可以选择某些药学上可接受的赋形剂,因为它们具有当给药至患者后便于将本发明的化合物从身体的一个器官或部分携带或输送至身体的另一器官或部分的能力。可以选择某些药学上可接受的赋形剂,因为它们具有增强患者依从性的能力。
适宜的药学上可接受的赋形剂包括以下赋形剂类型:稀释剂、填充剂、黏合剂、崩解剂、润滑剂、助流剂、成粒剂、包衣剂、润湿剂、溶剂、助溶剂、悬浮剂、乳化剂、甜味剂、调味剂、遮味剂、着色剂、防结块剂、湿润剂、螯合剂、增塑剂、增黏剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将理解的是,一些药学上可接受的赋形剂可以具有多于一种功能,且可以发挥替代功能,这取决于调配物中存在的赋形剂的量以及调配物中存在的其他成分。
技术人员拥有本领域的知识和技能以使他们能够选择合适的药学上可接受的赋形剂以适当的量用于本发明。此外,技术人员可以获得描述药学上可接受的赋形剂的资源,并且可以用于选择适宜的药学上可接受的赋形剂。示例包含Remington's PharmaceuticalSciences (Mack Publishing Company)、The Handbook of Pharmaceutical Additives(Gower Publishing Limited)和The Handbook of Pharmaceutical Excipients(theAmerican Pharmaceutical Association and the Pharmaceutical Press)。
在Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy, Lippincott Williams&Wilkins,Philadelphia和Encyclopedia ofPharmaceutical Technology,eds. J.Swarbrick and J.C.Boylan,1988-1999,MarcelDekker,New York(其中的每一个的内容通过引用并入本文)中,公开了用于配制药学上可接受的组合物的不同载体和它们已知的制备方法。除非任何常规的载体媒介与本发明的化合物不兼容,例如通过产生任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式相互作用,否则它们的使用被认为在本发明的范围内。
使用本领域技术人员已知的技术和方法来制备本发明的药物组合物。本技术领域常用的一些方法在Remington's Pharmaceutical Sciences(Mack Publishing Company)中描述。
因此,本发明的另一个方面涉及用于制备药物组合物的方法。该药物组合物含有本文所公开的化合物和药学上可接受的赋形剂、载体、佐剂、媒剂或其组合,该方法包含将各种成分混合。含有本文所公开的化合物的药物组合物可在例如正常环境温度和压力下制备。
通常将本发明的化合物配制成适于经由期望的给药途径向患者给药的剂型。例如,剂型包括适于(1)口服给药的剂型,例如片剂、胶囊、囊片、丸剂、锭剂、粉剂、糖浆剂、酏剂、悬浮液、溶液、乳液、药囊及扁囊剂;(2)肠胃外给药的剂型,例如无菌溶液、悬浮液及回溶粉剂(或重构粉剂,powders for reconstitution);(3)经皮给药的剂型,例如经皮贴剂;(4)直肠给药的剂型,如栓剂;(5)吸入给药的剂型,如气雾剂、溶液和干粉;以及(6)局部给药的剂型,例如乳膏剂、软膏剂、洗剂、溶液、糊剂、喷雾剂、泡沫剂和凝胶剂。
本文所提供的药物组合物可以以下述型式来提供:压缩片剂、研制锭剂(tablettriturates)、可咀嚼锭剂、速溶片剂、多重压缩片剂、或肠溶衣片剂、糖衣片剂或薄膜衣片剂。肠溶衣片剂是被可抵抗胃酸作用但在肠道中溶解或崩解的物质包覆的压缩片剂,由此保护活性成分免受胃中的酸性环境的影响。肠溶衣包括,但不限于脂肪酸、脂肪、水杨酸苯酯、蜡、虫胶、氨化虫胶和邻苯二甲酸醋酸纤维素。糖衣片剂是由糖衣包围的压缩锭剂,该糖衣可有益于掩盖令人不愉快的味道或气味且防止片剂氧化。薄膜衣片剂为被水溶性材料的薄层或薄膜覆盖的压缩片剂。薄膜衣包括,但不限于羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸醋酸纤维素。薄膜衣赋予与糖衣相同的一般特征。多重压缩片剂是由一个以上压缩循环制成的压缩片剂,其包括多层片剂、及压制包衣片剂或干包衣片剂。
片剂剂型可由粉末状、结晶状或粒状活性成分单独或与一种或多种本文所述的载体或赋形剂组合来制备,该载体或赋形剂包括黏合剂、崩解剂、受控释放聚合物、润滑剂、稀释剂和/或着色剂。调味剂和甜味剂尤其可用于形成咀嚼片剂和锭剂。
本文所提供的药物组合物可以以软胶囊或硬胶囊的型式来提供,其可以由明胶、甲基纤维素、淀粉或藻酸钙来制备。硬质明胶胶囊(亦称为干填充胶囊(DFC))由两部分组成,一部分套在另一部分上,因此完全包覆活性成分。软弹性胶囊(SEC)是软的球形外壳,例如明胶外壳,其通过添加甘油、山梨醇或类似的多元醇来塑化。软明胶外壳可含有防腐剂以防止微生物生长。适宜的防腐剂为本文所述的那些,包括对羟基苯甲酸甲酯和对羟基苯甲酸丙酯及和抗化学酸。可将本文所提供的液体、半固体和固体剂型囊封于胶囊中。适宜的液体和半固体剂型包括存于碳酸丙二酯、植物油或甘油三酯中的溶液及悬浮液。含有该溶液的胶囊可如美国专利第4,328,245号、第4,409,239号及第4,410,545号中所述来制备。该胶囊亦可如本领域技术人员已知来包覆以改良或维持活性成分的溶解。
本文所提供的药物组合物可以以液体和半固体剂型来提供,包括乳液、溶液、悬浮液、酏剂和糖浆。乳液为二相体系,其中一种液体以小球形式分散于另一种液体中,其可为水包油或油包水。乳液可包括药学上可接受的非水性液体或溶剂、乳化剂和防腐剂。悬浮液可包括药学上可接受的悬浮剂及防腐剂。水性醇溶液可包括药学上可接受的缩醛,例如低级烷基醛的二(低级烷基)缩醛,例如乙醛二乙缩醛;和具有一个或多个羟基基团的水可混溶溶剂,例如丙二醇及乙醇。酏剂是澄清的、甜味的水醇性溶液。糖浆是诸如蔗糖等糖的浓水溶液,且亦可含有防腐剂。对于液体剂型而言,例如,聚乙二醇中的溶液可经足量的药学上可接受的液体载体(例如水)稀释以便于量测来给药。
其他可用的液体和半固体剂型包括,但不限于含有本文所提供的活性成分和二烷基化的单-或聚-亚烷基二醇的那些,二烷基化的单-或聚-亚烷基二醇包括1,2-二甲氧基甲烷、二甘醇二甲醚、三甘醇二甲醚、四乙二醇二甲醚、聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚,其中350、550和750是指聚乙二醇的近似平均分子量。这些调配物可另外包含一种或多种抗氧化剂,例如二丁基羟基甲苯(BHT)、丁基羟基苯甲醚(BHA)、没食子酸丙酯、维生素E、氢醌、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨醇、磷酸、亚硫酸氢盐、偏亚硫酸氢钠、硫代二丙酸及其酯和二硫代氨基甲酸盐。
在适当的情况下,用于口服给药的剂量单位调配物可以被微胶囊化。还可以制备调配物以延长或维持释放,例如将微粒材料包覆或嵌入在聚合物、蜡或类似物中。
本文所提供用于口服给药的药物组合物亦可以以脂质体、胶粒、微球体或纳米体系的型式来提供。胶粒剂型可根据美国专利第6,350,458号中所述来制备。
本文所提供的药物组合物可以以非泡腾或泡腾颗粒剂和粉剂型式来提供以重构为液体剂型。用于非泡腾颗粒剂或粉剂中的药学上可接受的载体和赋形剂可包括稀释剂、甜味剂和润湿剂。用于泡腾颗粒剂或粉剂中的药学上可接受的载体和赋形剂可包括有机酸和二氧化碳来源。
着色剂和调味剂可用于所有上述剂型中。
本文所公开的化合物还可以偶联至作为标向药物载体的可溶性聚合物上。这样的聚合物可以包括被棕榈酰基取代的聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰氨基苯酚 (polyhydroxypropylmethacrylamidophenol)、聚羟基乙基天冬酰氨基苯酚 (polyhydroxyethylaspartamidophenol)或聚环氧乙烷多聚赖氨酸(polyethylene oxidepolylysine)。此外,这些化合物可以偶联至适于实现药物控制释放的一类生物可降解聚合物上,所述聚合物例如为聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯以及水凝胶的交联或两性嵌段共聚物。
本文所提供的药物组合物可配制成直接释放或调节释放剂型,包括延迟、持续、脉冲、受控、标向及程序化释放型式。
本文所提供的药物组合物可以与不损害所需治疗作用的其他活性成分或与补充所需作用的物质共同配制。
本文所提供的药物组合物可以借由注射、输注或植入进行肠胃外给药,用于局部或全身性给药。本文所用的肠胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌肉内、滑膜内和皮下给药。
本文所提供的药物组合物可以配制成适宜肠胃外给药的任何剂型,包括溶液、悬浮液、乳液、胶粒、脂质体、微球体、纳米体系、及适用于在注射前于液体中形成溶液或悬浮液的固体型式。这些剂型可依据药物科学技术领域中的技术人员所已知的习用方法来制备(参见 Remington:The Science and Practice of Pharmacy,如上所述)。
用于肠胃外给药的药物组合物可包括一种或多种药学上可接受的载体和赋形剂,包括,但不限于水性媒剂、水可混溶媒剂、非水性媒剂、抵抗微生物生长的抗微生物剂或防腐剂、稳定剂、促溶剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮剂和分散剂、润湿剂或乳化剂、络合剂、螯合剂或钳合剂、冷冻保护剂、冻干保护剂、增稠剂、pH调节剂和惰性气体。
适宜的水性媒剂包括,但不限于水、盐水、生理盐水或磷酸盐缓冲盐水(PBS)、氯化钠注射液、林格氏注射液、等渗右旋糖注射液、无菌水注射液、右旋糖及乳酸林格氏注射液。非水性媒剂包括,但不限于植物源不挥发性油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油、氢化植物油、氢化大豆油,和椰子油的中链甘油三酯、和棕榈籽油。水可混溶媒剂包括,但不限于乙醇、1,3-丁二醇、液体聚乙二醇(例如聚乙二醇 300和聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯啶酮、N,N-二甲基乙酰胺和二甲亚砜。
适宜的抗微生物剂或防腐剂包括,但不限于酚类、甲酚类、汞制剂、苯甲醇、氯丁醇、对-羟基苯甲酸甲酯(methyl p-hydroxybenzoate)及对-羟基苯甲酸丙酯(propyl p-hydroxybenzoate)、硫柳汞(thimerosal)、氯化苄烷铵(benzalkonium chloride)(例如氯化苄甲乙氧铵(也称为苄索氯铵,benzethonium chloride))、对羟基苯甲酸甲酯(methyl-paraben)及对羟基苯甲酸丙酯(propyl-paraben)和山梨酸。适宜的等渗剂包括,但不限于氯化钠、甘油和右旋糖。适宜的缓冲剂包括,但不限于磷酸盐和柠檬酸盐。适宜的抗氧化剂是本文所述的那些,包括亚硫酸氢盐及偏亚硫酸氢钠。适宜的局部麻醉剂包括,但不限于普鲁卡因盐酸盐 (procaine hydrochloride)。适宜的悬浮剂和分散剂是本文所述的那些,包括羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯啶酮。适宜的乳化剂包括本文所述的那些,包括聚氧乙烯山梨醇酐单月桂酸酯(polyoxyethylene sorbitan monolaurate)、聚氧乙烯山梨醇酐单油酸酯80 (polyoxyethylene sorbitan monooleate 80)和三乙醇胺油酸酯。适宜的螯合或钳合剂包括,但不限于EDTA。适宜的pH调节剂包括,但不限于氢氧化钠、盐酸、柠檬酸和乳酸。适宜的络合剂包括,但不限于环糊精,包括α-环糊精、β-环糊精、羟丙基-β-环糊精、磺丁基醚-β- 环糊精、及磺丁基醚7-β-环糊精(CAPTISOL,CyDex,Lenexa,Kans)。
可以将本文所提供的药物组合物配制为单或多剂量给药。单剂量调配物包装于安瓿瓶、小瓶或注射器中。多剂量肠胃外调配物需要含有细菌或真菌抑制浓度的抗微生物药剂。如本技术领域中已知及实践的,所有肠胃外调配物需要是无菌。
在一个实施例中,药物组合物以即用型无菌溶液来提供。在另一实施例中,药物组合物以在使用前用无菌媒剂重构的无菌干燥可溶性产品提供,其包括冻干粉剂及皮下注射片剂。在再一实施例中,药物组合物以即用型无菌悬浮液提供。在再一实施例中,药物组合物以在使用前用媒剂重构的无菌干燥非可溶性产品提供。在又一实施例中,药物组合物以即用型无菌乳液提供。
药物组合物可配制成悬浮液、固体、半固体或触变性液体以供作为植入储积物来给药。在一实施例中,将本文所提供的药物组合物分散于固体内基质中,该固体内基质被外部聚合膜包围,该聚合膜不溶于体液但允许药物组合物中的活性成分扩散通过。
适宜的内基质包括聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化或未塑化的聚氯乙烯、塑化尼龙、塑化聚对苯二甲酸乙二醇酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、有机硅碳酸酯共聚物、亲水性聚合物(例如丙烯酸酯及甲基丙烯酸酯的水凝胶)、胶原、交联聚乙烯醇、及交联且部分水解的聚乙酸乙烯酯。
适宜的外部聚合膜包括聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯酯、偏二氯乙烯、乙烯和丙烯的共聚物、聚对苯二甲酸乙二醇酯离聚物、丁基橡胶、环氧氯丙烷橡胶(epichlorohydrin rubber)、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物和乙烯/乙烯氧基乙醇共聚物。
在另一个方面,本发明的药物组合物被制备成适合经由吸入给药至患者的剂型,例如干粉剂、气雾剂、悬浮液或溶液组合物。在一个实施例中,本发明涉及适合以干粉经由吸入给药至患者的剂型。在一个实施例中,本发明涉及适合以干粉经由吸入给药至患者的剂型。经由吸入递送至肺部的干粉组合物通常包含作为细碎粉末的本文所公开的化合物或其药学上可接受的盐与作为细碎粉末的一种或多种药学上可接受的赋形剂。特别适合用于干粉剂的药学上可接受的赋形剂是本技术领域中技术人员已知的,并且包括乳糖、淀粉、甘露糖醇以及单醣、二醣和多醣。细碎粉末可以经由例如微粉化和研磨来制备。通常,尺寸减小(例如微粉化)的化合物可以由约1至约10微米的D50值(例如使用激光衍射测量)来定义。
气雾剂可以经由将本文所公开的化合物或其药学上可接受的盐悬浮或溶解在液化推进剂中来形成。适宜的推进剂包括卤代烃、碳氢化合物及其他液化气体。代表性的推进剂包括:三氯氟甲烷(推进剂11)、二氯氟甲烷(推进剂12)、二氯四氟乙烷(推进剂114)、四氟乙烷 (HFA-134a)、1,1-二氟乙烷(HFA-152a)、二氟甲烷(HFA-32)、五氟乙烷(HFA-12)、七氟丙烷 (HFA-227a)、全氟丙烷、全氟丁烷、全氟戊烷、丁烷、异丁烷和戊烷。包含式(A)的化合物或其药学上可接受的盐的气雾剂通常可借由定量吸入器(MDI)给药至患者。该装置为本技术领域中技术人员所已知的。
气雾剂可含有通常用于MDI的额外的药学上可接受的赋形剂,例如表面活性剂、润滑剂、助溶剂及其他赋形剂,以改善调配物的物理稳定性,改善阀性能、改善溶解性或改善味道。
适合经皮给药的药物组合物可以呈现为独立贴剂,旨在与患者表皮保持长期密切接触。示例而言,活性成分可藉由离子透入从贴剂释放出来,如在PharmaceuticalResearch,3(6), 318(1986)中所概述。
适合局部给药的药物组合物可配制成软膏剂、乳膏剂、悬浮液、洗剂、粉剂、溶液、糊剂、凝胶剂、喷雾剂、气雾剂或油状物。示例而言,软膏剂、乳膏剂和凝胶可以用水性或油性基材并添加适宜的增稠剂和/或胶凝剂和/或溶剂来配制。因此,该基材可例如包括水和/或油状物(例如液状石蜡)或植物油(例如花生油或蓖麻油)或溶剂(例如聚乙二醇)。可以依据基材的性质而使用的增稠剂及胶凝剂包括软石蜡、硬脂酸铝、十八醇十六醇混合物、聚乙二醇、羊毛脂、蜂腊、聚羧乙烯(carboxypolymethylene)和纤维素衍生物、和/或单硬脂酸甘油酯和/或非离子型乳化剂。
洗剂可以用水性或油性基材配制且通常亦含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂或增稠剂。
供外部施用的粉剂可借助任何适宜的粉末基材(例如滑石粉、乳糖或淀粉)来形成。滴剂可用水性或非水性基材配制且亦包含一种或多种分散剂、增溶剂、悬浮剂或防腐剂。
局部制剂可通过对受影响区域每日施用一次或多次来给药;可有利地使用封闭敷料盖住皮肤区域。可藉由黏合剂储存体系实现连续或长期递送。
本发明的化合物和组合物的用途
本文所公开的本发明的化合物或药物组合物可用于制备用于治疗、预防、改善或减轻受试者的神经和精神病症或疾病或癌症的药物、以及其他用于调节(如阻碍)谷氨酸传递功能失调的药物,且本发明的化合物具有优越的药物动力学和药效学性质,毒副作用较小。
具体而言,本发明组合物的化合物的量可有效且可检测地调节谷氨酸传递功能失调。本发明的化合物或药物组合物可用于预防、治疗或缓解与谷氨酸传递功能失调有关的疾病,其中该疾病包含神经胶质瘤、乳癌、黑色素瘤;肌萎缩侧索硬化症(ALS)、慢性神经病疼痛、多发性硬化症、运动失调、帕金森氏症、亨廷顿舞蹈症、妥瑞氏症、癫痫、肌张力不全症、 X染色体脆折症、由创伤性脑/脊髓损伤引起的病症、由脑缺血引起的病症;抑郁症、焦虑症、躁郁症、精神分裂症、强迫症、自闭症、酒精/药物成瘾;血管和阿兹海默氏痴呆症、青光眼诱发的视神经病和注意力缺陷/多动症(ADHD)。
治疗
在一个实施例中,本文公开的治疗包含向所需患者给药安全且有效量的本发明的化合物或含有本发明的化合物的药学组成物。本文公开的每个示例包含治疗上述疾病的方法,该方法包含向所需患者给药安全且有效量的本发明的化合物或含有本发明的化合物的药学组成物。
在一个实施例中,本发明的化合物或其药物组合物可经由任何适宜的给药途径来给药,包含全身性给药或局部给药。全身性给药包括口服给药、肠胃外给药、经皮给药和直肠给药。肠胃外给药是指不同于经肠或经皮给药的给药途径且通常藉由注射或输注来实施。肠胃外给药包括静脉内、肌内和皮下注射或输注。局部给药包括施用于皮肤以及经眼内、阴道内、吸入及鼻内给药。在一个实施例中,本发明的化合物或其药学组成物可藉由口服给药。在另一实施例中,本发明的化合物或其药学组成物可藉由吸入给药。在又一实施例中,本发明的化合物或其药学组成物可藉由鼻内给药。
在一个实施例中,本发明的化合物或其药物组合物可一次给药或根据给药方案给药,其中多个剂量在一段给定的时间内以不同时间间隔给药。例如,可以一天给药一次、二次、三次或四次剂量。在一个实施例中,一天给药一次剂量。在又一实施例中,一天给药两次剂量。可给药剂量直到达到所需治疗效果或无限期地给药以维持所需治疗效果。用于本发明化合物或其药物组合物的适宜的给药方案取决于该化合物的药物动力学性质,例如其吸收、分布以及代谢和消除的半衰期,其可以由技术人员确定。此外,用于本发明的化合物或其药物组合物的适宜给药方案(包括执行该方案的持续时间)取决于所治疗的病症、所治疗病症的严重性、所治疗患者的年龄和身体状况、所治疗患者的病史、并行治疗的性质、所需的治疗效果等因素,这在技术人员的知识和专业范围内。这些技术人员将进一步理解的是,考虑到个体患者对给药方案的耐受性不同或随着时间的推移,个体患者的需要发生改变,因此适合的给药方案可能需要调整。
本发明的化合物可与一种或多种其他治疗药剂一起、或在其之前或之后给药。本发明的化合物可经由与其他药剂相同或不同的给药途径分开给药,或者与其他药剂一起在相同的药物组合物中一起给药。
对于约50-70kg的受试者,本发明的药物组合物或组合的单位剂量为约1-1000mg的活性成分、优选为约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg的活性成分。本发明的化合物、药物组合物或其组合的治疗有效剂量依据受试者的种类、体重、年龄和个体情况、所治疗的病症或疾病或其严重程度来决定。具有普通技术的医师、临床医生或兽医能够容易地确定预防、治疗病症或疾病或抑制病症或疾病发展所需的每种活性成分的有效量。
上述剂量特性与有利地使用哺乳类动物(例如小鼠、大鼠、狗、非人灵长类(例如猴))或其分离的器官、组织及其制剂进行的体外和体内试验相关。本发明的化合物可以以溶液型式 (例如优选水溶液)体外给药,以及以悬浮液或水溶液型式经由局部、吸入、肠内或肠胃外、有利地静脉内体内给药。
在一个实施例中,本文公开的化合物的治疗有效剂量为每日约0.1mg至约1,000mg。药物组合物应提供约0.1mg至约1,000mg的化合物的剂量。在一特定实施例中,制备药物剂量单位型式以使每剂量单位型式提供约1mg至约1,000mg、约10mg至约500mg、约20mg至约200mg、约25mg至约100mg、或约30mg至约60mg的活性成分或必需成分的组合。在一特定实施例中,制备药物剂量单位型式以提供约1mg、5mg、10mg、20mg、25mg、50mg、 100mg、250mg、500mg、1000mg的活性成分。
本发明的优选实施例
一般合成方法
提供以下示例以便可以更充分地理解本发明。然而,应该理解到这些实施例仅提供了实践本发明的方法,并且本发明不限于这些实施例。
一般而言,本文公开的化合物可以经由本文所述的方法制备,其中取代基为如以上针对式(A)所定义,除非另有说明。提供以下非限制性方案和示例以进一步举例说明本发明。
本技术领域中的技术人员将认识到的是,所描述的化学反应可以容易地适用于制备本文所公开的许多其它化合物,并且用于制备本文所公开的化合物的替代方法被认为在本文所公开的范围内。本技术领域中的技术人员将认识到的是,如以下示例所表明的,起始原料可以变化并且可以使用附加步骤来制备本发明所涵盖的化合物。在某些情况下,可能需要保护某些反应性官能团以实现上述某些转化。通常,对于有机合成领域的技术人员来说,对基团进行保护的这种需求以及连接和去除这些基团所需的条件是清楚的。例如,根据本发明的非示例性化合物的合成可以经由本技术领域的技术人员所清楚的修改而成功地进行,例如经由适当地保护干扰基团,通过利用本技术领域中已知的除了所描述的那些之外的其他适宜的试剂,和/或经由对反应条件进行常规修改。可选地,已知的反应条件或本发明中公开的反应将被认为适用于制备本文公开的其他化合物。
在下面所描述的示例中,除非另有说明,否则所有的温度均以摄氏度表示。试剂购买于商业供货商如Aldrich Chemical Company、Arcos Chemical Company以及AlfaChemical Company,且未经过进一步纯化即使用,除非另有说明。
化合物的制备
本发明的化合物(包括其盐、酯、水合物、或溶剂化物)可以使用任何已知的有机合成技术来制备,并且可以根据多种可能的合成途径中的任何一种来合成。
用于制备本发明化合物的反应可以在合适的溶剂中进行,其可以由有机合成领域中的技术人员容易地选择。在进行反应的温度下(该温度例如可在溶剂的冻结温度至溶剂的沸腾温度的范围内),合适的溶剂可基本上不与起始材料(反应物)、中间物或产物进行反应。所给定的反应可在一种溶剂或一种以上溶剂的混合物中进行。根据特定的反应步骤,技术人员可以为特定的反应步骤选择合适的溶剂。
可根据本技术领域中已知的任何合适的方法监测反应。举例而言,产物形成可通过光谱手段进行监测,例如核磁共振光谱法(例如1H或13C)、红外光谱法、分光光度测定法(例如紫外-可见)、质谱,或通过色谱法进行监测,例如高效液相色谱(HPLC)、液相色谱-质谱(LCMS) 或薄层层析法(TLC)。化合物可由本领域技术人员利用多种方法进行纯化,包括高效液相色谱(HPLC)(“Preparative LC-MS Purification:Improved Compound SpecificMethod Optimization”Karl F.Blom,Brian Glass,Richard Sparks,Andrew P.CombsJ.Combi.Chem. 2004,6(6),874-883,其通过引用的方式全文并入本文中)和正相硅胶层析。
本发明的化合物可以使用下面描述的方法,以及合成有机化学领域中已知的合成方法或本领域技术人员所理解的其变化方法来合成。优选的方法包括但不限于下面描述的那些方法。具体而言,本发明式(A)的化合物可以遵循下面列举的示例性一般合成方案中概述的步骤来合成,并且反应物或包含在合成方案中的反应物的化学基团的缩写在示例中定义。
一般合成方案(1-13)如下所示:
方案1:Yq-取代的-苯并[d]噻唑-2-胺(XI)的一般合成
可以根据参考文献(Synlett,2012,23,15,2219-2222;WO2013/163244A1)中公开的相关程序进行具有式XI的化合物的合成,但不限于这些公开的程序。因此,苯胺衍生物1在适当的溶剂体系中用KSCN处理以形成化合物XI。
方案2:Yq-取代的苯并[d]噁唑-2-胺(XII)的一般合成
可以根据参考文献(Journal of Organic Chemistry,1990,55,17,4979–4981;Tetrahedron Letters,2011,52,34,4392–4394;Bioorganic and Medicinal ChemistryLetters,2014,24,15, 3521-3525)中公开的相关程序进行具有式XII的化合物的合成,但不限于这些公开的程序。因此,硝基苯衍生物2经氧化生成羟基化合物3,然后氢化,所得的氨基化合物4在适当的溶剂体系中用BrCN处理以形成化合物XII。
方案3:Yq-取代的1H-苯并[d]咪唑-2-胺(XIII)的一般合成
可以根据参考文献(European Journal of Organic Chemistry,2012,11,2123-2126;Journal of Medicinal Chemistry,2014,57,17,7325–7341;US2007/117818A1)中公开的相关程序进行具有式XIII的化合物的合成,但不限于这些公开的程序。因此,硝基苯衍生物5转化为化合物6,然后氢化,将得到的二氨基化合物7在适当的溶剂体系中用BrCN处理,形成化合物XIII。
方案4:Yq-取代的苯并[d][1,3]硒唑-2-胺(XIV)的一般合成
可以根据参考文献(European Journal of Medicinal Chemistry,2015,96,92-97;Synthesis, 2016,48,01,85-96;European Journal of Organic Chemistry,2011,25,4756-4759)中公开的相关程序进行具有式XIV的化合物的合成,但不限于这些公开的程序。因此,苯胺衍生物8 经溴化以提供化合物9,其进一步被转化为酰胺化合物10。化合物10用POCl3处理以产生化合物11,之后连续用Se和NH4OH处理,所得化合物13在适当的溶剂体系中环化以形成化合物XIV。
方案5:Yq-取代的噻唑并[5,4-b]吡啶-2-胺(XV)的一般合成
可以根据参考文献(Journal of Medicinal Chemistry,2009,52,19,6142-6152;US2009/270405A1)中公开的相关程序进行具有式XV的化合物的合成,但不限于这些公开的程序。因此,氨基吡啶衍生物14在适当的溶剂体系中用KSCN处理以形成化合物XV。
方案6:Yq-取代的噁唑并[5,4-b]吡啶-2-胺(XVI)的一般合成
可以根据参考文献(WO2013/177024A1;WO2009/147431A1)中公开的相关程序进行具有式XVI的化合物的合成,但不限于这些公开的程序。因此,吡啶衍生物15在适当的溶剂体系中用BrCN处理以形成化合物XVI。
方案7:Yq-取代的3H-咪唑并[4,5-b]吡啶-2-胺(XVII)的一般合成
可以根据参考文献(Chemical Communications,2014,50,85,12911–12914;Journal of Medicinal Chemistry,2014,57,13,5702-5713)中公开的相关程序进行具有式XVII的化合物的合成,但不限于这些公开的程序。因此,二氨基吡啶衍生物16在适当的溶剂体系中用BrCN 处理以形成化合物XVII。
方案8:Yq-取代的[1,3]硒唑并[5,4-b]吡啶-2-胺(XVIII)的一般合成
可以根据参考文献(US2003/171395A1;Synthesis,2001,14,2175–2179;Synthesis,2016, 48,01,85–96;European Journal of Organic Chemistry,2011,25,4756-4759)中公开的相关程序进行具有式XVIII的化合物的合成,但不限于这些公开的程序。因此,氨基吡啶衍生物 17经溴化以提供化合物18,其被进一步转化为酰胺化合物19。化合物19用POCl3处理以产生化合物20,之后连续用Se和NH4OH处理,所得化合物22在适当的溶剂体系中环化以形成化合物XVIII。
方案9:Yq-取代的噻唑并[4,5-b]吡啶-2-胺(XIX)的一般合成
可以根据参考文献(Journal of Heterocyclic Chemistry,2003,40,2,261–268;Phosphorus, Sulfur and Silicon and the Related Elements,2006,181,7,1665-1673)中公开的相关程序进行具有式XIX的化合物的合成,但不限于这些公开的程序。因此,氨基吡啶衍生物23用NH4SCN 处理以产生化合物24,其进一步在适当的溶剂体系中环化以形成化合物XIX。
方案10:Yq-取代的噁唑并[4,5-b]吡啶-2-胺(XX)的一般合成
可以根据参考文献(US2012/149718A1;DE2239311)中公开的相关程序进行具有式XX 的化合物的合成,但不限于这些公开的程序。因此,吡啶衍生物25在适当的溶剂体系中用 BrCN处理以形成化合物XX。
方案11:Yq-取代的1H-咪唑并[4,5-b]吡啶-2-胺(XXI)的一般合成
可以根据参考文献(Journal of Heterocyclic Chemistry,1990,27,6,1821–1824;Chemical Communications,2014,50,85,12911-12914)中公开的相关程序进行具有式XXI的化合物的合成,但不限于这些公开的程序。因此,二氨基吡啶衍生物26在适当的溶剂体系中用BrCN 处理以形成化合物XXI。
方案12:Yq-取代的[1,3]硒唑并[4,5-b]吡啶-2-胺(XXII)的一般合成
可以根据参考文献(Organic Letters,2016,18,5,984–987;European Journalof Medicinal Chemistry,2015,96,92-97;European Journal of Organic Chemistry,2011,25,4756-4759)中公开的相关程序进行具有式XXII的化合物的合成,但不限于这些公开的程序。因此,氨基吡啶衍生物27经溴化以提供化合物28,其被进一步转化为酰胺化合物29。化合物29用POCl3处理以产生化合物30,之后连续用Se和NH4OH处理,所得化合物32在适当的溶剂体系中环化以形成化合物XXII。
方案13:具有式A的Yq-取代的胺衍生物的一般合成
可以根据参考文献中公开的相关程序从具有式I-XXII的氨基化合物开始合成具有式A 的化合物,但不限于这些公开的程序。
其中,R1和R2不同时为H,Z为可选自Cl、Br或I的脱离基。该氨基化合物I-XXII可经由典型的N-酰化程序(Journal of Medicinal Chemistry,2012,55,11,5554-5565;US2015/225407 A1,Bioorganic and Medicinal Chemistry,2012,20,18,5642-5648;WO2010/100144 A1)转换为相应的N-酰基或N-酰氧基化合物。
其中,R1和R2不同时为H。氨基化合物I-XXII可经由各种方法(Synlett,2013,24,17, 2249-2254;Chemical Communications,2012,48,4,603-605;Journal of MedicinalChemistry, 1999,42,15,2828-2843;European Journal of Medicinal Chemistry,2014,74,703-716; Angewandte Chemie-International Edition,2015,54,31,9042-9046;US2004/44258 A1)转化为相应的N-烷基化合物。
示例性化合物的制备及表征
涵盖在本公开中的化合物可经由不同方案制备。以下描述经由各种方案制备10个示例性化合物的详细制备方法,并且列出了表征结果。
除非另有说明,否则所有试剂均从商业供货商购买而没有进一步纯化。当需要时经由标准方法进行溶剂干燥。用于薄层层析法(TLC)的板为预先在铝板上涂覆E.Merck硅胶60F254(0.24nm厚),然后在UV光(365nm和254nm)下或经由乙醇中的5%磷钼酸(也称为十二钼磷酸,dodecamolybdophosphoric acid)染色并随后加热显现。使用购自商业供货商的硅胶(200-400目)进行柱层析。1H NMR光谱在室温下用Agilent 400-MR NMR光谱仪(1H为400.00MHz)记录。溶剂信号用作1H NMR的参考(CDCl3,7.26ppm;CD3OD,3.31ppm; DMSO-d6,2.50ppm;D2O,4.79ppm)。以下缩写用于解释多重性:s=单峰、d=双峰、t=三重峰、q=四重峰、br.s.=宽单峰、dd=双重双峰、td=三重双峰、dt=双重三峰、dq=双重四峰、 m=多重峰。在实验细节中使用的其他缩写如下:δ=四甲基硅烷低场区下的化学位移(以百万分率表示)、Ar=芳基、Ac=酰基、Boc=叔丁氧基羰基、Bn=苄基、DCM=二氯甲烷、DMF=N,N’-二甲基甲酰胺、DIPEA=二异丙基乙胺、DMAP=4-(二甲氨基)吡啶、DMSO=二甲基亚砜、EA=乙酸乙酯、Et=乙基、Me=甲基、Hz=赫兹、HPLC=高效液相色谱、J=偶合常数(NMR)、min=分钟、h=小时、NMR=核磁共振、prep=制备型的、t-Bu=叔丁基、iPr=异丙基、TBAF=四丁基氟化铵、tert=叔、TFA=三氟乙酸、THF=四氢呋喃、TLC=薄层层析。
示例
应该注意的是,下面详细描述的本发明的实施例是示例性的,仅用于解释本发明,而不应被解释为限制本发明。没有提供特定技术或条件的示例可以根据本领域文献中的技术或条件或根据产品说明来实施。没有提供制造商的试剂或仪器可经由常规购买获得。本领域技术人员将认识到的是,如以下示例所表明的,可以改变起始材料以及采用其他的步骤来制备本发明所涵盖的化合物。
示例1:6-(五氟硫基)苯并[d]噻唑-2-胺(I)
在20℃下向搅拌的4-(五氟硫基)苯胺(33)(500mg,2.28mmol)的AcOH(10mL)溶液中一次加入KSCN(265mg,2.73mmol)。搅拌30分钟后,将反应混合物冷却至0℃,滴加Br2(365mg, 2.28mmol)的AcOH(1mL)溶液。然后移除冰浴,将反应混合物在20℃下搅拌16小时。将混合物倒入水(100mL)中,并用CH2Cl2(3×30mL)萃取。将合并的有机相用饱和NaHCO3水溶液(15mL)、饱和盐水溶液(15mL)洗涤,用无水Na2SO4干燥并蒸发。将残余物经由制备型HPLC纯化,得到为白色固体的标题化合物I(378mg,60%)。
1H NMR(400MHz,DMSO-d6)δ=8.34(d,J=2.0Hz,1H),7.97(s,2H),7.68(dd,J=2.2Hz,9.0 Hz,1H),7.40(d,J=9.2Hz,1H);
MS(ESI):[M+H+]=276.9。
示例2:5-(五氟硫基)苯并[d]噻唑-2-胺(II)
在20℃下向搅拌的3-(五氟硫基)苯胺(34)(400mg,1.83mmol)的AcOH(8mL)溶液中一次加入KSCN(355mg,3.65mmol)。搅拌30分钟后,将反应混合物冷却至0℃,滴加Br2(292mg,1.83mmol)的AcOH(1mL)溶液。然后移除冰浴,将反应混合物在20℃下搅拌16小时。将混合物倒入水(100mL)中,并用CH2Cl2(3×30mL)萃取。将合并的有机相用饱和NaHCO3水溶液 (15mL)、饱和盐水溶液(15mL)洗涤,用无水Na2SO4干燥并蒸发。将残余物经由柱层析(硅胶,石油醚/EtOAc=10:1-2:1)纯化,得到为白色固体的标题化合物II(135mg,27%)。
1H NMR(400MHz,DMSO-d6)δ=7.90(br.s,2H),7.87(s,1H),7.73(d,J=2.4Hz,1H), 7.50(dd,J=2.0,8.8Hz,1H);
MS(ESI):[M+H+]=276.8。
示例3:6-(五氟硫基)苯并[d]噁唑-2-胺(III)
步骤1:2-硝基-5-(五氟硫基)苯酚(36)
在-50℃下向搅拌的t-BuOK(337mg,3mmol)的CH3NH2(在THF中2M,5mL)溶液中滴加1-硝基-4-(五氟硫基)苯(35)(249mg,1mmol)和异丙苯过氧化氢(80%,0.2mL,1.1mmol)的干燥THF(1mL)溶液。将形成的棕色混合物在-50℃下搅拌15分钟,接着加入固体NH4Cl(1g)以及蒸发CH3NH2。将形成的混合物用HCl水溶液(1M)处理至pH1并用CH2Cl2(3×20mL)萃取。用NaOH水溶液(0.5M,3×15mL)洗涤合并的有机萃取物,收集碱性萃取物并用HCl水溶液(6M)酸化至pH1,然后用CH2Cl2(3×20mL)萃取。将合并的有机相用无水MgSO4干燥并蒸发。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1)纯化以得到黄色油状的标题化合物 36(238mg,90%)。
1H NMR(400MHz,CDCl3)δ=10.56(br.s,1H),8.23(d,J=9.2Hz,1H),7.62(d,J=2.4Hz,1H), 7.40(dd,J=2.4,9.6Hz,1H)。
步骤2:2-氨基-5-(五氟硫基)苯酚(37)
向2-硝基-5-(五氟硫基)苯酚(36)(616mg,2.32mmol)的乙醇(5mL)溶液中加入Pd(OH)2(200mg,10%,负载在炭上)。将混合物在H2气氛下搅拌3h。过滤混合物并将滤液浓缩获得黄色油状的标题化合物37(448mg,82%)。
1H NMR(400MHz,CDCl3)δ=7.21(dd,J=2.0,8.4Hz,1H),7.12(d,J=2.0Hz,1H),6.67(d, J=8.8Hz,1H),4.88(br.s,1H),4.08(br.s,2H)。
步骤3:6-(五氟硫基)苯并[d]噁唑-2-胺(III)
在20℃下向搅拌的2-氨基-5-(五氟硫基)苯酚(37)(410mg,1.74mmol)的CH3CN溶液 (10mL)中一次加入二(1H-咪唑-1-基)甲亚胺(562mg,3.49mmol)。将该反应混合物在80℃下搅拌6h。将溶剂蒸发并将残余物经由柱层析(硅胶,石油醚/EtOAc=10:1-2:1)纯化得到为白色固体的标题化合物III(296mg,65%)。
1H NMR(400MHz,DMSO-d6)δ=7.99(d,J=2.0Hz,1H),7.96(s,2H),7.64(dd,J=2.0,8.4Hz, 1H),7.30(d,J=8.8Hz,1H);
MS(ESI):[M+H+]=260.7。
示例4:5-(五氟硫基)苯并[d]噁唑-2-胺(IV)
步骤1:2-硝基-4-(五氟硫基)苯酚(39)
在-50℃下向搅拌的t-BuOK(100mg,3mmol)的CH3NH2(在THF中2M,2mL)溶液中滴加1-硝基-4-(五氟硫基)苯(38)(249mg,1mmol)和异丙苯过氧化氢(80%,84mg,1.1mmol)的干燥THF(1mL)溶液。将形成的棕色混合物在-50℃下搅拌15分钟,接着加入NH4Cl固体(1g) 并蒸发CH3NH2。将形成的混合物用HCl水溶液(1M)处理至pH1并用DCM(3×20mL)萃取。用NaOH水溶液(0.5M,3×15mL)洗涤合并的有机萃取物,收集碱性溶液并用HCl水溶液(6M) 酸化至pH1,然后用CH2Cl2(3×20mL)萃取。将合并的有机相用无水MgSO4干燥并蒸发。获得黄色油状的粗产物39(265mg,100%),其不经进一步纯化用于下一步骤。
1H NMR(400MHz,CDCl3)δ=10.78(br.s,1H),8.57(s,1H),7.96(d,J=8.4Hz,1H),7.51(s, 1H)。
步骤2:2-氨基-4-(五氟硫基)苯酚(40)
向2-硝基-4-(五氟硫基)苯酚(39)(150mg,0.40mmol)的乙醇(3mL)溶液中加入 Pd(OH)2(80mg,10%,负载在炭上)。将混合物在H2气氛下搅拌3h。过滤混合物并将滤液浓缩获得粗产物,其经由制备型TLC(硅胶,石油醚/EtOAc=3:1)纯化以获得黄色油状的标题化合物40(70mg,74%)。
1H NMR(400MHz,CDCl3)δ=7.14(d,J=2.4Hz,1H),7.07(dd,J=2.0,8.8Hz,1H),6.72(d, J=8.8Hz,1H),5.40(br.s,1H);
MS(ESI):[M+H+]=235.8。
步骤3:5-(五氟硫基)苯并[d]噁唑-2-胺(IV)
在20℃下向搅拌的2-氨基-4-(五氟硫基)苯酚(40)(70mg,0.30mmol)的CH3CN(1mL)溶液中一次加入二(1H-咪唑-1-基)甲亚胺(96mg,0.60mmol)。将反应混合物在80℃下搅拌6h。将溶剂蒸发并将残余物经由柱层析(硅胶,石油醚/EtOAc=10:1-2:1)纯化得到为白色固体的标题化合物IV(56mg,72%)。
1H NMR(400MHz,DMSO-d6)δ=7.85(s,2H),7.68(s,1H),7.52(s,1H);
MS(ESI):[M+H+]=260.8。
示例5:6-(五氟硫基)苯并[d][1,3]硒唑-2-胺(V)
步骤1:2-溴-4-(五氟硫基)苯胺(41)
在10℃下向搅拌的4-(五氟硫基)苯胺(33)(500.0mg,2.28mmol)的AcOH(5.0mL)溶液中缓慢加入Br2(364.6mg,2.28mmol)的AcOH(1.0mL)溶液。将混合物在10℃下搅拌3h。将混合物用冰水(60mL)骤冷,用EtOAc(2×30mL)萃取,将合并的萃取物用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-10:1)纯化以得到为黄色固体的标题化合物41(648mg,96%)。
1H NMR(400MHz,CDCl3)δ=7.81(d,J=2.4Hz,1H),7.49(dd,J=2.4,9.2Hz,1H),6.71(d, J=9.2Hz,1H),4.46(s,2H)。
步骤2:N-(2-溴-4-(五氟硫基)苯基)甲酰胺(42)
在20℃下向搅拌的2-溴-4-(五氟硫基)苯胺(41)(1.54g,5.17mmol)的干燥甲苯(20mL)溶液中滴加HCOOH(4.0mL,103.30mmol)。将反应在100℃下搅拌16h。之后,将反应混合物冷却至30℃,用EtOAc(60mL)稀释,依序用水(30mL)和饱和盐水溶液(30mL)洗涤,用无水 Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-5:1)纯化以获得为黄色固体的标题化合物42(1.63g,97%)。
1H NMR(400MHz,DMSO-d6)δ=10.07(s,1H),8.44(s,1H),8.39(d,J=8.8Hz,1H),8.22(d, J=2.4Hz,1H),7.96(dd,J=2.4,8.8Hz,1H)。
步骤3:2-溴-1-异氰基-4-(五氟硫基)苯(43)
在0℃下向N-(2-溴-4-(五氟硫基)苯基)甲酰胺(42)(400mg,1.23mmol)的干燥CH2Cl2(10mL)溶液中加入Et3N(0.5mL,3.68mmol),接着加入POCl3(282mg,1.84mmol)。将反应在0~20℃下搅拌3h。之后,缓慢加入饱和的Na2CO3水溶液。搅拌30分钟之后,用 CH2Cl2(2×20mL)萃取水相。合并的有机相用无水Na2SO4干燥并浓缩。将残余物经由柱层析 (硅胶,石油醚/EtOAc=50:1-20:1)纯化以获得深色油状的标题化合物43(236mg,62%)。
1H NMR(400MHz,CDCl3)δ=8.08(d,J=2.0Hz,1H),7.78(dd,J=2.0,8.8Hz,1H),7.56(d, J=8.8Hz,1H)。
步骤4:2-溴-1-异硒氰酸基-4-(五氟硫基)苯(44)
向2-溴-1-异氰基-4-(五氟硫基)苯(43)(517mg,1.68mmol)的CH2Cl2(10mL)悬浮液中加入 Se粉末(398mg,5.03mmol)、苄基三乙基氯化铵(19.10mg,0.084mmol),接着加入NaOH水溶液(50%,0.5mL)。将反应在40℃下搅拌3h。之后,将反应混合物用CH2Cl2(20mL)稀释,依序用水(10mL)和饱和盐水溶液(10mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由柱层析(硅胶,石油醚/EtOAc=50:1-20:1)纯化以获得黄色油状的标题化合物44(308mg,47%)。
1H NMR(400MHz,CDCl3)δ=8.00(d,J=2.4Hz,1H),7.71(dd,J=2.4,9.2Hz,1H),7.39(d, J=8.8Hz,1H)。
步骤5:1-(2-溴-4-(五氟硫基)苯基)硒脲(45)
在20℃下向2-溴-1-异硒氰酸基-4-(五氟硫基)苯(44)(308mg,0.80mmol)的CH2Cl2(6mL) 悬浮液中加入NH4OH(134mg,在水中25%)。将混合物在20℃下搅拌15分钟。将该混合物中的溶剂蒸发以得到为白色固体的目标化合物45(322mg,100%)。
1H NMR(400MHz,DMSO-d6)δ=9.88(s,1H),8.64(s,1H),8.19(d,J=2.0Hz,1H),7.96(br.s, 1H),7.90(dd,J=2.4,8.8Hz,1H),7.78(d,J=8.4Hz,1H)。
步骤6:6-(五氟硫基)苯并[d][1,3]硒唑-2-胺(V)
在20℃下向搅拌的1-(2-溴-4-(五氟硫基)苯基)硒脲(45)(322mg,0.80mmol)的DMSO(6mL) 溶液中加入CuI(15mg,0.08mmol)、1,10-菲啰啉(14mg,0.08mmol),接着加入Cs2CO3(130mg, 0.40mmol)。将反应在氮气下于80℃下搅拌30分钟。之后,将反应混合物用冰水(60mL)骤冷,用EtOAc(2×30mL)萃取。将合并的有机相用饱和盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由制备型HPLC纯化以获得为白色固体的标题化合物V(15mg,6%)。
1H NMR(400MHz,DMSO-d6)δ=8.30(d,J=2.4Hz,1H),8.00(s,2H),7.64(dd,J=2.4,8.8Hz, 1H),7.33(d,J=8.8Hz,1H);
MS(ESI):[M+H+]=324.7。
示例6:6-(三氟甲基)苯并[d][1,3]硒唑-2-胺(VI)
步骤1:N-(2-碘-4-(三氟甲基)苯基)甲酰胺(47)
在20℃下向搅拌的2-碘-4-(三氟甲基)苯胺(46)(3.0g,10.5mmol)的干燥甲苯(30mL)溶液中滴加HCOOH(4.0mL,114.5mmol)。将反应在100℃下搅拌16h。将混合物冷却至30℃,用EtOAc(80mL)稀释,依序用水(40mL)和饱和盐水溶液(40mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-10:1)纯化以获得为白色固体的标题化合物47(3.1g,94%)。
MS(ESI):[M+H+]=315.7。
步骤2:2-碘-1-异氰基-4-(三氟甲基)苯(48)
在0℃下向N-(2-碘-4-(三氟甲基)苯基)甲酰胺(47)(2.0g,6.35mmol)的干燥CH2Cl2(30mL) 溶液中加入Et3N(2.6mL,19.05mmol),接着加入POCl3(1.5g,9.52mmol)。将反应在0~20℃下搅拌3h,接着滴加Na2CO3饱和水溶液(10mL)。搅拌30分钟之后,用DCM(2×30mL)萃取水相。将合并的有机相用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚 /EtOAc=50:1-20:1)纯化以获得深色油状的标题化合物48(1.32g,70%)。
步骤3:2-碘-1-异硒氰酸基-4-(三氟甲基)苯(49)
向2-碘-1-异氰基-4-(三氟甲基)苯(48)(1.32g,4.44mmol)的CH2Cl2(30mL)悬浮液中加入 Se粉末(1.05g,13.33mmol)、苄基三乙基氯化铵(50.70mg,0.22mmol)和NaOH水溶液(50%, 2.0mL)。将反应在40℃下搅拌3h。将混合物用CH2Cl2(30mL)稀释,依序用水(20mL)和饱和的盐水溶液(20mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,PE/EA=50: 1-20:1)纯化以获得黄色油状的标题化合物49(0.90g,54%)。
1H NMR(400MHz,CDCl3)δ=8.08(s,1H),7.61(d,J=8.0Hz,1H),7.40(d,J=8.4Hz,1H)。
步骤4:1-(2-碘-4-(三氟甲基)苯基)硒脲(50)
在20℃下向2-碘-1-异硒氰酸基-4-(三氟甲基)苯(49)(300mg,0.80mmol)的CH2Cl2(6mL) 悬浮液中加入NH4OH(134mg,在水中25%)。将反应在20℃下搅拌15分钟。将溶剂蒸发以获得为白色固体的标题化合物50(314mg,100%)。
1H NMR(400MHz,DMSO-d6)δ=9.79(s,1H),8.48(s,1H),8.16(s,1H),7.76(s,1H),7.73(d, J=8.0Hz,1H),7.57(d,J=8.4Hz,1H)。
步骤5:6-(三氟甲基)苯并[d][1,3]硒唑-2-胺(VI)
在20℃下向搅拌的1-(2-碘-4-(三氟甲基)苯基)硒脲(50)(600.0mg,1.53mmol)的DMSO(10mL)溶液中加入CuI(29.1mg,0.15mmol)、1,10-菲啰啉(27.5mg,0.15mmol)和 Cs2CO3(248.0mg,0.76mmol)。将反应在氮气下于80℃下搅拌30分钟。将混合物用冰水(60mL) 骤冷,用EtOAc(2×30mL)萃取。将合并的有机相用饱和盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由柱层析(硅胶,石油醚/EtOAc=10:1-2:1)纯化以获得为淡黄色固体的标题化合物VI(226mg,56%)。
1H NMR(400MHz,DMSO-d6)δ=8.12(d,J=1.2Hz,1H),7.94(s,2H),7.48(dd,J=1.2,8.8Hz, 1H),7.40(d,J=8.8Hz,1H);
MS(ESI):[M+H+]=266.7。
示例7:6-(三氟甲氧基)苯并[d][1,3]硒唑-2-胺(VII)
步骤1:N-(2-溴-4-(三氟甲氧基)苯基)甲酰胺(52)
在20℃下向搅拌的2-溴-4-(三氟甲氧基)苯胺(51)(3.0g,11.7mmol)的干燥甲苯(30mL)溶液中滴加HCOOH(4.3mL,113.7mmol)。将反应在100℃下搅拌16h。将混合物冷却至30℃,用EtOAc(60mL)稀释,依序用水(30mL)和饱和盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-5:1)纯化以获得为白色固体的标题化合物52(3.2g,96%)。
1H NMR(400MHz,DMSO-d6)δ=9.90(s,1H),8.37(s,1H),8.14(d,J=8.8Hz,1H),7.78(d, J=2.0Hz,1H),7.45(d,J=8.8Hz,1H)。
步骤2:2-溴-1-异氰基-4-(三氟甲氧基)苯(53)
在0℃下向N-(2-溴-4-(三氟甲氧基)苯基)甲酰胺(52)(2.0g,7.04mmol)的干燥CH2Cl2(30mL)溶液中加入Et3N(2.1g,21.12mmol),接着加入POCl3(1.6g,10.56mmol)。将反应在0~20℃下搅拌3h,接着滴加Na2CO3饱和水溶液(10mL)。搅拌30分钟之后,用 CH2Cl2(2×30mL)对混合物进行萃取。将水相用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=50:1-20:1)纯化以获得深色油状的标题化合物53(1.8g,96%)。
1H NMR(400MHz,CDCl3)δ=7.55(d,J=1.6Hz,1H),7.51(d,J=9.2Hz,1H),7.24(dd,J=1.6, 9.2Hz,1H)。
步骤3:2-溴-1-异硒氰酸基-4-(三氟甲氧基)苯(54)
向2-溴-1-异氰基-4-(三氟甲氧基)苯(53)(1.80g,6.77mmol)的CH2Cl2(36mL)悬浮液中加入 Se粉末(1.60g,20.30mmol)、苄基三乙基氯化铵(77.52mg,0.34mmol),接着加入NaOH水溶液(50%,5mL)。将反应在40℃下搅拌3h。将混合物用CH2Cl2(50mL)稀释,依序用水(30mL) 和饱和的盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=50:1-20:1)纯化以获得为无色固体的标题化合物54(0.95g,41%)。
1H NMR(400MHz,CDCl3)δ=7.49(d,J=2.0Hz,1H),7.36(d,J=8.8Hz,1H),7.18(dd,J=1.2, 8.4Hz,1H)。
步骤4:1-(2-溴-4-(三氟甲氧基)苯基)硒脲(55)
在20℃下向2-溴-1-异硒氰酸基-4-(三氟甲氧基)苯(54)(820mg,2.38mmol)的CH2Cl2(10mL)悬浮液中加入NH4OH(400mg,25%在水中)。将反应在20℃下搅拌15分钟。将溶剂蒸发以获得为灰白色固体的标题化合物55(862mg,100%)。
1H NMR(400MHz,DMSO-d6)δ=9.78(s,1H),8.45(s,1H),7.76(d,J=2.0Hz,1H),7.74(br.s, 1H),7.56(d,J=9.2Hz,1H),7.42(dd,J=1.2,8.4Hz,1H)。
步骤5:6-(三氟甲氧基)苯并[d][1,3]硒唑-2-胺(VII)
在20℃下向搅拌的1-(2-溴-4-(三氟甲氧基)苯基)硒脲(55)(600.0mg,1.66mmol)的 DMSO(10mL)溶液中加入CuI(31.6mg,0.17mmol)、1,10-菲啰啉(30.0mg,0.17mmol),接着加入Cs2CO3(270.0mg,0.83mmol)。将反应在氮气下于80℃下搅拌30分钟。将混合物用冰水(60mL)骤冷,用EA(2×30mL)萃取。将合并的有机相用饱和盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由柱层析(硅胶,石油醚/EtOAc=10:1-2:1)纯化以获得为白色固体的标题化合物VII(106mg,23%)。
1H NMR(400MHz,DMSO-d6)δ=7.77(d,J=1.2Hz,1H),7.71(s,2H),7.33(d,J=8.8Hz,1H), 7.16(dd,J=1.2,8.4Hz,1H);
MS(ESI):[M+H+]=282.8。
示例8:5-(三氟甲基)苯并[d][1,3]硒唑-2-胺(VIII)
步骤1:N-(2-溴-5-(三氟甲基)苯基)甲酰胺(57)
在20℃下向搅拌的2-溴-5-(三氟甲基)苯胺(56)(4.0g,16.67mmol)的干甲苯(40mL)溶液中滴加HCOOH(6.4mL,166.70mmol)。将反应在100℃下搅拌16h。将混合物冷却至30℃,用 EtOAc(120mL)稀释,依序用水(30mL)和饱和盐水溶液(30mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-10:1)纯化以获得为白色固体的标题化合物57(4.2g,93%)。
1H NMR(400MHz,DMSO-d6)δ=10.05(s,1H),8.48(s,1H),8.42(s,1H),7.92(d,J=8.4Hz, 1H),7.43(d,J=8.4Hz,1H);
MS(ESI):[M+H++CH3CN]=310.8。
步骤2:2-溴-1-异氰基-5-(三氟甲基)苯(58)
在0℃下向N-(2-溴-5-(三氟甲基)苯基)甲酰胺(57)(3.0g,11.19mmol)的干燥CH2Cl2(40mL) 溶液中加入Et3N(4.7mL,33.58mmol),接着加入POCl3(2.6g,16.79mmol)。将反应在0~20℃下搅拌3h,接着滴加Na2CO3饱和水溶液。搅拌30分钟后,将混合物用CH2Cl2(2×50mL)萃取。将合并的有机相用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚 /EtOAc=50:1-20:1)纯化以获得深色油状的标题化合物58(2.02g,68%)。
1H NMR(400MHz,CDCl3)δ=7.83(d,J=8.0Hz,1H),7.71(s,1H),7.54(d,J=8.4Hz,1H)。
步骤3:2-溴-1-异硒氰酸基-5-(三氟甲基)苯(59)
向2-溴-1-异氰基-5-(三氟甲基)苯(58)(2.0g,8.08mmol)的CH2Cl2(40mL)悬浮液中加入Se 粉末(1.92g,24.24mmol)、苄基三乙基氯化铵(92mg,0.40mmol),接着加入NaOH水溶液(50%, 4.0mL)。将混合物在40℃下搅拌3h。将混合物用CH2Cl2(100mL)稀释,依序用水(50mL)和饱和盐水溶液(50mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚 /EtOAc=50:1-20:1)纯化以获得黄色油状的标题化合物59(1.56g,54%)。
1H NMR(400MHz,CDCl3)δ=7.75(d,J=8.4Hz,1H),7.56(s,1H),7.42(d,J=8.4Hz,1H)。
步骤4:1-(2-溴-5-(三氟甲基)苯基)硒脲(60)
在20℃下向2-溴-1-异硒氰酸基-5-(三氟甲基)苯(59)(580mg,1.76mmol)的CH2Cl2(10mL) 悬浮液中加入NH4OH(0.33mL,在水中25%)。将反应物在20℃下搅拌15分钟。将溶剂蒸发以获得为白色固体的标题化合物60(593mg,97%)。
1H NMR(400MHz,DMSO-d6)δ=9.87(s,1H),8.53(s,1H),7.90(d,J=8.4Hz,2H),7.86(s, 1H),7.55(dd,J=1.5,8.0Hz,1H);
MS(ESI):[M+H+]=346.7。
步骤5:5-(三氟甲基)苯并[d][1,3]硒唑-2-胺(VIII)
在20℃下向搅拌的1-(2-溴-5-(三氟甲基)苯基)硒脲(60)(500.0mg,1.53mmol)的DMSO(10mL)溶液中加入CuI(27.5mg,0.14mmol)、1,10-菲啰啉(26.0mg,0.14mmol),接着加入Cs2CO3(235.4mg,0.72mmol)。将反应在氮气下于80℃下搅拌30分钟。将混合物用冰水(60mL)骤冷,用EA(2×40mL)萃取。将合并的有机相用饱和盐水溶液(50mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由制备型HPLC(洗脱液中TFA为0.5%)纯化以获得为淡黄色固体的标题化合物VIII(200mg,52%)。
1H NMR(400MHz,DMSO-d6)δ=8.39(br.s,2H),7.98(d,J=8.0Hz,1H),7.57(s,1H),7.31(d, J=8.0Hz,1H);
MS(ESI):[M+H+]=266.7。
示例9:6-((三氟甲基)硫代)苯并[d][1,3]硒唑-2-胺(IX)
步骤1:2-溴-4-((三氟甲基)硫代)苯胺(62)
向搅拌的4-((三氟甲基)硫代)苯胺(61)(4.0g,20.72mmol)的DMF(40mL)溶液中加入N-溴代丁二酰亚胺(NBS)(3.87g,21.74mmol)。将混合物在30℃下搅拌2h。将混合物用冰水(120mL) 骤冷,用EtOAc(2×50mL)萃取。将合并的有机相依序用水(50mL)和饱和盐水溶液(50mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-10:1) 纯化以获得红色油状的标题化合物62(3.60g,64%)。
1H NMR(400MHz,CDCl3)δ=7.70(d,J=1.6Hz,1H),7.37(dd,J=1.6,8.0Hz,1H),6.75(d, J=8.4Hz,1H),4.41(br.s,2H);
MS(ESI):[M+H+]=273.8。
步骤2:N-(2-溴-4-((三氟甲基)硫代)苯基)甲酰胺(63)
在20℃下向搅拌的2-溴-4-((三氟甲基)硫代)苯胺(62)(3.0g,11.03mmol)的干燥甲苯 (30mL)溶液中滴加HCOOH(4.3mL,113.70mmol)。将反应在100℃下搅拌16h。将混合物冷却至30℃,用EtOAc(60mL)稀释,依序用水(50mL)和盐水(50mL)洗涤。将有机相用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=20:1-5:1)纯化以获得为白色固体的标题化合物63(3.1g,94%)。
1H NMR(400MHz,DMSO-d6)δ=10.00(s,1H),8.42(s,1H),8.29(d,J=8.4Hz,1H),8.03(d, J=1.6Hz,1H),7.74(dd,J=1.2,8.4Hz,1H);
MS(ESI):[M+H++CH3CN]=340.8。
步骤3:(3-溴-4-异氰苯基)(三氟甲基)硫烷(64)
在冰浴中向N-(2-溴-4-((三氟甲基)硫代)苯基)甲酰胺(63)(3.00g,10.0mmol)的干燥 CH2Cl2(30mL)溶液中加入Et3N(4.17mL,30.0mmol),接着加入POCl3(1.40mL,15.0mmol)。将反应在0~20℃下搅拌3h,接着滴加Na2CO3饱和水溶液(10mL)。在搅拌30分钟之后,将混合物用CH2Cl2(2×30mL)萃取。将合并的有机相用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=50:1-20:1)以获得为深色固体的标题化合物64(2.4g,84%)。
1H NMR(400MHz,CDCl3)δ=7.97(d,J=1.6Hz,1H),7.65(dd,J=1.6,8.0Hz,1H),7.49(d, J=8.8Hz,1H)。
步骤4:(3-溴-4-异硒氰酸苯基)(三氟甲基)硫化氢(65)
向(3-溴-4-异氰苯基)(三氟甲基)硫烷(64)(800mg,2.84mmol)的CH2Cl2(8mL)悬浮液中加入Se粉末(672mg,8.51mmol)、苄基三乙基氯化铵(33mg,0.14mmol),接着加入NaOH水溶液(50%,1.2mL)。将反应在40℃下搅拌2h。之后,将反应混合物用CH2Cl2(50mL)稀释。将有机相依序用水(50mL)和盐水(50mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由柱层析(硅胶,石油醚/EtOAc=50:1-20:1)纯化以获得为棕色固体的标题化合物65(0.78g,78%)。
1H NMR(400MHz,CDCl3)δ=7.90(d,J=1.6Hz,1H),7.60(dd,J=1.6,8.0Hz,1H),7.36(d, J=8.8Hz,1H)。
步骤5:1-(2-溴-4-((三氟甲基)硫代)苯基)硒脲(66)
在20℃下向(3-溴-4-异硒氰酸苯基)(三氟甲基)硫烷(65)(558mg,1.55mmol)的CH2Cl2(6mL)溶液中加入NH4OH(0.3mL,在水中25%)。将反应在20℃下搅拌30分钟。将溶剂蒸发以获得为黄色固体的标题化合物66(486mg,83%)。
1H NMR(400MHz,DMSO-d6)δ=9.82(s,1H),8.61(br.s,1H),8.02(d,J=1.6Hz,1H),7.94(br. s,1H),7.75(d,J=8.0Hz,1H),7.71(dd,J=1.6,8.4Hz,1H);
MS(ESI):[M+H+]=378.7。
步骤6:6-(三氟甲氧基)苯并[d][1,3]硒唑-2-胺(IX)
在20℃下向搅拌的1-(2-溴-4-((三氟甲基)硫代)苯基)硒脲(66)(400.0mg,1.06mmol)的 DMSO(6mL)溶液中加入CuI(20.2mg,0.11mmol)和1,10-菲啰啉(19.1mg,0.11mmol),接着加入Cs2CO3(172.4mg,0.53mmol)。将反应在氮气下于80℃下搅拌20分钟。将混合物用冰水 (60mL)骤冷,用EtOAc(2×30mL)萃取。将合并的有机相用饱和盐水溶液(50mL)洗涤,用无水Na2SO4干燥并浓缩。将残留物经由制备型HPLC纯化以获得为白色固体的标题化合物 IX(40mg,13%)。
1H NMR(400MHz,DMSO-d6)δ=8.21(s,1H),7.62(d,J=8.4Hz,1H),7.48(d,J=9.2Hz,1H);
MS(ESI):[M+H+]=298.8。
示例10:6-(五氟硫基)-1H-苯并[d]咪唑-2-胺(X)
步骤1:N-(4-(五氟硫基)苯基)乙酰胺(67)
向搅拌的4-(五氟硫基)苯胺(33)(100mg,0.46mmol)的CHCl3(1mL)溶液中加入Et3N(92.3mg,0.92mmol),接着加入Ac2O(61.2mg,0.46mmol)。将反应在20℃下搅拌3h,向其中加入H2O(20mL)。将混合物用CH2Cl2(2×10mL)萃取。将合并的有机相用无水Na2SO4干燥并浓缩以获得为黄色固体的标题粗化合物67(110mg,92%),其不经进一步纯化即用于下一步骤。
1H NMR(400MHz,CDCl3)δ=7.70(d,J=9.2Hz,2H),7.62(d,J=8.8Hz,2H),7.42(br.s,1H), 2.22(s,3H);
MS(ESI):[M+H+]=261.8。
步骤2:N-(2-硝基-4-(五氟硫基)苯基)乙酰胺(68)
在冰浴下向N-(4-五氟硫基)苯基)乙酰胺(67)(110mg,0.42mmol)的浓H2SO4(1mL)溶液中滴加HNO3(0.3mL,65%)。将反应在0~20℃下搅拌1h。之后,将反应混合物倒入冰水(30mL) 中,用CH2Cl2(2×15mL)萃取。将合并的有机相用无水Na2SO4干燥并浓缩以获得为黄色固体的标题粗化合物68(120mg,93%),其不经进一步纯化即用于下一步骤。
1H NMR(400MHz,CDCl3)δ=10.49(br.s,1H),8.99(d,J=9.6Hz,1H),8.65(d,J=2.4Hz,1H), 8.00(dd,J=2.4,9.6Hz,1H),2.34(s,3H)。
步骤3:2-硝基-4-(五氟硫基)苯胺(69)
将N-(2-硝基-4-(五氟硫基)苯基)乙酰胺(68)(120mg,0.39mmol)溶解在浓H2SO4(1mL)中,并将反应在100℃下搅拌15分钟。将混合物冷却至30℃再倒入至碎冰中,搅拌10分钟并用 CH2Cl2(2×15mL)萃取。将合并的有机相依序用水(20mL)和盐水(20mL)洗涤,用无水Na2SO4干燥并浓缩。获得为黄色固体的粗标题化合物69(100mg,97%),其不经进一步纯化即用于下一步骤。
1H NMR(400MHz,CDCl3)δ=8.58(d,J=2.4Hz,1H),7.70(dd,J=2.4,9.2Hz,1H),6.85(d, J=9.6Hz,1H),6.40(br.s,2H)。
步骤4:4-(五氟硫基)苯-1,2-二胺(70)
向2-硝基-4-(五氟硫基)苯胺(69)(100mg,0.39mmol)的EtOH(2mL)溶液中加入Pd/C(100mg,10%)。将反应在20℃和H2气氛下搅拌16h。将反应混合物过滤,将滤液浓缩以获得为黄色固体的粗标题化合物70(70mg,80%)。
MS(ESI):[M+H+]=234.8。
步骤5:6-(五氟硫基)-1H-苯并[d]咪唑-2-胺(X)
向搅拌的4-(五氟硫基)苯-1,2-二胺(70)(70mg,0.30mmol)的H2O(1mL)溶液中加入 BrCN(32.3mg,0.31mmol)。将反应在100℃和氮气下搅拌8h。将反应混合物用H2O(20mL)稀释,用NH4OH(25%)处理至pH 10-11,然后用EtOAc(2×10mL)萃取。将合并的有机相用饱和盐水溶液(20mL)洗涤,用无水Na2SO4干燥并浓缩。将残余物经由制备型TLC(硅胶,CH2Cl2/MeOH=8:1)纯化以获得为淡黄色固体的标题化合物X(30mg,38%)。
1H NMR(400MHz,DMSO-d6)δ=11.14(br.s,1H),7.55(s,1H),7.37(d,J=7.2Hz,1H), 7.19(d,J=8.4Hz,1H),6.71(br.s,2H);
MS(ESI):[M+H+]=259.8。
示例11:药理学研究
在该示例中,详细描述了具有式I-XXII的化合物的药理学性质。
A.化合物I-XXII对人类电压门控钠离子通道的抑制作用
依据所述方法通过手动膜片钳系统评估化合物I-XXII对人类电压门控钠离子通道(hNav1.2/1.7)的潜在抑制作用。本研究采用SCN2A/SCN9A基因稳定转染的HEK293细胞株且使用河豚毒素(TTX)作为阳性对照组以确保良好的分析质量。结果显示在下表1中,针对化合物I拟合的剂量-反应曲线显示在图1A及1B中。
一般方法:用人类Nav1.2或Nav1.7电压门控钠离子通道稳定转染HEK 293细胞。将该细胞常规维持在含有90%DMEM、10%FBS、100U/mL青霉素-链霉素和400mg/ml G418的培养基中。在分析之前,将细胞重新混悬并以5×105个细胞/每6cm细胞培养皿接种在盖玻片上以供使用。以配备有EPC10 USB(HEKA)或Multiclamp 700B放大器(Molecular Devices)的全细胞膜片钳系统,在室温(25℃)下从随机选择的转染细胞记录电压门控Nav1.2和Nav1.7 通道电流,同时电数据分别经由Digidata1440A以超过10kHz的采样频率数字化,并经由 Patchmaster或pClamp10获取。通过微电极拉制仪P-97(Sutter Instrument)制备电阻在2至 3.5MW范围内的玻璃电极并填充有内液(以mM计):140KCl、2MgCl2、10EGTA、10HEPES 和5MgATP(用KOH调节pH至7.35),将细胞浸泡在细胞外液(以mM计):132NaCl、4KCl、 3CaCl2、0.5MgCl2、11.1葡萄糖和10HEPES(用NaOH调节pH至7.35)。在破裂后,串联膜电阻至少有50%被补偿,且电容也被补偿。除非另有说明,所有细胞均被电压钳位至-80mV的保持电位。在内的钠电流由每15s施加的20ms电压脉冲引发,电压脉冲从-80mV至10mV。首先记录钠电流至少120秒以评估电流稳定性,并且最终仅使用记录参数超过接受标准的细胞来评估对局部灌注化合物I-XXII的剂量响应。首先将空白媒剂施用于膜片细胞以建立记录基线。至少5分钟后,当引发的钠电流达到稳定后,将测试化合物从低浓度到高浓度累积地灌注到记录室中。阳性对照物河豚毒素(TTX)也用于挑战同一批细胞,以确保记录系统的良好性能。对于IC50测定,所有实验均进行三组。收集数据之后,使用PatchMaster或pClamfit 软件从原始数据中提取波峰电流,而波峰电流抑制则由下面所示的公式定义。
以针对测试化合物剂量浓度的抑制%,使用Graphpad Prism 5.0软件绘制测试化合物的剂量响应曲线,然后将数据拟合成具有可变斜率的S形剂量-响应曲线,用于IC50测定。
表1测试化合物对人类Nav1.2/1.7通道的抑制作用
测试物 | hNav1.2 IC<sub>50</sub>(μM) | hNav1.7 IC<sub>50</sub>(μM) |
化合物I | 4.669 | 0.682 |
化合物V | 4.372 | 0.722 |
化合物VI | 10.144 | 0.745 |
化合物VII | 18.038 | 1.365 |
化合物IX | 15.312 | 1.174 |
B.化合物I关于SNL(脊神经结扎)大鼠的机械性异常性疼痛的测试
SNL模型是测量手术诱导的神经性疼痛的常用模型。该研究的目标是评估化合物I对减轻斯普拉-道来氏(Sprague-Dawley)大鼠SNL模型中机械性异常性疼痛的效果。
在本研究中,SNL模型是按照典型程序建立的,并将批准的药物他喷他多(Tapentadol, XW-TAP)作为参照化合物。加巴喷丁(Gabapentin)作为阳性对照用于模型的验证。
表2显示实验组。
表2:
剂量调配物:
1)5mg/kg化合物I:添加17.13mg化合物I至16.96mL 0.5%甲基纤维素的生理盐水溶液,涡旋以充分混合均匀。
2)10mg/kg他喷他多:添加39.39mg他喷他多至16.81mL生理盐水溶液,涡旋以充分混合均匀。
机械性异常性疼痛测量的方法:
1)将大鼠各自放入塑料笼中,该塑料笼底部具有网孔以使得能够充分接触脚爪。在测试之前使大鼠适应环境15分钟。
2)适应后,将中足底后爪用具有如下对数递增刚度的一系列8根纤毛机械刺激针(von Frey hairs)中的一根接触:3.61(0.4g)、3.84(0.6g)、4.08(1g)、4.31(2g)、4.56(4g)、4.74(6g)、 4.93(8g)和5.18(15g)。将纤毛机械刺激针垂直于足底表面,施加足够的力以引起抵靠爪子发生轻微弯曲并维持大约6-8秒。每5秒的间隔进行一次刺激,这使得可以明显分辨对先前刺激的任何行为的响应。如果爪子快速缩回,则为积极的响应。去除刺激针后立即退缩也被认为是积极的响应。行走被认为是一种模棱两可的响应,在这种情况下,重复进行刺激。
3)以纤毛丝4.31(2g)开始,依据有响应或无响应,研究人员基于Dixon序贯法(Dixon up-down method)分别使用刺激力递减或递增的纤毛丝。积极响应包括后爪明显从纤毛丝缩回,或在去除纤毛丝后立即退缩的行为。施加的最大力是纤毛丝5.18(15g)。
习惯化和给药前的机械性异常性疼痛基线测量:
手术后十天,将大鼠在测试环境中习惯15分钟,之后进行异常性疼痛测量,持续3天。给药前基线获自第13天。排除在该时间未显示异常性疼痛响应的大鼠(缩爪阀值>5g的大鼠)。
图2显示该些化合物在SNL大鼠中的抗异常性疼痛效果。(*p<0.05vs)。媒剂组经由单因子变异数分析(One-way ANOVA),接着进行Dunnett多重比较测试。
结果显示5mg/kg剂量的化合物I在给药后0.5小时的时间点恢复了SNL-诱导的机械性异常性疼痛。
C.药物动力学研究
对于大鼠药物动力学研究,将雄性Sprague-Dawley大鼠单独饲养并在使用前禁食过夜。根据美国国立卫生研究院实验动物护理和使用指南和动物福利法进行动物给药实验。对于化合物I,向分别经由静脉(IV)和口服(PO)给药的两组(n=5/组)中的每只大鼠给药5.8mg/kg的单剂量。用于IV给药的媒剂是10%(v/v)聚氧乙烯蓖麻油EL(CremophorEL)的90%PBS。用于 PO给药的媒剂是0.5%(w/v)甲基纤维素的生理盐水溶液。在向IV和PO组中的每只大鼠给药后,在特定时间点(给药前、30分钟、1小时、2小时、4小时、7小时、8小时、12小时、 24小时)收集血液样本。立即将血液样本在冰上凝结,然后经由离心分离血浆样本并冷冻 (-80℃)储存直至进行进一步分析。化合物I的浓度经由LC/MS/MS分析单独测定。使用PhoenixTM WinNonlin软件计算各种药物动力学参数。为量化化合物I在循环系统中的生物转化效率,计算PO给药后化合物I的生物利用性。
结果显示在表3及图3中。
表3:化合物I的药物动力学参数
最后,应该注意的是,还有其他方式可实践本发明。因此,本发明的实施例将作为示例性的描述,但是本发明不限于所描述的内容,可以在本发明的范围内或权利要求书中添加的等同物范围内进行进一步的修饰。
本文引用的所有出版物或专利均通过引用并入本发明中。
本说明书各处提及的“实施例”、“一些实施例”、“一个实施例”、“另一示例”、“示例”、“特定示例”或“一些示例”意指结合该实施例或示例所描述的特定特征、结构、材料或特性包括在本公开的至少一个实施例或示例中。因此,在本说明书各处出现的用语“在一些实施例中”、“在一个实施例中”或“在实施例中”、“在另一示例中”、“在示例中”、“在特定示例中”或“在一些示例中”不必涉及本公开的相同一实施例或示例。再者,这些特定的特征、结构、材料或特性可以在一个或多个实施例或示例中以任何合适的方式组合。
尽管已经示出和描述了说明性的实施例,但是本领域技术人员将会理解的是,上述的实施例不能被解释为限制本公开,并且在不偏离本公开的精神、原理和范围的情况下可以对实施例进行改变、替代和修饰。
Claims (9)
2.根据权利要求1所述的用途,其中所述药物包括利鲁唑。
5.根据权利要求4所述的用途,其中所述癌症选自神经胶质瘤、乳癌和黑色素瘤。
6.根据权利要求4所述的用途,其中所述药物包括化疗药剂。
7.根据权利要求6所述的用途,其中所述化疗药剂选自:5-氟尿嘧啶、6-巯嘌呤、6-硫鸟嘌呤、阿霉素、六甲蜜胺、氨鲁米特、安吖啶、阿那曲唑、阿糖胞苷、芳香化酶组合物、安维汀、比卡鲁胺、博来霉素、BMS 214662、白消安、C225、开普拓、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、氮芥、氯烯雌醚、顺铂、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、道诺霉素、脱氧助间型霉素、地塞米松、己烯雌酚、多西紫杉醇、阿霉素、屈洛昔芬、丙酸屈他雄酮、表柔比星、爱忆欣、雌莫司汀、依托泊苷、依西美坦、氟尿苷、磷酸氟达拉滨、氟甲睾酮、氟他胺、氟维司群、吉西他滨、戈舍瑞林、六甲三聚氰胺、羟孕酮、羟基脲、伊达比星、异环磷酰胺、伊立替康、L778、来曲唑、亚叶酸、亮丙瑞林、左旋咪唑、脂质体、洛莫司汀、L-门冬酰胺酶、醋酸甲羟孕酮、甲地孕酮、醋酸甲地孕酮、美法仑、甲氨蝶呤、甲基泼尼松龙、甲基睾酮、丝裂霉素-C、密妥坦、米托蒽醌、诺维本、奥沙利铂、紫杉醇、喷司他丁、哌泊溴烷、普卡霉素、卟吩姆钠、泼尼松龙、泼尼松、丙卡巴肼、雷洛昔芬、利妥昔单抗、RL15777、SCH 66336、链佐星、他莫昔芬、他克唑、泰素帝、替莫唑胺、替尼泊苷17α-炔雌醇、睾内酯、睾酮、埃博霉素、赛替派、替吡法尼、托泊替康、托瑞米芬、曲妥珠单抗、曲安奈德、三亚乙基蜜胺、三亚乙基硫代磷胺、乌拉莫司汀、戊柔比星、长春碱、长春新碱、长春地辛、长春瑞滨或前述的任意组合。
8.根据权利要求1至7中任一项所述的用途,其中所述药物包括口服调配物。
9.根据权利要求1至7中任一项所述的用途,其中所述药物包括经皮调配物。
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CN112321532B (zh) * | 2020-11-27 | 2022-09-20 | 温州大学 | 一种含硒杂环化合物的制备方法 |
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