TWI392664B - 作為β2腎上腺素受體激動劑之4-(2-胺基-1-羥乙基)酚之氟化衍生物 - Google Patents
作為β2腎上腺素受體激動劑之4-(2-胺基-1-羥乙基)酚之氟化衍生物 Download PDFInfo
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- TWI392664B TWI392664B TW095118023A TW95118023A TWI392664B TW I392664 B TWI392664 B TW I392664B TW 095118023 A TW095118023 A TW 095118023A TW 95118023 A TW95118023 A TW 95118023A TW I392664 B TWI392664 B TW I392664B
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- difluoro
- amino
- hexyl
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims description 6
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 title description 13
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 title description 13
- 239000000556 agonist Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 318
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 150000001412 amines Chemical class 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 12
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
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- 239000001257 hydrogen Substances 0.000 claims description 9
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- QAEDBMVGNDMFDR-NRFANRHFSA-N 4-[(1r)-2-[[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCC(F)(F)CCOCC(F)(F)C=2C=CC=CC=2)=C1 QAEDBMVGNDMFDR-NRFANRHFSA-N 0.000 claims description 3
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- BTYJTZWUPACARF-DEOSSOPVSA-N 4-[(1r)-2-[[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCC(F)(F)CCOCCCCC=2C=CC=CC=2)=C1 BTYJTZWUPACARF-DEOSSOPVSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
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- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 238000009835 boiling Methods 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 32
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- 239000002585 base Substances 0.000 description 30
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
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- CDMLLMOLWUKNEK-AOHDELFNSA-M methylprednisolone suleptanate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCCCCCC(=O)N(C)CCS([O-])(=O)=O)CC[C@H]21 CDMLLMOLWUKNEK-AOHDELFNSA-M 0.000 description 1
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- 239000001294 propane Substances 0.000 description 1
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- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
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- 229920005989 resin Polymers 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229950000915 revatropate Drugs 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
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- 239000008181 tonicity modifier Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- CMHHITPYCHHOGT-UHFFFAOYSA-N tributylborane Chemical compound CCCCB(CCCC)CCCC CMHHITPYCHHOGT-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229950008396 ulobetasol propionate Drugs 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
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- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
- C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
本發明係針對新穎β2腎上腺素受體激動劑。本發明亦係針對包含該等化合物之醫藥組合物,用該等化合物治療β2腎上腺素受體活性相關性之疾病的方法,以及可用於製備該等化合物之方法及中間物。
β2腎上腺素受體激動劑公認為治療肺部疾病之有效藥物,該等疾病諸如哮喘及慢性阻塞性肺部疾病(包括慢性支氣管炎及肺氣腫)。β2腎上腺素受體激動劑亦可用於治療早產、青光眼,且潛在可用於治療神經病症及心臟病症。
儘管用某些β2腎上腺素受體激動劑已獲得成功,目前之試劑具有較低所需效力、選擇性、發作及/或行為持續時間。因此,需要具有經改良特性之其他β2腎上腺素受體激動劑。較佳試劑尤其可具有以下特性:改良效力、選擇性、發作、改良安全限度、改良治療方法及/或行為持續時間。
本發明提供具有β2腎上腺素受體激動劑活性之新穎化合物。因此,本發明提供式(I)化合物:
其中:R1
係選自-CH2
OH、-NHC(O)H之基團,且R2
為氫原子;或R1
與R2
形成基團-NH-C(O)-CH=CH-,其中氮原子結合苯環中之碳原子以固持R1
,且碳原子結合苯環中之碳原子以固持R2
R3
係選自氫及鹵素原子或係選自以下基團-SO-R5
、-SO2
-R5
、-NH-CO-NH2
、-CONH2
、乙內醯基、C1 - 4
烷基、C1 - 4
烷氧基及-SO2
NR5
R6
R4
係選自氫原子、鹵素原子及C1 - 4
烷基R5
係C1 - 4
烷基或C3 - 8
環烷基R6
係獨立選自氫原子及C1 - 4
烷基n、p及q獨立為0、1、2、3或4 m及s獨立為0、1、2或3 r為0、1或2其限制條件為:m及r至少一者不為0 n+m+p+q+r+s之和為7、8、9、10、11、12或13 q+r+s之和為2、3、4、5或6或者其醫藥學上可接受之鹽或溶劑合物或立體異構體。
本發明亦提供包含本發明之化合物及醫藥學上可接受之載劑之醫藥組合物。本發明進一步提供包含本發明之化合物及一或多種其他治療劑之組合物,及包含該等組合物之醫藥組合物。
本發明亦提供治療哺乳動物中與β2腎上腺素受體活性相關之疾病或病情(例如,肺部疾病,諸如哮喘或慢性阻塞性肺部疾病、早產、青光眼、神經病症、心臟病症或炎症)的方法,其包含對哺乳動物投與治療有效量之本發明化合物。本發明進一步提供治療方法,其包含投與治療有效量之本發明化合物之組合物以及一或多種其他治療劑。
在單獨且獨特態樣中,本發明亦提供本文所描述之合成方法及中間物,其可用於製備本發明之化合物。
本發明亦提供如本文所述用於藥物治療之本發明化合物,以及本發明之化合物用於製造調配物或藥物的用途,該調配物或藥物係用於治療哺乳動物中與β2腎上腺素受體活性相關之疾病或病情(例如,肺部疾病,諸如哮喘或慢性阻塞性肺部疾病、早產、青光眼、神經病症、心臟病症或炎症)。
當描述本發明之化合物、組合物及方法時,除非另外指明,否則以下術語具有以下意義。
術語"治療有效量"係指當投與需要治療之患者時,足以達成治療之量。
如本文所用之術語"治療"係指包括以下情形之人類患者中疾病或醫學病情之治療:(a)預防疾病或醫學病情之發生,意即患者之預防治療;(b)改善疾病或醫學病情,意即引起患者疾病或醫學病情恢復;(c)抑制疾病或醫學病情,意即減緩患者疾病或醫學病情發展;或(d)減輕患者疾病或醫學病情之症狀。
短語"與β2腎上腺素受體活性相關之疾病或病情"包括現今公認,或將來發現與β2腎上腺素受體活性相關之所有病狀及/或病情。該等病狀包括(但不限於)肺部疾病,諸如哮喘及慢性阻塞性肺部疾病(包括慢性支氣管炎及肺氣腫)以及神經病症及心臟病症。亦已知β2腎上腺素受體活性與早產(參看國際專利申請公開案第WO 98/09632號)、青光眼及一些類型炎症(參看國際專利申請公開案第WO 99/30703號及專利申請公開案第EP 1 078 629號)相關。
術語"醫藥學上可接受之鹽"係指自鹼或酸製備、對於投與患者(諸如哺乳動物)而言為可接受之鹽。該等鹽可源自醫藥學上可接受之無機或有機鹼,且源自醫藥學上可接受之無機或有機酸。
衍生鹽之醫藥學上可接受之酸包括乙酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、反丁烯二酸、葡糖酸、麩胺酸、氫溴酸、鹽酸、乳酸、順丁烯二酸、蘋果酸、扁桃酸、甲磺酸、黏液酸、硝酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、對甲苯磺酸、xinafoic(1-羥基-2-萘酸)及類似酸。尤其較佳之鹽源自反丁烯二酸、氫溴酸、鹽酸、乳酸、硫酸、甲磺酸、xinafoic及酒石酸。
衍生鹽之醫藥學上可接受之無機鹼包括鋁、銨、鈣、銅、鐵、亞鐵、鋰、鎂、錳、亞錳、鉀、鈉、鋅及類似金屬。尤其較佳為銨、鈣、鎂、鉀及鈉鹽。
源自醫藥學上可接受之無機鹼之鹽包括以下物質之鹽:第一胺、第二胺及第三胺,包括經取代之胺、環狀胺、天然發生胺及類似胺,諸如精胺酸、甜菜鹼、咖啡因、膽鹼、N,N'-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、葡萄胺、葡糖胺、組胺酸、海卓胺(hydrabamine)、異丙胺、離胺酸、甲基葡萄胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因(procaine)、嘌令、可可鹼、三乙胺、三甲胺、三丙胺、緩血酸胺或類似物。
術語"溶劑合物"係指由一或多種溶質分子所形成之錯合物或聚集體,意即本發明化合物或其醫藥學上可接受之鹽及一或多種溶質分子。該等溶劑合物通常為具有大體上固定溶質與溶劑莫耳比之結晶固體。舉例而言,代表性溶劑包括水、甲醇、乙醇、異丙醇、乙酸及類似溶劑。當溶劑為水時,所形成之溶劑合物為水合物。
應瞭解術語"或其醫藥學上可接受之鹽或其立體異構體之溶劑合物"意欲包括所有置換鹽、溶劑合物及立體異構體,諸如式(I)化合物之立體異構體之醫藥學上可接受之鹽的溶劑合物。
術語"胺基保護基"係指適於防止胺基氮處非所需反應之保護基。代表性胺基保護基包括(但不限於)醛基;醯基,例如烷醯基,諸如乙醯基;烷氧基羰基,諸如第三丁氧基羰基(Boc);芳基甲氧基羰基,諸如苄氧基羰基(Cbz)及9-茀基甲氧基羰基(Fmoc);芳甲基,諸如苄基(Bn)、三苯甲基(Tr)及1,1-二-(4'-甲氧基苯基)甲基;矽烷基,諸如三甲基矽烷基(TMS)及第三丁基二甲基矽烷基(TBS)及類似基團。
術語"羥基保護基"係指適於防止羥基處非所需反應之保護基。代表性羥基保護基包括(但不限於)烷基,諸如甲基、乙基及第三丁基;醯基,例如烷醯基,諸如乙醯基;芳甲基,諸如苄基(Bn)、對甲氧基苄基(PMB)、9-茀甲基(Fm)及二苯甲基(二苯甲基,DPM);矽烷基,諸如三甲基矽烷基(TMS)及第三丁基二甲基矽烷基(TBS)及類似基團。
本發明之化合物含有至少一個對掌性中心。因此,本發明包括外消旋混合物、對映異構體及富集一或多種立體異構體之混合物。所描述及所主張之本發明的範疇涵蓋化合物之外消旋形式,以及單獨對映異構體、非對映異構體及富集立體異構體之混合物。
在一實施例中,本發明之化合物具有值為1之m及r中之至少一者。
在另一實施例中,本發明之化合物具有值為1之m+r總和。
在又一實施例中,本發明之化合物具有值為8、9或10之n+m+p+q+r+s總和。
在又一實施例中,本發明之化合物具有值為2、3或4之q+r+s總和。
在又一實施例中,本發明之化合物具有值為0或1之s。
在又一實施例中,本發明之化合物具有值為4、5或6之n+p總和。
在又一實施例中,本發明之化合物具有值為1、2、3或4之q+s總和。
在又一實施例中,本發明之化合物具有選自由氫原子、鹵素原子或甲基組成之群之R3
。
在又一實施例中,本發明之化合物具有選自由氯或氟原子組成之群之R3
。
在又一實施例中,本發明之化合物具有為甲基之R3
。
在又一實施例中,本發明之化合物具有為氫原子之R4
。
在又一實施例中,本發明之化合物具有為氯原子之R4
。
在又一實施例中,本發明之化合物具有值為0之m及s,值為1值r及q,值為6之n與q之總和,及均為氫原子之R5
與R6
。
尤其關注之化合物為:(R,S)-4-(2-{[6-(2,2-二氟-4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(4,4-二氟-4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-8-羥基喹啉-2(1H)-酮(R,S)-4-(2-{[6-(2,2-二氟-2-(3-甲基苯基)乙氧基)己基]胺基}-1-羥乙基]-2-(羥甲基)酚4-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R,S)-2-(羥甲基)-4-(1-羥基-2-{[4,4,5,5-四氟-6-(3-苯基丙氧基)己基]胺基}乙基)酚(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-2-羥苯基]甲醯胺(R,S)-4-[2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚(R,S)-N-[3-(1,1-二氟-2-{[6-({2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]脲(R,S)-3-[3-(1,1-二氟-2-{[6-({2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]咪唑啶-2,4-二酮(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-8-羥基喹啉-2(1H)-酮4-((1R)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(3,3-二氟-3-苯基丙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(2,2-二氟-3-苯基丙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚,鹽酸鹽及其醫藥學上可接受之鹽及溶劑合物。
本發明亦包含醫藥組合物,該醫藥組合物包含治療有效量之上文所定義之化合物及醫藥學上可接受之載劑。
在本發明之一實施例中,醫藥組合物進一步包含治療有效量之一或多種其他治療劑。
本發明之一實施例亦在於將醫藥組合物調配用於吸入投藥。
如上文所定義之本發明化合物亦可與一或多種其他治療劑結合,尤其係一或多種選自由以下各物組成之群的藥物:皮質類固醇、抗膽鹼劑及PDE4抑制劑。
在本發明之一較佳實施例中,該組合物包含如上文所定義之式(I)化合物及選自由以下各物組成之群之藥物:氟替卡松丙酸酯(fluticasone propionate)、6α,9α-二氟-17α-[-(2-呋喃基羰基)氧基]-11β-羥基-16α-甲基-3-酮基-雄固-1,4-二烯-17β-硫代碳酸S-氟甲酯及6α,9α-二氟-11β-羥基-16α-甲基-3-酮基-17α-丙醯氧基-雄固-1,4-二烯-17β-硫代碳酸S-(2-酮基-四氫-呋喃-3S-基)酯。
本發明亦針對於治療哺乳動物中與β2腎上腺素受體活性相關之疾病或病情之方法,該方法包含對哺乳動物投與治療有效量之包含本發明之β2腎上腺素受體激動劑之醫藥組合物。尤其適當的係該方法應用於治療肺部疾病,較佳為哮喘或慢性阻塞性肺部疾病之疾病或病情。
在本發明之範疇內治療疾病之方法亦可應用於治療選自以下各疾病組成之群之疾病或病情:早產、青光眼、神經病症、心臟病症及炎症。激動劑普通合成過程可用本文所描述之方法及過程或者用相似方法及過程製備本發明之化合物。應瞭解當給定典型或較佳處理條件(意即反應溫度、時間、反應物克分子比、溶劑、壓力等)時,除非另外說明,否則亦可使用其他處理條件。最佳反應條件可隨所使用之特定反應物或溶劑而變化,但該等條件可由熟習此項技術者藉由常規最佳化過程得以確定。
此外,如熟習此項技術者所瞭解,習知保護基團可為保護某些官能基免於非所需反應所必須。特定官能基之合適保護基團之選擇,以及保護及去保護之合適條件的選擇為此項技術所熟知。舉例而言,許多保護基團及其引入與去除描述於T.W.Greene及G.M.Wuts,Protecting Groups in Organic Synthesis,第3版,Wiley,New York,1999及其所引用之參考文獻。
提供製備本發明化合物之方法作為本發明之其他實施例,且藉由下文過程加以說明。
總言之,式(I)化合物藉由使式(II)化合物
與式(III)化合物反應而得到:
式(II)中R1
及R2
如上文所定義,P1
為習知羥基保護基團,諸如苄基;式(III)中n、m、p、q、r及s如上文所定義,且G1
係選自以下各基團之基團:、氫或鹵素原子或選自以下各基團之基團:C1 - 4
烷基、C1 - 4
烷氧基、S-R5
、SO-R5
及SO2
-R5
,其中R5
為C1 - 4
烷基及C3 - 6
環烷基,且R4
係選自氫原子、鹵素原子及C1 - 4
烷基。
反應基團G3
及G2
之性質取決於用於獲得式(I)化合物之偶合反應。化合物(II)(苯基乙醇胺部分)與其相應化合物(III)(經氟化部分)間之不同偶合反應總結於流程1,並在下文描述。
在第一替代方案中,在還原性烷基化步驟中,式(IIa)苯甲醯甲醛(對應通式(II)化合物,其中G3
為-CO-CHO基團)可與式(IIIf)化合物(對應通式(III)化合物,其中G2
為基團-CH2
NH2
)反應得到式(XI)中間物。可在多種溶劑中完成此步驟,例如四氫呋喃、醇,諸如甲醇、乙醇或異丙醇,以及溶劑混合物,諸如甲醇/四氫呋喃或二甲亞碸/甲醇,溫度範圍介於5℃與100℃之間;更特定言之介於15℃與70℃之間。還原劑可為氫化物,例如硼氫化鈉或氰基硼氫化鈉,以及氫加加氫催化劑,例如披鈀木炭。
在第二替代方案中,在類似還原性烷基化過程中,式(IIe)胺基醇(對應通式(II)化合物,其中G3
為-CH(OH)-CH2
NH2
基團)可與式(IIIc)(對應通式(III)化合物,其中G2為基團-CHO)醛化合物反應得到相同式(XI)中間物。在與先前所描述之相同條件及溶劑下進行此步驟。
在第三替代方案中,藉助例如雙羰基二咪唑之羰基化劑,或者涉及首先以二第三丁基碳酸氫鹽處理得到對應N-BOC衍生物及隨後以例如氫化鈉之鹼環化的兩步過程,將式(IIe)化合物(對應通式(II)化合物,其中G3
為-CH(OH)-CH2
NH2
基團)轉換成相應式(IIf)噁唑烷酮衍生物(對應通式(II)化合物,其中G3
為噁唑烷酮基)。在例如氫化鈉之鹼存在下,所得式(IIf)噁唑烷酮可與式(IIId)或(IIIb)烷基化劑(對應通式(III)化合物,其中G2
為基團-CH2
Br或基團-CH2
OMs(Ms代表甲磺酸鹽基團))反應,得到式(XII)中間物。藉助諸如鹼性氫氧化物或醇鹽(諸如三甲基矽醇化鉀)之鹼性試劑的隨後噁唑烷酮部分水解得到式(XI)化合物(對應通式(II)化合物,其中G2
為-CH(OH)-CH2
-NH-R)。
在第四替代方案中,式(IIb)苯甲醯甲基溴(其中G3
為-CO-CH2
-Br基團)可與式(IIIe)之經保護胺(對應通式(III)化合物,其中G2
為基團-CH2
-NH-P2
其中P2
為習知胺保護基團,諸如苄基)反應得到式(VIII)酮胺。此過程可在許多溶劑(例如四氫呋喃或二氯甲烷)中,在除酸劑存在下(例如第三胺,諸如三乙胺),且在5至60℃間之溫度下進行。式(VIII)化合物可經還原得到式(IX)胺基醇。可在多種溶劑中完成此步驟,例如四氫呋喃、醇,諸如甲醇、乙醇或異丙醇,以及溶劑混合物,諸如甲醇/四氫呋喃或二甲亞碸/甲醇,溫度範圍介於5℃與100℃之間;更特定言之介於15℃與70℃之間。還原劑可為氫化物,例如硼氫化鈉或氰基硼氫化鈉,以及氫加加氫催化劑,例如披鈀木炭。最後,通常為苄基之保護基團可藉助以相同催化劑及上述條件之加氫移除以得到式(XI)化合物。
在第五替代方案中,式(IId)之經保護溴醇(對應通式(II)化合物,其中G3
為基團-CH(OP3
)-CH2
-Br(P3
為習知羥基保護基,諸如矽烷基醚))可烷基化式(IIIf)第一胺(對應通式(III)化合物,其中G2
為基團-CH2
NH2
)得到式(X)中間物。在除酸劑(諸如第三胺或碳酸氫鈉)存在下,在各種溶劑(例如二噁烷、二甲亞碸)中亦或無溶劑下,在介於60℃與140℃間之溫度下進行此反應。藉助氟化物陰離子,例如以第四銨鹽(例如氟化四丁基銨)之形式,完成保護基PG之移除以得到式(XI)中間物。
在第六替代方案中,式(IIc)環氧化物(對應通式(II)化合物,其中G3
為氧基(oxyran group))亦可與式(IIIe)經保護胺(對應通式(III)化合物,其中G2
為基團-CH2
-NH-P2
,其中P2
為習知胺保護基,諸如苄基)反應得到式(IX)中間物。此過程可在許多溶劑,例如醇、四氫呋喃或根本無溶劑下,在介於20℃與140℃間之溫度下進行。
作為最後步驟,藉由習知方法使式(XI)化合物對式(I)目標化合物去保護。當保護基P1
為苄基時,用氫及加氫催化劑,例如披鈀木炭進行脫苄基作用。用各種溶劑,例如醇、四氫呋喃或其混合物,且在中性或略微酸性媒介中完成此步驟。氫之壓力介於6,90.104
Pa與2,76.105
Pa之間,且溫度介於10℃與30℃之間。
藉由文獻中熟知方法,自式(IIa)苯甲醯甲醛或對應水合物起始-自式(IV)對應苯乙酮製備,獲得式(IIa)、(IIb)、(IIc)、(IId)、(IIe)及(IIf)中間物(例如,參看EP 85166454,實例2;US 4,753,962描述54或GB 1247370,實例1)。
舉例而言,式(IIe)苯基乙醇胺可根據J.Med.Chem.,1976,19(9),1138,化合物19;DE 2461861,實例24所描述之方法獲得。式(IIb)苯甲醯甲基溴可根據Chem.Pharm.Bull.,1977,25(6),1368,化合物II;J.Med.Chem.,1974,17(1),49;EP 85166454,實例1中所描述之方法獲得。式(IId)之經保護溴醇可根據US2004059116實例9C,WO 2004/011416實例2及WO 2004/016578實例1ii中所描述之方法獲得。式(IIc)氧(oxyrane)可根據WO 01036375,製備12;J.Med.Chem.,1974,17(1),55中所描述之方法獲得。
許多該等中間物亦可以鏡像異構純形式存在(參看,例如Organic Process Research & Development 1998,2,96;Tetrahedron Lett.,1994,35(50),9375;WO 02070490實例1/X;EP 0147719)。
如前文已解釋,式(III)化合物中G2
基團之性質取決於用於獲得本發明化合物(I)之偶合反應。流程2說明具有不同G2
基團之式(III)化合物的互相轉換。
式(IIIa)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OBz)加氫得到式(IIIg)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH)。用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,在1,38.105
Pa至2,76.105
Pa壓力下進行此反應式(IIIg)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH)可與苄基溴或苄基氯反應得到式(IIIa)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OBz)。可用諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃之溫度下進行此反應。
式(IIId)溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)可藉由視情況以諸如三苯膦之催化劑,以諸如吡啶、苯、甲苯、亞甲基氯、氯仿、乙腈、乙醚、四氫呋喃或丙酮,在0℃至溶劑沸點間之溫度下,與溴化鋰、三溴化磷、氫溴酸、四溴化碳或亞硫醯溴反應而自式(IIIg)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH)獲得。
式(IIIa)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OBz)亦可獲自式(IIId)之溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)及苄基醇。可根據描述式(IIIg)醇與苄基溴或苄基氯之反應的相同實驗過程進行此反應。
式(IIIg)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH)可藉由與甲烷磺醯基氯在存在諸如三乙胺、二異丙基乙胺或吡啶之鹼下,以諸如二氯甲烷、氯仿或四氫呋喃之溶劑,在0℃至該溶劑之沸點的溫度下反應,而轉換成式(IIIb)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OMs)。
用諸如N-氧化N-甲基嗎啉、N-氧化2-二甲胺基-N,N-二甲基苯胺、N-氧化吡啶或N-氧化三甲胺之氧化劑氧化式(IIId)溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)得到式(IIIc)化合物(對應通式(III)化合物,其中G2
為基團-COH)。在諸如二甲基甲醯胺、二甲亞碸或乙腈之熔劑中,在室溫至該溶劑沸點間之溫度下進行該反應。
藉由式(IIIg)醇,藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯基氯於二甲亞碸中或Dess-Martin試劑於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃溫度下氧化反應亦可得到式(IIIc)醛(對應通式(III)化合物,其中G2
為基團-COH)。
式(IIIg)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH)可藉由式(IIIc)醛(對應通式(III)化合物,其中G2
為基團-COH)之還原而得以合成。可用諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下進行此反應。
式(IIId)溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)及式(IIIb)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OMs)可與鄰苯二甲醯亞胺鉀反應得到式(XIV)化合物。可在諸如二甲基甲醯胺、二甲亞碸、乙腈或四氫呋喃之溶劑中,視情況用諸如溴化(正十六基)三-正丁基鏻之催化劑,在室溫至該溶劑之沸點的溫度下進行此反應。
式(IIIh)化合物(對應通式(III)化合物,其中G2
為酞醯亞胺基甲基)與肼在諸如甲醇、乙醇、異丙醇或四氫呋喃之溶劑中,且在50至90℃之溫度下反應得到式(IIIf)胺(對應通式(III)化合物,其中G2為基團-CH2
-NH2
)。
藉由苄胺與式(IIId)溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)或與式(IIIb)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OMs)進行烷基化,隨後藉由脫苄基過程,可得到式(IIIf)胺(對應通式(III)化合物,其中G2
為基團-CH2
-NH2
)。
苄胺與式(IIIb)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OMs)或與式(IIId)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)進行烷基化,得到式(IIIe)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-NH-Bz)。可在諸如苄胺、三乙胺、二異丙基乙胺或碳酸鉀存在下,無溶劑或在諸如二甲基甲醯胺、丙酮、四氫呋喃或二噁烷中,且在0℃至該溶劑沸點之溫度下進行此反應。可用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯、乙酸或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,且在1,38.105
Pa至2,76.105
Pa壓力下進行得到式(IIIf)胺之脫苄基過程。
式(IIIe)胺(對應通式(III)化合物,其中G2
為基團-CH2
-NH-Bz)亦可獲自式(IIIc)醛(對應通式(III)化合物,其中G2
為基團-COH)及苄胺。可用諸如硼氫化鈉或氰基硼氫化鈉之氫化物在諸如乙醚、二異丙基醚、四氫呋喃或甲醇或其混合物之溶劑中,在室溫至該溶劑之沸點之溫度下進行此反應。
在一替代方案中,式(III)化合物
自式(XV)化合物起始
藉由下文所述之各種合成方法而獲得其中G1
、G2
、R4
、q、r、s如上文所定義,且G4
為鹵素原子,較佳為溴原子或羥基。
式(IIId)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)可藉由式(XVa)醇與式(XVI)二溴衍生物反應得到。可用諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃下進行此反應。
式(IIId)溴衍生物(對應通式(III)化合物,其中G2
為基團-CH2
-Br)可藉由經諸如N-氧化N-甲基嗎啉、N-氧化2-二甲胺基-N,N-二甲基苯胺、N-氧化吡啶或N-氧化三甲胺之氧化劑氧化而得以轉換成式(IIIc3)醛(對應通式(III)化合物,其中G2
為基團-COH)。在諸如二甲基甲醯胺、二甲亞碸或乙腈之溶劑中,在室溫至該溶劑沸點間之溫度下進行該反應。
式(IIIc3)醛(對應通式(III)化合物,其中G2
為基團-COH)與式(XIX)鹵基衍生物(其中X代表鹵素原子,諸如氯、溴或碘)及鎂之反應得到式(XX)醇。以諸如乙醚或四氫呋喃之溶劑,且在-78℃至80℃之溫度下進行此反應。
式(XX)醇藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應而得以完成產生式(XXI)酮之反應。
式(XXI)酮可藉由於氟化劑,諸如三氟化(二乙胺基)硫(DAST)或三氟化[二(甲氧基乙基)胺基]硫,視情況在諸如二氯甲烷、氯仿、甲醇、乙醇或四氫呋喃之溶劑存在下,且在室溫至該溶劑沸點之溫度下反應而轉化成式(XXII)化合物。
式(XXX)烯烴可藉由經高碘酸鈉或高碘酸鉀及催化劑量四氧化鋨氧化而轉換成式(IIIc2)醛(對應通式(III)化合物,其中G2
為基團-COH)。可在諸如二噁烷、四氫呋喃、甲醇、乙醇、乙腈或水之溶劑、或其混合物中,且在-78℃至100℃溫度下進行該反應。
在另一替代方案中,式(III)化合物(其中G1
、R4
、s、r及q如上文所定義)可根據流程4中所述方法獲得。
式(IIIg2)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH,m為0且p+n為2)可自式(XXIII)烯烴,藉由與硼烷四氫呋喃錯合物或硼烷-甲基硫醚錯合物及過氧化氫在諸如氫氧化鈉或氫氧化鉀之鹼於諸如四氫呋喃、二噁烷、水或二乙二醇二甲基醚之溶劑中,且在-78℃至100℃溫度下連續反應而得到。
藉由隨後與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸比啶鎓、草醯氯在二甲亞碸中或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃溫度下反應可完成式(IIIg2)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-OH,m為0且p+n為2)轉換成式(IIIc4)醛(對應通式(III)化合物,其中G2
為基團-COH,m為0且p+n為2)。
在又一替代方案中,式(IIIi)化合物(對應通式(III)化合物,其中G2
為基團-OH,G1
、R4
、s、r、q及p如上文所定義,且m及n均為1)可根據流程5中所述方法得到。
可藉由將式(IIIg3)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH,m為0)與硒基氰酸2-硝基苯酯,用諸如四氫呋喃、乙醚或二噁烷之溶劑,在室溫至該溶劑沸點之溫度下反應得到式(XXXI)烯烴(參看參考文獻Hart,D.J.;Kanai,K.-I.;J.Am.Chem.Soc.1983,105,1255;Hart,D.J.;J.Org.Chem.1981,46,3576)。式(XVIIb)醇亦可與對甲苯磺醯基氯或甲基磺醯基氯,在諸如四氫呋喃、乙醚、二噁烷或二氯甲烷之溶劑中,在室溫至該溶劑沸點之溫度下反應。所得中間物與諸如氫氧化鉀、氫氧化鈉、三乙胺或二異丙基乙胺之鹼反應得到式(XXXI)化合物。無溶劑或用諸如四氫呋喃、乙醚、二噁烷或二氯甲烷之溶劑,在20至250℃溫度下進行該反應。
可藉由將式(XXXI)烯烴與碘二氟乙酸乙酯在諸如鋅或銅之金屬存在下,視情況用諸如六水合氯化鎳及水,在諸如二甲基甲醯胺、四氫呋喃、二甲亞碸或二噁烷之溶劑中,且在20至60℃溫度下反應可得到式(XXXIII)酯(參看參考文獻J.Chem.Soc.Chem.Comm.,1992,233)。
式(IIIg4)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH,m為1且n為1)自式(XXXIII)酯之合成可藉由使其經諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑沸點之溫度下處理完成。
流程6在另一替代方案中,式(IIIg6)化合物(對應通式(III)化合物,其中G1
、R4
、s、r、q及m如上文所定義,p為1,m為2,且n為3)可根據流程6中所述方法得到。
可藉由使式(XXXIV)醇與式(XVg)溴衍生物(對應通式(XV)化合物,其中G4
為Br原子)反應得到式(IIIg5)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH且p及q均為1)。可用諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃下進行此反應。
式(IIIc3)醛可自式(XXXV)醇,藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應而得到。
式(IIIc6)醛(對應通式(III)化合物,其中G2
為-COH基團,p為1且n為1)可與式(XXVIII)磷烷(其中R8
代表C1 - 4
烷基且R9
代表C1 - 4
烷基或苯基)反應得到式(XXXVI)酯。可在諸如二氯甲烷、四氫呋喃、乙醚或甲苯之溶劑中,在室溫至該溶劑沸點間之溫度下進行該反應。
式(XXXVI)化合物加氫得到式(XXXVII)酯。用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,在1,38.105
Pa至2,76.105
Pa壓力下進行此反應。
式(IIIg6)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH,p為1且n為3)可藉由式(XXXVII)酯經諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑沸點之溫度下處理而得到。
在另一替代性方法中,式(III)化合物(其中G1
及R4
如上文所定義,p為1,r為0,n為3,q+s為3且G2
為基團-CH2
-OH)可根據流程7中所述方法獲得。
式(XXXIX)醇可藉由式(XXXIV)醇與式(XXXVIII)鹵基衍生物反應而得到。可用諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃下進行此反應。
式(XL)醛可自式(XXXIX)醇,藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應而得到。
式(XL)醛可與式(XXVIII)磷烷反應得到式(XLI)酯。可在諸如二氯甲烷、四氫呋喃、乙醚或甲苯之溶劑中,在室溫至該溶劑沸點間之溫度下進行反應。
式(XLI)化合物加氫得到式(XLII)酯。用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,在1,38.105
Pa至2,76.105
Pa壓力下進行此反應。
式(IIIg7)醇(對應通式(III)化合物,其中G2
為基團-CH2
-OH,q+s為3,r為0,p為1且n為3)可藉由式(XLII)酯經諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑沸點之溫度下處理而得到。
在另一替代方案中,式(IIIa)化合物
其中G1
、R4
、n、m、p、q、r及s如上文所定義(對應通式(III)化合物,其中G2
為基團-CH2
-O-Bz),自式(XLIII)化合物根據流程8中所述方法獲得
式(XLIII)醇藉由與式(XVb)溴衍生物在諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼存在下,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃下反應而轉換成式(IIIa)化合物(對應通式(III)化合物,其中G2
為基團-CH2
-O-Bz)。
式(XLIII)化合物可根據下文所述流程9至10至合成方法得到:在一替代方案中,式(XLIIIa)化合物(其中n及m均為1)可根據流程9中所述方法得到。
可藉由將式(XLVI)醇與硒基氰酸2-硝基苯酯,用諸如四氫呋喃、乙醚或二噁烷之溶劑,在室溫至該溶劑沸點之溫度下反應得到式(XLVII)烯烴(參看參考文獻Hart,D.J.;Kanai,K.-I.;J.Am.Chem.Soc.1983,105,1255;Hart,D.J.;J.Org.Chem.1981,46,3576)。
式(XLVI)醇亦可與對甲苯磺醯氯或甲基磺醯氯,在諸如四氫呋喃、乙醚、二噁烷或二氯甲烷之溶劑中,在室溫至該溶劑沸點之溫度下反應。所得中間物與諸如氫氧化鉀、氫氧化鈉、三乙胺或二異丙基乙胺之鹼反應得到式(XLVII)化合物。無溶劑或用諸如四氫呋喃、乙醚、二噁烷或二氯甲烷之溶劑,在20至250℃溫度下進行反應。
可藉由將式(XLVII)烯烴與碘二氟乙酸乙酯(XXXII)在諸如鋅或銅之金屬存在下,視情況用諸如六水合氯化鎳及水,在諸如二甲基甲醯胺、四氫呋喃、二甲亞碸或二噁烷之溶劑中,且在20至60℃溫度下反應可得到式(XLVIII)酯(參看參考文獻J.Chem.Soc.Chem.Comm.,1992,233)。
可藉由以諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下處理而完成式(XLIIIa)醇自式(XLVIII)酯之合成。
在另一提到之方法中,式(XLIIIc)化合物(m為上文所定義,且R8
代表C1 - 4
烷基或苯基)可根據流程10中所述方法獲得。
式(XLIIIb)醇可藉由式(XXXIV)醇與苄基溴反應而得到。可用諸如氫氧化鈉、氫氧化鉀或氫化鈉之鹼,視情況在諸如溴化四丁基銨之鹼轉運催化劑存在下,用諸如水、二甲基甲醯胺、二甲亞碸或二乙二醇二甲基醚之溶劑,在20℃至100℃下進行此反應。
式(XLIX)醛可自式(XLIIIb)醇,藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應得到。
式(XLIX)醛可與式(XXVIII)磷烷反應得到式(L)酯。可在諸如二氯甲烷、四氫呋喃、乙醚或甲苯之溶劑中,在室溫至該溶劑沸點間之溫度下進行反應。
式(L)化合物之加氫得到式(LI)酯。用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,在1,38.105
Pa至2,76.105
Pa壓力下進行此反應。
可藉由以諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下處理式(LI)酯而得到式(XLIIIc)醇。
式(XV)化合物可根據下文所述流程11至13至合成方法得到:
其中s及R4
如上文所定義,G1
係選自、氫或鹵素原子或係選自以下之基團:C1 - 4
烷基、C1 - 4
烷氧基、S-R5
、SO-R5
及SO2
-R5
其中R5
為C1 - 4
烷基或C3 - 6
環烷基;R4
係選自氫原子、鹵素原子及C1 - 4
烷基且R7
為C1 - 4
烷基。
式(XXV)化合物可藉由在氟化劑,諸如三氟化(二乙基胺基)硫(DAST)或三氟化[二(甲氧基乙基)胺基]硫,視情況在諸如二氯甲烷、氯仿、甲醇、乙醇或四氫呋喃之溶劑存在下,且在室溫至該溶劑沸點之溫度下反應而轉化成式(XXVI)化合物。
可藉由以諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下處理式(XXVI)酯而得到式(XVa)醇。
流程12式(XVc4)醇(對應通式(XV)化合物,其中x為n-4,且G2
為基團-COH)可根據流程12得到,其中s、G1
及R4
如上文所定義,且當反應在產物(XVa3)停止時,x為1至3之整數,或者當跟隨流程直至獲得產物(XVa4)時,x為1。
式(XVa2)醇(其中x至少為1)可藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑中於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應而轉換成式(XVc2)之醛。
可用Tebbe試劑或溴化甲基三苯基鏻在諸如氫化鈉或鈉胺之鹼存在下,以諸如四氫呋喃、二噁烷、二氯甲烷或二甲亞碸之溶劑,在-78℃至80℃之溫度下將式(XVc2)之醛轉化成式(XXVII)之烯烴。
式(XVa3)醇可自式(XXVII)之烯烴藉由與硼烷四氫呋喃錯合物或硼烷-甲基硫醚錯合物以過氧化氫在諸如氫氧化鈉或氫氧化鉀之鹼於諸如四氫呋喃、二噁烷、水或二乙二醇二甲基醚之溶劑中,且在-78℃至100℃之溫度下反應而得到。
式(XVa3)醇可藉由與三氧化鉻、二氧化錳、重鉻酸鉀、氯鉻酸吡啶鎓、草醯氯在二甲亞碸或Dess-Martin試劑於諸如吡啶、二氯甲烷、氯仿、二甲亞碸或乙腈之溶劑中,在-78℃至130℃之溫度下反應而轉換成式(XVc3)醛。
式(XVc3)醛可與式(XXVIII)磷烷(其中R8
為C1 - 4
烷基且R9
為C1 - 4
烷基或苯基)反應而得到式(XXIX)酯。可在諸如二氯甲烷、四氫呋喃、乙醚或甲苯之溶劑中,在室溫至該溶劑沸點間之溫度下進行該反應。
式(XXIX)化合物加氫得到式(XXX)酯。用諸如披鈀木炭或二氧化鉑之催化劑,在諸如乙醇、甲醇、乙酸乙酯或二甲基甲醯胺之溶劑中,在室溫至70℃之溫度下,在1,38.105
Pa至2,76.105
Pa壓力下進行此反應可藉由以諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下處理式(XXI)酯而得到式(XVa4)醇。
流程13式(XVa5)醇(其中s為0,且G1
及R4
如上文所定義)可根據流程13得到。
藉由使式(LVI)碘代苯與式(LVII)碘四氟丙酸烷酯(其中R7
為C1 - 4
烷基)在視情況諸如鈀錯合物催化劑存在下,在諸如二甲基甲醯胺、四氫呋喃、二甲亞碸或二噁烷之溶劑中,且在20至60℃溫度下反應得到式(LVIII)酯(參看參考文獻Journal of Fluorine Chemistry,2004,125(5),763-765)。
可藉由以諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下處理式(LVIII)酯而得到式(Xva5)醇。
根據流程14可獲得式(XVa6)醇(對應通式(XV)化合物,其中s為0、r為1、q為2且G4
為基團-OH),且G1
及R4
如上文所定義。
式(LX)化合物與氟化劑,諸如三氟化(二乙基胺基)硫(DAST)或三氟化[二(甲氧基乙基)胺基]硫(DEOXOFLUOR),視情況在諸如二氯甲烷、氯仿、甲醇、乙醇或四氫呋喃之溶劑存在下,且在室溫至該溶劑沸點之溫度下隨後反應而得到式(XVd)化合物。
在氫氧化鈉、氫氧化鉀或碳酸鈉水溶液中,視情況在諸如乙醇、甲醇或異丙醇之溶劑存在下,且在室溫至該溶劑沸點之溫度下,式(XVd)化合物中酯基團水解產生式(XVa6)醇。
根據流程15可獲得式(XVa7)醇(對應通式(XV)化合物,其中q、r及s均為1,且G4
為基團-OH),且G1
及R4
如上文所定義。
1-苯基乙酮(LXI)與溴(二氟)乙酸酯,在Zn之存在下在諸如四氫呋喃、二噁烷或乙醚溶劑中,且在室溫至該溶劑沸點之溫度下反應。
所得化合物(LXII)隨後與CS2
在諸如DMSO、DMF、四氫呋喃或二噁烷之溶劑中,在室溫至60℃下且在惰性氣氛中反應得到硫代酸(未展示),硫代酸與甲基碘或二甲基硫酸酯在室溫下反應得到式(LXIII)化合物。
在隨後步驟中,式(LXIII)化合物與氧化二苯基膦及tBuOOtBu(過氧化二第三丁基)於諸如四氫呋喃、二噁烷或乙醚之溶劑中,且在室溫至該溶劑沸點之溫度下反應得到式(LXIV)化合物。
在最終步驟中,式(LXIV)化合物與諸如氫化鋰鋁、硼氫化鈉或氫化二異丁基鋁之氫化物於諸如乙醚、二異丙基醚、四氫呋喃或甲醇之溶劑中,在室溫至該溶劑之沸點之溫度下反應得到醇(XVa7)。
如流程16所示,可獲得式(IIIb)化合物,其中m、n、p、q、r及s如上文所定義,R3
為乙內醯基且R4
=氫原子或C1
-4
烷基。
式(IIIa3)胺可藉由與雙(三甲基矽烷基)胺基鋰、雙(三甲基矽烷基)胺基鈉或胺基甲酸第三丁酯反應而自式(IIIa2)化合物得到。可用諸如乙氧化鈉、碳酸鉀或苯氧化鈉之鹼,用催化劑量之諸如二第三丁基膦、三鄰甲苯基膦或三苯膦之膦及諸如雙(二亞苄基丙酮)鈀或參(二亞苄基丙酮)-二鈀(0)之鈀催化劑,用諸如四氫呋喃、二噁烷、甲苯或苯之溶劑,且在-78℃至80℃之溫度下進行該反應。
式(IIIa3)胺可藉由與式(LII)異氰酸酯於諸如甲苯、苯或二噁烷之溶劑中,且在室溫至該溶劑沸點之溫度下反應而轉換成式(IIIa4)化合物。
式(IIIa4)化合物之皂化產生式(IIIa5)化合物。可用諸如氫氧化鈉或氫氧化鉀之鹼,用諸如甲醇、乙醇、水或其混合物之溶劑中,且在室溫至該溶劑沸點之溫度下進行此反應。
可藉由以諸如鹽酸或乙酸,以諸如甲醇、乙酸、乙醇或水或其混合物之溶劑,且在室溫至該溶劑沸點之溫度下對式(IIIa5)化合物進行環化而得到式(IIIa6)化合物。
根據流程2所示之相同途徑,可將式(IIIa6)化合物改質成對應醇、溴衍生物、甲磺酸鹽、醛或胺基衍生物。
如流程17所示,可獲得如下化合物,其中R4
、m、n、p、q、r及s如上文所定義,且R3
為醯胺基且G2
為-CH2
-Br基團(IIId)或苄氧基甲基(IIIa)。
藉由文獻中已知所述過程(Meyers A.I.,Temple D.L.,Haidukewych D.,Mihelich E.D.,J Org Chem,1974,39(18),2787;Svenson R.,Gronowitz S.,Chem Scr,1982,19,149;Meyers A.I.,Lutomski K.A.,Synthesis,1983,105)可自式(IIIa7)或(IIId3)化合物獲得式(IIIa8)或(IIId4)化合物。
式(IIIa8)或(IIId4)化合物於氯氧化磷反應得到式(IIIa9)或(IIId5)腈。可在諸如吡啶、三乙胺或二異丙基乙胺之鹼存在下,用諸如吡啶、苯或甲苯之溶劑,且在室溫至該溶劑沸點之溫度下進行反應。
可藉由在諸如阮尼鎳(Nickel-Raney)、披鈀木炭或二氧化鉑之催化劑存在下與氫,用諸如甲醇、乙醇、異丙醇或乙酸乙酯之溶劑,在室溫至60℃下,且在1,38.105
Pa至2,76.105
Pa下反應而完成自式(IIIa9)或(IIId5)腈合成式(IIIa10)或(IIId6)醯胺。
式(IIIa9)或(IIId5)腈亦可與濃硫酸反應得到式(IIIa10)或(IIId6)醯胺。可無溶劑或用諸如甲醇、乙醇或異丙醇之溶劑,且在室溫至150℃之溫度下進行反應。
式(IIIa9)或(IIId5)腈與過氧化氫反應亦可得到式(IIIa10)或(IIId6)醯胺。可在諸如氫氧化鈉、氫氧化鉀或碳酸鉀之鹼存在下,在諸如甲醇、乙醇、異丙醇、二甲亞碸或丙酮之溶劑中,且在-20℃至120℃溫度下進行該反應。
根據流程2所示之相同途徑,可將式(IIIa10)衍生物轉換成對應醇、甲磺酸鹽、醛或胺基衍生物。
如流程18所示,可得到式(I)化合物,其中R3
為脲基,P1
為氧保護基,諸如苄基,R4
為氫原子或C1 - 4
烷基,且R1
、R2
、n、m、p、q、r及s如上文所定義。
式(LIV)胺可藉由與雙(三甲基矽烷基)胺基鋰、雙(三甲基矽烷基)胺基鈉或胺基甲酸第三丁酯,用諸如乙氧化鈉、碳酸鉀或苯氧化鈉之鹼,用催化劑量之諸如二第三丁基膦、三鄰甲苯基膦或三苯膦之膦及諸如雙(二亞苄基丙酮)鈀或參(二亞苄基丙酮)-二鈀(0)之鈀催化劑,用諸如四氫呋喃、二噁烷、甲苯或苯之溶劑,且在-78℃至80℃之溫度下反應而自式(LIII)化合物得到。
式(LIV)胺可藉由與氰酸鉀在諸如鹽酸或乙酸水溶液之酸存在下,且在0℃至100℃之溫度下反應而轉換成式(LV)脲。
如流程19所示,可得到式(III)化合物,其中R3
為基團R5
-SO-或R5
-SO2
-,且G2
、R4
、n、m、p、q、r及s如上文所定義。
流程20如流程20所示,可得到式(III)化合物,其中R3為基團R5
R6
-NSO2
-,且G2
、R4
、n、m、p、q、r及s如上文所定義。
僅當R5
為甲基時,式(IIIo)或(IIIn)亞碸及式(IIIt)或(IIIm)碸可轉換成式(IIIs)磺醯胺。
式(IIIp)化合物氧化產生式(IIIq)磺醯胺。可用3-氯過氧苯甲酸、單過氧鄰苯二甲酸鎂或過氧硫酸鉀之氧化劑,在諸如丙酮、二氯甲烷、甲醇或乙醇或其混合物之溶劑中,且在10℃至40℃之溫度下完成該反應。
式(IIIq)碸可轉換成式(IIIr)化合物。可用諸如氫氧化鈉或氫氧化鉀之鹼,在諸如四氫呋喃、甲醇或乙醇或其混合物之溶劑中,且在0℃至80℃之溫度下進行該反應。
式(IIIr)化合物與羥基鄰磺酸反應產生式(IIIs)磺醯胺。可在諸如乙酸或水之溶劑中,在乙酸鈉存在下,且在0℃至100℃之溫度下進行過程。
式(IIIs)磺醯胺亦可獲自式(IIIt)碸。在第一步驟中,在諸如三乙基硼烷或三丁基硼烷之硼烷存在下,且在室溫下,式(IIIt)碸與諸如氯化甲基鎂或氯化乙基鎂之鎂衍生物反應。在諸如乙酸或水之溶劑中,在乙酸鈉存在下,且在0℃至100℃之溫度下得到最終磺醯胺。
一般.試劑、起始物質及溶劑購自供應商並按原樣使用。濃縮指在真空下用Bchi旋轉蒸發器蒸發。若需要,則可藉由於矽膠(40-63 μm)上用所指示溶劑系統急驟層析純化反應產物。於Varian Gemini 300分光計及Varian Inova 400分光計上記錄分光資料。於Bchi 535設備上記錄熔點。
中間物1. 2,2-二氟-4-苯基丁酸乙酯在2-酮基-4-苯基丁酸乙酯(1.0 g,4.85 mmol)於二氯甲烷(10 mL)之冷卻溶液中加入DAST(1.6 ml,12.1 mmol)。在室溫下隔夜攪拌混合物。用二氯甲烷(10 mL)稀釋粗反應物,用碳酸氫鈉飽和溶液(2×10 mL)及水(10 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。獲得褐色油狀標題化合物(1.02 g,91%)。
中間物2. 2,2-二氟-4-苯基丁-1-醇在中間物1(1.0 g,4.45 mmol)於四氫呋喃(15 mL)之冷卻溶液中加入氫化鋰鋁(0.22 g,5.78 mmol)。在室溫下隔夜攪拌混合物。在粗反應物中加入水(0.3 mL)、4 N氫氧化鈉(0.3 mL)及水(0.9 mL)。所得固體經矽藻土過濾,並在減壓下移除溶劑。用二氯甲烷(20 mL)稀釋殘餘物,並用水(10 mL)、2 N鹽酸(2×10 mL)及水(10 mL)洗滌,乾燥(Na2
SO4
),並濃縮。獲得褐色油狀標題化合物(0.6 g,72%)。
1
H-NMR(300 MHz,CDCl3
):2.10-2.35(m,2H);2.75-2.85(m,2H);3.75(t,JF - H
=14.0 Hz,2H);7.15-7.25(m,3H);7.25-7.35(m,2H)。
中間物3. {4-[(6-溴己基)氧基]-3,3-二氟丁基}苯在中間物2(0.60 g,3.22 mmol)於1,6-二溴己烷(1.74 mL,11.27 mmol)溶液中加入溴化四丁基鋁(21 mg,0.064 mmol)及50%氫氧化鈉(1.2 mL)。在室溫下隔夜攪拌混合物。用正己烷(20 mL)稀釋粗反應物,用水(2×10 mL)洗滌,乾燥(Na2
SO4
),且在減壓下移除溶劑。獲得標題化合物(2.1 g,52%純度),且不經進一步純化而用於下一步。
1
H-NMR(300 MHz,CDCl3
):1.30-1.50(m,4H);1.50-1.65(m,2H);1.70-1.90(m,2H);2.15-2.35(m,2H);2.75-2.90(m,2H);3.35-3.45(m,2H);3.45-3.70(m,4H);7.15-7.25(m,3H);7.25-7.35(m,2H)。
中間物4. (R,S)-2-{[6-(2,2-二氟-4-苯基丁氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇在中間物3(0.385 g,0.57 mmol純化合物)於二甲基甲醯胺(15 mL)溶液中加入碳酸鉀(0.31 g,2.28 mmol)及(R,S)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(0.26 g,1.14 mmol)。在80℃下攪拌混合物66小時。粗反應物經過濾,並在減壓下移除溶劑。藉由以二氯甲烷/甲醇(98:2至95:5)溶離之矽膠管柱層析純化殘餘物,以得到褐色油狀(R,S)-2-{[6-(2,2-二氟-4-苯基丁氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(0.2 g,71%)。
MS(M+):491
在70℃下加熱中間物4(0.20 g,0.4 mmol)於乙酸(10 mL)及水(2 mL)混合物中之溶液3小時。減壓下移除溶劑。藉由以二氯甲烷/甲醇/氫氧化銨(80:15:1.5)溶離之矽膠管柱層析純化所得油,得到油狀(R,S)-4-(2-{[6-(2,2-二氟-4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(104 mg,57%)。
1
H-NMR(400 MHz,二甲亞碸-D6);1.25-1.31(m,4H);1.34-1.41(m,2H);1.47-1.54(m,2H);2.12-2.25(m,2H);2.54-2.57(m,4H);2.71-2.75(m,2H);3.47(t,J=6.4 Hz,2H);3.66(t,JF - H
=13.3 Hz,2H);4.45-4.50(m,4H);4.90-4.92(m,1H);4.99(bs,1H);6.68(d,J=8.3 Hz,1H);6.97(dd,J1
=8.3 Hz,J2
=2.1 Hz,1H);7.17-7.31(m,6H);9.14(bs,1H)。
MS(M+):451。
中間物5. 二氟(苯基)乙酸乙酯藉由中間物1中所述之過程自(苯基)(酮基)乙酸乙酯(7.5 mL,47 mmol)獲得。藉由以正己烷/乙酸乙酯(純正己烷至10:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(13.2 g,70%)。
1
H-NMR(300 MHz,CDCl3
):1.30(t,J=7.1 Hz,3H);4.30(q,J=7.1 Hz,2H);7.43-7.51(m,3H);7.61-7.63(m,2H)。
中間物6. 2,2-二氟-2-苯基乙醇藉由中間物2中所述過程自中間物5(13.2 g,66 mmol)獲得。獲得油狀標題化合物(6.88 g,66%)。
1
H-NMR(300 MHz,CDCl3
):4.00(t,JF - H
=13.5 Hz,2H);7.45-7.48(m,3H);7.50-7.54(m,2H)。
中間物7. {2-[(6-溴己基)氧基]-1,1-二氟乙基}苯藉由中間物3中所述過程自中間物6(6.88 g,43.5 mmol)獲得。藉由以正己烷/乙酸乙酯(10:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(10.9 g,78%)。
1
H-NMR(300 MHz,CDCl3
):1.40-1.60(m,2H);1.78-1.90(m,4H);3.36-3.44(m,4H);3.52(t,J=6.5 Hz,2H);3.84(t,JF - H
=13.2 Hz,2H);7.43-7.46(m,3H);7.50-7.54(m,2H)。
中間物8. 2-[6-(2,2-二氟-2-苯基乙氧基)己基]-1H-異吲哚-1,3(2H)-二酮在中間物7(10.9 g,34 mmol)於二甲基甲醯胺(23 mL)中之溶液中加入鄰苯二甲醯亞胺鉀(7.56 g,40.8 mmol)及催化劑量之溴化(正十六基)三-正丁基鏻。在70℃下攪拌混合物3小時。減壓下移除溶劑。藉由用二氯甲烷溶離之矽膠管柱層析純化得到油狀標題化合物(6.41 g,49%)。
1
H-NMR(300 MHz,CDCl3
):1.28-1.33(m,4H);1.51-1.56(m,2H);1.62-1.66(m,2H);3.50(t,J=6.5 Hz,2H);3.63-3.68(m,2H);3.82(t,JF - H
=13.2 Hz,2H);7.42-7.44(m,3H);7.49-7.52(m,2H);7.69-7.72(m,2H);7.83-7.86(m,2H)。
中間物9. [6-(2,2-二氟-2-苯基乙氧基)己基]胺在中間物8(6.41 g,16.5 mmol)於乙醇(50 mL)中之溶液中加入單水合肼(12 mL,247 mmol)。在室溫下隔夜攪拌混合物,濃縮,並以異丙醇濕磨殘餘物。所得固體經過濾,並在減壓下移除溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(80:8:1)溶離之矽膠管柱層析純化殘餘物得到油狀標題化合物(2.31 g,54%)。
1
H-NMR(300 MHz,CDCl3
):1.27-1.32(m,4H);1.39-1.44(m,2H);1.53-1.58(m,2H);2.66(t,J=6.9 Hz,2H);3.52(t,J=6.5 Hz,2H);3.84(t,JF - H
=13.2 Hz,2H);7.43-7.46(m,3H);7.51-7.54(m,2H)。
中間物10. (R,S)-1-[4-(苄氧基)-3-(羥甲基)苯基]-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}乙醇室溫下攪拌中間物9(0.71 g,2.77 mmol)及4-(苄氧基)-3-(羥甲基)苯基](酮基)乙醛(0.75 g,2.77 mmol)於四氫呋喃(8 mL)及甲醇(8 mL)中之溶液1小時。將溶液冷卻至0℃,並緩慢加入硼氫化鈉(0.25 g,6.65 mmol)。在室溫下攪拌反應混合物2.5小時。加入水(2 mL),且在減壓下移除溶劑。用二氯甲烷(20 mL)及水處理殘餘物。用水(2×10 mL)、碳酸氫鈉飽和溶液(2×10 mL)及鹽水(10 mL)洗滌有機層,乾燥(Na2
SO4
),且在減壓下移除溶劑。獲得油狀(R,S)-1-[4-(苄氧基)-3-(羥甲基)苯基]-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}乙醇(1.43 g,100%)。
1
H-NMR(300 MHz,CDCl3
):1.25-1.35(m,4H);1.40-1.60(m,5H);2.57-2.64(m,3H);2.82-2.84(m,1H);3.53(d,J=5.2 Hz,2H);3.79-3.88(m,2H);4.60-4.70(m,1H);4.73(s,2H);5.12(s,2H);5.30-5.32(m,1H);6.92(d,J=8.2 Hz,1 H);7.26-7.50(m,10H)。
在中間物10(1.43 g,2.78 mmol)於甲醇(100 mL)中之溶液中加入披鈀木炭(150 mg)。混合物在20 psi經加氫6小時。催化劑經矽藻土過濾,並在減壓下移除溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)溶離之管柱層析純化所得油,得到油狀(R,S)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(0.75 g,64%)。
1
H-NMR(400 MHz,Cl3
CD):1.25-1.33(m,4H):1.41-1.47(m,2H);1.50-1.56(m,2H);2.51-2.74(m,4H);3.51(t,J=6.7 Hz,2H);3.79(bs,4H);3.84(t,JF - H
=13.1 Hz,2H);4.54(dd,J1
=8.8 Hz,J2
=3.7 Hz,1H);4.72(s,2H);6.77(d,J=8.2 Hz,1H);6.93(s,1H);7.08(dd,J1
=8.2 Hz,J2
=2.0 Hz,1H);7.42-7.44(m,3H);7.50-7.52(m,2H)。
MS(M+):423。
中間物11. [4-(烯丙氧基)丁基]苯在4-苯基丁-1-醇(0.60 g,3.99 mmol)於1,3-二溴丙烷(2.14 mL,10.60 mmol)中之溶液中加入溴化四丁基鋁(20 mg,0.064 mmol)及50%氫氧化鈉(1.5 mL)。在室溫下隔夜攪拌混合物。用正己烷(20 mL)稀釋粗反應物,用水(2×10 mL)洗滌,乾燥(Na2
SO4
),且在減壓下移除溶劑。藉由在減壓下蒸餾殘餘物獲得標題化合物(1.90 g,92%純度),且不經進一步純化而用於下一步。
1
H-NMR(300 MHz,CDCl3
):1.50-1.80(m,4H);2.50-2.70(m,2H);3.35-3.45(m,2H);3.90-4.00(m,2H);5.10-5.35(m,2H);5.80-6.00(m,1H);7.15-7.20(m,3H);7.20-7.35(m,2H)。
中間物12. 3-(4-苯基丁氧基)丙-1-醇將中間物11(0.40 g,2.10m mol)於THF(5 mL)中之溶液冷卻至0℃。加入BBN(5 mL,2.52 mmol)於THF中之0.5 M溶液,且在0℃下攪拌所得混合物1小時,並在室溫下攪拌2小時。連續加入2M NaOH(1 mL)及過氧化氫(1 mL,35%)溶液,且室溫下攪拌混合物1小時。隨後濃縮溶液,且將殘餘物溶解於乙醚(25 mL)中,用水(2×15 mL)及鹽水(15 mL)洗滌,乾燥(Na2
SO4
),且在減壓下移除溶劑。藉由矽膠上管柱層析(己烷/AcOEt,6:1)純化殘餘物得到油狀標題化合物(0.24 g,55%)。
1
H-NMR(300 MHz,CDCl3
):1.50-1.75(m,4H);1.75-1.90(m,2H);2.55-2.70(m,2H);3.35-3.50(m,2H);3.60(t,J=6.0 Hz,2H);3.70-3.85(m,2H);7.15-7.20(m,3H);7.20-7.35(m,2H)。
中間物13. 3-(4-苯基丁氧基)丙醛在中間物12(1.0 g,4.8 mmol)於CH2
Cl2
(20 mL)中之溶液中加入Dess-Martin高碘烷(2.4 g,5.76 mmol),且在室溫下攪拌反應物2小時。用CH2
Cl2
(40 mL)稀釋溶液,用水(2×20 mL)、碳酸氫鈉飽和溶液(2×20 mL)及水(20 mL)洗滌,乾燥(Na2
SO4
)並濃縮。藉由管柱層析(二氯甲烷/丙酮,20:1)純化殘餘物得到油狀標題化合物(580 mg,58%)。
1
H-NMR(300 MHz,CDCl3
):1.50-1.75(m,4H);2.55-2.75(m,4H);3.35-3.50(m,2H);3.70-3.80(m,2H);7.15-7.20(m,3H);7.20-7.35(m,2H);9.80(bs,1H)。
中間物14. 1-(4-苯基丁氧基)庚-6-烯-3-醇將中間物13(0.55 g,2.66 mmol)於THF(5 mL)中之溶液冷卻至-30℃。在此溶液中加入溴化3-丁烯基鎂(5.8 mL,2.92 mmol)於THF中之0.5 M溶液,且於-30℃下攪拌所得混合物2小時。使反應達到室溫;加入乙酸(0.1 mL)並濃縮。藉由以二氯甲烷/丙酮(20:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(410 mg,54%)。
1
H-NMR(300 MHz,CDCl3
):1.40-1.80(m,8H);2.00-2.15(m,2H);2.55-2.70(m,2H);3.15-3.25(bs,1H);3.35-3.50(m,2H);3.75-3.85(m,1H);4.90-5.10(m,2H);5.75-2.95(m,1H);7.15-7.20(m,3H);7.20-7.35(m,2H)。
中間物15. 1-(4-苯基丁氧基)庚-6-烯-3-酮藉由中間物13中所述過程自中間物14(0.41 g,1.56 mmol)獲得。藉由以二氯甲烷/丙酮(20:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(0.36 g,88%)。
中間物16. {4-[(3,3-二氟庚-6-烯-1-基)氧基]丁基}苯在中間物15(0.36 g,1.36 mmol)於二氯甲烷(1 mL)中之冷卻溶液中加入DAST(0.8 ml,6.0 mmol)。在室溫下隔夜攪拌混合物。用二氯甲烷(10 mL)稀釋粗反應物,用碳酸氫鈉飽和溶液(2×5 mL)及水(5 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以二氯甲烷/丙酮(20:1)作為溶離劑之矽膠管柱層析純化殘餘物。獲得褐色油狀標題化合物(110 mg,27%)。
中間物17. 4,4-二氟-6-(4-苯基丁氧基)己醛將中間物16(110 mg,0.39 mmo)溶解於THF(3 mL)與水(1 mL)之混合物中。在此溶液中加入偏過碘酸鈉(272 mg,1.27 mmol)及四氧化鋨(4%水溶液,0.15 ml)。在室溫下攪拌懸浮液12小時,過濾並濃縮。藉由用二氯甲烷/丙酮(10:1)作為溶離劑之矽膠管柱層析純化殘餘物得到油狀標題化合物(89 mg,81%)。
1
H-NMR(300 MHz,CDCl3
):1.50-1.75(m,4H);2.00-2.30(m,4H);2.55-2.70(m,4H);3.40(t,J=6.0 Hz,2H);3.55(t,J=9.0 Hz,2H);7.15-7.20(m,3H);7.20-7.35(m,2H);9.80(bs,1H)。
中間物18. (R,S)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇在中間物17(80 mg,0.28 mmol)於MeOH(5 mL)中之溶液中加入乙酸(0.1 mL)、分子篩(150 mg)及(R,S)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(125 mg,0.56 mmol)。室溫下攪拌混合物12小時,隨後加入氰基硼氫化鈉(21 mg,0.33 mmol),且另外攪拌混合物1小時。過濾混合物並濃縮。將殘餘物溶解於二氯甲烷(10 mL)中,並用鹽水(3×2 mL)、水(2×2 mL)洗滌,乾燥(Na2
SO4
)並濃縮。不經進一步純化而將殘餘物(200 mg)用於下一步。
MS(M+):491
藉由實例1中所述過程自中間物18(0.20 g,0.4 mmol)獲得。藉由以二氯甲烷/甲醇/氫氧化銨(80:15:1.5)溶離之矽膠管柱層析純化得到油狀(R,S)-4-(2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(69 mg,38%)。
1
H-NMR(400 MHz,二甲亞碸-D6),1.26-1.31(m,4H);1.35-1.41(m,2H);1.46-1.55(m,2H);2.12-2.25(m,2H);2.54-2.58(m,4H);2.71-2.75(m,2H);3.47(d,J=6.4 Hz,2H);3.65(t,JF - H
=13.5 Hz,2H);4.45-4.50(m,4H);4.91(bs,1H);5.00(bs,1H);6.7(d,J=8.3 Hz,1H);6.97(dd,J1
=7.9 Hz,J2
=1.7 Hz,1H);7.19-7.31(m,6H);9.17(bs,1H)。
MS(M+):452。
中間物19. 二氟(苯基)乙醛藉由中間物13中所述過程自中間物6(1.0 g,6.3 mmol)獲得。獲得油狀標題化合物(0.88 g,86%)。
中間物20. (2E)-4,4-二氟-4-苯基丁-2-烯酸乙酯將中間物19(0.88 g,5.64 mmol)溶解於THF(12 mL)中,且隨後加入(乙氧羰基亞甲基)三苯膦(1.96 g,5.64 mmol)。在50℃下攪拌溶液12小時。濃縮混合物,且藉由用正己烷/AcOEt(5:1)作為溶離劑之矽膠管柱層析純化殘餘物。獲得淺黃色油狀標題化合物(1.10 g,89%)。
1
H-NMR(300 MHz,CDCl3
):1.45(t,J=7.1 Hz,3H);4.45(q,J=7.1 Hz,2H);6.45(d,JF - H
=18 Hz,1H);7.15-7.30(m,1H);7.60-7.70(m,3H);7.70-7.75(m,2H)。
中間物21. 4,4-二氟-4-苯基丁酸乙酯在披鈀木炭(10 mg,10%)存在下,對中間物20(1 g,4.42 mmol)於甲醇(20 mL)中之溶液加氫3小時。混合物經矽藻土過濾,並在減壓下移除溶劑。不經進一步純化而將殘餘物(0.91 g)用於下一步。
中間物22. 4,4-二氟-4-苯基丁-1-醇藉由中間物2中所述過程自中間物21(0.9 g,4.1 mmol)獲得。獲得油狀標題化合物(0.65 g,85%)。
1
H-NMR(300 MHz,CDCl3
):1.50-1.75(m,2H);2.10-2.30(m,2H);3.55-3.65(m,2H);7.15-7.45(m,5H)。
中間物23. {4-[(6-溴己基)氧基]-1,1-二氟丁基}苯藉由中間物3中所述過程自中間物22(0.6 g,3.22 mmol)獲得。獲得油狀標題化合物(1.98 g,63%純度)。
中間物24. (R,S)-2-{[6-(4,4-二氟-4-苯基丁氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇藉由中間物4中所述過程自中間物23(0.4 g,0.6 mmol)獲得。獲得油狀標題化合物(0.21 g,70%)。
MS(M+):491
藉由實例1中所述過程自中間物24(0.2 g,0.4 mmol)獲得。獲得油狀標題化合物(98 mg,51%)。
1
H-NMR(400 MHz,二甲亞碸-D6);1.25-1.31(m,4H);1.34-1.41(m,2H);1.47-1.54(m,2H);2.12-2.25(m,2H);2.54-2.57(m,4H);2.71-2.75(m,2H);3.47(t,J=6.4 Hz,2H);3.66(t,JF - H
=13.3 Hz,2H);4.45-4.50(m,4H);4.90-4.92(m,1H);4.99(bs,1H);6.68(d,J=8.3 Hz,1H);6.97(dd,J1
=8.3 Hz,J2
=2.1 Hz,1H);7.17-7.31(m,6H);9.14(bs,1H)。
MS(M+):451
中間物25. (R,S)-8-(苄氧基)-5-(1-{[第三丁基(二甲基)矽烷基]氧基}-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}乙基)喹啉-2(1H)-酮在(R,S)-8-(苄氧基)-5-(2-溴-1-{[第三丁基(二甲基)矽烷基]氧基}乙基)喹啉-2(1H)-酮(1.58 g,3.25 mmol)及中間物9(1.0 g,3.9 mmol)於二甲亞碸(4.5 mL)中之溶液中加入碳酸氫鈉(0.82 g,9.7 mmol)及碘化鈉(0.73 m,4.87 mmol)。在140℃下攪拌混合物2小時。冷卻後,用水(20 mL)稀釋反應物,並用二乙醚(2×10 mL)萃取。用水(2×5 mL)及鹽水(10 mL)洗滌經組合之後有機萃取物,乾燥(Na2
SO4
),並在減壓下移除溶劑。獲得油狀標題化合物(2.14 g,99%)。
MS(M+):664
中間物26. (R,S)-8-(苄氧基)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)喹啉-2(1H)-酮在中間物25(2.14 g,3.21 mmol)於四氫呋喃(20 mL)中之溶液中加入氟化四正丁基鋁(1.68 g,6.42 mmol)。在室溫下隔夜攪拌混合物。減壓下移除溶劑。藉由用二氯甲烷/甲醇(95:5至85:15)作為溶離劑之管柱層析純化得到油狀(R,S)-8-(苄氧基)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]-胺基}-1-羥乙基)喹啉-2(1H)-酮(1.27 g,72%)。
MS(M+):550
在中間物26(1.27 g,2.3 mmol)於甲醇(50 mL)中之溶液中加入20%披鈀木炭(300 mg)。混合物在30 psi經加氫3小時。催化劑經矽藻土過濾,並濃縮溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(80:8:1至40:8:1)溶離之矽膠管柱層析純化所得油,得到油狀(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-8-羥基喹啉-2(1H)-酮(0.44 g,41%)。
1
H-NMR(400 MHz,二甲亞碸-D6):1.14-1.21(m,2H);1.28-1.65(m,6H);2.61-2.72(m,2H);3.14-3.18(m,2H);3.90(t,JF - H
=13.9 Hz,2H);4.96(dd,J1
=8.2 Hz,J2
=4.3 Hz,1H);6.55(d,J=9.8 Hz,1H);6.80(d,J=8.2 Hz,1H);7.00(d,J=8.2 Hz,1H);7.47-7.54(m,5H);8.16(d,J=9.8 Hz,1H)。
MS(M+):496
中間物27. (3-甲苯基)(酮基)乙酸乙酯二氧化硒(6.82 g,61.4 mmol)於乙醇(60 mL)中之懸浮液經回流10分鐘,且接著加入2-溴-1-間-甲苯基乙酮(13.1 g,61.4 mmol)。混合物經隔夜回流。經冷卻之反應物經矽藻土過濾,並在減壓下移除溶劑。用二氯甲烷(50 mL)稀釋殘餘物,用水(2×25 mL)洗滌,乾燥(Na2
SO4
)並濃縮。藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(9.6 g,81%)。
1
H NMR(300 MHz,CDCl3
):1.43(t,J=7.1 Hz,3H);2.43(s,3H);4.46(q,J=7.1 Hz,2H);7.38-7.49(m,2H);7.79-7.81(d,J=6.6 Hz,2H)。
中間物28. 二氟(3-甲苯基)(酮基)乙酸乙酯藉由中間物1中所述過程自中間物27(9.6 g,50 mmol)獲得。獲得油狀二氟(3-甲苯基)(酮基)乙酸乙酯(8.55 g,80%)。
1
H NMR(300 MHz,CDCl3
):1.43(t,J=7.1 Hz,3H);2.43(s,3H);4.46(q,J=7.1 Hz,2H);7.25-7.61(m,4H)。
中間物29. 2,2-二氟-2-(3-甲苯基)乙醇藉由中間物2中所述過程自中間物28(9.5 g,40 mmol)獲得。獲得油狀標題化合物(5.55 g,80%)。
1
H NMR(300 MHz,CDCl3
):2.43(s,3H);4.00(t,JF - H
=13.5 Hz,2H);7.25-7.35(m,4H)。
中間物30. 1-{2-[(6-溴己基)氧基]-1,1-二氟乙基}-3-甲苯藉由中間物3中所述過程自中間物29(5.55 g,32.2 mmol)獲得。藉由以正己烷/乙酸乙酯(純正己烷至10:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(10.99 g,100%)。
1
H-NMR(300 MHz,CDCl3
):1.40-1.60(m,2H);1.81-1.91(m,4H);2.39(s,3H);3.36-3.43(m,4H);3.53(t,J=6.5 Hz,2H);3.82(t,JF - H
=13.2 Hz,2H);7.24-7.26(m,1H);7.31-7.32(m,3H)
中間物31. 2-{6-[2,2-二氟-2-(3-甲苯基)乙氧基]己基}-1H-異吲哚-1,3(2H)-二酮藉由中間物8中所述過程自中間物30(8.77 g,26.2 mmol)獲得。藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(4.0 g,40%)。
1
H-NMR(300 MHz,CDCl3
):1.28-1.33(m,4H);1.51-1.56(m,2H);1.62-1.66(m,2H);2.39(s,3H);3.51(t,J=6.5 Hz,2H);3.63-3.68(m,2H);3.81(t,JF - H
=13.2 Hz,2H);7.30-7.31(m,4H);7.70-7.73(m,2H);7.83-7.86(m,2H)。
中間物32. {6-[2,2-二氟-2-(3-甲苯基)乙氧基]己基}胺藉由中間物9中所述過程自中間物31(4.0 g,14.4 mmol)獲得。獲得油狀{6-[2,2-二氟-2-(3-甲苯基)乙氧基]己基}胺(1.93 g,50%)。
1
H-NMR(300 MHz,CDCl3
):1.29-1.32(m,4H);1.37-1.44(m,2H);1.52-1.58(m,2H);2.39(s,3H);2.66(t,J=6.9 Hz,2H);3.53(t,J=6.5 Hz,2H);3.83(t,JF - H
=13.2 Hz,2H);7.30-7.32(m,4H)。
MS(M+):271。
中間物33. (R,S)-1-[4-(苄氧基)-3-(羥甲基)苯基]-2-({[6-(2,2-二氟-2-(3-甲苯基)乙氧基]己基}胺基)乙醇藉由中間物10中所述過程自中間物32(0.50 g,1.85 mmol)獲得。獲得油狀(R,S)-1-[4-(苄氧基)-3-(羥甲基)苯基]-2-({6-[2,2-二氟-2-(3-甲苯基)乙氧基]己基}胺基乙醇(0.98 g,100%)。
1
H-NMR(300 MHz,CDCl3
):1.31-1.33(m,4H);1.43-1.56(m,5H);2.39(s,3H);2.61-2.67(m,3H);2.83-2.88(m,1H);3.53(t,J=6.5 Hz,2H);3.82(t,JF - H
=13.3 Hz,2H);4.62-4.66(m,1H);4.74(s,2H);5.12(s,2H);6.92(d,J=8.2 Hz,1H);7.31-7.43(m,11H)。
藉由實例2中所述過程自中間物33(0.98 g,1.85 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)作為溶離劑之矽膠管柱層析純化得到油狀(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲苯基)乙氧基]甲基}胺基)-1-羥乙基]-2-(羥甲基)酚(0.44 g,55%)。
1
H-NMR(300 MHz,Cl3
CD),1.25-1.33(m,4H);1.43-1.56(m,4H);2.39(s,3H);2.58-2.70(m,4H);2.76-2.82(m,2H);2.98(m,4H);3.52(t,J=6.5 Hz,2H);3.82(t,JF - H
=13.5 Hz,2H);4.57-4.60(d,J=8.0 Hz,1H);4.77(s,2H);6.81(d,J=9.1 Hz,2H);7.0(s,1H);7.12(d,J=9.1 Hz,1H);7.26-7.27(m,1H);7.30-7.32(m,3H)。
MS(M+):437。
中間物34. (R)-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮在(R)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(2.53 g,11.3 mmol)於氯仿(12 mL)中之溶液中加入羰基二咪唑(2.75 g,17 mmol)及三乙胺(2.37 mL,17 mmol)。在室溫下隔夜攪拌混合物。在減壓下移除溶劑,且用乙酸乙酯(25 mL)稀釋殘餘物。用水(2×10 mL)、鹽水(10 mL)洗滌有機層,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以正己烷/乙酸乙酯(1:2)作為溶離劑之矽膠管柱層析純化得到標題化合物(1.63 g,51%)。
1
H NMR(300 MHz,CDCl3
):1.55(s,6H);3.54(t,J=8.1 Hz,1H);3.94(t,J=8.7 Hz,1H);4.86(s,2H);5.10(bs,1H);5.56(t,J=8.1 Hz,1H);6.85(d,J=8.5 Hz,1H);7.04-7.07(m,1H);7.15-7.18(m,1H)。
中間物35. (R)-3-[6-(2,2-二氟-2-苯基乙氧基)己基]-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮在60%氫化鈉(0.37 g,9.27 mmol)於二甲基甲醯胺(7.5 mL)中之經冷卻懸浮液中加入中間物34(1.65 g,6.62 mmol)於二甲基甲醯胺(15 mL)中之溶液。在0℃下攪拌混合物1小時。隨後在相同溫度下加入中間物7(3.19 g,9.93 mmol)於二甲基甲醯胺(9 mL)中之溶液。將混合物加熱至室溫,並攪拌2小時。將粗反應物冷卻至0℃,且隨後加入2 N HCl(1.5 mL)及水(20 mL)。用乙酸乙酯萃取溶液(2×20 mL)。用水(2×10 mL)洗滌有機層,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以正己烷/乙酸乙酯(1:1)溶離之矽膠管柱層析純化得到油狀(R)-3-[6-(2,2-二氟-2-苯基乙氧基)己基]-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮(1.5 g,46%)。
1
H NMR(300 MHz,CDCl3
):1.26-1.53(m,6H);1.55(s,6H);3.18-3.44(m,5H);3.52(t,J=6.3 Hz,1H);3.79-3.9(m,3H);4.12(q,J=7.1 Hz,1H);4.84(s,2H);5.37-5.44(m,1H);6.84(d,J=8.5 Hz,1H);7.00(s,1H);7.12(d,J=8.5 Hz,1H);7.41-7.46(m,3H);7.50-7.53(m,2H)。
中間物36. (1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇在中間物35(1.5 g,3.0 mmol)於四氫呋喃(60 mL)中之溶液中加入三甲基矽醇化鉀(1.54 g,12 mmol)。於70℃惰性氣氛下攪拌混合物2小時。在經冷卻反應混合物中加入氯化銨飽和溶液(60 mL)。用二氯甲烷(2×30 mL)萃取懸浮液。用水(2×25 mL)及鹽水(25 mL)洗滌有機層,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(100:8:1)作為溶離劑之矽膠管柱層析純化殘餘物。獲得油狀標題化合物(900 mg,65%)。
1
H NMR(300 MHz,CDCl3
):1.2-1.32(m,6H);1.53(s,6H);2.58-2.69(m,5H);2.83-2.88(m,1H);3.52(t,J=6.5 Hz,2H);3.84(t,JF - H
=13.2 Hz,1H);4.09-4.13(m,1H);4.58-4.61(m,1H);4.84(s,2H);6.78(d,J=8.5 Hz,1H);7.01(s,1H);7.12(d,J=8.5 Hz,1H);7.42-7.44(m,J1
=4.9 Hz,J2
=2.2 Hz,3H);7.50-7.51(m,J=3.3 Hz,2H)。
藉由實例1中所述過程自中間物35(0.90 g,1.94 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)作為溶離劑之矽膠管柱層析純化得到油狀4-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚(0.44 g,55%)。
1
H-NMR(300 MHz,Cl3
CD),1.27-1.31(m,4H);1.41-1.57(m,4H);2.18(bs,2H);2.55.2.68(m,4H);2.77-2.82(m,1H);3.50(s,1H);3.52(t,J=6.3 Hz,2H);3.84(t,JF - H
=13.3 Hz,2H);4.58(dd,J1
=9.2 Hz,J2
=3.4 Hz,1H);4.83(d,2H);6.84(d,J=8.2 Hz,1H);7.02(d,J=2.0 Hz,1H);7.16(dd,J1
=8.4 Hz,J2
=2.1 Hz,1H);7.42-7.44(m,3H);7.50-7.54(m,2H)。
MS(M+):423。
中間物37. 2,2,3,3-四氟-4-{[(2E)-3-苯基丙-2-烯-1-基]氧基}丁-1-醇在2,2,3,3-四氟-1,4-丁二醇(2.0 g,12.3 mmol)於二甲基甲醯胺(30 mL)中之溶液中加入60%氫化鈉(0.140 g,18.4 mmol)。室溫下攪拌混合物1.30小時。隨後加入苯烯丙基溴(3.2 g,12.3 mmol)於二甲基甲醯胺(40 mL)中之溶液。在室溫下隔夜攪拌混合物並濃縮。將殘餘物溶解於乙酸乙酯(50 mL)中,用水(2×25 mL)及鹽水(25 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以矽膠及正己烷/乙酸乙酯(純正己烷至5:1)之管柱層析純化得到油狀標題化合物(1.8 g,54%)。
1
H NMR(300 MHz,CDCl3
):2.78-3.18(bs,1H);3.80-4.05(m,4H);4.28(d,J=9Hz,2H);6.18-6.32(m,1H);6.58-6.62(m,1H);7.20-7.35(m,5H)。
中間物38. 2,2,3,3-四氟-4-{[(2E)-3-苯基丙-2-烯-1-基]氧基}丁醛藉由中間物13中所述過程自中間物37(1.80 g,6.47 mmol)獲得。獲得油狀2,2,3,3-四氟-4-{[(2E)-3-苯基丙-2-烯-1-基]氧基}丁醛(1.37 g,77%)。
1
H NMR(300 MHz,CDCl3
):3.80-4.05(m,4H);4.20-4.40(m,2H);6.18-6.32(m,1H);6.58-6.62(t,JF - H
=18 Hz,1H);7.20-7.35(m,5H);9.50(bs,1H)。
中間物39. (2E)-4,4,5,5-四氟-6-{[(2E)-3-苯基丙-2-烯-1-基]氧基}-己-2-烯酸乙酯藉由中間物20中所述過程自中間物38(1.37 g,4.96 mmol)獲得。藉由用正己烷/乙酸乙酯(15:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(1.2 g,70%)。
1
H NMR(300 MHz,CDCl3
):1.20-1.35(m,3H);3.80-4.05(m,2H);4.20-4.40(m,4H);5.90-6.10(q,JF - H
=13.5Hz,1H);6.20-6.38(m,2H);6.60-6.70(m,1H);7.21-7.31(m,5H)。
中間物40. 4,4,5,5-四氟-6-(3-苯基丙氧基)己酸乙酯藉由中間物21中所述過程自中間物39(1.2 g,3.46 mmol)獲得。獲得油狀4,4,5,5-四氟-6-(3-苯基丙氧基)己酸乙酯(1.0 g,82%)。
1
H NMR(300 MHz,CDCl3
):1.22(t,J=9Hz,3H);1.83-1.95(m,2H);2.30-2.55(m,2H);2.70-2.63(m,2H);2.65-2.80(m,2H);3.50-3.60(m,2H);3.80-3.95(q,JF - H
=18.0 Hz,2H);4.10-4.20(m,2H);7.15-7.25(m,3H);7.25-7.41(m,2H)。
中間物41. 4,4,5,5-四氟-6-(3-苯基丙氧基)己-1-醇藉由中間物2中所述過程自中間物40(1.0 g,2.85 mmol)獲得。藉由以正己烷/乙酸乙酯(10:1至5:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(0.68 g,82%)。
1
H NMR(300 MHz,CDCl3
):1.70-2.01(m,4H);2.05-2.15(m,2H);2.65-2.75(m,2H);3.50-3.60(m,2H);3.62-3.75(m,2H);3.78-3.95(t,JF - H
=18.0 Hz,2H);7.05-7.20(m,3H);7.20-7.35(m,2H)。
中間物42. 4,4,5,5-四氟-6-(3-苯基丙氧基)己醛藉由中間物13中所述過程自中間物41(0.68 g,2.20 mmol)獲得。獲得油狀4,4,5,5-四氟-6-(3-苯基丙氧基)己醛(0.32 g,47%)。
1
H NMR(300 MHz,CDCl3
):1.80-2.00(m,2H);2.25-2.55(m,2H);2.65-2.85(m,4H);3.50-3.65(m,2H);3.75-3.95(t,JF - H
=18.0 Hz,2H);7.05-7.20(m,3H);7.20-7.35(m,2H);9.80(bs,1H)。
中間物43. (R,S)-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-2-{[4,4,5,5-四氟-6-(3-苯基丙氧基)己基]胺基}乙醇藉由中間物18中所述過程自中間物42(0.32 g,1.05 mmol)獲得。藉由以二氯甲烷/三乙胺(100:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(0.17 g,32%)。
MS(M+):513。
藉由實例1中所述過程自中間物43(0.17 g,0.33 mmol)獲得。藉由以二氯甲烷/甲醇/氫氧化銨(40:4:0.2)作為溶離劑之矽膠管柱層析純化得到油狀(R,S)-2-(羥甲基)-4-(1-羥基-2-{[4,4,5,5-四氟-6-(3-苯基丙氧基)己基]胺基}乙基)酚(0.15 g,96%)。
1
H-NMR(400 MHz,二甲亞碸-D6):1.57-1.64(m,2H);1.78-1.86(m,2H);2.05-2.17(m,2H);2.56-2.63(m,4H);3.54(d,J=6.4 Hz,2H);3.91(d,JF - H
=14.9 Hz,3H);4.45-4.51(m,3H);4.91(t,J=5.6 Hz,1H);5.01(d,J=3.7 Hz,1H);6.68(d,J=7.9 Hz,1H);6.97(dd,J1
=8.3 Hz,J2
=2.1 Hz,1H);7.15-7.20(m,3H);7.25-7.30(m,3H);9.15(bs,1H)。
MS(M+):473。
中間物44. N-苄基-6-(2,2-二氟-2-苯基乙氧基)己-1-胺在120℃下加熱中間物7(5.0 g,15.6 mmol)及苄胺(3.4 mL,31.1 mmol)2小時。用乙醚處理粗反應物,並過濾所得固體。濃縮溶劑,且藉由以二氯甲烷/甲醇(99:1至95:5)作為溶離劑之矽膠管柱層析純化所得油得到油狀N-苄基-6-(2,2-二氟-2-苯基乙氧基)己-1-胺(3.2 g,59%)。
1
H NMR(300 MHz,CDCl3
):1.24-1.32(m,2H);1.46-1.63(m,4H);2.58-2.64(m,4H);3.49-3.53(t,J=6.5 Hz,2H);3.79-3.88(m,4H);7.30-7.33(m,5H);7.42-7.44(m,3H);7.50-7.54(m,2H)。
中間物45. (R,S)-2-{苄基[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-[4-(苄氧基)-3-硝基苯基]乙醇在120℃下加熱中間物44(3.2 g,9.22 mmol)及2-(3-硝基-4-苯氧基苯基)-氧(2.27 g,8.38 mmol)2小時。粗反應物之HPLC-MS分析顯示存在兩種主要產物:(R,S)-2-{苄基[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-[4-(苄氧基)-3-硝基苯基]乙醇與相應異構體(R,S)-1-{苄基[6-(2,2-二氟-2-苯基乙氧基))己基]胺基}-1-[4-(苄氧基)-3-硝基苯基]乙醇(60:40)。冷卻反應物,且所得油(5.18 g)不經進一步純化而用於下一步。
中間物46. (R,S)-1-[3-胺基-4-(苄氧基)苯基]-2-{苄基[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}乙醇在中間物45(5.18 g,8.38 mmol)於乙醇(110 mL)中之溶液中加入二氯化錫(6.34 g,33.5 mmol)。混合物經回流2小時。冷卻反應物,並在減壓下移除溶劑。不經進一步純化而將所得油(3.92 g)用於下一步。
於50℃下加熱甲酸(0.62 mL,13.32 mmol)及乙酸酐(0.78 g,7.65 mmol)之混合物15分鐘。將混合物冷卻至10℃,並逐滴加入中間物46(3.2 g)於四氫呋喃(18 mL)及甲苯(18 mL)中之溶液。在室溫下攪拌混合物20分鐘。減壓下移除溶劑。藉由以二氯甲烷/甲醇(98:2至95:5)作為溶離劑之矽膠管柱層析純化所得油,得到油狀(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]-胺基}-1-羥基-乙基)-2-羥苯基]甲醯胺(2.44 g)。在披鈀木炭(0.3 g)存在下對此油於乙醇(150 mL)中之溶液加氫4小時。混合物經矽藻土過濾,並在減壓下移除溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(80:8:1)作為溶離劑之矽膠管柱層析純化殘餘物,得到油狀(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]-胺基}-1-羥基-乙基)-2-羥苯基]甲醯胺(464 mg,14%三步總產率)。
1
H-NMR(400 MHz,二甲亞碸-D6):1.17-1.18(m,4H);1.26-1.33(m,2H);1.36-1.44(m,2H);2.44-2.47(m,2H);2.50-2.57(m,2H);3.41-3.45(d,J=6.5 Hz,2H);3.90(d,J=13.7 Hz,2H);4.42-4.48(m,1H);6.77(d,J=8.2 Hz,1H);6.85(dd,J1
=8.2 Hz,J2
=2.0 Hz,1H);7.45-7.53(m,5H);7.99(d,J=2.0 Hz,1H);8.24(s,1H);9.51(bs,1H)。
MS(M+):436。
中間物47. (3-溴苯基)(酮基)乙酸乙酯藉由中間物27中所述過程自2-溴-1-間-溴苯基乙酮(27.7 g,0.10 mmol)獲得藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(20.7 g,81%)。
1
H-NMR(300 MHz,CDCl3
):1.40(t,J=7.1 Hz,3H);4.45(q,J=7.1 Hz,2H);7.40(t,J=9.0 Hz,1H);7.80(d,J=9.0 Hz,1H);7.98(d,J=9.0 Hz,1H);8.20(s,1H)。
中間物48. (3-溴苯基)二氟乙酸乙酯藉由中間物1中所述過程自中間物47(28.80 g,0.112 mmol)獲得。藉由以正己烷/乙酸乙酯(4:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(26.3 g,84%)。
1
H-NMR(300 MHz,CDCl3
):1.30(t,J=7.1 Hz,3H);4.30(q,J=7.1 Hz,2H);7.30(t,J=9.0 Hz,1H);7.55(d,J=9.0 Hz,1H);7.65(d,J=9.0 Hz,1H);7.78(s,1H)。
中間物49. 2-(3-溴苯基)-2,2-二氟乙醇藉由中間物2中所述過程自中間物48(21.1 g,75.6 mmol)獲得。獲得油狀標題化合物(17.2 g,96%)。
1
H-NMR(300 MHz,CDCl3
):3.95(t,JF - H
=13.5 Hz,2H);7.30(t,J=9.0 Hz,1H);7.55(d,J=9.0 Hz,1H);7.65(d,J=9.0 Hz,1H);7.70(s,1H)。
中間物50. 1-溴-3-{2-[(6-溴己基)氧基]-1,1-二氟乙基}苯藉由中間物3中所述過程自中間物49(17.6 g,74 mmol)獲得。藉由蒸餾粗油得到60%純度之油狀標題化合物(9.5 g)。藉由以二氯甲烷作為溶離劑之矽膠管柱層析純化蒸餾殘餘物得到第二批65%純度之1-溴-3-{2-[(6-溴己基)氧基]-1,1-二氟乙基}苯(15.2 g)(總產率:53%)。
1
H NMR(300 MHz,CDCl3
):1.25-1.55(m,8H);1.81-1.88(m,1H);3.37-3.41(m,1H);3.46-3.53(m,2H);3.78-3.86(m,2H);7.30-7.34(m,1H);7.44-7.46(m,1H);7.58(d,J=8.0 Hz,1H);7.67(s,1H)。
中間物51. (R,S)-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮在(R,S)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(5.0 g,22.3 mmol)於二氯甲烷(100 mL)中之溶液中加入重碳酸二第三丁酯(5.35 g,24.5 mmol)及三乙胺(3.4 mL,24.5 mmol)。在室溫下攪拌混合物2小時。用水(2×10 mL)、鹽水(10 mL)洗滌有機層,乾燥(Na2
SO4
),並在減壓下減少溶劑。以乙酸乙酯濕磨得到灰白色固體狀經保護之起始胺(6.8 g,94%)。在氫化鈉(1.07 g,27 mmol)於二甲基甲醯胺(30 mL)中之冷卻懸浮液中逐滴加入此固體於二甲基甲醯胺(30 mL)中之溶液。使混合物達到室溫,且隨後在40℃下隔夜攪拌。減壓下移除溶劑。用乙酸乙酯(60 mL)稀釋殘餘物,且用2 N HCl酸化有機層,用水(2×30 mL)、鹽水(2×30 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。獲得油狀標題化合物(4.4 g,85%)。
1
H NMR(300 MHz,CDCl3
):1.52-1.61(m,6H);3.55(t,J=8.2 Hz,1H);3.94(t,J=8.7 Hz,1H);4.86(s,2H);5.42(bs,1H);5.55(t,J=8.1 Hz,1H);6.85(d,J=8.5 Hz,1H);7.04(d,J=1.6 Hz,1H);7.17(dd,J1
=8.4 Hz,J2
=2.3 Hz,1H)。
中間物52. (R,S)-3-{6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}-5-(2,2-二甲基-4H-1,3-苯并二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮藉由中間物35中所述過程自中間物50(4.6 g之50%純度,5.7 mmol)及中間物51(1.14 g,4.56 mmol)獲得。藉由以二氯甲烷/甲醇(純二氯甲烷至98:2)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(2.06 g,80%)。
1
H NMR(300 MHz,CDCl3
):1.30-1.32(m,4H);1.52-1.58(m,3H);1.54(s,6H);3.18-3.43(m,4H);3.48-3.54(m,2H);3.77-3.88(m,3H);4.84(s,2H);5.40(t,J=8.0 Hz,1H);6.84(d,J=8.5 Hz,1H);7.00(d,J=1.6 Hz,1H);7.12(dd,J1
=8.4 Hz,J2
=2.3 Hz,1H);7.31-7.34(m,1H);7.44-7.46(m,1H);7.56-7.59(d,J=8.0 Hz,1H);7.67(s,1H)。
中間物53. (R,S)-2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}胺基)-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇藉由中間物36中所述過程自中間物52(1.24 g,2.18 mmol)獲得。藉由以二氯甲烷/甲醇/氫氧化銨(100:8:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(0.9 g,76%)。
1
H NMR(300 MHz,CDCl3
):1.23-1.32(m,6H);1.54(s,6H);2.58-2.70(m,3H);2.84-2.89(m,1H);3.49-3.53(m,2H);3.69-3.86(m,4H);4.59-4.64(dd,J1
=9.2 Hz,J2
=3.4 Hz,1H);4.85(s,2H);6.79(d,J=8.5 Hz,1H);7.01(s,1H);7.11-7.14(m,1H);7.32(d,J=7.7 Hz,1H);7.44-7.47(m,1H);7.58(d,J=8.0 Hz,1H);7.67(s,1H)。
藉由實例1中所述過程自中間物53(0.90 g,1.66 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)作為溶離劑之矽膠管柱層析純化得到灰白色固體狀之(R,S)-4-[2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚(0.36 g,55%)。
1
H-NMR(300 MHz,Cl3
CD):1.27-1.30(m,4H);1.41-1.56(m,4H);2.51-2.77(m,4H);3.51(t,J=6.3 Hz,2H);3.53(bs,4H);3.82(t,JF - H
=12.8 Hz,2H);4.53-4.57(m,1H);4.76(s,2H);6.80(d,J=8.2 Hz,1H);6.96(d,J=1.9 Hz,1H);7.11(dd,J1
=8.0,J2
=1.9 Hz,1H);7.32(d,J=8.0 Hz,1H);7.44-7.47(m,1H);7.56-7.59(m,1H);7.67(s,1H)。
MS(M+):502。
中間物54. (R,S)-3-{6-[2-(3-胺基苯基)-2,2-二氟乙氧基]己基}-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮在惰性氣氛下,在中間物52(4.65 g,8.18 mmol)於甲苯(20 mL)之溶液中加入雙(二亞苄基丙酮)鈀(230 mg,0.4 mmol)、三-第三丁基膦(83 L,0.4 mmol)及雙(三甲基矽烷基)醯胺鋰、1 M於己烷(9 mL,9 mmol)中之溶液。在室溫下隔夜攪拌混合物。用乙基醚(20 mL)稀釋反應物,並加入2 N HCl(0.25 mL)。用2 N氫氧化鈉(2×20 mL)、水(20 mL)及鹽水(20 mL)洗滌有機層,乾燥之(Na2
SO4
),並在減壓下移除溶劑。藉由以二氯甲烷/甲醇(純二氯甲烷至98:2)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(2.71 g,66 %)。
1
H NMR(300 MHz,CDCl3
):1.30-1.38(m,4H);1.48-1.58(m,3H);1.55(s,6H);3.23-3.43(m,3H);3.52(t,J=6.3 Hz,2H);3.76-3.89(m,4H);4.85(s,2H);5.40(t,J=8.0 Hz,1H);6.72-6.76(m,1H);6.82-6.89(m,3H);7.01(d,J=1.1 Hz,1H);7.11-7.22(m,2H)。
中間物55. (R,S)-N-{3-[2-({6-[5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-2-酮基-1,3-噁唑烷-3-基]己基}氧基)-1,1-二氟乙基]苯基}脲在中間物54(2.71 g,5.4 mmol)於乙酸(20 mL)及水(10 ml)之溶液中加入氰化鉀(0.87 g,10.7 mmol)於水(20 mL)中之溶液。在惰性氣氛下隔夜攪拌混合物。用水稀釋粗反應物,並用乙酸乙酯(3×15 mL)萃取之。用水(2×15 mL)及鹽水(20 mL)洗滌組合之有機萃取物,乾燥之(Na2
SO4
),並濃縮之。藉由用乙酸乙酯作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(2.2 g,73%)。
1
H NMR(300 MHz,CDCl3
):1.30-1.38(m,4H);1.47-1.58(m,3H);1.55(s,6H);3.25-3.41(m,3H);3.45-3.51(m,2H);3.79-3.93(m,4H);4.85(s,2H);5.15(bs,2H);5.46(t,J=8.2 Hz,1H);6.87(d,J=8.5 Hz,1H);7.00(d,J=1.9 Hz,1H);7.12-7.16(m,2H);7.30-7.38(m,2H);7.88-7.90(m,1H);8.00(bs,1H)。
中間物56. (R,S)-N-(3-{2-[(6-{[2-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-2-羥乙基]胺基}己基)氧基]-1,1-二氟乙基}苯基)脲藉由中間物36中所述過程自中間物55(2.2 g,4 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(100:8:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(1.12 g,54%)。
1
H NMR(300 MHz,CDCl3
):1.22-1.28(m,4H);1.39-1.49(m,4H);1.53(s,6H);2.56-2.87(m,3H);3.48(t,J=6.0 Hz,2H);3.69-3.86(m,4H);4.68(dd,J1
=9.2 Hz,J2
=3.7 Hz,1H);4.82(s,2H);4.95(bs,2H);6.79(d,J=8.2 Hz,1H);7.00(d,J=1.6 Hz,1H);7.11-7.20(m,2H);7.33-7.39(m,2H);7.58-7.61(m,1H)。
藉由實例1中所述過程自中間物56(1.12 g,2.15 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)作為溶離劑之矽膠管柱層析純化得到灰白色固體狀(R,S)-N-[3-(1,1-二氟-2-[[6-({2-羥基-2-[4-羥基-3-羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]-脲(0.49 g,46%)。
1
H-NMR(300 MHz,DMSO-D6):1.20-1.26(m,4H);1.32-1.47(m,4H);2.54-2.57(m,4H);3.45(t,J=6.6 Hz,2H);3.86(t,JF - H
=13.9 Hz,2H);4.46-4.51(m,3H);4.94(bs,1H);5.04(bs,1H);5.92(s,2H);6.68(d,J=8.2 Hz,1H);6.98(dd,J1
=8.0,J2
=1.9 Hz,1H);7.03(d,J=8.0 Hz,1H);7.25(d,J=1.9 Hz,1H);7.32(t,J=7.8 Hz,1H);7.44-7.47(m,1H);7.65(s,1H);8.74(s,1H)。
MS(M+):481。
中間物57. 1-溴-3-{2-[(6-溴己基)氧基]-1,1-二氟乙基}苯將苄醇(3.2 mL,30.9 mmol)於二甲基甲醯胺(100 mL)中之溶液冷卻至0℃,且緩慢加入60%氫化鈉(1.23 g,30.9 mmol)。室溫下攪拌混合物0.5小時,且隨後再次冷卻至0℃,且緩慢加入中間物50(12.72 g,20.6 mmol)於二甲基甲醯胺(65 mL)中之溶液。在室溫下攪拌混合物4小時。將粗反應物冷卻至0℃,且加入水(3 mL),並隨後濃縮。用二氯甲烷(150 mL)溶解殘餘物,用水(2×75 mL)及鹽水(1×50 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(5.1g,57%)。
1
H NMR(300 MHz,CDCl3
):1.25-1.36(m,4 H);1.50-1.62(m,4 H);3.43-3.52(m,4 H);3.81(t,J=12.8 Hz,2 H);4.50(s,2 H);7.26-7.35(m,6 H);7.43-7.46(m,1 H);7.57(d,J=8.0 Hz,1 H);7.68(d,J=1.6 Hz,1 H)。
中間物58. [3-(2-{[6-(苄氧基)己基]氧基}-1,1-二氟乙基)苯基]胺藉由中間物54中所述過程自中間物57(5.04g,11.88 mmol)獲得。藉由以二氯甲烷/甲醇(純二氯甲烷至99:1)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(3.9 g,90%)。
1
H NMR(300 MHz,CDCl3
):1.28-1.38(m,4 H);1.52-1.66(m,4 H);3.43-3.54(m,4 H);3.80(t,J=13.5 Hz,2 H);4.50(s,2 H);6.73(dd,J1
=8.0 Hz,J2
=1.6 Hz,1 H);6.81-6.82(m,1 H);6.87(d,J=7.7 Hz,1 H);7.19(t,J=7.8 Hz,1 H);7.27-7.31(m,1 H);7.32-7.38(m,4H)。
中間物59. N-({[3-(2-{[6-(苄氧基)己基]氧基}-1,1-二氟乙基)苯基]-胺基}羰基)甘胺酸乙酯在中間物58(3.9 g,10.7 mmol)於二氯甲烷(35 mL)中之溶液中加入異氰酸基乙酸乙酯(1.38 mL,12.3 mmol)。在室溫下攪拌混合物5小時。將粗反應物冷卻至0℃,且加入甲醇(2.3 mL)。室溫下攪拌混合物0.5小時,並在減壓下移除溶劑。藉由以二氯甲烷/甲醇(純二氯甲烷至98:2)作為溶離劑之管柱層析純化得到油狀標題化合物(5.1 g,95%)。
1
H NMR(300 MHz,CDCl3
):1.27-1.36(m,7H);1.49-1.65(m,4H);3.51(m,4H);3.80(t,JF - H
=12.9 Hz,2H);4.02(s,2H);4.22(q,J=7.2 Hz,2H);4.53(s,2H);7.13-7.18(m,2H);7.30-7.36(m,6H);7.58(d,J=8.0 Hz,1H)。
中間物60. N-({[3-(2-{[6-(苄氧基)己基]氧基}-1,1-二氟乙基)苯基]-胺基}羰基)甘胺酸在中間物59(5.09 g,10 mmol)於乙醇(30 mL)中之溶液中加入2 N NaOH(18 mL,35 mmol)。室溫下攪拌混合物3小時。濃縮粗反應物,並用乙酸乙酯(50 mL)稀釋殘餘物,且用水(2×25mL)洗滌。用HCl將水性層酸化至pH值2,且隨後用乙酸乙酯(2×50 mL)萃取。乾燥(Na2
SO4
)有機層,且在減壓下移除溶劑。獲得標題化合物(4.23 g,88%)。
1
H NMR(300 MHz,CDCl3
):1.25-1.34(m,4H);1.49-1.58(m,4H);3.49(t,J=6.6 Hz,4H);3.80(t,JF - H
=12.9 Hz,2H);3.92(s,2H);4.52(s,2H);5.81(bs,1H);7.15(d,J=7.4 Hz,1H);7.29-7.34(m,6H);7.40(d,J=1.9 Hz,2H);7.66(bs,1H)。
中間物61. 3-[3-(2-{[6-(苄氧基)己基]氧基}-1,1-二氟乙基)苯基]咪唑啶-2,4-二酮在140℃下加熱中間物60(3.42 g,7.4 mmol)、水(20 mL)及濃HCl(5.5 mL)之溶液12小時。冷卻反應物。用乙酸乙酯(50 mL)萃取粗產物,並用碳酸氫鈉飽和溶液(2×20 mL)、水(2×20 mL)及鹽水(1×20 mL)洗滌,乾燥(Na2
SO4
)並濃縮。獲得油狀標題化合物(2.52 g,76%)。
1
H NMR(300 MHz,CDCl3
):1.33(bs,4H);1.58(bs,4H);3.43-3.54(m,4H);3.84(t,JF - H
=13.0 Hz,2H);4.13(s,2H);4.49(s,2H);5.56(bs,1H);7.34(bs,6H);7.53(bs,3H);7.61(s,1H)。
中間物62.3-(3-{1,1-二氟-2-[(6-羥己基)氧基]乙基}苯基)咪唑啶-2,4-二酮在中間物61(2.52 g,5.65 mmol)於乙醇(120 mL)中之溶液中加入披鈀木炭(300 mg)。混合物在40 psi經加氫4小時。催化劑經矽藻土過濾,且在減壓下移除溶劑得到油狀標題化合物(1.94 g,96%)。
1
H NMR(300 MHz,CDCl3
):1.23-1.32(m,4H);1.50-1.59(m,3H);3.50-3.62(m,4H);3.73(q,J=7.1 Hz,1H);3.86(t,JF - H
=12.8 Hz,2H);4.17(s,2H);5.99(bs,1H);7.52-7.56(m,4H);7.61(bs,1H)。
中間物63. 甲磺酸6-{2-[3-(2,5-二酮基咪唑啶-1-基)苯基]-2,2-二氟乙氧基}己酯將中間物62(1.94 g,5.45 mmol)溶解於二氯甲烷(15 mL)中,且隨後加入三乙胺(1.21 mL,8.72 mmol)。將混合物冷卻至0℃,且在相同溫度下緩慢加入甲磺醯氯(0.680 mL,8.72 mmol)於二氯甲烷(5 mL)中之溶液。室溫下攪拌混合物16小時。將粗反應物冷卻至0℃,且隨後加入50%水/氫氧化銨溶液(40 mL)。用水(2×40 mL)、鹽水(1×40 mL)洗滌有機層,乾燥(Na2
SO4
)並濃縮。獲得油狀標題化合物(2.4 g,100%)。
1
H NMR(300 MHz,CDCl3
):1.34-1.43(m,4H);1.54-1.72(m,6H);3.0(s,3H);3.53(t,J=6.2 Hz,2H);3.86(t,JF - H
=12.8 Hz,2H);4.17(s,2H);5.88(bs,1H);7.54(bs,4H);7.62(bs,1H)。
中間物64. 3-(3-{2-[(6-{[2-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-2-羥乙基]胺基}己基)氧基]-1,1-二氟乙基}苯基)咪唑啶-2,4-二酮在中間物63(2.4 g,5.4 mmol)於二甲基甲醯胺(30 mL)中之溶液中加入(R,S)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(1.64 g,7.33 mmol)及溴化四丁基銨(1.74 g,5.4 mmol)。室溫下攪拌混合物98小時。濃縮粗反應物,並用二氯甲烷(50 mL)稀釋殘餘物,且用水(2×25mL)洗滌。乾燥(Na2
SO4
)有機層,且在減壓下移除溶劑。藉由以二氯甲烷/乙醇/氫氧化銨(100:8:1)作為溶離劑之管柱層析純化得到油狀標題化合物(0.67 g,22%)。
1
H NMR(300 MHz,CDCl3
):1.22-1.33(m,3H);1.54(s,6H);2.57-2.67(m,3H);2.82-2.87(m,1H);3.52(t,J=6.5 Hz,2H);3.69-3.76(m,2H);3.81-3.90(m,2H);4.13(s,2H);4.64(dd,J1
=9.2 Hz,J2
=3.4 Hz,1H);4.85(s,2H);6.79(d,J=8.5 Hz,1H);7.01(s,1H);7.13(dd,J1
=8.4 Hz,J2
=2.1 Hz,1H);7.28(m,1H);7.51-7.56(m,2H);7.62(bs,1H)。
藉由實例1中所述過程自中間物64(0.67 g,1.20 mmol)獲得。藉由以二氯甲烷/乙醇/氫氧化銨(40:8:1)作為溶離劑之矽膠管柱層析純化得到油狀3-[3-(1,1-二氟-2-{[6-({2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]咪唑啶-2,4-二酮(0.04 g,10%)。
1
H NMR(300 MHz,二甲亞碸-D6):1.15-1.30(m,4H);1.35-1.45(m,4H);2.60-2.80(m,4H);3.46-3.50(m,2H);3.95(t,J=13.9 Hz,2H);4.07(s,2H);4.47(s,2H);4.60-4.70(m,1H);6.72(d,J=7.9 Hz,1H);7.01(d,J=8.2 Hz,1H);7.29(s,1H);7.51-7.61(m,4H);8.34(bs,1H)。
中間物65. 2-溴-1-(3-甲氧基苯基)乙酮在1-(3-甲氧基苯基)乙酮(5.5 mL,40 mmol)於氯仿(100 mL)中之溶液中逐滴加入溴(2.05 mL,40 mmol)於氯仿(20 mL)中之溶液。在室溫下隔夜攪拌混合物。減壓下移除溶劑。在二氯甲烷(50 mL)中稀釋殘餘物,且用水(2×25mL)洗滌。乾燥(Na2
SO4
)有機層,且在減壓下移除溶劑。藉由用二氯甲烷作為溶離劑之管柱層析純化得到油狀標題化合物(8.44 g,84%)。
1
H NMR(300 MHz,CDCl3
):3.9(s,3H);4.5(s,2H);7.14-7.18(dd,J=7.8,3.2 Hz,1H);7.43(t,J=8.0 Hz,1H);7.51-7.58(m,2H)。
中間物66.(3-甲氧基苯基)(酮基)乙酸乙酯使二氧化硒(4.08 g,37 mmol)於乙醇(35 mL)中之懸浮液回流10分鐘,且隨後加入中間物65(8.44 g,37 mmol)。混合物經隔夜回流。經冷卻之反應物經矽藻土過濾,並在減壓下移除溶劑。用二氯甲烷(50 mL)稀釋殘餘物,用水(2×25 mL)洗滌,乾燥(Na2
SO4
)並濃縮。藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(4.12 g,53%)。
1
H NMR(300 MHz,CDCl3
):1.43(t,J=7.1 Hz,3H);3.87(s,3H);4.46(q,J=7.3 Hz,2H);7.21(dd,J=8.2,2.7 Hz,1H);7.42(t,J=8.0 Hz,1H);7.54-7.59(m,2H)。
中間物67. 二氟(3-甲氧基苯基)乙酸乙酯藉由中間物1中所述過程自中間物66(4.12 g,20 mmol)獲得。獲得油狀二氟(3-甲氧基苯基)乙酸乙酯(4.35 g,94%)。
1
H NMR(300 MHz,CDCl3
):1.31(t,J=7.1 Hz,3H);3.84(s,3H);4.29(q,J=7.1 Hz,2H);7.02(dd,J=8.2,1.6 Hz,1H);7.13(s,1H);7.19(d,J=7.7 Hz,1H);7.37(t,J=8.0 Hz,1H)。
中間物68. 2,2-二氟-2-(3-甲氧基苯基)乙醇藉由中間物2中所述過程自中間物67(4.35 g,19 mmol)獲得。獲得油狀標題化合物(3.19 g,90%)。
1
H NMR(300 MHz,CDCl3
):3.84(s,3H);3.97(t,J=13.5 Hz,2H);6.99-7.11(m,3H);7.37(t,J=8.0 Hz,1H)。
中間物69. 1-{2-[(6-溴己基)氧基]-1,1-二氟乙基}-3-甲氧基苯在中間物68(3.19 g,16.95 mmol)於二甲基甲醯胺(20 mL)中之冷卻溶液中加入60%氫化鈉(1.36 g,33.9 mmol)及1,6-二溴己烷(5.2 mL,33.9 mmol)。在室溫下攪拌混合物2小時。用二氯甲烷(50 mL)稀釋粗產物,且用水(3×50 mL)洗滌,乾燥(MgSO4
)並濃縮。藉由減壓(P=0.15-0.18 mmHg,T=60-65℃)下蒸餾以消除過量1,6-二溴己烷,且藉由用二氯甲烷作為溶離劑之矽膠管柱層析純化粗產物。獲得油狀標題化合物(3.41 g,57%)。
1
H NMR(300 MHz,CDCl3
):1.22-1.48(m,4H);1.50-1.64(m,2H);1.76-1.90(m,2H);3.38(t,J=6.87 Hz,2H);3.52(t,J=6.457 Hz,2H);3.78-3.87(m,5H);6.98(dd,J=8.24 Hz,J=1.92 Hz,1H);7.05-7.10(m,2H);7.34(t,J=7.97 Hz,1H)。
中間物70. 3-{6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮藉由中間物35中所述過程自中間物69(3.41g,9.7 mmol)及中間物51(1.37 g,5.49 mmol)獲得。藉由以己烷/乙酸乙酯(1:2)作為溶離劑之矽膠管柱層析純化得到油狀標題化合物(1.96 g,69%)。
1
H NMR(300 MHz,CDCl3
):1.22-1.41(m,4H);1.49-1.63(m,4H);1.54(s,6H);3.16-3.45(m,4H);3.50-3.54(m,2H);3.81-3.84(m,5H);4.84(s,2H);5.40(t,J=8.0 Hz,1H);6.84(d,J=8.5 Hz,1H);6.96-7.14(m,5H);7.34(t,J=7.9 Hz,1H)。
中間物71. (R,S)-2-({6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}胺基)-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇藉由中間物36中所述過程自中間物70(1.96 g,3.77 mmol)獲得。獲得油狀標題化合物(1.78 g,96%)。
1
H NMR(300 MHz,CDCl3
):1.22-1.38(m,4H);1.49-1.63(m,4H);1.53(s,6H);2.53-2.74(m,4H);2.81-2.90(m,1H);3.46-3.57(m,2H);3.81-3.84(m,5H);4.60-4.70(m,1H);4.84(s,2H);6.79(d,J=8.5 Hz,1H);6.96-7.14(m,5H);7.34(t,J=7.9 Hz,1H)。
藉由實例1中所述過程自中間物71(1.78 g,3.61 mmol)獲得。藉由以二氯甲烷/甲醇/三乙胺(91:8:1)作為溶離劑之矽膠管柱層析純化得到油狀(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚(1.52g,93%)。
1
H NMR(300 MHz,CDCl3
):1.18-1.34(m,4H);1.43-1.50(m,2H);1.56-1.69(m,2H);2.85(d,J=20.1 Hz,4H);3.48(t,J=6.3 Hz,2H);3.72-3.87(m,5H);4.49(s,2H);4.80(bs,1H);6.70(d,J=8.2 Hz,1H);6.87-7.32(m,5H);7.34(t,J=7.8 Hz,1H);8.04(bs,1H)。
中間物72. 8-(苄氧基)-5-((1R)-1-{[第三丁基(二甲基)矽烷基]氧基}-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}乙基)喹啉-2(1H)-酮在8-(苄氧基)-5-((1R)-2-溴-1-{[第三丁基(二甲基)矽烷基]氧基}乙基)喹啉-2(1H)-酮(4.80 g,9.83 mmol)及中間物9(3.04 g,11.8 mmol)於二甲亞碸(13.5 mL)中之溶液中加入碳酸氫鈉(2.49 g,29.4 mmol)及碘化鈉(2.22 g,14.8 mmol)。在140℃下加熱混合物2小時。冷卻之後,用水(40 mL)稀釋反應物,並用二乙醚(2×20 mL)萃取。用水(2×10 mL)及鹽水(20 mL)洗滌所經組合之有機萃取物,乾燥(Na2
SO4
),並在減壓下移除溶劑。獲得油狀標題化合物(6.40 g,98%)。
1
H NMR(300 MHz,CDCl3
):0.20-0.31(m,5H);1.03-1.11(m,10 H);1.38-1.49(m,5H);1.63-1.80(m,5H);2.75-2.95(m,2H);3.08-3.15(m,H);3.66-3.73(m,2H);3.98-4.07(m,2H);5.35(s,2H);6.85(d,J=9.9Hz,1H);7.19(d,J=8.5Hz,1H);7.31-7.34(m,1H);7.45(s,2H);7.58-7.65(m,6H);7.69-7.71(m,2H);8.50(d,J=9.9Hz,1H)。
中間物73.8-(苄氧基)-5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)喹啉-2(1H)-酮在中間物72(6.4 g,9.63 mmol)於四氫呋喃(60 mL)中之溶液中加入氟化四正丁基銨(5.02 g,19.26 mmol)。在室溫下隔夜攪拌混合物。減壓下移除溶劑。藉由用二氯甲烷/甲醇(95:5至85:15)作為溶離劑之管柱層析純化得到油狀8-(苄氧基)-5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]-胺基}-l-羥乙基)喹啉-2(1H)-酮(1.1 g,20%)。
MS(M+):550。
藉由實例5中所述過程自中間物73(1.10 g,2.0 mmol)獲得。藉由以二氯甲烷/甲醇(95:5)溶離之矽膠管柱層析純化所得油得到油狀標題化合物(0.50 g,54%)。
1
H-NMR(300 MHz,二甲亞碸-D6):1.15-1.35(m,5H);1.40-1.50(m,3H);1.55-1.65(m,2H);2.80-3.02(m,6H);3.88-3.98(m,2H);5.35-5.45(m,1H);6.55(d,J=9.4 Hz,1H);7.00(d,J=7.7 Hz,1H);7.15(d,J=7.4 Hz,1H);7.45-7.62(m,5H);8.26(d,J=9.6Hz,1H)。
中間物74. (1R)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇藉由中間物18中所述過程自中間物17(0.39 g,1.38 mmol)及(R)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(0.62 g,2.77 mmol)獲得。獲得油狀標題化合物(0.42 g,60%),且不經進一步純化而用於下一步。
藉由實例1中所述過程自中間物74(0.41 g,0.83 mmol)獲得。藉由半製備型HPLC純化所得油得到油狀標題化合物(0.12 g,31%)。
1
H-NMR(300 MHz,Cl3
CD):1.54-1.63(m,4H);1.82-1.90(m,4H);2.01-2.12(m,4H);2.55-2.61(m,4H);3.37(t,J=6.0 Hz,2H);3.50(t,J=6.0 Hz,2H);4.38(bs,2H);4.78(bs,1H);6.64(bs,1H);6.83(bs,1H);6.95(bs,1H);7.12-7-26(m,5H);8.34(bs,1H)。
MS(M+):451。
中間物75. 乙酸3-酮基-3-苯基丙酯在3-氯-1-苯基丙-1-酮(1.0 g,5.93 mmol)於乙酸(8 mL)中之溶液中加入乙酸鈉(2.43 g,29.7 mmol)及碘化鉀(100 mg)。在130℃下之密封管中隔夜加熱混合物。冷卻之後,用水(20 mL)稀釋反應物,並用二氯甲烷(3×20 mL)萃取。用水(2×50 mL)、碳酸氫鈉飽和溶液(2×50 mL)及鹽水(20 mL)洗滌經組合之有機層,乾燥(Na2
SO4
),且在減壓下移除溶劑。獲得橙色油狀標題化合物(1.0 g,88%)。
1
H-NMR(300 MHz,Cl3
CD):2.03(s,3H);3.32(t,J=6.0 Hz,2H);4.52(t,J=6.0 Hz,2H);7.40-7.63(m,3H);7.89-8.02(m,2H)。
MS(M+):192。
中間物76. 乙酸3,3-二氟-3-苯基丙酯在中間物75(1.0 g,5.20mmol)於三氟化雙(2-甲氧基乙基)胺基硫(Deoxofluor)(1.7 mL,7.80 mmol)中之懸浮液中加入三氟化硼二甲基醚錯合物(99 μL,0.78 mmol)。在85℃下及氬氣下隔夜加熱混合物。冷卻至0℃之後,用二氯甲烷(10 mL)稀釋反應物,且隨後極為緩慢地加入碳酸氫鈉飽和溶液(20 mL)。用二氯甲烷萃取混合物(3×20 mL)。用水(2×20 mL)洗滌經組合之有機相,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以正己烷/乙酸乙酯(純正己烷至6:4)之矽膠管柱層析純化得到橙色油狀標題化合物(0.30 g,30%)。
1
H-NMR(300 MHz,Cl3
CD):1.94(s,3H);2.47-2.57(m,2H);4.22(t,J=6.0 Hz,2H);7.42-7.48(m,5H)。
中間物77. 3,3-二氟-3-苯基丙-1-醇在中間物76(0.30 g,1.40 mol)於乙醇(4 mL)中之溶液中加入35%氫氧化鈉溶液(1 mL)。在室溫下攪拌混合物2小時。用二氯甲烷(50 mL)稀釋粗反應物,用水(1×30 mL)及1N鹽酸(2×30 mL)洗滌,乾燥(Na2
SO4
),且在減壓下移除溶劑。獲得橙色油狀標題化合物(0.22 g,89%),且不經進一步純化而用於下一步。
1
H-NMR(300 MHz,Cl3
CD):2.36-2.52(m,2H);3.85(t,J=6.0 Hz,2H);7.44-7.51(m,5H)。
中間物78. 6-溴己基3,3-二氟-3-苯基丙基酯藉由中間物69中所述過程自中間物77(0.41 g,0.83 mmol)獲得。藉由以正己烷/乙酸乙酯(純正己烷至9:1)之矽膠管柱層析純化所得油得到油狀標題化合物(0.85 g之66%純度,64%)。
1
H-NMR(300 MHz,Cl3
CD):1.42-1.47(m,4H);1.81-1.89(m,4H);2.46-2.51(m,2H);3.32-3.43(m,4H);3.54(t,J=6.0 Hz,2H);7.42-7.47(m,5H)。
中間物79. (R,S)-3-[6-(3,3-二氟-3-苯基丙氧基)己基]-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮藉由中間物35中所述過程自中間物78(0.85 g之66%純度,1.86 mmol)及中間物51(0.93 g,3.72 mmol)獲得。藉由以正己烷/乙酸乙酯(純正己烷至1:1)之矽膠管柱層析純化得到油狀標題化合物(0.44 g,47%)。
1
H-NMR(300 MHz,Cl3
CD):1.32-1.61(m,8H);1.54(s,6H);2.46(h,J=9.0 Hz,2H),3.32-3.44(m,4H);3.54(t,J=6.0 Hz,2H);3.73(q,J=6.0 Hz,2H);4.84(s,2H);5.37-5.43(m,1H);6.83(d,J=9.0 Hz,1H);7.00(s,1H);7.12(d,J=9.0 Hz,1H);7.41-7.47(m,5H)。
MS(M+):503。
藉由中間物36及實例1中所述過程自中間物79(0.44 g,1.0 mmol)獲得。藉由半製備型HPLC純化所得油得到油狀標題化合物(44 mg,10%)。
1
H-NMR(300 MHz,Cl3
CD):1.22-1.66(m,8H);1.87-2.03(m,4H);2.40-2.54(m,4H);3.29-3.38(m,2H);3.50-3.56(m,2H);4.49(bs,2H);4.83(bs,1H);6.68-6.89(m,1H);6.91-6.93(m,1H);7.01(bs,1H);7.38-7.49(m,5H)。
MS(M+):437。
中間物80. 烯丙基2,2-二氟-2-苯基乙基醚藉由中間物11中所述過程自中間物6(10.0 g,63 mmol)及烯丙基溴(6.5 mL,76 mmol)獲得。藉由異二氯甲烷溶離之矽膠管柱層析純化得到油狀標題化合物(11.2 g,89%)。
1
H-NMR(400 MHz,Cl3
CD):3.76-3.90(m,2H);3.98-4.12(m,2H);5.14-5.32(m,2H);5.70-5.90(m,1H);7.35-7.59(m,5H)。
中間物81. 3-(2,2-二氟-2-苯基乙氧基)丙-1-醇藉由中間物12中所述過程自中間物80(10.6 g,53 mmol)獲得。藉由以乙酸乙酯/正己烷(1:4至純乙酸乙酯)溶離之矽膠管柱層析純化得到油狀標題化合物(10.7 g,96%)。
1
H-NMR(200 MHz,Cl3
CD):1.80(qt,J=5.8 Hz,2H),3.66-3.73(m,4H);3.86(t,JF - H
=12.9 Hz,2H),7.43-7.54(m,5H)。
中間物82. 3-(2,2-二氟-2-苯基乙氧基)丙醛藉由中間物13中所述過程自中間物81(3.0 g,14.4 mmol)獲得。藉由以二氯甲烷溶離之矽膠管柱層析純化得到油狀標題化合物(1.86 g,60%)。
1
H-NMR(200 MHz,Cl3
CD):2.67(td,J1=6.0 Hz,J2=1.8 Hz,2H);3.89(t,JF - H
=13.3 Hz,2H);3.89(t,J=6.0 Hz,2H);7.40-7.53(m,5H);9.72(t,J=1.8 Hz,1H)。
中間物83. 1-(2,2-二氟-2-苯基乙氧基)庚-6-烯-3-醇藉由中間物14中所述過程自中間物82(1.86 g,8.7 mmol)獲得。藉由以乙酸乙酯/正己烷(1:6)溶離之矽膠管柱層析純化得到油狀標題化合物(1.24 g,53%)。
1
H-NMR(200 MHz,Cl3
CD):1.46-1.88(m,4H);2.06-2.20(m,2H);3.63-3.83(m,3H);3.86(t,JF - H
=12.9 Hz,2H);4.92-5.07(m,2H);5.75-5.92(m,1H);7.43-7.55(m,5H)。
中間物84. 1-(2,2-二氟-2-苯基乙氧基)庚-6-烯-3-酮藉由中間物13中所述過程自中間物83(4.3 g,15.8 mmol)獲得。藉由以乙酸乙酯/正己烷(1:5)溶離之矽膠管柱層析純化得到油狀標題化合物(1.82 g,43%)。
1
H-NMR(200 MHz,Cl3
CD):2.25-2.34(m,2H);2.48(dt,J1=6.6 Hz,J2=1.6 Hz,2H);2.64(t,J=6.0 Hz,2H);3.81(t,J=6.0 Hz,2H);3.87(t,JF - H
=13.3 Hz,2H);4.94-5.06(m,2H);5.67-5.87(m,1H);7.41-7.52(m,5H)。
中間物85. 3,3-二氟庚-6-烯-1-基2,2-二氟-2-苯基乙基醚在中間物84(1.6 g,10 mmol)於二氯甲烷(8 mL)中之冷卻溶液中加入DAST(4.70 ml,40 mmol)。在40℃及氬氣下隔夜攪拌混合物。用二氯甲烷(50 mL)稀釋粗反應物,用冷水(25 mL)及碳酸氫鈉飽和溶液(2×25 mL)洗滌,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以乙酸乙酯/正己烷(1:8至1:6)作為溶離劑之矽膠管柱層析純化殘餘物。獲得油狀標題化合物(600 mg,21%)。
1
H-NMR(300 MHz,Cl3
CD):1.80-1.94(m,2H);2.08-2.24(m,4H);3.71(t,J=6.5 Hz,2H);3.85(t,JF - H
=13.0 Hz,2H);4.97-5.06(m,2H);5.70-5.81(m,1H);7.44-7.50(m,5H)。
中間物86. 6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己醛藉由中間物17中所述過程自中間物85(0.80 g,2.7 mmol)獲得。藉由以乙酸乙酯/正己烷(1:5)溶離之矽膠管柱層析純化得到油狀標題化合物(0.48 g,60%)。
1
H-NMR(300 MHz,Cl3
CD):2.05-2.19(m,4H);2.61(t,J=7.6 Hz,2H);3.71(t,J=6.2 Hz,2H);3.86(t,JF - H
=13.0 Hz,2H);7.44-7.52(m,5H);9.72(s,1H)。
中間物87. (R)-2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]胺基}-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇藉由中間物18中所述過程自中間物86(0.49 g,1.66 mmol)及(R)-2-胺基-1-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)乙醇(0.74 g,3.31 mmol)獲得。獲得油狀標題化合物(0.50 g,83%),且不經進一步純化而用於下一步。
藉由實例1中所述過程自中間物87(0.50 g,1.0 mmol)獲得。藉由以二氯甲烷/甲醇/氫氧化銨(200:20:1至150:20:1)溶離之矽膠管柱層析純化得到油狀(R)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]胺基}-1-羥乙基)-2-(羥甲基)酚(0.12 g,26%總產率)。
1
H-NMR(300 MHz,Cl3
CD):1.59-1.90(m,4H);2.03-2.18(m,2H);2.58-2.79(m,4H);3.70(t,J=6.3 Hz,2H);3.84(t,JF - H
=13.3 Hz,2H);4.28(bs,4H);4.55-4.59(m,1H);4.69(s,2H);6.78(d,J=8.0 Hz,1H);6.95(s,1H);7.05(d,J=8.0 Hz,1H);7.32-7.50(m,5H)。
MS(M+):459。
中間物88. 2,2-二氟-3-羥基-3-苯基丙酸乙酯在苯甲醛(3.0 g,28 mmol)於無水四氫呋喃(80 mL)中之溶液中加入鋅(2.4 g,36 mmol)。在惰性氣氛75℃下加熱混合物,且緩慢加入2-溴-2,2-二氟乙酸乙酯(4.4 mL,34 mmol)。在相同條件下加熱混合物2小時。冷卻之後,加入2 N鹽酸(25 mL)直至未反應鋅完全消耗。減壓下移除溶劑。用乙酸乙酯(150 mL)稀釋粗反應物,用鹽水(2×100 mL)洗滌,乾燥(Na2
SO4
),且在減壓下移除溶劑。獲得黃色油狀標題化合物(6.4 g,99%),且不經進一步純化而用於下一步。
1
H-NMR(300 MHz,Cl3
CD):1.28(t,J=7.1 Hz,3H);3.22(bs,1H);4.29(q,J=7.1 Hz,2H);5.15(dd,J1 ( F - H )
=15.7 Hz,J2
=8.0 Hz,1H);7.37-7.44(m,5H)。
中間物89. 2,2-二氟-3-{[(甲基硫)卡硫醯基]氧基}-3-苯基丙酸乙酯在中間物88(6.4 g,28 mmol)於二甲基甲醯胺(50 mL)中之溶液中加入1,5-二氮雜雙環(5,4,0)十一-5-烯(DBU)(17.0 mL,0.11 mol)及二硫化碳(16.9 mL,0.28 mol)。在惰性氣氛及室溫下攪拌混合物1小時30分鐘。隨後加入甲基碘(17.5 mL,280 mmol),且在相同條件下攪拌混合物1小時30分鐘。減壓下排除溶劑。用水(200 mL)處理粗產物,並用乙酸乙酯(3×100 mL)萃取。用鹽水(2×100 mL)洗滌經組合之有機相,乾燥(Na2
SO4
),並在減壓下移除溶劑。藉由以乙酸乙酯/正己烷(純正己烷至1:9)之矽膠管柱層析純化得到油狀標題化合物(6.8 g,76%)。
1
H-NMR(300 MHz,Cl3
CD):1.30(t,J=7.1 Hz,3H);2.57(s,3H);4.33(q,J=7.1 Hz,2H);6.97(dd,J1 ( F - H )
=16.5 Hz,J2
=8.0 Hz,1H);7.38-7.44(m,5H)。
中間物90. 2,2-二氟-3-苯基丙酸乙酯在中間物89(8.0 g,25 mmol)於二噁烷(100 mL)中之溶液中加入氧化二苯膦(5.0 g,25 mmol)及過氧化第三丁基(2.0 mL,11 mmol)。於110℃下惰性氣氛下加熱混合物48小時。冷卻之後,減壓下移除溶劑。藉由以乙酸乙酯/正己烷(1:8)溶離之矽膠管柱層析純化得到油狀標題化合物(2.2 g,42%)。
1
H-NMR(300 MHz,Cl3
CD):1.26(t,J=7.1 Hz,3H);3.38(t,JF - H
=16.3 Hz,2H);4.24(q,J=7.1 Hz,2H);7.24-7.33(m,5H)。
中間物91. 2,2-二氟-3-苯基丙-1-醇在中間物90(2.2 g,10.3 mmol)於甲醇(30 mL)中之冷卻溶液中加入硼氫化鈉(1.94 g,51 mmol)。在5℃下攪拌混合物20分鐘,且在室溫下攪拌2小時。在粗反應物中加入水(1 mL),且在減壓下移除溶劑。將殘餘物溶解於乙酸乙酯(50 mL),用鹽水(2×25 mL)洗滌,乾燥(Na2
SO4
)並濃縮。藉由以乙酸乙酯/正己烷(1:5)溶離之矽膠管柱層析純化得到油狀標題化合物(0.75 g,42%)。
1
H-NMR(300 MHz,Cl3
CD):1.87(bs,1H);3.25(t,JF - H
=16.5 Hz,2H);3.67(t,JF - H
=12.5 Hz,2H);7.27-7.36(m,5H)。
中間物92. 6-溴己基2,2-二氟-3-苯基丙基酯藉由中間物69中所述過程自中間物91(0.75 g,4.36 mmol)獲得。藉由以正己烷/乙酸乙酯(純正己烷至40:1)之矽膠管柱層析純化得到油狀標題化合物(0.53 g,36%)。
1
H-NMR(300 MHz,Cl3
CD):1.40-1.52(m,4H);1.57-1.68(m,2H);1.83-1.94(m,2H);3.23(t,JF - H
=16.5 Hz,2H);3.39-3.53(m,6H);7.28-7.40(m,5H)。
中間物93. (R,S)-3-[6-(2,2-二氟-3-苯基丙氧基)己基]-5-(2,2-二甲基-4H-1,3-苯幷二氧雜環己烯-6-基)-1,3-噁唑烷-2-酮藉由中間物35中所述過程自中間物92(0.53 g,1.58 mmol)及中間物51(0.38 g,1.52 mmol)獲得。藉由以正己烷/乙酸乙酯(5:1至1:1)之矽膠管柱層析純化得到油狀標題化合物(0.30 g,39 %)。
1
H-NMR(300 MHz,Cl3
CD):1.33-1.44(m,4H);1.52-1.67(m,4H);1.54(s,6H);3.23(t,J=16.8 Hz,2H);3.31-3.52(m,7H);3.87(t,J=8.0 Hz,1H);4.84(s,2H);5.40(t,J=8.0 Hz,1H);6.82(d,J=8.5 Hz,1H);7.01(s,1H);7.12(dd,J1=8.5 Hz,J2=1.9 Hz,1H);7.27-7.33(m,5H)。
MS(M+):503。
在室溫下攪拌中間物93(30 mg,0.06 mmol)於二噁烷(1 mL)中之溶液及濃鹽酸(0.1 mL)2小時。減壓下移除溶劑。藉由以二氯甲烷/甲醇(15:1至10:1)溶離之矽膠管柱層析純化得到油狀標題化合物(5 mg,19%)。
1
H-NMR(300 MHz,Cl3
CD):1.21-1.44(m,4H);1.48-1.68(m,4H);2.66-2.76(m,4H);3.21(t,JF - H
=16.5 Hz,2H);3.41-3.50(m,4H);4.58(bs,8H);6.72(d,J=7.7 Hz,1H);6.93-6.98(m,2H);7.23-7.36(m,5H)。
MS(M+):437。
醫藥調配物可便利地以單位劑型存在,且可藉由醫藥領域所熟知之任何方法製備。所有方法均包括使活性成份與載劑相聯繫之步驟。總言之,藉由均一且緊密地將活性成份與液體載劑或經精細分開之固體載劑或兩者相聯繫,且隨後(若需要)將產物成形於所需調配物中來製備調配物。
適於口服投藥之本發明調配物可以離散單元形式存在,諸如各含有預定量之活性成份的膠囊、藥包或錠劑;以散劑或顆粒形式存在;以含水液體或不含水液體中之溶液或懸浮液形式存在;或者以水包油液體乳液或油包水液體乳液形式存在。活性成份亦可以大丸劑、舐劑或糊劑形式存在。
糖漿調配物通常由化合物或鹽於例如乙醇、花生油、橄欖油、甘油或水之液體載劑及調味劑或著色劑中之懸浮液或溶液組成。
當組合物為錠劑形式時,可使用任何通常用於準備固體調配物之醫藥載劑。該等載劑之實例包括硬脂酸鎂、滑石粉、明膠、阿拉伯膠、硬脂酸、澱粉、乳糖及蔗糖。可藉由壓縮或模塑,視情況以一或多種附加成份製備錠劑。可藉由於合適機器中將活性成份壓縮成自由流動形式(諸如散劑或顆粒),視情況與黏合劑、潤滑劑、惰性稀釋劑、潤滑界面活性劑或分散劑混合來製備經壓縮錠劑。
可藉由於合適機器中模塑經惰性液體稀釋劑潮濕之粉末狀化合物之混合物來製備經模塑錠劑。錠劑視情況可經塗覆或刻痕,且可經調配以提供其中活性成份緩慢或經控制釋放。
當組合物為膠囊形式時,任何常規包裝均為合適,例如使用前述硬明膠膠囊中之載劑。當組合物為軟明膠膠囊時,可考慮通常用於製備分散液或懸浮液之任何醫藥載劑,例如含水膠、纖維素、矽酸鹽或油,且將其併入軟明膠膠囊中。舉例而言,用於藉由吸入而局部傳輸至肺部之乾燥散劑組合物可用於吸入器或吹入器中之(例如)明膠之膠囊及藥筒或(例如)薄層鋁箔的發泡藥形式存在。調配物通常含有用於吸入本發明化合物之散劑及合適散劑基(載劑物質),諸如乳糖或澱粉。使用乳糖為較佳。
各膠囊或藥筒通常可含有2 μg與150 μg間之各種治療活性成份。或者,活性成份可以無賦形劑形式存在。
調配物之包裝可適於單位劑量或多劑量傳輸。在多劑量傳輸情形中,調配物可為預計量或在使用中計量。因此將乾燥散劑吸入器劃分為三組:(a)單獨劑量,(b)多單元劑量及(c)多劑量裝置。
對於該第一類型吸入器而言,已由廠商將單獨劑量稱重於小容器中,其主要為硬明膠膠囊。必須將膠囊自單獨盒或容器取出,並插入至吸入器之接受區域。接著,必須打開膠囊或者以針或刀刃穿孔以使部分吸入氣流穿過膠囊用於帶走粉末,或者藉助吸入期間之離心力將粉末自膠囊通過該等穿孔卸下。吸入之後,再次將排空之膠囊自吸入器移除。分解吸入器對於插入及移除膠囊通常為必須,其對於一些患者而言可為困難且繁重之運作。
與將硬明膠膠囊用於吸入散劑相關之其他缺點為(a)抗由周圍空氣所吸收之潮濕的弱保護性,(b)在膠囊先前已暴露於極度相對濕度後之打開或穿孔的問題,其引起破碎或凹痕,及(c)可能吸入膠囊碎片。此外,對於許多膠囊吸入器而言,已報導不完全排出(例如Nielsen等人,1997)。
如WO 92/03175中所描述,一些膠囊吸入器具有藥盒(magazine),單獨膠囊可自該藥盒轉移至接受室,接受室中發生穿孔及排空。其他膠囊吸入器具有旋轉藥盒,其中膠囊室可與用於卸下劑量之空氣管道成一直線(例如WO91/02558及GB 2242134)。其包含多單位劑量類型吸入器及發泡藥吸入器,其在碟片或條帶上供給中具有有限數目之單位劑量。
發泡藥吸入器比膠囊吸入器提供更佳之藥物潮濕保護。藉由穿孔蓋子以及發泡藥箔,或藉由剝去蓋箔以獲得進入散劑。當使用發泡藥條帶以代替碟片時,可增加劑量數目,但患者難以替換空條帶。因此,以已併入之劑量系統通常可任意使用該等裝置,其包括用於傳輸條帶且打開發泡藥囊之技術。
多劑量吸入器不含有預量測量之散劑調配物。其由相對大之容器及由患者所操作之劑量量測原理組成。容器具有由體積排量自大批散劑單獨分離之多劑量。存在多種劑量量測原理,其包括可旋轉膜(例如,EP0069715)或碟片(例如,GB 2041763;EP 0424790;DE 4239402及EP 0674533)、可旋轉圓柱體(例如,EP 0166294;GB 2165159及WO 92/09322)及可旋轉截頭體(例如,WO 92/00771),所有該等均具有填充有自容器之散劑之空穴。其他多劑量裝置具有量測滑片(例如,US 5201308及WO 97/00703)或量測活塞,其中局部或圓周凹穴將一定體積之散劑自容器轉移至傳輸室或空氣導管,例如EP 0505321、WO 92/04068及WO 92/04928。
可重現之劑量量測係多劑量吸入器裝置的一個主要關注點。由於填充劑量量測杯或空穴主要係在重力影響下,因此散劑調配物必須展示良好且穩定之流動特性。
對於再裝單獨劑量及多單位劑量吸入器而言,廠商保證劑量量測精準性及可再現性。另一方面,多劑量吸入器可含有極多之劑量,而用於填裝劑量之操作的數目較少。
由於多劑量裝置中吸入氣流通常直越劑量量測空穴,且由於多劑量吸入器之大且剛性之劑量量測系統不可有此吸入氣流攪動,因此散劑塊自空穴簡單地輸送,且在卸下期間內獲得極少之解聚。
因此,單獨崩解手段為必須。然而,在實踐中,其並不一直為吸入器設計之部分。由於多劑量裝置中之大數目劑量,因此必須最小化散劑於空氣導管內壁上之黏附及解聚手段及/或該等部分之普通清潔必須為可能,而不影響裝置中之殘餘劑量。一些多劑量吸入器具有可在採用規定數目劑量後經替換之可任意使用之藥物容器(例如WO 97/000703)。對於該等具有可任意使用之藥物容器之半永久多劑量吸入器而言,阻止藥物堆積之需要更為嚴格。
除藉由乾燥散劑吸入器之應用之外,本發明之組合物可在氣霧劑中投藥,其係經由推進氣體或藉助所謂噴霧器運作,醫藥活性物質之溶液經由此可在高壓下噴霧,因此引起可吸入散劑之薄霧。噴霧器之優勢在於使用推進氣體可完全將其分散。舉例而言,該等噴霧器描述於PCT專利申請案第WO 91/14468號及國際專利申請案第WO 97/12687號中,其內容以引用的方式併入本文。
舉例而言,用於藉由吸入而局部傳輸至肺部之噴霧組合物可以使用合適液化推進劑經調配成含水溶液或懸浮液或自壓力包裝中傳輸之噴霧劑,諸如計量劑量吸入器。適於吸入之噴霧劑組合物可為懸浮液或溶液,且通常含有活性成份及合適推進劑,諸如碳氟化合物或含氫之氯氟碳化物或其混合物,尤其係氫氟鏈烷,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷,尤其係1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟-正丙烷或其混合物。二氧化碳或其他合適氣體亦可用作推進劑。
噴霧劑組合物可無賦形劑,或者可視情況含有此項技術熟知之其他調配物賦形劑,諸如界面活性劑,例如油酸或卵磷脂及共溶劑,例如乙醇。加壓調配物通常可保留於濾毒罐(例如鋁濾毒罐)中,其係以閥(例如計量閥)關閉,且裝配至具有接口之致動器中。
用於吸入投藥之藥物需要具有經控制之粒子大小。用於吸入至支氣管系統之最佳粒子大小通常為1-10 μ,較佳為2-5 μ。當吸入到達小氣道時,具有大於20 μ大小之粒子通常過大。為達到該等粒子大小,可藉由習知手段(例如,藉由微粉化)減少活性成份之粒子大小。可藉由空氣分類或過篩分離出所需部分。粒子較佳為結晶。
難以用經微粉化散劑達到高劑量再現性,此係由於其較差流動性及極度凝聚趨勢。為了改良乾燥散劑組合物之效力,當粒子在吸入器中時,其應較大,但當排出呼吸道時,其應較小。因此,通常採用諸如乳糖或葡萄糖之賦形劑。賦形劑之粒子大小通常顯著大於本發明內之經吸入藥物之粒子大小。當賦形劑為乳糖時,其通常以經研磨乳糖,較佳為結晶α
乳糖單水合物存在。加壓噴霧劑組合物通常可經填充至裝配有閥(尤其係計量閥)之濾毒罐中。如WO 96/32150中所述,濾毒罐視情況可塗覆有塑料物質,例如碳氟化合物聚合物。濾毒罐將被裝備至適於口腔內傳輸之致動器中。
用於經鼻傳輸之典型組合物包括上文所提及用於吸入之彼等組合物,且進一步包括以視情況與習知賦形劑(諸如緩衝液、抗菌劑、張力修飾劑及黏度修飾劑)組合之溶液或懸浮液於惰性載劑(諸如水)形式的可藉由鼻泵(nasal pump)投放之非加壓組合物。
典型皮膚及經皮膚調配物包含習知含水或不含水媒劑,例如乳劑、軟膏、洗液或糊劑,或者為加藥膏藥、貼片或膜之形式。
組合物較佳為單位劑型,例如錠劑、膠囊或計量噴霧劑劑量,因此患者可投與單獨劑量。
各劑量單位合適地含有1 μg至100 μg之根據本發明的2-激動劑,且較佳為5 μg至50 μg之根據本發明的2-激動劑。
當然,達到治療作用所需之各活性的量可隨特定活性、投藥途徑、治療下之受檢者及所治療之特定病症或疾病而變化。
每天可投放活性成份1至6次,其足以展示所需活性。活性成份較佳每天投與一次或兩次。
本發明之組合物可視情況包含一或多種已知可用於治療呼吸道病症之其他活性物質,諸如PDE4抑制劑、皮質類固醇或糖皮質激素及/或抗膽鹼劑。
可與β2-激動劑結合之合適PDE4抑制劑之實例為登布茶鹼(denbufylline)、咯利普蘭(rolipram)、西潘茶鹼(cipamfylline)、阿羅茶鹼(arofylline)、非明司特(filaminast)、吡拉米特(piclamilast)、梅索普蘭(mesopram)、鹽酸屈他維林(drotaverine hydrochloride)、利利司特(lirimilast)、羅氟司特(roflumilast)、西洛司特(cilomilast)、6-[2-(3,4-二乙氧基苯基)塞唑-4-基]吡啶-2-羧酸、(R)-(+)-4-[2-(3-環戊氧基-4-甲氧基苯基)-2-苯基乙基]吡啶、N-(3,5-二氯-4-吡啶基)-2-[1-(4-氟苄基)-5-羥基-1H-吲哚-3-基]-2-酮基乙醯胺、9-(2-氟苄基)-N6-甲基-2-(三氟甲基)腺嘌呤、N-(3,5-二氯-4-吡啶基)-8-甲氧基喹啉-5-羧醯胺、N-[9-甲基-4-酮基-1-苯基-3,4,6,7-四氫吡咯并[3,2,1-jk][1,4]苯幷二氮呯-3(R)-基]吡啶-4-羧醯胺、3-[3-(環戊氧基)-4-甲氧基苄基]-6-(乙胺基)-8-異丙基-3H-嘌呤鹽酸鹽、4-[6,7-二乙氧基-2,3-雙(羥甲基)萘-1-基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮、2-甲氧羰基-4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環己1-酮、順[4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環己-1-醇、ONO-6126(Eur Respir J 2003,22(增刊45):摘要2557)及PCT專利申請案第WO03/097613號及PCT/EP03/14722以及西班牙專利申請案第P200302613號中所主張之化合物。
可與β2-激動劑結合之合適皮質類固醇之實例為潑尼龍(prednisolone)、甲潑尼龍(methylprednisolone)、地塞松(dexamethasone)、萘非可特(naflocort)、地夫可特(deflazacort)、鹵潑尼松乙酸鹽(halopredone acetate)、布地奈德(budesonide)、二丙酸倍氯米松(beclomethasone dipropionate)、氫化可的松(hydrocortisone)、曲安奈德(triamcinolone acetonide)、氟西奈德(fluocinolone acetonide)、醋酸氟輕鬆(fluocinonide)、丙酸氯氟美松(clocortolone pivalate)、醋丙甲潑尼龍(methylprednisolone aceponate)、地塞米松棕櫚酸酯(dexamethasone palmitoate)、替潑尼旦(tipredane)、醋丙氫可的松(hydrocortisone aceponate)、潑尼卡酯(prednicarbate)、阿氯米松二丙酸鹽(alclometasone dipropionate)、鹵甲松(halometasone)、磺庚甲潑尼龍(methylprednisolone suleptanate)、莫米松糠酸酯(mometasone furoate)、利美索龍(rimexolone)、法呢酸潑尼松龍酯(prednisolone farnesylate)、環索奈德(ciclesonide)、迪普羅酮丙酸酯(deprodone propionate)、氟替卡松丙酸酯(fluticasone propionate)、鹵倍他索丙酸酯(halobetasol propionate)、氯替潑諾(loteprednol etabonate)、倍他米松丁酸丙酸酯(betamethasone butyrate propionate)、氟尼縮松(flunisolide)、莫潑尼松(prednisone)、地塞米松磷酸鈉(dexamethasone sodium phosphate)、曲安奈德(triamcinolone)、17-戊酸倍他米松(betamethasone 17-valerate)、倍他米松(betamethasone)、倍他米松二丙酸酯(betamethasone dipropionate)、醋酸氫化可的松(hydrocortisone acetate)、氫化可的松琥珀酸鈉(hydrocortisone sodium succinate)、潑尼松龍磷酸鈉(prednisolone sodium phosphate)及氫化可的松。
可與β2-激動劑結合之合適M3拮抗劑(抗膽鹼劑)之實例為噻托銨(tiotropium)鹽、氧托銨(oxitropium)鹽、氟托銨(flutropium)鹽、異丙托銨(ipratropium)鹽、格隆溴銨(glycopyrronium)鹽、曲司銨(trospium)鹽、瑞伐托酯(revatropate)、艾帕托酯(espatropate)、3-[2-羥基-2,2-雙(2-噻吩基)乙醯氧基]-1-(3-苯氧基丙基)-1-氮鎓雙環[2.2.2]辛烷鹽、1-(2-苯基乙基)-3-(9H--9-基羰氧基)-1-氮鎓雙環[2.2.2]辛烷鹽、2-酮基-1,2,3,4-四氫喹唑啉-3-羧酸內-8-甲基-8-氮雜雙環[3.2.1]辛-3-基酯鹽(DAU-5884)、3-(4-苄基哌嗪-1-基)-1-環丁基-1-羥基-1-苯基丙-2-酮(NPC-14695)、N-[1-(6-胺基吡啶-2-基甲基)哌啶-4-基]-2(R)-[3,3-二氟-1(R)-環戊基]-2-羥基-2-苯基乙醯胺(J-104135)、2(R)-環戊基-2-羥基-N-[1-[4(S)-甲基己基]哌啶-4-基]-2-苯基乙醯胺(J-106366)、2(R)-環戊基-2-羥基-N-[1-(4-甲基-3-戊烯基)-4-哌啶]-2-苯基乙醯胺(J-104129)、1-[4-(2-胺基乙基)哌啶-1-基]-2(R)-[3,3-二氟環戊-1(R)-基]-2-羥基-2-苯基乙-1-酮(Banyu-280634)、N-[N-[2-[N-[1-(環己基甲基)哌啶-3(R)-基甲基]胺甲醯基]乙基]胺甲醯基甲基]-3,3,3-三苯基丙醯胺(Banyu CPTP)、2(R)-環戊基-2-羥基-2-苯基乙酸4-(3-氮雜雙環[3.1.0]己-3-基)-2-丁炔酯(Ranbaxy 364057)。UCB-101333、Merck's OrM3、7-內-(2-羥基-2,2-二苯基乙醯氧基)-9,9-二甲基-3-氧雜-9-氮鎓三環[3.3.1.0(2,4)]壬烷鹽、7-(2,2-二苯基丙醯氧基)-7,9,9-三甲基-3-氧雜-9-氮鎓三環[3.3.1.0*
2,4*
]壬烷鹽、7-羥基-7,9,9-三甲基-3-氧雜-9-氮鎓三環[3.3.1.0*
2,4*
]壬烷9-甲基-9H-茀-9-羧酸酯鹽,所有該等視情況以其外消旋體、其對映異構體、其非對映異構體及其混合物形式存在,且視情況以其醫藥學可兼容酸加成鹽形式存在。在該等鹽中,較佳為氯化物、溴化物、碘化物及甲磺酸鹽。
本發明之組合物可用於治療呼吸道疾病,其中預計支氣管舒張劑(bronchodilating agent)對例如哮喘、急性或慢性支氣管炎、肺氣腫或慢性阻塞性肺部疾病(COPD)之疾病具有有益作用。
本發明之活性化合物(意即本發明之β2-激動劑及PDE4抑制劑、皮質類固醇或糖皮質激素及/或抗膽鹼劑)可在相同醫藥組合物中或者在意欲單獨、同時、伴隨或相繼投放之不同組合物中藉由相同或不同途徑一併投放。
預期所有活性劑可同時投藥或在極短的時間內投藥。或者,可在早晨採用一或兩種活性,且在當天晚些時刻採用其他活性。或者在另一方案中,可每天兩次採用一或兩種活性,且其他為每天一次,其同時為所發生之每天兩次劑量的一種或單獨。較佳為同時採用至少兩種活性,更佳為同時採用所有活性。較佳為至少兩種活性可作為混合物投藥,更佳為所有活性可作為混合物投藥。
本發明之活性物質組合物較佳以用於以吸入器輔助傳輸之吸入組合物形式投藥,尤其係乾燥散劑吸入器,然而,可使用任何其他形式或者非經腸或口服應用。本文所吸入之組合物的應用包含較佳應用形式,尤其係在阻塞性肺部疾病之治療或哮喘之治療中。
本發明活性化合物之調配物的其他合適載劑可見於Remington:The Science and Practice of Pharmacy,第20版,Lippincott Williams & Wilkins,Philadelphia,Pa.,2000中。以下非限制性實例說明本發明之代表性醫藥組合物。
調配物實例1(口服懸浮液)
調配物實例2(用於口服投藥之硬明膠膠囊)
調配物實例3(用於吸入之明膠藥筒)
調配物實例4(用於以DPI吸入之調配物)
調配物實例5(用於MDI之調配物)
本發明之化合物及其醫藥學上可接受之鹽展示生物活性,且可用於藥物治療。可用下文測試A至E證明化合物結合β腎上腺素受體之能力,以及其選擇性、激動劑效力及內在活性,或者可用此項技術已知之其他測試證明。
人類腎上腺素1及2受體結合檢定用自Sf9細胞製備之商業膜來進行結合人類腎上腺素1及2受體的研究,其中其為過量表現(Perkin Elmer)。
用0.14 nM3
H-CGP12177(Amersham)及經+0.3% PEI預處理之GFC Multiscreen 96孔板(Millipore)中之終體積250 μl之不同濃度測試化合物培養檢定緩衝液中之膜懸浮液(每孔16 μg之1及每孔5 μg之2)、具有12.5 mM MgCl2
及2 mM EDTA pH=7.4之75 mM Tris/HCl。在存在1 μM普萘洛爾(propanolol)下量測非特異性結合。在室溫且在溫和振盪同時培養60分鐘。藉由過濾及以2.5體積之Tris/HCl 50 mM pH=7.4洗滌以終止結合反應。藉由使用至少6種不同濃度之測試化合物且一式兩份來確定各測試化合物與受體之親合力。藉由使用SAS之非線性回歸獲得IC5 0
值。
發現本發明之例示性化合物對2受體具有小於25 nM之IC50,且對1受體具有小於140 nM之IC5 0
。
人類腎上腺素3受體結合檢定將自American Type Culture Collection之人類SK-N-MC神經腫瘤細胞製備之膜用作3受體來源。生長細胞,且根據P.K.Curran及P.H.Fishman,Cell.Signal,1996,8(5),355-364中所描述之方法製備膜。
在所提及之公開案中詳述之檢定過程可總結如下:SK-N-MC細胞系表現1與3受體,且因此為了選擇結合3,用1 nM1 2 5
I-CYP((-)-3-[1 2 5
I]碘氰基品多洛爾(Amersham))及0.3 μM CGP20712A(1拮抗劑)於50 mM HEPES、4 mM MgCl2
及0.4%牛血清白蛋白,pH=7.5(檢定緩衝液)中及不同濃度之測試化合物來培養膜。檢定之終體積為250 μl。藉由100 μM烯丙洛爾(alprenolol)界定非特異性結合。在30℃下邊振盪邊培養樣品90分鐘。
藉由經Whatman GF/C膜過濾來終止結合反應,該膜係用BRANDEL M-24收集器在4℃下以檢定緩衝液預濕潤。各用4 ml之50 mM Tris/HCl及4 mM MgCl2
pH 7.4洗滌濾紙三次,且量測保留於濾紙上之放射性。
藉由使用至少8種不同濃度之測試化合物且一式兩份來確定各測試化合物與受體之親合力。藉由使用SAS之非線性回歸獲得IC5 0
值。發現本發明之例示性化合物對β3受體具有大於1200 nM之IC5 0
值。
激動劑活性確定,經電刺激之豚鼠氣管的發作及補償製備經分離之氣管條藉由頭部敲擊隨後放血來殺死成年雄性豚鼠(400-500 g),切離氣管,且將其置於皮氏培養皿(Petri dish)中之Krebs溶液中。切開所附結締組織,且用Krebs溶液溫和沖洗內腔。將每根氣管切成含有3-4根軟骨帶之環,且打開該等環以藉由在平滑肌帶相反一側切開軟骨形成條。一根長棉線連接於軟骨條之一端以連接張力計,且在另一端連接一根棉線以錨定含有2.8 μM吲哚美辛(indomethacin)之懸浮液隔室中之組織。將雙極鉑電極安置於與經澆注組織平行並與其緊密靠近。隨後將組織靜置一小時以穩定。
電刺激以每2分鐘一次5 Hz頻率及0.1 ms持續時間之10秒鍛煉輸送電刺激(Coleman及Nials,1989)。在各實驗中,根據電壓依賴反應曲線之構建自8-16 V,並選擇10-15%最大反應內之超大劑量來選擇電壓。為了建立基線,在此超大電壓下刺激氣管條最短20分鐘(10個峰)。
組織澆注先前已描述該等實驗中之移除設備(Coleman及Nials,1989)。將製劑安於1 g靜止張力下。對於整個實驗持續時間而言,在37℃下、2 ml min- 1
下以經氧化(5% CO2
於O2
中)之Krebs Henseleit溶液澆注氣管條。
藥物製備藉由將化合物溶解於水中來製備儲備藥物溶液。隨後在Krebs Henseleit溶液中稀釋儲液來製備各化合物的不同濃度範圍。
激動劑活性確定藉由在30分鐘期間內相繼注入增加濃度之製備於Krebs溶液中之藥物來確定激動劑活性。量測各反應之等級,並表示為經電誘導收縮反應之抑制百分比。以絕對項表示-腎上腺素激動劑效力值(誘導50%抑制所需之濃度,EC5 0
)。
確定行為發作將達到50%行為發作之時間(T5 0
發作)定義為EC5 0
藥物濃度下,自藥物激動劑投藥至達到50%最大反應間之時間。
將達到最大行為發作之時間(Tm a x
)定義為藥物EC5 0
濃度下,自藥物激動劑投藥至達到100%最大反應間之時間。
確定行為補償將50%行為補充之時間定義為投藥結束至達到50%鬆馳恢復所耗時間。
在相同實驗中,行為補償亦表示為投藥後8 h所達恢復之百分比。
在此檢定中所測試之本發明例示性化合物展示50%恢復時間超過500分鐘之EC5 0
值小於10 nM。
有知覺豚鼠中組織胺誘導之支氣管痙攣測試化合物及產物將測試化合物溶解於蒸餾水中。其中一些需要用10%聚乙二醇300溶解。由Sigma(編號H 7250)供應組織胺HCl,並溶於蒸餾水中。
實驗過程由Harlan(Netherlands)供應雄性豚鼠(325-450 g),且維持於22±2℃恆溫下、40-70%濕度下,每小時10次循環之室內空氣。以12小時循環(7 h am至7 h pm)之人造光對其照明。在動物經測試化合物給藥前進行最短5天之適應環境。實驗開始之前,對動物禁食18小時而水隨意供應。
將每組五隻動物置於連接於超音波噴霧器(Devilbiss Ultraneb 2000,Somerset,PA,USA)之甲基丙烯酸酯盒中(47×27×27 cm)。在30秒期間內藉由0.1與1000 μg/ml間濃度之噴霧劑投與測試化合物(2-腎上腺素激動劑)。投與測試化合物後5或180 min後,在30 s期間內噴霧250 μg/ml組織胺以誘導支氣管痙攣。在組織胺投藥後5分鐘期間內觀察動物,且記錄投藥至第一支氣管痙攣所耗時間。
確定活性、行為持續時間及計算對於各處理及劑量而言,用下式計算支氣管痙攣延遲之百分比:支氣管痙攣延遲%=[(t'-t)/(tm a x
-t)]×100,其中tm a x
=最大觀察時間(5 min),t=對照組動物中至第一支氣管痙攣延遲所耗時間,且t'=經化合物處理之動物中至第一支氣管痙攣延遲所耗時間。將EC5 0
定義為引起50%支氣管痙攣延遲之濃度劑量。計算組織胺攻毒前5分鐘或180分鐘時所投與化合物之EC5 0
,且分別指定為5 min之EC5 0
及180 min之EC5 0
。
藉由EC5 0
5 min/EC5 0
180 min比率確定測試化合物之行為持續時間。認為展示低於100之EC5 0
5 min/EC5 0
180 min之化合物為長效。
本發明之例示性化合物展示行為之長期持續時間。
豚鼠中乙醯膽鹼誘導之支氣管收縮測試化合物及產物將測試化合物溶解於蒸餾水中。其中一些需要最多用10%聚乙二醇300溶解。由Sigma(編號A 6625)供應乙醯膽鹼HCl,並溶於鹽水中。
實驗過程由Harlan(Netherlands)供應雄性豚鼠(450-600 g),且維持於22±2℃恆溫下、40-70%濕度下,每小時10次循環之室內空氣。以12小時循環(7 h am至7 h pm)之人造光對其照明。在動物經測試化合物給藥前進行最短5天之適應環境。實驗開始之前,對動物禁食18小時而水隨意供應。
將豚鼠暴露於測試化合物或媒劑之噴霧劑中。用Devilbiss噴霧器(Model Ultraneb 2000,Somerset,PA,SA)自水溶液產生該等噴霧劑。氣體混合物(CO2
=5%,O2
=21%,N2
=74%)以3 L/min通過噴霧器。將此噴霧器連接於其中每組放置一隻動物之甲基丙烯酸酯盒中(17×17×25 cm)。8隻豚鼠維持在盒中總共10分鐘。各噴霧劑在0及5分鐘時在60秒期間內產生(大約5 mL溶液經噴霧)。
投與0.1與300 μg/ml之化合物間之噴霧劑濃度。用MumedPR 800系統在給藥後1小時或24小時評價測試化合物之支氣管保護作用。
確定支氣管保護作用及計算以肌肉內注射1 ml/kg體積之氯胺酮(ketamine)(43.75 mg/kg)、甲苯噻嗪(xylazine)(83.5 mg/kg)及乙醯丙嗪(acepromazine)(1.05 mg/kg)來麻醉豚鼠。在刮去手術部位毛髮之後,在頸部切開2-3 cm中線切口。分離頸筋脈,且插入聚乙烯導管(Portex Ld.)以允許4-min間隔之靜脈推注乙醯丙嗪(10及30 μg/kg iv)。對頸動脈插入導管,且藉由Bentley Tracer轉換器量測血壓。切開氣管,且插入鐵氟龍(teflon)管,並連於呼吸速度描記器Fleisch來量測氣流。用Ugo Basile泵以60呼吸/分鐘速率之10 ml/kg體積對動物通風。用連接於Celesco轉換器之食道套管(Venocath-14,Venisystems)量測肺與肺內腔間之壓差。一旦完成套管插入,Mumed肺部量測電腦程式使得收集肺部值為可能。基線值符合在0.3-0.9 mL/cm H2
O範圍內,且肺抗性(lung resistance)(RL
)在每秒0.1-0.199 cm H2
O/mL範圍內。
用引起由30 μg/kg靜脈內乙醯膽鹼誘導之支氣管收縮50%抑制(EC5 0
)的測試化合物濃度來確定所吸入化合物之支氣管保護作用。
確定行為持續時間本發明之例示性化合物展示行為之長期持續時間。
Claims (26)
- 一種式(I)化合物:
- 如請求項1之化合物,其中m及r中至少一者為1。
- 如請求項2之化合物,其中m+r之和為1。
- 如請求項1至3中任一項之化合物,其中n+m+p+q+r+s之和為8、9或10。
- 如請求項1至3中任一項之化合物,其中q+r+s之和為2、3或4。
- 如請求項1至3中任一項之化合物,其中s係選自0及1之整數。
- 如請求項1至3中任一項之化合物,其中n+p之和為4、5或6。
- 如請求項1至3中任一項之化合物,其中q+s之和為1、2、3或4。
- 如請求項1至3中任一項之化合物,其中R3 為氫原子、鹵素原子或甲基。
- 如請求項9之化合物,其中R3 為氯原子或氟原子。
- 如請求項9之化合物,其中R3 為甲基。
- 如請求項1至3中任一項之化合物,其中R4 為氫原子。
- 如請求項1至3中任一項之化合物,其中R4 為氯原子。
- 如請求項1之化合物,其係選自由下列所組成之群:(R,S)-4-(2-{[6-(2,2-二氟-4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥 基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(4,4-二氟-4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-8-羥基喹啉-2(1H)-酮(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲基苯基)乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚4-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R,S)-2-(羥甲基)-4-(1-羥基-2-{[4,4,5,5-四氟-6-(3-苯基丙氧基)己基]胺基}乙基)酚(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-2-羥苯基]甲醯胺(R,S)-4-[2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚(R,S)-N-[3-(1,1-二氟-2-{[6-({2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]脲3-[3-(1,1-二氟-2-{[6-({2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}乙基)苯基]咪唑啶-2,4-二酮(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}胺基)-1-羥乙基]-2-(羥甲基)酚5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥 乙基)-8-羥基喹啉-2(1H)-酮4-((1R)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]胺基}-1-羥基-乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(3,3-二氟-3-苯基丙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]胺基}-1-羥乙基)-2-(羥甲基)酚(R,S)-4-(2-{[6-(2,2-二氟-3-苯基丙氧基)己基]胺基}-1-羥乙基)-2-(羥甲基)酚,鹽酸鹽及其醫藥學上可接受之鹽及溶劑合物。
- 如請求項14之化合物,其係選自由下列所組成之群:(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥基-乙基)-8-羥基喹啉-2(1H)-酮5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-8-羥基喹啉-2(1H)-酮及其醫藥學上可接受之鹽及溶劑合物。
- 如請求項15之化合物,其係為5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]胺基}-1-羥乙基)-8-羥基喹啉-2(1H)-酮及其醫藥學上可接受之鹽及溶劑合物。
- 如請求項1至3及14至16中任一項之化合物,其係用於治療人類或動物個體。
- 一種醫藥組合物,其包含治療有效量之如請求項1至16中任一項之化合物及醫藥學上可接受之載劑。
- 如請求項18之醫藥組合物,其中該組合物進一步包含治療有效量之一或多種其他治療劑。
- 如請求項19之醫藥組合物,其中該其他治療劑係皮質類固醇、抗膽鹼劑或PDE4抑制劑。
- 如請求項18至20中任一項之醫藥組合物,其中該組合物係經調配以用於吸入投藥。
- 一種醫藥組合,其包含如請求項1至16中任一項之化合物及一或多種其他治療劑。
- 如請求項22之醫藥組合,其中該其他治療劑係皮質類固醇、抗膽鹼劑或PDE4抑制劑。
- 如請求項1至3及14至16中任一項之化合物,其係用於治療選自由肺部疾病、早產、青光眼、神經病症、心臟病症及炎症組成之群的疾病或病情。
- 如請求項24之化合物,其中該肺部疾病係哮喘或慢性阻塞性肺部疾病。
- 一種如請求項1至16中任一項之化合物之用途,其係用於製造供治療如請求項24至25中任一項所定義之疾病或病情之藥物。
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EP2228368A1 (en) | 2009-03-12 | 2010-09-15 | Almirall, S.A. | Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one |
DE202009006441U1 (de) | 2009-05-02 | 2009-07-09 | Nies, Klaus-Dieter | Verpackungseinheit eines Dämmstoffproduktes |
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Patent Citations (1)
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GB2140800A (en) * | 1983-04-18 | 1984-12-05 | Glaxo Group Ltd | Phenethanolamine derivatives |
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