CN1235870C - 苯基杂烷基胺衍生物的新应用 - Google Patents
苯基杂烷基胺衍生物的新应用 Download PDFInfo
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- CN1235870C CN1235870C CNB018054897A CN01805489A CN1235870C CN 1235870 C CN1235870 C CN 1235870C CN B018054897 A CNB018054897 A CN B018054897A CN 01805489 A CN01805489 A CN 01805489A CN 1235870 C CN1235870 C CN 1235870C
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- Prior art keywords
- benzonitrile
- chloro
- amino
- oxygen base
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 phenyl hetero alkylamine Chemical class 0.000 title claims description 142
- 150000001875 compounds Chemical class 0.000 claims abstract description 269
- 238000000034 method Methods 0.000 claims abstract description 120
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 238000011282 treatment Methods 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 33
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims abstract description 28
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 13
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 10
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 381
- 229910052760 oxygen Inorganic materials 0.000 claims description 280
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 262
- 239000001301 oxygen Substances 0.000 claims description 262
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 77
- 229910052731 fluorine Inorganic materials 0.000 claims description 68
- 239000011737 fluorine Substances 0.000 claims description 67
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 64
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 230000004048 modification Effects 0.000 claims description 33
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 21
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
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- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 6
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
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- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical compound CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 claims description 5
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- 125000004076 pyridyl group Chemical group 0.000 claims description 5
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 4
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 claims description 4
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims description 2
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 2
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 113
- 239000007787 solid Substances 0.000 description 88
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 238000003756 stirring Methods 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 41
- 238000001704 evaporation Methods 0.000 description 40
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 40
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- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 38
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- 238000000605 extraction Methods 0.000 description 28
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- 150000003577 thiophenes Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940108519 trasylol Drugs 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- WTFFOOAJSDVASL-UHFFFAOYSA-N tributyl(pyrimidin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CC=N1 WTFFOOAJSDVASL-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- VJCHUDDPWPQOLH-UHFFFAOYSA-N trimethyl(1,3-thiazol-2-yl)silane Chemical compound C[Si](C)(C)C1=NC=CS1 VJCHUDDPWPQOLH-UHFFFAOYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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Abstract
本发明公开了式(I)化合物、及其可药用盐、对映体或外消旋体在制备用于治疗或预防可受益于一氧化氮合酶活性抑制的疾病或病症的药物中的应用,其中R1、R2、X、Y、V、W和Z如说明书中所定义。本发明还公开了一些新的式(Ia)化合物、及其可药用盐、对映体或外消旋体;及其制备方法,含有它们的组合物,和它们在治疗中的应用。式(I)和(Ia)化合物是酶一氧化氮合酶抑制剂,并因此可用于治疗或预防炎性疾病。
Description
发明领域
本发明涉及苯基杂烷基胺衍生物作为酶一氧化氮合酶抑制剂的应用。本发明还公开了一些新的苯基杂烷基胺衍生物及其制备方法,含有它们的组合物及其在治疗中的应用。
发明背景
在哺乳动物细胞中,通过特定一氧化氮合酶(NOS)的作用由L-精氨酸产生一氧化氮。这些酶属于两个不同类别—组成型NOS(cNOS)和诱导型NOS(iNOS)。目前已经鉴定出了两种组成型NOS和一种诱导型NOS。在组成型NOS当中,内皮酶(ecNOS)涉及平滑肌松弛和血压以及血流的调控,而神经元酶(ncNOS)起神经递质的作用,并且似乎涉及多种生物功能例如脑缺血的调控。已表明诱导型NOS特别涉及炎性疾病的发病机理。因此,这些酶的调控应当具有很大的治疗多种疾病的可能性(J.E.Macdonald,Ann.Rep.Med.Chem.,1996,31,221-230)。
人们已经付出了很多努力来确定可用作酶一氧化氮合酶的一种或多种同功型的特异性抑制剂的化合物。这样的化合物在治疗中的应用也已经广泛地在专利中要求保护。
专利申请EP 0 273 658公开了下式化合物
其中Ar代表任选被卤素、C1-4烷基、C1-3烷氧基或CF3取代的苯基,或任选取代的萘基;R1代表C5-7环烷基、噻吩基、卤代噻吩基、(C1-4烷基)-取代的噻吩基、呋喃基、吡啶基或噻唑基;且R2和R3分别独立地为H或甲基。所述化合物是血清素和去甲肾上腺素摄取的有效选择性抑制剂,因此申请人声称其可用于治疗人类疾病例如焦虑症、抑郁症和肥胖。
U.S.专利4,314,081公开了下式化合物
其中Ar代表任选被卤素、C1-4烷基、C1-3烷氧基或C3-4链烯基取代的苯基;或者Ar代表萘基;且R1、R2和R3分别独立地为H或甲基。所述化合物是血清素和去甲肾上腺素摄取的有效选择性抑制剂,因此申请人声称其可用于治疗人类疾病例如抑郁症和肥胖。
专利申请WO 92/19210公开了下式化合物
其中Ar1和Ar2独立地代表任选被不同取代基取代的苯基,条件是Ar1和Ar2当中至少有一个被至少一个卤素原子取代;且R1和R2分别独立地为H或C1-4烷基。申请人声称所述化合物可用于成像脑中的神经递质再摄取系统。
专利申请DE 29 07 217公开了下式化合物
其中Ar1代表被硝基取代的苯基,所述苯基任选被选自C1、Br、CF3、Me或OMe的另一个取代基取代;Ar2代表任选被Cl、Br或F取代的苯基;R1代表H或C1-5烷基;且R2代表C1-5烷基。申请人声称这些化合物可用于治疗饮食障碍和抑郁症。
专利申请GB 2 060 620公开了下式化合物
其中Ar1代表任选被C1-6烷基、C2-6链烯基、CF3、卤素、硝基、氨基或酰基氨基取代的苯基;Ar代表被至少一个选自C1-6烷基、C1-6烷氧基、CF3、硝基或氨基的基团取代的苯基;R1、R2和R4独立地代表H或C1-6烷基;且R3代表H、C1-6烷基或苄基。申请人声称这些化合物可用作抗抑郁剂。
专利申请GB 2 060 621公开了下式化合物
其中Ar代表任选被C1-6烷基或卤素取代的苯基;Ar1代表被NO2、氨基或酰基氨基取代的苯基;R1和R2独立地代表H或C1-6烷基。申请人声称这些化合物可用作抗抑郁剂。
专利申请EP 318 727公开了下式化合物
其中R1可代表任选取代的烷基或环烷基,且R2可代表任选取代的苯基。这些化合物阻止脑细胞中的钙超载,并因此可用于治疗缺氧症、偏头痛、局部缺血和癫痫。
专利申请EP 399 504公开了下式化合物
其中Ar代表任选取代的苯基;R可代表任选取代的苯基;且R1和R2可代表任选取代的烷基或环烷基。这些化合物阻止脑细胞中的钙超载,并因此可用于治疗缺氧症、偏头痛、局部缺血和癫痫。
专利申请EP 576 766公开了下式化合物
其中Ar代表任选取代的苯基;R可代表任选取代的苯基;且R1和R2可代表任选取代的烷基或环烷基;或者基团NR1R2代表任选被取代的5-7元环。这些化合物阻止脑细胞中的钙超载,并因此可用于治疗缺氧症、外伤性损伤、神经变性疾病、偏头痛、局部缺血和癫痫。
专利申请EP 571 685公开了类似于EP 576 766的化合物,但是其中Ar代表任选取代的呋喃基、噻吩基或吡咯基。
本发明涉及下述令人惊奇的发现,即一组苯基杂烷基胺衍生物,包括在一些上述背景技术文件的一般范围内的某些化合物是酶一氧化氮合酶的抑制剂。
发明内容
本发明提供了式(I)化合物或其可药用盐、对映体或外消旋体
其中:
X和Y独立地代表C1-4烷基、C1-4烷氧基、卤素、CF3、OCF3、CN、C≡CH、S(O)mCH3、S(O)pCF3、NO2或NHCHO;
m和p独立地代表整数0、1或2;
Z代表氢或氟;
V代表O;
W代表苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环;所述苯基或芳杂环可任选被一个或多个独立地选自卤素、C1-4烷基、C1-4烷氧基、OH、CN、NO2或NR4R5的取代基取代;所述烷基或烷氧基可任选被一个或多个氟原子取代;
R1和R2独立地代表H、C1-4烷基或C3-6环烷基;所述烷基任选被下列基团取代:C1-4烷氧基、卤素、羟基、NR6R7、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3、CN或NO2取代;
或者基团NR1R2一起代表任选还包含一个选自O、S或NR8的另外的杂原子的4-8元饱和氮杂环;所述环任选被C1-4烷基、C1-4烷氧基或OH取代;所述烷基任选被C1-4烷氧基、OH或NR9R10取代;
或者基团NR1R2一起代表任选还包含一个另外的N原子的5元芳族氮杂环的一部分;
R4、R5、R6、R7、R9和R10独立地代表H或C1-4烷基;
R8代表H或C1-6烷基;所述烷基任选被下列基团取代:C1-4烷氧基、OH、NR11R12、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3、CN或NO2取代;
R11和R12独立地代表H或C1-4烷基;
在制备用于治疗或预防可受益于一氧化氮合酶活性被抑制的疾病或病症的药物中的应用。
在另一个方面,本发明提供了式(I)化合物或其可药用盐、对映体或外消旋体在制备用于治疗或预防可受益于一氧化氮合酶诱导同功型活性被抑制的疾病或病症的药物中的应用。
本发明一个更特定的方面提供了式(I)化合物或其可药用盐、对映体或外消旋体在制备用于治疗或预防炎性疾病的药物中的应用。
本发明还提供了治疗可受益于一氧化氮合酶活性被抑制的疾病或病症或者减小所述疾病或病症的危险性的方法,包括给患有或者有危险患有所述疾病或病症的人施用治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体。
此外,本发明还提供了治疗可受益于一氧化氮合酶诱导同功型活性被抑制的疾病或病症或者减小所述疾病或病症的危险性的方法,包括给患有或者有危险患有所述疾病或病症的人施用治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体。
更特别地,本发明还提供了在患有或者有危险患有炎性疾病的人中治疗炎性疾病或者减小炎性疾病危险性的方法,所述方法包括给所述人施用治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体。
在另一个方面,本发明提供了用于治疗或预防可受益于一氧化氮合酶活性抑制的疾病或病症的药物制剂,其中包含治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体和与其混合的可药用助剂、稀释剂或载体。
在另一个优选方面,本发明提供了用于治疗或预防可受益于一氧化氮合酶诱导同功型活性被抑制的疾病或病症的药物制剂,其中包含治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体和与其混合的可药用助剂、稀释剂或载体。
在另一个更特别方面,本发明提供了用于治疗或预防炎性疾病的药物制剂,其中包含治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体和与其混合的可药用助剂、稀释剂或载体。
有利起见,式(I)化合物还可以与另一种药物活性物质联合使用,特别是与环加氧酶诱导同功型(COX-2)抑制剂联合使用。因此,在另一个方面,本发明提供了式(I)化合物或其可药用盐、对映体或外消旋体与COX-2抑制剂相结合在治疗炎症、炎性疾病或炎性相关疾病中的应用。本发明还提供了为患有或者有危险患有所述疾病或病症的人治疗炎症、炎性疾病和炎性相关疾病或者减小其危险性的方法,包括给所述人联合施用治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体与COX-2抑制剂。
在一个优选的实施方案中,X和Y独立地代表Br、Cl、CH3、CF3或CN。X特别优选代表Br、Cl或CF3。Y特别优选代表Cl或CN。
W优选代表含有1-3个独立地选自O、S和N的杂原子的任选取代的5或6元芳杂环。特别优选的实例是其中W代表噻吩基、呋喃基、吡啶基、噻唑基、噁唑基、异噁唑基或嘧啶基的那些。
R1和R2优选独立地代表H或任选被C1-4烷氧基或羟基取代的C1-4烷基。R1和R2更优选独立地代表H或甲基。
下列式(I)化合物及其可药用盐、对映体或外消旋体的应用明确地包括在本发明范围内:
2-(3-氨基-1-苯基丙氧基)-4-氯苄腈;
4-氯-2-(3-(甲基氨基)-1-苯基丙氧基)苄腈;
4-溴-2-[(1R)-3-(甲基氨基)-1-苯基丙氧基]苄腈;
γ-R-(2-溴-5-氯苯氧基)-N-甲基苯丙胺;
4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}苄腈;
4-甲氧基-2-[3-(甲基氨基)-1-苯基氨基-1-苯基丙氧基]苄腈;
4-甲基-2-{[(1R)-3-(甲基氨基)-1-苯基丙基]氧基}苄腈;
R-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺;
S-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺;
2-[[(3R)-3-(2,5-二氯苯氧基)-3-(2-噻吩基)丙基]氨基]乙醇;
4-氯-2-{[(1R)-3-(4-甲基-1-哌嗪基)-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-(4-羟基-1-哌啶基)-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(2-羟基乙基)甲基氨基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-(4-吗啉基)-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3R)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3S)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈;
2-{[(1R)-3-氨基-1-苯基丙基]氧基}-5-氟-4-甲基苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(2-嘧啶基)丙氧基]苄腈;
4-氯-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(2-甲氧基乙基)氨基]丙基}氧基)苄腈;
4-甲氧基-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]-苄腈;
γ-(2-溴-5-氟苯氧基)-N-甲基-苯丙胺;
(R)-γ-(5-溴-2-氯苯氧基)-N-甲基苯丙胺;
(R)-γ-(2-溴-5-硝基苯氧基)-N-甲基苯丙胺;
4-氯-5-氟-2-[[(1R)-3-[(2-甲氧基乙基)氨基]-1-苯基丙基]氧基]-苄腈;
4-氯-2-{[(1R)-3-(环丙基氨基)-1-苯基丙基]氧基}-5-氟苄腈;
4-氯-2-{[(1R)-3-(环丙基氨基)-1-(3-呋喃基)丙基]氧基}-5-氟苄腈;
4-氯-2-{[(1R)-3-(环丙基氨基)-1-(3-噻吩基)丙基]氧基}-5-氟苄腈;
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(苯基)丙基]氧基}-5-氟苄腈;
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(3-呋喃基)丙基]氧基}-5-氟苄腈;
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(3-噻吩基)丙基]氧基}-5-氟苄腈;
4-氯-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-(3-羟基丙基)氨基]丙基]氧基}苄腈;
4-氯-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
4-溴-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-溴-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(3-羟基丙基)氨基]丙基}氧基)苄腈;
4-溴-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-(三氟甲基)苄腈;
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯苄腈;
4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]苄腈;
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯-5-氟苄腈;
γ-[5-氯-2-(三氟甲基)苯氧基]-N-甲基苯丙胺;
2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]-4-(三氟甲基)苄腈;
4-氯-5-氟-2-[[(1R)-3-[[(5-甲基吡嗪基)甲基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(1H-咪唑-2-基甲基)氨基]-1-苯基丙基]氧基]苄腈;
4-氯-2-[[(1R)-3-[[2-(二甲基氨基)乙基]氨基]-1-苯基丙基]氧基]-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(4-吗啉基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-1-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-4-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-苯基丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-苯基丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-1-苯基-3-[(3,3,3-三氟丙基)氨基]丙基]氧基]苄腈;
2-{[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基}-4-氯苄腈;
4-氯-2-{[(1R)-3-(甲基氨基)-1-(2-噻唑基)丙基]氧基}苄腈;
(R)-γ-(2,5-二氯苯氧基)-2-噻唑丙胺;
2-[3-氨基-1-(2-噁唑基)丙氧基]-4-氯苄腈;
γ-(2,5-二氯苯氧基)-2-噁唑丙胺;
2-[[-3-氨基-1-(3-吡啶基)丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(3-吡啶基)丙氧基]苄腈;
γ-[2-氯-5-(三氟甲基)苯氧基]-3-吡啶丙胺;
2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(1,6-二氢-6-氧代-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(6-溴-3-吡啶基)丙氧基]-4-氯苄腈;
2-[[3-氨基-1-(5-异噁唑基)丙基]氧基]-4-氯苄腈;
4-氯-2-[3-[(2-羟基乙基)氨基]-1-(5-异噁唑基)丙氧基]苄腈;
(R)-γ-(2,5-二氯苯氧基)-5-异噁唑丙胺;
(R)-γ-(2,5-二氯苯氧基)-N-甲基-苯丙胺;
(R)-γ-[2-氯-5-(三氟甲基)苯氧基]-N-甲基-苯丙胺;
4-氯-2-[[(1R)-3-(甲基氨基)-1-(2-噻吩基)丙基]氧基]苄腈;
2-[[(1R)-3-氨基-1-(3-呋喃基)丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-甲基氨基)丙基]氧基]-苄腈;
4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-(3-噻吩基)丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-噻吩基)丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟-苄腈;
2-[[(1R)-3-氨基-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟苄腈;
4-氯-2-[3-(甲基氨基)-1-(2-噻唑基)丙氧基]-苄腈;
2-[[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基]-4-氯-5-氟-苄腈;
γ-(2-氯-5-硝基苯氧基)-N-甲基苯丙胺;
(R)-γ-(5-氯-2-硝基苯氧基)-N-甲基苯)丙胺;
4-氯-5-氟-2-{(1R)-3-[(2-氟乙基)氨基]-1-苯基丙基]氧基}苄腈;
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-溴-5-氟苄腈;
3-[[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]氨基]-1-丙醇;
1-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-4-哌啶甲醇;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-2-噻吩甲胺;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-5-甲基-2-呋喃甲胺;
4-氯-2-[[(1R)-1-苯基-3-(1-哌嗪基)丙基]氧基]苄腈;
5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]-4-甲基苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈;
4-氯-2-[[(1R)-3-[(1,1-二甲基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈;
(R)-γ-(2,5-二氯苯氧基)-3-异噁唑丙胺;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)-苄腈;
(R)-γ-[2-氯-5-(三氟甲基)苯氧基]-2-吡啶丙胺;
2-[[(1R)-3-氨基-1-(5-甲基-3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈。
在本文中,除非另有说明,否则术语“C1-4烷基”是指具有1-4个碳原子的直链或支链烷基。这样的基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
术语“C1-6烷基”应当作类似解释。
在本文中,除非另有说明,否则术语“C3-6环烷基”是指具有3-6个碳原子的环烷基。这样的基团的实例包括环丙基、环戊基和环己基。
在本文中,除非另有说明,否则术语“C1-4烷氧基”是指具有1-4个碳原子的直链或支链烷氧基。这样的基团的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基和叔丁氧基。
“任选被一个或多个氟原子取代的C1-4烷基或C1-4烷氧基”的实例包括CF3、CF3CF2、CF3CH2、CH2FCH2、CH3CF2、CF3CH2CH2、OCF3和OCH2CF3。
在本文中,除非另有说明,否则术语“卤素”是指氟、氯、溴和碘。
任选还包含一个选自O、S或N的另外的杂原子的4-8元饱和氮杂环的实例包括吡咯烷、哌啶、哌嗪、吗啉和全氢氮杂。
含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环的实例包括呋喃、噻吩、吡啶、噻唑、咪唑、噁唑、三唑、噁二唑、噻二唑和嘧啶。
含有1-3个独立地选自O、S和N的杂原子的5或6元饱和杂环的实例包括吡咯烷、四氢呋喃、哌啶和哌嗪。
任选还包含一个另外的N原子的5元芳族氮杂环的实例包括吡咯和咪唑。
一些式(I)化合物是新的。因此,本发明另一方面提供了式(Ia)化合物或其可药用盐、对映体或外消旋体
其中:
X和Y独立地代表C1-4烷基、C1-4烷氧基、卤素、CF3、OCF3、CN、C≡CH、S(O)mCH3、S(O)pCF3、NO2或NHCHO;
m和p独立地代表整数0、1或2;
Z代表氢或氟;
V代表O;
W代表苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环;所述苯基或芳杂环可任选被一个或多个独立地选自卤素、C1-4烷基、C1-4烷氧基、OH、CN、NO2或NR4R5的取代基取代;所述烷基或烷氧基可任选被一个或多个氟原子取代;
R1和R2独立地代表H、C1-4烷基或C3-6环烷基;所述烷基任选被下列基团取代:C1-4烷氧基、卤素、羟基、NR6R7、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3、CN或NO2取代;
或者基团NR1R2一起代表任选还包含一个选自O、S或NR8的另外的杂原子的4-8元饱和氮杂环;所述环任选被OH或C1-4烷基取代,所述烷基被C1-4烷氧基、OH或NR9R10取代;
或者基团NR1R2一起代表任选还包含一个另外的N原子的5元芳族氮杂环的一部分;
R4、R5、R6、R7、R9和R10独立地代表H或C1-4烷基;
R8代表H或C1-6烷基;所述烷基任选被下列基团取代:C1-4烷氧基、OH、NR11R12、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3、CN或NO2取代;
R11和R12独立地代表H或C1-4烷基;
条件是:当W代表任选取代的苯基、噻吩基、呋喃基或吡咯基;且R1代表H、C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代时,R2不代表H、C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代;和
条件是:当W代表噻唑基或吡啶基时,Z代表F;或者X和Y当中至少有一个代表CN;或者R1和R2不独立地代表H或CH3。
在另一个方面,本发明涉及式(Ia)化合物,其中X、Y、V、W、Z、R1和R2如上所定义,条件是:当R1是H时,R2不是H、C1-4烷基或苄基;和条件是:当R1代表C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代时,R2不代表C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代。
在一个优选的实施方案中,式(Ia)中的X和Y独立地代表Br、Cl、CH3、CF3或CN。X特别优选代表Br、Cl或CF3。Y特别优选代表Cl或CN。
式(Ia)中的W优选代表含有1-3个独立地选自O、S和N的杂原子的任选取代的5或6元芳杂环。特别优选的实例是其中W代表噻吩基、呋喃基、吡啶基、噻唑基、噁唑基、异噁唑基或嘧啶基的那些。
式(Ia)中的R1和R2优选独立地代表H或任选被C1-4烷氧基或羟基取代的C1-4烷基。R1和R2更优选独立地代表H或甲基。
特别优选的式(Ia)化合物包括:
2-[[(3R)-3-(2,5-二氯苯氧基)-3-(2-噻吩基)丙基]氨基]乙醇;
4-氯-2-{[(1R)-3-(4-羟基-1-哌啶基)-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(2-羟基乙基)甲基氨基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3R)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3S)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(2-嘧啶基)丙氧基]苄腈;
4-氯-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-(3-羟基丙基)氨基]丙基]氧基}苄腈;
4-氯-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
4-溴-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-溴-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(3-羟基丙基)氨基]丙基}氧基)苄腈;
4-溴-5-氟-2-[[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
4-氯-5-氟-2-[[(1R)-3-[[(5-甲基吡嗪基)甲基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(1H-咪唑-2-基甲基)氨基]-1-苯基丙基]氧基]苄腈;
4-氯-2-[[(1R)-3-[[2-(二甲基氨基)乙基]氨基]-1-苯基丙基]氧基]-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(4-吗啉基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-1-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-4-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-苯基丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-苯基丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-1-苯基-3-[(3,3,3-三氟丙基)氨基]丙基]氧基]苄腈;
2-{[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基}-4-氯苄腈;
4-氯-2-{[(1R)-3-(甲基氨基)-1-(2-噻唑基)丙基]氧基}苄腈;
2-[3-氨基-1-(2-噁唑基)丙氧基]-4-氯苄腈;
γ-(2,5-二氯苯氧基)-2-噁唑丙胺;
2-[[3-氨基-1-(3-吡啶基)丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(3-吡啶基)丙氧基]苄腈;
2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(1,6-二氢-6-氧代-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(6-溴-3-吡啶基)丙氧基]-4-氯苄腈;
2-[[3-氨基-1-(5-异噁唑基)丙基]氧基]-4-氯苄腈;
4-氯-2-[3-[(2-羟基乙基)氨基]-1-(5-异噁唑基)丙氧基]苄腈;
(R)-γ-(2,5-二氯苯氧基)-5-异噁唑丙胺;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-噻吩基)丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟-苄腈;
4-氯-2-[3-(甲基氨基)-1-(2-噻唑基)丙氧基]-苄腈;
2-[[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基]-4-氯-5-氟-苄腈;
4-氯-5-氟-2-{[(1R)-3-[(2-氟乙基)氨基]-1-苯基丙基]氧基)苄腈;
3-[[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]氨基]-1-丙醇;
1-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-4-哌啶甲醇;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-2-噻吩甲胺;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-5-甲基-2-呋喃甲胺;
5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]-4-甲基苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈;
4-氯-2-[[(1R)-3-[(1,1-二甲基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈;
(R)-γ-(2,5-二氯苯氧基)-3-异噁唑丙胺;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)-苄腈;
2-[[(1R)-3-氨基-1-(5-甲基-3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈;
和它们的可药用盐、对映体或外消旋体。
本发明还提供了用作药物的式(Ia)化合物或其可药用盐、对映体或外消旋体。
本发明还提供了制备式(Ia)化合物或其可药用盐、对映体或外消旋体的方法,所述方法包括:
(a)将式(II)化合物
其中X、Y、V和Z如式(Ia)中所定义,
与式(III)化合物反应
其中W、R1和R2如式(Ia)中所定义;或者
(b)将式(IV)化合物
其中X、Y和Z如式(Ia)中所定义,且L1是离去基团,
与式(V)化合物反应
其中R1、R2、V和W如式(Ia)中所定义;或者
(c)将式(VI)化合物
其中X、Y、V、W和Z如式(Ia)中所定义,且L2是离去基团,
与式(VII)化合物反应
HNR1R2 (VII)
其中R1和R2如式(Ia)中所定义;或者
(d)将式(II)化合物
其中X、Y、V和Z如式(Ia)中所定义,
与式(VIII)化合物反应
其中R1、R2和W如式(Ia)中所定义,且L3是离去基团;或者
(e)将式(IX)化合物还原
其中X、Y、V、W和Z如式(Ia)中所定义,且G代表通过还原能转化成NR1R2的基团;
需要时将所得式(Ia)化合物或其另一种盐转化成其可药用盐;或者将所得式(Ia)化合物转化成另外的式(Ia)化合物;以及需要时将所得式(Ia)化合物转化成其旋光异构体。
在方法(a)中,使用例如Mitsunobu条件在惰性溶剂例如四氢呋喃中将反应物(II)与(III)偶合在一起。因此,例如,在合适的温度下,通常在0℃-溶剂的沸点温度下,用膦衍生物和偶氮衍生物处理反应物。合适的膦衍生物包括三苯基膦和三丁基膦。合适的偶氮衍生物包括偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯和1,1′-(偶氮二羰基)二哌啶。
在方法(b)中,反应是通过在惰性溶剂中用式(IV)亲电子试剂处理式(V)亲核试剂来进行的。合适的离去基团L1包括卤化物离子,特别是氟化物离子。该反应一般是在非亲核碱例如氢化钠存在下进行的。合适的有机溶剂是例如N-甲基-2-吡咯烷酮、四氢呋喃、C1-4醇和二甲亚砜。该反应一般在0℃-溶剂的沸点温度下进行。
另一选择,在方法(b)中,反应是使用合适的钯源例如乙酸钯(II)在合适的膦配体例如BINAP存在下进行的。
在方法(c)中,胺化反应是通过将(VI)化合物与式(VII)胺在惰性溶剂中进行的。合适的离去基团L2包括磺酸根,三氟磺酸根,甲苯磺酸根,和选自氯化物离子、溴化物离子或碘化物离子的卤化物离子。亲核试剂可以是在碱存在下的伯胺或仲胺。碱可以是过量的胺亲核试剂,或者可以加到反应混合物中的碱添加剂。可能的碱添加剂是金属碳酸盐,尤其是碱金属碳酸盐,金属氧化物和氢氧化物,以及叔胺碱。合适的有机溶剂是例如乙腈、二噁烷、N,N-二甲基甲酰胺、N-甲基-2-吡咯烷酮、四氢呋喃、二甲亚砜、环丁砜和C1-4醇。
在方法(d)中,反应是通过在惰性溶剂中用式(VIII)亲电子试剂处理式(II)亲核试剂来进行的。合适的离去基团L3包括卤化物离子,特别是氯化物离子或溴化物离子。该反应一般是在非亲核碱例如氢化钠存在下进行的。合适的有机溶剂是例如N-甲基-2-吡咯烷酮、四氢呋喃、C1-4醇和二甲亚砜。该反应一般在0℃-溶剂的沸点温度下进行。
在方法(e)中,G优选代表叠氮基(N3)。所需的还原可通过用合适的还原剂例如Sn(II)或三苯基膦处理式(IX)化合物来实现的。优选地,还原剂是三苯基膦,并且该还原在合适的惰性溶剂例如四氢呋喃中进行。
在上述方法中,对于本领域技术人员来说是显而易见的是,可能需要或必须将胺、羟基或其它可能的反应性基团保护起来。合适的保护基以及加上和除去保护基的方法的详细描述可参见标准教科书“Protecting Groups in Organic Synthesis”,2nd Edition(1991),Greene和Wuts。在一个优选的实施方案中,胺基团作为氨基甲酸酯衍生物例如叔丁氧基氨基甲酸酯被保护起来。因此,其中R1是H的式(Ia)化合物可通过将氨基甲酸酯保护基从其中R1是氨基甲酸酯基例如叔丁氧基氨基甲酸酯基的式(Ia)化合物上除去,而方便地制得。除去氨基甲酸酯基可用氯化氢在二噁烷中方便地进行。
本发明包括盐形式、特别是酸加成盐形式的式(Ia)化合物。合适的盐包括用有机酸和无机酸形成的盐。这样的酸加成盐一般是可药用盐,尽管非可药用盐可用于制备和纯化本发明化合物。因此,优选的盐包括与下列酸形成的盐:盐酸、氢溴酸、硫酸、磷酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、琥珀酸、富马酸、马来酸、甲磺酸和苯磺酸。
式(Ia)化合物的盐可通过将游离碱、或其盐、对映体或外消旋体与一或多当量的适当酸反应来形成。该反应可通过在盐不溶于其中的溶剂或介质中或者在盐溶于其中的溶剂中进行,这样的溶剂有例如水、二噁烷、乙醇、四氢呋喃或乙醚,或者在溶剂混合物中进行,溶剂可真空除去或者通过冷冻干燥除去。该反应还可以是置换反应,或者可在离子交换树脂上进行。
一些式(III)、(V)、(VI)、(VIII)和(IX)中间体形成了本发明另一方面。
式(III)化合物可这样制得:将式(IX)化合物
其中R1和R2如式(Ia)中所定义,
与W-M所示有机金属衍生物反应,
其中W如式(Ia)中所定义,且M代表金属残基例如锂或镁卤化物。
式(IX)化合物可这样制得:
(a)将如上所定义的式(II)化合物与式(XI)化合物反应
其中W和G如上所定义;或者
(b)将如上所定义的式(IV)化合物与式(XII)化合物反应
其中V、W和G如上所定义。
式(II)、(IV)、(VII)、(X)、(XI)和(XII)化合物是已知的或者可用已知方法制得。本文的实施例中举例说明了一些这样的方法。其它合适的方法对于本领域技术人员来说是显而易见的。
中间体化合物可以以自身的形式或者以保护的形式使用。保护基及其除去的方法的详细描述可参见Greene和Wuts的标准教科书“Protecting groups in Organic Synthesis”,2nd Edition(1991)。
可使用标准技术将本发明化合物及其中间体从其反应混合物中分离出来,并且如果需要的话可进一步纯化。
式(Ia)化合物可以以对映体形式存在。因此,所有对映体、非对映体、外消旋体及其混合物都包括在本发明范围内。可使用常规技术例如分步结晶或HPLC将各种旋光异构体从化合物的外消旋混合物中分离出来。
中间体化合物也可以以对映体形式存在,并且可作为纯的对映体、非对映体、外消旋体或混合物使用。
式(Ia)化合物、及其可药用盐、对映体和外消旋体都是有用的,因为它们在动物中具有药理活性。特别是,式(I)和(Ia)化合物具有作为酶一氧化氮合酶抑制剂的活性。更特别地,它们是酶一氧化氮合酶诱导同功型的抑制剂,因此预计可用于治疗,例如用作抗炎剂。它们还具有作为酶一氧化氮合酶神经元同功型的抑制剂的用途。
式(I)和(Ia)化合物及其可药用盐、对映体和外消旋体可用于治疗或预防其中一氧化氮合酶的合成或过度合成是致病因素的疾病或病症。特别是,这些化合物可用于治疗包括人在内的哺乳动物中的炎性病症。
可具体提及的病症有:
骨关节炎、类风湿性关节炎、类风湿性脊椎炎、痛风性关节炎和其它关节炎病症、发炎的关节;
湿疹、牛皮癣、皮炎或其它炎性皮肤病症例如晒伤;
炎性眼睛病症,包括眼色素层炎、青光眼和结膜炎;
涉及炎症的肺病症例如哮喘、支气管炎、慢性堵塞性肺病、养鸽者的疾病、农民肺、急性呼吸窘迫综合征;
菌血症、内毒素血症(脓毒性休克)、口疮性溃疡、龈炎、胃灼热(pyresis)、疼痛、脑脊膜炎和胰腺炎;
胃肠道病症,包括炎性肠病、局限性回肠炎、萎缩性胃炎、痘疹状胃炎、溃疡性结肠炎、腹腔疾病、局部回肠炎、消化性溃疡、过敏性肠综合征、回流性食管炎,由于感染例如幽门螺旋杆菌感染所致的胃肠道损伤,或者由于用非甾体抗炎药物治疗所致的胃肠道损伤;和其它与炎症有关的病症。
由于具有作为酶一氧化氮合酶抑制剂的药理活性,这些化合物还可用于治疗和减轻急性疼痛或顽固性炎性疼痛或神经痛或中枢性疼痛。
我们特别关注炎性肠病、类风湿性关节炎、骨关节炎、慢性堵塞性肺病和疼痛。
式(I)和(Ia)化合物及其可药用盐、对映体和外消旋体还可用于治疗或预防除了上述疾病或病症之外的疾病或病症。例如,这些化合物可用于治疗动脉粥样硬化、胞囊纤维变性、与脓毒性和/或中毒性休克有关的低血压,用于治疗免疫系统机能障碍,作为佐药减轻器官移植治疗中的免疫抑制,用于控制糖尿病发作,用于维持糖尿病中的胰腺功能,用于治疗与糖尿病有关的血管并发症,和用于与细胞因子例如TNF或白介素进行联合治疗。
式(I)和(Ia)化合物还可用于治疗缺氧,例如治疗心搏停止和中风中的缺氧,神经变性疾病,包括疾病例如局部缺血、缺氧、低血糖、癫痫、和外伤(例如脊髓和头部损伤)中的神经变性和/或神经坏死,高压氧惊厥和中毒,痴呆例如早老性痴呆,阿尔茨海默氏病和与爱滋病有关的痴呆,西登哈姆氏舞蹈病,帕金森氏病,特雷特氏综合征,亨廷顿氏舞蹈病,肌萎缩性侧索硬化,多发性硬化,科尔萨科夫病,与脑颅病有关的低能,睡眠障碍,精神分裂症,孤独症,季节性情感性精神病,时差反应和脓毒性休克。预计式(I)和(Ia)化合物还在下列方面表现出活性:预防和逆转药物成瘾或耐受,例如对鸦片制剂和二氮杂药物耐受,治疗偏头痛和其它血管性头痛、神经原性炎症,治疗胃肠道能动性障碍,癌症和引导分娩。
我们特别关注中风、阿尔茨海默氏病、帕金森氏病、多发性硬化、精神分裂症、偏头痛、癌症和脓毒性休克。
预防与以前已经发作过疾病或病症或者认为患该疾病或病症的危险性增加了的人的治疗特别有关。有患上特定疾病或病症的危险的人包括具有该疾病或病症的家族史的人,或已通过基因测试或筛选确定了特别易于发生该疾病或病症的人。
对于上述治疗适应征,给药剂量当然随着所用的化合物、给药方式和所需的治疗而变。然而,一般情况下,当化合物在固体剂型中以1mg-2000mg/天的剂量施用时能获得满意的结果。
式(Ia)化合物及其可药用衍生物可以以自身的形式使用,或者以其中化合物或衍生物与可药用辅剂、稀释剂或载体混合的适当药物组合物的形式使用。给药可通过但不限于经肠(包括经口、舌下或直肠)、鼻内、静脉内、局部或其它非胃肠道途径来进行。选择和制备合适的药物制剂的常规方法描述在例如“Pharmaceuticals-The Science ofDosage Form Designs”,M.E.Aulton,Churchill Livingstone,1988中。药物组合物优选包含小于80%、更优选小于50%的式(Ia)化合物、或其可药用盐、对映体或外消旋体。
本发明还提供了制备这样的药物组合物的方法,包括将各组分混合。
有利起见,式(I)和(Ia)化合物及其可药用衍生物还可以与COX-2抑制剂联合使用。特别优选的COX-2抑制剂是Celecoxib和MK-966。NOS抑制剂和COX-2抑制剂可配制在用于以单一剂量单位施用的同一药物组合物内,或者将每一组分单独地配制,这样分隔的剂量可同时或依次施用。
通过下列实施例来举例说明本发明,但这些实施例决不是限制性的。
实施例1
2-(3-氨基-1-苯基丙氧基)-4-氯苄腈盐酸盐
a)(3-羟基-3-苯基丙基)氨基甲酸1,1-二甲基乙酯
将α-(2-氨基乙基)苯甲醇(1.21g,8mmol)溶解在无水四氢呋喃(50ml)中,依次用二碳酸二叔丁酯(1.92g,8.8mmol)和三乙胺(1.34ml,9.6mmol)处理,并将该混合物搅拌18小时。将该反应混合物蒸发,将残余物从快速色谱柱上洗脱下来,使用乙醚/异己烷(1∶1)作为洗脱剂,获得了产物(974mg,48%),为粘稠的黄色油状物。
1H NMR 300MHz(CDCl3)7.35(4H,m),7.26(1H,m),4.89(1H,br s),4.75(1H,m),3.49(1H,br m),3.17(2H,m),1.86(2H,m),1.45(9H,s).
b)2-(3-氨基-1-苯基丙氧基)-4-氯苄腈盐酸盐
三苯基膦(67mg,2.56mmol)溶解在甲苯(50ml)中,并将该溶液冷却至0℃。滴加重氮二甲酸二乙酯(45mg,2.56mmol),并将该溶液搅拌20分钟。滴加在甲苯(25ml)和四氢呋喃(10ml)中的4-氯-2-羟基苄腈(36mg,2.34mmol),然后加入在甲苯(25ml)中的(3-羟基-3-苯基丙基)氨基甲酸1,1-二甲基乙酯(59mg,2.34mmol)。用一个周末将该反应混合物温热至室温,蒸发,并将残余物从快速色谱柱上洗脱下来,使用10%乙醚/异己烷作为洗脱剂,获得了所需的作为氨基甲酸叔丁酯保护起来的产物。将产物与4M氯化氢的二噁烷溶液(8ml)搅拌2小时,将溶剂蒸发,并用无水乙醚研制残余物,获得了本标题化合物(64mg,8.5%),为无色固体。
MS APCI+ve m/z 287([M+H)+).
1H NMR 300MHz(d6-DMSO)8.02(3H,br s),7.79(1H,d),7.44-7.29(5H,m),7.22(1H,d),7.16(1H,d of d),5.88(1H,m),2.93(2H,br m),2.32(1H,m),2.19(1H,m).
实施例2
4-氯-2-(3-(甲基氨基)-1-苯基丙氧基)苄腈盐酸盐
a)3-羟基-3-苯基丙基)甲基氨基甲酸1,1-二甲基乙酯
将在甲醇(150ml)中的[2-(甲基氨基)乙基]苯甲醇(10.8g,65.5mmol)依次用二碳酸二叔丁酯(14.7g,67.4mmol)和三乙胺(19.0ml,136mmol)处理,并将该反应混合物搅拌4小时。将溶剂蒸发,并将残余物从快速色谱柱上洗脱下来,使用乙醚/异己烷(1∶1)作为洗脱剂,获得了所需产物(15.7g,90%),为粘稠的油状物。
GC/MS m/z 165(M-100)+.
b)4-氯-2-[3-(甲基氨基)-1-苯基丙氧基]苄腈盐酸盐
在氮气氛、搅拌下,用2分钟向在无水四氢呋喃(10ml)内的三苯基膦(0.38g,1.46mmol)中滴加偶氮二甲酸二异丙酯(0.29ml,1.46mmol)。将该反应混合物搅拌20分钟,然后加入在无水四氢呋喃(5ml)中的4-氯-2-羟基苄腈(0.22g,1.46mmol),5分钟后,加入在无水四氢呋喃(5ml)中的3-羟基-3-苯基丙基)甲基氨基甲酸1,1-二甲基乙酯(0.39g,1.46mmol),并将该反应混合物搅拌过夜。将该混合物用乙酸乙酯稀释,依次用10%碳酸钠水溶液(2×50ml)和盐水洗涤,用碳酸镁干燥。将溶剂蒸发,将残余物从快速色谱柱上洗脱下来,首先用乙醚/异己烷(1∶1)洗脱,然后用乙醚/异己烷(3∶7)再洗脱较澄清的级分,获得了酰胺保护的产物。将其与4M氯化氢的二噁烷溶液(5ml)搅拌1小时,蒸发,用乙醚研制残余物,获得了本标题化合物(96mg,20%),为无色固体。
MS APCI+ve m/z 301([M+H]+).
1H NMR 300MHz(d6-DMSO)7.78(1H,d),8.93(2H,br s),7.44-7.31(5H,m),7.27(1H,d),7.16(1H,d of d),5.91(1H,m),2.98(2H,m),2.57(3H,s),2.41-2.15(2H,m).
实施例3
4-溴-2-[(1R)-3-(甲基氨基)-1-苯基丙氧基]苄腈盐酸盐
a)[(3R)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯
按照实施例2(a)的方法制备,获得了所需产物(6.0g,78%),为粘稠的油状物。
MS APCI+ve m/z 166([M-100+H]+).
b)[(3R)-3-(5-溴-2-氰基苯氧基)-3-苯基丙基]甲基氨基甲酸1,1-二甲基酯
将[(3R)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯(0.4g,1.5mmol)和4-溴-2-氟苄腈(0.3g,1.5mmol)溶解在四氢呋喃(10ml)中。加入60%氢化钠(0.08g,2.0mmol),并将该混合物搅拌4小时。然后用水骤冷该反应混合物,用乙酸乙酯萃取,用硫酸镁干燥,过滤并旋转蒸发。通过快速色谱法纯化,用20%乙酸乙酯/己烷作为洗脱剂,获得了所需产物(0.49g,73%),为无色油状物。
MS APCI+ve m/z 345/7([M-100+H]+).
c)4-溴-2-[(1R)-3-(甲基氨基)-1-苯基丙氧基]苄腈盐酸盐
将[(3R)-3-(5-溴-2-氰基苯氧基)-3-苯基丙基]甲基氨基甲酸1,1-二甲基酯(0.45g,1mmol)在4M氯化氢的二噁烷溶液(10ml)中搅拌4小时。将溶剂蒸发,用乙醚处理残余物,获得了所需产物(0.34g,89%),为白色固体。
MS APCI+ve m/z 345/7([M+H]+).
1H NMR 300MHz(d6-DMSO)9.03(2H,s),7.71(1H,d),7.41-7.45(5H,m)7.36(1H,m),7.27(1H,d),5.94(1H,m),2.94-3.04(2H,m),2.56(3H,s),2.31-2.40(1H,m),2.19-2.26(1H,m).
实施例4
γ-R-(2-溴-5-氯苯氧基)-N-甲基苯丙胺盐酸盐
将α-[2-(甲基氨基)乙基]-(α1R)-苯甲醇(0.395g,2.39mmol)溶解在二甲亚砜(3ml)中,并加入60%氢化钠(0.19g,4.78mmol)。将该混合物在40℃加热30分钟,加入1-溴-4-氯-2-氟苯(0.5g,2.39mmol),并将该混合物在50℃搅拌20小时。将该混合物冷却至室温,用水骤冷处理,用乙酸乙酯萃取,用硫酸镁干燥,过滤并蒸发。通过快速色谱法纯化残余物,用5%7M氨-甲醇在二氯甲烷中的溶液作为洗脱剂,获得了所需产物(0.47g,50%),为白色固体。
MS APCI+ve m/z 354/5/6/7/8([M+H]+).
1H NMR 300MHz(d6-DMSO)9.05(2H,s),7.59(1H,d),7.39-7.42.(5H,m),7.31-7.34(1H,m),6.92(1H,d),5.82(1H,m),2.95-3.00(2H,m),2.56(3H,s),2.28-2.37(1H,m),2.19-2.25(1H,m).
实施例5
4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}苄腈盐酸盐
a)4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}苄腈
在氮气氛下,在冰浴内,将(S)-α-(2-氯乙基)苯甲醇(170mg,1.0mmol)、4-氯-2-羟基苄腈(154mg,1.0mmol.)和三苯基膦(260mg,1.0mmol.)在无水四氢呋喃(5ml)中搅拌,同时加入偶氮二甲酸二乙酯(0.16ml,1.0mmol.)。将该反应混合物温热至室温,并搅拌3天。将溶剂蒸发,并将残余物溶解在甲苯中,加到快速色谱柱的顶部,用10%乙醚/异己烷洗脱,获得了产物(220mg,72%),为粘稠的油状物。
1H NMR 300MHz(CDCl3)7.21(1H,d),7.24-7.33(5H,m),6.92(1H,d ofd),6.75(1H,d),5.43(1H,m),3.80(1H,m),3.56(1H,m),2.50(1H,m),2.18(1H,m).
b)4-氯-2-{[(1R)-3-碘-1-苯基丙基]氧基}苄腈
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}苄腈(220mg,0.718mmol)溶解在预先用碘化钠饱和的丙酮(20ml)中,并将该溶液加热回流18小时。将该反应混合物冷却,过滤,蒸发,并将残余物在水与乙酸乙酯之间分配。分离出有机层,用水洗涤2次,并干燥(用硫酸镁)。将溶剂蒸发,获得了0.24g(84%)产物,为黄色油状物。该产物不用纯化直接用于下一步骤。
c)4-氯-2-{[(1R)-3-(甲基氨基)-1-苯基丙基]氧基}苄腈盐酸盐
将4-氯-2-{[(1R)-3-碘-1-苯基丙基]氧基}苄腈(240mg,0.604mmol.)溶解在四氢呋喃(10ml)中,用40%甲胺水溶液(5ml)处理,并在室温搅拌5小时。真空除去溶剂,将残余物溶解在水中,并萃取到乙酸乙酯中,将其干燥(用硫酸镁)。将溶剂蒸发,将残余物与4M氯化氢的二噁烷溶液(5ml)搅拌1小时。将溶剂蒸发,将残余物与乙醚共沸2次,最后用乙醚研制,获得了所需产物(155mg,76%),为淡黄褐色固体。
MS APCI+ve m/z 301([M+H]+).
1H NMR 300MHz(d6-DMSO)8.86(2H,br s),7.79(1H,d),7.44-7.31(5H,m),7.26(1H,d),7.16(1H,d of d),5.90(1H,m),3.01(2H,br m),2.57(3H,t),2.41-2.15(2H,m).
实施例6
4-甲氧基-2-[3-(甲基氨基)-1-苯基氨基-1-苯基丙氧基]苄腈盐酸盐
本标题化合物是通过实施例2(b)的方法,使用2-羟基-4-甲氧基-苄腈制得的,获得了0.13g(27%)产物,为玻璃状固体。
MS APCI+ve m/z 297([M+H]+).
1H NMR 300MHz(d6-DMSO)8.92(2H,br s),7.64(1H,d),7.46-7.30(5H,m),6.66(1H,d),6.63(1H,d of d),5.85(1H,m),3.73(3H,s),3.00(2H,br m),2.57(3H,s),2.37-2.18(2H,m).
实施例7
4-甲基-2-{[(1R)-3-(甲基氨基)-1-苯基丙基]氧基}苄腈盐酸盐
本标题化合物是通过实施例1(b)的方法,最初使用[(3R)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯和2-羟基-4-甲基苄腈制得的,获得了0.35g(73%)产物,为无色固体。
MS APCI+ve m/z 281([M+H]+).
1H NMR 300MHz(d6-DMSO)9.09(2H,br),7.58(1H,d),7.39-7.46(4H,m),7.32(1H,m),7.02(1H,s),6.87(1H,d),5.g4(1H,m),3.00(2H,m),2.55(3H,s),2.30-2.39(1H,m),2.19-2.25(1H,m),2.25(3H,s).
实施例8
R-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺
a)2-[(1R)-3-氯-1-(2,5-二氯苯氧基)丙基]噻吩
在0℃,将偶氮二甲酸二乙酯(0.7ml)加到S-α-(2-氯乙基)-2-噻吩甲醇(657mg)、2,5-二氯苯酚(607mg)和三苯基膦(1.17g)在甲苯(10ml)内的溶液中,并将该混合物在0℃搅拌3小时,在20℃搅拌14小时。真空除去溶剂,通过硅胶色谱纯化残余物,用汽油-乙醚(9∶1)洗脱,获得了本标题化合物,为无色油状物(788mg)。
1H NMR(CDCl3)7.32-6.84(6H,m),5.72-5.65(1H,m),3.87-3.81(1H,m),3.68-3.60(1H,m),2.69-2.58(1H,m),2.41-2.32(2H,m).
b)2-[(1R)-1-(2,5-二氯苯氧基)-3-碘丙基]噻吩
将步骤(a)产物(788mg)和碘化钠(4.5g)在丙酮(30ml)中的溶液加热回流18小时。真空除去溶剂,加入水,用乙醚将该混合物萃取2次。将有机层干燥(用硫酸镁),蒸发,并通过硅胶色谱纯化,用汽油-乙醚(19∶1)洗脱,获得了本标题化合物,为浅黄色油状物(742mg)。
1H NMR(CDCl3)7.30-7.23(2H,m),7.09(1H,d),6.99-6.86(3H,m),5.59-5.53(1H,m),3.47-3.39(1H,m),3.29-3.21(1H,m),2.72-2.60(1H,m),2.47-2.36(1H,m).
c)R-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺富马酸盐
将步骤(b)产物(217mg)在40%甲胺水溶液(5ml)和四氢呋喃(5ml)中的溶液搅拌2.5天。真空除去溶剂,加入水,用乙酸乙酯将该混合物萃取3次。将有机层干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用二氯甲烷-7M氨的甲醇溶液(19∶1)洗脱,获得了油状物(116mg)。向该油状物在乙酸乙酯内的溶液中加入富马酸(43mg)的甲醇溶液。收集沉淀,干燥,获得了本标题化合物,为细小的白色固体(127mg)。
MS(APCI)m/z 316[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.53(1H,d),7.44(1H,d),7.30(1H,s),7.21(1H,d),7.04-6.95(2H,m),6.43(2H,s),6.05(1H,dd),2.97-2.85(2H,m),2.49(3H,s),2.44-2.16(2H,m).
实施例9
S-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺
a)2-[(1S)-3-氯-1-(2,5-二氯苯氧基)丙基]噻吩
本标题化合物是按照实施例8(a)的方法,使用R-α-(2-氯乙基)-2-噻吩甲醇制得的。
1H NMR 300MHz(CDCl3)7.32-6.84(6H,m),5.72-5.65(1H,m),3.87-3.81(1H,m),3.68-3.60(1H,m),2.69-2.58(1H,m),2.41-2.32(1H,m).
b)2-[(1S)-1-(2,5-二氯苯氧基)-3-碘丙基1噻吩
本标题化合物是按照实施例8(b)的方法,使用步骤(a)产物制得的。
1H NMR 300MHz(CDCl3)7.30-7.23(2H,m),7.09(1H,d),6.99-6.86(3H,m),5.59-5.53(1H,m),3.47-3.39(1H,m),3.29-3.21(1H,m),2.72-2.60(1H,m),2.47-2.36(1H,m).
c)S-γ-(2,5-二氯苯氧基)-N-甲基-2-噻吩丙胺富马酸盐
本标题化合物是按照实施例8(c)的方法,使用步骤(b)产物制得的。
MS(APCI)m/z 316[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.53(1H,d),7.44(1H,d),7.30(1H,s),7.21(1H,d),7.04-6.95(2H,m),6.43(2H,s),6.04-6.60(1H,m),2.95-2.84(2H,m),2.48(3H,s),2.43-2.29(1H,m),2.23-2.13(1H,m).
实施例10
2-[[(3R)-3-(2,5-二氯苯氧基)-3-(2-噻吩基)丙基]氨基]乙醇富马酸盐
将实施例8(b)产物(214mg)和乙醇胺(0.1ml)在四氢呋喃(5ml)中的溶液搅拌2.5天。真空除去溶剂,加入水,用乙酸乙酯将该混合物萃取3次。将有机层干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用二氯甲烷-7M氨的甲醇溶液(19∶1)洗脱,获得了油状物(116mg)。向该物质在乙酸乙酯内的溶液中加入富马酸(43mg)在甲醇中的溶液。收集沉淀,并干燥,获得了本标题化合物,为细小的无色固体(127mg)。
MS(APCI)m/z 346[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.51(1H,d),7.43(1H,d),7.32(1H,s),7.20(1H,d),7.01-6.98(2H,m),6.43(2H,s),6.01(1H,t),3.53(2H,t),2.84-2.74(4H,m),2.38-2.28(1H,m),2.18-2.1(1H,m).
实施例11
4-氯-2-{[(1R)-3-(4-甲基-1-哌嗪基)-1-苯基丙基]氧基}-苄腈二盐酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈(0.17g)、4-甲基哌嗪(0.2g)、碘化钾(0.02g)在N-甲基吡咯烷酮(5ml)中于100℃加热3小时。将该反应混合物冷却至室温,倒入水中,并将产物萃取到乙酸乙酯中。将该乙酸乙酯溶液用水、盐水洗涤,用硫酸镁干燥,并蒸发至干,获得了油状物。用1M氯化氢的乙醚溶液研制该油状物,获得了作为二盐酸盐的产物(0.135g)。
MS APCI+ve m/z 370[(M+H)+].
1H NMR(d6-DMSO)7.78(1H,dd),7.33-7.48(5H,m),7.29(1H,s),7.16(1H,dd),5.89(1H,m),3.2-4.8(10H,m),2.82(3H,s),2.45-2.50(2H,m).
实施例12
4-氯-2-{[(1R)-3-(4-羟基-1-哌啶基)-1-苯基丙基]氧基}-苄腈富马酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈与4-羟基-哌啶如实施例11中所述进行反应,获得了本标题化合物。通过用1当量的富马酸甲醇溶液研制将其转化成富马酸盐。
MS APCI+ve m/z 371[(M+H)+].
1H NMR(d6-DMSO)7.51(1H,d),7.26-7.38(5H,m),6.97(1H,d),6.9(1H,s),6.70(2H,s),5.50(1H,m),3.65-3.75(1H,m),2.85-2.95(2H,m),2.6-2.82(2H,m),2.35-2.50(2H,m),2.2-2.3(1H,m),2.05-2.01(1H,m),1.86-2.0(2H,m),1.6-1.7(2H,m).
实施例13
4-氯-2-{[(1R)-3-[(2-羟基乙基)甲基氨基]-1-苯基丙基]氧基}-苄腈盐酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈与(2-甲基氨基)乙醇如实施例11中所述进行反应,获得了本标题化合物。
MS APCI+ve m/z 345[(M+H)+].
1H NMR(CDCl3)7.48(1H,d),7.31-7.45(5H,m),7.00(1H,dd),6.88(1H,d),5.66(1H,dd),5.01(1H,bs),4.00(2H,m),3.27(1H,bs),2.92(3H,s),2.53-2.60(6H,m).
实施例14
4-氯-2-{[(1R)-3-(4-吗啉基)-1-苯基丙基]氧基}-苄腈富马酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈与吗啉如实施例11中所述进行反应,获得了本标题化合物。通过用1当量的富马酸甲醇溶液研制将其转化成富马酸盐。
MS APCI+ve m/z 357[(M+H)+].
1H NMR(d6-DMSO)7.49(1H,dd),7.29-7.38(5H,m),7.29(1H,dd),6.92(1H,d),6.76(2H,s),5.42(1H,m),3.71(4H,m),2.5-2.7(2H,m),2.43-2.49(4H,m),2.24-2.31(1H,m),2.02-2.22(1H,m).
实施例15
4-氯-2-{[(1R)-3-[(3R)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈富马酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈与(3R)-3-羟基吡咯烷如实施例11中所述进行反应,获得了本标题化合物。通过用1当量的富马酸甲醇溶液研制将其转化成富马酸盐。
MS APCI+ve m/z 357/359[(M+H)+].
1H NMR(d6-DMSO)7.76(1H,d),7.25-7.45(5H,m),7.20(1H,s),7.10(1H,dd),6.55(2H,s)5.75(1H,m),4.24(1H,m),2.95(1H,m),2.91(1H,m),2.82(2H,m),2.51(2H,m)2.18-2.3(1H,m),1.97-2.05(2H,m),1.62-1.64(1H,m).
实施例16
4-氯-2-{[(1R)-3-[(3S)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈富马酸盐
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-苄腈与(3S)-3-羟基吡咯烷如实施例11中所述进行反应,获得了本标题化合物。通过用1当量的富马酸甲醇溶液研制将其转化成富马酸盐。
MS APCI+ve m/z 357/359[(M+H)+].
1H NMR(d6-DMSO)7.76(1H,d),7.25-7.45(5H,m),7.20(1H,s),7.10(1H,dd),6.55(2H,s)5.75(1H,m),4.24(1H,m),2.95(1H,m),2.91(1H,m),2.82(2H,m),2.51(2H,m),2.18-2.3(1H,m),1.97-2.05(2H,m),1.62-1.64(1H,m).
实施例17
2-{[(1R)-3-氨基-1-苯基丙基]氧基}-5-氟-4-甲基苄腈富马酸盐
a)5-氟-2-羟基-4-甲基苄腈
在0℃、搅拌下,向1M三氯化硼在二氯甲烷内的溶液(48ml,48mmol)中依次加入4-氟-3-甲基苯酚(4.44ml,40mmol)在二氯甲烷(40ml)中的溶液、硫氰酸甲酯(3.3ml,48mmol)和无水氯化铝(5.4g,40mmol)。将该反应混合物加热回流3小时,并在室温搅拌过夜。将溶剂蒸发,用二氯乙烷代替,并加到冰和4N氢氧化钠(132ml)中。将该混合物在搅拌下加热回流0.5小时,冷却至室温,分离出有机层,用二氯乙烷洗涤水层。用2M盐酸将水层酸化,通过过滤收集沉淀出的固体,并用水充分洗涤。将固体溶解在乙酸乙酯中中,用硫酸镁干燥,蒸发,并在冰冷却下用异己烷研制残余物,获得了3.5g(58%)本子标题化合物,为无色固体。
1H NMR 300MHz(d6-DMSO)7.12(1H,d),6.81(1H,d),2.29(3H,s).
b)2-[[(1R)-3-氯-1-苯基丙基]氧基]-5-氟-4-甲基苄腈
该合适的化合物是通过实施例5(a)的方法,使用5-氟-2-羟基-4-甲基苄腈和S-α-(2-氯乙基)苯甲醇制得的。
1H NMR 300MHz(CDCl3)7.41-7.29(5H,m),7.16(1H,d),6.63(1H,d),5.45(1H,m),3.89(1H,m),3.63(1H,m),2.55(1H,m),2.24(1H,m),2.17(3H,s).
c)5-氟-2-[[(1R)-3-碘-1-苯基丙基]氧基]-4-甲基苄腈
该合适的化合物是通过实施例5(b)的方法,使用5-氟-2-[[(1R)-3-氯-1-苯基丙基]氧基]-5-氟-4-甲基苄腈制得的。
1H NMR 300MHz(CDCl3)7.39-7.31(5H,m),7.16(1H,d),6.64(1H,d),5.33(1H,m),3.47(1H,m),3.28(1H,m),2.54(1H,m),2.31(1H,m),2.18(3H,s).
d)2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-5-氟-4-甲基苄腈
将碘化合物17(c)(504mg,1.28mmol)和叠氮化钠(124mg,1.91mmol)在二甲亚砜(5ml)和水(2滴)中搅拌3小时。将该反应混合物倒入水中,用乙酸乙酯萃取,然后用盐水洗涤,并用无水硫酸镁干燥。将溶剂蒸发,获得了361mg(91%)浅黄色油状物。
1H NMR 300MHz(CDCl3)7.39-7.29(5H,m),7.16(1H,d),6.59(1H,d),5.30(1H,m),3.67(1H,m),3.46(1H,m),2.31(1H,m),2.17(3H,t),2.08(1H,m).
e)2-{[(1R)-3-氨基-1-苯基丙基]氧基}-5-氟-4-甲基苄腈富马酸盐
将在四氢呋喃(15ml)中的叠氮化物17(d)依次用三苯基膦(512mg,1.95mmol)和水(1.5ml)处理。将该反应混合物倒入水中,并在搅拌下加热回流2小时,蒸发,将残余物从快速色谱柱上洗脱下来,先用乙酸乙酯洗脱,然后用5%7M氨的甲醇溶液/二氯甲烷洗脱,获得了186mg粘稠的油状物。将其溶解在最少量的乙醇中,用富马酸(75.7mg,0.652mmol)处理,温热至完全溶解,并用乙醚处理直至变浑浊。静置1小时后,通过过滤收集晶体,用少量乙腈洗涤,并在40℃真空干燥,获得了159mg(30%)本标题化合物,为无色固体。
MS APCI+ve m/z 285[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.63(1H,d),7.43-7.28(5H,m),7.08(1H,d),6.39(2H,s),5.73(1H,m),2.87(2H,t),2.30-2.03(2H,m),2.17(3H,s).
实施例18
4-氯-5-氟-2-[3-(甲基氨基)-1-(2-嘧啶基)丙氧基]苄腈盐酸盐
a)[3-羟基-3-(2-嘧啶基)丙基]甲基氨基甲酸1,1-二甲基乙酯
在氮气氛下,向溶解在冷却至-78℃的无水四氢呋喃(10ml)内的2-(三丁基甲锡烷基)嘧啶(690mg,1.87mmol)中加入2.4M正丁基锂的己烷溶液(0.8ml,1.87mmol)。搅拌0.5小时后,在-78℃迅速加入在无水四氢呋喃(10ml)中的甲基(3-氧代丙基)氨基甲酸1,1二甲基乙酯。将该反应混合物温热至室温,用饱和氯化铵水溶液处理,并用乙酸乙酯萃取,用盐水洗涤,并用无水硫酸镁干燥。将溶剂蒸发,将残余物从快速色谱柱上洗脱下来,先使用10%乙酸乙酯/二氯甲烷洗脱,然后使用10%甲醇/二氯甲烷洗脱,获得了260mg(43%)本子标题化合物,为粘稠的黄色油状物。
MS APCI+ve m/z 268[(M+H)+].
b)[3-(5-氯-2-氰基-4-氟苯氧基)-3-(2-嘧啶基)丙基]甲基氨基甲酸,1,1-二甲基乙酯
将在无水N,N-二甲基甲酰胺(15ml)中的醇18(a)(255mg,0.955mmol)用氢化钠(60%矿物油悬浮液,40mg,0.955mmol)处理,并将该反应混合物在氮气下搅拌直至泡腾停止。加入4-氯-2,5-二氟苄腈(166mg,0.955mmol),并将该反应混合物在氮气氛下于40℃加热1小时。将该反应冷却,在盐水与乙酸乙酯之间分配,分离出有机层,依次用水(5×)和盐水洗涤,用无水硫酸镁干燥。将溶剂蒸发,将残余物从快速色谱柱上洗脱下来,使用30%乙酸乙酯/异己烷作为洗脱剂,获得了140mg(35%)本子标题化合物,为粘稠的油状物。
1H NMR 300MHz(CDCl3)8.76(2H,d),7.33(1H,d),7.26(1H,m),6.92(1H,br m),5.33(1H,br m),3.65(1H,br m),3.41(1H,m),2.89(3H,s),2.45-2.30(2H,m),1.38(9H,s).
c)4-氯-5-氟-2-[3-(甲基氨基)-1-(2-嘧啶基)丙氧基]苄腈盐酸盐
将氨基甲酸酯18(b)(140mg,0.333mmol)用4M HCl的二噁烷溶液(10ml)处理,并搅拌1小时。通过过滤收集沉淀出的固体,用乙醚洗涤,并干燥,获得了97mg(80%)所需产物,为无色固体。
MS APCI+ve m/z 321[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.98(2H,br m),8.88(2H,d),8.04(1H,d),7.52(1H,t),7.41(1H,d),5.90(1H,t),3.12(2H,m),2.58(2H,t),2.49(3H,s).
实施例19
4-氯-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(2-甲氧基乙基)氨基]丙基}氧基)苄腈草酸盐
a)(R)-α-(2-氯乙基)-3-呋喃甲醇
该化合物是按照实施例74(d)的制备方法分两个步骤由1-(3-呋喃基)-2-丙烯-1-酮制得的,获得了无色固体。
1H NMR 300MHz(CDCl3)7.43-7.41(2H,m),6.42(1H,s),4.98-4.92(1H,m),3.79-3,73(2H,m),2.30-2.10(2H,m).
b)4-氯-5-氟-2-[{(1R)-1-(3-呋喃基)-3-[(2-甲氧基乙基)氨基]丙基}氧基)苄腈草酸盐
在室温将(R)-α-(2-氯乙基)-3-呋喃甲醇(100mg,0.62mmol)溶解在四氢呋喃(5ml)中。向该溶液中加入60%氢化钠在矿物油中的悬浮液(37mg,0.93mmol),将该混合物搅拌10分钟,然后一次性加入固体4-氯-2,5-二氟苄腈(107.6mg,0.62mmol)。将所得混合物搅拌1小时,然后加入水(2ml),并将该混合物真空浓缩。将残余物在二氯甲烷与水之间分配。收集有机相,用硫酸镁干燥,过滤并真空浓缩至干。将所得残余物溶解在N,N-二甲基甲酰胺(2ml)中,并用碘化钠(93mg,0.62mmol)、三乙胺(172μl,1.24mmol)和2-甲氧基乙胺(107μl,1.24mmol)处理,然后在60℃加热72小时。将该混合物冷却,过滤,并经由反相HPLC纯化,获得了游离碱形式的本标题化合物,将其用50%草酸在乙醚中的饱和溶液处理。经由过滤收集所得白色固体,获得了本标题化合物(61mg,28%)。
MS APCI+ve m/z 353/355[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.02(1H,d),7.82(1H,s),7.70(1H,s),7.59(1H,s),5.72(2H,t),3.57(2H,m),3.31(3H,s),3.16(2H,m),3.09-2.98(2H,b),2.37(1H,bm),2.27(1H br m).
实施例20
4-甲氧基-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]-苄腈盐酸盐
(a)[(3R)-3-(2-氰基-5-甲氧基苯氧基)-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯
在氮气氛下,向2-氰基-5-甲氧基苯酚(149mg,1.00mmol)和[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯(265mg,1.00mmol)在四氢呋喃(10ml)内的搅拌着的混合物中加入三苯基膦(290mg,1.10mmol),然后加入重氮二甲酸二乙酯(192mg,1.10mmol)。将该反应混合物在室温搅拌24小时,然后蒸发至干。将残余物从快速色谱柱上洗脱下来,使用30%乙酸乙酯/异己烷作为洗脱剂,获得了275mg(69%)本子标题化合物,为油状物。
1H NMR 300MHz(CDCl3)7.26-7.45(6H,m),6.43(1H,dd),6.25(1H,s),5.19(1H,bs),3.67(3H,s),3.50(2H,bs),2.87(3H,s),2.25(1H,bs),2.10(1H,m),1.38(9H,s).
b)4-甲氧基-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]-苄腈富马酸盐
将[(3R)-3-(2-氰基-5-甲氧基苯氧基)-3-苯基丙基]甲基氨基甲酸1,1二甲基乙酯(270mg,0.682mmol)溶解在4M氯化氢的二噁烷溶液(8ml)中。将所得溶液在室温搅拌20小时,然后用含有氨的碳酸氢钠溶液稀释,并用二氯甲烷萃取3次。将合并的有机相用盐水洗涤,然后用硫酸镁干燥。将溶剂蒸发,把残余物溶解在乙醇中。向该溶液中加入富马酸的乙醇溶液,并将溶剂蒸发。将残余物从乙醇/乙醚中重结晶,获得了128mg(46%)本标题化合物,为白色固体。
MS APCI+ve m/z 297[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.62(1H,d),7.29-7.44(5H,m),6.61(2H,m),6.44(2H,s),5.74(1H,dd),3.71(3H,s),2.89(2H,t),2.50(3H,s),2.22(1H,m),2.11(1H,m).
实施例21
γ-(2-溴-5-氟苯氧基)-N-甲基-苯丙胺富马酸盐
该化合物是通过实施例2(b)的方法,使用(3-羟基-3苯基丙基)甲基氨基甲酸1,1-二甲基乙酯和2-溴-5-氟苯酚制得的,并转化成富马酸盐形式的本标题化合物(白色固体)(11.3mg,3.2%)。
MS APCI+ve m/z 338[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.61-7.56(1H,dd),7.40-7.30(5H,m),6.90-6.86(1H,dd),6.75-6.69(1H,dt),6.43(2H,s),5.69-5.65(1H,m),3.35(3H,s),2.90-2.845(2H,t),2.27-2.06(2H,m).
实施例22
(R)-γ-(5-溴-2-氯苯氧基)-N-甲基苯丙胺富马酸盐
按照类似于实施例2(b)中描述的方法,将[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯与5-溴-2-氯苯酚反应,获得了富马酸盐形式的本标题化合物(白色固体)(449mg,52%)。
1H NMR 400MHz(d6-DMSO)7.40-7.36(5H,m),7.34-7.29(1H,m),7.19-7.19(1H,d),7.10-7.08(1H,dd),6.44(2H,s),5.72-5.70(1H,m),2.90-2.86(2H,t),2.52-2.48(3H,s),2.29-2.05(2H,m).
实施例23
(R)-γ-(2-溴-5-硝基苯氧基)-N-甲基苯丙胺富马酸盐
按照类似于实施例2(b)中描述的方法,将[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯与2-溴-5-硝基苯酚反应,获得了富马酸盐形式的本标题化合物(黄色固体)(278mg,49.8%)。
MS APCI+ve m/z 365[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.91-7.88(1h,d),7.72-7.67(2H,m),7.46-7.28(5H,m),6.43(2H,s),5.88-5.84(1H,dd),2.93-2.89(2H,t),2.53-2.43(3H,s),2.38-2.10(2H,m).
实施例24
4-氯-5-氟-2-[[(1R)-3-[(2-甲氧基乙基)氨基]-1-苯基丙基]氧基]-苄腈草酸盐
将4-氯-5-氟-2-[[(1R)-3-碘-1-苯基丙基]氧基]-苄腈(0.481mmol,通过实施例43(b)的方法制得的)溶解在2-甲氧基乙基胺(2.4mmol)中,并将所得黄色溶液在室温搅拌24小时。将过量胺蒸发,并将残余物在碳酸氢钠水溶液与乙酸乙酯之间分配。将粗产物萃取到乙酸乙酯中,然后用无水硫酸钠干燥。过滤,蒸发,获得了油状物,通过色谱法和反相HPLC纯化。使用草酸和甲醇将残余物转化成草酸盐,获得了48mg(22%)本标题化合物。
MS APCI+ve m/z 363[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.03-8.01(1H,d),7.45-7.41(5H,m),7.37-7.32(1H,m),5.79-5.76(1H,m),3.55-3.52(2H,t),3.29(3H,s),3.11-2.97(2H,m),2.52-2.49(2H,m),2.34-2.17(2H,m).
实施例25
4-氯-2-{[(1R)-3-(环丙基氨基)-1-苯基丙基]氧基}-5-氟苄腈草酸盐
将(R)-α-(2-氯乙基)苯甲醇(341mg,2mmol)溶解在四氢呋喃(10ml)中,并用60%氢化钠在矿物油中的悬浮液(480mg,3mmol)处理,10分钟后,加入4-氯-2,5-二氟苄腈(347mg,2mmol)。将该混合物在室温搅拌18小时,然后依次用甲醇(1ml)和水(10ml)处理。通过将反应器在80℃加热并施加氮气流来除去四氢呋喃。一旦将四氢呋喃蒸发,即将残余物萃取到二氯甲烷中,用硫酸镁干燥,并真空浓缩。将所得物质再溶解在二甲基甲酰胺(8ml)中,用碘化钠(305mg,2.03mmol)、三乙胺(565μl,4.06mmol)和环丙基胺(114mg,2mmol)处理,并在60℃加热5天。将该混合物过滤,将粗的反应产物经由RPHPLC纯化。然后将纯化的化合物用50%草酸在乙醚中的饱和溶液处理,获得了74mg经由过滤收集的白色粉末。
MS APCI +ve m/z 345/347[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.97-7.87(m,1H),7.53-7.25(m,6H),5.69(m,1H),3.28-3.07(m,2H),2.80-2.68(m,1H),2.45-2.29(m,1H),2.29-2.12(m,1H),0.85-0.74(m,4H).
实施例26
4-氯-2-{[(1R)-3-(环丙基氨基)-1-(3-呋喃基)丙基]氧基}-5-氟苄腈草酸盐
该化合物是这样制得的:通过实施例25的方法,首先使用(R)-α-(2-氯乙基)-3-呋喃甲醇(321mg,2mmol)和4-氯-2,5-二氟苄腈(347mg,2mmol),然后经由原位转化成碘化合物和用环丙基胺处理来转化成本标题化合物。用50%草酸在乙醚中的饱和溶液处理该游离碱。经由过滤收集所得白色固体,获得了本标题化合物(14mg,1.6%)。
MS APCI+ve m/z 335/337[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.01(d,1H),7.70(s,1H),7.70(s,1H),7.59(d,1H),6.53(s,1H),5.72(t,1H),3.15-2.99(m,2H),2.97-2.87(m,1H),2.40-2.26(m,1H),2.24-2.09(m,1H),0.78-0.66(m,4H).
实施例27
4-氯-2-{[1R)-3-(环丙基氨基)-1-(3-噻吩基)丙基]氧基}-5-氟苄腈草酸盐
该化合物是这样制得的:通过实施例25的方法,首先使用(R)-α-(2-氯乙基)-3-噻吩甲醇(实施例74(d))和4-氯-2,5-二氟苄腈,然后经由原位转化成碘化合物和用环丙基胺处理来转化成本标题化合物。用50%草酸在乙醚中的饱和溶液处理该游离碱。经由过滤收集所得白色固体,获得了本标题化合物(24mg,3%)。
MS APCI+ve m/z 351[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.02(d,1H),7.60(s,2H),7.50(d,1H),7.14(d,1H),5.83(t,1H),3.14-2.99(m,2H),2.76-2.62(m,1H),2.42-2.29(m,2H),2.27-2.13(m,2H),0.84-0.63(m,4H).
实施例28
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(苯基)丙基]氧基}-5-氟苄腈草酸盐
该化合物是这样制得的:通过实施例25的方法,首先使用(R)-α-(2-氯乙基)苯甲醇和4-溴-2,5-二氟苄腈,然后经由原位转化成碘化合物和用环丙基胺处理来转化成本标题化合物。用50%草酸在乙醚中的饱和溶液处理该游离碱。经由过滤收集所得白色固体,获得了本标题化合物(41mg,4.2%)。
MS APCI+ve m/z 390[(M+H)+].
1H NMR 400MHz(d6-DMSO)δ7.96(d,1H),7.49(d,1H),7.45-7.39(m,3H),7.39-7.31(m,2H),5.82-5.74(m,1H),3.16-3.00(m,2H),2.74-2.64(m,1H),2.38-2.25(m,1H),2.24-2.11(m,1H),0.79-0.64(m,4H).
实施例29
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(3-呋喃基)丙基]氧基}-5-氟苄腈草酸盐
该化合物是这样制得的:通过实施例25的方法,首先使用(R)-α-(2-氯乙基)苯甲醇和4-溴-2,5-二氟苄腈,然后经由原位转化成碘化合物和用环丙基胺处理来转化成本标题化合物。用50%草酸在乙醚中的饱和溶液处理该游离碱。经由过滤收集所得白色固体,获得了本标题化合物(41mg,4.2%)。
MS APCI+ve m/z 380[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.95(d,1H),7.81(s,1H),7.71-7.66(m,2H),6.53(s,1H),5.77-5.69(m,1H),3.15-2.99(m,2H),2.73-2.65(m,1H),2.41-2.29(m,1H),2.25-2.12(m,1H),0.80-0.67(m,4H).
实施例30
4-溴-2-{[(1R)-3-(环丙基氨基)-1-(3-噻吩基)丙基]氧基}-5-氟苄腈草酸盐
该化合物是这样制得的:通过实施例25的方法,首先使用(R)-α-(2-氯乙基)-3-噻吩甲醇和4-溴-2,5-二氟苄腈,然后经由原位转化成碘化合物和用环丙基胺处理来转化成本标题化合物。用50%草酸在乙醚中的饱和溶液处理该游离碱。经由过滤收集所得白色固体,获得了本标题化合物(47mg,4.8%)。
MS APCI+ve m/z 396[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.95(d,1H),7.63-7.57(m,3H),7.14(d,1H),5.83(t,1H),3.14-3.00(m,2H),2.73-2.65(m,1H),2.40-2.30(m,1H),2.26-2.15(m,1H),0.78-0.67(m,4H).
实施例31
4-氯-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈草酸盐
通过实施例25的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(67mg,7.4%)。
MS APCI+ve m/z 363/365[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.03(d,1H),7.43(m,4H),7.40(d,1H),7.35(m,1H),5.81-5.74(m,1H),3.47(t,2H),3.13-3.00(m,2H),3.02-2.95(m,2H),2.39-2.27(m,1H),2.23-2.12(m,1H),1.77-1.67(m,2H).
实施例32
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-(3-羟基丙基)氨基]丙基]氧基}苄腈草酸盐
通过实施例26的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(49mg,5.5%)。
MS APCI+ve m/z 353/355[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.01(d,1H),7.81(s,1H),7.70-7.69(m,1H),7.59(d,1H),6.54-6.53(m,1H),5.76-5.71(m,1H),3.48(t,2H),3.07-3.01(m,2H),3.02-2.97(m,2H),2.41-2.31(m,1H),2.26-2.15(m,1H),1.78-1.69(m,2H).
实施例33
4-氯-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈草酸盐
通过实施例27的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(74mg,8%)。
MS APCI+ve m/z 369[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.02(d,1H),7.62-7.60(m,2H),7.50(d,1H),7.16-7.13(m,1H),5.87-5.82(m,1H),3.47(t,2H),3.09-3.02(m,2H),3.02-2.96(m,2H),2.42-2.32(m,1H),2.27-2.16(m,1H),1.77-1.68(m,2H).
实施例34
4-溴-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈草酸盐
通过实施例28的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(25mg,2.5%)。
MS APCI+ve m/z 407/409[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.97(d,1H),7.49(d,1H),7.45-7.40(m,4H),7.39-7.32(m,2H),5.80-5.74(m,1H),3.47(t,2H),3.13-3.03(m,2H),3.02-2.96(m,2H),2.38-2.28(m,1H),2.23-2.14(m,1H),1.77-1.68(m,2H).
实施例35
4-溴-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(3-羟基丙基)氨基]丙基}氧基)苄腈草酸盐
通过实施例29的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(42mg,4.3%)。
MS APCI+ve m/z 399/401[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.94(d,1H),7.81-7.80(m,1H),7.71-7.67(m,2H),6.54-6.52(m,1H),5.74(t,1H),3.48(t,2H),3.10-3.01(m,2H),3.02-2.97(m,2H),2.42-2.31(m,1H),2.26-2.16(m,1H),1.78-1.70(m,2H).
实施例36
4-溴-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3噻吩基)丙基]氧基}苄腈草酸盐
通过实施例30的方法,但是用3-氨基-1-丙醇(150mg,2mmol)处理中间体碘化合物,获得了本标题化合物(42mg,4.3%).
MS APCI+ve m/z 414/416[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.95(d,1H),7.64-7.57(m,3H),7.16-7.12(m,1H),5.88-5.81(m,1H),3.47(t,2H),3.10-3.01(m,2H),3.02-2.97(m,2H),2.42-2.30(m,1H),2.28-2.16(m,1H),1.78-1.68(m,2H).
实施例37
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-(三氟甲基)苄腈草酸盐
a)(R)-α-(2-叠氮基乙基)苯甲醇
将(R)-α-(2-氯乙基)苯甲醇(0.73g,4.3mmol)和叠氮化钠(417mg,1.5当量)在DMSO(3ml)中搅拌并在40℃加热1.5小时。用水(50ml)稀释该反应混合物,并将产物萃取到乙酸乙酯内(2×75ml)。将合并的萃取液干燥(用硫酸镁),并浓缩至油状物。在硅胶上纯化,用50%乙醚/异己烷洗脱,获得了叠氮化物,为无色油状物(0.6g,79%)。
1H NMR 300MHz(CDCl3)7.61-7.27(5H,m),4.88-4.82(1H,m),3.55-3.35(2H,m),2.11-1.89(2H,m).
b)2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-(三氟甲基)苄腈
在氮气氛下,将叠氮基醇37(a)(0.49g,2.77mmol)和2-氟-4-(三氟甲基)苄腈(0.523g,2.77mmol)在无水四氢呋喃(30ml)中的混合物用氢化钠(60%分散液,111mg,2.77mmol)处理。将该混合物搅拌并在60℃加热1.5小时,然后用水(150ml)骤冷处理。将产物萃取到乙醚(2×100ml)内。将合并萃取液用硫酸镁干燥,过滤并浓缩至油状物。在硅胶上纯化该粗产物,用10%乙醚/异己烷洗脱,获得了本标题化合物,为无色油状物(770mg,80%)。
MS APCI+ve m/z 319[(M+H-28)].
c)2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-(三氟甲基)苄腈草酸盐
将2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-(三氟甲基)苄腈(770mg,2.2mmol)在四氢呋喃(50ml)中的溶液用三苯基膦(1.5当量)和水(0.5ml)处理。将该混合物在室温搅拌24小时,然后浓缩至油状物。在硅胶上纯化胺粗产物,用乙酸乙酯洗脱,然后用10%7N氨的甲醇溶液/二氯甲烷洗脱。使用1当量草酸的乙醇溶液将所得油状物转化成草酸盐,获得了本标题化合物,为无色固体(510mg,56%)。
MS APCI+ve m/z 321[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.0(1H,d),7.44-7.31(7H,m),5.93(1H,dd),3.04-2.9(2H,m),2.4-2.1(2H,m).
实施例38
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯苄腈
a)2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-氯苄腈
本子标题化合物是通过实施例37(b)的方法,但是使用4-氯-2-氟苄腈制得的。
1H NMR 400MHz(CDCl3)7.48-7.32(6H,m),6.95(1H,dd),6.79(1H,d),5.34(1H,dd),3.69-3.63(1H,m),3.5-3.44(1H,m),2.39-2.32(1H,m),2.14-2.05(1H,m).
b)2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯苄腈草酸盐
本子标题化合物是通过实施例37(c)的方法,但是使用2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-氯苄腈制得的。
MS APCI+ve m/z 287/9[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.79(1H,d),7.46-7.31(5H,m),7.19-7.14(2H,m),5.81(1H,dd),3.01-2.74(2H,m),2.35-2.08(2H,m).
实施例39
4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]苄腈
a)[(3R)-3-(5-氯-2-氰基-4-氟苯氧基)-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯
本子标题化合物是通过实施例3(b)的方法,使用4-氯-2,5二氟苄腈,并且用二甲基甲酰胺作为溶剂制得的。
MS APCI+ve m/z 319/21[(M-(C4H9)+H)+].
b)4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]苄腈草酸盐
将[(3R)-3-(5-氯-2-氰基-4-氟苯氧基)-3-苯基丙基]甲基氨基甲酸1,1二甲基乙酯(220mg,0.525mmol)在4N氯化氢的二噁烷溶液(20ml)中搅拌20分钟。将盐酸盐施加到硅胶柱上,并用10%7N氨的甲醇溶液/二氯甲烷洗脱。然后用1当量草酸的乙醇溶液将该游离碱转化成草酸盐。获得了本标题化合物,为无色固体(175mg,82%)。
MS APCI+ve m/z 319/321[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.02(1H,d),7.43-7.31(6H,m),5.79(1H,dd),3.09-2.93(2H,m),2.53(3H,s),2.4-2.1(2H,m).
实施例40
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯-5-氟苄腈草酸盐
a)2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-氯-5-氟苄腈
在氮气氛下,将叠氮基醇37(a)(8g,0.045mol)和4-氯-2,5二氟苄腈(7.83g,0.045mol)在无水二甲基甲酰胺(70ml)中的混合物用氢化钠(60%分散液,1.81g,0.045mol)处理。将该混合物搅拌并在60℃加热2小时,然后用水(500ml)骤冷处理。将产物萃取到乙醚内(2×300ml)。将合并的萃取液用硫酸镁干燥,过滤并浓缩至油状物。在硅胶上纯化粗产物,用20%乙醚/异己烷洗脱,获得了本标题化合物,为无色油状物(9.4g,80%)。
1H NMR 300MHz(CDCl3)7.43-7.3(6H,m),6.84(1H,dd),5.29(1H,dd),3.7-3.42(2H,m),2.4-2.04(2H,m).
b)2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯-5-氟苄腈草酸盐
按照类似于实施例37(c)中描述的方法将2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-氯-5-氟苄腈(实施例40(a))还原。
MS APCI+ve m/z 305/7[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.01(1H,d),7.44-7.31(6H,m),5.78(1H,dd),2.91-2.81(2H,m),2.28-2.05(2H,m).
实施例41
γ-[5-氯-2-(三氟甲基)苯氧基]-N-甲基苯丙胺盐酸盐
本标题化合物是通过实施例3(b)的方法,使用外消旋(3-羟基-3-苯基丙基)氨基甲酸1,1-二甲基乙酯和2,4-二氯-1-(三氟甲基)苯制得的,获得了70mg产物,为无色固体。
MS APCI+ve m/z 344/6[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.93-8.79(m,2H),7.65(d,1H),7.45-7.39(m,4H),7.38-7.30(m,1H),7.15(s,1H),7.13(d,1H),5.88(dd,1H),3.01-2.90(m,2H),2.55(s,3H),2.37-2.12(m,2H).
实施例42
2-[[(1R)-3-(甲基氨基)-1-苯基丙基]氧基]-4-(三氟甲基)苄腈盐酸盐
本标题化合物是通过实施例3(b)的方法,使用2-氟-4-(三氟甲基)苄腈制得的,获得了290mg产物,为白色固体。
MS APCI+ve m/z 335[(M+H)+].
1H NMR 400MHz(d6-DMSO)9.12-8.99(m,2H),8.00(d,1H),7.50-7.30(m,7H),6.06(dd,1H),3.10-2.96(m,2H),2.57(s,3H),2.46-2.20(m,2H).
实施例43
4-氯-5-氟-2-[[(1R)-3-[[(5-甲基吡嗪基)甲基]氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
a)4-氯-2-[[(1R)-3-氯-1-苯基丙基]氧基]-5-氟苄腈
将4-氯-2,5-二氟苄腈(1.0g,5.8mmol)和S-α-(2-氯乙基)苯甲醇(1.0g,5.86mmol)溶解在二甲基甲酰胺(10ml)中,并用5分钟滴加60%NaH(350mg,8.7mmol)。将该混合物搅拌2小时,用水骤冷处理,并用乙酸乙酯萃取。将萃取液用水洗涤(×3),用硫酸镁干燥,过滤并蒸发。通过快速色谱法纯化(5%乙酸乙酯/己烷),获得了1.8g(96%)产物,为无色油状物。
1H NMR 300MHz(CDCl3)7.44-7.32(m,5H),7.31(d,1H),6.87(d,1H),5.44(dd,1H),3.93-3.82(m,1H),3.67-3.57(m,1H),2.64-2.51(m,1H),2.31-2.18(m,1H).
b)4-氯-5-氟-2-{[(1R)-3-碘-1-苯基丙基]氧基}苄腈
将4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-5-氟苄腈(1.8g,5.6mmol)和碘化钠(12.8g,100mmol)溶解在丙酮(50ml)中,并加热回流24小时。将该反应混合物冷却,过滤并蒸发。将该半固体残余物溶解在甲苯中,再次过滤并蒸发,获得了2.3g粗产物,为黄色油状物。该产物不用纯化直接用于下一步骤。
c)4-氯-5-氟-2-[[(1R)-3-[[(5-甲基吡嗪基)甲基]氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
将4-氯-5-氟-2-{[(1R)-3-碘-1-苯基丙基]氧基}苄腈(200mg,0.48mmol)、5-甲基-2-吡嗪甲胺(120mg,0.96mmol)和三乙胺(335μl,2.4mmol)在DMSO(5ml)中搅拌48小时。将该混合物用水洗涤,并通过色谱法纯化(5%1M氨-甲醇/二氯甲烷)。将洗脱液蒸发,将残余物用4M氯化氢的二噁烷溶液(5ml)洗脱。将溶剂蒸发,与甲苯共沸2次,并用乙醚研制,获得了所需产物,为白色固体。
MS APCI+ve m/z 411[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.71(s,1H),8.58(s,1H),8.01(d,1H),7.49(d,1H),7.46-7.30(m,5H),5.96(dd,1H),4.36(t,2H),3.20-3.02(m,2H),2.53(s,3H),2.52-2.28(m,2H).
实施例44
4-氯-5-氟-2-[[(1R)-3-[(1H-咪唑-2-基甲基)氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用1H-咪唑-2-甲胺制得的,获得了本标题化合物,为白色固体。
MS APCI+ve m/z 385[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.01(d,1H),7.72(s,2H),7.51(d,2H),7.49-7.32(m,5H),6.00(dd,1H),4.54(s,2H),3.26-3.12(m,2H),2.50-2.25(m,2H).
实施例45
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)-苄腈富马酸盐
a)2-[[(1R)-3-叠氮基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)苄腈
使用实施例93(b)中描述的方法,将实施例93(a)产物(0.17g)与4-(三氟甲基)-2-氟-苄腈(0.3g)反应,获得了产物,为树胶状物,将其直接用于下一步骤。
b)2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)苄腈富马酸盐
用步骤(a)产物进行实施例90(b)中描述的方法,获得了产物,为固体(0.1g)。
MS APCI+ve m/z 312[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.99(1H,d),8.03(1H,d),7.60(1H,s),7.50(1H,d),6.74(1H,d),6.43(2H,s),6.24-6.15(1H,m),2.98(2H,dd),2.48-2.35(1H,m),2.34-2.21(1H,m).
实施例46
4-氯-2-[[(1R)-3-[[2-(二甲基氨基)乙基]氨基]-1-苯基丙基]氧基]-5-氟苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用N1,N1-二甲基-1,2-乙二胺制得的,获得了产物,为白色固体。
MS APCI+ve m/z 376[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.02(d,1H),7.52(d,1H),7.48-7.32(m,5H),535(dd,3H),3.47-3.39(m,2H),3.39-3.30(m,2H),3.19-3.03(m,2H),2.83(s,6H),2.47-2.22(m,2H).
实施例47
4-氯-5-氟-2-[[(1R)-3-[[2-(4-吗啉基)乙基]氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用4-吗啉乙胺制得的,获得了产物,为白色固体。
MS APCI+ve m/z 418([M+H]+].
1H NMR 400MHz(d6-DMSO)9.75-9.50(m,2H),8.02(d,1H),7.51(d,1H),7.48-7.32(m,5H),5.95(dd,1H),4.07-3.91(m,2H),3.86-3.70(m,2H),3.61-3.34(m,6H),3.22-3.01(m,4H),2.50-2.20(m,2H).
实施例48
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-1-基)乙基]氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用1H-咪唑-1-乙胺制得的,获得了产物,为白色固体。
MS APCI+ve m/z 399[(M+H)-].
1H NMR 300MHz(d6-DMSO)9.17-9.12(m,1H),8.01(d,1H),7.82-7.78(m,1H),7.69-7.65(m,1H),7.53(d,1H),7.49-7.30(m,5H),5.98(dd,1H),4.61(t,2H),3.50(t,2H),3.13-2.99(m,2H),2.45-2.22(m,2H).
实施例49
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-4-基)乙基]氨基]-1-苯基丙基]氧基]苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用1H-咪唑-4-乙胺制得的,获得了产物,为白色固体。
MS APCI+ve m/z 399[(M+H)-].
实施例50
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-苯基丙基]氧基]苄腈盐酸盐
本标题化合物是通过实施例43(c)的方法,使用2-氨基乙醇制得的,获得了产物,为白色固体。
MS APCI+ve m/z 349[(M+H)-].
1H NMR 400MHz(d6-DMSO)9.10-8.90(m,2H),8.02(d,1H),7.49(d,1H),7.47-7.39(m,4H),7.38-7.32(m,1H),5.91(dd,1H),5.26(t,2H),3.67(q,2H),3.13-2.96(m,2H),2.46-2.21(m,2H).
实施例51
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-苯基丙基]氧基]-4-氯-5-氟苄腈二盐酸盐
本标题化合物是通过实施例43(c)的方法,使用1,2-乙二胺制得的,获得了产物,为白色固体。
MS APCI+ve m/z 348[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.01(d,1H),7.51(d,1H),7.48-7.32(m,5H),5.98(dd,1H),3.37-3.30(m,2H),3.26-3.16(m,2H),3.13-3.04(m,2H),2.48-2.20(m,2H).
实施例52
4-氯-5-氟-2-[[(1R)-1-苯基-3-[(3,3,3-三氟丙基)氨基]丙基]氧基]苄腈三氟乙酸盐
将2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-氯-5-氟苄腈(300mg,0.99mmol)和3,3,3-三氟丙醛(123mg,1.2mmol)溶解在二氯甲烷(10ml)中,加入4埃分子筛,然后加入三乙酰氧基硼氢化钠(320mg,1.5mmol),并搅拌20小时。将该反应混合物用饱和碳酸氢钠水溶液洗涤,用硫酸镁干燥,过滤并蒸发。通过反相色谱纯化残余物(0.1%三氟乙酸水溶液/甲醇),获得了280mg产物,为白色固体。
MS APCI+ve m/z 401[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.99-8.82(m,2H),8.04(d,5H),7.48-7.30(m,2H),5.78(dd,1H),3.26(t,2H),3.21-3.03(m,2H),2.79-2.61(m,2H),2.43-2.13(m,2H).
实施例53
2-([(1R)-3-氨基-1-(2-噻唑基)丙基]氧基}-4-氯苄腈盐酸盐
a)[3-氧代-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯
在-78℃、氮气氛下,用30分钟向2-溴噻唑(5.035g,30.7mmol)在无水四氢呋喃(125ml)内的溶液中加入正丁基锂的己烷溶液(1.6M,17.6ml,28.2mmol),然后用30分钟加入[3-(甲氧基甲基氨基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯(2.976g,12.8mmol)在无水四氢呋喃(30ml)中的溶液。将该反应混合物温热至0℃,用饱和氯化铵骤冷处理,并用乙酸乙酯萃取(3×100ml)。将合并的萃取液用水(3×50ml)和饱和盐水溶液(1×100ml)洗涤,干燥(用硫酸镁),并真空浓缩,获得了粗的橙色油状物。通过快速色谱纯化(二氧化硅,25%乙酸乙酯在异己烷中的混合物),获得了2.2g浅黄色油状物(67%).
MS APCI+ve m/z 201([(M(-C4H9)+H)+].
1H NMR 300MHz(CDCl3)8.01(1H,m),7.69(1H,m),5.05(1H,br s),3.57(2H,q),3.39(2H,t),1.46(9H,s).
b)[(3R)-3-羟基-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯
在-10℃、氮气氛下,向(S)-3-甲基-CBS-氧杂氮杂硼杂环戊烯(1M甲苯溶液,0.43ml)在无水四氢呋喃(30ml)内的溶液中加入硼烷-四氢呋喃络合物(1M的四氢呋喃,2.58ml),并在-10℃搅拌15分钟。用45分钟滴加[3-氧代-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯(1.1g,4.3mmol)在无水四氢呋喃(20ml)中的溶液,并用16小时将所得混合物温热至室温。加入甲醇(10ml),并将该混合物在室温搅拌15分钟,然后减压除去溶剂。再加入甲醇(10ml),并减压除去,获得了粗的黄色油状物。通过快速色谱纯化(二氧化硅,25-100%乙酸乙酯在异己烷中的混合物),获得了0.75g澄清的树胶状物(67%)。
MS APCI+ve m/z 259[(M+H)+].
1H NMR 300MHz(CDCl3)7.72(1H,d),7.29(1H,d),5.06-5.02(1H,m),4.92(1H,br s),4.71(1H,s),3.70-3.58(1H,m),3.25-3.16(1H,m),2.24(1H,m),1.93-1.87(1H,m),1.44(9H,s).
c)[(3R)-3-(5-氯-2-氰基苯氧基)-3-(2-噻唑基)丙基]氨基甲酸1,1二甲基乙酯
向4-氯-2-氟苄腈(156mg,1mmol)和[(3R)-3-羟基-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯(258mg,1mmol)在无水二甲基甲酰胺(3ml)内的溶液中加入氢化钠(60%的油分散液,40mg,1mmol),并将该混合物在室温搅拌16小时。用甲醇聚冷处理该反应,并在乙酸乙酯与水之间分配。将合并的萃取液用水(3×25ml)和饱和盐水溶液洗涤,干燥(用硫酸镁),并真空浓缩,获得了粗的黄色树胶状物。通过快速色谱纯化(二氧化硅,15%乙酸乙酯在异己烷中的混合物),获得了345mg白色固体(86%)。
MS APCI+ve m/z 394/396[(M+H)+].
1H NMR 300MHz(CDCl3)7.79(1H,d),7.49(1H,d),7.38(1H,d),7.06(1H,d),7.02(1H,dd),5.72(1H,dd),4.80(1H,bd s),3.56-3.20(2H,m),2.50-2.20(2H,m),1.44(9H,s).
d)2-{[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基}-4-氯苄腈盐酸盐
向[(3R)-3-(5-氯-2-氰基苯氧基)-3-(2-噻唑基)丙基]-氨基甲酸1,1-二甲基乙酯(140mg,0.36mmol)在无水二噁烷(3ml)内的溶液中加入4M HCl的二噁烷溶液(1ml),并将该混合物在室温搅拌16小时。收集沉淀,用乙酸乙酯洗涤,并真空干燥,获得了106mg白色固体(90%)。
MS APCI+ve m/z 294/296[(M+H)+].
1H NMR 300MHz(d6-DMSO)δppm:8.16(3H,br s),7.90-7.83(3H,m),7.52(1H,d),7.26(1H,dd),6.31(1H,dd),3.10-2.96(2H,m),2.48-2.38(2H,m).
实施例54
4-氯-2-{[(1R)-3-(甲基氨基)-1-(2-噻唑基)丙基]氧基}苄腈盐酸盐
a)[(3R)-3-(5-氯-2-氰基苯氧基)-3-(2-噻唑基)丙基]甲基氨基甲酸1,1-二甲基乙酯
向[(3R)-3-(5-氯-2-氰基苯氧基)-3-(2-噻唑基)丙基]-氨基甲酸1,1-二甲基乙酯(200mg,0.51mmol)在无水四氢呋喃(10ml)内的溶液中加入氢化钠(56mg,60%的油悬浮液,1.41mmol),并在室温搅拌15分钟。加入碘甲烷(1.325g,0.58ml,4.7mmol)。将该反应在室温搅拌18小时,用饱和氯化铵溶液骤冷处理,并在乙酸乙酯与水之间分配。将合并的萃取液用水(3×25ml)和饱和盐水溶液洗涤,干燥(用硫酸镁),并真空浓缩,获得了粗的黄色树胶状物。通过快速色谱纯化(二氧化硅,25%乙酸乙酯在异己烷中的混合物),获得了175mg不透明的油状物(98%)。
MS APCI+ve m/z 408/410[(M+H)+].
1H NMR 300MHz(CDCl3)7.79(1H,d),7.49(1H,d),7.37(1H,d),7.07(1H,s),7.01(1H,d),5.68-5.63(1H,m),3.70-3.56(1H,m),3.43-3.33(1H,m),2.88(3H,s),2.45-2.28(2H,m),1.44(9H,s).
b)4-氯-2-{[(1R)-3-(甲基氨基)-1-(2-噻唑基)丙基]氧基]苄腈盐酸盐
本标题化合物是使用与实施例53(d)相同的方法制得的,获得了175mg白色固体(99%)。
MS APCI+ve m/z 308/310[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.90-7.83(3H,m),7.56-7.51(1H,m),7.27(1H,d),6.35-6.25(1H,m),3.29(3H,s),3.09(2H,t),2.60-2.54(2H,m).
实施例55
(R)-γ-(2,5-二氯苯氧基)-2-噻唑丙胺盐酸盐
a)[(3S)-3-羟基-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯
在-10℃、氮气氛下,向(R)-3-甲基-CBS-氧杂氮杂硼杂环戊烯(1M甲苯溶液,0.43ml)在无水四氢呋喃(30ml)内的溶液中加入硼烷-四氢呋喃络合物(1M四氢呋喃溶液,2.58ml),并在-10℃搅拌15分钟。用45分钟滴加[3-氧代-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯(1.1g,4.3mmol)在无水四氢呋喃(20ml)中的溶液,并用16小时将所得混合物温热至室温。加入甲醇(10ml),并将该混合物在室温搅拌15分钟,然后减压除去溶剂。再加入甲醇(10ml),并减压除去,获得了粗的黄色油状物。通过快速色谱纯化(二氧化硅,25-100%乙酸乙酯在异己烷中的混合物),获得了0.74g(67%)澄清的树胶状物。
MS APCI+ve m/z 259[(M+H)+].
1H NMR 300MHz(CDCl3)7.72(1H,d),7.29(1H,d),5.06-5.02(1H,m),4.95(1H,bd s),4.75(1H,s),3.70-3.58(1H,m),3.25-3.16(1H,m),2.24-2.16(1H,m),1.93-1.87(1H,m),1.44(9H,s).
b)[(3R)-3-(2,5-二氯苯氧基)-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯
在0℃、氮气氛下,用5分钟向2,5-二氯苯酚(163mg,1mmol)、[(3S)-3-羟基-3-(2-噻唑基)丙基]氨基甲酸1,1-二甲基乙酯(258mg,1mmol)和三苯基膦(315mg,1.2mmol)在无水四氢呋喃(30ml)内的溶液中滴加偶氮二甲酸二异丙酯(243mg,0.24ml,1.2mmol)。将该混合物在室温搅拌16小时,然后将该反应真空浓缩,获得了粗的黄色树胶状物。通过快速色谱纯化(二氧化硅,15%乙酸乙酯在异己烷中的混合物),获得了245mg澄清的油状物(63%)。
MS APCI+ve m/z 403/405/407[(M+H)+].
1H NMR 300MHz(CDCl3)7.79(1H,d),7.35(1H,d),7.29(1H,d),6.93(1H,d),6.90(1H,dd),5.66(1H,dd),5.03(1H,bd s),3.50-3.20(2H,m),2.45-2.25(2H,m),1.43(9H,s).
c)(R)-γ-(2,5-二氯苯氧基)-2-噻唑丙胺盐酸盐
本标题化合物是使用实施例53(d)的方法制得的,获得了144mg白色固体(70%)。
MS APCI+ve m/z 303/305[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.95(3H,m),7.78(1H,d),7.56(1H,d),7.53(1H,d),7.34(1H,dd),5.36-5.30(1H,m),3.08-2.84(2H,m),2.46-2.26(2H,m).
实施例56
2-[3-氨基-1-(2-噁唑基)丙氧基]-4-氯苄腈草酸盐
a)3-氯-1-(2-噁唑基)-1-普鲁本辛
在-70℃、氮气氛下,向噁唑(2.93g,42.5mmol)在四氢呋喃(150ml)内的溶液中滴加正丁基锂(17ml 2.5M己烷溶液),并将该溶液搅拌20分钟。加入氯化锌(84.9ml 1M乙醚溶液),用45分钟将该溶液温热至0℃。加入固体碘化亚铜(8.09g,42.5mmol),10分钟后,加入3-氯丙酰氯(8.38ml,87.8mmol)。1小时后,加入乙酸乙酯和氯化铵水溶液。分离出有机层,依次用氯化铵水溶液、水和盐水洗涤。将该溶液干燥(用硫酸钠),并蒸发,获得了15.5g粗产物,为红色油状物。该混合物不用进一步纯化直接使用。
1H NMR 300MHz(CDCl3)7.86(1H,s),7.36(1H,s),3.93(2H,t),3.57(2H,m).
b)R-α-(2-叠氮基乙基)-2-噁唑甲醇
在氮气氛下将(S)-2-甲基-CBS-氧杂氮杂硼杂环戊烯(0.72ml 1M甲苯溶液)加到四氢呋喃(5ml)中,并将该溶液冷却至-5℃。滴加硼烷-四氢呋喃络合物(7.2ml 1M四氢呋喃溶液),并将该溶液搅拌10分钟。滴加实施例56(a)粗产物(约7.24mmol)在四氢呋喃(7ml)中的溶液,用16小时将该反应缓慢地温热至0℃。小心地加入甲醇(20ml),并真空除去挥发性物质。再进行2次加入甲醇/溶剂蒸发循环。通过快速色谱法纯化残余物,使用10-40%乙酸乙酯/异己烷作为洗脱剂,获得了724mg无色油状物。将油状物置于二甲亚砜(5ml)中,加入固体叠氮化钠(450mg),并将该反应在65℃加热16小时。冷却至室温后,加入水,用乙醚将该溶液萃取3次(3×)。将合并的有机萃取液干燥(用硫酸钠),真空除去溶剂,获得了490mg本子标题化合物,为橙色油状物,不用进一步纯化直接使用。
1H NMR 300MHz(CDCl3)7.65(1H,s),7.10(1H,s),4.97(1H,dt),3.63-3.47(2H,m),3.05(1H,bs),2.28-2.07(2H,m).
c)2-[3-氨基-1-(2-噁唑基)丙氧基]-4-氯苄腈草酸盐
向实施例56(b)产物(160mg)在二甲基甲酰胺(2ml)内的溶液中加入氢化钠(76mg 60%的矿物油分散液),并将该反应搅拌1小时。加入固体4-氯-2-氟-苄腈(296mg),并将该反应搅拌2小时。加入水,并用乙醚萃取该溶液。分离出有机萃取液,干燥(用硫酸钠),并真空除去溶剂。将残余物置于四氢呋喃(4ml)中,并加入三苯基膦(283mg)。5分钟后,加入水(1ml),并将该反应搅拌16小时。再加入水(2ml),将该反应在55℃搅拌3小时,然后在室温搅拌48小时。将该反应倒入乙酸乙酯/1N氢氧化钠水溶液中。分离出有机萃取液,干燥(用硫酸钠),并真空除去溶剂。通过RP-HPLC纯化,获得了游离碱形式的本标题产物(20mg),为白色固体。将该产物置于乙醚/二氯甲烷(1∶1)中,加入草酸(15mg)在乙醚(1ml)中的溶液。过滤出所得固体,并真空干燥,获得了4mg本标题产物,为吸湿性白色固体。
MS APCI[+ve m/z 278[(M+H)+].
1H NMR 400MHz(d4-MeOH)7.87(1H,s),7.66(1H,d),7.34(1H,s),7.22(1H,d),7.17(1H,s),3.21(1H,m),3.10(1H,m),2.73(1H,ddd),2.46(1H,ddd).
实施例57
γ-(2,5-二氯苯氧基)-2-噁唑丙胺草酸盐
本标题化合物是按照类似于实施例56(c)的方法由实施例56(b)产物和1,4-二氯-2-氟苯制得的。通过重结晶(用2-丙醇/甲醇/乙醚)进行最后的纯化,获得了米色固体。
MS APCI+ve m/z 287[(M+H)+].
1H NMR 400MHz(d4-MeOH)7.96(1H,s),7.37(1H,d),7.23(1H,s),7.18(1H,m),7.02(1H,dd),5.70(1H,dd),3.28(2H,m),2.59(1H,m),2.47(1H,m).
实施例58
2-[[-3-氨基-1-(3-吡啶基)丙基]氧基]-4-氯-5-氟苄腈草酸盐
a)[3-氧代-3-(3-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
在0℃将异丙基溴化镁(7.1ml,2M四氢呋喃溶液,14.2mmol)加到3-溴吡啶(2.24g,14.2mmol)在四氢呋喃(15ml)内的溶液中,并在20℃搅拌1小时。加入[3-(甲氧基甲基氨基)-3-氧代丙基氨基甲酸1,1-二甲基乙酯(1.08g,4.65mmol)在四氢呋喃(6ml)中的溶液,并将该混合物搅拌18小时。用饱和氯化铵水溶液骤冷处理该混合物,用乙醚萃取(3次),将合并的有机萃取液干燥(用硫酸钠),并蒸发,获得了油状物。通过二氧化硅色谱纯化,用汽油-丙酮洗脱,获得了568mg(49%)本子标题化合物,为无色油状物。
MS APCI+ve m/z 251[(M+H)+].
b)[3-羟基-3-(3-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
在0℃,将硼烷(3.0ml,1M四氢呋喃溶液)加到(3αS)-四氢-1-甲基-3,3-二苯基-3H-吡咯并[1,2-c][1,3,2]氧杂氮杂硼杂环戊二烯(0.22ml,1M甲苯溶液)在四氢呋喃(5ml)内的溶液中。用30分钟加入步骤(a)产物(1.13g,4.52mmol)在四氢呋喃(3ml)中的溶液,然后在20℃搅拌24小时。加入甲醇,将该溶液蒸发,加入甲醇(15ml)和2M盐酸(5ml),并搅拌45分钟。加入碳酸钾水溶液和二碳酸二叔丁酯(250mg),并用乙酸乙酯(2×)和二氯甲烷(4×)萃取该混合物。将有机萃取液干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用二氯甲烷-甲醇洗脱,获得了928mg(73%)本子标题化合物,为无色油状物。
MS APCI+ve m/z 253[(M+H)+].
c)[(3-(5-氯-2-氰基-4-氟苯氧基)-3-(3-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
将氢化钠(141mg,60%的油悬浮液)加到步骤(b)产物(785mg,2.96mmol)和4-氯-2,5-二氟苄腈(546mg,3.75mmol)在四氢呋喃(9ml)内的溶液中,并将所得悬浮液搅拌0.5小时。用饱和氯化铵水溶液骤冷处理该混合物,碱化至pH 8,并用乙酸乙酯萃取(3次)。将合并的有机萃取液干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用汽油-丙酮洗脱,获得了1.05g(88%)本子标题化合物,为无色油状物。
MS APCI+ve m/z 406[(M+H)+].
d)2-[[-3-氨基-1-(3-吡啶基)丙基]氧基]-4-氯-5-氟苄腈草酸盐
将步骤(c)产物(227mg,0.56mmol)在4M HCl的二噁烷溶液(4ml)中的溶液搅拌0.5小时。加入碳酸钾水溶液,用二氯甲烷萃取该混合物,将有机萃取液干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用二氯甲烷-3M氨的甲醇溶液洗脱,获得了浅黄色树胶状物(167mg)。向该胺在异丙醇(3ml)内的溶液中加入草酸(23mg)在热甲醇(0.3ml)中的溶液。收集冷却所形成的晶体,干燥,获得了180mg(100%)本标题化合物,为白色固体。
MS APCI+ve m/z 306[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.66(d,1H),8.56(dd,1H),8.02(d,1H),7.82(dt,1H),7.52(d,1H),7.46(dd,1H),6.42(s,2H),5.32(dd,1H),2.89(t,2H),2.37-2.27(m,1H),2.21-2.10(m,1H).
实施例59
4-氯-5-氟-2-[3-(甲基氨基)-1-(3-吡啶基)丙氧基]苄腈草酸盐
a)[(3-(5-氯-2-氰基-4-氟苯氧基)-3-(3-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
将氢化钠(34.2mg,60%的油悬浮液,0.86mmol)加到实施例58(c)产物(219mg,0.54mmol)和甲基碘(0.2ml,3.2mmol)在四氢呋喃(4ml)内的溶液中,并搅拌3小时。加入氯化铵水溶液,用二氯甲烷萃取该混合物(3次)。将合并的有机萃取液干燥(用硫酸钠),蒸发,并通过硅胶色谱纯化,用汽油-丙酮洗脱,获得了本子标题化合物,为无色油状物(157mg,69%)。
MS APCI+ve m/z 420[(M+H)+].
b)4-氯-5-氟-2-[3-(甲基氨基)-1-(3-吡啶基)丙氧基]苄腈草酸盐
本标题化合物是通过实施例58(d)的方法由实施例59(a)产物制得的。
MS APCI+ve m/z 320[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.67(d,1H),8.57(d,1H),8.03(d,1H),7.83(d,1H),7.54(d,1H),7.47(dd,1H),5.88(t,1H),3.11-2.95(m,2H),2.59(s,3H),2.45-2.32(m,1H),2.30-2.19(m,1H).
实施例60
γ-[2-氯-5-(三氟甲基)苯氧基]-3-吡啶丙胺草酸盐
a)[(3-(2-氯-5-三氟甲基苯氧基)-3-(3-吡啶基)丙基]-氨基甲酸1,1-二甲基乙酯
在0℃,将偶氮二甲酸二乙酯(0.71ml,4.47mmol)加到[3-羟基-3-(3-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯(实施例58(b))(291mg,1.15mmol)、2-氯-5-三氟甲基苯酚(232mg,1.18mmol)和三苯基膦(455mg,1.73mmol)在四氢呋喃(6ml)内的溶液中,并在20℃搅拌18小时。将该反应真空浓缩,通过二氧化硅色谱纯化残余物,用汽油-乙醚洗脱,获得了本子标题化合物(394mg,79%)。
MS APCI+ve m/z 431[(M+H)+].
b)γ-[2-氯-5-(三氟甲基)苯氧基]-3-吡啶丙胺草酸盐
本标题化合物是通过实施例58(d)的方法用实施例60(a)产物制得的。
MS APCI+ve m/z 331[(M+H)+].
1H NMR 300MHz(d6-DMSO)δ8.64(d,1H),8.54(dd,1H),7.99(s,2H),7.81(dt,1H),7.69(d,1H),7.44(dd,1H),7.36-7.28(m,2H),5.93(dd,1H),3.02-2.91(m,2H),2.42-2.12(m,2H).
实施例61
2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苄腈草酸盐
a)[3-(6-甲氧基-2-吡啶基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯
在-78℃,将丁基锂(2.5M己烷溶液,1.4ml)加到6-溴-2-甲氧基吡啶(690mg,4.0mmol)在四氢呋喃(4ml)内的溶液中,并搅拌1小时。加入[3-(甲氧基甲基氨基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯(344mg,1.42mmol)在四氢呋喃(3ml)中的溶液,并用3小时将该混合物温热至0℃。用饱和氯化铵水溶液骤冷处理该混合物,用乙酸乙酯萃取(3次)。将合并的有机萃取液干燥(用硫酸钠),蒸发,并通过二氧化硅色谱纯化,用汽油-丙酮洗脱,获得了本子标题化合物,为无色油状物(291mg,73%)。
MS APCI+ve m/z 281[(M+H)+].
b)[3-羟基-3-(6-甲氧基-2-吡啶基)-丙基]氨基甲酸1,1-二甲基乙酯
将实施例61(a)产物(489mg,1.75mmol)和四氢硼酸钠(133mg,3.52mmol)在四氢呋喃(4ml)中的混合物搅拌5小时。加入2M盐酸,将该混合物用乙酸乙酯萃取(3次)。将合并的有机萃取液干燥(用硫酸钠),蒸发,并通过二氧化硅色谱纯化,用汽油-乙醚洗脱,获得了本子标题化合物,为无色油状物(446mg,90%)。
MS APCI+ve m/z 283[(M+H)+].
c)[(3-(5-氯-2-氰基-4-氟苯氧基)-3-(6-甲氧基-2-吡啶基)-丙基]-氨基甲酸1,1-二甲基乙酯
本子标题化合物是通过实施例58(c)的方法,使用[3-羟基-3-(6-甲氧基-2-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯(实施例61(b))和4-氯-2,5-二氟苄腈制得的。
MS APCI+ve m/z 436[(M+H)+].
d)2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苯甲酰胺草酸盐
本标题化合物是通过实施例58(d)的方法由实施例61(c)产物制得的。
MS APCI+ve m/z 336[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.05(d,1H),7.76(t,1H),7.48(d,1H),7.04(d,1H),6.80(d,1H),5.71(t,1H),3.85(s,3H),3.04-2.95(m,2H),2.39-2.25(m,2H).
实施例62
2-[[(1R)-3-氨基-1-(5-甲基-3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈富马酸盐
通过实施例89步骤(a)-(c)和实施例93步骤(a)-(c)中描述的方法,将5-甲基异噁唑-3-甲酸转化成本标题化合物,获得了固体。
MS APCI+ve m/z 310[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.04(1H,d),7.58(1H,d),6.40(2H,s),6.34(1H,s),5.99-5.91(1H,m),2.94(2H,t),2.40(3H,s),2.38-2.29(1H,m),2.26-2.15(1H,m).
实施例63
2-[3-氨基-1-(1,6-二氢-6-氧代-2-吡啶基)丙氧基]-4-氯-5-氟苄腈草酸盐
将实施例61(d)产物(313mg,0.932mmol)在62%溴化氢水溶液(2ml)中的溶液于70℃加热5.5小时。加入碳酸钾水溶液,并用二氯甲烷萃取该混合物。将有机萃取液干燥(用硫酸钠),蒸发,并通过二氧化硅色谱纯化,用二氯甲烷-7M氨的甲醇溶液洗脱,然后用甲醇洗脱,依次获得了:2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苯甲酰胺,33.8mg。草酸盐是通过实施例58(d)的方法制得的,为固体(31.7mg)。
MS APCI+ve m/z 354[(M+H)+].1H NMR 400MHz(d6-DMSO)8.11-7.88(m,4H),7.73(ddd,1H),7.65(d,1H),7.38(d,1H),7.07(d,1H),6.78(d,1H),5.76-5.70(m,1H),3.85(s,3H),3.04-2.89(m,2H),2.38-2.20(m,2H);
2-[3-氨基-1-(1,6-二氢-6-氧代-2-吡啶基)丙氧基]-4-氯-5-氟苄腈,9.5mg,按照实施例58(d)的方法将其转化成草酸盐,获得了固体(5.3mg)。
MS APCI+ve m/z 322[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.08(d,1H),7.99-7.76(m,2H),7.53(t,1H),7.34(d,1H),6.45(d,2H),5.48(s,1H),2.94(s,2H),2.39-2.17(m,2H).
实施例64
(R)-γ-[2-氯-5-(三氟甲基)苯氧基]-2-吡啶丙胺二盐酸盐
a)[3-氧代-3-(2-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
在氮气氛下,将2-溴吡啶(3.16g)在无水乙醚(50ml)中冷却至-60℃。滴加正丁基锂(2.5M己烷溶液,8.5ml),并在-60℃继续搅拌15分钟。滴加(甲氧基甲基氨基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯(2.32g)在乙醚(20ml)中的溶液,将该反应在-40℃搅拌1小时,然后在0℃搅拌0.5小时。用饱和氯化铵水溶液骤冷处理该反应,并用乙酸乙酯萃取。将有机萃取液依次用水、盐水洗涤,用硫酸镁干燥,蒸发至油状物,将其过硅胶柱,用己烷∶乙酸乙酯(4∶1)洗脱,获得了产物,为浅黄色油状物(1.4g)。
MS APCI+ve m/z 251[(M+H)+].
1H NMR 300MHz(CDCl3)8.68(1H,dt),8.03(1H,d),7.84(1H,td),7.48(1H,ddd),5.10(1H,s),3.56(2H,q),3.43(2H,t),1.43(9H,s).
b)[(3S)-3-羟基-3-(2-吡啶基)丙基]氨基甲酸,1,1-二甲基乙酯
通过实施例68(a)的方法将步骤(a)产物(0.6g)还原,获得了澄清的油状物(0.24g)。
1H NMR 400MHz(CDCl3)8.53(1H,d),7.70(1H,dd),7.36(1H,d),7.20(1H,dd),5.04(1H,s),4.82(1H,dt),4.65(1H,s),3.45(1H,m),3.33-3.17(1H,m),2.09(1H,dd),1.84-1.71(1H,m),1.44(9H,s).
c)(R)-3-[2-氯-5-(三氟甲基)苯氧基]-3-(2-吡啶基)丙基]氨基甲酸1,1-二甲基乙酯
用步骤(b)产物(0.24g)和2-氯-4-三氟甲基苯酚进行实施例8(a)中描述的方法,获得了产物,为油状物(0.3g)。
MS APCI+ve m/z 431[(M+H)+].
1H NMR 400MHz(CDCl3)8.60(1H,dd),7.67(1H,td),7.47(1H,d),7.37(1H,d),7.22(1H,ddd),7.11(1H,dd),6.95(1H,d),5.44(1H,dd),5.15(1H,s),3.45(1H,dq),3.30(1H,dt),2.38-2.20(2H,m),1.40(9H,s).
d)(R)-γ-[2-氯-5-(三氟甲基)苯氧基]-2-吡啶丙胺二盐酸盐
用步骤(c)产物(0.3g)进行实施例88(b)中描述的方法,获得了产物,为白色固体(0.25g)。
MS APCI+ve m/z 331[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.63(1H,dd),8.11(3H,s),7.88(1H,td),7.71(1H,d),7.47(1H,d),7.40(1H,ddd),7.30(1H,d),7.24(1H,d),5.84(1H,dd),3.01(2H,d),2.43-2.23(2H,m).
实施例65
2-[3-氨基-1-(6-溴-3-吡啶基)丙氧基]-4-氯苄腈草酸盐
a)[3-(6-溴-3-吡啶基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯
本子标题化合物是通过实施例58(a)的方法由2,5-二溴吡啶和[3-(甲氧基甲基氨基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯制得的。
1H NMR 300MHz(CDCl3) 8.90(1H,d),8.07(1H,dd),7.62(1H,dd),5.07(1H,s),3.53(1H,q),3.50(1H,q),3.19(2H,t),1.43(9H,s).
b)[3-(6-溴-3-吡啶基)-3-羟基丙基]氨基甲酸1,1-二甲基乙酯
将实施例65(a)产物(645mg,1.96mmol)与四氢硼酸钠(115mg,3.04mmol)在四氢呋喃(5ml)中的混合物搅拌18小时。加入2M盐酸,用乙酸乙酯萃取该混合物(3次)。将合并的有机萃取液干燥(用硫酸镁),蒸发,并通过硅胶色谱纯化,用乙醚洗脱,获得了本子标题化合物,为无色油状物(6.60g)。
1H NMR 300MHz(CDCl3)8.33(1H,d),7.63(1H,dd),7.46(1H,d),4.95-4.86(1H,m),4.78-4.69(1H,m),4.33-4.27(1H,m),3.68-3.51(1H,m),3.22-3.09(1H,m),1.89-1.66(2H,m),1.46(9H,s).
c)[3-(6-溴-3-吡啶基)-3-(5-氯-2-氰基苯氧基)丙基]氨基甲酸1,1-二甲基乙酯
本子标题化合物是通过实施例60(a)的方法由实施例65(b)产物和4-氯-2-羟基苄腈制得的。
1H NMR 300MHz(CDCl3)8.40(1H,d),7.65(1H,dd),7.55-7.41(1H,m),7.33(1H,d),7.06-6.93(1H,m),6.80(1H,d),5.38(1H,dd),4.84(1H,s),3.45-3.28(2H,m),2.36-2.03(2H,m),1.44(9H,s).
d)2-[3-氨基-1-(6-溴-3-吡啶基)丙氧基]-4-氯苄腈草酸盐
本标题化合物是通过实施例58(d)的方法由实施例65(c)产物制得的。
MS APCI+ve m/z 366[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.50(s,1H),7.85-7.70(m,3H),7.31(s,1H),7.21(dd,1H),5.96-5.88(m,1H),2.94-2.86(m,2H),2.39-2.07(m,2H).
实施例66
2-[[3-氨基-1-(5-异噁唑基)丙基]氧基]-4-氯苄腈草酸盐
a)N-甲氧基-N-甲基-5-异噁唑甲酰胺
将异噁唑-5-甲酸(2.81g)、N-甲氧基-N-甲基胺盐酸盐(2.49g)、EDCI(4.96g)、二甲基氨基吡啶(3.15g)和4-甲基吗啉(2.8ml)在二氯甲烷(20ml)中的溶液搅拌18小时。加入2M盐酸,用二氯甲烷萃取该混合物(3次)。将有机层依次用碳酸氢钠水溶液和盐水洗涤,合并,干燥(用硫酸镁),蒸发,并通过硅胶色谱纯化,用汽油-乙醚洗脱,获得了本子标题化合物,为无色油状物(2.94g,76%)。
1H NMR 300MHz(CDCl3)8.35(1H,d),6.89(1H,d),3.83(3H,s),3.39(3H,s).
b)3-氯-1-(5-异噁唑基)-1-普鲁本辛
在-78℃,将乙烯基溴化镁(20ml,1M四氢呋喃溶液)加到实施例66(a)产物(2.59g,16.6mmol)在四氢呋喃(35ml)内的溶液中,并用2.5小时温热至0℃。冷却至-50℃后,将该混合物缓慢地倒入过量冰冷的2M盐酸中。用乙醚萃取该混合物(5次)。将有机萃取液干燥(用硫酸镁),并蒸发,获得了棕色油状物。加入1M氯化氢的乙醚溶液(20ml),并搅拌40分钟。真空除去溶剂,获得了本子标题化合物(2.0g,75%)。
1H NMR 300MHz(CDCl3)8.39(1H,s),6.96(1H,s),3.91(2H,t),3.49(2H,t).
c)α-(2-氯乙基)-5-异噁唑甲醇
在0℃,将硼烷(4.2ml,1M四氢呋喃溶液)加到(3αS)-四氢-1-甲基-3,3-二苯基-3H-吡咯并[1,2-c][1,3,2]氧杂氮杂硼杂环戊二烯(0.06ml,1M甲苯溶液)在四氢呋喃(5ml)内的溶液中。缓慢地加入实施例66(b)产物(998mg,6.25mmol)在四氢呋喃(5ml)中的溶液,然在20℃搅拌4小时。加入甲醇,将该溶液蒸发,将残余物与甲醇共沸。通过二氧化硅色谱纯化,用汽油-乙醚纯化,获得了本子标题化合物,为无色油状物(562mg,56%)。
MS APCI+ve m/z 162[(M+H)+].
d)4-氯-2-[3-氯-1-(5-异噁唑基)丙氧基]-苄腈
该化合物是通过实施例8(a)的方法使用α-(2-氯乙基)-5-异噁唑甲醇和4-氯-2-羟基苄腈制得的。
1H NMR 300MHz(CDCl3)8.26(1H,d),7.52(1H,dd),7.09(1H,dt),7.02(1H,s),6.36(1H,t),5.82-5.74(1H,m),3.95-3.84(1H,m),3.81-3.70(1H,m),2.75-2.61(1H,m),2.54-2.40(1H,m).
e)2-[[3-氨基-1-(5-异噁唑基)丙基]氧基]-4-氯苄腈草酸盐
将实施例66(d)产物(100mg,0.34mmol)和叠氮化钠(34mg,0.52mmol)在DMSO(0.8ml)中的溶液搅拌3天。加入三苯基膦(88mg,0.34mmol)、四氢呋喃(2ml)和水(0.5ml),并将该溶液搅拌2天。通过二氧化硅色谱纯化,用二氯甲烷-7M氨的甲醇溶液洗脱,获得了浅黄色树胶状物(27mg)。向该胺在异丙醇(3ml)内的溶液中加入草酸(9mg)在甲醇(0.3ml)中的溶液。收集在冷却下形成的晶体,干燥,获得了本标题化合物,为白色固体(91mg,97%)。
MS APCI+ve m/z 278[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.61(1H,d),7.82(1H,d),7.51(1H,d),7.25(1H,dd),6.68(1H,d),6.15(1H,t),5.46(3H,s),2.88(2H,t),2.42-2.21(2H,m).
实施例67
4-氯-2-[3-(2-羟基乙基)氨基]-1-(5-异噁唑基)丙氧基]苄腈草酸盐
a)4-氯-2-[3-碘-1-(5-异噁唑基)丙氧基]苄腈
将实施例66(d)氯化物(106mg,0.356mmol)和碘化钠(1g)在丙酮(10ml)中的溶液在20℃搅拌2天,在55℃搅拌1天。真空除去溶剂,加入水,用二氯甲烷萃取该混合物(3次)。将有机层干燥(用硫酸钠),蒸发,获得了本子标题化合物(159mg,100%)。
1H NMR 300MHz(CDCl3)8.26(1H,d),7.53(1H,d),7.08(1H,dd),7.03(1H,s),6.35(1H,s),5.66(1H,dd),3.53-3.30(2H,m),2.72-2.04(2H,m).
b)4-氯-2-[3-[(2-羟基乙基)氨基]-1-(5-异噁唑基)丙氧基]苄腈草酸盐
将4-氯-2-[3-碘-1-(5-异噁唑基)丙氧基]苄腈(159mg,0.41mmol)和乙醇胺(0.2ml)在四氢呋喃(2ml)中的溶液搅拌2天。加入水,用二氯甲烷萃取该混合物。将合并的有机萃取液干燥(用硫酸钠),蒸发,并通过二氧化硅色谱纯化,用二氯甲烷-7M氨的甲醇溶液洗脱,获得了橙色树胶状物(40mg)。按照实施例58(d)的方法制备草酸盐,获得了本标题化合物,为白色固体(40mg,30%)。
MS APCI+ve m/z 322[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.63(d,1H),7.83(d,1H),7.52(d,1H),7.27(dd,1H),6.69(d,1H),6.17(t,1H),3.94(s,2H),3.65(t,4H),3.10(t,1H),3.04(t,1H),2.48-2.43(m,2H).
实施例68
(R)-γ-(2,5-二氯苯氧基)-5-异噁唑丙胺草酸盐
a)(S)-α-(2-氯乙基)-5-异噁唑甲醇
在-10℃,将硼烷(18ml,1M四氢呋喃溶液)加到(3αR)-四氢-1-甲基-3,3-二苯基-3H-吡咯并[1,2-c][1,3,2]氧杂氮杂硼杂环戊二烯(1.3ml,1M甲苯溶液)在四氢呋喃(10ml)内的溶液中。缓慢地加入3-氯-1-(3-异噁唑基)-1-普鲁本辛(实施例66(b))(6g,37.6mmol)在四氢呋喃(12ml)中的溶液,然后在-10℃至20℃搅拌18小时。加入甲醇,将该溶液蒸发,将残余物与甲醇共沸。通过二氧化硅色谱纯化,用汽油-乙醚洗脱,获得了本子标题化合物,为无色油状物(774mg,13%)。
MS APCI+ve m/z 162[(M+H)+].
b)(S)-α-(2-叠氮基乙基)-5-异噁唑甲醇
将实施例68(a)产物(767mg,4.76mmol)和叠氮化钠(342mg,5.26mmol)在DMSO(8ml)中的溶液在65℃加热18小时。加入水,并用乙酸乙酯萃取该混合物(3次)。将合并的有机萃取液干燥(用硫酸镁),蒸发,并通过二氧化硅色谱纯化,用汽油-乙醚洗脱,获得了本子标题化合物,为无色油状物(454mg,57%)。
1H NMR 300MHz(CDCl3)8.22(1H,d),6.26(1H,t),5.12-5.03(1H,m),3.65-3.46(2H,m),2.54(1H,d),2.18-2.05(2H,m).
c)(R)-γ-(2,5-二氯苯氧基)-5-异噁唑丙胺草酸盐
在0℃,将偶氮二甲酸二乙酯(0.23ml,1.46mmol)加到三苯基膦(355mg,1.35mmol)在四氢呋喃(3ml)内的溶液中。10分钟后,加入实施例68(b)产物(151mg,0.90mmol)和2,5-二氯苯酚(164mg,1.0mmol)在四氢呋喃(3ml)中的溶液,并在20℃搅拌3小时。加入三苯基膦(268mg,1.02mmol)和水(1ml),并搅拌2.5天。将该反应真空浓缩,通过二氧化硅色谱纯化残余物,用二氯甲烷-7M氨的甲醇溶液洗脱,获得了浅黄色树胶状物(91mg)。向该胺在异丙醇(3ml)内的溶液中加入草酸(26mg)在甲醇(1ml)中的溶液。收集在冷却下形成的晶体,干燥,获得了本标题化合物,为白色固体(37mg,14%)。
MS APCI+ve m/z 287[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.61(1H,d),7.50(1H,d),7.34(1H,d),7.11(1H,d of d),6.62(1H,d),6.02(1H,d of d),2.98(2H,t),2.44-2.24(2H,m).
实施例69
(R)-γ-(2,5-二氯苯氧基)-N-甲基-苯丙胺富马酸盐
按照在实施例2(b)中描述的方法,使用[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯(266mg,1.0mmol)和2,5-二氯苯酚(163mg,1.0mmol)制得了本标题化合物,最后将其转化成富马酸盐。
MS APCI+ve m/z 310[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.45-7.28(6H,m),7.08(1H,d),6.98-6.95(1H,dd),6.45(2H,s),5.75-5.71(1H,m),2.95-2.90(2H,t),2.50(3H,s),2.34-2.08(2H,m).
实施例70
(R)-γ-[2-氯-5-(三氟甲基)苯氧基]-N-甲基-苯丙胺富马酸盐
按照实施例2(b)中描述的方法,使用[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯(281mg,1.06mmol)和4-氯-3-羟基三氟甲苯(208mg,1.06mmol),制得了本标题化合物,最后将其转化成富马酸盐。
MS APCI+ve m/z 344[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.67-7.64(1H,dd),7.44-7.23(7H,m),6.44(2H,s),5.86-5.82(1H,m),2.94(2H,t),2.50(3H,s),2.38-2.12(2H,m).
实施例71
4-氯-2-[[(1R)-3-(甲基氨基)-1-(2-噻吩基)丙基]氧基]苄腈草酸盐
a)4-氯-2-[[(1R)-3-氯-1-(2-噻吩基)丙基]氧基]苄腈
按照实施例5(a)中描述的方法,使用4-氯-2-羟基苄腈(303mg,1.97mmol)和(S)-α-(2-氯乙基)噻吩甲醇(349mg,1.97mmol),制得了本标题化合物,为白色固体结晶(373mg,61%)。
1H NMR 300MHz(CDCl3)7.48-7.45(1H,d),7.33-7.31(1H,dd),7.14-7.13(1H,m),7.03-6.97(3H,m),5.82-5.77(1H,q),3.91-3.83(1H,m),3.67-3.59(1H,m),2.70-2.63(1H,m).2.42-2.33(1H,m).
b)4-氯-2-[[(1R)-3-碘-1-(2-噻吩基)丙基]氧基]苄腈
按照实施例5(b)中描述的方法将步骤(a)产物(368mg,1.18mmol)转化成本标题化合物,获得了浅棕色油状物(408mg,86%)。该产物直接用于下一步骤。
c)4-氯-2-[[(1R)-3-(甲基氨基)-1-(2-噻吩基)丙基]氧基]苄腈草酸盐
按照实施例5(c)中描述的方法,使用步骤(b)产物(400mg,0.99mmol)来制备本标题化合物,但是要制成草酸盐(135mg,34%)。
MS APCI+ve m/z 307[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.79-7.77(1H,d),7.58-7.56(1H,d),7.47-7.46(1H,d),7.27-7.26(1H,m),7.20-7.18(1H,dd),7.05-7.03(1H,m),6.17-6.14(1H,t),3.09-2.94(2H,m),2.59(3H,s),2.50-2.39(1H,m),2.33-2.22(1H,m).
实施例72
2-[[(1R)-3-氨基-1-(3-呋喃基)丙基]氧基]-4-氯-5-氟苄腈富马酸盐
a)[3-(3-呋喃基)-3-氧代丙基]-氨基甲酸1,1-二甲基乙酯
将3-溴呋喃(5.88g,40mmol)溶解在无水四氢呋喃(60ml)中,并将该溶液冷却至-78℃。滴加正丁基锂(2.29M,17.5ml,40mmol),并将该溶液在-78℃搅拌。用1小时滴加[3-(甲氧基甲基氨基)-3-氧代丙基]氨基甲酸1,1-二甲基乙酯在四氢呋喃(40ml)中的溶液。将该溶液搅拌过夜,同时温热至室温。加入饱和氯化铵水溶液(30ml),并用乙酸乙酯萃取该混合物(3×70ml)。将合并的有机萃取液用水洗涤(3×30ml),干燥(用硫酸钠)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用己烷∶乙酸乙酯(7∶3)洗脱,获得了本标题化合物,为浅黄色固体(3.03g,63%)。
1H NMR 300MHz CDCl3 8.05(1H,d),7.40-7.50(1H,m),6.72-6.82(1H,m),5.07(1H,s),3.41-3.60(2H,m),2.90-3.09(2H,m),1.43(9H,s).
b)[(3R)-3-(3-呋喃基)-3-羟基丙基]氨基甲酸1,1-二甲基乙酯
将(S)-2-甲基-CBS-氧杂氮杂硼杂环戊烯(1M甲苯溶液,0.84ml,0.836mmol)加到无水四氢呋喃(50ml)中,并将该溶液冷却至0℃。然后滴加硼烷:四氢呋喃络合物(1M,5.02ml,5.02mmol),同时将温度保持在0℃。将该混合物搅拌15分钟,然后用1小时滴加步骤(a)产物(2.0g,8.36mmol)在四氢呋喃(50ml)中的溶液,同时将温度保持在0℃。搅拌过夜,同时温热至室温。用甲醇(5ml)骤冷处理该反应,并搅拌半小时。真空除去溶剂,加入另一等分试样的甲醇(20ml)。真空除去溶剂,通过快速二氧化硅色谱纯化残余物,用己烷∶乙酸乙酯(1∶1)洗脱,获得了本标题化合物,为无色油状物(1.685g,84%)。
1H NMR 300MHz(CDCl3)7.35-7.43(2H,m),6.40(1H,t),4.85(1H,s),4.69-4.77(1H,m),3.41-3.60(1H,m),3.09-3.30(2H,m),1.80-1.92(2H,m),1.51(9H,s).
c)[(3R)-3-(5-氯-2-氰基-4-氟苯氧基)-3-(3-呋喃基)丙基]-氨基甲酸1,1-二甲基乙酯
将步骤(b)产物(277mg,1.15mmol)和4-氯-2,5-二氟苄腈(199mg,1.15mmol)溶解在二甲基甲酰胺(10ml)中,一次性加入氢化钠(60%,48mg,1.2mmol)。将该反应在室温搅拌2小时,然后用饱和氯化铵水溶液(30ml)骤冷处理,并用乙酸乙酯萃取(3×60ml)。将合并的有机萃取液用水洗涤(3×20ml),干燥(用硫酸钠)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用己烷∶乙酸乙酯(3∶1)洗脱,获得了本标题化合物,为白色固体结晶(330mg,73%)。
1H NMR 300MHz(CDCl3)7.39-7.51(2H,m),7.36(1H,s),7.05(1H,d),6.43(1H,t),5.27-5.36(1H,m),5.19(1H,s),3.18-3.43(2H,m),2.20-2.33(1H,m),2.02-2.13(1H,m),1.49(9H,s).
d)2-[[(1R)-3-氨基-1-(3-呋喃基)丙基]氧基]-4-氯-5-氟苄腈富马酸盐
将步骤(c)产物(150mg,0.3mmol)溶解在4M HCl的二噁烷溶液(10ml)中,并在室温搅拌10分钟。将该反应置于冰浴中,小心地加入饱和碳酸氢钠水溶液(30ml)。用乙酸乙酯萃取该混合物(3×50ml),将合并的萃取液用水(20ml)洗涤,干燥(用硫酸钠)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用5%7N氨的甲醇溶液在二氯甲烷中的混合物洗脱。将产物溶解在甲醇(5ml)中,用一当量的富马酸处理。搅拌10分钟,然后真空除去溶剂,用少量乙酸乙酯研制固体残余物。过滤出白色固体,并干燥,获得了本标题化合物(50mg,40%)。
MS APCI+ve m/z 295/297[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.05(1H,d),7.87(1H,s),7.75(1H,d),7.65(1H,d),6.65(1H,s),6.51(2H,s),5.77-5.89(1H,m),2.95(2H,t),2.10-2.44(2H,m).
实施例73
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-甲基氨基)丙基]氧基]-苄腈富马酸盐
a)[(3R)-3-(5-氯-2-氰基-4-氟苯氧基)-3-(3-呋喃基)丙基]氨基甲酸1,1-二甲基乙酯
将实施例72(c)产物(460mg,1.17mmol)溶解在无水四氢呋喃(10ml)中,一次性加入氢化钠(60%,104mg,2.6mmol)。将该反应搅拌10分钟,然后加入甲基碘(0.66ml,10.53mmol),并将该反应在室温搅拌24小时。用饱和氯化铵水溶液(30ml)骤冷处理该反应,用乙酸乙酯萃取该混合物(3×70ml)。将合并的萃取液用水洗涤(3×30ml),干燥(用硫酸钠)并真空蒸发,获得了本标题化合物(360mg,75%)。
1H NMR 300MHz(CDCl3)7.42(2H,d),7.26-7.36(1H,m),6.99(1H,d),6.42(1H,s),5.16-5.26(1H,m),3.27-3.56(2H,m),2.87(3H,s),2.21-2.43(1H,m),2.02-2.20(1H,m),1.40(9H,s).
b)4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-甲基氨基)丙基]氧基]-苄腈富马酸盐
使用步骤(a)产物(355mg,0.87mmol)和实施例72(d)中描述的方法,制得了本标题化合物,为白色固体(210mg,78%)。
MS APCI+ve m/z 309/311[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.98(1H,d),7.80(1H,s),7.68(1H,t),7.61(1H,d),6.53(1H,t),6.44(2H,s),5.76(1H,t),2.90(2H,t),2.57(3H,s),2.33(1H,五重峰),2.17(1H,m).
实施例74
4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-(3-噻吩基)丙基]氧基]苄腈草酸盐
a)N-甲氧基-N-甲基-3-噻吩甲酰胺
将3-噻吩甲酸(10.04g,78.3mmol)溶解在二氯甲烷(250ml)中,并加入4-二甲基氨基吡啶(9.57g,78.3mmol)、N,O-二甲基羟基胺盐酸盐(7.64g,78.3mmol)、N-甲基吗啉(8.6ml,78.3mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(15.01g,78.3mmol),并将所得溶液在室温搅拌24小时。用二氯甲烷(100ml)将该反应稀释,依次用2M盐酸(3×30ml)、饱和碳酸氢钠水溶液(2×30ml)和水(3×30ml)洗涤。将有机相干燥(用硫酸镁),过滤并蒸发,获得了本标题化合物,为无色油状物(12.3g,92%)。
1H NMR 300MHz(CDCl3)8.07(1H,dd),7.58(1H,dd),7.26-7.33(1H,m),3.66(3H,s),3.37(3H,s).
b)1-(3-噻吩基)-2-丙烯-1-酮
将步骤(a)产物(2.074g,12.1mmol)溶解在无水四氢呋喃(30ml)中,并将该溶液冷却至-10℃。滴加乙烯基溴化镁(1M,14.5ml,14.5mmol),同时将温度保持在0℃以下。将所得溶液在0℃搅拌2.5小时,然后温热至室温。将该反应混合物缓慢地倒入2M盐酸(200ml)和冰中。用乙酸乙酯萃取(3×70ml),将合并的萃取液用水(2×30ml)和盐水(20ml)洗涤,干燥(用硫酸镁)并真空蒸发,获得了本标题化合物(1.288g,77%)。
1H NMR 300MHz(CDCl3)8.06-8.12(1H,m),7.58-7.64(1H,m),7.32-7.39(1H,m),6.99-7.12(1H,m),6.46(1H,dd),5.89(1H,dd).
c)3-氯-1-(3-噻吩基)-1-普鲁本辛
将步骤(b)产物(1.288g,9.3mmol)溶解在乙醚(30ml)和二氯甲烷(20ml)的混合物中,加入1M氯化氢的乙醚溶液(25ml)。将该反应在室温搅拌18小时。真空除去溶剂,获得了本标题化合物(1.482g,91%)。
1H NMR 300MHz(CDCl3)8.02-8.12(1H,m),7.51-7.61(1H,m),7.30-7.40(1H,m),3.90(2H,t),3.37(2H,t).
d)(R)-α-(2-氯乙基)-3-噻吩甲醇
使用实施例72(b)中描述的方法和3-氯-1-(3-噻吩基-1-普鲁本辛(984mg,5.6mmol),制得了本标题化合物,为无色油状物(647mg,65%)。
1H NMR 300MHz(CDCl3)7.29-7.36(1H,m),7.20-7.27(1H,m),7.04-7.12(1H,m),5.02-5.09(1H,m),3.70-3.82(1H,m),3.52-3.62(1H,m),2.08-2.34(2H,m),1.95(1H,d).
e)4-氯-2-[[(1R)-3-氯-1-(3-噻吩基)-丙基]氧基]-5-氟-苄腈
使用步骤(d)产物(322mg,1.84mmol)、4-氯-2,5-二氟苄腈(320mg,1.84mmol)和实施例72(c)中描述的方法,制得了本标题化合物(540mg,89%)。
1H NMR 300MHz(CDCl3)7.35-7.40(1H,m),7.29-7.34(1H,m),7.25-7.28(1H,m),7.11(1H,dt),6.95-6.99(1H,m),5.54-5.63(1H,m),3.78-3.90(1H,m),3.55-3.66(1H,m),2.53-2.65(1H,m),2.21-2.35(1H,m).
f)4-氯-5-氟-2-[[(1R)-3-碘-1-(3-噻吩基)-丙基]氧基]苄腈
使用实施例5(b)的方法和4-氯-2-[[(1R)-3-氯-1-(3-噻吩基)丙基]氧基]-5-氟苄腈(520mg,1.57mmol),制得了本标题化合物(640mg,97%)。
1H NMR 300MHz(CDCl3)7.35-7.39(1H,m),7.29-7.34(2H,m),7.09-7.12(1H,m),6.95-6.99(1H,m),5.42-5.51(1H,m),3.37-3.47(1H,m),3.16.3.26(1H,m),2.51-2.61(1H,m),2.26-2.38(1H,m).
g)4-氯-5-氟-2-[[(1R)-3-(甲基氨基)-1-(3-噻吩基)丙基]氧基]苄腈草酸盐
使用步骤(f)产物(210mg,0.5mmol)和实施例5(c)中描述的方法,用草酸代替盐酸,制得了本标题化合物(148mg,71%)。
MS APCI+ve m/z 325/327[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.01(1H,d),7.58-7.64(2H,m),7.51(1H,d),7.12-7.16(1H,m),5.80-5.90(1H,m),2.90-3.08(2H,m),2.63(3H,s),2.30-2.43(1H,m),2.13-2.28(1H,m).
实施例75
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-噻吩基)丙基]氧基]苄腈草酸盐
将实施例74(f)产物(200mg,0.47mmol)溶解在无水四氢呋喃(40ml)中,加入乙醇胺(5ml),并将该混合物在室温搅拌3天。加入水(30ml),用乙酸乙酯萃取该反应(3×60ml)。将合并的有机萃取液用水洗涤(3×20ml),干燥(用硫酸镁)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用10%7N氨的甲醇溶液在二氯甲烷中的混合物洗脱,将产物溶解在甲醇中,用一当量的草酸处理。将该混合物搅拌10分钟,然后真空除去溶剂,用乙酸乙酯研制残余物。过滤出白色固体,干燥,获得了本标题化合物。
MS APCI+ve m/z 355/357[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.01(1H,d),7.61(2H,t),7.52(1H,d),7.08-7.17(1H,m),5.79-5.93(1H,m),3.64(2H,t),3.03(4H,dd),2.32-2.47(1H,m),2.18-2.32(1H,m).
实施例76
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟-苄腈草酸盐
将实施例74(f)产物(200mg,0.47mmol)溶解在无水四氢呋喃(40ml)中,加入乙二胺(5ml),并将该混合物在室温搅拌3天。加入水(30ml),用乙酸乙酯萃取该反应(3×60ml)。将合并的有机萃取液用水洗涤(3×20ml),干燥(用硫酸镁)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用10%7N氨的甲醇溶液在二氯甲烷中的混合物洗脱,将产物溶解在甲醇中,并用一当量的草酸处理。将该混合物搅拌10分钟,真空除去溶剂,将残余物在乙酸乙酯中研制。过滤出白色固体,干燥,获得了本标题化合物。
MS APCI+ve m/z 354/356[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.00(1H,d),7.56-7.68(2H,m),7.52(1H,d),7.15(1H,dd),5.72-6.01(1H,m),3.01-3.14(4H,m),2.91-3.01(2H,m),2.25-2.42(1H,m),2.12-2.24(1H,m).
实施例77
2-[[(1R)-3-氨基-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟苄腈草酸盐
a)2-[[(1R)-3-叠氮基-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟苄腈
将实施例74(e)产物(540mg,1.64mmol)溶解在无水二甲亚砜(20ml)中,加入叠氮化钠(170mg,2.62mmol)。将该反应加热至65℃,并搅拌12小时,冷却,并加入水(60ml)。用乙酸乙酯萃取该混合物(3×70ml),合并的萃取液用水洗涤(5×50ml),干燥(用硫酸镁)并真空蒸发,获得了本标题化合物(535mg,97%)。
1H NMR 300MHz(CDCl3)7.35-7.41(1H,m),7.27-7.34(2H,m),7.07-7.11(1H,m),6.91-6.95(1H,m),5.38-5.47(1H,m),3.58-3.70(1H,m),3.39-3.51(1H,m),2.28-2.45(1H,m),2.02-2.20(1H,m).
b)2-[[(1R)-3-氨基-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟苄腈草酸盐
将步骤(a)产物(529mg,1.57mmol)溶解在无水四氢呋喃(80ml)中,加入三苯基膦(1.235g,4.71mmol),并将该反应混合物在室温搅拌1小时。加入水(5ml),并将该反应搅拌64小时。加入水(100ml),用乙酸乙酯萃取该反应(4×70ml)。将合并的有机萃取液用水洗涤(3×25ml),干燥(用硫酸钠)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用5%7N氨的甲醇溶液在二氯甲烷中的混合物洗脱,将产物溶解在甲醇中,用1当量的草酸处理。将该混合物搅拌10分钟,然后真空除去溶剂,用乙酸乙酯研制固体残余物。过滤出白色固体并干燥,获得了本标题化合物(380mg,60%)。
MS APCI+ve m/z 311/313[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.01(1H,d),7.55-7.67(2H,m),7.47(1H,d),7.13(1H,dd),5.85(1H,dd),2.81-2.99(2H,m),2.25-2.39(1H,m),2.09-2.23(1H,m).
实施例78
4-氯-2-[3-(甲基氨基)-1-(2-噻唑基)丙氧基]-苄腈草酸盐
a)[3-羟基-3-(2-噻唑基)丙基]甲基氨基甲酸1,1-二甲基乙酯
将2-溴噻唑(482mg,2.94mmol)溶解在无水四氢呋喃(15ml)中,并将该溶液冷却至-78℃。滴加正丁基锂(2.4M,1.25ml,3.0mmol),并将该反应在-70℃搅拌半小时。然后在-78℃将该溶液滴加到甲基(3-氧代丙基)-氨基甲酸1,1-二甲基乙酯(600mg,3.2mmol)在无水四氢呋喃(15ml)内的溶液中。加入完成后,将该反应缓慢地温热至室温过夜。加入饱和氯化铵水溶液(20ml),并用乙酸乙酯萃取该反应(3×70ml)。将合并的萃取液用水(20ml)洗涤,干燥(用硫酸镁)并真空蒸发。通过快速二氧化硅色谱纯化残余物,用乙酸乙酯洗脱,获得了本标题化合物,为浅橙色油状物(320mg,40%)。
1H NMR 300MHz(CDCl3)7.72(1H,d),7.28(1H,d),5.32-5.44(1H,bs),4.85-4.94(1H,m),3.88-4.01(1H,m),2.99-3.12(1H,m),2.90(3H,s),2.80-2.89(1H,m),2.26-2.41(1H,m),1.77-1.91(1H,m),1.50(9H,s).
b)[3-(5-氯-2-氰基苯氧基)-3-(2-噻唑基)丙基]甲基氨基甲酸1,1-二甲基乙酯
将步骤(a)产物(312mg,1.15mmol)、2-羟基-4-氯苄腈(176mg,1.15mmol)和三苯基膦(330mg,1.26mmol)溶解在无水四氢呋喃(20ml)中,并将该溶液冷却至0℃。滴加偶氮二甲酸二乙酯(219mg,1.26mmol),将该溶液缓慢地温热至室温,并搅拌18小时。真空除去溶剂,通过快速二氧化硅色谱纯化,用己烷∶乙酸乙酯(1∶1)洗脱,获得了本标题化合物(200mg,43%)。
1H NMR 300MHz(CDCl3)7.79(1H,d),7.34-7.53(2H,m),6.92-7.09(2H,m),5.61-5.71(1H,m),3.52-3.74(1H,m),3.31-3.45(1H,m),2.91(3H,s),2.82-2.92(1H,m),2.24-2.48(1H,m),1.40(9H,s).
c)4-氯-2-[3-(甲基氨基)-1-(2-噻唑基)丙氧基]苄腈草酸盐
将步骤(b)产物(200mg,0.49mmol)溶解在4M氯化氢的二噁烷溶液中,并搅拌2.5小时。真空除去溶剂,将残余物施加到酸性SCX树脂上,用甲醇(150ml)洗涤,并用7N氨的甲醇溶液(50ml)释放产物。真空除去溶剂,将残余物溶解在甲醇(5ml)中,并用1当量的草酸处理。搅拌15分钟,然后真空除去溶剂,用少量乙酸乙酯研制残余物。过滤出白色固体,并干燥,获得了本标题化合物(17mg,11%)。
MS APCI+ve m/z 308/310[(M+H)+].
1H NMR 300MHz(d6-DMSO)7.79-7.93(3H,m),7.51(1H,d),7.26(1H,dd),6.20-6.29(1H,m),3.07(2H,t),2.59(3H,s),2.39-2.62(2H,m).
实施例79
2-[[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基]-4-氯-5-氟-苄腈盐酸盐
a)[3-氧代-3-[5-(三甲基甲硅烷基)-2-噻唑基]丙基]氨基甲酸1,1-二甲基乙酯
使用2-(三甲基甲硅烷基)噻唑(2.59g,16.5mmol)和实施例72(a)中描述的方法,改变之处是加入完成后在-70℃搅拌2小时,并在-65℃中止反应,制得了本标题化合物(1.48g,55%)。
1H NMR 300MHz(CDCl3)7.60(1H,s),4.76(1H,s),3.21(2H,q),2.91-3.08(2H,m),1.12(9H,s),0.01(9H,s).
b)[[(3R)-3-羟基-3-[5-(三甲基甲硅烷基)-2-噻唑基]丙基]氨基甲酸1,1-二甲基乙酯
使用步骤(a)产物(1.47g,4.47mmol)和实施例72(b)中描述的方法,制得了本标题化合物(700mg,47%)。
1H NMR 300MHz(CDCl3)7.42(1H,s),4.68-4.79(1H,m),4.64(1H,s),4.28(1H,s),3.18-3.37(1H,m),2.79-2.95(1H,m),1.77-1.92(1H,m),1.51-1.65(1H,m),1.14(9H,s),0.03(9H,s).
c)[(3R)-3-(5-氯-2-氰基-4-氟苯氧基)-3-(2-噻唑基)丙基]氨基甲酸,1,1-二甲基乙酯
使用步骤(b)产物和实施例72(c)中描述的方法制得了本标题化合物(376mg,43%)。
1H NMR 300MHz(CDCl3)7.79(1H,d),7.31-7.42(2H,m),7.14(1H,d),5.66(1H,dd),4.79(1H,s),3.44-3.60(1H,m),3.22-3.33(1H,m),2.36-2.51(1H,m),2.20-2.34(1H,m),1.43(9H,s).
d)2-[[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基]-4-氯-5-氟-苄腈盐酸盐
将步骤(c)产物(370mg,0.9mmol)溶解在4M氯化氢的二噁烷溶液中,并在室温搅拌半小时。真空除去溶剂,用乙酸乙酯和甲醇的混合物(14∶1)研制残余物。过滤出白色固体,干燥,获得了本标题化合物(243mg,70%)。
MS APCI+ve m/z 312/314[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.23(3H,br s),8.08(1H,d),7.9(1H,d),7.85(1H,d),7.74(1H,d),6.29(1H,dd),2.90-3.07(2H,m),2.35-2.48(2H,m).
实施例80
γ-(2-氯-5-硝基苯氧基)-N-甲基苯丙胺盐酸盐
a)[3-(2-氯-5-硝基苯氧基)-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯
该化合物是按照实施例2的方法,使用α-[2-(甲基氨基)乙基]苯甲醇和2-氯-5-硝基苯酚制得的。
MS APCI+ve m/z 321/323[(M-Boc+H)+].
b)γ-(2-氯-5-硝基苯氧基)-N-甲基苯丙胺盐酸盐
将[3-(2-氯-5-硝基苯氧基)-3-苯基丙基]甲基氨基甲酸,1,1-二甲基乙酯(132mg,0.282mmol)在4N HCl的二噁烷溶液(1ml)中搅拌16小时,过滤出所得固体,获得了产物,为盐酸盐(60mg)。
MS APCI+ve m/z 321/323[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.89-8.73(2H,br m),7.83-7.73(3H,m),7.47-7.39(4H,m),7.36-7.30(1H,m),5.92(1H,m),3.11-3.00(2H,m),2.58(3H,s),2.42-2.31(1H,m),2.28-2.18(1H,m).
实施例81
(R)-γ-(5-氯-2-硝基苯氧基)-N-甲基苯)丙胺富马酸盐
a)[(3R)-3-(5-氯-2-硝基苯氧基)-3-苯基丙基]甲基氨基甲酸,1,1-二甲基乙酯
该化合物是通过实施例20(a)的方法,使用[(3S)-3-羟基-3-苯基丙基]甲基氨基甲酸1,1-二甲基乙酯和5-氯-2-硝基苯酚制得的。
APCI+ve m/z 321/323[(M-BOC+H)+].
b)(R)-γ-(5-氯-2-硝基苯氧基)-N-甲基苯)丙胺富马酸盐
该化合物是通过实施例20(b)的方法制得的,产物是作为富马酸盐分离到的。
MS APCI+ve m/z 321/323[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.92(1H,d),7.45-7.39(4H,m),7.36-7.31(1H,m),7.27(1H,d),7.14(1H,m),6.46(2H,s),5.88(1H,m),2.96-2.86(2H,m),2.50(3H,s),2.29-2.19(1H,m),2.17-2.09(1H,m).
实施例82
4-氯-5-氟-2-([(1R)-3-[(2-氟乙基)氨基]-1-苯基丙基]氧基)苄腈草酸盐
该化合物是通过实施例43(b)的方法,使用2-氟乙基胺和4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}-5-氟苄腈制得的。将游离碱转化成草酸盐。
MS APCI+ve m/z 351[(M+H)+].
1H NMR 400MHz(d6-DMSO)8.02(1H,d),7.46-7.41(5H,m),7.38-7.33(1H,m),5.80-5.76(1H,m),4.73(1H,t),4.61(1H,t),3.4-3.2(2H,m),3.15-3.0(2H,m),2.4-2.3(1H,m),2.21-2.10(1H,m).
实施例83
2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-溴-5-氟苄腈草酸盐
a)4-溴-2,5-二氟苯甲醛
在-70℃,将正丁基锂(1.95M己烷溶液,10.2ml))滴加到1,4-二溴-2,5-二氟苯(5g,18.4mmol)在乙醚(60ml)内的搅拌溶液中。1小时后,用1小时将该溶液温热至0℃,用水稀释,分离各层,用硫酸钠将乙醚层干燥,并蒸发。通过柱色谱(Biotage)纯化,用5%乙酸乙酯/己烷洗脱,获得了黄色油状物(1.82g)。
1H NMR 300MHz(CDCl3)10.28(1H,s),7.61(1H,dd),7.48(1H,dd).
b)4-溴-2,5-二氟苄腈
将4-溴-2,5-二氟苯甲醛(1.82g,8.3mmol)和羟基胺-O-硫酸(1.1当量,1.03g)在水(40ml)中于100℃加热6小时,冷却,并用乙酸乙酯萃取。将有机层干燥(用硫酸钠),并蒸发,获得了本标题化合物,为浅黄色固体(1.2g)。
1H NMR 300MHz(CDCl3)7.51(1H,t),7.39(1H,t).
(c)4-溴-2-[[(1R)-3-氯-1-苯基丙基]氧基1-5-氟苄腈
该化合物是通过实施例43(a)的方法,使用4-溴-2,5二氟苄腈和
(R)-α-(2-氯乙基)苯甲醇制得的。
1H NMR 300MHz(CDCl3)8.02(1H,s),7.42-7.26(5H,m),7.06-7.03(1H,m),5.46-5.43(1H,m),3.82-3.62(1H,m),3.75-3.60(1H,m),2.75-2.5(1H,m),2.55-2.30(1H,m).
d)2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-溴-5-氟苄腈
该化合物是通过实施例68(b)的方法,使用4-溴-2-[[(1R)-3-氯-1-苯基丙基]氧基]-5-氟苄腈和叠氮化钠制得的。
MS APCI+ve m/z 351[(M-N2+H)+].
e)2-[[(1R)-3-氨基-1-苯基丙基]氧基]-4-溴-5-氟苄腈草酸盐
该化合物是通过实施例77(b)的方法,使用2-[[(1R)-3-叠氮基-1-苯基丙基]氧基]-4-溴-5-氟苄腈制得的。
MS APCI+ve m/z 349/350[(M+H)+].
1H NMR 400MHz(d6-DMSO)7.96(1H,d),7.48-7.40(5H,m),7.36-7.32(1H,m),5.79-5.75(1H,dd),2.95-2.82(2H,m),2.32-2.20(1H,m),2.10-2.03(1H,m).
实施例84
3-[[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]氨基]-1-丙醇盐酸盐
a)1,4-二氯-2-[[(1R)-3-氯-1-苯基丙基]氧基]苯
用2,5-二氯苯酚(1.65g)进行实施例5(a)的方法,获得了产物,为澄清的油状物(2.26g)。
1H NMR 300MHz(CDCl3)7.39-7.36(5H,m),7.24(1H,s),6.82(1H,dd),6.74(1H,d),5.40(1H,dd),3.93-3.80(1H,m),3.69-3.57(1H,m),2.61-2.44(1H,m),2.33-2.18(1H,m).
b)1,4-二氯-2-[[(1R)-3-碘-1-苯基丙基]氧基]苯
用步骤(a)产物(2.26g)进行实施例5(b)的方法,获得了产物,为黄色油状物(2.78g)。
1H NMR 300MHz(CDCl3)7.39-7.36(5H,m),7.25-7.23(1H,m),6.84-6.80(1H,m),6.76-6.73(1H,m),5.32-5.25(1H,m),3.50-3.39(1H,m),3.33-3.24(1H,m),2.60-2.49(1H,m),2.39-2.26(1H,m).
c)3-[[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]氨基]-1-丙醇盐酸盐
将步骤(b)产物(0.2g)和3-氨基-丙醇(0.11g)溶解在二甲基甲酰胺(4ml)中,并搅拌24小时。将该反应倒入水中,并萃取到乙酸乙酯中。用盐水洗涤有机萃取液,用硫酸镁干燥,并蒸发至干,用1N HCl的乙醚溶液研制,获得了产物,为白色固体。
MS APCI+ve m/z 354[(M+H)+].
1H NMR(d6-DMSO)8.76(1H,s),7.50-7.37(6H,m),7.09(1H,d),6.99(1H,dd),5.77(1H,dd),4.73(1H,s),3.47(2H,t),3.11-2.91(4H,m),2.39-2.26(1H,m),2.26-2.14(1H,m),1.80-1.67(2H,m).
实施例85
1-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-4-哌啶甲醇盐酸盐
用实施例84(b)产物(0.2g)和4-哌啶甲醇(0.11g)进行实施例84(c)的方法,获得了产物,为白色固体。
MS APCI+ve m/z 394[(M+H)+].
1H NMR 300MHz(d6-DMSO)9.97(1H,s),7.48-7.28(6H,m),7.11(1H,d),6.99(1H,dd),5.77-5.67(1H,m),4.68-4.59(1H,m),3.56-3.44(2H,m),3.28-3.20(2H,m),3.19-3.07(2H,m),2.99-2.83(2H,m),1.86-1.74(2H,m),1.68-1.53(1H,m),1.51-1.35(2H,m),2.44-2.24(2H,m).
实施例86
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-2-噻吩甲胺盐酸盐
用实施例84(b)(0.2g)和2-噻吩甲胺(0.06g)进行实施例84(c)的方法,获得了产物,为白色固体。
MS APCI+ve m/z 392[(M+H)+].
1H NMR 400MHz(d6-DMSO)9.40-9.24(2H,m),7.63(1H,dd),7.49-7.36(5H,m),7.36-7.28(2H,m),7.12-7.05(2H,m),7.03-6.95(1H,m),5.83-5.74(1H,m),4.46-4.37(2H,m),3.16-2.97(2H,m),2.40-2.29(1H,m),2.28-2.18(1H,m).
实施例87
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-5-甲基-2-呋喃甲胺盐酸盐
用实施例84(b)产物(0.2g)和5-甲基-2-呋喃甲胺(0.06g)进行实施例84(c)的方法,获得了产物,为白色固体。
MS APCI+ve m/z 390[(M+H)+].
1H NMR 300MHz(d6-DMSO)9.36-9.17(2H,m),7.51-7.29(6H,m),7.10-7.04(1H,m),7.02-6.94(1H,m),6.48(1H,d),6.12(1H,dd),5.82-5.71(1H,m),4.20(2H,s),3.12-2.94(2H,m),2.39-2.13(2H,m),2.26(3H,s).
实施例88
4-氯-2-[[(1R)-1-苯基-3-(1-哌嗪基)丙基]氧基]苄腈二盐酸盐
a)4-[(3R)-3-(5-氯-2-氰基苯氧基)-3-苯基丙基]-1-哌嗪甲酸1,1-二甲基乙酯
用4-氯-2-{[(1R)-3-氯-1-苯基丙基]氧基}苄腈(0.3g)和哌嗪甲酸1,1-二甲基乙酯(0.4g)进行实施例11所述的方法,获得了产物,为澄清的树胶状物(0.35g)。
1H NMR 400MHz(CDCl3)7.45(1H,d),7.41-7.34(5H,m),6.92(1H,dd),6.86(1H,d),5.36(1H,dd),3.49-3.34(4H,m),2.62-2.21(7H,m),2.11-1.96(1H,m),1.47(9H,d).
b)4-氯-2-[[(1R)-1-苯基-3-(1-哌嗪基)丙基]氧基]-苄腈二盐酸盐
将步骤(a)产物(0.35g)在4M HCl的二噁烷溶液(10ml)中搅拌3小时,然后倒入饱和碳酸氢钠溶液(100ml)中,并萃取到乙酸乙酯内。将萃取液蒸发至干,用1N HCl的乙醚溶液研制残余物,获得了产物,为白色固体。
MS APCI+ve m/z 356[(M+H)+].
1H NMR 400MHz(d6-DMSO)9.81-9.42(2H,m),7.78(1H,d),7.53-7.25(6H,m),7.15(1H,d),5.99-5.84(1H,m),3.94-3.03(12H,m).
实施例89
5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]-4-甲基苄腈富马酸盐
a)N-甲氧基-N-甲基-3-异噁唑甲酰胺
将3-异噁唑甲酸(4.2g)、4-二甲基氨基吡啶(5.1g)、N,O-二甲基羟基胺盐酸盐(4.0g)、N-甲基吗啉(4.2g)和1-(3-二乙基氨基丙基)-3-乙基碳二亚胺盐酸盐(7.5g)在二氯甲烷(175ml)中的混合物在室温搅拌过夜。将该反应混合物依次用2N盐酸(100ml、饱和碳酸氢钠(100ml)、盐水洗涤,用硫酸镁干燥,并蒸发,获得了产物,为暗橙色油状物(3.7g)。
1H NMR 300MHz(CDCl3)8.48(1H,d),6.72(1H,br s),3.8(3H,s),3.4(3H,s).
b)1-(3-异噁唑基)-2-丙烯-1-酮
在氮气氛下,将步骤(a)产物(0.66g)溶解在无水四氢呋喃(20ml)中,并冷却至-30℃。用5分钟滴加溴化乙烯基镁(1M,6ml),将该反应混合物温热至0℃,并在该温度下搅拌2小时。将该混合物倒入冰冷的2N盐酸(50ml)中,并萃取到乙酸乙酯中。用水、盐水洗涤萃取液,用硫酸镁干燥,并蒸发,获得了暗色油状物(0.4g)。
1H NMR 300MHz(CDCl3)8.53-8.48(1H,m),7.36-7.22(1H,m),6.88-6.81(1H,m),6.76-6.64(1H,m),6.07-6.00(1H,m).
c)3-氯-1-(3-异噁唑基)-1-普鲁本辛
将步骤(b)产物用1M HCl乙醚溶液(5ml)处理,在室温搅拌4小时。然后减压除去溶剂,获得了产物,为暗色树胶状物(0.42g)。
1H NMR 300MHz(CDCl3)8.51(1H,d),6.79(1H,d),3.92(2H,t),3.57(2H,t).
d)(S)-α-(2-氯乙基)-3-异噁唑甲醇
通过实施例68(a)中描述的方法将步骤(c)产物(1g)还原,获得了产物,为澄清的油状物(0.5g)。
1H NMR 300MHz(CDCl3)8.47-8.36(1H,m),6.43-6.38(1H,m),5.18(1H,dt),3.87-3.75(1H,m),3.73-3.62(1H,m),2.71-2.61(1H,m),2.36-2.18(2H,m).
e)2-[[(1R)-3-氯-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈
按照实施例5(a)中描述的方法,将步骤(d)产物(0.47g)与5-氟-2-羟基-4-甲基苄腈反应,获得了产物,为白色固体(0.4g)。
1H NMR 300MHz(CDCl3)8.42(1H,t),7.18(1H,d),6.94(1H,d),6.47(1H,d),5.78(1H,dd),3.97-3.82(1H,m),3.80-3.67(1H,m),2.73-2.56(1H,m),2.43-2.29(1H,m),2.31(3H,s).
f)5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]-4-甲基-苄腈富马酸盐
按照实施例11的方法,将步骤(e)产物(0.16g)与乙醇胺(0.3g)进行反应,获得了产物,为白色固体(0.14g)。
MS APCI+ve m/z 320[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.97(1H,s),7.67(1H,d),7.26(1H,d),6.68(1H,s),6.48(2H,s),5.93(1H,s),3.60(2H,s),2.96(4H,d),2.47-2.35(1H,m),2.33-2.10(4H,m).
实施例90
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈富马酸盐
a)2-[[(1R)-3-叠氮基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈
将实施例89(e)产物(0.2g)与叠氮化钠(0.045g)在二甲亚砜(5ml)中于60℃加热24小时,获得了产物。
MS APCI+ve m/z 274[(M-28)+].
b)2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈富马酸盐
将在步骤(a)中的溶液用四氢呋喃(10ml)、水(1ml)和三苯基膦(0.3g)处理,并在室温搅拌36小时。将该混合物倒入饱和碳酸氢钠(20ml)中,并萃取到乙酸乙酯内。将萃取液蒸发至干,将残余物负载到离子交换树脂(SCX isolute)上,并用乙腈和甲醇洗涤。用7M氨的甲醇溶液将产物从柱上洗脱下来,获得了油状物,将其转化成富马酸盐(0.104g)。
MS APCI+ve m/z 276[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.97(1H,d),7.68(1H,d),7.24(1H,d),6.68(1H,d),6.41(2H,s),5.99-5.85(1H,m),3.01-2.89(2H,m),2.43-2.29(1H,m),2.27-2.16(1H,m),2.24(3H,s).
实施例91
4-氯-2-[[(1R)-3-[(1,1-二甲基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]苄腈富马酸盐
a)(R)-α-(2-氯乙基)-3-异噁唑甲醇
用实施例66(c)中描述的方法将实施例89(c)产物(3g)还原,获得了产物,为澄清的油状物(1.1g)。
1H NMR 300MHz(CDCl3)8.40(1H,d),6.40(1H,d),5.25-5.13(1H,m),3.88-3.61(2H,m),2.42(1H,d),2.33-2.21(2H,m).
b)4-氯-2-[[(1R)-3-氯-1-(3-异噁唑基)丙基]氧基]苄腈
将步骤(a)产物(0.19g)和2-氟-4-氯苄腈(0.17g)溶解在二甲基甲酰胺(5ml)中,并用氢化钠(60%的油悬浮液,0.06g)处理。2小时后,将该反应混合物倒入2N盐酸(10ml)中,并萃取到乙酸乙酯(50ml)内。将萃取液依次用饱和碳酸氢钠、盐水洗涤,用硫酸镁干燥,并蒸发,获得了黄色油状物(0.29g)。
MS APCI+ve m/z 298[(M+H)+].
1H NMR 300MHz(CDCl3)8.44(1H,d),7.49(1H,d),7.13(1H,d),7.04(1H,dd),6.46(1H,d),5.82(1H,dd),3.88(1H,ddd),3.73(1H,dt),2.73-2.57(1H,m),2.47-2.26(1H,m).
c)4-氯-2-[[(1R)-3-[1,1-二甲基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]苄腈富马酸盐
按照实施例12中描述的方法将步骤(b)产物(0.14g)与叔丁基胺(0.5g)反应,获得了产物,为白色固体(0.085g)。
MS APCI+ve m/z 334[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.96(1H,d),7.77(1H,d),7.40(1H,d),7.20(1H,dd),6.71(1H,t),6.46(2H,s),6.15-5.90(1H,m),2.95(2H,t),2.45-2.34(1H,m),2.33-2.19(1H,m),1.22(9H,s).
实施例92
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈富马酸盐
a)2-[[(1R)-3-叠氮基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈
用实施例91(b)产物进行实施例90(a)中描述的方法,获得了产物,然后将该产物直接进行下一步骤。
b)2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈富马酸盐
使用步骤(a)产物(0.14g)进行实施例90(b)中描述的方法,获得了产物,为白色固体(0.05g)。
MS APCI+ve m/z 278[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.99(1H,d),7.81(1H,d),7.41(1H,d),7.23(1H,dd),6.72(1H,d),6.41(2H,s),6.08(1H,dd),2.95(2H,t),2.44-2.31(1H,m),2.31-2.19(1H,m).
实施例93
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈
a)(R)-α-(2-叠氮基乙基)-3-异噁唑甲醇
将实施例91(a)产物(0.17g)和叠氮化钠(0.08g)在二甲亚砜(3ml)中于70℃加热4小时。然后将该混合物倒入水中,并用乙酸乙酯萃取。用水、盐水洗涤萃取液,用硫酸镁干燥,蒸发,获得了产物,为澄清的油状物(0.15g)。
MS APCI+ve m/z 141[(M-28)+].
1H NMR 300MHz(CDCl3)8.47(1H,d),6.50(1H,d),5.18-4.98(1H,m),3.72-3.40(2H,m),2.70-2.47(1H,m),2.16-1.98(2H,m).
b)2-[[(1R)-3-叠氮基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟苄腈
用步骤(a)产物(0.1g)和2,5-二氟-4-氯-苄腈(0.18g)以及氢化钠(60%的油悬浮液,0.035g)进行实施例90(a)中描述的方法,获得了产物,为树胶状物(0.15g)。
MS APCI+ve m/z 294[(M-28)+].
c)2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈富马酸盐
用步骤(b)产物(0.15g)和三苯基膦(0.3g)进行实施例90(b)中描述的方法,获得了产物,为固体(0.105g)。
MS APCI+ve m/z 296[(M+H)+].
1H NMR 300MHz(d6-DMSO)8.99(1H,d),8.04(1H,d),7.61(1H,d),6.74-6.68(1H,m),6.40(2H,s),6.09-6.00(1H,m),3.00-2.89(2H,m),2.43-2.32(1H,m),2.29-2.18(1H,m).
实施例94
(R)-γ-(2,5-二氯苯氧基)-3-异噁唑丙胺富马酸盐
a)3-[(1R)-3-叠氮基-1-(2,5-二氯苯氧基)丙基]异噁唑
使用实施例93(b)中描述的方法,将实施例93(a)产物(0.17g)与2,5-二氯-氟苯(0.4g)进行反应,获得了产物,为树胶状物,将其用于下一步骤。
b)(R)-γ-(2,5-二氯苯氧基)-3-异噁唑丙胺富马酸盐
用步骤(a)产物(0.1g)进行实施例90(b)中描述的方法,获得了产物,为固体(0.03g)。
MS APCI+ve m/z 287[(M+H)+].
1H NMR 300MHz(CD30D)8.72(1H,d),7.39(1H,d),7.13(1H,d),7.02(1H,dd),6.70(2H,s),6.56(1H,d),5.86-5.77(1H,m),3.28-3.19(2H,m),2.60-2.46(1H,m),2.43-2.28(1H,m).
筛选
在下列筛选中测试本发明化合物的药理活性。
筛选1
可通过基于Frstermann等人,Eur.J.Pharm.,1992,225,161-165的方法来筛选式(I)化合物、或其可药用盐、对映体或外消旋体的一氧化氮合酶抑制活性。一氧化氮合酶将3H-L-精氨酸转化成3H-L-瓜氨酸,该瓜氨酸可通过阳离子交换色谱来分离,并且可通过液体闪烁计数来定量测定。
诱导后,由培养的鼠巨噬细胞系J774A-1(得自Imperial CancerResearch Fund的实验室)制备酶。将J774A-1细胞在补充10%胎牛血清、4mM L-谷氨酰胺和抗生素(100单位/ml青霉素G,100mg/ml链霉素&0.25mg/ml两性霉素B)的Dulbeccos Modified EaglesMedium(DMEM)中培养。让细胞在含有35ml培养基、并在含有5%CO2的湿润气氛中于37℃保持的225cm3烧瓶中进行常规生长。
一氧化氮合酶是由细胞在对干扰素-g(IFNg)和脂多糖(LPS)起反应时产生的。从铺满培养物的烧瓶中取出培养基,并用含有1mg/ml LPS和10单位/ml IFNg的25ml(每个烧瓶)新鲜培养基替换。培养17-20小时后,通过将细胞片从烧瓶表面上刮擦到培养基内来完成细胞收获。通过离心(1000g,10分钟)收集细胞,并通过将细胞离心团加到含有50mM Tris-HCl(pH 7.5,在20℃)、10%(v/v)甘油、0.1%(v/v)Triton-X-100、0.1mM二硫苏糖醇和包含亮抑蛋白酶肽(2mg/ml)、大豆胰蛋白酶抑制剂(10mg/ml)、抑肽酶(5mg/ml)和苯基甲基磺酰氟(50mg/ml)的蛋白酶抑制剂合剂的溶液中来制备溶胞产物。
为了进行测定,将25μl底物合剂(50mM Tris-HCl(pH 7.5,20℃)、400μM NADPH、20μM黄素腺嘌呤二核苷酸、20μM黄素单核苷酸、4μM四氢生物蝶呤、12μM L-精氨酸和0.025mCi L-[3H]精氨酸)加到含有25μl测试化合物在50mM Tris-HCl中的溶液的96孔滤板的孔中(0.45μM孔径)。通过加入50μl细胞溶胞产物(如上所述制备的)来开始反应,在室温培养1小时后,通过加入50μl 3mM硝基精氨酸和21mM EDTA水溶液来终止反应。
使用Dowex AG-50W将标记的L-瓜氨酸与标记的L-精氨酸分隔开。将150μl 25%Dowex 50W(Na+形式)的水浆液加到测定混合物中,然后将整个混合物过滤到96孔平板内。取出75μl滤液样本,并加到含有固体闪烁剂的96孔平板中。将样本干燥后,通过闪烁计数来定量测定L-瓜氨酸。
在典型的实验中,基底活性是300dpm/75μl样本,在试剂对照中增加至1900dpm。化合物活性以IC50(在测定中将酶抑制50%的药物的浓度)表示,IC50(50%抑制浓度)为10μM的氨基胍作为标准进行测试以校验该方法。测试一定范围浓度的化合物,并从所获得的抑制计算IC50值。在100μM将酶抑制至少25%的化合物规为活性化合物,并再进行至少一次重复测试。
筛选2
可在下列测定中证实化合物还表现出抗人诱导型一氧化氮合酶的活性。
将人结肠直肠癌细胞系DLD-1(得自European Collection ofAnimal Cell Culture-细胞系号90102540)在补充有10%(v/v)胎牛血清、和2mM L-谷氨酰胺的RPMI 1640中于5%CO2、37℃条件下生长。
通过加入含有人重组γ-IFN(1000单位/ml)、TNF-α(200U/ml)、IL-6(200U/ml)和IL-1-β(250U/ml)的培养基来在细胞中诱导一氧化氮合酶。在37℃培养18小时后,取出培养基,并用温热的磷酸盐缓冲盐水洗涤细胞。在有和没有测试化合物存在下,将细胞在含有100μM L-精氨酸和100μM维拉帕米-HCl的RPMI 1640中于37℃/5%CO2条件下再培养5小时。
通过将等体积的培养基与格里斯试剂(10mg/ml磺胺、1mg N-(1-萘基)乙二胺,在1ml 2.5%(v/v)磷酸中)混合来测定亚硝酸盐积聚。相对于由未处理细胞产生的亚硝酸盐水平来计算在化合物存在下的抑制。从%抑制对化合物浓度的半对数图估计IC50值。
在测试时,实施例1-94的化合物在至少一个上述筛选中表现出低于25μM的IC50值,这意味着预计它们表现出有用的治疗活性。
Claims (16)
1.式(I)化合物或其可药用盐、对映体或外消旋体
其中:
X和Y独立地代表C1-4烷基、C1-4烷氧基、卤素、CF3、OCF3、CN或NO2;
Z代表氢或氟;
V代表O;
W代表苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环;所述苯基或芳杂环可任选被一个或多个独立地选自卤素、C1-4烷基、C1-4烷氧基或OH的取代基取代;
R1和R2独立地代表H、C1-4烷基或C3-6环烷基;所述烷基任选被下列基团取代:C1-4烷氧基、卤素、羟基、NR6R7、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被C1-4烷基取代;
或者基团NR1R2一起代表任选还包含一个选自O或NR8的另外的杂原子的5或6元饱和氮杂环;所述环任选被C1-4烷基或OH取代;所述烷基任选被OH取代;
R6和R7独立地代表H或C1-4烷基;
R8代表H或C1-6烷基;
在制备用于治疗或预防可受益于一氧化氮合酶活性抑制的疾病或病症的药物中的应用。
2.权利要求1的应用,其中主要抑制诱导型一氧化氮合酶。
3.如权利要求1所定义的式(I)化合物、或其可药用盐、对映体或外消旋体在制备用于治疗或预防炎性疾病的药物中的应用。
4.权利要求3的应用,其中所述疾病是炎性肠病。
5.权利要求3的应用,其中所述疾病是类风湿性关节炎。
6.权利要求3的应用,其中所述疾病是骨关节炎。
7.如权利要求1所定义的式(I)化合物、或其可药用盐、对映体或外消旋体在制备用于治疗或预防疼痛的药物中的应用。
8.用于治疗或预防可受益于一氧化氮合酶活性抑制的疾病或病症的药物制剂,其中包含治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体和与其混合的可药用助剂、稀释剂或载体。
9.用于治疗或预防可受益于一氧化氮合酶诱导同功型活性被抑制的疾病或病症的药物制剂,其中包含治疗有效量的式(I)化合物或其可药用盐、对映体或外消旋体和与其混合的可药用助剂、稀释剂或载体。
10.式(Ia)化合物或其可药用盐、对映体或外消旋体
其中:
X和Y独立地代表C1-4烷基、C1-4烷氧基、卤素、CF3、OCF3、CN或NO2;
Z代表氢或氟;
V代表O;
W代表苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环;所述苯基或芳杂环可任选被一个或多个独立地选自卤素、C1-4烷基、C1-4烷氧基或OH的取代基取代;
R1和R2独立地代表H、C1-4烷基或C3-6环烷基;所述烷基任选被下列基团取代:C1-4烷氧基、卤素、羟基、NR6R7、苯基或含有1-3个独立地选自O、S和N的杂原子的5或6元芳族或饱和杂环;所述苯基或芳杂环可任选被C1-4烷基取代;
或者基团NR1R2一起代表任选还包含一个选自O或NR8的另外的杂原子的5或6元饱和氦杂环;所述环任选被OH或C1-4烷基取代,所述烷基被OH取代;
R6和R7独立地代表H或C1-4烷基;
R8代表H或C1-6烷基;
条件是:当W代表任选取代的苯基、噻吩基、呋喃基或吡咯基;且R1代表H、C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代时,R2不代表H、C1-4烷基或C3-6环烷基,其中所述基团任选被C1-4烷氧基取代;和
条件是:当W代表噻唑基或吡啶基时,Z代表F;或者X和Y当中至少有一个代表CN;或者R1和R2不独立地代表H或CH3。
11.权利要求10的式(Ia)化合物,其中X和Y独立地代表Br、Cl、CH3、CF3或CN。
12.权利要求10的式(Ia)化合物,其中W代表任选取代的含有1-3个独立地选自O、S和N的杂原子的5或6元芳杂环。
13.权利要求10的式(Ia)化合物,其中R1和R2独立地代表H或甲基。
14.权利要求10的式(Ia)化合物,其中所述化合物是:
2-[[(3R)-3-(2,5-二氯苯氧基)-3-(2-噻吩基)丙基]氨基]乙醇;
4-氯-2-{[(1R)-3-(4-羟基-1-哌啶基)-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(2-羟基乙基)甲基氨基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3R)-3-羟基吡咯烷基]-1-苯基丙基]氧基}-苄腈;
4-氯-2-{[(1R)-3-[(3S)-3-羟基吡略烷基]-1-苯基丙基]氧基}-苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(2-嘧啶基)丙氧基]苄腈;
4-氯-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-氯-5-氟-2-[[(1R)-1-(3-呋喃基)-3-(3-羟基丙基)氨基]丙基]氧基}苄腈;
4-氯-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
4-溴-5-氟-2-({(1R)-3-[(3-羟基丙基)氨基]-1-苯基丙基}氧基)苄腈;
4-溴-5-氟-2-({(1R)-1-(3-呋喃基)-3-[(3-羟基丙基)氨基]丙基}氧基)苄腈;
4-溴-5-氟-2-{[(1R)-3-[(3-羟基丙基)氨基]-1-(3-噻吩基)丙基]氧基}苄腈;
4-氯-5-氟-2-[[(1R)-3-[[(5-甲基吡嗪基)甲基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(1H-咪唑-2-基甲基)氨基]-1-苯基丙基]氧基]苄腈;
4-氯-2-[[(1R)-3-[[2-(二甲基氨基)乙基]氨基]-1-苯基丙基]氧基]-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(4-吗啉基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-1-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[[2-(1H-咪唑-4-基)乙基]氨基]-1-苯基丙基]氧基]苄腈;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-苯基丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-苯基丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[[(1R)-1-苯基-3-[(3,3,3-三氟丙基)氨基]丙基]氧基]苄腈;
2-{[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基}-4-氯苄腈;
4-氯-2-{[(1R)-3-(甲基氨基)-1-(2-噻唑基)丙基]氧基}苄腈;
2-[3-氨基-1-(2-噁唑基)丙氧基]-4-氯苄腈;
γ-(2,5-二氯苯氧基)-2-噁唑丙胺;
2-[[3-氨基-1-(3-吡啶基)丙基]氧基]-4-氯-5-氟苄腈;
4-氯-5-氟-2-[3-(甲基氨基)-1-(3-吡啶基)丙氧基]苄腈;
2-[3-氨基-1-(6-甲氧基-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(1,6-二氢-6-氧代-2-吡啶基)丙氧基]-4-氯-5-氟苄腈;
2-[3-氨基-1-(6-溴-3-吡啶基)丙氧基]-4-氯苄腈;
2-[[3-氨基-1-(5-异噁唑基)丙基]氧基]-4-氯苄腈;
4-氯-2-[3-[(2-羟基乙基)氨基]-1-(5-异噁唑基)丙氧基]苄腈;
(R)-γ-(2,5-二氯苯氧基)-5-异噁唑丙胺;
4-氯-5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-噻吩基)丙基]氧基]苄腈;
2-[[(1R)-3-[(2-氨基乙基)氨基]-1-(3-噻吩基)丙基]氧基]-4-氯-5-氟-苄腈;
4-氯-2-[3-(甲基氨基)-1-(2-噻唑基)丙氧基]-苄腈;
2-[[(1R)-3-氨基-1-(2-噻唑基)丙基]氧基]-4-氯-5-氟-苄腈;
4-氯-5-氟-2-{[(1R)-3-[(2-氟乙基)氨基]-1-苯基丙基]氧基}苄腈;
3-[[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]氨基]-1-丙醇;
1-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-4-哌啶甲醇;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-2-噻吩甲胺;
N-[(3R)-3-(2,5-二氯苯氧基)-3-苯基丙基]-5-甲基-2-呋喃甲胺;
5-氟-2-[[(1R)-3-[(2-羟基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]-4-甲基苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-5-氟-4-甲基-苄腈;
4-氯-2-[[(1R)-3-[(1,1-二甲基乙基)氨基]-1-(3-异噁唑基)丙基]氧基]苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-苄腈;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈;
(R)-γ-(2,5-二氯苯氧基)-3-异噁唑丙胺;
2-[[(1R)-3-氨基-1-(3-异噁唑基)丙基]氧基]-4-(三氟甲基)-苄腈;
2-[[(1R)-3-氨基-1-(5-甲基-3-异噁唑基)丙基]氧基]-4-氯-5-氟-苄腈;
和它们的可药用盐、对映体或外消旋体。
15.包含权利要求10-14任一项的式(Ia)化合物、或其可药用盐、对映体或外消旋体和与其混合的可药用辅助剂、稀释剂或载体的药物组合物。
16.制备权利要求10-14任一项的式(Ia)化合物、或其可药用盐、对映体或外消旋体的方法,其中所述方法包括:
(a)将式(II)化合物
其中X、Y、V和Z如权利要求10中所定义,
与式(III)化合物反应
其中W、R1和R2如权利要求10中所定义;或者
(b)将式(IV)化合物
其中X、Y和Z如权利要求10中所定义,且L1是离去基团,
与式(V)化合物反应
其中R1、R2、V和W如权利要求10中所定义;或者
(c)将式(VI)化合物
其中X、Y、V、W和Z如权利要求10中所定义,且L2是离去基团,
与式(VII)化合物反应
HNR1R2 (VII)
其中R1和R2如权利要求10中所定义;或者
(d)将式(II)化合物
其中X、Y、V和Z如权利要求10中所定义,
与式(VIII)化合物反应
其中R1、R2和W如权利要求10中所定义,且L3是离去基团;或者
(e)将式(IX)化合物还原
其中X、Y、V、W和Z如权利要求10中所定义,且G代表通过还原能转化成NR1R2的基团;需要时可将所得式(Ia)化合物或其另一种盐转化成其可药用盐;或者将所得式(Ia)化合物转化成另外的式(Ia)化合物;以及需要时可将所得式(Ia)化合物转化成其旋光异构体。
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CA2452347A1 (en) * | 2001-07-31 | 2003-02-13 | Pharmacia & Upjohn Company | Treatment of chronic pain with 3-aryloxy-3-phenylpropanamines |
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2000
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2001
- 2001-02-20 DE DE60107820T patent/DE60107820T2/de not_active Expired - Fee Related
- 2001-02-20 AT AT01906492T patent/ATE284860T1/de not_active IP Right Cessation
- 2001-02-20 WO PCT/SE2001/000373 patent/WO2001062704A1/en active IP Right Grant
- 2001-02-20 EP EP01906492A patent/EP1263711B1/en not_active Expired - Lifetime
- 2001-02-20 AU AU34315/01A patent/AU781141B2/en not_active Ceased
- 2001-02-20 IL IL15063501A patent/IL150635A0/xx unknown
- 2001-02-20 BR BR0108613-8A patent/BR0108613A/pt not_active IP Right Cessation
- 2001-02-20 CA CA002397234A patent/CA2397234A1/en not_active Abandoned
- 2001-02-20 JP JP2001561714A patent/JP2003523988A/ja not_active Withdrawn
- 2001-02-20 US US10/204,742 patent/US6887871B2/en not_active Expired - Fee Related
- 2001-02-20 MX MXPA02008203A patent/MXPA02008203A/es active IP Right Grant
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- 2001-02-20 CO CO01013437A patent/CO5261625A1/es not_active Application Discontinuation
- 2001-02-20 NZ NZ520107A patent/NZ520107A/en not_active Application Discontinuation
- 2001-02-20 KR KR1020027010975A patent/KR100706736B1/ko not_active IP Right Cessation
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AU781141B2 (en) | 2005-05-05 |
CA2397234A1 (en) | 2001-08-30 |
NO20024014D0 (no) | 2002-08-22 |
AU3431501A (en) | 2001-09-03 |
JP2003523988A (ja) | 2003-08-12 |
ATE284860T1 (de) | 2005-01-15 |
MXPA02008203A (es) | 2002-11-29 |
BR0108613A (pt) | 2002-11-12 |
WO2001062704A1 (en) | 2001-08-30 |
CO5261625A1 (es) | 2003-03-31 |
KR20020076331A (ko) | 2002-10-09 |
KR100706736B1 (ko) | 2007-04-12 |
GB0004153D0 (en) | 2000-04-12 |
US20030158185A1 (en) | 2003-08-21 |
DE60107820T2 (de) | 2005-12-01 |
EP1263711B1 (en) | 2004-12-15 |
CN1411435A (zh) | 2003-04-16 |
EP1263711A1 (en) | 2002-12-11 |
US6887871B2 (en) | 2005-05-03 |
NO20024014L (no) | 2002-09-25 |
DE60107820D1 (de) | 2005-01-20 |
IL150635A0 (en) | 2003-02-12 |
NZ520107A (en) | 2006-02-24 |
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