TWI457341B - 胺基亞丙基衍生物 - Google Patents
胺基亞丙基衍生物 Download PDFInfo
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- TWI457341B TWI457341B TW098125787A TW98125787A TWI457341B TW I457341 B TWI457341 B TW I457341B TW 098125787 A TW098125787 A TW 098125787A TW 98125787 A TW98125787 A TW 98125787A TW I457341 B TWI457341 B TW I457341B
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- Taiwan
- Prior art keywords
- compound
- thiabenzo
- dihydro
- indole
- oxa
- Prior art date
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- -1 Aminopropyl Chemical class 0.000 title claims description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 231
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 30
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 28
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 23
- 239000000739 antihistaminic agent Substances 0.000 claims description 22
- 230000001387 anti-histamine Effects 0.000 claims description 17
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- SBUXRMKDJWEXRL-ZWKOTPCHSA-N trans-body Chemical compound O=C([C@@H]1N(C2=O)[C@H](C3=C(C4=CC=CC=C4N3)C1)CC)N2C1=CC=C(F)C=C1 SBUXRMKDJWEXRL-ZWKOTPCHSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 169
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- 238000004519 manufacturing process Methods 0.000 description 52
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- 239000002904 solvent Substances 0.000 description 34
- 239000013078 crystal Substances 0.000 description 31
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 24
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 229960001340 histamine Drugs 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 230000009471 action Effects 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 235000019260 propionic acid Nutrition 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- 206010041349 Somnolence Diseases 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 7
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 6
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
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- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
本發明是關於胺基亞丙基衍生物及其在藥學上可容許的鹽及水合物。該衍生物有用於做為醫藥組成物，尤其是抗組織胺藥等的有效成分。
組織胺(histamine)是引發過敏反應的化學介質(chemical mediator)的代表性物質，引起過敏反應的物質進入體內則會從肥胖細胞及嗜鹼性球等的細胞釋放出來。被釋放出來的組織胺會與組織胺1型受體(H1受體)蛋白質結合，發揮血壓降低、血管透過性亢進、平滑肌收縮、血管擴張、腺分泌促進等的藥理作用，而參與過敏反應或炎症的表現。如此，組織胺關係到人的種種疾病，藉由抑制其作用，就可以預防或治療過敏病症及炎症，市面上有多種抑制組織胺游離或阻礙其與受體結合的藥劑(抗組織胺藥)，被使用於支氣管氣喘、過敏性鼻炎、花粉症、蕁麻疹、異位性皮膚炎等的疾患。
但是，以往所知的抗組織胺藥，會發生基於中樞作用的鎮靜作用、睡意、暈眩、疲倦感等，或基於抗膽鹼作用的口渴、黏膜乾燥感、視調節障礙等的不良副作用，所以有禁止在開車前服用等的使用限制，成為不容易使用的原因。因此，在病患及醫療現場有需求解決此種問題且會發揮優良效果的抗組織胺藥。本發明者等發現了本發明的胺基亞丙基衍生物，係對中樞性副作用少且具有強力的抗組織胺作用。
關於具有硫代苯並薁(thiabenzo azulene)骨架的胺基亞丙基衍生物，在非專利文獻1有提示在噻吩環(thiophene ring)或苯環上有鹵原子、甲氧基、二甲基胺基磺醯基取代的化合物，但只是報告其合成而已，並未具體記載其具有抗組織胺作用等的藥理作用。
[非專利文獻]Helvetica Chimica Acta,Vol. 49,26,214-234,(1966)(參照220-221頁，表3)
本發明的目的在於提供一種化合物，該化合物可作為睡意等中樞性副作用少且優良的醫藥組成物，特別是抗組織胺藥等的有效成分。
本發明者等對具有如上述特徵的抗組織胺化合物精意進行研究的結果，發現下述構造式(I)表示的胺基亞丙基衍生物具有優良的抗組織胺作用，且為有用於做為減輕睡意等中樞性副作用的醫藥的化合物，而完成本發明。
本發明的胺基亞丙基衍生物具有優良的抗組織胺受體拮抗作用，又，在小鼠經口給藥的腦內受體結合試驗中表現腦內移行性低的結果，對睡意等中樞性副作用的減輕有效果，做為抗組織胺藥等醫藥組成物的有效成分具有所期望的特性，其有用性很高。
本發明是關於一種可做為抗組織胺藥等醫藥有用的下述一般式(I)表示的胺基亞丙基衍生物及其在藥學上可容許的鹽及水合物。
[式中，R1
及R2
為相同或不同，表示氫原子或由下述(a)至(c)所選出的取代基(但排除雙方都是氫原子的情況)
(a)羥基、烷氧基或羥基烷胺基取代的羰基，
(b)羥基或烷氧基取代的羰基烷基，
(c)丙烯酸(包含烷基酯)，
R3
及R4
可以相同或不同而表示氫原子、可經苯基取代的烷基、或環烷基，或R3
與R4
與將其結合的氮原子一起形成雜環，形成吡咯烷基、可經側氧基(oxo group)或N-哌啶基(piperidino)取代的N-哌啶基，經烷基或苯基取代的哌基(piperazinyl)、N-嗎啉基(morpholino)或硫代N-嗎啉基(thiomorpholino)，A為無取代或表示側氧基，B表示碳或氧，X及Y之任一方表示碳而另一方表示硫，虛線部分表示單鍵或雙鍵，波狀線表示順式體及或/反式體。]
前述一般式(I)中，烷基(包含上述羰基烷基、丙烯酸烷基酯、羥基烷基胺基、烷基哌基等上述取代基中的「烷基」)，理想的是甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、戊基、異戊基、新戊基、己基、異己基等碳數1至6的直鏈狀或支鏈狀的烷基。
烷氧基而言，理想的是表示甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、二級丁氧基、三級丁氧基、正戊氧基、正己氧基等碳數1至6的直鏈狀或支鏈狀的烷氧基。
環烷基而言，理想的是表示環丙基、環丁基、環戊基、環己基等碳數3至6的環狀烷基。
鹵原子表示氟、氯、溴、碘等。
本發明化合物中，理想的化合物如下。
鹽酸(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-基]丙烯酸乙酯[化合物1]
鹽酸(E,Z)-4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-羧酸乙酯[化合物3]
(E,Z)-4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-羧酸[化合物4]
鹽酸(E)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-基]乙酸[化合物5]
鹽酸(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]丙烯酸乙酯[化合物6]
(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]丙烯酸[化合物7]
(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-基]羧酸[化合物8]
鹽酸(E,Z)-4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-羧酸-(2-羥乙基)醯胺[化合物9]
(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-基]丙烯酸[化合物11]
鹽酸(E,Z)-4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-羧酸-(2-羥乙基)醯胺[化合物12]
鹽酸(E,Z)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丙烯酸乙酯[化合物13]
(E,Z)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丙烯酸[化合物14]
(E,Z)-3-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]羧酸[化合物15]
(Z)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]羧酸[化合物16]
鹽酸(E)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]乙酸[化合物17]
鹽酸(Z)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]乙酸[化合物18]
(E)-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物19]
(Z)-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物20]
鹽酸(E,Z)-2-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]-2-甲基丙酸乙酯[化合物21]
(E,Z)-2-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]-2-甲基丙酸[化合物22]
(E,Z)-2-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]-2-甲基丙酸[化合物23]
鹽酸(E,Z)-2-[4-(3-二甲基胺基亞丙基)-10-側氧基-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]-2-甲基丙酸乙酯[化合物24]
(E)-{2-甲基-2-[4-(3-甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]}丙酸[化合物25]
(E)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物26]
(Z)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物27]
(Z)-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基]乙酸[化合物28]
(E)-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基]乙酸[化合物29]
(E)-[4-(3-乙基甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物30]
(Z)-[4-(3-乙基甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物31]
(E)-{4-[3-(嗎啉-4-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物32]
(Z)-{4-[3-(嗎啉-4-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物33]
(E)-{4-[3-(哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物34]
(Z)-{4-[3-(哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物35]
(E)-4-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}丁酸[化合物36]
(Z)-4-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}丁酸[化合物37]
(E)-[4-(3-乙基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物38]
(Z)-[4-(3-乙基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物39]
(E)-[4-(3-苄甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物40]
(Z)-[4-(3-苄甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物41]
(E)-[4-(3-苄基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物42]
(Z)-[4-(3-苄基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物43]
(E)-[4-(3-環戊基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物44]
(Z)-[4-(3-環戊基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物45]
(E)-[4-(3-異丙基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物46]
(Z)-[4-(3-異丙基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸[化合物47]
(E)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丙酸[化合物48]
(Z)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丙酸[化合物49]
(E)-{4-[3-(4-甲基哌-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物50]
(Z)-{4-[3-(4-甲基哌-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物51]
(E)-3-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}丙酸[化合物52]
(Z)-3-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}丙酸[化合物53]
(E)-{4-[3-(4-苯基哌-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物54]
(Z)-{4-[3-(4-苯基哌-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物55]
鹽酸(E)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基]丙酸[化合物56]
鹽酸(Z)-3-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基]丙酸[化合物57]
(E)-3-{4-[3-(吡咯烷-1-基)胺基亞丙基]-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基}丙酸[化合物58]
(Z)-3-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基}丙酸[化合物59]
(E)-4-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丁酸[化合物60]
(Z)-4-[4-(3-二甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丁酸[化合物61]
(E)-{4-[3-(4-側氧基哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物62]
(Z)-{4-[3-(4-側氧基哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物63]
(E)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-6-基]乙酸[化合物64]
鹽酸(Z)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-6-基]乙酸[化合物65]
二甲酸(E)-{4-[3-([1,4’]聯哌啶-1’-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物66]
二甲酸(Z)-{4-[3-([1,4’]二哌啶-1’-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物67]
(E,Z)-{4-[3-(硫代嗎啉-4-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物68]
(E,Z)-二甲基-2-{4-[3-(哌啶-1-基)亞丙基]-9,10-二氫-4H-1-硫雜苯並[f]薁-6-基}丙酸[化合物69]
鹽酸(E)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物70]
鹽酸(Z)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸[化合物71]
上述的本發明中，更理想的化合物，可舉後述表9及10所記載的化合物，再者，以表12中記載的抗組織胺作用優異，且腦內移行性低的化合物尤其理想。
以下呈示本發明化合物的一般性製法。上述一般式(I)表示的本發明化合物可由下面記載的方法製造。但是，對業者而言，用於製造特定化合物的正確方法，可視其化學構造而改變是很明白的事。
上述一般式(I)表示的化合物中，4-(胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁化合物，是依據Helvetica Chimica Acta,Vol. 49,Fasc. Emile Cherbuliez,No. 26,214-233(1966)記載的方法或Collect. Czech. Chem. Commun. Vol. 59,667-674(1994)記載的方法，4-(胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁化合物，是依據Helvetica Chimica Acta,Vol. 54,Fasc. 1,277-282(1971)記載的方法，4-(胺基亞丙基)-4H-1-硫雜苯並[f]薁化合物及4-(胺基亞丙基)-4H-3-硫雜苯並[f]薁化合物，是依據Helvetica Chimica Acta,Vol. 49,Fasc. Emile Cherbuliez No. 26,214-233(1966)記載的方法，4-(胺基亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁化合物及4-(胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁化合物，是依據特開昭63-10784或WO2005/003131記載的方法，4-(胺基亞丙基)-10-側氧基-9,10-二氫-4H-1-硫雜苯並[f]薁化合物是依據Helvetica Chimica Acta,Vol. 59,Fasc. 3,866-877(1976)記載的方法為基本而可製造。又，取代基的導入則可預先選擇在對應的位置有任意的取代基的原料而達成。
一般式(I)的化合物，是可由一般式(II)的化合物的Wittig反應，Wittig-Horner反應，McMurry反應而製造。例如使用Wittig反應時，可遵照J. Org. Chem. Vol. 44,22,3760-3765(1979)、J. Med. Chem. Vol. 35,2074-2084(1992)等記載的方法而進行。即，使用對應於一般式(I)化合物的3-胺基丙基鏻(aminopropyl phosphonium)鹽等，在正丁基鋰、丁醇鉀(potassium butoxide)等鹼的存在下，在THF(四氫呋喃)、甲苯、二乙醚、CPME(環戊基甲基醚)等無水溶媒中，理想的是在0℃與溶媒沸點間的合宜溫度下，與一般式(II)的化合物反應即可製造。
又，一般式(II)的化合物進行Grignard反應後生成的一般式(III)表示的化合物經脫水反應而可轉變成一般式(I)的化合物。這個製法可遵照Helvetica Chimica Acta,Vol. 54,Fasc. 1,277-283(1971)記載的方法進行。例如，可使用對應的3-胺基丙基鹵化鎂等的Grignard試藥，在THF、甲苯、二乙醚、CPME等的無水溶媒中，在溶媒的融點至沸點間適宜的溫度下，與一般式(II)的化合物進行Grignard反應。接下來的脫水反應可使用鹽酸、三氟乙酸、亞硫醯氯(thionyl chloride)等，在無溶媒或水、乙醇、二氯甲烷等的合適的溶媒中，在溶媒的融點至沸點間的最適反應溫度下進行。
另有其他方法，也可使用Collect. Czech. Chem. Commun. Vol. 59,667-674(1994)記載的方法。即，由鎂與溴化丙烷等調製的Grignard試藥，在THF、甲苯、GPME等的無水溶媒中，在溶媒的融點至沸點間的適當反應溫度下與一般式(II)的化合物進行反應，得到一般式(IV)表示的化合物後，使用氫溴酸、溴化三甲基矽烷、亞硫醯氯等，在水、乙酸、二氯甲烷、三氯甲烷、1,4-二氧雜環己烷(dioxane)等合適的溶媒中，在0℃至溶媒的沸點間合適的溫度下進行鹵化反應，變換為一般式(V)表示的化合物。繼而將所得鹵化物在丙酮、甲醇、乙醇、THF、1,4-二氧雜環己烷、乙腈(acetonitrile)等溶媒中，與對應的胺化合物，理想的是在室溫至溶媒的沸點間合適的溫度下進行反應，可製造化合物(I)。在該胺化反應中，可視需要而適宜使用碳酸鉀、氫化鈉、三乙基胺等鹼。
一般式(II)的化合物可遵照日本特開昭49-69677,Helvetica Chimica Acta,Vol. 54,Fasc. 1,214-233(1966),Helvetica Chimica Acta,Vol. 54,Fasc. 1,277-282(1971),WO2005/003131,特願2008-019121等記載的方法製造。
芳環的官能基化，也可由一般式(I)的化合物、一般式(II)的化合物、以前述Grignard試藥合成的一般式(III)或(IV)的化合物，與使用烷基鋰試藥的鋰化反應(lithio reaction)、Friedel-Crafts醯化反應、Vilsmeier甲醯化反應(formylation)等而達成。再者，也可以選擇芳環被溴化的化合物為開始原料，藉由使用或不使用鈀等過渡金屬觸媒的羰化反應、Heck反應、氰化反應、甲醯化反應、Ullmann反應、鈴木耦合反應等而變換為所期望的官能基。這一類的反應也可利用J. Am. Chem. Soc.,Vol. 124,12557-12565(2002),Tetrahedron Lett.,Vol. 40,8193-8195(1991)等記載的方法。
例如，烷基化反應而言，可使用乙酸乙酯、乙酸三級丁酯、異丁酸乙酯等酯衍生物，以丁醇鉀、氫化鉀、LiHMDS(六甲基二矽胺鋰，Lithium Hexamethyldisilazide)、LiNCy2
(二環己基醯胺鋰,lithium dicyclohexylamide)等，在Pd(dba)2
(雙(二亞苄基丙酮)鈀(0)，bis(dibenzylideneacetone)paradium 0))、Pd2
(dba)3
(三(二亞苄基丙酮)二鈀(0))、Pd(OAc)2
(乙酸鈀(II))、Pd(PPh3
)4
(四(三苯基膦)鈀(0)、tetrakis triphenylphosphine)paradium(0))等過渡金屬觸媒的存在下，使用DPPF(1,1’-雙(二苯膦基)二茂鐵(1,1’-bis diphenylphosphino)ferrocene))、PPh3
(三苯基膦，triphenylphosphine)、P(o-Tol)3
(三(2-甲苯基)膦)、P(t-Bu)3
(三-三級丁基膦)、氯化N,N’-(2,6-二異丙基苯基)二氫嘧唑鎓(dihydroimidazolium chloride)等配位基(ligand)，與芳環被溴化的化合物反應而製造。該反應可在甲苯、苯、戊烷、環己烷或這些之混合物等溶媒中，理想的是在室溫至溶媒沸點間的合適溫度下進行。
前述一般式(I)的化合物包含順-反異構物的混合物，這些可用液體層析法，或使用或不使用合適的抗衡離子(counter ion)的優先結晶法(preferencial crystallization)等而分離。例如，使用高速液體層析法之情況，以填充十八烷基矽基(silyl)化氧化矽凝膠等的管柱，適宜的配合甲醇、乙腈等有機溶媒，與視需要而加入甲酸或三氟乙酸的水溶液的混合物做為沖洗液而達成。
前述一般式(I)表示的化合物，有其藥學上可容許的鹽存在時則包含其各種鹽，例如可舉與鹽酸、草酸、反丁烯二酸、對甲苯磺酸、順丁烯二酸、琥珀酸、乙酸、檸檬酸、碳酸、硝酸、甲酸等而成的酸附加鹽。又，羧基的鹽，也可包含鈉、鉀、鈣等適當的鹼金屬鹽。這些鹽由公知的方法即可製造游離的各化合物，或可互相變換。又，以順-反異構物、光學異構物、配位異構物等立體異構物或水合物或金屬錯合物的狀態存在時，本發明也包含其任何立體異構物、水合物及錯合物。
本發明可與適當的醫藥用擔體或稀釋劑組合而成為醫藥，可使用通常之任何方法製劑化，做為錠劑、膠囊劑、粉末劑、液劑等的口服劑，或皮下、肌肉內、直腸內、鼻腔內給藥的非口服劑而成為製劑。在處方時，可將本發明化合物以其在藥學上可容許的鹽的形態使用，可單獨或適當組合而使用，又，也可做為其他醫藥活性成分的配合劑。
經口給藥製劑而言，可單獨或與適當的添加劑，例如與乳糖、甘露醇、玉米澱粉、馬鈴薯澱粉等的慣用賦形劑一起，與結晶纖維素、纖維素衍生物、阿拉伯樹膠、玉米澱粉、明膠等結合劑，玉米澱粉、馬鈴薯澱粉、羧甲基纖維素鉀等崩壞劑，滑石、硬脂鎂等光滑劑，其他增量劑、濕潤劑、緩衝劑、保存劑、香料等適當組合而做成錠劑、散劑、顆粒劑或膠囊劑。
又，可視疾患的種類或患者，做成對其治療最適當的上述以外的劑形，例如，注射劑、栓劑、吸入劑、氣膠劑、漿劑、點眼劑、軟膏等的外用劑等的製劑。
本發明化合物的理想給藥量，會視給藥對象、劑形、給藥方法、給藥期間等而有不同，但為了要得到所期望的效果，則可對一般成人每日投與本發明化合物0.5至1000mg，理想的是1至500mg，1日分1次至數次經口給藥。非經口給藥(例如注射劑)時，每日之給藥量以前述各個給藥量的3至10分之1的用量為理想。
以下舉實施例具體說明本發明，但本發明並不受其任何限定。
融點是將試料填入於毛細管內，以大和(Yamato)MP-21型融點測定器測定。未進行溫度計的校正。MS譜是以POLARIS Q(Thermo Quest公司)測定。1
H-NMR是以ARX500型核磁共振裝置(Bruker公司)測定，於重氫化有機溶媒中測定時的化學位移值，是以添加做為內部標準之TMS(δ=0ppm)為基準而以ppm表示。又，在重水中測定時，以水的尖峰值的4.67ppm當做內部標準。矽膠管柱層析法是以層析用矽膠PSQ 100B或NH-DM1020(富士Silicia化學公司)進行。薄層層析法是使用Silica gel F254(Merck公司，No. 5715)或TLC plate NH(富士Silicia化學公司)，以UV燈及5%磷鉬酸-乙醇發色試藥檢出。幾何異構物混合物的分離是以高速液體層析法進行，液體輸送幫浦是880-PU(日本分光公司)，檢出器是875-UV(日本分光公司)，製備用管柱是STR PREP-ODS(20mmI.D.×250mm)(信和化工公司)。
在2-溴-9,10-二氫-3-硫雜苯並[f]薁-4-酮(7.00g)的DMF(50mL)溶液中，加三乙胺(34mL)、丙烯酸乙酯(27.5mL)、乙酸鈀(0.4g)、P(o-Tol)3
(1.5g)，在氬氣環境、80℃下混合一夜。在反應混合物中添加飽和氯化銨水溶液，以乙酸乙酯抽出後，將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。將在減壓下餾去溶媒而得的殘渣，以矽膠管柱層析法(三氯甲烷-甲醇=9：1)精製，得到標題化合物的非晶質固體6.39g(85%)。
1
H-NMR(DMSO-d6
)δ：1.26(t,J=7.1Hz,3H),3.10-3.19(m,4H),4.19(q,J=7.1Hz,2H),6.55(d,J=16Hz,1H),7.40-7.44(m,2H),7.55-7.59(m,2H),7.80-7.82(m,1H),8.59(s,1H)。
(dimethylaminopropyltriphenylphosphonium bromide hydrobromide)(23.5g)的THF(100mL)溶液中，加1.6mol/L正丁基鋰-己烷溶液(42mL)，在室溫下混合1小時。在該溶液中添加實施例1所得的化合物(6.11g)的THF(100mL)溶液，再混合一夜。在減壓下餾去溶媒，殘渣加飽和氯化銨水溶液，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。殘渣以矽膠管柱層析法(三氯甲烷-甲醇=9：1)精製，所得精製物溶解於二氧雜環己烷(20mL)中，加4mol/L氯化氫-二氧雜環己烷溶液(1.1mL)而在室溫下混合1小時。在減壓下餾去溶媒，將析出的結晶過濾乾燥而得標題化合物的E-體、Z-體混合物0.51g(6%)。
在氬氣環境下，在冰冷下的六甲基二矽氮烷(3.53g)中滴入1.6mol/L正丁基鋰-己烷溶液(14mL)。在該溶液中滴入乙酸三級丁酯(1.2mL)而混合30分鐘。加Pd(dba)2
(0.30g)、氯化N,N’-(2,6-二異丙基苯基)二氫嘧唑鎓(0.22g)、(E,Z)-[3-(6-溴-10H-9-氧雜-3-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺(2.01g)，將混合物升溫到室溫，混合一夜。在反應混合物中添加飽和氯化銨水溶液，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=19：1)精製，得到標題化合物的油狀的E體、Z體混合物0.80g(36%)。
MS(EI)：m/z400[M+
+1]。1
H-NMR(DMSO-d6
)δ：1.35-1.42(m,9H),2.07-2.66(m,10H),3.51-3.55(m,2H),5.05-5.12(m,2H),5.84-6.06(m,1H),6.77-7.53(m,5H)。
在實施例3所得的化合物(1.53g)中緩緩加三氟乙酸(2.0mL)，在室溫下混合2小時。在減壓下餾去三氟乙酸，在殘渣中加5%碳酸鉀水溶液後，以稀鹽酸調pH為7，以三氯甲烷抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。減壓下餾去溶媒而得標題化合物的油狀的E體、Z體混合物1.20g(91%)。
將在實施例4所得的化合物(1.20g)溶解於0.2%甲酸水溶液/甲醇混液30mL中，將以0.45μm的過濾膜過濾的試樣溶液以液體層析法(沖洗液：0.2%甲酸水溶液/甲醇混液(3：2))分離精製。流速為6.5mL/分，測定波長為254nm。化合物19在20分至24分間，化合物20在15分至18分間流出。分取的個別流出液的溶媒在減壓下餾去，將析出的白色結晶過濾乾燥，分別得到化合物19及化合物20，各0.53g(44%)及0.28g(23%)。
在加熱下對金屬鎂(2.5g)滴下溴化環丙烷(8.3mL)的無水THF(50mL)溶液。滴完後，加無水THF(20mL)，再加熱回流2小時後放冷，將該溶液滴入於在冰浴冷卻下的(4-側氧基-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基)乙酸甲酯(10.0g)的無水THF(mL)溶液中。混合30分鐘後，在反應混合物中添加飽和氯化銨水溶液，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=5：1)精製，得到標題化合物的油狀物9.0g(79%)。
1
H-NMR(DMSO-d6
)δ：0.16-0.18(m,1H),0.29-0.31(m,1H),0.44-0.47(m,1H),0.60-0.62(m,1H),1.74-1.78(m,1H),3.60-3.65(m,5H),4.78(d,J=15.4Hz,1H),5.36(d,J=15.4Hz,1H),6.10(s,1H),6.72-6.73(m,1H),7.07-7.51(m,4H)
在實施例6所得的化合物(9.0g)的二氯甲烷(100mL)溶液中，在室溫下滴入溴化三甲基矽烷(3.6mL)的二氯甲烷(20mL)溶液，進行溴化反應。混合1小時後，加飽和碳酸氫鈉水溶液，分離有機層。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=9：1)精製，得到標題化合物的油狀的E體、Z體的混合物9.3g(87%)。
1
H-NMR(DMSO-d6
)δ：2.76-3.10(m,2H),3.60-3.79(m,7H),5.06-5.14(m,2H),5.83-6.06(m,1H),6.79-7.56(m,5H)
在實施例7所得的化合物(1.00g)的THF(20mL)溶液中,加吡咯烷(0.4mL)、碳酸鉀(0.7g)、碘化鉀(0.9g)，加熱回流一夜。放冷後，加飽和氯化銨水溶液，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=5：1)精製，得到標題化合物的油狀的E體、Z體的混合物0.50g(51%)。
MS(EI)：m/z 383[M+
].1
H-NMR(DMSO-d6
)δ：1.63-1.67(m,4H),2.35-2.58(m,8H),3.60-3.69(m,5H),5.05-5.12(m,2H),5.80-6.09(m,1H),6.78-7.53(m,5H)
在實施例8所得的化合物(2.80g)的乙醇(30mL)溶液中添加1mol/L氫氧化鈉(22mL)在室溫下混合2小時。餾去溶媒後，殘渣中加水，將該水溶液以稀鹽酸調至pH7，以三氯甲烷抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得油狀物由二乙醚固化而得標題化合物的E體、Z體的混合物的結晶2.21g(82%)。
使用在實施例9所得的E-體、Z-體的混合物(1.99g)，依實施例5同樣的操作而分離精製，分別得化合物26及化合物27的白色結晶各1.09g(55%)及0.31g(16%)。
使用6-溴-10H-9-氧雜-3-硫雜苯並[f]薁-4-酮(5.10g)，由依實施例6、7之順序進行同樣操作而得的化合物，與50%二甲基胺水溶液，依實施例8同樣的操作而得[3-(6-溴-10H-9-氧雜-3-硫雜苯並[f]薁-4-亞基)-丙基]二甲基胺的E-體、Z-體混合物的油狀物3.62g(58%)。將該異構物混合物(1.0g)溶解於1,4-二氧雜環己烷(10mL)，在室溫下混合1小時。減壓下餾去溶媒，將析出的結晶過濾乾燥而得標題化合物的E體、Z體的混合物的鹽酸鹽0.85g(77%)。
在化合物2(11.6g)的DMF(150mL)溶液中加氰酸鋅(2.27g)、Pd2
(dba)3
(1.14g)、DPPF(3.47g)，在氬氣環境下，120℃下混合一夜。放冷後，加水於反應混合物，過濾不溶物，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。在減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=9：1)精製，得到標題化合物的油狀的E體、Z體的混合物1.70g(17%)。
MS(EI)：m/z 311[M+
+1]。1
H-NMR(DMSO-d6
)δ：2.09-2.13(m,6H),2.31-2.58(m,4H),5.16-5.23(m,2H),6.13-6.16(m,1H),6.81-7.96(m,5H)
在實施例12所得化合物(1.70g)的乙醇(25mL)溶液中，加1mol/L氫氧化鈉(27mL)，加熱回流6小時。之後依實施例9同樣的操作而得標題化合物的E體、Z體的混合物結晶1.26g(70%)。
將化合物4(0.50g)的乙醇(50mL)溶液以冰浴冷卻後，加亞硫醯氯(1.1mL)，在80℃下混合一夜。將反應混合物放冷後，減壓餾去溶媒，殘渣溶解於乙酸乙酯，以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨。以無水硫酸鈉乾燥後，減壓下餾去溶媒，殘渣以矽膠管柱層析法(己烷-乙酸乙酯=9：1)精製，得到游離的標題化合物的油狀的E體、Z體的混合物。之後依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的E體、Z體的混合物結晶0.37g(64%)。
使用由2-溴-9,10-二氫-3-硫雜苯並[f]薁-4-酮依實施例11同樣的操作所得之(E,Z)-[3-(2-溴-9,10-二氫-3-硫雜苯並[f]薁-2-基)丙基]二甲基胺(2.00g)，依實施例3同樣的操作而得[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-2-基]乙酸的E體、Z體混合物的油狀物0.30g(20%)。之後依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的白色結晶0.15g(45%)。
由2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-酮依實施例11同樣的操作所得的游離(E,Z)-[3-(2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺(2.82g)的DMF(60mL)溶液，在氬氣環境下，加丙烯酸乙酯(8.5mL)、三乙基胺(11mL)、乙酸鈀(0.14g)、Pd(o-Tol)3
(0.47g)，在80℃下混合一夜。放冷後，反應混合物中加水，以乙酸乙酯抽出。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥。減壓下餾去溶媒，殘渣以矽膠管柱層析法(己烷-乙酸乙酯=9：1)精製，得到游離的標題化合物的油狀的E體、Z體的混合物2.29g(77%)。使用該異構物混合物(0.76g)，依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的E體、Z體的混合物0.57g(68%)。
使用實施例16所得的游離的化合物(1.53g)，依實施例9同樣的操作而得標題化合物的E體、Z體的混合物結晶0.94g(66%)。
由2-溴-9,10-二氫-3-硫雜苯並[f]薁-4-酮依實施例11同樣的操作所得之(E,Z)-[3-(2-溴-9,10-二氫-3-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺(6.33g)，依實施例12、13的順序進行同樣操作，而得標題化合物的E體、Z體的混合物結晶2.12g(37%)。
將由2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-酮依實施例18同樣的操作所得之E-體、Z體混合物(E,Z)-[4-(3二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]羧酸(0.70g)、N-羥基琥珀醯亞胺(0.25g)及鹽酸1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(0.41g)的二氯甲烷(20mL)溶液在室溫下混合一夜。將反應混合物以飽和氯化銨水溶液、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨，減壓下餾去溶媒。將殘渣溶解於二氯甲烷(20mL)，加2-羥基乙基胺(0.13mL)，在室溫下混合一夜。將反應混合物以飽和氯化銨水溶液、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨，減壓下餾去溶媒。所得殘渣以矽膠管柱層析法(三氯甲烷-甲醇=19：1)精製，得到游離的標題化合物的油狀的E體、Z體的混合物0.50g(56%)。之後，依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的E體、Z體的混合物結晶0.29g(34%)。
使用2-溴-10-甲氧基-1-硫雜苯並[f]薁-4-酮(2.04g)，依實施例11同樣的操作而得標題化合物的E體、Z體的混合物結晶1.31g(50%)。
使用實施例18所得的化合物8(0.50g)，依實施例19同樣的操作而得標題化合物的白色結晶0.14g(25%)。
使用實施例11所得的化合物2(3.05g)，依實施例16同樣的操作而得標題化合物的E體、Z體的混合物結晶3.03g(86%)。
使用化合物13(1.92g)，依實施例9同樣的操作而得標題化合物的E體、Z體的混合物結晶1.25g(77%)。
將由2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-酮依實施例11、12、13的順序同樣的操作，而得的標題化合物的E體、Z體的混合物(1.20g)，依實施例5同樣的操作分離精製而得化合物15及化合物16的個別白色結晶0.53%(44%)及0.28g(23%)。
使用(E,Z)-[3-(2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺(6.0g)，依實施例3、4的順序同樣的操作，而得游離的標題化合物的E體、Z體的油狀物，將其由二乙醚固化。所得的E體、Z體混合物，由乙酸乙酯-乙醇混液再結晶，獲得(E)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]乙酸1.02g(18%)。又，將由再結晶後的濾液在減壓下餾去溶媒所得之殘渣，依實施例5同樣的操作而分離精製，得(Z)-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]乙酸的油狀物0.25g(4%)。使用該經精製的各化合物，依實施例11的鹽酸鹽的調製法同樣的操作，獲得化合物17及化合物18的個別白色結晶，0.80g(73%)及0.21g(75%)。
在氬氣環境下，將二環己胺(1.45g)冰冷之，滴入1.6mol/L正丁基鋰-己烷溶液(5.0mL)。在該溶液中滴入異丁酸乙酯(0.9mL)，混合30分鐘。加Pd(dba)2
(0.26g)、10%P(t-Bu)3
-己烷溶液(1.0mL)、(E,Z)-[3-(6-溴-10H-9-氧雜-3-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺(1.60g)，將混合物升溫至室溫，混合一夜。加飽和氯化銨水溶液於反應混合物，以乙酸乙酯抽出。有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥。減壓下餾去溶媒，所得殘渣以矽膠管柱層析法(己烷-乙酸乙酯=19：1)精製。之後依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的E體、Z體的混合物結晶1.24g(65%)。
使用化合物21(0.98g)，依實施例9同樣的操作而得標題化合物的E體、Z體的混合物結晶0.32g(39%)。
使用由(E,Z)-[3-(2-溴-9,10-二氫-1-硫雜苯並[f]薁-4-亞基)丙基]二甲基胺，依實施例27同樣使用鈀觸媒的反應所得之(E,Z)-2-[4-(3-二甲基胺基亞丙基)-9,10-二氫-4H-1-硫雜苯並[f]薁-2-基]-2-甲基丙酸乙酯(1.03g)，依實施例9同樣的操作而得標題化合物的E體、Z體的混合物結晶0.32g(33%)。
使用由2-溴-10-甲氧基-1-硫雜苯並[f]薁-4-酮依實施例6同樣的操作所得的2-溴-4-環丙基-10-甲氧基-4H-1-硫雜苯並[f]薁-4-醇(3.20g)，依實施例27同樣的操作而得(2-環丙基-4-羥基-10-甲氧基-4H-1-硫雜苯並[f]薁-2-基)-2-甲基丙酸乙酯的E體、Z體的油狀混合物1.78g(50%)。之後，依實施例11之鹽酸鹽的調製法同樣的操作而得標題化合物的E體、Z體的混合物的非晶質固體0.67g(33%)。
由(E,Z)-[3-(6-溴-10H-9-氧雜-3-硫雜苯並[f]薁-4-亞基)丙基]甲基胺，依實施例27同樣的操作而得的化合物(2.74g)，依實施例9同樣的操作，獲得標題化合物的E體、Z體的混合物1.68g(66%)。使用該異構物的混合物，依實施例5同樣的操作分離精製而得標題化合物0.60g(34%)。
由(4-側氧基-4,10-二氫-9,1-硫雜苯並[f]薁-6-基)乙酸甲酯依實施例11、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.68g)，依實施例5同樣的操作分離精製而得化合物28及化合物29的個別白色結晶0.39g(23%)及0.58g(36%)。
由實施例7所的化合物與N-乙基甲基胺，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.00g)，依實施例5同樣的操作分離精製而得化合物30及化合物31的個別白色結晶0.21g(21%)及0.09g(9%)。
由實施例7所得的化合物與嗎啉，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.52g)，依實施例5同樣的操作分離精製而得化合物32及化合物33的個別白色結晶0.42g(28%)及0.15g(10%)。
由實施例7所的化合物與哌啶依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.25g)，依實施例5同樣的操作分離精製而得化合物34及化合物35的個別白色結晶0.70g(56%)及0.08g(6%)。
由4-(4-側氧基-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基)丁酸甲酯以實施例6、7、8、9的順序進行同樣操作所得之標題化合物的E體、Z體的混合物(1.31g)，依實施例5同樣的操作分離精製而得化合物36及化合物37的個別白色結晶0.60g(46%)及0.16g(12%)。
由實施例7所得之化合物及乙基胺鹽酸鹽依以實施例8、9的順序進行同樣操作所得之標題化合物的E體、Z體的混合物(0.66g)，依實施例5同樣的操作分離精製而得化合物38及化合物39的個別白色結晶0.46g(70%)及0.08g(12%)。
由實施例7所得之化合物及N-苄基甲基胺，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.54g)，依實施例5同樣的操作分離精製而得化合物40及化合物41的個別白色結晶0.65g(42%)及0.10g(6%)。
由實施例7所得之化合物及苄基胺以實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.51g)，依實施例5同樣的操作分離精製而得化合物42的非晶質固體0.62g(41%)及化合物43的白色結晶0.23g(15%)。
由實施例7所得之化合物及環戊基胺，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.00g)，依實施例5同樣的操作分離精製而得化合物44及化合物45的個別白色結晶0.54g(54%)及0.10g(10%)。
由實施例7所得之化合物及異丙基胺，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(2.02g)，依實施例5同樣的操作分離精製而得化合物46及化合物47的個別白色結晶0.38g(19%)及0.05g(2%)。
由3-(4-側氧基-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基)丙酸甲酯，依實施例6、7的順序進行同樣操作而得(E,Z)-3-[4-(3-溴化亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丙酸甲酯。將使用該E體、Z體的混合物及二甲基胺鹽酸鹽，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.32g)，依實施例5同樣的操作分離精製而得化合物48的非晶質固體0.33g(25%)及化合物49的白色結晶0.06g(5%)。
由實施例7所得之化合物及1-甲基哌以實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(0.61g)，依實施例5同樣的操作分離精製而得化合物50及化合物51的個別白色結晶0.25g(41%)及0.03g(5%)。
由3-(4-側氧基-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基)丙酸甲酯依實施例6、7、8、9的順序進行同樣操作而得的標題化合物的E體、Z體的混合物(1.21g)，依實施例5同樣的操作分離精製而得化合物52的白色結晶0.33g(27%)及化合物53的非晶質固體及0.06g(5%)。
由實施例7所得之化合物及1-苯基哌依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.08g)，依實施例5同樣的操作分離精製而得化合物54及化合物55的個別白色結晶0.11g(10%)及0.05g(5%)。
由3-(4-側氧基-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基)丙酸甲酯依實施例6、7的順序進行同樣操作而得(E,Z)-3-[4-(3-溴化亞丙基)-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基]丙酸甲酯。使用該E體、Z體的混合物及二甲基胺鹽酸鹽，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(0.89g)，依實施例5同樣的操作分離精製，而得非晶質固體的游離的化合物56及化合物57。繼而依實施例11的鹽酸鹽調製法同樣的操作而得化合物56及化合物57的個別白色結晶0.10g(11%)及0.08g(9%)。
由3-(4-側氧基-4,10-二氫-9-氧雜-1-硫雜苯並[f]薁-6-基)丙酸甲酯依實施例6、7、8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.20g)，依實施例5同樣的操作分離精製，而得化合物58及化合物59的個別非晶質固體0.37g(31%)及0.22g(18%)。
由4-(4-側氧基-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基)丁酸甲酯依實施例6、7的順序進行同樣操作而得(E,Z)-4-[4-(3-溴化亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]丁酸甲酯。使用該E體、Z體的混合物及二甲基胺鹽酸鹽，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(1.52g)，依實施例5同樣的操作分離精製，而得化合物60的白色結晶0.33g(22%)及化合物61的非晶質固體0.09g(6%)。
使用實施例7所得的化合物及4-哌啶酮(piperidone)依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(0.60g)，依實施例5同樣的操作分離精製而得化合物62及化合物63的個別白色結晶0.28g(47%)及0.10g(17%)。
由(4-側氧基-9,10-二氫-4H-3-硫雜苯並[f]薁-6-基)乙酸乙酯以實施例6、7的順序進行同樣操作而得(E,Z)-4-[4-(3-溴化亞丙基)-9,10-二氫-4H-3-硫雜苯並[f]薁-6-基]乙酸乙酯。使用該E體、Z體的混合物及50%二甲基胺水溶液，依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(0.91g)，依實施例5同樣的操作分離精製，而得化合物64的白色結晶0.35g(38%)及游離的化合物65的非晶質固體0.20g(22%)。由游離的化合物65依實施例11的鹽酸鹽調製法同樣的操作，得標題化合物65的白色結晶0.15g(68%)。
使用實施例7所得的化合物及4-哌啶基哌啶(4-piperidinopiperidine)依實施例8、9的順序進行同樣操作所得的標題化合物的E體、Z體的混合物(0.83g)，依實施例5同樣的操作分離精製，而得化合物66及化合物67的個別非晶質固體0.44g(53%)及0.14g(16%)。
由實施例7所得的化合物(2.00g)及硫代嗎啉依實施例8、9的順序進行同樣操作，而得標題化合物的E體、Z體的混合物結晶0.83g(37%)。
由6-溴-9,10-二氫-3-硫雜苯並[f]薁-4-酮依實施例6、7的順序進行同樣操作而得的(E,Z)-1-[3-(6-溴-9,10-二氫-3-硫雜苯並[f]薁-4-亞基)丙基]吡咯烷(3.01g)，依實施例27、9的順序進行同樣操作，而得標題化合物的E體、Z體的混合物結晶1.53g(51%)。
使用實施例10所得的化合物26(1.09g)依實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的白色結晶1.10g(92%)。
使用實施例10所得的化合物27(0.31g)，以實施例11的鹽酸鹽的調製法同樣的操作而得標題化合物的白色結晶0.31g(90%)。
在上述實施例製造而得的本發明化合物的物性數據示於表1至表8。
重組人組織胺H1受體質體(recombinant histamine H1 receptor plasmid,在Invitrogen公司製作)是使用Lipofactamine2000(Invitrogen公司)，對HEK293A細胞進行轉染(transfect)。人組織胺H1受體安定表現細胞(H1receptor stable expression cell)是使用遺傳黴素(geneticin)(Invitrogen公司)篩選。細胞是使用含有10%胎牛血清、0.1mmol/L MEM非必需胺基酸溶液、2mmol/L L-麩醯胺酸及0.7mg/mL遺傳黴素的Dulbecco’s Modified Eagle Medium，在37℃的5%二氧化碳培養箱內持續培養。人組織胺H1受體安定表現細胞是使用含有0.1%牛血清白蛋白的50mmol/L Tris-HCl(pH 7.5)(以下簡稱為緩衝液)調製成為3×106
個細胞/mL，做為細胞標本。在96孔盤(96 well plate)的各孔添加50μL的緩衝液、50μL各種濃度的試驗物質溶液及50μL的[3
H]吡拉明(pyrilamine)溶液(最後濃度3nmol/L)並攪拌後，加100μL的細胞標本(3×105
個細胞/孔)而開始反應。
在室溫下培養60分鐘後，在0.5%聚乙烯亞胺溶液浸過的UniFilter GF/C盤(Packard公司製)上，使用細胞收穫器(cell harvester,IH-110,殷諾科技(Innotech)公司)過濾而停止反應，以緩衝液洗淨。充分乾燥洗淨後的盤後，各孔加20μL的閃爍劑(MaxiLight,Hidex公司)，以多功能微定量盤式分析測讀儀(multilabel microplate reader,Plate Chameleo II,Hidex公司)計測每分鐘計數值(count per minute,cpm)。以加30μmol/L的吡拉明時的cpm做為非專一性結合。實驗以n=3實施，至少重複3次。
將結果的一例示於表9。本發明化合物在體外人組織胺H1受體結合實驗中，表現非常強大的活性。
將180g的SD系雄性大鼠(SPF)，在溫度22℃、濕度55%及1日12小時(照明期間上午8時至下午8時)的人工照明設定環境下，使其自由攝取固形飼料及自來水而進行預備飼養1週以上，斷食一夜後供實驗。組織胺2鹽酸鹽(以下簡稱組織胺)及伊文思藍(Evans blue)是在使用時溶解於生理食鹽液而使用。供試物質是以注射用水溶解或懸浮於0.5%羧基甲基纖維素鈉，對大鼠經口給藥(給藥容量為5mL/kg體重)。給藥1小時後，在乙醚麻醉下於以電剪髮器剪毛的大鼠背部，將生理食鹽液及組織胺溶液(20μg/0.05mL/部位)分別在兩處進行皮內注射。0.5%伊文思藍生理食鹽溶液(1mL/200g體重)是在欲皮內注射組織胺之前注入尾靜脈內。
30分鐘後，將動物斷頭放血致死，剝離皮膚，測定藍色染色部位的漏出色素量。漏出色素量的測定，是切取色素漏出部位的皮膚2處，在試管內加1mL的2mol/L的氫氧化鉀溶液，在37℃下放置一夜而溶解後，加0.67mol/L的磷酸及丙酮的1：3混液6mL，強烈振動10分鐘。之後過濾，測定濾液在620nm下的吸光度。以注射生理食鹽液的部位2處所得的吸光度作為空白值用於校正。色素漏出量是由在620nm的伊文思藍的標準線算出。
結果的一例示於表10。本發明化合物在大鼠組織胺誘發血管透過性亢進反應中，表現非常強的拮抗活性。
將6週齡的ICR系雄性小鼠，在溫度22℃、濕度55%及1日12小時的人工照明設定環境下，使其自由攝取固形飼料及自來水而做預備飼養1週以上，斷食一夜後供實驗。供試物質是以注射用水溶解或懸浮於0.5%羧基甲基纖維素溶液，對小鼠經口給藥(給藥容量為0.1mL/10g體重)。給藥1小時後斷頭，迅速摘出除去小腦及延髓的全腦。摘出的腦組織於冰冷的50mmol/L磷酸緩衝生理食鹽液(pH7.4,100mg/1.9mL)中以Polytron(Kinematica公司)均質化。
在反應用試管(TPX-管)中加入腦均質液180μL及3
H-吡拉明溶液(最後濃度2nmol/L)10μL，及無標誌吡拉明溶液(最後濃度200μmol/L)或50mmol/L磷酸緩衝生理食鹽液10μL，在室溫下培養45分鐘後，加冰冷的50mmol/L磷酸緩衝生理食鹽液2.0mL，停止反應。反應液以GF/B過濾器(Advantech公司)過濾，放入小瓶(vial)中，在60℃下乾燥一夜。乾燥後，添加閃爍劑(AL-1,甲苯基質，同仁化學研究所公司)10mL，每分鐘之分解量(dpm,disinter gration per minute)以液體閃爍計數器(美國Packard公司，TRI-CAB 2700TR)計測(5分鐘/小瓶)。
結果的一例示於表11。在本實驗中，本發明化合物要佔有腦內受體必須為高濃度，表示其腦內移行性低。由此結果，可知本發明化合物在腦內不移行而係在末梢選擇性地表現抗組織胺作用，可減輕睡意等中樞性副作用。
由上述實施例57及58的結果，將腦內受體結合試驗的ID50
值(表11)除以組織胺誘發血管透過性亢進反應試驗的ED50
值(表10)的值示於表12。腦內受體結合試驗的ID50
值(表11)越大，表示腦內移行性越低，組織胺誘發血管透過性亢進反應試驗的ED50
值(表10)越小，表示抗組織胺作用越強。因此，ID50
值÷ED50
值的值越大，表示有越強的抗組織胺作用，且睡意等中樞性副作用越小而可做為指標。如表12所示，本發明化合物比既有的抗組織胺藥酮替芬(ketotifen)，表現較大的ID50
值÷ED50
值的值，可知本發明化合物具有可做為具有強力抗組織胺作用，且睡意等中樞性副作用少的醫藥組成物，尤其是抗組織胺藥的有效成分的理想特性。
本發明之胺基亞丙基衍生物，如表9所示，具有強力的組織胺H1受體結合能，又如表10所示，對大鼠組織胺誘發血管透過性亢進反應，表現強力的組織胺受體拮抗活性。再者，由表11可知，在小鼠經口給藥的腦內受體結合試驗中，也表現低的腦內移行性，本發明之胺基亞丙基衍生物在睡意等中樞性副作用減輕之點而言是理想的。由這些組織胺受體結抗活性與腦內移行性的兩者合併評估的表12的值，也可知本發明之胺基亞丙基衍生物是強有力的組織胺受體拮抗物質，且睡意等的中樞性副作用少，是具有適合於做為抗組織胺藥等的醫藥組成物的有效成分所期望的特性，其有用性非常高。
Claims (6)
- 一種下述一般式(I)表示的胺基亞丙基衍生物或其藥學上可容許的鹽或水合物：
- 如申請專利範圍第1項之胺基亞丙基衍生物或其藥學上可容許的鹽或水合物，其中，R2 為氫。
- 如申請專利範圍第1項之胺基亞丙基衍生物或其藥學上可容許的鹽或水合物，其中R1 為經羥基取代的羰基碳數1至6的烷基。
- 一種由下列中所選出的胺基亞丙基衍生物，或其藥學上可容許的鹽或水合物：(E)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸、(Z)-{4-[3-(吡咯烷-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸、(E)-[4-(3-乙基甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸、(Z)-[4-(3-乙基甲基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸、(E)-{4-[3-(哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸、(Z)-{4-[3-(哌啶-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸、(Z)-[4-(3-苄基胺基亞丙基)-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基]乙酸、及(E)-{4-[3-(4-甲基哌-1-基)亞丙基]-4,10-二氫-9-氧雜-3-硫雜苯並[f]薁-6-基}乙酸。
- 一種醫藥，係含有申請專利範圍第1項至第4項中任一項之胺基亞丙基衍生物及其藥學上可容許的鹽及水合 物之至少一種。
- 如申請專利範圍第5項之醫藥，係抗組織胺藥。
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| US6613905B1 (en) * | 1998-01-21 | 2003-09-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| WO2008038711A1 (en) * | 2006-09-29 | 2008-04-03 | Nippon Zoki Pharmaceutical Co., Ltd. | Oxepin derivative |
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| FR1502857A (fr) * | 1965-10-01 | 1967-11-24 | Sandoz Sa | Nouveaux dérivés du benzo-cyclohepta-thiophène et leur préparation |
| JPS522393Y2 (zh) * | 1971-02-15 | 1977-01-19 | ||
| CH568312A5 (zh) * | 1972-01-24 | 1975-10-31 | Sandoz Ag | |
| SE388858B (sv) | 1972-09-20 | 1976-10-18 | Sandoz Ag | Analogiforfarande for framstellning av nya 2-alkyl-4(1-alkyl-4-piperidyliden)bensocykloheptatiofenderivat |
| JPS6310784A (ja) | 1986-03-03 | 1988-01-18 | Kyowa Hakko Kogyo Co Ltd | 抗アレルギー剤 |
| US4882351A (en) * | 1987-10-14 | 1989-11-21 | Roussel Uclaf | Tricyclic compounds |
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| AU2004253898A1 (en) * | 2003-06-27 | 2005-01-13 | Janssen Pharmaceutica N.V. | Tricyclic delta opioid modulators |
| JP5103388B2 (ja) * | 2005-06-17 | 2012-12-19 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 環状アミン側鎖を含有する新規な四環式テトラヒドロフラン誘導体 |
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- 2009-07-31 BR BRPI0917550A patent/BRPI0917550A2/pt not_active IP Right Cessation
- 2009-07-31 PL PL09803043T patent/PL2319840T3/pl unknown
- 2009-07-31 PT PT98030430T patent/PT2319840E/pt unknown
- 2009-07-31 RU RU2011107744/04A patent/RU2483063C2/ru not_active IP Right Cessation
- 2009-07-31 TW TW098125787A patent/TWI457341B/zh not_active IP Right Cessation
- 2009-07-31 EP EP09803043.0A patent/EP2319840B1/en active Active
- 2009-07-31 CN CN200980130369.1A patent/CN102112462B/zh not_active Expired - Fee Related
- 2009-07-31 CA CA2732282A patent/CA2732282C/en not_active Expired - Fee Related
-
2013
- 2013-09-25 JP JP2013198040A patent/JP5503793B2/ja not_active Expired - Fee Related
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2015
- 2015-08-03 HK HK15107411.9A patent/HK1206742A1/zh unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3770728A (en) * | 1970-03-11 | 1973-11-06 | Sandoz Ltd | Substituted 4h-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9h)-ones |
| US6613905B1 (en) * | 1998-01-21 | 2003-09-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| WO2008038711A1 (en) * | 2006-09-29 | 2008-04-03 | Nippon Zoki Pharmaceutical Co., Ltd. | Oxepin derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2732282C (en) | 2016-03-29 |
| PL2319840T3 (pl) | 2016-03-31 |
| US20110124856A1 (en) | 2011-05-26 |
| JP5379139B2 (ja) | 2013-12-25 |
| RU2011107744A (ru) | 2012-09-10 |
| US8653285B2 (en) | 2014-02-18 |
| EP2319840A4 (en) | 2012-05-16 |
| PT2319840E (pt) | 2016-02-10 |
| JP2013253115A (ja) | 2013-12-19 |
| CN104693215A (zh) | 2015-06-10 |
| CA2732282A1 (en) | 2010-02-04 |
| JPWO2010013805A1 (ja) | 2012-01-12 |
| RU2483063C2 (ru) | 2013-05-27 |
| TW201011038A (en) | 2010-03-16 |
| CN102112462B (zh) | 2015-02-18 |
| KR20110049773A (ko) | 2011-05-12 |
| EP2319840A1 (en) | 2011-05-11 |
| EP2319840B1 (en) | 2015-12-16 |
| HK1206742A1 (zh) | 2016-01-15 |
| HK1159612A1 (zh) | 2012-09-21 |
| DK2319840T3 (en) | 2016-01-25 |
| JP5503793B2 (ja) | 2014-05-28 |
| BRPI0917550A2 (pt) | 2015-11-17 |
| WO2010013805A1 (ja) | 2010-02-04 |
| AU2009277496B2 (en) | 2013-09-26 |
| CN102112462A (zh) | 2011-06-29 |
| ES2561227T3 (es) | 2016-02-25 |
| AU2009277496A1 (en) | 2010-02-04 |
| KR101375680B1 (ko) | 2014-03-19 |
| CN104693215B (zh) | 2017-09-01 |
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