CN1152006C - 联苯基衍生物 - Google Patents
联苯基衍生物 Download PDFInfo
- Publication number
- CN1152006C CN1152006C CNB008047812A CN00804781A CN1152006C CN 1152006 C CN1152006 C CN 1152006C CN B008047812 A CNB008047812 A CN B008047812A CN 00804781 A CN00804781 A CN 00804781A CN 1152006 C CN1152006 C CN 1152006C
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- formula
- trifluoromethyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000005557 antagonist Substances 0.000 title claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- -1 alkoxy halogen Chemical class 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 5
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 229940047889 isobutyramide Drugs 0.000 claims description 5
- CGSGWUYTPATAOM-UHFFFAOYSA-N n-[2-(2-aminophenyl)phenyl]-2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethylpropanamide Chemical compound C=1C=CC=C(C=2C(=CC=CC=2)N)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CGSGWUYTPATAOM-UHFFFAOYSA-N 0.000 claims description 5
- OQUTZMMCYIZSMK-UHFFFAOYSA-N n-[5-amino-2-(2-methylphenyl)phenyl]-2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethylpropanamide Chemical compound C=1C(N)=CC=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OQUTZMMCYIZSMK-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 15
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- 108010040718 Neurokinin-1 Receptors Proteins 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 48
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- ADTNSTHKMIPKIJ-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]-n-methylmethanamine Chemical compound CNCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ADTNSTHKMIPKIJ-UHFFFAOYSA-N 0.000 description 5
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- DWWKYALASTWIHZ-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethyl-n-[2-(2-methylphenyl)-5-nitrophenyl]propanamide Chemical compound C=1C([N+]([O-])=O)=CC=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 DWWKYALASTWIHZ-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及通式(I)的化合物,其中,R为氢、低级烷基、低级烷氧基、卤素、氨基、-N(R6)2或三氟甲基;R1为氢、低级烷氧基或卤素;R和R1可一起为-CH=CH-CH=CH-;R2为卤素、低级烷基或三氟甲基;R3为氢或低级烷基;R4为氢或环状叔胺,任选被低级烷基取代;R5为氢、硝基、氨基或-N(R6)2;R6为氢或低级烷基;X为-C(O)N(R6)-、-(CH2)nO-、-(CH2)nN(R6)-、-N(R6)C(O)-或-N(R6)(CH2)n-;n为1或2;还涉及所述化合物的可药用酸加成盐。式I的化合物可用于治疗与NK-1受体有关的疾病。
Description
本发明涉及以下通式的化合物
其中,
R为氢、低级烷基、低级烷氧基、卤素、氨基、-N(R6)2或三氟甲基;
R1为氢、低级烷氧基或卤素;
R和R1可一起为-CH=CH-CH=CH-;
R2为卤素、低级烷基或三氟甲基;
R3为氢或低级烷基;
R4为氢或环状叔胺,任选被低级烷基取代;
R5为氢、硝基、氨基或-N(R6)2;
R6为氢或低级烷基;
X为-C(O)N(R6)-、-(CH2)nO-、-(CH2)nN(R6)-、-N(R6)C(O)-或-N(R6)(CH2)n-;且
n为1-2;
还涉及所述化合物的可药用酸加成盐,但化合物
N-[(4-甲基苯基)甲基]-[1,1’-联苯基]-2-甲胺和
N-[[4-(1,1-二甲基乙基)苯基]甲基]-N-甲基-[1,1’-联苯基]-2-甲胺,盐酸盐排除在外。
式I的化合物和其盐的特征是具有有价值的治疗性质。令人惊奇地发现,本发明的化合物为神经激肽1(NK-1,P物质)受体的拮抗剂。P物质为天然的十一肽,属于肽的速激肽家族,而后者这样命名的原因在于,它们能够促进对血管外平滑肌组织的收缩作用。
P物质的受体是G蛋白偶联受体的超家族中的一员。
P物质(NK-1)的神经肽受体广泛分布于哺乳动物神经系统(特别是大脑和脊神经节)、循环系统和外周组织(特别是十二指肠和空肠)中,它们参与调节大量的不同生物学过程。
哺乳动物速激肽P物质的中枢与外周作用与大量炎性疾病有关,包括偏头痛、类风湿病性关节炎、哮喘和炎性肠疾病,并介导呕吐反射和调节中枢神经系统(CNS)疾病如帕金森氏病(Neurosci.Res.,1996,7,187-214)、焦虑(Can.J.Phys.,1997,75,612-621)和抑郁(科学(Science),1998,281,1640-1645)。
在“速激肽受体和速激肽受体拮抗剂”,J.Auton.Pharmacol.,13,23-93,1993中综述性地描述了速激肽受体拮抗剂对以下病症有用的证据:疼痛、头痛(特别是偏头痛)、早老性痴呆、多发性硬化症、吗啡戒除减毒、心血管变化、水肿(例如由热损伤引起的水肿)、慢性炎性疾病(如类风湿性关节炎)、哮喘/支气管过度反应性(bronchialhyperreactivity)和其它呼吸疾病包括变应性鼻炎、肠道炎性疾病包括溃疡性结肠炎和局限性回肠炎、眼损伤和眼炎性疾病。
进而,已对神经激肽1受体拮抗剂进行了研究,用于治疗大量的与速激肽,特别是P物质的过量或失衡相关的生理学疾病。与P物质有关的疾病的实例包括中枢神经系统疾病,如焦虑、抑郁症和精神病(WO 95/16679、WO 95/18124和WO 95/23798)。
神经激肽-1受体拮抗剂还用于治疗运动性疾病及诱导性呕吐。
此外,在文献The New England Journal of Medicine,第340卷,No.3 190-195,1999中,还描述了通过选择性神经激肽1受体拮抗剂来缓减顺铂引起的呕吐。
进而,US 5,972,938描述了一种治疗精神免疫学(psychoimmunologic)或心身障碍的方法,包括施用速激肽受体,如NK-1受体拮抗剂。
本发明的目的是提供式I的化合物和其可药用盐,上述化合物的制备方法,包含所述化合物的药物和其生产方法以及上述化合物在控制或预防疾病特别是前面提及的疾病和病症中的用途,或者上述化合物在生产相应药物中的用途。
本发明最优选的适应症为那些包括中枢神经系统疾病在内的疾病,例如,通过施用NK-1受体拮抗剂用于治疗或预防某些抑郁性疾病或呕吐。重症抑郁发作被定义为至少两个星期的发作期,在此期间,大多数日子和几乎每一天有抑郁的心情或完全失去兴趣或快乐,或者失去几乎所有的活力。
不论下述术语单独使用或组合使用,其在本发明中均具有下述定义。
本文中,术语“低级烷基”是指包含1-7个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等。
优选的低级烷基是具有1-4个碳原子的烷基。
术语“低级烷氧基”是指这样一种基团,其中,烷基残基具有前文给出的定义,且该基团经一个氧原子连接。
术语“卤素”是指氯、碘、氟和溴。
术语“环烷基”是指含3-6个碳原子的饱和碳环基团。
术语“环状叔胺”是指例如吡咯-1-基、咪唑-1-基、哌啶-1-基、哌嗪-1-基、吗啉-4-基、硫代吗啉-4-基、1-氧代-硫代吗啉-4-基或1,1-二氧代-硫代吗啉-4-基。优选哌嗪基团。
术语“可药用酸加成盐”包括与无机酸和有机酸的盐,这些酸如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
优选的实例为基团X为-C(O)N(R6)-,其中R6为甲基的那些化合物,例如下述化合物:
2′-甲基-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺,
2′-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺和
2′-氯-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺。
进一步优选的是这样的化合物,其中,X为-N(R6)-CO-,其中,R6为甲基。这种化合物的实例为:
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2′-甲基-4-硝基-联苯-2-基)-异丁酰胺,
N-(4-氨基-2′-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺,
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2′-甲基-4-甲基氨基-联苯-2-基)-异丁酰胺,
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2′-甲基-联苯-2-基)-异丁酰胺,和
N-(2′-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺。
本发明式I的化合物和其可药用盐可由现有技术中已知的方法制备,例如通过下述方法来制备,该方法包括:
a)使式II的化合物与式III的化合物
反应得到式I-1的化合物
其中,R1-R6、R和n具有上文给出的意义,或者
(b)使式IV的化合物与式V的化合物
反应得到式I-2的化合物
其中,R1-R6、R和n具有上文给出的意义,或者
(c)将式I-2的化合物
还原得到式I-4的化合物
其中,取代基的定义在上文中给出,或者
(d)使式VI的化合物与式VII的化合物
反应得到式I-2的化合物
其中,取代基的定义在上文中给出,或者
(e)使式VIII的化合物与式VII的化合物
反应得到式I-5的化合物
其中,取代基的定义在上文中给出,或者
(f)将式I-1的化合物
还原得到式I-3的化合物
其中,取代基的定义在上文中给出,或者
(g)使式XII的化合物与式XIII的化合物
反应得到式I-5的化合物
其中,取代基的定义在上文中给出,或者
(h)将式I-41的化合物
进行甲基化得到式I-42的化合物
其中,取代基在前文中给出,或者
(i)使式II的化合物与式XIII的化合物
反应得到式I-1的化合物
其中,取代基的定义在上文中给出,或者
(j)在上述定义范围内对一种或多种取代基R1-R6或R进行修饰,和
如果需要的话,将获得的化合物转化成可药用盐。
按照前述的方法(a),向式II的化合物如2’-甲基-4-硝基-联苯基-2-胺和DIPEA(N-乙基二异丙基胺)的冷却溶液中加入一种式III化合物如2-(3,5-二-三氟甲基-苯基)-2-甲基-丙酰氯的二氯甲烷溶液,将混合物在35-40℃下搅拌。在纯化后,以良好收率获得式I-1的目的化合物。
方法(b)描述了式IV的化合物与式V的化合物反应以获得式I-2的化合物。该反应以常规方式进行,例如在一种溶剂如甲苯中,在三乙胺存在下进行。将混合物回流约1小时。
按照方法(c),式I-2的化合物被还原成式I-4的化合物。该反应采用一种还原剂,如LiAlH4或BH3·THF,以常规方式进行。
方法(d)描述了使式VI的化合物与式VII的化合物反应以获得式I-2的化合物。该反应通过用KHMDS(六甲基二硅氮化钾(potassiumhexamethyldisilazide))对式VI的化合物进行脱质子化、再加入式VII的化合物来进行。适宜的溶剂为四氢呋喃。该反应在室温下进行。
按照方法(e),制备式I-5的化合物。该反应通过用NaH使式VIII的化合物脱质子化、随后加入式VII的化合物来进行。该反应以常规方式进行。
用于制备式I化合物的另一种方式如方法(f)所述。以常规方式,将式I-1的化合物还原成式I-3的化合物,例如采用LiAlH4或BH3·THF来进行。
按照方法(g),式XII的化合物与式XIII的化合物反应获得式I-5的化合物。该反应以常规方式采用NaH在溶剂如DMF存在下进行。
反应(h)描述了用福尔马林和NaBH4使式I-41的化合物甲基化而形成式I-42的化合物。
方法(i)描述了用于制备式I-1化合物的方法,其中,式XIII的化合物用CDI进行活化,随后加入式II的化合物而获得式I-1的化合物。
盐的形成按照现有技术中已知的方法于室温下进行,这是本领域技术人员所熟知的。不仅可考虑无机酸形成的盐,也可考虑有机酸形成的盐。这种盐的实例为盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、柠檬酸盐、乙酸盐、马来酸盐、琥珀酸盐、甲磺酸盐、对甲苯磺酸盐等。
下述反应方案1-5更详细地描述了制备式I化合物的方法。式II、III、IX、X、XI、XII、XIII、XIV和XV的原料物质均是已知的化合物,可按照本领域已知的方法制备。
在反应方案中,采用下述简写:
EDCI N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐
HOBT 1-羟基苯并-三唑
DMF 二甲基甲酰胺
CDI 1,1’-羰基二咪唑四氢呋喃
TMEDA N,N,N’,N’-四甲基乙二胺
KHMDS 六甲基二硅氮化钾
NaBH4 氢硼化钠
NaCNBH4 氰基硼氢钠
TFA 三氟乙酸
DIEA N,N-二异丙基乙基胺
反应方案1
取代基的定义在上文中给出。
反应方案2
取代基的定义在上文中给出。
反应方案3
取代基的定义在上文中给出。
反应方案4
取代基的定义在上文中给出。
反应方案5
取代基的定义在上文中给出。
反应方案6
取代基的定义在上文中给出。
反应方案7
取代基的定义在上文中给出。
如前面所提及的,式I的化合物和其可药用加成盐具有有价值的药理学性质。已发现,本发明的化合物为神经激肽1(NK-1,P物质)受体的拮抗剂。
按照以下给出的实验对这些化合物进行研究。
实验化合物与NK1受体的亲合性在用人NK1受体(采用Semliki病毒表达系统)感染的并用[3H]P物质(最终浓度0.6nM)放射性标记的CHO细胞中的人NK1受体上进行评价。结合实验在HEPES缓冲液(50mM,pH 7.4)中进行,所述缓冲液包含BSA(0.04%)、亮抑酶肽(8μg/ml)、MnCl2(3mM)和膦酰二肽(2μM)。结合实验由250μl的膜悬浮液(1.25×105细胞/实验管)、0.125μl的置换剂的缓冲液和125μl的[3H]P物质组成。置换曲线用至少七个浓度的化合物测定。实验管在室温下孵育60分钟,此后,在真空下将管的内容物迅速通过GF/C滤器过滤,所述滤器已用PEI(0.3%)预浸渍60分钟,之后用2×2ml HEPES缓冲液(50mM,pH 7.4)洗涤。残留于滤器上的放射性通过闪烁计数器测量。所有的实验均在至少2个分开的实验中重复三次。
对于优选的化合物来说,NK-1受体的亲合力(以pKi给出)为8.00-9.00。这种化合物的实例为:
N-(4-氨基-2’-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺 | 8.28 |
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-4-甲基氨基-联苯-2-基)-异丁酰胺 | 8.01 |
2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺 | 8.84 |
式I的化合物及其可药用酸加成盐可用作药物,例如以药物制剂的形式。药物制剂可口服给药,如以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊、溶液、乳剂或悬浮液。但是,也可通过直肠给药,例如以栓剂形式,或者非肠胃给药,如以注射溶液形式。
式I的化合物及其可药用酸加成盐可与药学上惰性的无机或有机赋形剂一起进行加工以生产片剂、包衣片剂、糖衣丸和硬明胶胶囊。对于例如片剂、糖衣丸和硬明胶胶囊来说,这种赋形剂可采用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等。
适用于软明胶胶囊的赋形剂是例如植物油、蜡、脂肪、半固体和液体多元醇等。
适用于生产溶液和糖浆的赋形剂是例如水、多元醇、蔗糖、转化糖、葡萄糖等。
适用于注射溶液的赋形剂为例如水、醇、多元醇、甘油、植物油等。
适用于栓剂的赋形剂为例如天然或硬化油、蜡、脂肪、半固体或液体多元醇等。
而且,药物制剂可包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们也可包含其它治疗上有价值的物质。
剂量可在宽范围内变化,当然,在每一种具体的情况下,应适合个体的需要。通常,每人每日的口服剂量为约10-1000mg通式I的化合物是适合的,当然必要时也可超过上述上限。
下述实施例用于说明本发明,但它们并非对本发明的限制。所有的温度均为摄氏温度。
实施例1
联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
a)联苯基-2-甲酸3,5-二-三氟甲基-苄基
向0.79g(4mmol)联苯基-2-甲酸在30ml二氯甲烷里的溶液中加入1.12ml(8mmol)三乙胺,0.60g(4mmol)1-羟基-苯并三唑和0.76g(4mmol)N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐,1.167g(4mmol)3,5-二-三氟甲基-苄基胺。将反应混合物搅拌16小时。将反应混合物用20ml二氯甲烷稀释,用50ml 0.5N盐酸和50ml水洗涤。水层用50ml二氯甲烷反萃。将合并后的有机层干燥(硫酸镁),过滤和蒸发。将残余物进行色谱纯化(SiO2,二氯甲烷/甲醇40∶1),得到0.93g(73%)联苯基-2-甲酸3,5-二-三氟甲基-苄基酰胺,为一种无色固体,m.p.86-87℃。
b)联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
向0.63g(1.50mmol)联苯基-2-甲酸3,5-二-三氟甲基-苄基酰胺在10ml N,N-二甲基甲酰胺的溶液中加入0.08g(1.98mmol)氢化钠(60%,矿物油分散液),将反应混合物搅拌1小时。在0℃下加入0.15ml(2.4mmol)甲基碘后,将反应混合物在室温下搅拌3小时。将反应混合物在50ml水、50ml盐水和50ml二氯甲烷间进行分配。进行相分离,水层用50ml二氯甲烷洗涤两次。将合并后的有机层干燥(硫酸镁),过滤和蒸发。将残余物进行色谱纯化(SiO2,乙酸乙酯/二氯甲烷15∶1),得到0.50g(76%)联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色固体,m.p.97-88℃。
实施例2
联苯基-2-甲酸(3,5-二氯-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式,由联苯基-2-甲酸和3,5-二氯苄基胺获得联苯基-2-甲酸3,5-二氯-苄基酰胺,为一种无色固体,m.p.152-153℃,将其按照实施例1b)所述进行甲基化处理,得到联苯基-2-甲酸(3,5-二氯-苄基)-甲基-酰胺,为一种无色固体,m.p 126-128℃。
实施例3
联苯基-2-甲酸甲基-(3-甲基-5-三氟甲基-苄基)-酰胺
以与实施例1a)所述类似的方式,由联苯基-2-甲酸和3-甲基-5-三氟甲基-苄基胺获得联苯基-2-甲酸3-甲基-5-三氟甲基-苄基酰胺,为一种无色固体,m.p.126.7-127.1℃,将其按照实施例1b)所述进行甲基化处理,得到联苯基-2-甲酸甲基-(3-甲基-5-三氟甲基-苄基)-酰胺,为一种无色油,MS(EI):383(M+)。
实施例4
2’-溴-联苯基-2-甲酸3,5-二-三氟甲基-苄基酰胺
以与实施例1a)所述类似的方式,由2’-溴-联苯基-2-甲酸和3,5-二-三氟甲基-苄基胺获得2’-溴-联苯基-2-甲酸3,5-二-三氟甲基-苄基酰胺,为一种无色固体,MS(EI):502(M+)。
实施例5
2’-溴-联苯基-2-甲酸3,5-二氯-苄基酰胺
以与实施例1a)所述类似的方式,由2’-溴-联苯基-2-甲酸和3,5-二氯苄基胺获得2’-溴-联苯基-2-甲酸3,5-二氯-苄基酰胺,为一种无色固体,m.p.122.5-123.2℃。
实施例6
2’-溴-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式,由2’-溴-联苯基-2-甲酸和(3,5-二-三氟甲基-苄基)-甲基-胺获得2’-溴-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色固体,MS(EI):514(M-H+)。
实施例7
N-(3,5-二-三氟甲基-苄基)-N-甲基-2-萘-1-基-苯甲酰胺
以与实施例1a)所述类似的方式,由2-萘-1-基-苯甲酸和(3,5-二-三氟甲基-苄基)-甲基-胺获得N-(3,5-二-三氟甲基-苄基)-N-甲基-2-萘-1-基-苯甲酰胺,为一种无色固体,MS(EI):514(M-H+)。
实施例8
2’-甲氧基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式,由2’-甲氧基-联苯基-2-甲酸和(3,5-二-三氟甲基-苄基)-甲基-胺获得2’-甲氧基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色油,MS(ISP):468.2(M+H)+。
实施例9
2’-甲氧基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式,由3’-甲氧基-联苯基-2-甲酸和(3,5-二-三氟甲基-苄基)-甲基-胺获得3’-甲氧基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色油,MS(ISP):468.1(M+H)+。
实施例10
2’-甲基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式,由2’-甲基-联苯基-2-甲酸和(3,5-二-三氟甲基-苄基)-甲基-胺获得2’-甲基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色油,MS(EI):450(M-H)+。
实施例11
2-(3,5-二-三氟甲基-苄氧基甲基)-联苯基
向1.53g(6.26mmol)(3,5-二-三氟甲基-苯基)-甲醇在15mlN,N-二甲基甲酰胺的溶液中加入0.30g(7.52mmol)氢化钠(60%矿物油分散液),将反应混合物搅拌1小时。在0℃下加入于5ml N,N-二甲基甲酰胺中的1.27g(6.26mmol)2-氯甲基-联苯基后,将反应混合物在室温下搅拌3小时。将反应混合物在50ml水、50ml盐水和50ml二氯甲烷间进行分配。进行相分离,水层用50ml二氯甲烷洗涤两次。将合并后的有机层干燥(硫酸镁),过滤和蒸发。将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯40∶1),得到1.25g(47%)2-(3,5-二-三氟甲基-苄氧基甲基)-联苯基,为一种无色油,MS(EI):410(M+)。
实施例12
(3,5-二-三氟甲基-苄基)-(2’-甲氧基-联苯-2-基甲基)-胺
向0.55g(2.3mmol)3,5-二-三氟甲基苯甲醛在15ml甲醇中的溶液中加入0.50g(2.34mmol)(2’-甲氧基-联苯-2-基)-甲基胺,将反应混合物搅拌1小时。在加入0.13g(3.45mmol)NaBH4后,将反应混合物搅拌1小时,然后倒入冰/水中。水相用60ml二氯甲烷萃取三次。将合并后的有机层干燥(硫酸钠),过滤和蒸发。将残余物进行色谱纯化(SiO2,二氯甲烷),得到0.82g(81%)(3,5-二-三氟甲基-苄基)-(2’-甲氧基-联苯-2-基甲基)-胺,为一种无色油,MS(ISP):440.3(M+H)+。
实施例13
(3,5-二-三氟甲基-苄基)-(2’-甲氧基-联苯-2-基甲基)-甲基-胺
向0.40g(0.91mmol)(3,5-二-三氟甲基-苄基)-(2’-甲氧基-联苯-2-基甲基)-胺在5ml乙腈和0.35ml(4.55mmol)福尔马林(36%水溶液)里的溶液中分多次加入0.091g(1.46mmol)氰基硼氢钠。将反应混合物搅拌45分钟,然后倒入水中。水相用60ml二氯甲烷萃取三次。将合并后的有机层干燥(硫酸钠),过滤和蒸发。将残余物进行色谱纯化(SiO2,二氯甲烷),得到0.33g(80%)(3,5-二-三氟甲基-苄基)-(2’-甲氧基-联苯-2-基甲基)-甲基-胺,为一种无色油,MS(ISP):454.4(M+H)+。
实施例14
N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-N-甲基-乙酰胺
在0℃下,一次性地向272mg(1.0mmol)3,5-二(三氟甲基)苯基乙酸在1ml四氢呋喃的溶液中在加入162mg(1.0mmol)1,1’-羰基二咪唑。将反应混合物在室温下搅拌2小时,再加入147mg(0.8mmol)联苯-2-基-甲基-胺。再在室温下搅拌3天。将反应混合物蒸发,将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯3∶1),得到160mg(46%)N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-N-甲基-乙酰胺,为白色结晶,MS(ISP):438.2(M+H)+。
实施例15
(R,S)-N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-N-甲基-丙酰胺
a)N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-乙酰胺
以与实施例14所述类似的方式,由2-氨基联苯基和3,5-二(三氟甲基)苯基乙酸获得N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-乙酰胺,为白色结晶,MS(ISP):424.2(M+H)+。
b)(R,S)-N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-N-甲基-丙酰胺
在0℃下,在氩气氛下,向288mg(0.68mmol)N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-乙酰胺在0.5ml N,N-二甲基甲酰胺中的溶液中加入204mg(1.02mmol)六甲基二硅氮化钾。在室温下继续搅拌1小时,再将反应混合物冷却至0℃。在该温度下,加入160mg(1.07mmol)甲基碘。在室温下搅拌3小时后,加入乙酸乙酯,有机层用盐水洗涤,干燥(硫酸镁),蒸发。将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯4∶1),得到200mg(65%)的N-联苯-2-基-2-(3,5-二-三氟甲基-苯基)-N-甲基-丙酰胺,为白色结晶,MS(ISP):452.2(M+H)+。
实施例16
2-(3,5-二-三氟甲基-苯基)-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺
a)2’-甲基-4-硝基-联苯-2-基胺
将1.0g(4.6mmol)2-溴-5-硝基苯胺,20ml苯,10ml 2N碳酸钠溶液,159mg(0.14mmol)四(三苯膦)钯(O)和725mg(5.07mmol)邻甲苯基硼酸的混合物在氩气氛和60℃下加热20小时。在冷却至室温后,分离出水相,用甲苯洗涤两次。将合并后的有机层用盐水洗涤,干燥(硫酸钠)和蒸发。将残余物进行色谱纯化(SiO2,二氯甲烷/己烷2∶1)得到950mg(91%)的2’-甲基-4-硝基-联苯-2-基胺,为一种浅黄色油,MS(EI):228(M+)。
b)2-(3,5-二-三氟甲基-苯基)-N-(2’-甲基-4-硝基-联苯-2-基)-异
丁酰胺
将925mg(4.05mmol)2’-甲基-4-硝基-联苯-2-基胺和1.03ml(6.08mmol)N-乙基二异丙基胺在9ml二氯甲烷中的溶液在冰浴中冷却,滴加入1.42g(4.46mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基-丙酰氯在1ml二氯甲烷中的溶液。将反应混合物在室温下保持2小时。在加入二氯甲烷后,有机层用1N氢氧化钠溶液和1N盐酸溶液洗涤,干燥(硫酸镁)和蒸发,得到1.84g(89%)2-(3,5-二-三氟甲基-苯基)-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺,为黄色结晶,MS(ISP):511.3(M+H)+。
实施例17
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺
在氩气氛下,在0℃下,向1.75g(3.43mmol)2-(3,5-二-三氟甲基-苯基)-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺在11ml N,N-二甲基甲酰胺的溶液中滴加4.1ml(4.1mmol)的1M六甲基二硅氮化钾的四氢呋喃溶液。在室温下继续搅拌1小时,将反应混合物再冷却至0℃。在此温度下,再加入0.32ml(5.14mmol)甲基碘。在室温下搅拌3小时后,加入乙酸乙酯,有机层用盐水洗涤,干燥(硫酸镁)和蒸发。将残余物进行色谱纯化(SiO2,乙酸乙酯/己烷1∶1),得到1.0g(56%)2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺,为黄色结晶,MS(EI):524(M+)。
实施例18
N-(4-氨基-2’-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
向950mg(1.81mmol)2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺在12ml四氢呋喃和3ml水中的溶液中加入608mg(10.87mmol)的铁粉和3滴三氟乙酸。在85℃下加热3小时后,将反应混合物冷却至室温,蒸发。将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯1∶4),得到890mg(99%)N-(4-氨基-2’-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺,为浅黄色结晶,MS(ISP):495.2(M+H)+。
实施例19
2-(3,5-二-三氟甲基-苯基)-N-(4-二甲基氨基-2’-甲基-联苯-2-基)-N-甲基-异丁酰胺
向300mg(0.61mmol)N-(4-氨基-2’-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺在3ml丙酮的溶液中加入420mg(3.03mmol)碳酸钾和0.057ml(0.91mmol)甲基碘。在室温下继续搅拌过夜。将反应混合物过滤,将滤液蒸发。将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯1∶4),得到96mg(30%)2-(3,5-二-三氟甲基-苯基)-N-(4-二甲基氨基-2’-甲基-联苯-2-基)-N-甲基-异丁酰胺,为浅黄色油,MS(ISP):532.2(M+H)+。
实施例20
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-4-甲基氨基-联苯-2-基)-异丁酰胺
在纯化2-(3,5-二-三氟甲基-苯基)-N-(4-二甲基氨基-2’-甲基-联苯-2-基)-N-甲基-异丁酰胺过程中,分离出标题化合物,为一种黄色油,MS(ISP):509.1(M+H)+,(44mg,14%)。
实施例21
2-(3,5-二-三氟甲基-苯基)-N-(2’-甲氧基-联苯-2-基)-N-甲基-异丁酰胺
将53mg(0.25mmol)(2’-甲氧基-联苯-2-基)-甲基-胺和0.064ml(0.375mmol)N-乙基二异丙基胺在4ml二氯甲烷中的溶液于冰浴上冷却,滴加入88mg(0.275mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基-丙酰氯在1ml二氯甲烷中的溶液。将反应混合物在室温下搅拌过夜。加入乙酸乙酯,有机层用饱和碳酸钠溶液、1N盐酸溶液洗涤,干燥(硫酸镁)和蒸发。将残余物进行色谱纯化(SiO2,己烷/乙酸乙酯4∶1),得到107mg(87%)2-(3,5-二-三氟甲基-苯基)-N-(2’-甲氧基-联苯-2-基)-N-甲基-异丁酰胺,为一种橙色结晶,MS(ISP):496.1(M+H)+。
实施例22
2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-联苯-2-基)-异丁酰胺
以与实施例21所述类似的方式,由(2’-甲基-联苯-2-基)-甲基-胺和2-(3,5-二-三氟甲基-苯基)-2-甲基-丙酰氯获得2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2’-甲基-联苯基-2-基)-异丁酰胺,为白色结晶,MS(ISP):480.2(M+H)+。
实施例23
2-(3,5-二-三氟甲基-苯基)-N-(2’-氯-联苯-2-基)-N-甲基-异丁酰胺
以与实施例21所述类似的方式,由(2’-氯-联苯-2-基)-甲基-胺和2-(3,5-二-三氟甲基-苯基)-2-甲基丙酰氯获得2-(3,5-二-三氟甲基-苯基)-N-(2’-氯-联苯-2-基)-N-甲基-异丁酰胺,为白色结晶,MS(ISP):502.2(M+H)+。
实施例24
N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-异丁酰胺
以与实施例16所述类似的方式,由2,2’-二氨基联苯基和2-(3,5-二-三氟甲基-苯基)-2-甲基-丙酰氯获得N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-异丁酰胺,为白色结晶,MS(ISP):467.2 (M+H)+。
实施例25
N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺
在氩气氛下,在0℃下,向151mg(0.32mmol)N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-异丁酰胺在1ml N,N-二甲基甲酰胺的溶液中加入130mg(0.65mmol)六甲基二硅氮化钾。继续在室温下搅拌1小时,再将反应混合物冷却至0℃。在此温度下,加入115mg(0.81mmol)甲基碘。在室温下搅拌3小时后,加入乙酸乙酯,有机层用盐水洗涤,干燥(硫酸镁)和蒸发。将残余物进行色谱纯化(SiO2,乙酸乙酯/二氯甲烷1∶1),得到56mg(36%)N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺,为一种无色油,MS(ISP):481.1(M+H)+。
实施例26
2-(3,5-二-三氟甲基-苯基)-N-(2’-二甲基氨基-联苯-2-基)-异丁酰胺
在N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺的纯化过程中,分离出标题化合物,为白色结晶,MS(ISP):495.2(M+H)+,(14mg,9%)。
实施例27
2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
a)2-氯-4-氟-N-甲基-苯甲酰胺
在0℃下,向1.00g(5.73mmol)的2-氯-4-氟苯甲酸中加入4.16ml(57.3mmol)的亚硫酰氯和3滴DMF。在回流下加热混合物过夜,过量的亚硫酰氯通过蒸馏除去。将油状的褐色残余物溶解于5ml二氯甲烷中。将溶液在0℃下用甲基胺处理,直至不再观察到放热反应。将形成的悬浮液用20ml二氯甲烷/水稀释。进行分层,水层用3份10ml的二氯甲烷萃取。将有机层干燥(硫酸钠),蒸发,得到1.07g(99.6%)2-氯-4-氟-N-甲基-苯甲酰胺,为一种淡黄色固体,MS(EI):187(M+)。
b)2-氯-N-甲基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺
在密封的玻璃管中,将316mg(1.68mmol)2-氯-4-氟-N-甲基-苯甲酰胺和0.94ml(8.4mmol)1-甲基哌嗪的混合物在140℃下加热7小时。在冷却至室温后,通过在50℃/0.5毫巴下进行蒸馏除去过量的1-甲基哌嗪。将残余物在25ml二氯甲烷/2N氢氧化钠溶液间进行分配。进行分层,水层用3份5ml的二氯甲烷萃取。将合并后的有机萃取液干燥(硫酸钠),蒸发。进行色谱处理(SiO2,二氯甲烷/甲醇19∶1),得到236mg(52%)2-氯-N-甲基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺,为淡黄色固体,MS(EI):267(M+)。
c)2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸甲基酰胺
在-78℃下,向125mg(0.467mmol)2-氯-N-甲基-4-(4-甲基-哌嗪-1-基)-苯甲酰胺和0.22ml(1.5mmol)N,N,N’,N’-四甲基乙二胺在2ml THF中的溶液中滴加入邻甲苯基锂,所述邻甲苯基锂是通过在-78℃下将2.5ml(3.8mmol)的1.5M叔丁基锂的戊烷溶液加至0.23ml(1.9mmol)2-溴甲苯在2ml乙醚中的溶液中制得的。将反应混合物在2小时内升温至-25℃。在用1ml水于-25℃下使反应停止后,将混合物升温至室温,再用10ml乙酸乙酯稀释,用10ml 1N氢氧化钠溶液洗涤。进行分层,水层用2份10ml的乙酸乙酯进行萃取。将合并后的有机层干燥(硫酸钠)和蒸发。进行色谱处理(SiO2,二氯甲烷/甲醇19∶1),得到55mg(36%)2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸甲基酰胺,为一种无色油,MS(EI):324(M+)。
d)2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲
基-苄基)-甲基-酰胺
在0℃下,向50mg(0.15mmol)2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸甲基酰胺在2ml THF中的溶液中加入0.2ml的1M(0.2mmol)六甲基二硅氮化钾的THF溶液。20分钟后,向形成的悬浮液中滴加入0.028ml(0.15mmol)3,5-二(三氟甲基)苄基溴。在1.5小时后,用水使反应停止。将混合物用5ml 2N氢氧化钠溶液稀释,用3份5ml的乙酸乙酯萃取。将合并后的有机提取物干燥(硫酸钠)和蒸发。进行色谱处理(SiO2,二氯甲烷/甲醇19∶1),得到25mg(29%)2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,MS(ISP):550.5(M+H)+。
实施例28
2’-氯-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
采用2-溴氯苯代替步骤c)中的邻溴甲苯,以与制备2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺(实施例27)类似的方式,制得2’-氯-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺(MS(570,M+H)+)。
实施例29
4’-氟-2’-甲基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺
以与实施例1a)所述类似的方式由4’-氟-2’-甲基-联苯基-2-甲酸和(3,5-二-三氟甲基)-甲基苄基胺获得4’-氟-2’-甲基-联苯基-2-甲酸(3,5-二-三氟甲基-苄基)-甲基-酰胺,为一种无色油,MS(EI):468(M-H)+。
作为原料物质的4’-氟-2’-甲基-联苯基-2-甲酸由下述过程获得:
a)(4’-氟-2’-甲基-联苯-2-基亚甲基)-异丙基-胺
将14.57g(81mmol)N-(2-甲氧基亚苄基)异丙基胺在50ml THF中的溶液滴加至格利雅试剂中,所述试剂是由18.01g(90mmol)2-溴-5-氟甲苯和2.19g(90mmol)镁屑在50ml THF中制得的。将混合物在回流下加热12小时。在剧烈搅拌下,将混合物倒入氯化铵水溶液(25%)中,再搅拌1小时。用二氯甲烷萃取,干燥(硫酸钠)和蒸发,得到20.83g(98%)(4’-氟-2’-甲基-联苯-2-基亚甲基)-异丙基胺,为一种浅黄色油。
b)4’-氟-2’-甲基-联苯基-2-甲醛
将20.36g(79.8mmol)(4’-氟-2’-甲基-联苯-2-基亚甲基)-异丙基-胺在110ml 4N硫酸中的溶液在回流下加热6小时。在冷却至室温后,将该溶液用150ml二氯甲烷萃取两次。将合并后的有机层干燥(硫酸钠),过滤和蒸发。将残余物进行色谱纯化(二氧化硅,二氯甲烷/己烷1∶1),得到4’-氟-2’-甲基-联苯基-2-甲醛,为一种浅黄色油。
c)4’-氟-2’-甲基-联苯基-2-甲酸
向2.70g(12.6mmol)4’氟-2’-甲基-联苯基-2-甲醛在75ml丙酮和25ml水中的溶液中加入3.38g(21.4mmol)的KMnO4,将混合物搅拌20小时。蒸发出溶剂,将残余物用100ml水和100ml二氯甲烷处理,将水相的pH值用浓硫酸调节至1。在用Hyflo过滤后,进行相分离,水相用100ml的二氯甲烷洗涤两次。将合并后的有机层干燥(硫酸钠),过滤和蒸发。将残余物进行色谱纯化(二氧化硅,二氯甲烷/甲醇19∶1),得到4’-氟-2’-甲基-联苯基-2-甲酸,为一种无色固体,MS(EI):230,(M+)。
实施例A
以常规方式生产具有下述组成的片剂:
mg/片
活性物质 5
乳糖 45
玉米淀粉 15
微晶纤维素 34
硬脂酸镁 1
总重100
实施例B
生产具有下述组成的胶囊:
mg/胶囊
活性物质 10
乳糖 155
玉米淀粉 30
滑石 5
胶囊填充重量200
首先在混合器中将活性物质、乳糖和玉米淀粉混合,然后在粉碎机中粉碎。将混合物返回混合器中,加入滑石并充分混合。通过机器将混合物填充入硬明胶胶囊中。
实施例C
生产具有下述组成的栓剂:
mg/栓剂
活性物质 15
栓剂基料 1285
总重1300
将栓剂基料在玻璃或钢制容器中熔化,充分混合并冷却至45℃。此后,加入微细粉末化的活性物质,搅拌直至其完全分散。将混合物倒入适宜尺寸的栓剂模具中,使其冷却,然后从模具中取出栓剂,单个地包含于蜡低或金属箔中。
Claims (8)
1.通式I的化合物
其中,
R为氢,(C1-C7)-烷基、(C1-C7)-烷氧基、卤素、氨基、-N(R6)2或三氟甲基;
R1为氢,(C1-C7)-烷氧基或卤素;或
R和R1合在一起为-CH=CH-CH=CH-;
R2为卤素、(C1-C7)-烷基和三氟甲基;
R3为氢或(C1-C7)-烷基;
R4为氢或环状叔胺,该环状叔胺选自吡咯-1-基、咪唑-1-基、哌啶-1-基、哌嗪-1-基、吗啉-4-基、硫代吗啉-4-基、1-氧代-硫代吗啉-4-基和1,1-二氧代-硫代吗啉-4-基,非必要地被(C1-C7)-烷基取代;
R5为氢、硝基、氨基或-N(R6)2;
R6为氢或(C1-C7)-烷基;
X为-C(O)N(R6)-、-(CH2)nO-、-(CH2)nN(R6)-、-N(R6)C(O)-或-N(R6)(CH2)n-;且
n为1或2;
和其可药用酸加成盐,但化合物
N-[(4-甲基苯基)甲基]-[1,1’-联苯基]-2-甲胺和
N-[[4-(1,1-二甲基乙基)苯基]甲基]-N-甲基-[1,1’-联苯基]-2-甲胺,盐酸盐排除在外。
2.权利要求1的化合物,其中,X为-C(O)N(R6)-,且R6为甲基。
3.权利要求2的化合物,其为
2’-甲基-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺,
2’-甲基-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺,和
2’-氯-5-(4-甲基-哌嗪-1-基)-联苯基-2-甲酸-(3,5-二-三氟甲基-苄基)-甲基-酰胺。
4.根据权利要求1化合物,其中,X为-N(R6)-C(O)-,且R6为甲基。
5.权利要求4的化合物,其为
2-(3,5-二-三氟甲基-苯基)-N-甲基-N’-(2’-甲基-4-硝基-联苯-2-基)-异丁酰胺,
N-(4-氨基-2’-甲基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺,
2-(3,5-二-三氟甲基-苯基)-N-甲基-N’-(2’-甲基-4-甲基氨基-联苯-2-基)-异丁酰胺,
2-(3,5-二-三氟甲基-苯基)-N-甲基-N’-(2’-甲基-联苯-2-基)-异丁酰胺,和
N-(2’-氨基-联苯-2-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺。
6.用于治疗与神经激肽-1受体拮抗剂相关的疾病的药物,该药物包含权利要求1-5之任一项的一种或多种化合物和可药用赋形剂。
7.权利要求1定义的式I化合物的制备方法,该方法包括:
a)使式II的化合物与式III的化合物
反应得到式I-1的化合物
其中,R1-R6、R和n具有权利要求1中给出的意义,或者
b)使式IV的化合物与式V的化合物
反应得到式I-2的化合物
其中,R1-R6、R和n具有权利要求1中给出的意义,或者
b)将式I-2的化合物
还原得到式I-4的化合物
其中,取代基的定义在权利要求1中给出,或者
d)使式VI的化合物与式VII的化合物
反应得到式I-2的化合物
其中,取代基的定义在权利要求1中给出,或者
e)使式VIII的化合物与式VII的化合物
反应得到式I-5的化合物
其中,取代基的定义在权利要求1中给出,或者
f)将式I-1的化合物
还原得到式I-3的化合物
其中,取代基的定义在权利要求1中给出,或者
g)使式XII的化合物与式XIII的化合物
反应得到式I-5的化合物
其中,取代基的定义在权利要求1中给出,或者
h)将式I-41的化合物
进行甲基化得到式I-42的化合物
其中,取代基的定义在权利要求1中给出,或者
i)使式II的化合物与式XIII的化合物
反应得到式I-1的化合物
其中,取代基的定义在权利要求1中给出,或者
j)在权利要求1中给出的定义范围内对一种或多种取代基R1-R6或R进行修饰,和
非必要地,将获得的化合物转化成可药用酸加成盐。
8.权利要求1-5之任一项的化合物在生产包含一种或多种式I化合物的用于治疗与神经激肽-1受体有关的疾病的药物中的用途。
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JP3839518B2 (ja) * | 1996-03-27 | 2006-11-01 | ポーラ化成工業株式会社 | 抗真菌剤 |
HUP0001910A2 (hu) | 1997-04-18 | 2000-10-28 | Pfizer Inc. | Eljárás 4'-trifluormetil-bifenil-2-karbonsav-(1,2,3,4-tetrahidroizokinolin-6-il)- amid előállítására, és az eljáráshoz felhasználható köztitermékek |
US5972938A (en) | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
SE1035115T5 (sv) * | 1999-02-24 | 2015-08-04 | Hoffmann La Roche | 4-fenylpyridin-derivat och deras anvaendning som NK-1 receptor-antagonister |
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