CN1139927A - 取代的吗啉衍生物及其作为治疗剂的用途 - Google Patents
取代的吗啉衍生物及其作为治疗剂的用途 Download PDFInfo
- Publication number
- CN1139927A CN1139927A CN94194722A CN94194722A CN1139927A CN 1139927 A CN1139927 A CN 1139927A CN 94194722 A CN94194722 A CN 94194722A CN 94194722 A CN94194722 A CN 94194722A CN 1139927 A CN1139927 A CN 1139927A
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- Prior art keywords
- phenyl
- trifluoromethyl
- compound
- methyl
- formula
- Prior art date
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- Granted
Links
- 239000003814 drug Substances 0.000 title claims description 17
- 150000002780 morpholines Chemical class 0.000 title description 3
- 229940124597 therapeutic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 361
- 150000003839 salts Chemical class 0.000 claims abstract description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 68
- 239000001257 hydrogen Substances 0.000 claims abstract description 62
- 229940002612 prodrug Drugs 0.000 claims abstract description 57
- 239000000651 prodrug Substances 0.000 claims abstract description 57
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 31
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 25
- 206010047700 Vomiting Diseases 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 17
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 9
- 206010027599 migraine Diseases 0.000 claims abstract description 9
- 208000002193 Pain Diseases 0.000 claims abstract description 8
- 230000036407 pain Effects 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 7
- 230000004054 inflammatory process Effects 0.000 claims abstract description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 4
- -1 4Be hydrogen Chemical class 0.000 claims description 180
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 122
- 239000000203 mixture Substances 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 109
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 68
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- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 29
- RXXYJBUUGPAHIJ-LLVKDONJSA-N (3s)-3-(4-fluorophenyl)-4-methylmorpholine Chemical compound CN1CCOC[C@@H]1C1=CC=C(F)C=C1 RXXYJBUUGPAHIJ-LLVKDONJSA-N 0.000 claims description 24
- OIYANYVIFQBNMS-LLVKDONJSA-N (3S)-4-methyl-3-phenylmorpholine Chemical compound C1(=CC=CC=C1)[C@@H]1N(CCOC1)C OIYANYVIFQBNMS-LLVKDONJSA-N 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 108060008037 tachykinin Proteins 0.000 claims description 20
- 102000003141 Tachykinin Human genes 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
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- 230000008673 vomiting Effects 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
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- 150000000182 1,3,5-triazines Chemical class 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
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- ZRYRFSOCXPYOPS-OPYAIIAOSA-N 3-[(2R,3S)-2-[(1S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxyethoxy]-3-methyl-3-phenylmorpholin-4-yl]-1,4-dihydro-1,2,4-triazol-5-one Chemical compound O=C1NNC(=N1)N1[C@]([C@H](OCC1)O[C@H](CO)C1=CC(=CC(=C1)C(F)(F)F)F)(C1=CC=CC=C1)C ZRYRFSOCXPYOPS-OPYAIIAOSA-N 0.000 claims description 2
- DJPMDMLUMKNEDG-OPYAIIAOSA-N 3-[(2R,3S)-3-(4-fluorophenyl)-2-[(1S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxyethoxy]-3-methylmorpholin-4-yl]-1,4-dihydro-1,2,4-triazol-5-one Chemical compound O=C1NNC(=N1)N1[C@]([C@H](OCC1)O[C@H](CO)C1=CC(=CC(=C1)C(F)(F)F)F)(C1=CC=C(C=C1)F)C DJPMDMLUMKNEDG-OPYAIIAOSA-N 0.000 claims description 2
- MGEUZFSNEOPBGZ-FGTMMUONSA-N 5-[(2r,3s)-2-[(1s)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholin-4-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1([C@@H]2N(CCO[C@@H]2O[C@H](CO)C=2C=C(C=CC=2)C(F)(F)F)C=2NNC(=O)N=2)=CC=CC=C1 MGEUZFSNEOPBGZ-FGTMMUONSA-N 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- 125000006239 protecting group Chemical group 0.000 claims description 2
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 230000007794 irritation Effects 0.000 claims 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 188
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 68
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
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- 235000002639 sodium chloride Nutrition 0.000 description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
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- 238000005481 NMR spectroscopy Methods 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
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Abstract
本发明涉及式(I)化合物和其可药用盐和前药:其中R1是氢、卤素、C1-6烷基、C1-6烷氧基、CF3、NO2、CN、SRa、SORa、SO2Ra、CO2Ra、CONRaRb、C2-6链烯基、C2-6炔基或被C1-4烷氧基取代的C1-4烷基,其中Ra和Rb是氢或C1-4烷基;R2是氢、卤素、C1-6烷基,被C1-4烷氧基或CF3取代的C1-6烷氧基;R3是氢、卤素或CF3;R4选自R1的定义;R5选自R2的定义;R6是5-元或6-元含2或3个氮原子的任选地被=O,=S或C1-4烷基取代的杂环,其任选地被氨基烷基取代;R9a和R9b是氢或C1-4烷基,式R9a或R9b结合形成C5-7环;X是C1-4亚烷基,其任选地被氧代取代;和Y是任选被羟基取代的C1-4烷基;其前体是如果Y是C1-4烷基,R6至少被氨基烷基取代。该化合物在治疗疼痛,炎症,偏头痛和呕吐是特别有用的。
Description
本发明涉及用作速激肽拮抗剂的一类芳族化合物。具体而言,本发明的化合物含有胺取代的偶氮杂环部分。
速激肽是一类天然存在的肽,人们发现其广泛地分布在哺乳类动物组织中,包括在中枢神经系统中和在外周神经系统以及循环系统中。
速激肽的特征在于其保存有下列C-端序列:Phe-X-Gly-Leu-Met-NH2。
目前,有三种已知的哺乳类动物速激肽,它们被称为P物质,神经激肽A(NKA,K物质,neuromedin L)和神经激肽B(NKB,neuromedin K)(其综述参见J.E.Maggio,Peptides(1985)6(增刊3),237-242)。现在的名称指示三种介导P物质,NKA和NKB的生物作用的速激肽受体分别是NK1、NK2和NK3受体。
速激肽受体拮抗剂在疼痛、头痛,尤其是周期性偏头痛,早老性痴呆,多发性硬化,吗啡脱瘾的减弱,心血管变化,浮肿,如由热损伤引起的浮肿。慢性炎症如类风湿性关节炎,哮喘支气管/反应过度和其他呼吸疾病包括变应性鼻炎,肠炎症包括溃疡性结肠炎和节段性回肠炎,眼损伤和眼炎症,增生的玻璃体视网膜病,肠激惹综合征和膀胱功能紊乱包括膀胱炎和膀胱逼肌高度反射中的应用的证据在“Tachykinin Receptors and Tachykinin Receptor Antagonists”,C.A.Maggi,R.Patacchini,P.Rovero和A.Giachetti,J.Auton.Pharmacol.(1993)13,23-93中进行了综述。
例如,P物质据信在痛觉神经传递中[Otsuka等人,“Role ofSubstance P as a Sensory Transmitter in Spinal Cord andSympathetic Ganglia”在1982 Substance P in the NervousSystem,Ciba Foundation Symposium 91,13-34(由Pitman出版)和Otsuka和Yanagisawa,“Does Substance P Act as a PainTransmitter?”TIPS(1987)8,506-510],尤其是在周期性偏头痛的传递中(B.E.B.Sandberg等,J.Med.Chem.,(1982)25,1009)和在关节炎中[Levine等人,Science(1984)226,547-549]尤其被涉及到。速激肽在胃肠道的胃肠(GI)机能失调和疾病如肠炎疾病[Mantyh等人,Neuroscience(1988)25(3),817-37和D.Regoli在“Trends in Cluster Headache”Ed.Sicuteri等ElsevierScientific Publishers,Amsterdam(1987)第85页)]和呕吐[F.D.Tattersall等人,Eur.J.Pharmacol.,(1993)250,R5-R6]中也被涉及。还假定存在关节炎的神经原机理,其中P物质可以起作用[Kidd等,“A Neurogenic Mechanism for SymmetricalArthritis”在The Lancet,1989,11,11,和Grnblad等,“Neuropeptides in Synovium of Patients with RheumatoidArthritis and Osteoarthritis”在J.Rheumatol.(1988)15(12),1807-10]。因此,P物质据信在与疾病如类风湿性关节炎和骨关节炎和纤维积炎相应的炎症反应[O′Byrne等,Arthritis and Rheumatism(1990)33,1023-8]中被涉及。速激肽被认为是有用的其他疾病领域是过敏性病症[Hamelet等,Can.J.Pharmacol,Physiol.(1988)66,1361-7],免疫调节[Lotz等,Science(1988)241,1218-21和Kimball等,J.Immunol.(1988)141(10),3564-9],血管舒张,支气管痉挛,内脏的反射或神经控制[Mantyh等,PNAS(1988)85,3235-9]和在阿尔茨默型的老年性痴呆、早老性痴呆和唐氏综合征中可能是通过抑制或缓减β-淀粉样蛋白介导的神经变性的变化[Yankner等,Science(1990)250,279-82]。
速激肽拮抗剂也可以用于治疗小细胞癌,尤其是小细胞肺癌(SCLC)[Langdon等,Cancer Research(1992)52,4554-7]。
P物质在脱神经髓鞘疾病如多发性硬化和肌萎缩性侧索硬化症[J.Luber-Narod等,Poster C.I.N.P.X VIII th Congress,28th June-2nd July 1992],和在膀胱功能紊乱如膀胱逼肌高度反射(Lancet,16th May 1992,1239)中也起作用。
进一步被提到的是速激肽在下列病症中有效用:抑郁症,精神抑郁症,慢性阻塞性气道疾病,过敏性疾病如毒常青藤,血管痉挛疾病如咽峡炎和雷诺尔德疾病,纤维化和胶原性疾病如硬皮病和嗜曙红细胞增多性片吸虫病,反射交感神经营养不良如肩/手综合征,成瘾性疾病如酒精中毒,与紧张有关的躯体病症,神经病,神经痛,与免疫增强作用和压抑有关的病症如全身性红斑狼疮(EP0436334),眼疾如结膜炎,春季结膜炎,等等,和皮肤病如接触性皮炎,特应性皮炎,荨麻疹,和其他湿疹样疹皮炎(EP0394989)。
EP0577394(1994年1月5日出版)公开了下列通式的吗啉和硫代吗啉速激肽受体拮抗剂其中R1a是各种取代基;R2a和R3a尤其是氢;R4a尤其是R5a尤其是任选被取代的苯基;R6a、R7a和R8a是各种取代基;Xa是O、S、SO或SO2Ya尤其是O;和Za是氢或C1-4烷基。
现在我们找到了另一类非肽化合物,其是速激肽(尤其是P物质)`的有效拮抗剂。
理想的情况是化合物可以口服和通过注射给药。现在人们发现化合物可以作为有效的非肽速激肽拮抗剂,并且根据其有利的水溶性,化合物特别容易例如在水性介质中被配制,以便通过口服和注射给药。
而且,本发明的化合物具有特别有利的活性性能,其在NK1受体上具有有效的拮抗剂活性并且具有长的作用时间。本发明化合物,特别是它们可药用的酸加成盐,根据它们的溶解性也是特别适用于各种药物制剂。
本发明提供了式(I)化合物和其可药用盐和前药:其中
R1是氢,卤素,C1-6烷基,C1-6烷氧基,CF3,NO2,CN,SRa,SORa,SO2Ra,CO2Ra,CONRaRb,C2-5链烯基,C2-5炔基或被C1-4烷氧基取代的C1-4烷基,其中Ra和Rb各自独立地表示氢或C1-4烷基;
R2是氢,卤素,C1-6烷基,被C1-4烷氧基取代的C1-6烷氧基或CF3;
R3是氢,卤素或CF3;
R4是氢,卤素,C1-6烷基,C1-6烷氧基,CF3,NO2,CN,SRa,SORa,SO2Ra,CO2Ra,CONRaRb,C2-6链烯基,C2-6炔基或被C1-4烷氧基取代的C1-4烷基,其中Ra和Rb各自独立地表示氢或C1-4烷基;
R5是氢,卤素,C1-6烷基,被C1-4烷氧基取代的C1-6烷氧基或CF3;
R6是含2或3个氮原子的5元或6元杂环,其任选地被=O,=S或C1-4烷基取代,和任选地被式ZNR7R8基团取代,其中
Z是C1-6亚烷基或C3-6亚环烷基;
R7是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基;
R8是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被一个或两个选自C1-4烷氧基,羟基或含一个或两个选自N,O和S杂原子的4,5或6元脂族杂环取代基取代的C2-4烷基;
或者R7,R8和与它们相连的氮原子一起形成4至7个环原子的脂族杂环,其任选地被一个或两个选自羟基或任选被C1-4烷氧基或羟基取代的C1-4烷基取代,和其任选地含有双键,该环可以任选地含有氧或硫环原子,基因S(O)或S(O)2或将是NH或NRc部分之部分的第二个氮原子,其中Rc是任选被羟基或C1-4烷氧基取代的C1-4烷基;
或者R7,R8与和它们相连的氮原子一起形成6至12个环原子的非芳族氮杂二环系;
或者Z,R7和与它们相连的氮原子形成可以任选地含有氧环原子的4至7个环原子的脂族杂环;
R9a和R9b各自独立地是氢或C1-4烷基,或者R9a和R9b与和它们连接的碳原子连接在一起形成C5-7环;
X是任选地被氧代取代的1至4个碳原子的亚烷基链;和
Y是任选地被羟基取代的C1-4烷基;
其前提条件是如果Y是C1-4烷基,R6至少被如上述所定义的式ZNR7R8基团取代。
本发明某些特别适合的化合物包括其中R1是氢,C1-4烷基,C1-4烷氧基,卤素或CF3的化合物。
最适合的R2是氢,C1-4烷基,C1-4烷氧基,卤素或CF3。
最适合的R3是氢,氟,氯或CF3。
有利的R1是氟,氯或CF3。
有利的R2是氢,氟,氯或CF3。
有利的R3是氢,氟,氯或CF3。
任选R1和R2是在苯环的3位和5位上。
更优选的R1是3-氟代或3-CF3。
更优选的R2是5-氟代或5-CF3。
更优选的R3是氢。
最优选的R1是3-F或3-CF3,R2是5-CF3和R3是氢。
最适合的R4是氢。
最适合的R5是氢,氟,氯或CF3。
优选R4是氢和R5是氢或4-氟。
最适合的是R9a和R9b各自独立地是氢或甲基。
优选R9a是氢。优选R9b是氢。最优选R9a和R9b都是氢。
根据上述内容。可以被理解的是本发明化合物的特别适合的一类化合物是式(Ia)的化合物和其可药用盐和前药:其中A1是氟或CF3;
A2是氟或CF3;
A3是氟或氢;和X、Y和R6如式(I)中所定义。
根据本发明的第二或另一方面,式(I)或(Ia)化合物的优选的一类化合物是其中Y表示被羟基取代的C1-4烷基的化合物;或其可药用盐或前药。
根据本发明的另外的或另一可选择的方面,式(I)或(Ia)化合物的另一类优选化合物是其中Y表示C1-4烷基的化合物,其前提是R6至少如上述所定义的式ZNR7R8的基团取代,或其可药用盐或前药。
根据本发明的另一方面,式(I)或(Ia)的另一类优选的化合物是下述式(I)或(Ia)化合物或其可药用盐或前药,其中
Y表示C1-4烷基;和
R6表示含2或3个氮原子的5元或6元杂环,其任选地被=O或=S取代和被式ZNR7R8基团取代,其中
Z是C1-6亚烷基或3-6亚环烷基;
R7是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基;
R8是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被一个或两个选自C1-4烷氧基,羟基或含有一或两个选自N,O和S杂原子的4、5或6元脂族杂环取代的C2-4烷基;
或R7,R8和与它们相连的氮原子一起形成4至7个环原子的脂族杂环,其任选地被羟基取代,和任选地含有双键,该环可以任选地含有氧或硫环原子,基团S(O)或S(O)2或是NH或NRc部分之一部分的第二个氮原子,其中Rc是任选地被羟基或C1-4烷氧基取代的C1-4烷基;
式Z,R7和与它们相连的氮原子形成4至7个环原子的脂族杂环,其可以任选地含有氧环原子。
根据本发明的另一方面,式(I)或(Ia)化合物的一类优选的化合物是下述式(I)或(Ia)化合物或其可药用盐或前药,其中
Y表示C1-4烷基;和
R6是含2或3个氮原子的5元或6元杂环,其任选被=O或=S取代和被式ZNR7R8取代,其中
Z是C1-6亚烷基或C3-6亚环烷基;
R7是氢或C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基,R8是氢或C1-4烷基或被C1-4烷氧基,羟基或含一个或两个选自N,O和S的杂原子的5或6元脂族杂环取代的C2-4烷基;
或者R7,R8和与它们相连的氮原子形成4至7个环原子的脂族杂环,其任选地被羟基取代,该环任选地可以含有氧或硫原子,基团S(O)或S(O)2或是NH或NRc部分之一部分的第二个氮原子,其中Rc是任选地被羟基或C1-4烷氧基取代的C1-4烷基;
或者Z,R7和与它们相连的氮原子形成可以任选地含有氧环原子的4至7个环原子的脂族杂环。
根据本发明的另一方面,式(I)或(Ia)化合物的另一类优选化合物是下述式(I)或(Ia)化合物或其可药用盐或前药,其中
Y表示被羟基取代的C1-4烷基;和
R6是含2或3个氮原子的5元或6元杂环,其任选地被=O或=S取代和任选地被式ZNR7R8基团取代,其中
Z是C1-6亚烷基或C3-6亚环烷基;
R7是氢或C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基,R8是氢或C1-4烷基或被C1-4烷氧基或羟基取代的C2-4烷基;
或者R7,R8和与它们相连的氮原子形成4至7个环原子的脂族杂环,该环可以任选地含有氧环原子或是NH或NRc部分之一部分的第二个氮原子,其中Rc是被羟基或C1-4烷氧基任选取代的C1-4烷基;
或者Z,R7和与它们相连的氮原子形成可以任选地含有氧环原子的4至7个环原子的脂族杂环;
根据本发明的另一方面,式(I)或(Ia)化合物的另一类优选的化合物是下述式(I)或(Ia)化合物或其可药用盐或前药,其中
R6是含2或3个氮原子的5元或6元杂环,其任选地被=O或=S取代和任选地被式ZNR7R8基团取代,其中
Z是C1-6亚烷基或C3-6环烷基;
R7是氢或C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基,R8是氢或C1-4烷基或被C1-4烷氧基或羟基取代的C2-4烷基;
或者R7,R8和与它们相连的氮原子形成4至7个环原子的脂族杂环,其可以任选地含有氧环原子或是NH或NRc部分之一部分的第二个氮原子,其中Rc是任选地被羟基或C1-4烷氧基取代的C1-4烷基;
或Z,R7和与它们相连的氮原子形成可以任选地含有氧环原子的4至7个环原子的脂族杂环;
式(I)或(Ia)化合物优选的Y基团是CH2OH基团。
式(I)或(Ia)化合物另一优选的Y基团是CH3。
式(I)或(Ia)化合物特别适合的X包括CH2,CH(CH3)和CH2CH2,其中CH2是优选的。
有利的R6是5元环。
R6表示的特别优选的杂环是:
对于式(I),(Ia),(Ib),(Ic)和(Id)化合物,Z可以是直链,支链或环状基团。有利的是Z含有1至4个碳原子和最优选的是含1或2个碳原子。特别有利的基团Z是CH2。
对于式(I),(Ia),(Ib),(Ic)和(Id)化合物,R7适合地可以是C1-4烷基或被羟基或C1-2烷氧基取代的C2-4烷基,R8适当地可以是C1-4烷基或被羟基或C1-2烷氧基取代的C1-4烷基,或者R7和R6可以和与它们相连的氮原子连接在一起形成氮杂环丁烷基,吡啶烷基,哌啶基,吗啉代,硫代吗啉代,哌嗪基或在氮原子上被C1-4烷基或被羟基或C1-2烷氧基取代的C2-4烷基取代的哌嗪基。
当基团NR7R8表示4至7个环原子的脂族杂环和所说的环含有双键时,特别优选的基团是3-吡咯啉。
当基团NR7R8表示非芳族氮杂二环系时,该环系可以含有6至12,优选7至10个环原子。适当的环包括5-氮杂双环[2.1.1]己烷基,5-氮杂双环[2.2.1]庚烷基,6-氮杂双环[3.2.1]辛烷基,2-氮杂双环[2.2.2]辛烷基,6-氮杂双环[3.2.2]壬基,6-氮杂双环[3.3.1]壬烷基,6-氮杂双环[3.2.2]癸烷基,7-氮杂双环[4.3.1]癸烷基,7-氮杂双环[4.4.1]十一烷基和8-氮杂双环[5.4.1]十二烷基,尤其是5-氮杂双环[2.1.1]庚烷基和6-氮杂双环[3.2.1]辛烷基。
当R8表示被含有一或两个选自N、O和S的杂原子的5或6元脂族杂环取代的C2-4烷基时,适当的环包括吡咯烷子基(pyrrolidino),哌啶子基,哌嗪子基(piperazino),吗啉代,或硫代吗啉代。特别优选的是含氮脂族杂环,尤其是吡咯烷子基和吗啉代环。
特别适合的ZNR7R8部分包括其中Z是CH2或CH2CH2和NR7R8是氨基,甲基氨基,二甲氨基,二乙氨基,氮杂环丁烷基,吡咯烷子基和吗啉代。
用ZNR7R8表示的另一优选部分是其中Z是CH2或CH2CH2,R7表示氢,C1-4烷基或C3-6环烷基和R8是被一或两个选自羟基,C1-2烷氧基,氮杂环丁烷基,吡咯烷子基,哌啶子基,吗啉代或硫代吗啉代的取代基取代的C2-4烷基。
具体而言,Z优选是CH2和NR7R8优选是二甲氨基,氮杂环丁烷基或吡咯烷子基,尤其是二甲氨基。
对于式(Ia),(Ib),(Ic)和(Id)化合物,A1优选是氟或CF3;A2优选是CF3;和A3优选是氟。
本文中使用的术语“烷基”或“烷氧基”作为基团或基团的一部分意指该基团是直链的或支链的。适当的烷基的实例包括甲基,乙基,正丙基,异丙基,正丁基,仲丁基和叔丁基。适当的烷氧基的例子包括甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,仲丁氧基和叔丁氧基。
本文涉及的环烷基可以是,例如,环丙基,环丁基、环戊基或环己基。适当的环烷基烷基可以是,例如,环丙基甲基。
本文中使用的术语“链烯基”和“炔基”作为基团或基团的一部分意指该基团是直链或支链的。适当的链烯基的实例包括乙烯基和烯丙基。适当的炔基是炔丙基。
本文中使用的术语“卤素”是指氟,氯,溴和碘。最适合的卤素是氟和氯,其中优选氟。
本发明范围内的具体化合物包括:
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-5-(N,N-二甲氨基)甲基-2-氧代-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-5-(N,N-二甲氨基)甲基-2-氧代-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(4-羟基哌啶子基)甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-5-吗啉代甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-吗啉代甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
4-(5-氮杂环丁烷基甲基-2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基-2-(R)-(1′-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(N-甲基哌嗪基)甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(N-(2-吗啉代乙基)氨甲基)-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-(N-(2-吡咯烷子基乙基)氨甲基)-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二甲基氨基)甲基-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(N-(N′-甲基氨基乙基)-1,2,4-三唑-3-基)甲基吗啉;和其可药用盐或前药。
本发明进一步优选的化合物包括:
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(N-甲基氨基甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-氨基甲基)-1,2,3-三唑-4-基)甲基-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-吡咯烷子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(氮杂环丁烷基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(5-(吡咯烷子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基-4-(5-(吗啉代甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-(三氟甲基)苯基)乙氧基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(N′-甲基哌嗪子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-(1-(2-吡咯烷子基乙基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(2-(2-吡咯烷子基乙基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(吗啉代甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(氮杂环丁烷基甲基)-1,2,3-三唑-4-基)甲基-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氢基)-3-(S)-(4-氟代苯基)-4-(5-(吡咯啉子基甲基(pyrrolino)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二(甲氧基乙基)氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(2-氯-5-吗啉代甲基-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N-(2,2-二甲氧基乙基)-N-甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(2-甲氧基乙基)氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-(2-甲氧基乙基)-N-甲基)氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-异丙基-N-(2-甲氧基乙基)氨基甲基--1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-环丙基-N-(2-甲氧基乙基)氨基甲基--1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N,N-二丁基氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N,N-二异丙基氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;和其可药用盐或前药。
本发明范围内的另外的优选化合物包括:
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)--3--(S)-(4-氟代苯基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟乙氧基)吗啉;
4-(2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)-3-(S)-苯基-2-(R)-(1-(S)-(3-(三氟甲基)苯基)-2-羟乙氧基)吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-苯基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)-3-(S)-苯基甲基吗啉;
3-(S)-苯基-4-(1,2,4-三唑-3-基)-2-(R)-(1-(S)-3-(三氟甲基)苯基)-2-羟乙氧基)吗啉;和其可药用盐或前药。
本发明范围中的进一步优选化合物在本文描述的实施例中被描述。
在本发明的另一方面,式(I)化合物优选以可药用盐,尤其是酸加成盐形式被制备。
对于在药物中使用,式(I)化合物的盐应该是非毒性的可药用盐。但是,其他盐可以用于本发明化合物或其非毒性可药用盐的制备。本发明化合物的适当的可药用盐包括酸加成盐,其可以,例如,通过将本发明化合物的溶液与可药用酸的溶液混合形成,这种可药用酸是例如盐酸、富马酸、对甲苯磺酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸或硫酸。胺基的盐也可以包含季铵盐,其中氨基氮原子带有适当的有机基团如烷基、链烯基、炔基或芳烷基部分。而且,当本发明的化合物带有酸性部分时,其适当的可药用盐可以包括金属盐如碱金属盐,例如钠或钾盐;和碱土金属盐,例如钙或镁盐。
本发明在其范围中包括了上述式(I)化合物的前药。通常,这种前药应该是式(I)化合物的官能衍生物,其在体内容易转化成所需的式(I)化合物。选择和制备适当的前药衍生物的常见方法描述在,例如,“Design of Prodrugs”,ed.H.Bundgard,Elsevier,1985中。
前药可以是生物活性物质(“母体药”或“母体分子”)的药理学非活性衍生物,其需要在体内转化以便释放活性药,并且前药比母体药物分子具有改善的运送性质。在体内的转化可以是,例如,某些代谢过程的结果,如羧酸、磷酸或硫酸酯的化学或酶促水解过程,或敏感的官能度的还原或氧化过程。
因此,例如,某些优选的前药可以不是速激肽(特别是P物质)的拮抗剂,其可以在任何明显程度上是没有活性的(或者根本没有活性)。但是,这种化合物在治疗本文描述的各种病症中仍然是有利的,尤其是当可注射制剂被优选时。
前药的优点可以在于其物理性质,如与母体药相比其增加了胃肠外给药的水溶性,或其可以增强从消化道的吸收,或其可以增加药品长期储藏的稳定性。理想的前药应该改善母体药的总的功效,例如通过控制它们的吸收,血药浓度,代谢作用,分布和细胞摄取量来降低药物的毒性和副作用。
本发明化合物的特别优选的一类前药是其中在式(I)中基团Y的羟基部分(当Y是被羟基取代的C1-4烷基时)被衍生的前药。
可以被理解的是本发明化合物的另一类前药是其中在式(I)中的R6表示的杂环基被衍生的前药,或另一方面,是其中在式(I)中的基团Y的羟基部分(当Y是被羟基取代的C1-4烷基时)和用R6表示的杂环基都被衍生的前药。适当的前药衍生物包括:(a)-(CHR10)n-PO(OH)O-.M+;(b)-(CHR10)n-PO(O-)2.2M+;(c)-(CHR10)n-PO(O-)2.D2+;(d)-(CHR10)n-SO3 -.M+;(e)-COCH2CH2CO2 -.M+;(f)-COH;(g)-CO(CH2)nN(R10)2;和(h)-(CH(R10)O)n-COR11,其中n是零或1;M+是可药用的单价抗衡离子;D2+是可药用的二价抗锁离子;R10是氢或C1-3烷基;和R11选自-O(CH2)2NH3 +·M-;-O(CH2)2NH2(R12)+.M-;-OCH2CO2 -.M+;-OCH(CO2 -.M+)CH2CO2 -.M+;-OCH2CH(NH3 +)CO2 -;-OC(CO2 -.M+)(CH2CO2 -.M+)2;和其中M-是可药用的单价抗衡离子,和R12是氢,C1-4烷基或被羟基或C1-4烷氧基取代的C2-4烷基。
特别优选的前药衍生物是:(a)-(CHR10)n-PO(OH)O-.M+;(b)-(CHR10)n-PO(O-)2.2M+;(c)-(CHR10)n-PO(O-)2.D2+;尤其其中n是零。
术语“母体分子”、“母体化合物”或“母体药”是指生物活性实体,其在前药给药之后通过代谢或分解代谢过程的酶促作用,或通过化学过程被释放出来。母体化合物也可以是制备其相应的前药的起始原料。
当所有通常的给药途径是使用上述的前药时,优选的给药途径是口服和静脉内给药。在胃肠吸收或静脉内给药之后,前药在体内被水解或另一方面被分解成相应的式(I)母体化合物,或其可药用盐。因为母体化合物在含水溶液中的溶解性会较差,上述前药凭着其相对被增强的水溶性提供了明显的优点。
本文中定义为“M-”的负性单价抗衡离子的例子包括乙酸根、己二酸根、苯甲酸根、苯磺酸根、硫酸氢根、丁酸根、樟脑酸根、樟脑磺酸根、柠檬酸根、乙磺酸根、富马酸根、半硫酸根、2-羟基乙磺酸根、庚酸根、己酸根、盐酸根、氢溴酸根、氢碘酸根、乳酸根、苹果酸根、马来酸根、甲磺酸根、2-萘磺酸根、草酸根、双羟萘酸根、过硫酸根、苦味酸根、新戊酸根、丙酸根、水杨酸根、硬脂酸根、琥珀酸根、硫酸根、酒石酸根、甲苯磺酸根(对-甲苯磺酸根),和十一烷酸根。
碱盐(其是本文定义为“M+”的可药用的单价阳离子或本文定义为“D2+”的可药用的二价阳离子,如果适当的话)包括铵盐,碱金属盐如钠,锂和钾盐,碱土金属盐如铝,钙和镁盐,与有机碱形成的盐如二环己基胺盐,N-甲基-D-葡糖胺,和与氨基酸如精氨酸、赖氨酸、鸟氨酸,等等形成的盐。如果M+是单价阳离子,可以被认可的是如果存在2M+定义的话,每个M+可以相同或不同。另外,可以类似被认可的是如果存在2M+定义的话,二价阳离子D2+可以替代之存在。同样,含氮碱性基团可以用下列试剂季铵化,这类试剂如:低级烷基卤化物,如甲基、乙基、丙基、和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲基、二乙基和二丁基酯;硫酸二戊基酯;长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基溴化物等等。非毒性可药用盐是优选的,尽管其他盐也是有用的,如用于产物的分离或提纯中。
盐可以通过常见的方法生成,如通过将产物的游离碱形式与一或数当量的适当的酸在其中该盐不溶的溶剂或介质中,或者溶剂如水中反应生成,在其中溶剂可以在真空中或通过冷冻干燥被除去,或者通过在适当的离子交换树脂上用其他阴离子交换现存盐的阴离子。
本发明化合物的特别优选的一类前药是由式(Ie)定义的化合物和其可药用盐:其中R1,R2、R3、R4、R5、R6、R9a、R9b和X如式(I)中所定义和在环中的P是PO(OH)O-.M+,PO(O-)2.2M+,或PO(O-)2.D2+。
本发明化合物另一类优选的前药是由式(If)定义的化合物和其可药用盐:其中A1,A2和A3如式(Ia)中所定义,X和R6如式(I)中所定义,和环中的P是PO(OH)O-.M+,PO(O-)2.2M+,或PO(O-)2.D2+。
本发明化合物的一类特别优选的前药是由式(Ig)定义的化合物和其可药用盐:其中A1,A2和A3如式(Ia)中所定义,Q1如式(IC)中所定义和环中的P是PO(OH)O-.M+,PO(O-)2.2M+,或PO(O-)2.D2+。
本发明化合物的另一类优选的前药是由式(Ih)定义的化合物和其可药用的盐:其中A1,A2和A3如式(Ia)中所定义,Q1和Q2如式(Ic)和(Id)中分别定义,和环中的P是PO(OH)O-.M+,PO(O-)2.2M+,或PO(O-)2.D2+。
本发明范围内的具体的前药衍生物包括:
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉;
(2)-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-3-氟-5-(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-苯基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-苯基吗啉;和其可药用盐。
对于式(If),(Ig)和(Ih)化合物,A1优选是氟或CF3;A2优选是CF3;和A3优选是氟。
本发明在其范围内包括了式(I)化合物及其盐的溶剂化物,例如,水合物。
本发明的化合物至少具有三个不对称中心,可以相应地存在对映体和非对映异构体。可以被理解的是所有这些异构体和其混合物都被包含在本发明的范围内。
式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、(Ig)和(Ih)的优选的化合物应该具有顺式的2位和3位取代基并且在2位上的优选的立体化学构型是象实施例1中的化合物所具有的那样(即2-(R)-),在3位上的优选的立体化学构型是象实施例1的化合物所具有的那样(即3-(S)),基团Y连接的碳原子的优选的立体化学构型或者是(R)(当Y是C1-4烷基(例如甲基)时)或者是(S)(当Y是被羟基取代的C1-4烷基(例如CH2OH)时)。因此,其实例如下列式(Ii)所示:
本发明还提供了含有一种或多种式(I)化合物和与之相结合的可药用载体的药物组合物。
根据本发明的优选的组合物是以单位剂量形式如片剂,丸剂,胶囊剂,粉剂、粒剂,溶液剂或悬浮液剂,或栓剂形式,经口服,非胃肠道或直肠给药,或通过吸入法或吹入法给药。
为了制备固体组合物如片剂,将主要活性组分与可药用载体,例如常规的压片组分如玉米淀粉,乳糖,蔗糖,山梨糖醇,滑石粉,硬脂酸,硬脂酸镁,磷酸二钙或树胶,和其他药用稀释剂,例如水混合形成含有本发明化合物或其非毒性可药用盐的均匀混合物的固体预制剂组合物。当称这些预制剂组合物是均匀时,这意味着活性组分在整个组合物中被完全分散以至于该组合物容易被分成等效的单位剂量形式如片剂,丸剂和胶囊剂。这种固体的预制剂组合物然后被分成含有0.1至约500mg的本发明活性组分的上述类型的单位剂量形式。该新组合物的片剂或丸剂可以被包衣或另一方面被配合以提供获得延长作用优点的剂量形式。例如,片剂或丸剂可以含有内部剂量和外部剂量成分,后者是作为前者的包衣形式。这两种成分可以用肠溶层分离,该层用于阻止在胃中崩解和允许内部成分完整地通过进入十二指肠或被延持释放。许多材料可以用于这种肠溶层或包衣层,该材料包括许多聚合酸和聚合酸与这种材料如虫胶,鲸蜡基醇和纤维素乙酸酯的混合物。
本发明的新的组合物可以被掺入其中的经口服或注射给药的液体形式包括水溶液剂,适当经调味的糖浆剂,水或油悬浮剂液剂,和用食用油如棉籽油,芝麻油,椰子油或花生油经调味的乳剂,以及酏剂和类似的药用载体。用于水悬浮液剂的适当的分散或悬浮剂包括合成的和天然的树胶如黄蓍胶,阿拉伯树胶,藻酸盐,葡聚糖,羧甲基纤维素钠,甲基纤维素,聚乙烯吡咯烷酮或明胶。
经注射给药的优选的组合物包括那些含有作为活性组分的式(I)化合物,以及与之结合的表面活性剂(或润湿剂或表面活性剂)的组合物或以乳剂(如油包水或水包油乳剂)形式的组合物。
适当的表面活性剂包括阴离子型试剂如双一(2一乙基己基)磺基琥珀酸钠(docusate sodium),阳离子型试剂如溴化烷基三甲基铵(例如溴化鲸蜡基三甲基铵(cetrimide)),和尤其是非离子型试剂,如聚氧乙烯脱水山梨醇(例如TweenTM20,40,60,80或85)和其他脱水山梨醇(例如SpanTM20,40,60,80或85)。使用表面活性剂的组合物适宜地含有0.05%至5%,优选0.1%至2.5%的表面活性剂。可以被理解的是,如果需要的话,可以加入其他组分,例如甘露糖醇或其他可药用载体。
适当的乳剂可以使用市场上可以买到的脂肪乳化剂,如IntralipidTM,LiposynTM,InfonutrolTM,LipofundinTM和LipiphysanTM制备。活性组分可以是或者被溶于预混合的乳化剂组合物中,或者另一方面其可以被溶于油(例如豆油,红花油,棉籽油,芝麻油,玉米油或杏仁油)和当与磷脂(例如卵磷脂,大豆磷脂或大豆卵磷脂)和水混合时,形成了乳剂。可以被理解的是可以加入其他组分,例如甘油或葡萄糖,以调节乳剂的张力。适当的乳剂典型地含有最高达20%的油,例如,在5%至20%之间。脂肪乳化剂优选含有0.1至1.0μm,尤其是0.1至0.5μm的脂肪滴,并且具有5.5至8.0的pH值范围。
特别优选的乳剂组合物是那些通过将式(I)化合物与IntralipidTM或其成分(豆油,卵磷脂,甘油和水)混合制备的乳剂组合物。
吸入法或吹入法给药的组合物包括可药用的溶液和悬浮剂,水性溶剂或有机溶剂,或其混合物,和粉剂。液体或固体组合物可以含有上面提到的适当的可药用赋形剂。组合物优选地通过口服或鼻吸入途径对局部或全身作用给药。在优选经消毒的可药用溶剂中的组合物可以用惰性气体喷雾。所喷雾的溶液可以从喷雾装置直接被呼吸或者喷雾装置可以被附在面罩,帐篷或间歇式正压力呼吸器上。溶液剂、悬浮剂或粉剂组合物可以优选地经口服或鼻吸入从以适当方式传送制剂的装置被给药。
本发明还提供了制备含有式(I)化合物的药物组合物的方法,该方法包括将式(I)化合物加入与之结合的可药用载体或赋形剂中。
式(I)化合物具有治疗许多临床病症的价值,这些病症的特征在于存在过量的速激肽(尤其是P物质)活性。这些病症可以包括中枢神经系统紊乱如焦虑症,抑郁症,精神病和精神分裂症;癫痫;神经变性疾病如痴呆,包括阿尔茨海默型老年性痴呆,早老性痴呆和唐氏综合征;脱神经髓鞘疾病如MS和ALS和其他神经病理学疾病如外周末梢神经病,例如糖尿病和化学疗法诱发的神经病,和带状疱疹后的和其他的神经痛;小细胞癌如小细胞肺癌;呼吸疾病,尤其是那些与过量粘液分泌有关的疾病如慢性阻塞性气管疾病,支气管肺炎,慢性支气管炎,囊性纤维变形和哮喘,和支气管痉挛;炎性疾病如肠炎疾病,牛皮癣,纤维积炎,骨关节炎,类风湿关节炎,瘙痒和晒斑,过敏如湿诊和鼻炎;过敏性症状如毒常青藤;眼疾病如结膜炎,春季结膜炎,等等;与细胞增殖有关的眼疾如增生的玻璃体视网膜病,皮肤病如接触性皮炎,特应性皮炎,荨麻疹,和其他湿疹样疹性皮炎;癖嗜症如酒精中毒;与紧张有关的躯体疾病;反射交感神经营养不良如肩/手综合征;精神抑郁症;不良的免疫学反应如被移殖组织的排斥和与免疫增强作用或压抑相关病症如全身性红斑狼疮;胃肠(GI)症状和胃肠(GI)道疾病如与内脏神经控制有关的疾病,溃疡性结肠炎,节段性回肠炎,肠激惹综合征和呕吐,包括急性、延迟的或预期的呕吐如由化学疗法,,放射、毒素,病毒或细菌感染,妊娠,前庭疾病,运动,外科手术,偏头痛,和颅内压力变化诱发的呕吐,尤其是,例如,药物或放射诱发的呕吐或手术后的恶心和呕吐;膀胱机能紊乱如膀胱炎,膀胱逼肌高度反射和失禁;纤维化和胶原蛋白疾病如硬皮痛和嗜曙红细胞片吸虫病;由血管舒张和血管痉挛疾病诱发的血流疾病如咽峡炎,偏头痛和雷诺尔德疾病;和疼痛或损伤,例如,由于或与任何前述症状,尤其是在偏头痛中的疼痛传递有关的疼痛或损伤。
式(I)化合物也具有治疗上述疾病的结合病症的价值,尤其是治疗手术后疼痛和手术后恶心和呕吐的结合病症。
式(I)化合物特别适用于治疗呕吐,包括急性的,被延迟的或预期的呕吐,如由化学疗法,放射,毒素,妊娠,前庭疾病,运动,外科手术,偏头痛,和颅内压力变化诱发的呕吐。最特别的是,式(I)化合物适用于治疗由抗肿瘤(细胞毒素)剂包括那些日常用于癌症化疗的试剂诱发的呕吐。
这种化疗试剂的实例包括烷基化试剂,例如,氮芥子,吖丙啶化合物,烷基磺酸酯和其他具有烷基化作用的化合物如亚硝基脲,顺铂和氮烯唑胺;抗代谢物,例如,叶酸,嘌呤或嘧啶拮抗剂;细胞分裂抑制剂,例如,长春花生物碱和鬼臼毒素衍生物;和细胞毒素抗菌素。
化疗剂的具体实例描述在,例如,D.J.Stewart在Nausea andVomiting:Recent Research and Clinical Advances.Eds.J.Kucharczyk等,CRC Press Inc.,Boca Raton,Florida,USA(1991)第177-203页,尤其是第188页。通常使用的化疗剂包括:顺铂,氮烯唑胺(DTIC),放线菌素D,甲基二氯乙基胺(氮芥),链脲霉素,环磷酰胺,卡氮芥(BCNU),罗氮芥(CCNU),阿霉素(亚德里亚霉素),柔红霉素,甲基苄肼,丝裂霉素,阿糖胞苷,鬼臼乙叉甙,甲氨蝶呤,5-氟尿嘧啶,长春碱,新长春碱,博来霉素和苯丁酸氮芥[R.J.Gralla等在Cancer Treatment Reports(1984)68(1),163-172]。
式(I)化合物也用于治疗由放射包括放射治疗如在治疗癌症中放射治疗诱发的呕吐,或放射疾病;和用于手术后恶心和呕吐的治疗。
可以被理解的是式(I)化合物可以与另一治疗剂一起作为结合制剂同时,分隔或顺序被提供用于缓解呕吐。这种结合制剂可以以双包裹的形式。
本发明的另一方面包含式(I)化合物与5-HT3拮抗剂,如恩丹西酮(ondansetron),格雷西隆(granisetron)或托匹西隆(tropisetron),或其他抗呕吐药物,例如,多巴胺拮抗剂如灭吐灵相结合。此外,式(I)化合物可以与抗炎性皮质甾类,如地塞米松相结合给药。而且,式(I)化合物可与如上所述的化疗剂如烷基化剂,抗代谢药物、细胞分裂抑制剂或细胞毒素抗菌素结合给药。通常,用于该结合的已知治疗剂的目前可行的剂量形式是适当的。
当本发明的化合物在F.D.Tattersall等,在Eur.J.Pharmacol.,(1993)250,R5-R6中描述的由顺铂诱发的呕吐的白鼬模型中被测试时,人们发现该类化合物减轻了由顺铂诱发的恶心和呕吐。
本发明的式(I)化合物也特别适用于治疗疼病或痛感和/或与如下疾病相关的炎症和疾病,这些疾病是,例如,神经病,如糖尿病和化疗诱发的神经病,带状疱疹后的和其他的神经痛,哮喘,骨关节炎,类风湿关节炎和尤其是偏头痛。
本发明还提供了式(I)化合物在治疗中的应用。
根据本发明另一方面,本发明提供了式(I)化合物在制备用于治疗与速激肽,尤其是P物质过量有关的生理疾病的药物中的应用。
本发明还提供了治疗或预防与速激肽,尤其是P物质过量有关的生理疾病的方法,该方法包含对需要所述治疗的患者施用能降低速激肽的剂量的式(I)化合物或含有式(I)化合物的组合物。
为了治疗某些病症,最好将本发明化合物与另一药理学活性剂相结合使用。例如,为了治疗呼吸疾病如哮喘,式(I)化合物可以与支气管扩张药,如β2-肾上腺素能受体拮抗剂或在NK-2受体上起作用的速激肽拮抗剂相结合使用。式(I)化合物和支气管扩张药可以对患者同时,顺序地或结合给药。
本发明提供了治疗呼吸疾病,如哮喘的方法,该方法包含对需要该治疗的患者施用有效量的式(I)化合物和有效量的支气管扩张药。
本发明也提供了含有式(I)化合物,支气管扩张药,和可药用载体的组合物。
本发明化合物的杰出的药理学特性使得它们能够以低的剂量用于治疗过程,从而使不良副作用的危险降至最小。
在治疗与速激肽的过多有关的病症过程中,适当的剂量范围为约0.001~约50mg/kg·每天,尤其是约0.01~约25mg/kg·每天,例如约0.05~约10mg/kg·每天。
例如,在治疗与疼痛感觉的神经传递有关的病症过程中,适当的剂量范围是约0.001~25mg/kg·每天,优选约0.005~10mg/kg·每天,尤其是约0.005~5mg/kg·每天。化合物可每天给药1~4次,优选每天一次或两次。
在使用可注射的制剂治疗呕吐的过程中,适当的剂量范围是约0.001~10mg/kg·每天,优选约0.005~5mg/kg·每天,特别是0.01~2mg/kg·每天。化合物可每天给药1~4次,优选每天一次或两次。
显然,用于任何治疗中所需的式(I)化合物的量不仅将随所选择的特定的化合物或组合物变化,而且将随给药途径、所治疗的病症的性质和患者的年龄和状态变化,并且主要将由主治医生决定。
根据一般方法(A),本发明的化合物可由式(II)化合物与式(III)化合物反应制备:其中R1、R2、R3、R4、R5和Y如式(I)中所定义,
X1-X-R6a (III)其中X如式(I)中所定义,R6a如式(Ia)中所定义的式R6基团或其前体,X1是离去基团,如溴或氯;并且,如果R6a是前体基团的话,将其转化为基团R6(在该过程中,根据需要,任何活性基团可被保护,并随后脱保护)。
该反应可以常规的方式,例如,在有机溶剂,如二甲基甲酰胺中,在酸性接受体,如碳酸钾存在下进行。
根据另一个方法(B),其中R6表示被CH2NR7R8取代的1,2,3-三唑-4-基和X是-CH2-的式(I)化合物可通过使式(IV)化合物:与叠氮化物,例如叠氮化钠,在适当的溶剂,如二甲基亚砜中,在40℃~100℃的温度下反应,随后使用适当的还原剂,如氢化锂铝,在-10C至室温的温度下,通常在室温下还原与-NR7R8相邻的羰基来制备。
此外,根据方法(C),其中R6表示被CH2NR7R8取代的1,2,3-三唑-4-基,X是-CH2-的式(I)化合物可通过使式(V)化合物:与式NHR7R8的胺反应来制备,该反应在适当的溶剂,例如醚,如二噁烷,在高温下,如50C~100℃之间,在密封管或类似容器中进行。该反应基于Chemische Berichte(1989),122,第1963页中的描述。
该反应通常在适当的有机溶剂,如乙腈中,在升高的温度,如80~90℃,优选约82℃下进行。
根据另-个方法(E),其中R6表示取代或未取代的1,2,4-三嗪的式(I)化合物可通过使如下式(VII)中间体与如下式(VIII)的二羰基化合物反应制备:其中R35表示H或适当的取代基,如ZNR7R8。
该反应可方便地在适当的溶剂,例如醚,如四氢呋喃中,方便地在环境温度下进行。
根据另一个方法(F),其中R6表示取代的1,2,4-三唑基的式(I)化合物可通过使式(II)中间体与如下式(IX)化合物在碱存在下反应:其中X如式(I)中所定义,Hal是卤素原子,例如溴、氯或碘,和R18是H、CONH2或OCH3(其在反应条件下转化成氧代取代基),随后在需要时,例如,通过还原CONH2基团为CH2NH2转化成式(I)化合物而制备。
在反应中使用的适当的碱包括碱金属碳酸盐,例如碳酸钾。该反应方便地在无水有机溶剂,例如无水二甲基甲酰胺中,优选在升高的温度,例如约140℃下进行。
适当的用于基团CONH2的还原剂是在-10℃至室温下使用的氢化锂铝。
用于该反应的适当的碱包括有机碱,例如1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)。反应方便地在适当的有机溶剂,例如醇,如丁醇中进行。
适当的步骤将在所附的实施例中更详细地描述。
式(I)化合物也可以由其他式(I)化合物使用适当的互变方法制备。例如,其中X是C1-4烷基的式(I)化合物可由其中X表示被氧代取代的C1-4烷基的式(I)化合物通过还原,例如,使用硼烷或氢化锂铝制备。适当的互变方法对于本技术领域的熟练技术人员来说是显而易见的。
式(IV)中间体可由式(II)中间体通过与式HC≡C-CH2-Hal的乙炔化合物在碱,例如碳酸钾存在下,在适当的溶剂,如二甲基甲酰胺中,方便地在室温下反应,随后,使所生成的乙炔中间体与式Hal-CO-NR7R8的酰胺在适当的催化剂存在下,在适当的溶剂,例如三乙胺中,优选在回流条件下反应而制备,其中,上述催化剂包括双(三苯膦)氯化钯(II)、碘化铜(I)和三苯膦。
式(XI)化合物可通过向式Hal-CH2-C≡C-CH2-Hal的二卤代乙炔中滴加式(II)中间体制备,上式中每个Hal独立地是氯、溴或碘,特别是氯。该反应方便地在适当的溶剂,例如二甲基甲酰胺中在碱,例如碳酸钾存在下进行。
式(VI)中间体可以由式(II)中间体通过与式Hal-X-C(NH)NH2的化合物反应制备,该式中,Hal和X是如上文定义的。
式(VII)中间体可由式(II)中间体通过与式Hal-X-C(NH)NHNH-Boc(其中,Hal和X是如上文定义的,Boc表示叔丁氧羰基)反应,随后在酸性条件下脱保护制备。
式(VIII)化合物是商业上可获得的或可由商业上可获得的化合物通过已知方法制备。
式(IX)化合物可如J.Med.Chem,(1984)27,849中所述制备。
式(X)中间体可由相应的酯通过用肼处理制备。该反应方便地在适当的有机溶剂,例如醇,如乙醇中在升高的温度下进行。
对于其中R6是被ZNR7R8(其中Z是CH2)取代的杂环的化合物,式(I)的某些有利的化合物可由相应的化合物通过用ZNR7R8代替氢原子制备。因此,例如,其中R6是带有CH2NR7R8部分的咪唑啉酮基团的式(I)化合物可由没有CH2NR7R8部分的相应化合物通过与甲醛的胺NHR7R8在常规的曼尼期反应条件下,例如在加热的甲醇中反应制备。如果需要,可采用预生成的试剂,例如R7R8N+=CH2I-,叔胺,例如三乙胺用作酸接受体。
此外,其中R6是没有CH2NR7R8的咪唑啉酮基团的式(I)化合物可与仲甲醛和胺,例如仲胺,如吡咯烷反应得到其中咪唑啉酮环被CH2NR7R8取代的化合物,其中R7、R8和与它们相连接的氮原子形成4-7个环原子的杂环脂族环,其任意地含有一个氧环原子或一个将是NH或NRc部分的一部分的和第二氮原子,其中Rc是如上文定义的。
该反应可以常规的方式,例如,在适当的溶剂,例如醇,如甲醇中在最高至溶剂沸点的升高温度下进行。
用于制备式(I)的某些化合物的另一种方法包括如上文定义的式(II)中间体与如下式(XII)的化合物之一的反应:其中每个LG可以是相同或不同的,是离去基团,例如烷基-或芳基磺酰氧基(例如甲磺酸酯基或甲苯磺酸酯基)或,特别是卤素原子(例如溴、氯或碘)和X和Z是如式(I)中所定义的,随后使得到的化合物与胺NHR7R8反应以完成ZNR7R8部分。
该反应方便地在有机溶剂,例如二甲基甲酰胺中,在酸性接受体,例如碳酸钾存在下进行。
显然,在需要时,活性基团可被保护,例如,式(XIIa)的咪唑啉酮的NH基团可被任何适当的胺保护基,例如乙酰基保护。
本发明化合物的优选的磷酸酸前药可由其中Y是,例如,-CH2OH-的式(I)化含物按分步的方式制备。
于是,羟基化合物首先在适当的溶剂,例如四氢呋喃中,优选在酸性催化剂,例如四唑存在下用二苄氧基二乙基氨基膀处理。得到的化合物(Y=CH2OP(OCH2Ph)2)随后被,例如4-甲基吗啉-N-氧化物氧化得到二苄基保护的磷酸酯。通过在适当的溶剂,例如回流的甲醇中催化氢化或转移氢化(披钯碳催化剂和甲酸铵)脱保护产生所需的磷酸酯前药,其可通过常规的方法转化为任何所需的盐。
在另一个两步法中,式(I)的羟基化合物可与适当的碱,例如氢化钠在四氢呋喃中反应,加入四苄基焦磷酸酯得到二苄基保护的磷酸酯,其可如上所述脱保护。
L-Selectride是三仲丁基硼氢化锂。
一旦热练的技术人员阅读了本文所公开的内容,如下参考文献描述了熟练的技术人员可用于上文所述的化学合成的方法:
(i) D.A.Evans et al.,J.Am.Chem.Soc.,(1990)112,4011.
(ii) I.Yanagisawa et al.,J.Med.Chem.,(1984)27,849.
(iii) R.Duschinsky et al.,J.Am.Chem.Soc.,(1948)70,657
(iv) F.N.Tebbe et al.,J.Am.Chem.Soc.,(1978)100,3611.
(v) N.A.Petasis et al.,J.Am.Chem.Soc.,(1990)112,6532.
(vi) K.Takai et al.,J.Org.Chem.,(1987)52,4412
本发明描述的实施例主要制备优选的异构体,不期望的异构体也作为较少的组分被制备。如果需要,它们可以通过常规方法,例如使用合适的色谱柱的色谱法分离并用于制备不同的立体异构体。然而,对于熟练技术人员显然的是,尽管实施例最适宜于制备优选的异构体,但溶剂、试剂,色谱法前的政变可容易地用于制备其他异构体。
其中R6含有=O或=S取代基的式(I)化合物可以互变异构体的形式存在,所有这些互变异构体形式和它们的混合物均包括在本发明的范围之内。R6中最合适的=O或=S取代基是=O取代基。
当上述式(III)中间体不能由商业上获得时,它可由所附的实施例中描述的方法或本领域技术人员已知的其他方法制备。
在任何上述的合成过程中,保护任何所涉及的分子中的敏感或活性基团是必需的和/或所期望的。这可通过常规的保护基团,例如在Protective Groups in Organic Chemistry,等.J.F.W.McOmie,Plenum Press,1973和T.W.Greene和P.G.M.Wuts,ProtectiveGroups in Organic Synthesis,John Wiley & Sons,1991中那些保护基团获得。保护基团可在随后的步骤中使用现有技术中的已知方法除去。
本发明举例说明的化合物通过国际专利说明书No.WO93/01165的第36-39页中描述的方法测试。化合物或在前药的情况下,母体化合物按照上述测试方法证实是具有活性其对NK1受体的IC50值低于10nM。
说明1(S)-(4-氟代苯基)甘氨酸通过手性合成:步骤A:3-(4-氟代苯基)乙酰基-4-(S)-苄基-2-噁
唑烷酮
用氮气冲洗装有隔膜、氮气入口、温度计和磁性搅拌棒的烘干的1升3颈烧瓶,加入5.09g(33.0mmol)4-氟代苯基乙酸在100ml无水乙醚中的溶液。将该溶液冷却至-10℃,用5.60ml(40.0mmol)三乙胺处理,然后用4.30ml(35.0mmol)三甲基乙酰氯处理。立即形成白色沉淀物,得到的混合物在-10℃搅拌40分钟,随后冷却至-78℃。
用氮气冲洗装有隔膜和磁性搅拌棒的烘干的250ml圆底烧瓶,在其中加入5.31g(30.0mmol)4-(S)-苄基-2-噁唑烷酮在40ml无水THF中的溶液。将该溶液在干冰/丙酮浴中搅拌10分钟,然后缓慢加入18.8ml 1.6M的正丁基锂的己烷溶液。10分钟后,经插管将锂化的噁唑烷酮溶液加入在3颈烧瓶中的上述混合物中。从得到的混合物移去冷却浴,使温度上升至0℃。用100ml饱和氯化铵水溶液中止反应,移至1升烧瓶中,真空除去乙醚和THF。浓缩的混合物在300ml二氯甲烷和50ml水之间分配,将两层分开。有机层用100ml2N盐酸水溶液、300ml饱和碳酸氢钠水溶液洗涤,用硫酸钠干燥并真空浓缩。经快速色谱法(40g硅胶,用3∶2v/v己烷/乙醚作洗脱剂)得到8.95g油状物,其在静置下缓慢固化。由10∶1己烷/乙醚重结晶得到7.89g(83%)标题化合物,白色固体:mp:64-66℃。
MS(FAB):m/z 314(M++H,100%),177(M-ArCH2CO+H,85%).1H NMR(400MHz,CDCl3)δ2.76(1H,dd,J=13.2,9.2),3.26(dd,J=13.2,3.2),4.16-4.34(4H,m),4.65(1H,m),7.02-7.33(9H,m).元素分析 C18H16FNO3;C,69.00;H,5.15;N,4.47;F,6.06;实测值:C,68.86;H,5.14;N,4.48;F,6.08步骤B:3-((S)-叠氮基-(4-氟代苯基)乙酰基-4-(S)
-苄基-2-噁唑烷酮
用氮气冲洗装有隔膜、氮气入口、温度计和磁搅拌棒的烘干的l升3颈烧瓶,向其中加入58.0ml 1M的二(三甲基甲硅烷基)氨基化钾的甲苯溶液和85ml THF,冷却至-78℃。用氮气冲洗装有隔膜和磁搅拌棒的烘干的250ml圆底烧瓶,向其中加入7.20g(23.0mmol)3-(4-氟代苯基)乙酰基-4-(S)-苄基-2-噁唑烷酮(来自步骤A)在40ml THF中的溶液。酰基噁唑烷酮溶液在于冰/丙酮浴中搅拌10分钟,随后经导管以使混合物的内部温度保持低于-70℃的速率转移至二(三甲基甲硅烷基)氨基化钾溶液中。酰基噁唑烷酮烧瓶用15ml THF冲洗,将冲洗溶液经导管加入反应混合物中,得到的混合物在-78℃搅拌3D分钟。用氮气冲洗装有隔膜和磁搅拌棒的烘干的250ml圆底烧瓶,向其中加入10.89g(35.0mmol)2,4,6-三异丙基苯基磺酰基叠氮化物在40ml THF中的溶液。叠氮化物溶液在干冰/丙酮浴中搅拌10分钟,然后经导管以使混合物的内部温度保持在低于-70℃的速率加入反应混合物中。2分钟后,用6.0ml冰醋酸中止反应,移去冷却浴,将混合物在室温下搅拌18小时。中止了反应的混合物在300ml乙酸乙酯和300ml 50%饱和碳酸氢钠水溶液之间分配。分出有机层,用硫酸镁干燥,并真空浓缩。经快速包谱法(500g硅胶,用2∶1v/v,随后1∶1v/v己烷/二氯甲烷作洗脱剂)纯化,得到5.45g(67%)油状的标题化合物。IR光谱(净,cm-1):2104,1781,1702.1H NMR(400MHz,CDCl3)δ2.86(1H,dd,J=13.2,9.6),3.40(1H,dd,J=13.2,3.2),4.09-4.19(2H,m),4.62-4.68(1H,m),6.14(1H,s),7.07-7.47(9H,m).元素分析 C18H15FN4O3;C61.01;H,4.27;N,15.81;F,5.36;实测值:C,60.99;H,4.19;N,15.80;F,5.34.步骤C:(S)-叠氮基-(4-氟代苯基)乙酸
将5.40g(15.2mmol)3-((S)-叠氮基-(4-氟代苯基)乙酰基-4-(S)-苄基-2-噁唑烷酮(来自步骤B)在200ml3∶1v/v THF/水中的溶液在冰浴中搅拌10分钟。一次加入1.28g(30.4mmol)氢氧化锂单水合物,得到的混合物冷却搅拌30分钟。反应混合物在100ml二氯甲烷和100ml 25%饱和碳酸氢钠水溶液之间分配,将两层分开,水层用2×100ml二氯甲烷洗涤,用2N盐酸水溶液酸化至pH2。得到的混合物用2×200ml乙酸乙酯提取,合并提取液,用50ml饱和氯化钠水溶液洗涤,用硫酸镁干燥,并经真空浓缩得到2.30g(77%)标题化合物油状物,它无需进一步提纯,直接用于以下步骤。IR光谱(净,cm-1):2111,1724。1H NMR(400MHz,CDCl3)δ5.06(1H,s),7.08-7.45(4H,m),8.75(1H,brs).步骤D:(S)-(4-氟代苯基)甘氨酸
将2.30g(11.8mmol)(S)-叠氮基-(4-氟代苯基)乙酸(来自步骤C)、250mg 10%披钯碳催化剂和160ml 3∶1v/v水/乙酸混合物在1个氢气压力下搅拌18小时。反应混合物通过硅藻土过滤,烧瓶和滤饼用约1升3∶1v/v水/乙酸充分冲洗。真空浓缩滤液至约50ml体积。加入300ml甲苯,浓缩混合物得到固体。将该固体悬浮于1∶1v/v甲醇/乙醚中,过滤并干燥得到1.99g(100%)标题化合物。1H NMR(400MHz,D2O+NaOD)δ3.97(1H,s),6.77(2H,appt,J=8.8),7.01(2H,appt,J=5.6).通过拆分步骤A′:(4-氟代苯基)乙酰氯
在40℃,将150g(0.974mol)4-氟代苯基)乙酸和1ml N,N-二甲基甲酰胺在500ml甲苯中的溶液用20ml亚硫酰氯处理,并加热至40℃,在1.5小时内滴加另外61.2ml亚硫酰氯。滴加后,将溶液在50℃加热1小时,真空除去溶剂,残余油状物经减压(1.5mmHg)蒸馏得到150.4g(89.5%)标题化合物。bp=68-70℃。步骤B′:2-溴-3-(4-氟代苯基)乙酸甲酯
在40-50℃,用石英灯照射150.4g(0.872mol)4-(氟代苯基)乙酰氯(来自步骤A′)和174.5g(1.09mol)溴的混合物5小时。将反应混合物滴加至400ml甲醇中,将溶液搅拌16小时。真空除去溶剂,残余油状物经减压(1.5mmHg)蒸馏得到198.5g(92%)标题化合物,bp=106-110℃。步骤C′:(±)-(4-氟代苯基)甘氨酸甲酯
用6.8g(0.105mol)叠氮化钠处理24.7g(0.1mmol)2-溴-2-(4-氟代苯基)乙酸甲酯(来自步骤B′)和2.28g(0.01mol)苄基三乙基氯化铵在25ml甲醇中的溶液,将得到的混合物在室温下搅拌20小时。将反应混合物过滤,滤液用50ml甲醇稀释,在0.5g10% Pd/C存在下在50psi下氢化1小时。将溶液过滤,真空除去溶剂。将残余物在10%碳酸钠水溶液和乙酸乙酯之间分配,有机相用水、饱和氯化钠水溶液洗涤,用硫酸镁干燥并真空浓缩得到9.8g油状的标题化合物。步骤D′:(S)-(4-氟代苯基)甘氨酸甲酯
将58.4g(±)4-(氟代苯基)甘氨酸甲酯(来自步骤C′)在110ml 7∶1v/v乙醇/水中的溶液与28.6g(0.0799mol)O,O′-(+)-二苯甲酰基酒石酸((+)-DBT)在110ml 7∶1v/v乙醇∶水中的溶液混合,使得到的溶液在室温下陈化。在结晶完全后加入乙酸乙酯(220ml)使得到的混合物冷却至-20℃,经过滤得到32.4g(S)-(4-氟代苯基)甘氨酸甲酯,(+)-DBT盐(ee=93.2%)。真空浓缩母液,通过在乙酸乙酯和碳酸钠水溶液之间分配析出游离碱。将所得到的游离碱在110ml 7∶1v/v乙醇/水中的溶液与28.6g(0.0799mol)O,O′-(-)-二苯甲酰基酒石酸((-)-DBT)在110ml 7∶1乙醇∶水中的溶液混合,使得到的溶液在室温下陈化。在结晶完成后加入乙酸乙酯(220ml),将得到的混合物冷却至-20℃,经过滤得到47.0g(R)-(4-氟代苯基)甘氨酸甲酯,(-)-DBT盐(ee=75.8%)。循环母液并加入(+)-DBT得到第二批产物7.4g(S)-(4-氟代苯基)甘氨酸酯,(+)-DBT盐(ee=96.4%)。在200ml 7∶1v/v乙醇/水中合并(S)-氨基酯的两批产物(39.8g),加热30分钟,并冷却至室温。加入乙酸乙酯、冷却和过滤得到31.7g(S)-(4-氟代苯基)甘氨酸酯,(+)-DBT盐(ee>98%)。用手性HPLC(Crownpak CR(+)5%在含水HClO4中的甲醇中,pH2,1.5ml/min 40℃200nm)测定对映体过量。
将17.5g(S)-(4-氟代苯基)甘氨酸酯,(+)-DBT盐和32ml 5.5N HCl(32ml)的混合物回流加热1.5小时。真空浓缩反应混合物,将残余物溶解于40ml水中,用3×30ml乙酸乙酯洗涤水溶液,并分层。用氢氧化铵调节水层的pH至7,过滤出沉淀的固体得到7.4g标题化合物(ee=98.8%)。
说明24-苄基-3-(S)-(4-氟代苯基)-2-吗啉酮步骤A:N-苄基-(S)-(4-氟代苯基)甘氨酸
在0℃,用165mg(4.4mmol)硼氢化钠处理1.87g(11.05mmol)(S)-(4-氟代苯基)-甘氨酸(来自说明1)和1.12ml(11.1mmol)苯甲醛在11.1ml lN氢氢化钠水溶液和11ml甲醇中的溶液。移去冷却浴,得到的混合物在室温下搅拌30分钟。在反应混合物中加入第二部分苯甲醛(1.12ml(11.1mmol))和硼氢化钠(165mg(4.4mmol)),持续搅拌1.5小时。将反应混合物在100ml乙醚和50ml水之间分配,将两层分开。分离出水层,过滤除去少量不溶物质,用2N盐酸水溶液酸化滤液至pH5,过滤出沉淀的固体,用水,随后用乙醚充分冲洗,经干燥得到1.95g标题化合物。1H NMR(400MHz,D2O+NaOD)δ3.33(2H,ABq,J=8.4),3.85(1H,s),6.79-7.16(4H,m).步骤B:4-苄基-3-(S)-(4-氟代苯基)-2-吗啉酮
将1.95g(7.5mmol)N-苄基(S)-(4-氟代苯基)甘氨酸、3.90ml(22.5mmol)N,N-二异丙基乙胺、6.50ml(75.0mmol)1,2-二溴乙烷和40ml N,N-二甲基甲酰胺的混合物在100℃搅拌20小时(通过加热使所有固体溶解)。将反应混合物冷却,并真空浓缩。将残余物在250ml乙醚和100ml 0.5N硫酸氢钾溶液之间分配,将两层分开。有机层用100ml饱和碳酸氢钠水溶液、3×150ml水洗涤,用硫酸镁干燥并真空浓缩。经快速色谱法(125g硅胶,使用3∶1v/v己烷/乙醚作洗脱剂)纯化得到1.58g(74%)油状的标题化合物。1H NMR(400MHz,CDCl3)δ2.65(1H,dt,J=3.2,12.8),3.00(1H,dt,J=12.8,2.8),3.16(1H,d,J=13.6),3.76(1H,d,J=13.6),4.24(1H,s),4.37(1H,dt,J=13.2,3.2),4.54(1H,dt,J=2.8,13.2),7.07-7.56(9H,m).
说明34-苄基-2-(R)-(3,5-二(三氟甲基)苯甲酰氧基)-3-(S)-(4-氟代苯基)吗啉
将2.67g(10.0mmol)4-苄基-3-(S)-(4-氟代苯基)-2-吗啉酮(说明2)在40ml无水THF中的溶液冷却至-78℃。用12.5ml 1.0M L-Selectride(三仲丁基硼氢化锂)的THF溶液处理冷的溶液,在处理过程中保持内部反应温度低于-70℃。将得到的溶液冷搅拌45分钟,在反应溶液中加入3.60ml(20.0mmol)3,5-二(三氟甲基)苯甲酰氯。将得到的黄色混合物冷搅拌30分钟,用50ml饱和碳酸氢钠水溶液中止反应。将中止了反应的混合物在300ml乙醚和50ml水之间分配,将两层分开。有机层用硫酸镁干燥,水层用300ml乙醚提取,将提取液干燥,并与最初的有机层合并。真空浓缩合并的有机层,经快速色谱法(150g硅胶,用37∶3v/v己烷/乙醚作洗脱剂)纯化得到4.06g(80%)固体标题化合物。1H NMR(200MHz,CDCl3)δ2.50(1H,dt,J=3.4,12.0),2.97(1H,appd,J=12.0),2.99(1H,d,J=13.6),3.72-3.79(1H,m),3.82(1H,d,J=2.6),4.00(1H,d,J=13.6),4.20(dt,J=2.4,11.6),6.22(1H,d,J=2.6),7.22-7.37(7H,m),7.57(2H,近似d,J=6.8),8.07(1H,s),6.47(2H,s).MS(FAB)m/z528(M+H,25%),270(100%)元素分析C26H20F7NO3:C,59.21;H,3.82;N,2.68;F,25.21.实测值C,59.06;H,4.05;N,2.50;F,25.18
说明4
4-苄基-2-(R)-(1-(3,5-二(三氟甲基)苯基)乙烯氧基)-3-(S)-(4-氟代苯基)吗啉步骤A:二甲基二茂钛
在黑暗中在0℃,用17.5ml 1.4M甲基锂的乙醚溶液处理2.49g(10.0mmol)二氯化二茂钛在50ml乙醚中的溶液,在此期间保持内部温度低于5℃。将得到的黄色/橙色混合物在室温下搅拌30分钟,通过缓慢加入25g冰中止反应。用50ml乙醚和25ml水稀释中止了反应的混合物,将两层分开。有机层用硫酸镁干燥并真空浓缩得到2.03g(98%)标题化合物,为光敏感固体。在0℃下二甲基二茂钛作为在甲苯中的溶液可贮存至少两周而不会发生化学降解。1H NMR(200MHz,CDCl3)δ-0.15(6H,s),6.06(10H,s)。步骤B:4-苄基-2-(R)-(1-(3,5-二(三氟甲基)苯基)乙烯氧基)-3-(S)-(4-氟代苯基)吗啉
将说明3的化合物(2.50g,4.9mmol)和2.50g(12.0mmol)二甲基二茂钛(来自步骤A)在35ml 1∶1v/v THF/甲苯中的溶液在80℃的油浴中搅拌16小时。将反应混合物冷却并真空浓缩。用快速色谱法(150g硅胶,用3∶1v/v己烷/二氯甲烷作洗脱剂)纯化得到1.71g(69%)固体标题化合物。由异丙醇中重结晶得到分析试样。1H NMR(400MHz,CDCl3)δ2.42(1H,dt,J=3.6,12.0),2.90(1H,近似d,J=12.0),2.91(1H,d,J=13.6),3.62-3.66(1H,m),3.72(1H,d,J=2.6),3.94(1H,d,J=13.6),4.09(1H,dt,J=2.4,12.0),4.75(1H,d,J=3.2),4.82(1H,d,J=3.2),5.32(1H,d,J=2.6),7.09(2H,t,J=8.8),7.24-7.33(5H,m),7.58-7.62(2H,m),7.80(1H,s),7.90(2H,s),MS(FAB)526(M+H,75%),270(100%).元素分析 C27H22F7NO2:C,61.72;H,4.22;N,2.67;F,25.31.实测值:C,61.79;H,4.10;N,2.65;F,25.27%.
说明5
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉
将说明4的化合物(4.0g)溶解于乙酸乙酯(50ml)和异丙醇(16ml)中,在该溶液中加入披钯碳(1.5g),使混合物在40psi下氢化36小时。通过硅藻土过滤除去催化剂,真空除去溶剂。残余物用快速色谱法纯化(硅胶,先用100%乙酸乙酯,然后用在乙酸乙酯中的1~l0%甲醇洗脱),得到异构体A 500mg(15%)和异构体B2.6g(80%),为透明油状物-异构体B在静置状态下结晶。对于标题化合物:1H NMR(400MHz,CDCl3)δ1.16(3H,d,J=6.8MHz),1.80(1H,brs),3.13(1H,dd,J=3.2,12.4Hz),3.23(1H,dt,J=3.6,12.4Hz),3.63(1H,dd,J=2.4,11.2Hz),4.01(1H,d,J=2.4Hz),4.13(1H,dt,J=3.2,12.0Hz),4.42(1H,d,J=2.4Hz),4.19(1H,q,J=6.8Hz),7.04-7.09(2H,m),7.27-7.40(4H,m),7.73(1H,s);MS(FAB)438(M+H,75%),180(100%).
HCl盐形成。向游离碱(0.77g)在乙醚(10ml)中的溶液中加入1M HCl甲醇溶液(1.75ml)。将溶液蒸发至干,加入乙醚,形成结晶。过滤溶液,残余物用乙醚洗涤得到标题化合物盐酸盐:mp:248-250℃.实测值:C.50.46;H,3.85;N,3.01;Cl,7.31.C20H18F7NO2.HCl理论值C,50.70;H,4.04;N,2.96;Cl,7.48%.
说明6
4-苄基-3-(S)-(4-氟代苯基)-2-(R)-(3-氟-5-(三氟甲基)苯甲酰氧基)吗啉
根据说明3中所述的方法,通过使说明2的化合物与3-氟-5-(三氟甲基)苯甲酰氯反应制备标题化合物。1HNMR(360MHz,CDCl3)δ2.50(1H,dt,J=3.3,12.0),2.96(1H,d,J=12.0),2.98(1H,d,J=13.6),3.75(1H,dd,J=1.7,11.5),3.80(1H,d,J=2.5),3.92(1H,d,J=13.6),4.19(1H,dt,J=2.1,12.0),6.20(1H,d,J=2.5),6.99(2H,t,J=8.7),7.2-7.37(5H,m),7.51-7.55(3H,m),7.89(1H,d,J=8.4),8.09(1H,s).MS(Cl+)m/z478(M++1,100%).元素分析 C25H20F5NO3:C,62.88;H,4.23;N,2.93.实测值:C,62.59;H,4.03;N,3.07%.
说明7
4-苄基-3-(S)-(4-氟代苯基)-2-(R)-(1-(3-氟-5-(三氟甲基)苯基)乙烯氧基)吗啉
根据说明4中所述的方法,由说明6的化合物以85%产率制备标题化合物。1H NMR(360MHz,CDCl3)δ2.42(1H,dt,J=3.6,12.0),2.90(1H,d,J=12.0),2.91(1H,d,J=13.6),3.60-3.62(1H,m),3.72(1H,d,J=2.6),3.92(1H,d,J=13.6),4.09(1H,dt,J=2.4,12.0),4.67(1H,d,J=2.9),4.76(1H,d,J=2.9),5.28(1H,d,J=2.6),7.07(2H,t,J=8.7),7.2-7.37(7H,m),7.53(1H,s),7.57-7.61(2H,m).MS(Cl+)476(M+1,100%).
说明8
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉
根据说明5所述的方法氢化说明7的化合物。得到透明油状的2个差向异构产物异构体A和异构体B(主产物)。对于标题化合物:1H NMR(360MHz,CDCl3)δ1.42(3H,d,J=6.6Hz),1.91(1H,s),3.11(1H,dd,J=3.2,12.4Hz),3.22(1H,dt,J=3.6,12.4Hz),3.58-3.62(1H,m),4.01(1H,d,J=2.3Hz),4.11(1H,dt,J=3.2,12.0Hz),4.41.(1H,d,J=2.3Hz),4.80(1H,q,J=6.6Hz),6.41(1H,d,J=9.2Hz),6.86(1H,s),7.02(2H,t,J=8.7Hz),7.08(2H,d,J=9.2Hz),7.21-7.26(2H,m).MS(Cl+)m/z387(M+1,100%).元素分析C19H18F5NO2:C,58.91;H,4.69;N,3.62.实测值:C,58.88;H,4.81;N,3.76%。
说明9
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基吗啉
将说明5的化合物(1g)、N,N-二乙酰基-4-溴甲基-2-咪唑啉酮(0.62g)(根据Dolan and Dushinsky JACS 1948,70,657的方法制备)和碳酸钾(0.63g)在10ml二甲基甲酰胺中的混合物在室温搅拌15分钟。反应混合物用乙酸乙酯(100ml)稀释,用水和盐水洗涤。将乙酸乙酯层干燥(MgSO4)和真空蒸发。得到的油状物溶解于乙醇(10ml)中,加入33%甲胺乙醇溶液(1ml),将混合物在室温搅拌10分钟。真空浓缩混合物得到固体。从乙酸乙酯/甲醇中重结晶得到标题化合物(0.63g)。mp:192-194℃。1H NMR(360MHz,DMSO-d6)δ1.35(3H,d,J=6.5Hz).2.25(1H,dt,J=8.7Hz),2.60(1H,d,J=13.8Hz),2.89(1H,d,J=11.6Hz),3.28-3.36(2H,m),3.62(1H,d,J=10.2Hz),4.1(1H,t,J=10.0Hz),4.31(1H,d,J=2.7Hz),4.92(1H,q,J=6.5Hz),5.97(1H,s),7.06(2H,t,J=8.8Hz),7.36(2H,s),7.65-7.85(2H,m),7.84(1H,s),9.58(1H,s),9.8(1H,s).
说明10
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-三氟甲基)苯基)乙氧基)-4-(2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基吗啉
使用类似于说明9的方法,由说明8的化合物制备标题化合物。mp209-210℃.[α]D=+92.8(c=1.0,甲醇).1H NMR(360MHz,DMSO-d6)δ1.31(3H,d,J=6.5Hz),2.24(1H,dt,J=3.0,11.9Hz),2.6(1H,d,J=13.9Hz),3.61(1H,d,J=11.2Hz),4.1(1H,t,J=11.0Hz),4.29(1H,d,J=2.3Hz),4.8(1H,q,J=6.5Hz),6.00(1H,s),6.55(1H,d,J=9.3Hz),6.94(1H,s),7.11(2H,t,J=8.7Hz),7.39(1H,d,J=8.4Hz),7.51(2H,s),9.59(1H,s),9.84(1H,s).
说明11
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉
将说明5的化合物(3.77g)和碳酸钾(3.59g)在无水二甲基甲酰胺(7ml)中的溶液在室温下搅拌10分钟。加入N-甲酰基-2-氯乙酰氨基腙(根据I.Yanagiswa,J.Med.Chem.(1984),27,849所述的方法制备),将反应混合物在60℃加热1小时。随后使温度升至140℃保持2小时。将混合物冷却,在乙酸乙酯和水之间分配,有机相用水、盐水洗涤、干燥(MgSO4)并蒸发得到棕色油状物。残余物经色谱法(硅胶,用1-5%在二氯甲烷中的甲醇作洗脱剂)纯化,得到白色泡沫状产物(2.99g)。1H NMR(360MHz,DMSO)δ8.25(1H,s),7.85(1H,s),7.50(2H,t),7.37(2H,s),7.11(2H,t,J=9.0Hz),4.93(1H,q,J=6.6Hz),4.32(1H,d,J=2.8Hz),4.09(1H,dt,J=11.5Hz),3.63(1H,d,J=14.1Hz),3.59(1H,d,J=3.0Hz),3.17(1H,d,J=14.0Hz),2.49(1H,dt,J=15.7Hz),1.36(3H,d,J=6.6Hz).MS(Cl+)m/z519.元素分析 C23H19F7N4O2:C,53.29;H,4.08;N,10.81;实测值:C,52.92;H,3.94;N,10.33.
说明12
4-苄基-3-(S)-(4-氟代苯基)-2-(R)-(3-(三氟甲基)苯甲酰氧基)吗啉
根据说明3中所述的方法,通过说明2的化合物与3-(三氟甲基)苯甲酰氯反应制备标题化合物。1H NMR(360MHz,CDCl3)δ2.48(1H,dt,J=12.0,3.5),2.94(1H,d,J=13.6),3.73(1H,app.d,J=11.4),3.78(1H,d,J=2.7),3.91(1H,d,J=13.6),4.21(1H,dt,J=11.7,2.4),6.20(1H,d,J=2.8),6.97(2H,t,J=8.7),7.25-7.37(5H,m),7.53(2H,m),7.61(1H,t,J=7.8),7.84(1H,d,J=8.0),8.21(1H,d,J=7.8),8.30(1H,s).MS(Cl+)m/z460(M+1,100%).
说明13
4-苄基-3-(S)-(4-氟代苯基)-2-(R)-(1-(3-(三氟甲基)苯基)乙烯氧基)吗啉
根据说明4中所述的方法由说明12的化合物制备标题化合物。
1H NMR(360MHz,CDCl3)δ2.40(1H,dt,J=11.9,3.6Hz),2.87(1H,app.d,J=11.8Hz),2.89(1H,d,J=13.5Hz),3.62(1H,app.d,J=11.5Hz),3.70(1H,d,J=2.7Hz),3.91(1H,d,J=13.5Hz),4.12(1H,dt,J=11.7,2.4Hz),4.62(1H,d,J=2.7Hz),4.74(1H,d,J=2.7Hz),5.30(1H,d,J=2.7Hz),7.07(2H,t,J=8.7Hz),7.21-7.32(5H,m),7.40(1H,t,J=7.8Hz),7.53-7.63(4H,m),7.74(1H,s).MS(Cl+)m/z458(M+1,100%).
说明14
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-(三氟甲基)苯基)乙氧基)吗啉
根据说明5中所述的方法氢化说明13的化合物,得到2个大致相等量的差向异构产物异构体A和异构体B,为黄色油状物。标题化合物(异构体B):1H NMR(360MHz,CDCl3)δ1.43(3H,d,J=6.6),3.11(1H,dd,J=12.6,2.9),3.22(1H,dt,J=12.4,3.7),3.60(1H,dd,J=11.1,2.8),3.99(1H,d,J=2.2),4.13(1H,dt,J=11.6,3.2),4.42(1H,d,J=2.2),4.81(1H,q,J=6.6),6.84(1H,d,J=7.8),6.96-7.03(3H,m),7.16-7.27(3H,m),7.38(1H,d,J=7.5).MS(Cl+)m/z370(M+1,100%).元素分析
C19H19F4NO2:C,61.77;H,5.20;N,3.79.实测值:C,61.60;H,5.16;N,3.95%.
说明15
4-苄基-3-(S)-苯基-2-吗啉酮步骤A:N-苄基-(S)-苯基甘氨酸
用1.0ml(10mmol)苯甲醛处理1.51g(10.0mmol)(S)-苯基甘氨酸在5ml 2N氢氧化钠水溶液中的溶液,并在室温下搅拌20分钟。溶液用5ml甲醇稀释,冷却至0℃,并小心地用200mg(5.3mmol)硼氢化钠处理。移去冷却浴,反应混合物在室温下搅拌1.5小时。用20ml水稀释反应溶液,并用2×25ml二氯甲烷提取。水层用浓盐酸酸化至pH6,过滤出沉淀的固体,用50ml水、50ml 1∶1v/v甲醇/乙酸乙酯和50ml乙醚洗涤,干燥后得到1.83g(76%)产物,mp:230-232℃ 。元素分析:C15H15NO2:C,74.66;H,6.27;N,5.81。实测值:C,74.17;H,6.19;N,5.86。步骤B:4-苄基-3-(S)-苯基-2-吗啉酮
将4.00g(16.6mmol)N-苄基-(S)-苯基甘氨酸(来自步骤A)、5.00g(36.0mmol)碳酸钾、10.0ml 1,2-二溴乙烷和25mlN,N-二甲基甲酰胺的混合物在100℃搅拌20小时。将混合物冷却,在200ml乙酸乙酯和100ml水之间分配。将两层分开,有机层用3×50ml水洗涤,用硫酸镁干燥并真空浓缩。残余物用快速色谱法(125g硅胶,用9∶1v/v,随后用4∶1己烷/乙酸乙酯洗脱)纯化得到2.41g(54%)固体产物,mp:98-100℃。1H NMR(250MHz,CDCl3)δ2.54-2.68(1H,m),2.96(1H,dt,J=12.8,2.8),3.14(1H,d,J=13.3),3.75(1H,d,J=13.3),4.23(1H,s),4.29-4.37(1H,m),4.53(dt,J=3.2,11.0),7.20-7.56(10H,m).MS(FAB):m/z268(M+H;100%). 元素分析 C17H17NO2.C,76.38;H,6.41;N,5.24.实测值:C,76.06;H,6.40;N,5.78.
说明16
4-苄基-2-(R)-(3,5-二(三氟甲基)苯甲酰氧基)-3-(S)-苯基吗啉
将2.67g(10.0mmol)说明15的化合物在40ml无水THF中的溶液冷却至-78℃。用12.5ml 1.0M L-Selectride的THF溶液处理冷的溶液,期间保持内部反应温度低于-70℃。得到的溶液冷搅拌45分钟。在其中加入3.60ml(20.0mmol)3,5-二(三氟甲基)苯甲酰氯。将得到的黄色混合物冷搅拌30分钟,用50ml饱和碳酸氢钠水溶液中止反应。中止了反应的混合物在300ml乙醚和50ml水之间分配,将两层分开。有机层用硫酸镁干燥。水层用300ml乙醚提取,将提取液干燥,并与最初的有机层合并。真空浓缩合并的有机物,经快速色谱法(150g硅胶,用37∶3v/v己烷/乙醚作洗脱剂)纯化得到4.06g(80%)固体标题化合物。1H NMR(200MHz ppm,CDCl3)δ2.50(1H,dt,J=3.4,12.0),2.97(1H,app d,J=12.0),2.99(1H,d,J=13.6),3.72-3.79(1H,m),3.82(1H,d,J=2.6),4.00(1H,d,J=13.6),4.20(dt,J=2.4,11.6),6.22(1H,d,J=2.6),7.22-7.37(7H,m),7.57(2H,appd,J=6.8),8.07(1H,s),8.47(2H,s). 元素分析 C26H21F6NO3:C,61.29;H.4.16;N,2.75;F,22.38.实测值:C,61.18;H,4.14;N,2.70;F,22.13
说明17
4-苄基-2-(R)-(1-(3,5-二(三氟甲基)苯基)乙烯氧基)-3-(S)-苯基吗啉
将2.50g(4.9mmol)说明16的化合物和2.50g(12.0mmol)二甲基二茂钛(说明4a)在35ml 1∶1v/v THF/甲苯中的溶液在80℃的油浴中搅拌16小时。将反应混合物冷却,并真空浓缩。经快速色谱法(150g硅胶,使用3∶1v/v己烷/二氯甲烷作洗脱剂)纯化,得到1.71g(69%)固体标题化合物。1H NMR(400MHz,CDCl3)δ2.42(1H,dt,J=3.6,12.0),2.89(appd,J=11.6),2.92(1H,d,J=13.6),3.61-3.66(1H,m),3.73(1H,d,J=2.8),4.00(1H,d,J=13.6),4.09(1H,dt,J=2.4,11.6),4.75(1H,d,J=2.8),4.79(1H,d,J=2.8),5.36(1H,d,J=2.4),7.23-7.41(7H,m),7.63(1H,appd,J=7.2),7.79(1H,s),7.91(2H,s).MS(FAB)m/z 508(M+1,25%). 元素分析C27H23F6NO2:C,63.90;H,4.57;N,2.76;F,22.46.实测值:C,63.71;H,4.53;N,2.68;F,22.66.
说明18
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基吗啉
在氢气气氛下,将说明17的化合物(1.5g)和10%披钯碳催化剂(750mg)在异丙醇/乙酸乙酯的混合物(25ml,3∶2v/v)中的混合物搅拌48小时。通过硅藻土过滤除去催化剂,反应烧瓶和过滤填料用乙酸乙酯(500ml)冲洗。真空浓缩滤液,经快速色谱法得到透明油状的差向异构体A(106mg)和差向异构体B(899mg)。标题化合物,差向异构体B具有如下分析值:
1H NMR(CDCl3,400MHz)δ1.46(3H,d,J=6.8Hz),1.92(1H,brs),3.13(1H,dd,J=3.0,12.6Hz),3.24(1H,dt,J=3.6,12.6Hz),3.62(1H,dd,J=3.6,11.2Hz),4.04(1H,d,J=2.4Hz),4.14(1H,dt,J=3.0,11.2Hz),4.48(1H,d,J=2.4Hz),4.90(1H,q,J=6.8Hz),7.21-7.32(7H,m),7.64(1H,s).MS(Cl+)m/z420(M++1,20%),178(100%). 元素分析 C20H19F6NO2:C,57.28;H,4.57;N,3.34;F,27.18.实测值:C,57.41;H,4.61;N,3.29;F,27.23.
说明19
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(1,2,4-三唑-3-基)甲基吗啉
按照说明11中所述的方法,由说明18的化合物制备标题化合物。MS(Cl+)m/z501(M++1,100%)。
说明20
4-苄基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)吗啉
将说明4的化合物(12.8g)溶解于四氢呋喃(50ml)中,将混合物在冰中冷却。滴加入甲硼烷(49ml 1.0M的四氢呋喃溶液),反应混合物在室温下搅拌3小时。将溶液在冰中冷却,仔细地滴加氢氧化钠(120ml,1M)和过氧化氢(36ml,30wt%)。将所得到的混合物搅拌1小时,用水(200ml)稀释,用乙酸乙酯(3×50ml)提取。有机提取物用亚硫酸钠,然后用盐水洗涤。有机相经干燥(MgSO4)和蒸发得到透明油状物。Tlc(50∶50乙酸乙酯/己烷)表明两个主要产物,它们用快速色谱法(硅胶,使用在己烷中的1-30%乙酸乙酯的梯度洗脱剂)分离。首先洗脱出较少的产物(2.3g),最后洗脱出主要的产物(8g)。主要产物作为白色泡沫状物质分离。1H NMR(360MHz,DMSO-d6)δ2.23-2.29(1H,m),2.73(1H,d),2.80(1H,d,J=13.0Hz),3.48(1H,d,J=3.5Hz),3.45-3.52(2H,m),3.56-3.65(2H,m),4.00-4.06(1H,m),4.37(1H,d,J=3.0Hz),4.81(1H,t,J=6.0Hz),4.92(1H,t,J=5.5Hz),7.14(2H,t,J=9.0Hz),7.23-7.33(5H,m),7.35(2H,s,ArH),7.57(2H,t,ArH),7.85(1H,s,ArH).MS(Cl+)m/z544(M++1,100%).
说明21
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)吗啉
将说明20的化合物(8g)溶解于乙酸乙酯(100ml)和异丙醇(50ml)中,在溶液中加入披钯碳(1.5g)。经过滤除去催化剂,真空除去溶剂。残余物经快速硅胶色谱法(使用在二氯甲烷中的1~10%甲醇作洗脱剂)纯化,得到白色粉末产物(5.7g,90%)。1H NMR(360MHz,CDCl3)δ2.68-2.73(1H,m),3.03-3.15(1H,m),3.43-3.65(3H,m),3.95(1H,d,J=3.0Hz),4.12-4.22(1H,m),4.40(1H,d,J=3.0Hz),4.89(1H,t,J=7.0Hz),6.99(t,J=9.0Hz,ArH),7.15(2H,s,ArH),7.26-7.31(1H,m,ArH),7.62(1H,s,ArH).MS(Cl+)m/z454(M++1,100%).
说明22
3-(S)-(4-氟代苯基)-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)吗啉步骤A:4-苄基-3-(S)-(4-氟代苯基)-2-(R)-(1-
(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧
基)吗啉
将说明7的化合物(0.8g)在室温下溶解于四氢呋喃(5ml)中,添加甲硼烷(5ml,1.0M的四氢呋喃溶液)。将溶液在氮气氛下搅拌30分钟直到所有起始物料发生反应。在冷却(0℃)的溶液中滴加过氧化氢(5ml,29%水溶液)和氢氧化钠(10ml,4N),产生大量泡沫。得到的混合物用乙酸乙酯提取,有机相用亚硫酸氢钠和盐水洗涤,干燥(MgSO4)并蒸发,得到无色油状物(1g)。该物质无需进一步提纯而如下列步骤中所述用于反应。步骤B:3-(S)-(4-氟代苯基)-2-(R)-(1-(S)-
(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)吗
啉
将上述(a)的化合物(1g)溶解于乙酸乙酯/2-丙醇(20ml,3∶1)中,用披钯碳(100mg)处理。混合物在60psi下氢化12小时。经过滤除去催化剂,真空除去溶剂。残余物用中压色谱法(硅胶,(Lobar),使用在二氯甲烷中的5%甲醇作洗脱液)纯化。产物由乙醚中重结晶。
1H NMR(360MHz,DMSO-d6)δ2.77-3.04(3H,m),3.36-3.51(2H,m),3.93(1H,brs),4.05-4.13(1H,m),4.36(1H,d,J=2.0Hz)4.72(1H,t,J=5.0Hz),4.98(1H,t,J=7.0Hz),6.66(1H,d,J=9.2Hz),6.89(1H,s),7.10(2H,t,J=9.0Hz),7.33-7.37(2H,m),7.41(1H,d,J=9.0Hz);MS(Cl+)m/z404(M++1,100).
说明23
N-甲酯基-2-氯乙酰氨基腙
(ClCH2 C(=NH)NHNHCOOCH3)
在0℃将甲醇钠(20mg,1M)加入氯乙腈(54.1g)在无水甲醇(100ml)中的溶液中。混合物在室温下搅拌30分钟,随后用乙酸(1.2ml)中和。将肼基羧酸甲酯(64.5g,真空预蒸馏)溶解于加热的二甲基甲酰胺(35ml)和甲醇(300ml)中,并在0℃下加入反应混合物中。将混合物搅拌30分钟,经过滤除去已形成的结晶,用乙酸乙酯洗涤得到标题化合物:mp138-140℃。
说明24
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉步骤A:4-苄基-2-(R)-(1-(S)-(3,5-二(三氟甲基)
苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉
按照说明20中所述的方法使说明17的化合物与乙硼烷反应,随后与碱性过氧化氢反应。中间体不用纯化,而用于如下步骤中的反应。步骤B:2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基-2
-羟基乙氢基)-3-(S)-苯基吗啉
上述(a)的化合物如说明21中所述通过氢解脱保护,得到为白色固体的标题化合物。
1H NMR(360MHz,CDCl3)δ2.85(1H,appd,J=11.0Hz),3.15(1H,dt,J=12.0,3.5Hz),3.58(1H,dd,J=11.0,3.0Hz),3.63-3.71(2H,m),4.02(1H,d,J=3.0Hz),4.25(dt,J=12.0,3.0Hz),4.53(1H,d,J=3.0Hz),4.93(1H,t,J=5.0Hz),7.22(2H,s),7.35(5H,brs),7.67(1H,s).MS(Cl+)m/z 436(M+1,100%).
说明25
4-苄基-2-(R)-(3-氟-5-(三氟甲基)苯甲酰氧基)-3-(S)-苯基吗啉
根据说明3中所述的方法,说明15的化合物与L-Seletride反应,随后与3-氟-5-(三氟甲基)苯甲酰氯反应得到透明油状的标题化合物。 1H NMR(250MHz,CDCl3)δ2.47(1H,dt,J=8.5,2.5Hz),2.93-2.97(2H,m),3.72-3.76(1H,m),3.79(1H,d,J=3.0Hz),3.97(1H,d,J=9.5Hz),4.17(1H,dt,J=8.5,2.5Hz),6.22(1H,d,J=3.0Hz),7.19-7.35(8H,m),7.45-7.56(3H,m),7.88(1H,brd),8.09(1H,s).MS(Cl+)m/z 460(M+1,100%).
说明26
4-苄基-2-(R)-(3-氟-5-(三氟甲基)苯基)乙烯氧基)-3-(S)-苯基吗啉
根据说明4中所述的方法,使说明25的化合物与二甲基二茂钛反应,由此得到透明油状的标题化合物(66%)。1H NMR(250MHz,CDCl3)δ2.29-2.39(1H,m),2.79-2.86(2H,m),3.53-3.64(2H,m),3.92(1H,d,J=13.5Hz),4.00-4.09(1H,m),4.61(1H,d,J=3.0Hz),4.66(1H,d,J=3.0Hz),5.25(1H,d,J=3.0Hz),7.14-7.35(10H,m),7.47(1H,s),7.56(2H,brd).MS(Cl+)m/z458(M+1,100%).
说明27
2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉步骤A:4-苄基-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉
根据说明20中所述的方法,使说明26的化合物与乙硼烷反应,随后用碱性过氧化氢处理,得到透明油状物。MS(Cl+)m/z476(M+1,100%)。步骤B:2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉
上述(a)的化合物按照说明21中所述的方法脱保护,得到标题化合物,为白色固体。元素分析C19H19F4NO3:C,59.22;H,4.97;N,3.63。实测值:C,59.18;H,5.12;N,3.62%。MS(Cl+)m/z386(M+1,100%)。
说明28
4-苄基-3-(S)-苯基-2-(R)-(3-(三氟甲基)苯甲酰氧基)吗啉
根据说明3中所述的方法,由说明15的化合物制备。1H NMR(250MHz,CDCl3)δ2.47(1H,dt),2.89-2.99(2H,m),3.69-3.82(2H,m),3.98(1H,d),4.23(1H,dt),6.22(1H,d),7.22-7.40(8H,m),7.54-7.66(3H,m),7.83(1H,d),8.22(1H,d),8.31(1H,s).
说明29
4-苄基-3-(S)-苯基-2-(R)-(1-(3-三氟甲基)苯基)乙烯氧基)吗啉
根据说明4中所述的方法,由说明28的化合物制备标题化合物。1H NMR(250MHz,CDCl3)δ2.41(1H,dt),2.84-2.96(2H,m),3.58-3.66(1H,m),3.72(1H,d,3.99(1H,d),4.13(1H,dt),4.63(1H,d),4.72(1H,d),5.34(1H,d),7.21-7.43(9H,m),7.50-7.68(4H,m),7.75(1H,s).
说明30
3-(S)-苯基-(2-(R)-(1-(S)-(3-(三氟甲基)苯基)-2-羟基乙氧基)吗啉步骤A:4-苄基-3-(S)-苯基-2-(R)-(1-(S)-
(3-(三氟甲基)苯基)-2-羟基乙氧基)吗啉
根据说明20中所述的方法,由说明29的化合物制备标题化合物。步骤B:3-(S)-苯基-2-(R)-(1-(S)-(3-(三
氟甲基)苯基)-2-羟基乙氧基)吗啉
按照说明21中所述的方法进行反应,无需纯化得到标题化合物.1HNMR(250MHz,CDCl3)δ2.81-2.90(1H,brd),3.16(1H,dt),3.54-3.68(3H,m),4.02(1H,d),4.28(1H,dt),4.53(1H,d),4.85-4.92(1H,m),6.85(1H,d),6.99(1H,s),7 15-7.24(1H,m),7.34-7.45(6H,m).
实施例1
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氢基)-4-(2,3-二氢-5-(N,N-二甲氨基甲基)-2-氧代-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
用N,N-二甲基亚甲基碘化铵(0.48g)和三乙胺(111μl)在四氢呋喃(10ml)中的溶液处理说明9的化合物(0.35g),混合物回流加热4小时。真空除去溶剂,残余物用色谱法(硅胶,用在二氯甲烷中的1~10%甲醇作洗脱剂)纯化得到标题化合物(0.2g)。1HNMR(250MHz,CDCl3)δ9.72(1H,s),9.68(1H,s),7.86(1H,s),7.50-7.60(2H,m),7.36(2H,s),7.07(2H,t,J=8.8Hz),4.96-4.89(1H,q,J=6.5Hz),4.31(1H,d,J=2.7Hz),4.08(1H,t,J=10.1Hz),3.62(1H,d,J=10.1Hz),3.34(2H,s),3.24(1H,d,J=13.6Hz),3.00(1H,d,J=13.4Hz),2.85(1H,d,J=11.1Hz),2.62(1H,d,J=13.6Hz),2.25(1H,t,J=11Hz),2.01(6H,s),和1.35(3H,d,J=6.5Hz).MS(Cl+)m/z591(M+1).
实施例2
4-(2,3-二氢-5-(N,N-二甲氨基甲基)-2-氧代-13-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉
根据类似于实施例1中所述的方法,由说明10的化合物制备,1H NMR(250MHz,CDCl3)δ1.38(3H,d,J=6.2Hz),2.22(6H,s),2.78(1H,d,J=14Hz),2.92(1H,d,J=11.2Hz)3.14(2H,app.q,J=14Hz),3.34(1H,d,J=2.8Hz),3.46(1H,d,J=11.2Hz),3.60(1H,d,J=10Hz),4.22(2H,m),4.26(1H,dJ=2.8Hz),4.74(1H,q,J=6.2Hz),6.32(1H,d,J=8.4Hz),6.72(1H,s),7.06(3H,t,J=8.4Hz),7.36(2H,brs),8.70(1H,brs),9.20(1H,brs).
实施例3
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉
在90℃,将说明10的化合物(0.1g)、仲甲醛(0.012g)和吡咯烷(0.04ml)在甲醇(2ml)中的混合物加热1小时。再加入等量的仲甲醛(12mg),再持续加热30分钟。将混合物冷却,真空除去溶剂。残余物经色谱法(硅胶,用在二氯甲烷中的0.5%氨水和5%甲醇)纯化,得到泡沫状产物。该产物作为盐酸盐进一步纯化。mp:157-9℃。
1H NMR(250MHz,(游离碱)CDCl3)δ1.40(3H,t,J=6.2Hz),1.72(4H,brs),2.41(4H,brs),2.76(1H,d,J=12.9Hz),2.92(1H,d,J=11.2Hz),3.14-3.50(5H,m),3.62(1H,d,J=11.2Hz),4.16(1H,d,J=12.9Hz),4.26(1H,d,J=2.8Hz),4.71(1H,q,J=6.2Hz),6.30(1H,d,J=8.4Hz),6.75(1H,s),7.06(3H,t,J=8.4Hz),7.34(2H,brs),8.86(1H,brs),9.14(1H,brs).MS(Cl+)m/z567(M++H).
实施例4
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉
在冰冷却下,将说明5的化合物在无水二甲基甲酰胺(15ml)中的溶液在5分钟内滴加到4,5-二(溴甲基)-1,3-二乙酰基-2-咪唑啉酮(1.8g)(根据Dolan and Dushinsky JACS(1948)70,657的方法制备)在含有碳酸钾(1.4g)的二甲基甲酰胺(10ml)中的搅拌的溶液中。反应混合物搅拌10分钟,一次加入吡咯烷(1.1g),继续搅拌20分钟。反应混合物用水(250ml)稀释,用乙酸乙酯(3×50ml)提取。合并的有机提取物用水(2×50ml)和盐水(1×50ml)洗涤,随后干燥(K2CO3)并真空干燥。残余物用色谱法(硅胶,使用二氯甲烷(100%)至二氯甲烷/甲醇/氨水混合物(85∶15∶0.5))梯度洗脱得到泡沫状标题化合物。
1H NMR(360MHz.DMSO-d6)δ9.63(2H,brs),7.84(1H,s),7.53(2H,brt),7.36(2H,s),7.06(2H,t,J=8.7Hz),4.94-.4.90(1H,q,J=6.5Hz),4.31(1H,d,J=2.68Hz),4.07(1H,t,J=11.4Hz),3.61(1H,d,J=11.20Hz),3.34(1H,J=2.7Hz),3.27(1H,d,J=13.7Hz),3.17(1H,d,J=13.4Hz),3.00(1H,d,J=13.4Hz),2.86(1H,d,J=11.6Hz),2.62(1H,d,J=13.6Hz),2.40-2.20(5H,m),1.64-1.58(2H,m),1.35(3H,d,J=6.5Hz).MS(Cl+)m/z615(M++H).
表1中的实施例5~11化合物以类似于实施例4中所述的方法由适当的吗啉、4,5-二(溴甲基)-1,3-二乙酰基-2-咪唑啉酮和适当的胺制备。
实施例12
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基-4-(5-(二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉方法Aa)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基-3-(S)-(4-氟代苯基)-4-炔丙基吗啉
在23℃,将炔丙基溴(1.9ml)加入说明5的化合物(5g)和碳酸钾(4.76g)在无水二甲基甲酰胺中的搅拌的混合物中。15分钟后,用水(250ml)稀释反应混合物,用乙酸乙酯(3×100ml)提取。合并的有机相用盐水(1×100ml)洗涤,随后干燥(K2CO3)并浓缩至油状物。其经色谱法(硅胶,使用在己烷中的乙酸乙酯(1∶9,随后1∶4)作洗脱剂)纯化得到油状标题化合物。
1H NMR(250MHz,CDCl3)δ1.50(3H,d,J=6.6Hz),2.21(1H,s),2.84(1H,d,J=11.1Hz),2.97(1H,td,J=3.2,11.7Hz),3.26(2H,d,J=1.8Hz),3.62(1H,d,J=2.2Hz),3.71(1H,dd,J=2.3,11.1Hz),4.33(2H,m),4.89(1H,q,J=6.6Hz),7.03(2H,t,J=8.6Hz),7.18(2H,s),7.38(2H,brs),7.63(1H,s).MS(Cl+)m/z476(MH,100%).b)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基-4-(4-二甲氨基-4-氧代-丁-2-炔基)-3-(S)-(4-氟代苯基)吗啉
在惰性气氛下,将N,N-二甲基氨基甲酰氯(0.195ml)、碘化铜(2mg)、二(三苯基膦)氯化钯(II)(2mg)、三苯基膦(3mg)和上述(a)中所述的化合物(1g)在三乙胺(4ml)中的混合物在90℃加热5小时。将混合物冷却至23℃,加入甲醇(1ml),真空除去溶剂。残余物在水和乙酸乙酯之间分配,将两层分开。水相用乙酸乙酯(2×20ml)提取,合并的有机相用水、盐水洗涤,干燥(MgSO4)并浓缩至油状物。残余物经色谱法(硅胶,使用在己烷中的乙酸乙酯(1∶1),然后用乙酸乙酯作提取剂)纯化得到标题化合物,为油状物。1H NMR(250MHz,CDCl3)δ1.49(3H,d,J=6.6Hz),2.84-3.06(2H,m),3.00(3H,s),3.17(3H,s),3.44(2H,s),3.64(1H,brs),3.73(1H,dd,J=2.0,11.1Hz),4.33(2H,m),4.88(1H,q,J=6.6Hz),7.03(2H,t,J=8.7Hz),7.17(2H,s),7.38(2H,brs),7.63(1H,s).MS(Cl+)m/z547(MH,100%).c)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N,N-二甲基羧酰氨基(carboxamido)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
将上述(b)中所述的化合物(1.1g)和叠氮化钠(0.65g)在二甲基亚砜(7.5ml)中的混合物在70℃加热17小时。将混合物冷却至23℃。经真空蒸馏除去过量的二甲基亚砜。残余物在盐水和乙酸乙酯之间分配。将两层分开,有机层用盐水(2×20ml)洗涤,随后干燥(MgSO4),并浓缩至油状物。将其用色谱法(硅胶,使用在己烷中的乙酸乙酯(1∶2,随后1∶1),随后用乙酸乙酯作洗脱剂)纯化得到标题化合物,为浅黄色泡沫状物质。1H NMR(360MHz,CDCl3)δ1.47(3H,d,J=6.6Hz),2.64(1H,m),2.90(1H,d,J=11.6Hz),3.09(3H,s),3.34(3H,s),3.65(3H,m),3.92(1H,d,J=15.5Hz),4.27(1H,td,J=2.1,9.5Hz),4.35(1H,d,J=2.6Hz),4.89(1H,q,J=6.6Hz),7.01(2H,t,J=8.7Hz),7.16(2H,s),7.39(2H,brs),7.64(1H,s).m/z590(MH,100%).d)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二甲氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
在隋性气氛下,在23℃,将氢化锂铝(0.47ml,1M,四氢呋喃溶液)添加到上述(c)中所述的化合物(0.11g)在无水四氢呋喃(1ml)中的溶液中。30分钟后,加入氢氧化钠(10滴,1M),随后加入水(5滴)。加入乙酸乙酯(50ml),得到的混合物通过Hyflo填充物过滤。真空浓缩滤液,残余物用色谱法(硅胶,使用在甲醇中的乙酸乙酯(9∶1,随后4∶1)作洗脱剂)纯化,得到泡沫状标题化合物。
1H NMR(360MHz,CDCl3)δ1.44(3H,d,J=6.6Hz),2.25(6H,s),2.57(1H,td,J=3.4,8.55Hz),2.90(1H,d,J=11.7Hz),3.25(1H,d,J=14.0Hz),3.43(1H,d,J=13.6Hz),3.45(1H,d,J=2.2Hz),3.53(1H,d,J=13.6Hz),3.61(1H,d,J=11.2Hz),3.78(1H,d,J=14.0Hz),4.22(1H,t,J=9.3Hz),4.32(1H,d,J=2.2Hz),4.86(1H,q,J=6.6Hz),7.06(2H,t,J=8.7Hz),7.16(2H,s),7.48(2H,brs),7.63(1H,s)m/z576(MH).方法B2-(R)-1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(4-氯丁-2-炔基)吗啉a)将说明5的产物(游离碱,5g)在N,N-二甲基甲酰胺(20ml)中的溶液缓慢加入1,4-二氯丁-2-炔(2.2ml)和碳酸钾(4.8g)在N,N-二甲基甲酰胺(20ml)中的加热(50℃)的溶液中。将溶液在50℃再加热5小时,随后真空除去溶剂。在残余物中加入水(400ml),产物用乙酸乙酯(3×150ml)提取。合并的有机相用水、饱和盐水洗涤并干燥(MgSO4)。真空除去溶剂,残余物经硅胶色谱法(使用在石油醚(bp60-80℃)中的10%乙酸乙酯洗脱)纯化得到标题化合物。1H NMR(250MHz,CDCl3)δ1.41(3H,d,J=6.6Hz),2.80(1H,app.t,J=10.8Hz),2.87(1H,td,J=3.5Hz,11.7Hz),3.22(2H,t,J=1.9Hz),3.52(1H,d,J=2.8Hz),3.68(1H,d,J=1.4Hz.,11.1Hz),4.00(2H,t,J=1.9Hz),4.22-4.32(2H,m),4.81(1H,q,J=6.6Hz),6.96(2H,t,J=8.7Hz),7.10(2H,s),7.31(2H,brs),7.56(1H,s).m/z(Cl+)524(M+H,100%)b)N-(4-叠氮基丁-2-炔基)-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉
在2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(4-氯丁-2-炔基)吗啉(4g)在二甲基亚砜(17ml)中的溶液中加入叠氮化钠(0.562g)。将溶液搅拌20小时,加入含水氯化铵和乙酸乙酯。有机相用水(2倍)、饱和盐水洗涤,并干燥(MgSO4)。真空除去溶剂,残余物经硅胶色谱法(用在石油醚(bp60-80℃)中的20%乙酸乙酯洗脱)纯化得到标题化合物。1H NMR(360MHz,CDCl3)δ1.48(3H,s,J=6.6Hz),2.87(1H,appt,J=10.2Hz),2.98(1H,td,J=3.6,11.7Hz),3.35(2H,t,J=1.9Hz),3.61(1H,d,J=2.8Hz),3.72(1H,dq,J=1.4Hz,10.0Hz),3.92(2H,t,J=1.9Hz),4.30-4.40(2H,m),4.89(1H,q,J=6.6Hz),7.03(2H,t,J=8.7Hz),7.17(2H,s),7.27(2H,brs),7.63(1H,s).c)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二甲氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
在加压管中,使二甲胺(约10ml)在-80℃缩合,向其中加入N-(4-叠氮基丁-2-炔基)-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉(3.2g)在二噁烷(15ml)中的溶液。将管密封,使溶液在90℃加热16小时。将溶液蒸发至干,使残余物用硅胶色谱法(用含0.25%氨的在二氯甲烷中的5%甲醇(SG 0.88)洗脱)纯化,将含有所期望的产物的馏分蒸发至干得到标题化合物。向残余物在乙醚中的溶液中加入1M HCl甲醇溶液,将溶液蒸发至干,重新溶解于乙醚中,得到标题化合物盐酸盐的结晶,m.p.194-198℃,[α]D 25+65.0°(c=0.5,H2O)。结晶被证实在40℃,在40℃/75%相对湿度:在80℃和在2000LUX下至少稳定5天。
实施例13
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(N-(2-甲基氨基乙基)-1,2,4-三唑-3-基)甲基吗啉:区域异构体B(Regioisomer B)a)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(N-甲酯基甲基-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉
将说明11的化合物(2.94g)、碳酸钾(2.03g)和溴代乙酸甲酯(0.74ml)在二甲基甲酰胺中加热45分钟。反应溶液在乙酸乙酯和水之间分配,洗涤(盐水)、干燥(MgSO4)并用硅胶(使用汽油-乙酸乙酯混合物)纯化,作为白色泡沫得到两个产物,异构体A和异构体B。
异构体A:1H NMR(360MHz,DMSO)δ7.89(1H,s),7.84(1H,s),7.48(3H,s),7.33-7.30(3H,m,J=10.1),5.26(1H,d,J=17.8),5.07(1H,d,J=17.8),4.96(1H,q,J=6.5),4.39(1H,d,J=2.8),4.04(1H,brt,J=10.1Hz),3.72(3H,s),3.58(2H,d,J=14.0),3.51(1H,d,J=2.8),3.20(1H,d,J=14.0),2.55(1H,d,J=11.5),2.37(1H,brt,J=3.5),1.40(3H,d,J=6.6).
异构体B:1H NMR(360MHz,DMSO)δ8.43(1H,s),7.82(1H,s),7.44(2H,d,J=1.4),7.37(2H,s),7.31-7.25(3H,m,J=3.2),5.16(2H,s),4.91(1H,q,J=6.5),4.35(1H,d,J=2.8),4.08(1H,brt,J=10.1),3.69(3H,s),3.60(1H,d,J=8.8),3.55(1H,d,J=2.7),3.30(1H,d,J=8.7),3.08(1H,d,J=13.7),2.95(1H,d,J=11.5),2.47(1H,brt,J=3.4),1.35(3H,d,J=6.5).MS(Cl+)m/z573(M+1)b)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(N-(N′-甲基羧酰氨基)甲基-1,2,4-三唑-3-基)甲基吗啉
将甲胺气体鼓入上述(a)的化合物(375mg,异构体B)在甲醇(25ml)中的溶液中10分钟,然后密封16小时。蒸发反应混合物,将其重新溶解于乙酸乙酯中,并真空浓缩得到白色固体(374mg)。
1H NMR(250MHz,CDCl3)δ8.09(1H,s),7.61(1H,s),7.45(2H,brs),7.33(2H,s),7.31(1H,brs),7.13(2H,brs),4.85(1H,q,J=6.5Hz),4.76(2H,s),4.37(1H,brs),4.36(1H,brs),3.85(1H,d),3.66(1H,brs),3.63(1H,brs),3.49(1H,d),3.03(1H,brs),2.82(3H,d),2.80(1H,brs),1.46(3H,d).MS(Cl+)573(M++1).c)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(N-(2-甲基氨基乙基)-1,2,4-三唑-3-基)甲基吗啉
将上述(b)的化合物(302mg)在四氢呋喃(5ml)和甲硼烷-四氢呋喃配合物(1.59ml,1M)中的冷却的溶液搅拌60分钟,然后再加热(60℃)60分钟。蒸发反应溶液,重新溶解于含K2CO3的CH3OH中,随后回流加热30分钟。将反应溶液倒入乙酸乙酯中,并洗涤(水×2,盐水)、干燥(MgSO4)。在硅胶上(使用CH3OH-二氯甲烷混合物)纯化得到无色油状的标题化合物(54mg)。1H NMR(250MHz,CDCl3)δ7.97(1H,s),7.53(1H,s),7.39(2H,brs),7.29-7.23(3H,m,J=2.6),7.06(2H,s),4.77(1H,q,J=6.6),4.29(1H,d,J=2.9),4.25(1H,brt,J=2.6),4.13(2H,t,J=5.7),3.76(1H,d,J=14.2),3.57(1H,t,J=3.5),3.53(1H,d,J=2,8),3.31(1H,d,J=14.1),2.95(1H,t,J=9.3),2.92(2H,t,J=5.9),2.56(1H,brt,J=3.5),2.36(3H,s),2.16(1H,brs),1.37(3H,d,J=6.6).MS(Cl+)m/z558(M++1).
按照类似于实施例12,方法B中所述的方法,由适当的N-(4-叠氮基丁-2-炔基)吗啉和适当的胺制备表2中的实施例14-21的化合物。
实施例22
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(1-(2-吡咯烷子基乙基)-1,2,4-三唑-3-基)甲基吗啉a)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(1-(2-氧代-2-吡咯烷子基乙基)-1,2,4-三唑-3-基)甲基-3-(S)-苯基吗啉
将说明19的化合物(2.86g)、碳酸钾(2.37g)和1-溴代乙酰基吡咯烷(1.21g)在二甲基甲酰胺(15ml)中的溶液在60℃加热。将混合物冷却,并在水和乙酸乙酯之间分配。有机相用水、盐水洗涤并干燥(MgSO4)。真空除去溶剂,残余物被纯化(硅胶,使用在二氯甲烷中的15%甲醇作洗脱剂)得到2个产物异构体A和异构体B。异构体A(在1,2,4-三唑的2位上烷基化):1H NMR(250MHz,CDCl3)δ7.83(1H,s),7.61(1H,s),7.39-7.30(5H,m),7.16(2H,s),5.00(1H,d,J=16.4Hz),4.88(1H,q,J=6.6Hz),4.57(1H,d,J=16.4Hz),4.35(1H,d,J=2.8Hz),4.20(1H,brt,J=11.6Hz),3.77(1H,d,J=14.4Hz),3.62(1H,dd,J=11.3Hz),3.51-3.44(4H,m),3.39(1H,s),3.33(1H,d,J=14.4Hz),2.90(1H,d,J=11.4Hz),2.74(1H,brt,J=11.8Hz),2.12-2.02(2H,m),1.97-1.86(2H,m),1.45(3H,d,J=6.6Hz).异构体B(在1,2,4-三唑的1位上烷基化):1H NMR(250MHz,CDCl3)δ8.19(1H,s),7.60(1H,s),7.47(2H,brs),7.36-7.27(3H,m),7.14(2H,s),4.89(2H,s),4.85(1H,q,J=6.6Hz),4.36(1H,d,J=2.8Hz),4.31(1H,brt,J=11.4Hz),3.86(1H,d,J=14.0Hz),3.60(1H,dd,J=11.3Hz),3.59(1H,d,J=2.7Hz),3.53-3.48(4H,m),3.35(1H,d,J=14.1Hz),3.03(1H,d,J=11.8Hz),2.60(1H,brt,J=11.9Hz),2.08-2.00(2H,m),1.94-1.84(2H,m),1.44(3H,d,J=6.6Hz).b)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(1-(2-吡咯烷子基乙基)-1,2,4-三唑-3-基)甲基吗啉
将氢化锂铝(1.0M的四氢呋喃溶液,1.9ml)在0℃加入上述(a)中所述的化合物(异构体B)在四氢呋喃(5ml)中的溶液中。将混合物温热至室温并搅拌1小时。中止混合物的反应(氢氧化钠和水),通过硅藻土过滤除去无机物。蒸发滤液并纯化(硅胶,使用在二氯甲烷中的10%甲醇作洗脱剂),得到黄色油状的产物。 1H NMR(250MHzCDCl3)δ8.08(1H,s),7.60(1H,s),7.49(2H,brs),7.37-7.31(3H,m),7.13(2H,s),4.85(1H,q,J=6.6Hz),4.36(1H,d,J=2.8Hz),4.33-4.24(1H,m),4.22(2H,t,J=6.5Hz),3.86(1H,dd,J=14.1Hz),3.63(1H,d,J=9.2Hz),3.60(1H,d,J=2.9Hz),3.38(1H,dd,J=14.0Hz),3.00(1H,d,J=11.7Hz),2.89(2H,t,J=6.6Hz),2.59(1H,brt,J=11.9Hz),2.59-2.49(4H,m),1.79(4H,m),1.43(3H,d,J=6.5Hz)
实施例23
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(2-(2-吡咯烷子基乙基)-1,2,4-三唑-3-基)甲基吗啉
将实施例22a中所述的化合物(异构体A)根据实施例22b中所述的方法反应,得到黄色油状的标题化合物。 1H NMR(250MHz,CDCl3)δ7.80(1H,s,CH),7.61(1H,s,ArH),7.53-7.48(2H,m,PhH),7.38-7.34(3H,m),7.17(2H,s),4.88(1H,q,J=6.5Hz),4.36(1H,d,J=2.9Hz).4.34-4.20(1H,m),4.23-4.07(3H,m),3.83(1H,d,J=14.0Hz),3.66(1H,m),3.42(1H,d,J=2.8Hz),3.27(1H,d,J=14.1Hz),2.88-2.73(1H,m),2.88-2.73(2H,m),2.88-2.73(1H,m),2.50(3H,brs),1.73(4H,brs),1.4(4H,d,J=6.6Hz).
实施例24
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-吗啉代甲基-1,2,3-三唑-4-基)甲基吗啉
根据实施例12(方法A)中描述的方法制备该化合物,经色谱法(硅胶,使用乙酸乙酯、石油醚(60-80℃)和甲醇(3∶10∶0,随后1∶0∶0,然后9∶0∶1)作洗脱剂)纯化得白色泡沫状的标题化合物。 1H NMR(360MHz,CDCl3)δ1.44(3H,d.J=6.6Hz),2.43(4H,m),2.57(1H,dd,J=11.9,3.4Hz),2.90(1H,d,J=11.6Hz),3.27(1H,d,J=14.1Hz),3.46-3.67(8H,m),3.82(1H,d,J=14.1Hz),4.23(1H,m),4.32(1H,d,J=2.8Hz),4.87(1H,m),7.06(2H,t,J=8.7Hz),7.16(2H,s),7.48(2H,brs),7.64(1H,s)MS(ES+)m/z618(MH+,54%).
以实施例12,方法B中描述的类似方法,由适当的N-(4-叠氮基丁-2-炔基)吗啉和适当的胺制备实施例25~27中化合物。
实施例28
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(2-氯-5-吗啉代甲基-1,3-咪唑-4-基)-3-(S)-(4-氟代苯基)吗啉
将实施例7的化合物(0.2g)和磷酰氯(0.5ml)回流加热20小时。将混合物冷却,在二氯甲烷和碳酸钾水溶液之间分配。将有机层洗涤(H2O)、干燥(MgSO4)和真空蒸发。用色谱法(硅胶,用100%乙酸乙酯,随后用5%甲醇∶95%乙酸乙酯作洗脱剂)纯化产物得到标题化合物油状物。MS(ES+)m/z651(MH+,100%)。
实施例29
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲氨基甲基)咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
将4,5-二(氯甲基)咪唑盐酸盐(英国专利说明书,No.GB-2,068,362-A)与说明5的化合物按实施例4中所述的方法反应得到标题化合物,为白色固体。 1H NMR(250MHz,CDCl3)δ1.44(3H,d,J=6Hz),2.19(3H,s),2.46-2.62(1H,m),2.92-3.07(2H,m),3.25-3.44(3H,m),3.56-3.70(2H,m),4.16-4.33(2H,m),4.85(1H,q,J=6Hz),7.01-7.17(4H,m),7.38-7.67(4H,m).MS(ES)m/z575(M+1+,100%).
实施例30
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲氨基甲基)-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉
将3,5-二(氯甲基)三唑(J.Het.Chem.(1986)23,361-368)与说明5的化合物根据实施例4中所述的方法反应得到标题化合物,为固体。
1H NMR(250MHz,CDCl3)δ1.27(3H,d,J=6.6Hz),2.15(6H,s,CH3),2.43(1H,dt,J=11.7,3.2Hz),2.79-2.83(1H,m),3.16(1H,d,J=14.5Hz),3.38(1H,d,J=2.8Hz),3.43-3.48(1H,m),3.48(2H,s,CH2),3.63(1H,d,J=14.5Hz),4.12(1H,dt,J=11.7,3.2Hz),4.15(1H,d,J=2.8Hz),4.69(1H,q,J=6.6Hz),6.85(2H,t,J=8.75Hz),6.97(2H,s),7.27(2H,brt),7.45(1H,s).MS(ES)m/z576(M++1,100%).
根据实施例12,方法B中所述的类似的方法,由适当的N-(4-叠氮基丁-2-炔基)吗啉和适当的胺制备表2中实施例31-37的化合物。
根据实施例4中所述的类似的方法,由适当的吗啉、4,5-二(溴甲基)-1,3-二乙酰基-2-咪唑啉酮和适当的胺制备表1中实施例38-41的化合物。
实施例42
2-(R)-(1-(R)-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-硫代吗啉代甲基-1,3-味唑-4-基)甲基吗啉S-氧化物
在氮气氛下,将实施例38的化合物(67mg,1eq)溶解于CF3CO2H(0.3ml),然后冷却到0℃,加入CF3CO3H(2M的CF3CO2H溶液;57μl,1.1eq)。在0℃搅拌1小时后,真空除去溶剂,将残余物溶解于EtOAc中,用饱和NaHCO3溶液洗涤,干燥(K2CO3)并浓缩至黄色泡沫状物。将其用柱色谱法(使用MeOH/CH2Cl2/NH3(3∶97∶0.25)作洗脱剂)纯化得到标题化合物,为白色固体。1H NMR(250MHz,CDCL3)δ9.48(1H,s),8.66(1H,s),7.64(1H,s),7.40(2H,m),7.14(2H,s),7.06(2H,t,J=8.6Hz),4.87(1H,q,J=6.5Hz),4.30(1H,d,J=2.7Hz),4.23(1H,t,J=10.0Hz),3.65(1H,d,J=9.6Hz),3.45(1H,m),3.75(1H,m),3.36(1H,d,J=2.7Hz),3.30(1H,d,J=14Hz),3.20(1H,d,J=14Hz),3.05-2.60(9H,m),2.36(1H,m),1.46(3H,d,J=6.5Hz).
按照类似于实施例12,方法B中描述的方法,由适当的N-(4-叠氮基丁-2-炔基)吗啉和适当的胺制备表2中实施例43至62中的化合物。
实施例63
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(1-(2-(N,N-二异丙基氨基)乙基)-1,2,4-三唑-3-基)甲基-3-(S)-苯基吗啉(a)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(1-(2-羟基乙基)-1,2,4-三唑-3-基)甲基-3-(S)-苯基吗啉
将说明19的化合物(3.90g,7.8mM)在含有2-溴乙醇(1.66ml,23.4mM)和碳酸钾(3.23g,23.4mM)的二甲基甲酰胺(20ml)中的溶液中加热(60℃)2小时。将反应溶液倾入乙酸乙酯中,用水和盐水洗涤,干燥(MgSO4)并蒸发。纯化和分离(硅胶,用甲醇-二氯甲烷混合物作洗脱剂)两个异构体(3.06g)。MS(ES+)m/z545。(b)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(1-(2-甲苯磺酰氧基乙基)-1,2,4-三唑-3-基)甲基吗啉
将上述步骤(a)的醇(1.81g,3.22mM)溶解于二氯甲烷(20ml)中,加入甲苯磺酰氯(1.84g,9.66mM)和三乙胺(1.34ml,3.66mM),反应溶液在室温搅拌18小时,除去溶剂,残余物再溶解于乙酸乙酯中,用水和盐水洗涤,干燥(MgSO4)和蒸发。纯化(硅胶,用甲醇-二氯甲烷混合物作洗脱剂)产物(1.87g)。(c)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(1-(2-N,n-二异丙基氨基)乙基)-1,2,4-三唑-3-基)甲基-3-(S)-苯基吗啉
将上述步骤(b)的甲苯磺酸酯(0.29g,0.41mM)溶解于二甲基甲酰胺(5ml)中,加入二异丙基胺(0.18ml,1.24mM)和三乙胺(0.18ml,1.24mM),将反应溶液在密封管中加热18小时。将残余物溶解于乙酸乙酯中,用水和盐水洗涤,干燥(MgSO4)和蒸发。经纯化(硅胶,用甲醇-二氯甲烷混合物作洗脱剂)得到标题化合物(0.095g)。 1H NMR(360MHz,d6-DMSO)δ8.31(1H,s),7.82(1H,s),7.46-7.42(2H,m),7.36(2H,s),7.32-7.22(3H,m),4.89-4.92(1H,q,J=6.5Hz),4.34(1H,d,J=2.8Hz),4.18-4.04(3H,m),3.60-3.56(3H,m),3.09(1H,d,J=13.6Hz),3.94(1H,d,J=11.5Hz),2.71(2H,t,J=5.8Hz),2.44-2.40(1H,m),2.30(4H,t,J=7.0Hz),1.34(3H,d,J=6.5Hz),1.32-1.20(4H,m)和0.73(6H,t,J=7.4Hz).M/S+628.
按照类似于实施例63中所述的方法,由适当的1,2,4-三唑-3-基甲基吗啉和适当的胺制备表3中实施例64至74的化合物。
实施例75
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲氨基甲基)-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉(a)2-(R)-(1-(R)-3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(1-(四氢-2-吡喃基)-5-(N,N-二甲基氨基甲基)-1H-1,2,4-三唑-3-基)甲基吗啉
将说明5的化合物(1g,2.28mM)溶解于异丙醇(20ml)中,加入3,5-二(氯甲基)-1-(四氢-2-吡喃基)-1H-1,2,4-三唑(1.14g,4.57mM)(通过Bradshaw,J.Het.Chem(1986),23,361的方法制备)和碳酸钾(0.95g,6.84mM),将反应溶液在60℃加热18小时。随后加入二甲胺(3eq),将试剂移至密封管中,再加热18小时。随后除去溶剂,残余物经纯化(硅胶,用甲醇、二氯甲烷-氨混合物洗脱)得到标题化合物(0.62g)。(b)2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉
将上述步骤(a)的保护的胺(0.62g,0.94mM)溶解于甲醇(15ml)中,用HCl甲醇溶液(1N,25ml)处理,在室温下搅拌1小时。随后除去溶剂,残余物经纯化(硅胶,用甲醇-二氯甲烷氨混合物洗脱)得到标题化合物(0.48g)。 1H NMR(250MHz,CDCl3)δ7.45(1H,s),7.30-7.22(2H,m),6.97(2H,s),6.85(2H,t,J=8.7Hz),4.72-4.66(1H,q,J=6.5Hz),4.15(1H,d,J=2.8Hz),4.15-4.07(1H,m),3.63(1H,d,J=14.4Hz),3.48(4H,s),3.44-3.41(1H,m),3.38(1H,d,J=2.8Hz),3.16(1H,d,J=14.5Hz),2.81(1H,d,J=11.1Hz),2.50-2.39(1H,m),2.15(6H,s)和1.27(3H,d,J=6.6Hz).M/S ES+576.
实施例76
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲硫基-5-(三氟甲基)苯基)乙氧基)吗啉
将实施例57的化合物(270mg,0.51mmol)与硫代甲醇钠(178mg,2.55mmol)在无水THF中(10ml)在120℃加热2-5小时。冷却的溶液用水(150ml)稀释,用乙酸乙酯提取(4×40ml),干燥(MgSO4)和真空浓缩至粗油状物(372mg),将其用快速硅胶色谱法(在5-10%甲醇/二氯乙烷中)强化得到标题化合物,为粘稠的胶状物/玻璃状物(170mg,60%)。 1H NMR(360MHz,CDCl3)δ1.31(3H,d,J=6.6Hz),2.17(6H,s),2.28(3H,s),2.47(1H,dt,J=12.1,3.4Hz),2.82(1H,d,J=11.6Hz),3.14(1H,d,J=13.9Hz),3.35(2H,m),3.46(1H,d,J=13.5Hz),3.52(1H,dd,J=11.2,1.9Hz),3.70(1H,d,J=13.9Hz),4.14(1H,dt,J=11.6Hz),4.26(1H,d,J=2.7Hz),4.66(1H,q,J=6.5Hz),6.64(2H,s),6.99(2H,t,J=8.6Hz),7.11(1H,s),7.41(2H,brs),10.0-10.8(1H,vbrs);MS(ES+)m/z554(M+1,100%).
实施例77
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲硫基-5-(三氟甲基)苯基)乙氧基)-4-(5-吡咯烷子基甲基-1,2,3-三唑-4-基)甲基吗啉
由实施例18的化合物按照实施例76的方法制备标题化合物,为泡沫状物质(620mg,81%)。
1H NMR(360MHz,CDCl3)δ1.40(3H,d,J=6.6Hz),1.79(4H,brs),2.36(3H,s),2.5-2.6(5H,m),2.87(1H,d,J=11.7Hz),3.23(1H,d,J=13.9Hz),3.43(1H,d,J=2.8Hz),3.57-3.64(2H,m),3.71(1H,d,J=13.7Hz),3.78(1H,d,J=14.0Hz),4.21(1H,m),4.33(1H,d,J=2.8Hz),4.74(1H,q,J=6.5Hz),6.71(2H,s),7.06(2H,t,J=8.7Hz),7.19(1H,s),7.47(2H,brs);MS(ES+)m/z580(M+1,100%).
实施例78
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲硫基-5-(三氟甲基)苯基)-乙氧基)-4-(5-吗啉代甲基)-1,2,3-三唑-4-基)甲基吗啉
根据实施例76的方法,由实施例19的化合物制备标题化合物,为泡沫状物质(126mg.66%)。
1H NMR(360MHz,CDCl3)δ1.40(3H,s,J=6.6Hz),2.37(3H,s),2.32-2.49(4H,m),2.54(1H,dt,J=11.9,3.4Hz),2.90(1H,d,J=11.7Hz),3.25(1H,d,J=13.9Hz),3.48(1H,d,J=13.5Hz),3.57-3.68(7H,m),3.82(1H,d,J=14.1Hz),4.23(1H,m),4.35(1H,d,J=2.8Hz),4.75(1H,q,J=6.5Hz),6.71(2H,s),7.06(2H,t,J=8.7Hz),7.19(1H,s),7.49(2H,brs);MS(ES+)m/z596(M+1,55%),203(100%).
实施例79
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-2-(R)-(1-(R)-(3-甲硫基-5-(三氟甲基)苯基)乙氧基)-3-(S)-苯基吗啉
根据实施例76的方法由实施例102的三唑制备标题化合物,为泡沫状物(116mg,36%)。
1H NMR(250MHz,CDCl3)δ1.39(3H,d,J=6.5Hz),2.24(6H,s),2.32(3H,s),2.59(1H,dt,J=11.8,3.3Hz),3.25(1H,d,J=13.8Hz),3.38-3.44(2H,m),3.52(1H,d,J=13.6Hz),3.62(1H,dd,J=11.2,1.8Hz),3.81(1H,d,J=13.9Hz),4.23(1H,m),4.39(1H,d,J=2.6Hz),4.75(1H,q,J=6.5Hz),6.71(2H,s),7.17(1H,s),7.34-7.41(3H,m),7.49(2H,brs);MS(ES+)m/z536(M+1,100%).
实施例80
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-叔丁基硫基-5-(三氟甲基)苯基)乙氧基)吗啉
根据实施例76的方法,由实施例57的化合物制备标题化合物,为泡沫状物质(117mg,68%)。
1H NMR(360MHz,CDCl3)δ1.19(9H,s),1.42(3H,d,J=6.6Hz),2.23(6H,s),2.57(1H,dt,J=12.0,3.5Hz),2.92(1H,d,J=11.6Hz),3.24(1H,d,J=13.9Hz),3.39-3.44(2H,m),3.51(1H,d,J=14.8Hz),3.62(1H,m),3.80(1H,d,J=13.9Hz),4.23(1H,m),4.41(1H,d,J=2.7Hz),4.77(1H,q,J=6.5Hz),6.89(1H,s),7.14(1H,s),7.31-7.35(3H,m),7.46(2H,brs),7.51(1H,s);MS(ES+)m/z578(M+1,100%).实施例81
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲基亚磺酰基-5-(三氟甲基)苯基)乙氧基)吗啉
将实施例76的硫醚(155mg,0.28mmol)溶解于冷却至0℃的三氟乙酸(800μl)中,用2.0M的三氟过乙酸在三氟乙酸(153μl,0.308mmol)中的溶液处理,搅拌30分钟,将反应混合物倒入0.5M碳酸氢钠溶液(50ml)中,用二氯甲烷(3×15ml)提取,干燥(MgSO4)并真空浓缩。得到的粗制固体(200mg)用快速硅胶色谱法(在8%甲醇∶二氯甲烷中)纯化得到标题化合物,为未拆分的立体异构体,为白色泡沫状物质(81mg,51%)。
1H NMR(360MHz,CDCl3)δ1.44和1.46(3H总,2×d,J=6.6Hz),2.24(6H,s),2.56(1H,m),2.59和2.62(3H总,2×s),2.88(1H,d,J=11.9Hz),3.23和3.26(1H总,2×d,J=13.9Hz),3.42-3.55(3H,m),3.62(1H,brd,J=11.3Hz),3.75和3.79(1H总,2×d,J=14.4Hz),4.22(1H,m),4.32和4.35(1H总,2×d,J=2.7Hz),4.89(1H,m),6.85(H,s),7.04-7.13(3H,m),7.24(H,s),7.50(2H,brs),7.73和7.75(1H总,2×s);MS(ES+)m/z570(M+1,100%).
实施例82
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲基亚磺酰基-5-(三氟甲基)苯基)乙氧基)-4-(5-吡咯烷子基甲基-1,2,3-三唑-4-基)甲基吗啉
根据实施例81的方法,由实施例77制备标题化合物,为未拆分的立体异构体混合物,泡沫状物质(90mg,63%)。
1H NMR(360MHz,CDCl3)δ1.44和1.46(3H总,2×d,J=6.6),1.86(4H,brs),2.50-2.60(1H,m),2.59和2.62(3H总,2×s),2.70-2.90(5H,m),3.24.和3.26(1H,2×d,J=14.0),3.46(1H,d,J<2),3.62(1H,brd,J=11.2),3.71-3.86(3H,m),4.20(1H,m),4.32和4.35(1H总,2×d,J=2.7),4.89(1H,m),6.89(H,s),7.03-7.13(3H,m),7.25(H,s),7.49(2H,brs),7.73和7.75(1H总,2×s);MS(ES+)m/z596(M+1),100%).
实施例83
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲基亚磺酰基-5-(三氟甲基)苯基)乙氧基)-4-(5-吗啉代甲基-1,2,3-三唑-4-基)甲基吗啉
根据实施例81的方法,由实施例78制备标题化合物,为未拆分的立体异构体混合物,泡沫状物质(113mg,92%)。1H NMR(360MHz,CDCl3)δ1.3和1.41(3H总,2×d,J=6.6),2.54和2.57(3H总,2×s),2.54-2.65(1H,m),2.82-2.89(1H,m),3.05-3.25(4H,vbrs),3.35(1H,m),3.50(1H,m),3.61(1H,m),3.72和3.74(1H,2×d,J=14.5),3.85-4.22(6H,m),4.29和4.33(1H,2×d,J=2.5),4.81(1H,m),6.99-7.09(3H,m),7.30(H,s),7.42(2H,brs),7.64和7.66(1H总,2×s);MS(ES+)m/z612(M+1,100%).
实施例84
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-甲基磺酰基-5-(三氟甲基)苯基)乙氧基)-4-(5-
吗啉代甲基-1,2,3-三唑-4-基)甲基吗啉
将实施例83的亚砜(78mg,0.128mmol)溶解于冷却至0℃的三氟乙酸(500μl)中,用2.0M的三氟过乙酸在三氟乙酸(70μl,0.140mmol)中的溶液,搅拌
小时。然后再加入等量的三氟过乙酸(70μl,0.140mmol),3小时后,按照实施例81的方法纯化产物,得到泡沫状的标题化合物(27mg,34%)。 1HNMR(360MHz,CDCl3)δ1.47(3H,d,J=6.6Hz),2.38-2.45(4H,m),2.57(1H,dt,J=11.9,3.5),2.90(1H,d,J=11.7Hz),2.96(3H,s),3.26(1H,d,J=14.0Hz),3.46-3.51(2H,m),3.56-3.68(6H,m),3.79(1H,d,J=14.1Hz),4.22(1H,m),4.35(1H,d,J=2.8Hz),4.90(1H,q,J=6.8Hz),7.07(2H,t,J=8.6Hz),7.17(1H,s),7.50(2H,brd),7.67(1H,s),7.97(1H,s);MS(ES+)m/z628(M+1,100%).
实施例85
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2-(5-((S)-(+)-2-甲氧基甲基吡咯烷子基甲基)-1,2,3-三唑-4-基)乙基)吗啉步骤A:2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)
乙氧基)-4-(丁-3-炔基)-3-(S)-(4-氟
代苯基)吗啉
将说明5的化合物(1.24g,1eq)、3-丁炔-1-醇-甲苯磺酸酯(1.43g,2.5eq)、K2CO3(1.32g,3.7eq)和NaI(催化量)在无水DMF(7ml)中的溶液在100℃加热12小时。在冷却至室温后,将反应混合物在H2O和EtOAc之间分配。将两层分开,用EtOAc(2×)提取水相。将合并的有机相干燥(MgSO4)并浓缩,残余物经色谱法(己烷/EtOAc 9∶1~4∶1)纯化得到标题化合物,为透明无色油状物。MSm/z490(MH+)。步骤B:2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)
乙氧基)-3-(S)-(4-氟代苯基)-4-(4-羟
基丁-3-炔基)吗啉
将步骤A的乙炔(1.2g,1.0eq)溶解于无水THF(5ml)中,然后冷却至-78℃,加入n-BuLi(2.5M己烷溶液;1ml;1.05eq)。反应混合物在-78℃搅拌1小时,通过鼓泡HCHO气体直到溶液被饱和。反应混合物被温热至室温,搅拌1小时。加工(NH4Cl/EtOAc),随后纯化(硅胶,己垸/EtOAc 9∶1~4∶1)得到标题化合物,为透明粘稠油状物。MSm/z520(MH+)。步骤C:2-((R)-(1-(R)-(3,5-二(三氟甲基)苯
基)乙氧基)-4-(4-氯丁-3-炔基)-3-(S)
-(4-氟代苯基)吗啉
将步骤B的醇(0.429,1eq)在N2下溶解于无水THF(5ml)中,加入三光气(84mg,0.35eq),随后加入吡啶(128μl,2.0eq)。反应混合物在室温下搅拌
小时,然后EtOAc稀释,用H2O和盐水洗涤,干燥(MgSO4)并浓缩至黄色油状物。将其用色谱法(己烷/EtOAc9∶1→4∶1)纯化得到标题化合物,为透明粘稠的油状物。MSm/z538,540(MH+)。步骤D:N-(4-叠氮基丁-3-缺基)-2-(R)-(1-
(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-
(S)-(4-氟代苯基)吗啉
在室温下,将步骤C的氯化物(0.23g,1.eq)和NaN3(31mg,1eq)在DMSO中搅拌14小时。经处理(NH4Cl/EtOAc)得到标题化合物,为油状物,其无需进-步纯化即可使用。步骤E:2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)
乙氧基)-3-(S)-(4-氟代苯基)-4-(2-
(5-((S)-(+)-2-甲氢基甲基吡咯烷子基甲基)
-1,2,3-三唑-4-基)乙基)吗啉
将步骤D的叠氮化物(0.205g,1eq)和(S)-(+)-2-甲氧基甲基吡咯烷(114μl,3eq)的溶液在N2气氛下在80℃加热,真空除去溶剂,残余物经色谱法(使用CH2Cl2/MeOH/NH3(98∶2∶0.1,随后97∶3∶0.1)作洗脱剂)纯化得到白色泡沫状标题化合物。 1H NMR(250MHz,CDCl3)δ7.62(1H,s),7.24(2H,m),7.14(2H,s),6.95(2H,t,J=8.7Hz),4.87(1H,q,J=8.5Hz),4.30(2H,m),3.95(1H,d,J=14Hz),3.70(1H,dd,J=2,11.3Hz),3.53-3.34(7H,m),3.19(1H,d,J=11.6Hz),2.86-2.56(6H,m),2.29(1H,m),2.09(1H,m),1.88(1H,m),1.70(3H,m),1.45(3H,d,J=6.5Hz).MS m/z=680.
实施例86
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉步骤A:2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-叔丁基二甲基甲硅烷氧基乙氧基)-3-(S)-(4-氟代苯基)吗啉
在氮气氛下,将说明21的产物(2g)溶解于无水二氯甲烷(16ml),冷却至0℃。随后加入2,6-二甲基吡啶(0.5ml)和叔丁基二甲基三氟甲磺酸酯(1.0ml),混合物搅拌15分钟。将反应混合物洗涤(H2O、盐水)、干燥(MgSO4)并真空蒸发。经重力硅胶柱(使用20%-50%乙酸乙酯/汽油作洗脱剂)得到无色透明油状的标题化合物。
1H NMR(250MHz,CDCl3)δ-0.04(3H,s),0.00(3H,s),0.87(9H,s),3.15-3.36(2H,m),3.64-3.70(2H,m),3.90-3.96(1H,m),4.10(1H,d,J=2.2Hz),4.22-4.53(1H,m),4.53(1H,d,J=2.2Hz),4.91(1H,t,J=5.9Hz),7.04-7.14(2H,m),7.29-7.36(4H,m),7.74(1H,brs).MS(ES+)m/z=567.步骤B:2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-叔丁基二甲基甲硅烷氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(4-氯丁-2-炔基)吗啉
以类似于实施例12,方法B的步骤(a)的方法,使用上述步骤A的产物制备得到透明油状的标题化合物。1H NMR(360MHz,CDCl3)δ0.00(3H,s),0.04(3H,s),0.91(9H,s),2.95-3.09(2H,m),3.40(2H,brs),3.72-3.83(3H,m),4.01(1H,dd,J=10.2,J=5.5Hz),4.25(2H,m),4.50(2H,m),4.9(1H,t,J=5.9Hz),7.15(2H,t,J=8.7Hz),7.29(2H,s),7.52(2H,brs),7.76(1H,s).步骤C:2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-叔丁基二甲基甲硅烷氧基乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
以类似于实施例12,方法B的步骤(b)和(c)的方法,使用上述步骤B的产物制备得到标题化合物。1H NMR(250MHz,CDCl3)δ-0.02(3H,s),0.00(3H,s),0.88(9H,s),2.30(6H,s),2.60-2.70(1H,m),2.93-2.98(1H,brd,J=11.6Hz),3.30(1H,d,J=13.8Hz),3.48-3.63(3H,m),3.68-3.74(2H,m),3.84-3.97(2H,m),4.33-4.41(1H,m),4.46(1H,d,J=2.8Hz),4.90(1H,t,J=5.6Hz),7.16(2H,t,J=8.7Hz),7.25(2H,brs),7.59(2H,vbrm),7.74(1H,brs).步骤D:2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉
将上述步骤C的产物(0.2g)在无水四氢呋喃(2ml)中与四丁基氟化铵(1.0M)在四氢呋喃(0.42ml)中的溶液一起搅拌30分钟。混合物在氯化铵溶液和乙酸乙酯之间分配,将有机层洗涤(H2O,盐水)、干燥(MgSO4)并真空蒸发,经重力硅胶柱(用4-10%MeOH/0.1%NH4OH/二氯甲烷洗脱)纯化得到标题化合物。
1H NMR(250MHz,CDCl3)δ2.26(6H,s),2.51(1H,m),3.09(2H,m),3.35(2H,m),3.51-3.63(4H,m),3.78(2H,d,J=13.8Hz),4.30-4.36(2H,m),4.88(1H,m),7.01-7.10(4H,m),7.50(2H,vbrs),7.59(1H,brs).
实施例87
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N-乙基-N-异丙基氨基甲基)-1(或2或3)-甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉
在室温和氮气氛下,将实施例101的产物(2g)溶解于N,N-二甲基甲酰胺(4ml)中,加入碘甲烷,随后加入氢化钠(60%)(14mg),混合物搅拌16小时。将反应混合物在乙酸乙酯和水之间分配,将有机相洗涤(H2O×2,盐水),干燥(MgSO4)并真空蒸发。经重力硅胶色谱法(用100%乙酸乙酯,随后用10%甲醇/0.1%NH4OH/二氯甲烷洗脱)纯化得到标题化合物。
1H NMR(250MHz,CDCl3)δ0.85-1.02(9H,m),1.44(3H,d,J=6.6Hz),2.25-2.40(2H,m),2.57-2.68(1H,m),2.75-2.85(1H,m),2.96(1H,brd,J=13.5Hz),3.15(1H,d,J=13.5Hz),3.38(1H,d,J=2.7Hz),3.44(2H,s),3.60-3.73(2H,m),4.07(3H,s),4.18(1H,m),4.35(1H,d,J=2.8Hz),4.83(1H,m),7.15(2H,brs),7.33(3H,m),7.48(2H,vbrs),7.61(1H,brs).MS(ES+)m/z=613(MH+,100%).
实施例88
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)-4-2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉
将说明6的化合物(0.5g)、N-甲酯基-2-氯乙酰氨基腙(说明23)(182mg)和碳酸钾(0.3g)悬浮于二甲基甲酰胺(3.6ml)中,混合物在60℃加热2小时。随后混合物在140℃再加热2小时。将混合物冷却,经硅藻土过滤除去无机材料。通过与二甲苯共沸真空除去溶剂。残余物经快速硅胶色谱法(使用在二氯甲烷中的1~10%的甲醇洗脱)纯化,得到白色粉末状的标题化合物(300mg)。1H NWR(360MHz,DMSO-d6)δ2.38-2.41(1H,m),2.78(1H,d,J=14.0Hz),2.81-2.84(1H,m),3.36(1H,d,J=14.0Hz),3.45-3.48(1H,m),3.52(1H,d,J=3.0Hz),3.58-3.61(2H,m),4.81(1H,t,J=6.0Hz),4.88(1H,brt),7.09(2H,t,J=9.0Hz),7.33(2H,s),7.50(2H,brt),7.85(1H,s),11.26(1H,s),11.30(1H,s).MS(Cl+)m/z551(M+1,10%),454(M+-CH2三唑酮,20)
实施例89
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉
在60℃,将说明6的化合物(270mg)、无水碳酸钾(250mg)和N-甲酰基-2-氯乙酰氨基腙(92mg)(根据I.Yanagisawa,J.Med.Chem.(1984),27,849的方法制备)在无水二甲基甲酰胺中加热1小时,然后在140℃加热2小时。将反应混合物冷却,用水(100ml)稀释。用乙酸乙酯(3×50ml)提取产物,有机层用盐水洗涤,干燥(MgSO4)并真空蒸发。。残余物经色谱法(硅胶,用在二氯甲烷中的7%甲醇作洗脱剂)纯化,得到白色固体的标题化合物(200mg,60%)。1H NMR(360MHz,DMSO-d6)δ2.47(1H,t,J=9.0Hz),2.89(1H,d,J=11.0Hz),3.18(1H,d,J=14.0Hz),3.44-3.49(1H,m),3.55-3.61(4H,m),3.64(1H,d,J=6Hz),4.25(1H,t,J=11.0Hz),4.34(1H,d,J=3.0Hz),4.81(1H,t,J=5.0Hz),7.11(2H,t,J=9.0Hz),7.34(2H,s),7.52(2H,m),7.85(1H,s),8.19(1H,brs).MS(Cl)m/z535(M+1,10%).
实施例90
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)吗啉
将在二甲基甲酰胺中的说明22的化合物(350mg)、N-甲酯基-2-氯乙酰氨基腙(150mg)(说明23)和碳酸钾(150mg)在60℃加热3小时直到所有起始物料被消耗。混合物随后在140℃加热3小时。将混合物冷却,经硅藻土过滤除去无机物。残余物经用二甲苯蒸发共沸残余的二甲基甲酰胺。残余物经色谱法(硅胶,使用在二氯甲烷中的1-10%甲醇作洗脱剂)纯化,得到泡沫状的标题化合物,将其从乙醚中重结晶。 1H NMR(360MHz,DMSO-d6)δ2.34-2.46(1H,m),2.74-2.84(2H,m),3.34-3.43(3H,m),3.50-3.60(2H,m),4.21-4.31(2H,m),4.68(1H,t,J=5.0Hz),4.90(1H,t,J=7.0Hz),6.54(1H,d,J=9.0Hz),6.88(1H,s),7.14(t,J=9.0Hz),7.42(1H,d,J=9.0Hz),7.44(2H,m).
实施例91
4-(2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)吗啉
在室温下,将说明6的化合物(2g)、4-溴甲基-1,3-二乙酰基-2-咪唑酮(1.38g)(由Dolan和Dushinsky,JACS(1948)70,657的方法制备)和碳酸钾(1.2g)在二甲基甲酰胺(14ml)中的混合物搅拌30分钟,直到所有起始的吗啉已反应。将混合物用水(150ml)稀释和乙酸乙酯(3×50ml)提取。合并的提取物用盐水洗涤,真空蒸发有机溶剂。将残余物油溶解于乙醇(20ml)中,加入甲胺(2ml的8M乙醇溶液)。将溶液搅拌1小时。然后真空除去溶剂。将残余油状物纯化(硅胶,用在二氯甲烷中的1-10%甲醇作洗脱剂),得到白色泡沫状的产物(2g,83%)。将其进-步用盐酸甲醇溶液处理,从水中重结晶得到白色固体。 1H NMR(360MHz.DMSO-d6)δ2.22-2.34(1H,m),2.62(1H,d,J=14.0Hz),2.89(1H,近似d,J=11.0Hz),3.26(1H,d,J=14.0Hz),3.38(1H,d,J=3.0Hz),3.43-3.50(1H,m),3.57-3.62(2H,m),4.19-4.28(1H,m),4.32(1H,d,J=3.0Hz),4.81(1H,t,J=5.5Hz),4.93(1H,t,J=6.0Hz),6.00(1H,s),7.09(1H,t,J=9.0Hz),7.33(2H,s),7.54(2H,brt),7.86(1H,s),9.63(1H,s),9.83(1H,s)MS(Cl)m/z550(M+1,20%),454(80)116(100).
实施例92
4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-(4-氟代苯基)吗啉
在室温下,将说明6的化合物(1.8g)、4,5-二(溴甲基)-1,3-二乙酰基-2-咪唑酮(由Dolan和Dushinsky,JACS(1948)70,657的方法制备)(2.2g)和碳酸钾在二甲基甲酰胺(13ml)中的混合物搅拌10分钟直到所有起始物料反应。在所得到的棕色混合物中滴加吡咯烷(1.65mg,过量),产生放热反应。真空除去溶剂,残余物用乙酸乙酯(3×50ml)提取,用盐水洗涤。将有机相干燥(MgSO4),真空除去溶剂。棕色残余物经中压反相C18硅胶色谱法(使用在0.1%含水三氟乙酸中的30%乙腈作洗脱剂),得到标题化合物,为米色固体(1g)。 1H NMR(360MHz,DMSO-d6)δ1.61(4H,brs),2.26-2.30(5H,m),2.66(1H,d,J=14.0Hz),2.83-2.87(1H,brd),3.02(1H,d,J=13.5Hz),3.15(1H,d,J=13.5Hz),3.23(1H,d,J=14.0Hz),3.37(1H,d,J=3.0Hz),3.42-3.47(1H,m),3.57-3.60(2H.m),4.17-4.24(1H,m),4.32(1H,d,J=3.0Hz),4.79(1H,t,J=5.5Hz),4.89(1H,t,J=5.5Hz),7.08(2H,t,J=9.0Hz),7.32(2H,s),7.56(2H,mc),7.85(1H,s),9.61(1H,s),9.65(1H,s).MS(Cl+)m/z633(M++1),454(50%).
实施例93
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉
将在无水四氢呋喃中的实施例88的化合物(200mg)用二苄基氧基二乙氨基膦(200mg)和四唑(100mg)处理。将反应溶液搅拌2小时,再用100mg二苄基氧基二乙基氨基膀处理,1小时后用四唑(100mg)处理。再搅拌1小时后,加入4-甲基吗啉-N-氧化物(1.0g),搅拌16小时。将反应溶液倒入碳酸钾溶液,用乙酸乙酯提取。将有机层干燥(MgSO4)、过滤,蒸发和用色谱法(硅胶,使用甲醇/二氯甲烷(4∶96)作洗脱剂)纯化得到油状物。将其溶解于甲醇(2ml)中,加入甲酸铵(100mg)和氢氧化钯(载于碳,20%)。反应混合物回流加热1小时,然后过滤,蒸发和由乙腈/水中冻干得到标题化合物的铵盐(93mg); 1H NMR(360MHz,D6-DMSO)δ11.29(1H,s),7.85(1H,s),7.53(2H,s),7.36(2H,m),7.06(2H,t,J=7.2Hz),4.96(1H,t,J=5.4Hz),4.34(1H,d,J=3.6Hz),4.29(1H,t,J=11.2Hz),3.92-3.85(1H,m),3.68-3.63(1H,m),3.62-3.55(1H,m),3.49(1H,d,J=3.6Hz),3.38(1H,d,J=14.4Hz),2.82-2.79(1H,m),2.77(1H,d,J=14.4Hz),2.41-2.35(1H,m);MS(ES+)631(M+H.
实施例94
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉
采用实施例93的方法,由实施例89的化合物制备标题化合物的铵盐。1H NMR(250MHz,D6-DMSO+0.1%TFA)δ8.74(1H,s),7.95(1H,s),7.68(2H,宽s),7.54(2H,s),7.30(2H,t,J=8.7Hz),5.16(1H,dd,J=7Hz和5Hz),4.72(1H,d,J=1Hz),4.66(1H,d,J=1Hz),4.42(1H,t,J=11Hz),3.95-4.27(3H,m),3.72(1H,d,J=11Hz)和3.41-3.55(1H,m).
实施例95
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)-3-(S)-苯基-2-(R)-(1-(S)-(3-(三氟甲基)苯基)-2-羟基乙氧基)吗啉
按照实施例88中所述的方法,由说明30的化合物制备。MS(Cl+)m/z465(M+1)+,71%)。
实施例96
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟基乙氧基)-3-(S)-苯基吗啉
根据实施例88中所述的方法,使说明27的化合物(600mg)、N-甲酯基-2-氯乙酰氨基腙(271mg)和碳酸钾(258mg)在二甲基甲酰胺中反应。从乙醚/己烷中重结晶,得到白色固体产物(220mg,30%)。1H NMR(360MHz,DMSO-d6)δ2.38(1H,m),2.78(1H,d,J=14.0Hz),2.84(1H,s),3.38-3.39(2H,m),3.45(1H,d,J=14.0Hz),3.50(1H,d,J=3.0Hz),3.56(1H,d,J=11.0Hz),4.26(1H,t,J=11.0Hz),4.34(1H,d,J=3.0Hz),4.68(1H,t,J=6.0Hz),4.85(1H,t,J=6.0Hz),6.40(1H,d,J=9.0Hz),6.96(1H,s),7.33(3H,m),7.36(1H,d,J=9.0Hz),7.49(2H,m).MS(Cl+)m/z483(M+1,20%).
实施例97
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-苯基吗啉
采用实施例93的方法,由实施例96的化合物制备标题化合物的铵盐。1H NMR(360MHz,DMSO-d6)δ11.29(1H,s),7.49-7.29(5H,m),7.38(1H,d,J=10.8Hz),6.96(1H,s),6.45(1H,d,J=10.8Hz),4.84(1H,d,J=7.2Hz),4.34(1H,d,J=3.6Hz),4.28(1H,t,J=10.8Hz),3.80-3.76(1H,m),3.57(1H,d,J=3.6Hz),3.57-3.49(2H,m),3.47(1H,d,J=14.4Hz),2.83-2.76(1H,m),2.78(1H,d,J-14.4Hz),2.46-2.36(1H,m).
实施例98
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟基乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-苯基吗啉
根据实施例88的方法,使说明17的化合物与N-甲酯基-2-氯乙酰氨基腙(说明23)和碳酸钾反应,得到白色固体产物。1H NMR(360MHz,DMSO-d6)δ2.42(1H,dt,J=12.0,3.5Hz),2.76(1H,d,J=14.0Hz),2.83(1H,d,J=12.0Hz),3.39(1H,d,J=14.0Hz),3.44-3.47(1H,m),3.50(1H,d,J=3.0Hz),3.60(2H,m),4.22-4.28(1H,m),4.40(1H,d,J=3.0Hz),4.77-4.83(2H,m),7.25-7.34(3H,m),7.41(2H,s),7.48-7.50(2H,m),7.82(1H,s),11.20(1H,s),11.25(1H,s),MS(Cl)m/z533(M+1,30%)434(20),117(100).
实施例99
2(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-苯基吗啉
采用实施例93的方法,由实施例88的化合物制备标题化合物的铵盐。 1H NMR(360MHz,d6-DMSO)δ11.26(1H,s),7.83(1H,s),7.48-7.24(7H,m),4.95(1H,t,J=5.4),4.39(1H,d,J=3.6),4.29(1H,t,J=11.2),3.92-3.89(1H,m),3.60-3.64(1H,m),3.55-3.59(1H,m),3.48(1H,d,J=3.6),3.42(1H,d,J=14.4),2.84-2.79(1H,m),2.78(1H,d,J=14.4),2.42(1H,m)。HPLC,用Zorbax Z-Ph(250×4.6mm i.d.5μM)柱,用在含0.2%三乙胺的25mM KH2PO4中的40%乙腈(pH3.0)洗脱,流速1ml/分钟,UV检测器210nM。保留时间4.68分钟。
实施例100
3-(S)-苯基-4-(1,2,4-三唑-3-基)-2-(R)-(1-(S)-3-(三氟甲基)苯基)-2-羟基乙氧基)吗啉
按照实施例89中所述的方法,由说明30的化合物制备标题化合物的盐酸盐。MS(ES+)m/z449(M+1)+100%)。
表2(续) | ||||
实施例序号 | R1 | R4 | -NR7R8 | 数据 |
32 | CF3 | H | -NH(CH2)2OCH3 | 1H NMR(250MHz,CDCl3)δ1.45(3H,d,J=6.5Hz),2.50(1H,dt,J=3.4,12.0Hz),2.79-2.87(3H,m),3.16(1H,d,J=14.0Hz),3.35(3H,s),3.41(1H,d,J=2.7Hz),3.51-3.67(3H,m),3.75-3.87(3H,m),4.24(1H,brt),4.36(1H,d,J=2.7Hz),4.87(1H,q,J=6.5Hz),7.16(2H,s),7.33-7.39(3H,m),7.46(2H,m),7.61(1H,s).MS(ES)m/z588(M++1,100%). |
33 | CF3 | H | -N(CH3)(CH2)2OCH3 | 1H NMR(250MHz,CDCl3)δ1.43(3H,d,J=6.5Hz),2.24(3H,s),2.58(2H,t,J=3.5Hz),2.65(1H,brt),2.94(1H,brd),3.29(1H,d,J=9.5Hz),3.36(3H,s),3.43(1H,d,J=2.0Hz),3.49(2H,t,J=3.5Hz),3.56(2H,s),3.63(1H,dd,J=1.3,7.75Hz),3.80(1H,d,J=9.5Hz),4.23(1H,dt,J=15,8.0Hz),4.36(1H,d,J=2.0Hz),4.84(1H,q,J=6.5Hz),7.15(2H,s),7.32-7.36(3H,m),7.45(2H,m),7.61(1H,s).MS(ES)m/z602(M++1,100%). |
34 | CF3 | H | -N[CH(CH3)2](CH2)2OCH3 | 1H NMR(250MHz,CDCl3)δ0.99(3H,d,J=6.5Hz),1.02(3H,d,J=6.5Hz),1.43(3H,d,J=6.5Hz),2.64-2.71(3H,m),2.91-2.98(2H,m),3.26(1H,d,J=14.0Hz),3.39(6H,s),3.43(1H,d,J=2.6Hz),3.49-3.81(3H,m),4.22(1H,dt,J=2.0,11.5Hz),4.35(1H,d,J=2.6Hz),4.86(1H,q,J=6.5Hz),7.14(2H,s),7.31-7.35(3H,m),7.45(2H,m),7.61(1H,s).MS(ES)m/z630(M++1,100%). |
表2(续) | ||||
实施例序号 | R1 | R4 | -NR7R8 | 数据 |
48 | CF3 | F | -N[CH(CH3)2]CH2CH2OH | 1H NMR(250MHz,CDCl3)δ7.64(1H,s),7.49(2H,brs),7.27(2H,s),7.06(2H,t,J=8.7Hz),4.86(1H,q,J=6.5Hz),4.31(1H,d,J=2.7Hz),4.14(1H,m),3.76-3.43(7H,m),3.17(1H,d,J=13.8Hz),3.04-2.89(2H,m),2.75-2.53(3H,m),1.43(3H,d,J=6.5Hz),1.5(6H,d,J=6.6Hz).M/Sm/z634(MH+). |
49 | CF3 | F | -N(CH3)C(CH3)3 | 1H NMR(25DMHz,CDCl3)δ7.63(1H,s),7.45(2H,brs),7.15(2H,s),7.05(2H,t,J=8.74Hz),4.87(1H,q,J=6.58Hz),4.31(1H,d,J=2.79Hz),4.23(1H,m),3.75(1H,d,J=14.16Hz),3.64(1H,m),3.54(1H,d,J=14.40Hz),3.48(1H,d,J=14.40Hz),3.46(1H,d,J=2.79Hz),3.32(1H,d,J=14.16Hz),2.94(1H,d,J=11.73Hz),2.65(1H,td,J=10.33,3.51Hz),2.09(3H,s),1.45(3H,d,J=6.58Hz),1.15(9H,s).M/S(ES+)618. |
50 | CF3 | F | 2,5-二甲基吡咯烷子基 | MS(ES+)m/z629(MH+,100%) |
51 | CF3 | F | -N(CH2CH3)2 | 1H NMR(250MHz,CDCl3)δ1.00(6H,t,J=7.2Hz),1.44(3H,d,J=6.6Hz),2.46-2.55(4H,m),2.62(1H,m),2.91(1H,d,J=11.7Hz),3.27(1H,d,J=14.0Hz),3.46(1H,d,J=2.7Hz),3.56(2H,s),3.62(1H,m),3.77(1H,d,J=14.1Hz),4.24(1H,m),4.31(1H,d,J=2.8Hz),4.86(1H,m),7.05(2H,t,J=8.7Hz),7.15(2H,s),7.47(2H,brs),7.64(1H,s).MS(ES+)m/z603 |
52 | CF3 | H | -N(CH3)2 | 元素分析 C26H29N5O2F6HCl.H2O:C,51.03;H,5.27;N,11.44.实测值C,51.21;H,5.24;N,11.10%.M.pt.127-129℃. |
如下实施例举例说明本发明的药物组合物。实施例103A含有1-25mg化合物的片剂
量,mg式(I)化合物 1.0 2.0 25.0微晶纤维素 20.0 20.0 20.0改性的食用玉米淀粉 20.0 20.0 20.0乳糖 58.5 57.5 34.5硬脂酸镁 0.5 0.5 0.5实施例103B含26-100mg化合物的片剂
量mg式(I)化合物 26.0 50.0 100.0微晶纤维素 80.0 80.0 80.0改性的食用玉米淀粉 80.0 80.0 80.0乳糖 213.5 189.5 139.5硬脂酸镁 0.5 0.5 0.5
将式(I)化合物、纤维素、乳糖和一部分玉米淀粉混合,用10%玉米淀粉糊状物造粒。将得到的颗粒筛分、干燥并与其余的玉米淀粉和硬脂酸镁混合。得到的颗粒随后被压成每片含1.0mg、2.0mg、25.0mg、26.0mg、50.0mg和100mg活性化合物的片剂。实施例104胃肠外注射剂
量式(I)化合物 1~100mg柠檬酸单水合物 0.75mg磷酸钠 4.5mg氯化钠 9mg注射用水 至10ml
将磷酸钠、柠檬酸单水合物和氯化钠溶解于一部分水中,将式(I)化合物溶解或悬浮于溶液中,配成所需体积。实施例105局部制备
量式(I)化合物 1-10g乳化石蜡 30g液体石蜡 20g白色软石蜡 至100g
将白色软石蜡加热熔融,加入液体石蜡和乳化石蜡,搅拌直到溶解。加入式(I)化合物,持续搅拌直到分散。将混合物随后冷却至固体。实施例106A-(表面活性剂)注射制剂式(I)化合物 最高达10mg/kgTween 80TM 最高达2.5%
[在5%含水甘露醇(等渗)中]
将式(I)化合物直接溶解于商业上可得到的Tween 80TM(聚氧乙烯山梨糖醇单油酸酯)和5%含水甘露醇(等渗)的溶液中。实施例106B-(乳剂)注射制剂式(I)化合物 最高达30mg/mlIntralipidTM(10-20%)
将式(I)化合物直接溶解于商业上可得到的IntralipidTM(10或20%)中形成乳剂。实施例106C-另一种(乳剂)注射制剂
量式(I)化合物 0.1-10mg豆油 100mg卵磷脂 6mg甘油 22mg注射用水 至1ml
将所有物料消毒,除去致热原。将式(I)化合物溶解于豆油中,通过将该溶液与卵磷脂、甘油和水混合成乳剂,将乳剂密封在无菌小瓶中。
Claims (26)
R1是氢,卤素,C1-6烷基,C1-6烷氧基,CF3,NO2,CN,SRa,SORa,SO2Ra,CO2Ra,CONRaRb,C2-6链烯基,C2-6炔基或被C1-4烷氧基取代的C1-4烷基,其中Ra和Rb各自独立地表示氢或C1-4烷基;
R2是氢,卤素,C1-6烷基,被C1-4烷氧基取代的C1-6烷氧基或CF3;
R3是氢,卤素或CF3;
R4是氢,卤素,C1-6烷基,C1-6烷氧基,CF3,NO2,CN,SRa,SORa,SO2Ra,CO2Ra,CONRaRb,C2-6链烯基,C2-6炔基或被C1-4烷氧基取代的C1-4烷基,其中Ra和Rb各自独立地表示氢或C1-4烷基;
R5是氢,卤素,C1-6烷基,被C1-4烷氧基取代的C1-6烷氧基或CF3;
R6是含2或3个氮原子的5元或6元杂环,其任选地被=O,=S或C1-4烷基取代,和任选地被式ZNR7R8基团取代,其中
Z是C1-6亚烷基或C3-6亚环烷基;
R7是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被C1-4烷氧基或羟基取代的C2-4烷基;
R8是氢,C1-4烷基,C3-7环烷基或C3-7环烷基C1-4烷基,或被一个或两个选自C1-4烷氧基,羟基或含一个或两个选自N,O和S杂原子的4,5或6元脂族杂环取代基取代的C2-4烷基;
或者R7,R8和与它们相连的氮原子一起形成4至7个环原子的脂族杂环,其任选地被一个或两个选自羟基或任选被C1-4烷氧基或羟基取代的C1-4烷基取代,和其任选地含有双键,该环可以任选地含有氧或硫环原子,基团S(O)或S(O)2或将是NH或NRc部分之部分的第二个氮原子,其中Rc是任选被羟基或C1-4烷氧基取代的C1-4烷基;
或者R7,R8与和它们相连的氮原子一起形成6至12个环原子的非芳族氮杂二环系;
或者Z,R7和与它们相连的氮原子形成可以任选地含有氧环原子的4至7个环原子的脂族杂环;
R9a和R9b各自独立地是氢或C1-4烷基,或者R9a和R9b与和它们连接的碳原子连接在一起形成C5-7环:
X是任选地被氧代取代的1至4个碳原子的亚烷基链;和
Y是任选地被羟基取代的C1-4烷基;
其前提条件是如果Y是C1-4烷基,R6至少被如上述所定义的式ZNR7R8基团取代。
2.根据权利要求1的式(Ia)化合物或其可药用盐或前药:其中A1是氟或CF3;
A2是氟或CF3;
A3是氟或氢;和X、Y和R6如权利要求1中定义。
3.根据权利要求1或2的化合物或其可药用盐或前药,其中Y表示被羟基取代的C1-4烷基。
4.根据权利要求1或2的化合物或其可药用盐或前药,其中Y表示C1-4烷基,其前提条件是R6至少被如权利要求1中定义的式ZNR7R8的基团取代。
9.选自下列的化合物或其可药用盐或前药:
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-5-(N,N-二甲氨基)甲基-2-氧代-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-5-(N,N-二甲氨基)甲基-2-氧代-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(4-羟基哌啶子基)甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
3-(S)-(4-氟代苯基)-2(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(2,3-二氢-5-吗啉代甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-吗啉代甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
4-(5-氮杂环丁烷基甲基-2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(4-氟代苯基)吗啉:
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(N-甲基哌嗪基)甲基-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-5-(N-(2-吗啉代乙基)氨甲基)-2-氧代-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-2-氧代-5-(N-(2-吡咯烷子基乙基)氨甲基)-1,3-咪唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二甲基氨基)甲基-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(N-(N′-甲基氨基乙基)-1,2,4-三唑-3-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(N-甲基氨基甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-氨基甲基)-1,2,3-三唑-4-基)甲基-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-吡咯烷子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(氮杂环丁烷基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基)-4-(5-(吡咯烷子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-氟-5-(三氟甲基)苯基)乙氧基-4-(5-(吗啉代甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(N,N-二甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(R)-(3-(三氟甲基)苯基)乙氧基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(N′-甲基哌嗪子基甲基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-(1-(2-吡咯烷子基乙基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-苯基-4-(2-(2-吡咯烷子基乙基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(吗啉代甲基)-1,2,3-三唑-4-基)甲基吗啉;
4-(5-(氮杂环丁烷基甲基)-1,2,3-三唑-4-基)甲基-2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟代苯基)-4-(5-(吡咯啉子基(pyrrolino)甲基)-1,2,3-三唑-4-基)甲基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(二(甲氧基乙基)氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(2-氯-5-吗啉代甲基-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,3-咪唑-4-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N,N-二甲基氨基甲基)-1,2,4-三唑-3-基)甲基-3-(S)-(4-氟代苯基)吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N-(2,2-二甲氧基乙基)-N-甲基氨基甲基)-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(2-甲氧基乙基)氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-(2-甲氧基乙基)-N-甲基)氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-异丙基-N-(2-甲氧基乙基)氨基甲基--1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-(N-环丙基-N-(2-甲氧基乙基)氨基甲基--1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N,N-二丁基氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(R)-(3,5-二(三氟甲基)苯基)乙氧基)-4-(5-N,N-二异丙基氨基甲基-1,2,3-三唑-4-基)甲基-3-(S)-苯基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-(4-氟代苯基)-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟乙氧基)吗啉;
4-(2,3-二氢-2-氧代-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-2-氧代-5-吡咯烷子基甲基-1,3-咪唑-4-基)甲基-2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-(4-氟代苯基)吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)-3-(S)-苯基-2-(R)-(1-(S)-(3-(三氟甲基)苯基)-2-羟乙氧基)吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-(3-氟-5-(三氟甲基)苯基)-2-羟乙氧基)-3-(S)-苯基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-羟乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)-3-(S)-苯基甲基吗啉;
3-(S)-苯基-4-(1,2,4-三唑-3-基)-2-(R)-(1-(S)-3-(三氟甲基)苯基)-2-羟乙氧基)吗啉。
14.选自下列的化合物或其可药用盐:
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-(4-氟代苯基)-4-(1,2,4-三唑-3-基)甲基吗啉;
4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-2-(R)-(1-(S)-3-氟-5-(三氟甲基)苯基)-2-磷酰氧基乙氧基)-3-(S)-苯基吗啉;
2-(R)-(1-(S)-(3,5-二(三氟甲基)苯基)-2-磷酰氧基乙氧基)-4-(2,3-二氢-3-氧代-1,2,4-三唑-5-基)甲基-3-(S)-苯基吗啉。
16.根据前述任何权利要求的在治疗中的应用的化合物。
17.含有权利要求1至15中任一权项的化合物和与之相结合的可药用载体或赋形剂的药物组合物。
18.一种治疗或预防与速激肽过量有关的生理疾病的方法,该方法包含给需要所述防治作用的患者施用可使速激肽降低的剂量的权利要求1化合物,或其盐或前药,或含有权利要求1的化合物或其盐或前药的组合物。
19.根据权利要求18的方法,用于治疗或预防疼痛或炎症。
20.根据权利要求18的方法,用于治疗或预防偏头痛。
21.根据权利要求18的方法,用于治疗或预防呕吐。
22.根据权利要求1的化合物在制备用于治疗与速激肽过量有关的生理疾病的药物中的应用。
23.根据权利要求1的化合物在制备用于治疗疼痛或炎症的药物中的应用。
24.根据权利要求1的化合物在制备用于治疗偏头痛的药物中的应用。
25.根据权利要求1的化合物在制备用于治疗呕吐的药物中的应用。
26.制备根据权利要求1的式(I)化合物的方法,该方法包含:
(A)将式(II)化合物与式(III)化合物反应:其中R1、R2、R3、R4、R5和Y如式(1)中所定义,
X1-X-R6a (III)其中X如权利要求1中定义,R6a是如权利要求1中定义的式R6基团或其前体和X1是离去基团如溴或氯;和,如果R6a是前体基团,将其转化成基团R6;或
(C)其中R6表示被CH2NR7R8取代的1,2,3-三唑-4-基和X是-CH2-,通过将式(V)化合物:与式NHR7R8的胺反应,或者
(D)其中R6表示取代的或未取代的1,3,5-三嗪,通过将式(VI)化合物:与取代或未取代的1,3,5-三嗪反应;或者
(E)其中R6表示取代的或未取代的1,2,4-三嗪,通过将式(VII)化合物与式(VIII)的二羧基化合物反应:其中R35表示H或适当的取代基如ZNR7R8;或
(F)其中R6表示取代的1,2,4-三唑基,通过将式(II)化合物与式(IX)化合物反应:其中X如权利要求1中定义,Hal是卤原子,和R18是H,CONH2或OCH3(在反应条件下其被转化成氧代取代基),反应在碱存在下进行,如果需要的话接着转化成式(I)化合物;或
(H)其中R6被ZNR7R8基团取代,将式(XII)化合物反应:其中每个LG可以相同或不同,可以是离去基团,和X和Z如权利要求1定义,接着通过将得到的化合物与NHR7R8胺反应来完成ZNR7R8部分;或者
(J)通过式(I)化合物的相互转化变成另一式(I)化合物;
如果需要的话,在每种方法之后除去任何存在的保护基;
和当得到的式(I)化合物是对映体或非对映异构体的混合物时,任选地拆分该混合物得到所需对映体;
和/或,如果需要,将得到的式(I)化合物或其盐转化成其可药用盐或前药。
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GB9326480.2 | 1993-12-29 | ||
GB9326480A GB9326480D0 (en) | 1993-12-29 | 1993-12-29 | Therapeutic agents |
GB9407189.1 | 1994-04-12 | ||
GB9407189A GB9407189D0 (en) | 1994-04-12 | 1994-04-12 | Therapeutic agents |
GB9408065A GB9408065D0 (en) | 1994-04-22 | 1994-04-22 | Therapeutic agents |
GB9408065.2 | 1994-04-22 | ||
GB9416428A GB9416428D0 (en) | 1994-08-15 | 1994-08-15 | Therapeutic agents |
GB9416428.2 | 1994-08-15 |
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