TWI388553B - 經雜環醯胺取代之咪唑類 - Google Patents
經雜環醯胺取代之咪唑類 Download PDFInfo
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- TWI388553B TWI388553B TW095105843A TW95105843A TWI388553B TW I388553 B TWI388553 B TW I388553B TW 095105843 A TW095105843 A TW 095105843A TW 95105843 A TW95105843 A TW 95105843A TW I388553 B TWI388553 B TW I388553B
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- phenyl
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- alkyl
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- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 trifluoromethyl Oxy, difluoromethoxy, monofluoromethoxy Chemical group 0.000 claims description 81
- 238000000034 method Methods 0.000 claims description 79
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- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 9
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- 238000001816 cooling Methods 0.000 description 9
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 8
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
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- SRRKNRDXURUMPP-UHFFFAOYSA-N sodium disulfide Chemical compound [Na+].[Na+].[S-][S-] SRRKNRDXURUMPP-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
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- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
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- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- PSZXPGFNGPBEFR-UHFFFAOYSA-N trisodium butan-1-olate Chemical compound [Na+].[Na+].[Na+].CCCC[O-].CCCC[O-].CCCC[O-] PSZXPGFNGPBEFR-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
本發明係有關經雜環基醯胺-取代之咪唑類及其製法、其於治療與/或預防疾病上之用途,及其於製備供治療與/或預防疾病之醫藥上之用途,特定言之作為抗病毒劑,尤其對抗巨細胞病毒上之用途。
WO 99/23091說明以芳香系雜環化合物作為消炎劑,特別適用於治療病毒感染。
市面上可取得具有抗病毒活性且結構式不同之藥劑;然而,目前使用甘昔洛飛(ganciclovir)、弗甘昔洛飛(valganciclovir)、弗斯卡美(foscamet)與希得飛(cidofovir)之療法均與嚴重副作用有關,例如:腎毒性、嗜中性白小球減少症或血小板減少症。此外,經常可能發展出抗性。因此需要有效療法之新穎藥劑。
本發明一項目的在於提供具有相同或改善之抗病毒作用,供治療人類與動物病毒感染疾病之化合物。現已驚人地發現,本發明說明之經取代之咪唑類具有高度抗病毒活性。
本發明提供如下式化合物:
其中R1
代表如下式基團
其中*
代表羰基之附接點,R4
代表苯基或5-或6-員雜芳基,其中苯基與雜芳基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、氧代基、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基、C1
-C6
-烷氧基、羥基羰基、C1
-C6
-烷氧基羰基、胺基、C1
-C6
-烷基胺基、胺基羰基與C1
-C6
-烷基胺基羰基,R5
代表苯基或5-或6-員雜芳基,其中苯基與雜芳基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、氧代基、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基、C1
-C6
-烷氧基、羥基羰基、C1
-C6
-烷氧基羰基、胺基、C1
-C6
-烷基胺基、胺基羰基與C1
-C6
-烷基胺基羰基,及R6
與R7
分別獨立代表氫、甲基或乙基,R2
代表C1
-C6
-烷基,其中烷基可經一個取代基取代,其中取代基係選自下列各物所組成群中:C3
-C6
-環烷基、C6
-C1 0
-芳基與5-或6-員雜芳基,其中環烷基、芳基與雜芳基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、氧代基、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基、C1
-C6
-烷氧基、羥基羰基、C1
-C6
-烷氧基羰基、胺基、C1
-C6
-烷基胺基、胺基羰基與C1
-C6
-烷基胺基羰基,R3
代表苯基,其中苯基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基與C1
-C6
-烷氧基,與其鹽類、其溶合物及其鹽之溶合物。
根據本發明化合物為式(I)化合物與其鹽類、溶合物及該鹽之溶合物;下式(I)所包括之化合物及其鹽類、溶合物及該鹽之溶合物;及若下式(I)所包括之化合物及下文所述之化合物尚未形成鹽類、溶合物及該鹽之溶合物時,為式(I)化合物及下文中具體實施例所述及之化合物,與其鹽類、溶合物及該鹽之溶合物。
本發明化合物可依其結構出現立體異構型(對映異構物、非對映異構物)。因此本發明係有關對映異構物或非對映異構物與其個別混合物。純立體異構性組成可自此等對映異構物與/或非對映異構物之混合物中,依已知方式單離出。
當本發明化合物出現互變異構型時,本發明包括所有互變異構型。
較適用於本發明目的之鹽類為本發明化合物之生理上可接受之鹽類。然而,亦包括其本身不適合醫藥用途,但可用於例如:單離或純化本發明化合物之鹽類。
本發明化合物之生理上可接受之鹽類包括無機酸、羧酸與磺酸之酸加成鹽類,例如:鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、蘋果酸、檸檬酸、富馬酸、馬來酸與苯甲酸之鹽類。
本發明化合物之生理上可接受之鹽類亦包括習知鹼類之鹽類,如,較佳實例為鹼金屬鹽類(例如:鈉與鉀鹽類)、鹼土金屬鹽類(例如:鈣與鎂鹽類)與衍生自氨或含1至16個碳原子有機胺之銨鹽類,如,較佳實例為乙基胺、二乙基胺、三乙基胺、乙基二異丙基胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲基胺基乙醇、普卡因、二苯甲基胺、N-甲基嗎啉基、精胺酸、離胺酸、乙二胺、與N-甲基哌啶。
溶合物
在本發明目的中指彼等透過與溶劑分子配位而形成固態或液態複合物之本發明化合物型式。水合物為一種特殊之溶合物型式,其係與水發生配位。
此外,本發明亦包括根據本發明化合物之前藥。"前藥"一詞所包括之化合物部份可能有或沒有生物活性,但當其於體內滯留時,可(例如:經代謝或水解)轉化成根據本發明化合物。
本發明之目的中,除非另有說明,否則取代基之定義為:烷基本身與烷氧基、烷基胺基、烷氧基羰基與烷基胺基羰基中之"烷"與"烷基"
代表一種通常含有1至6個(“C1
-C6
-烷基”),較佳為1至4個,特別佳為1至3個碳原子之直鏈或分支烷基,較佳實例為甲基、乙基、正丙基、異丙基、第三丁基、正戊基與正己基。
烷氧基
之較佳實例為甲氧基、乙氧基、正丙氧基、異丙氧基、第三丁氧基、正戊氧基、與正己氧基。
烷基胺基
代表具有1或2個(分別獨立選出之)烷基取代基之烷基胺基,較佳實例為:甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、第三丁基胺基、正戊基胺基、正己基胺基、N,N-二甲基胺基、N,N-二乙基胺基、N-乙基-N-甲基胺基、N-甲基-N-正丙基胺基、N-異丙基-N-正丙基胺基、N-第三丁基-N-甲基胺基、N-乙基-N-正戊基胺基與N-正己基-N-甲基胺基。C1
-C3
-烷基胺基為例如:具有1至3個碳原子之單烷基胺基或每個烷基取代基分別具有1至3個碳原子之二烷基胺基。
烷氧基羰基
代表之較佳實例為甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基、第三丁氧基羰基、正戊氧基羰基與正己氧基羰基。
烷基胺基羰基
代表具有一個或二個(分別獨立選出之)烷基取代基之烷基胺基羰基,其較佳實例為甲基胺基羰基、乙基胺基羰基、正丙基胺基羰基、異丙基胺基羰基、第三丁基胺基羰基、正戊基胺基羰基、正己基胺基羰基、N,N-二甲基胺基羰基、N,N-二乙基胺基羰基、N-乙基-N-甲基胺基羰基、N-甲基-N-正丙基胺基羰基、N-異丙基-N-正丙基胺基羰基、N-第三丁基-N-甲基胺基羰基、N-乙基-N-正戊基-胺基羰基與N-正己基-N-甲基胺基羰基。C1
-C3
-烷基胺基羰基代表例如:具有1至3個碳原子之單烷基胺基羰基或代表每個烷基取代基具有1至3個碳原子之二烷基胺基-羰基。
芳基
代表通常具有6至10個碳原子之單環或雙環芳香系碳環基,較佳實例為苯基與萘基。
本發明內容中,5或6員雜若基
通常代表具有5或6個環原子及至多4個選自S、O與/或N雜原子之芳香系單環基團。雜芳基可利用碳或雜原子附接。可述及下列較佳實例:噻吩基、呋喃基、吡咯基、噻唑基、唑基、吡唑基、咪唑基、吡啶基、嘧啶基與嗒基。
環烷基
代表通常具有3至8個,較佳為3至6個碳原子之環烷基,其較佳實例為環丙基、環丁基、環戊基、環己基與環庚基。
鹵素
代表氟、氯、溴與碘。
本發明內容中,較佳式(I)化合物中R1
代表如下式基團:
其中*
代表羰基之附接點,R4
代表苯基或5-或6-員雜芳基,其中苯基與雜芳基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、氧代基、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基、C1
-C6
-烷氧基、羥基羰基、C1
-C6
-烷氧基羰基、胺基、C1
-C6
-烷基胺基、胺基羰基與C1
-C6
-烷基胺基羰基,R2
代表C1
-C6
-烷基,其中烷基可經一個取代基取代,其中取代基係選自C3
-C6
-環烷基與苯基所組成群中:其中環烷基與苯基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、氧代基、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基、C1
-C6
-烷氧基、羥基羰基、C1
-C6
-烷氧基羰基、胺基、C1
-C6
-烷基胺基、胺基羰基與C1
-C6
-烷基胺基羰基,R3
代表苯基,其中苯基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、羥基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、三氟甲硫基、C1
-C6
-烷基與C1
-C6
-烷氧基,與其鹽類、其溶合物及其鹽類之溶合物。
本發明內容中,亦較佳式(I)化合物中R1
代表如下式基團:
其中*
代表羰基之附接點,R4
代表苯基或吡啶基,其中苯基與吡啶基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、C1
-C4
-烷基與C1
-C4
-烷氧基,R2
代表甲基、乙基或正丁基,其中甲基、乙基與正丁基可經一個取代基取代,其中取代基係選自環丙基與苯基所組成群中,其中苯基可經一個三氟甲基取代基取代,R3
代表苯基,其中苯基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:氟、氯、三氟甲氧基、二氟甲氧基、三氟甲硫基與甲基,與其鹽類、其溶合物與其鹽類之溶合物。
本發明內容中,亦較佳之式(I)化合物中R1
代表如下式基團
其中*
代表羰基之附接點,與R4
代表苯基或吡啶基,其中苯基與吡啶基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:鹵素、硝基、氰基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、單氟甲氧基、C1
-C4
-烷基與C1
-C4
-烷氧基。
本發明內容中,亦較佳之式(I)化合物為其中R3
代表苯基,其中苯基可經1至3個取代基取代,其中取代基分別獨立選自下列各物所組成群中:氟、氯、三氟甲氧基、二氟甲氧基、三氟甲硫基與甲基。
本發明進一步提供一種製備式(I)化合物之方法,其中依據製法[A],由如下式化合物
其中R1
與R2
如上述定義,於第一個步驟中,與還原劑反應,於第二個步驟中,於碳酸衍生物之存在下,與如下式化合物反應,H2
N-R3
(III),其中R3
如上述定義,或依據製法[B],由式(II)化合物於第一個步驟中,與還原劑反應,及於第二個步驟中,與如下式化合物反應OCN-R3
(IV),其中R3
如上述定義,或依據製法[C],由如下式化合物
其中R2
與R3
如上述定義,與R8
代表甲基或乙基,於第一步驟中與鹼反應,及於第二步驟中與如下式化合物Rl-H (VI)其中R1
如上述定義,於脫水劑之存在下反應。
式(III)、(IV)與(VI)化合物係已知者或可依已知製法,由適當起始物製備。
製法[A]與[B],步驟1中,適用於下列條件:反應通常在惰性溶劑中,最好在溫度範圍0℃至溶劑回流溫度下,於常壓至3巴壓力下進行。
還原劑為例如:鈀-碳與氫、甲酸/三乙基胺/鈀-碳、鋅、鋅/鹽酸、鐵、鐵/鹽酸、硫酸鐵(II)/鹽酸、硫化鈉、二硫化鈉、連二亞硫酸鈉、多硫化銨、氫硼化鈉/氯化鎳、二氯化錫、三氯化鈦或阮來鎳及肼水溶液,較佳係使用阮來鎳與肼水溶液、鈀-碳與氫或甲酸/三乙基胺/鈀-碳。
惰性溶劑為例如:醚類,如:乙醚、甲基第三丁基醚、1,2-二甲氧基乙烷、二烷、四氫呋喃、乙二醇二甲基醚或二乙二醇二甲基醚,醇類,如:甲醇、乙醇、正丙醇、異丙醇、正丁醇或第三丁醇,烴類,如:苯、二甲苯、甲苯、己烷、環己烷或礦物油餾份,或其他溶劑,如:二甲基甲醯胺、二甲基乙醯胺、乙腈或吡啶,若為水可互溶之溶劑時,亦可使用其與水之混合物;較佳溶劑為甲醇、乙醇、異丙醇,及若使用阮來鎳時,使用肼水溶液、四氫呋喃。
製法[A]步驟2中,適用於下列條件:該反應通常在惰性溶劑中,最好於室溫至40℃之溫度範圍內,於常壓下進行。
碳酸衍生物為例如:N,N-羰基二咪唑、磷醯氯、二光氣、三光氣、氯甲酸苯基酯或氯甲酸4-硝基苯基酯;較佳為N,N-羰基二咪唑。
惰性溶劑為例如:鹵化烴類,如:二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚類,如:乙醚、甲基第三丁基醚、1,2-二甲氧基乙烷、二烷、四氫呋喃、乙二醇二甲醚或二乙二醇二甲醚,烴類,如:苯、二甲苯、甲苯、己烷、環己烷或礦物油餾份,或其他溶劑,如:乙酸乙酯、丙酮、二甲基甲醯胺、二甲基乙醯胺、2-丁酮、二甲亞碸、乙腈或吡啶,若為水可互溶之溶劑時,亦可使用其與水之混合物;較佳為二甲亞碸。
製法[B]步驟2中,適用於下列條件:該反應通常在惰性溶劑中進行,若適當時,在鹼之存在下,最好在室溫至溶劑回流溫度之範圍內,於常壓下進行。
惰性溶劑為例如:鹵化烴類,如:二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚類,如:乙醚、甲基第三丁基醚、1,2-二甲氧基乙烷、二烷、四氫呋喃、乙二醇二甲基醚或二乙二醇二甲基醚,烴類,如:苯、二甲苯、甲苯、己烷、環己烷或礦物油餾份,或其他溶劑,如:乙酸乙酯、丙酮、二甲基甲醯胺、二甲基乙醯胺、2-丁酮、二甲亞碸、乙腈或吡啶;較佳為四氫呋喃或二氯甲烷。
鹼類為例如:鹼金屬碳酸鹽,如:碳酸銫、碳酸鈉或碳酸鉀、或第三丁醇鉀或其他鹼類,如:氫化鈉、DBU、三乙基胺或二異丙基乙胺,較佳為三乙基胺。
製法[C]步驟1中,適用於下列條件:該反應通常於惰性溶劑中,最好在0℃至溶劑回流溫度範圍內,於常壓下進行鹼類為例如:鹼金屬氫氧化物,如:氫氧化鈉、氫氧化鋰或氫氧化鉀,或鹼金屬碳酸鹽,如:碳酸銫、碳酸鈉或碳酸鉀,較佳為氫氧化鈉。
惰性溶劑為例如:鹵化烴類,如:二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚類,如:乙醚、甲基第三丁基醚、1,2-二甲氧基乙烷、二烷、四氫呋喃、乙二醇二甲基醚或二乙二醇二甲基醚,醇類,如:甲醇、乙醇、正丙醇、異丙醇、正丁醇或第三丁醇,烴類,如:苯、二甲苯、甲苯、己烷、環己烷或礦物油餾份,或其他溶劑,如:二甲基甲醯胺、二甲基乙醯胺、二甲亞碸、乙腈或吡啶;或其與水之混合物,較佳溶劑為乙醇與水之混合物。
製法[C]步驟2中,適用於下列條件:該反應通常在惰性溶劑中,若適當時,在鹼之存在下,最好在-70℃至40℃之溫度範圍內,於常壓下進行。
適用於此目的之脫水劑為例如:碳化二亞胺,如,例如:N,N'-二乙基-、N,N'-二丙基-、N,N'-二異丙基-、N,N'-二環己基碳化二亞胺、N-(3-二甲基-胺基異丙基)-N'-乙基碳化二亞胺鹽酸鹽(EDC)、N-環己基碳化二亞胺-N'-丙基氧甲基-聚苯乙烯(PS-碳化二亞胺)或羰基化合物,如:羰基二咪唑,或1,2-唑鎓化合物,如:2-乙基-5-苯基-1,2-唑鎓-3-硫酸鹽或2-第三丁基-5-甲基異唑鎓過氯酸鹽,或醯基胺基化合物,如:2-乙氧基-1-乙氧基羰基-1,2-二氫喹啉,或丙烷膦酸酐,或氯甲酸異丁基酯,或雙(2-氧代基-3-唑啶基)磷醯基氯或苯并三唑基氧三(二甲基胺基)鏻六氟磷酸鹽或O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽(HBTU)、2-(2-氧代基-1-(2H)-吡啶基)-1,1,3,3-四甲基脲鎓四氟硼酸鹽(TPTU)或O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽(HATU)或1-羥基苯并三唑(HOBt)或苯并三唑-1-基氧參(二甲基胺基)鏻六氟磷酸鹽(BOP),或其與鹼之混合物。
鹼類為例如:鹼金屬碳酸鹽,如,例如:碳酸鈉或碳酸鉀,或碳酸氫鈉或碳酸氫鉀,或有機鹼類,如:三烷基胺類,例如:三乙基胺、N-甲基嗎啉、N-甲基哌啶、4-二甲基-胺基吡啶或二異丙基乙基胺,或DBU、DBN、吡啶;較佳為三乙基胺。
該縮合法最好使用羰基二咪唑進行。
惰性溶劑為例如:鹵化烴類,如:二氯甲烷、三氯甲烷、四氯化碳、三氯乙烷、四氯乙烷、1,2-二氯乙烷或三氯乙烯,醚類,如:乙醚、甲基第三丁基醚、1,2-二甲氧基乙烷、二烷、四氫呋喃、乙二醇二甲基醚或二乙二醇二甲基醚,烴類,如:苯、二甲苯、甲苯、己烷、環己烷或礦物油餾份,或其他溶劑,如:乙酸乙酯、丙酮、二甲基甲醯胺、二甲基乙醯胺、2-丁酮、二甲亞碸、乙腈或吡啶,若為水可互溶之溶劑時,亦可使用其與水之混合物;較佳為二甲基甲醯胺。
式(II)化合物係已知者或可由如下式化合物
其中R2
如上述定義,與R8
代表甲基或乙基,於第一步驟中,與鹼反應,及於第二步驟中,與式(VI)化合物,於脫水劑之存在下反應製得。
該反應係依製法[C]之說明進行。
式(VII)化合物係已知者或可由如下式化合物
其中R2
如上述定義,與R8
代表甲基或乙基,與發煙硝酸、濃硝酸、硝化酸或其他混合比例之硫酸與硝酸,若適當時,於乙酸酐作為溶劑下,最好在室溫至60℃之溫度範圍內進行。
式(V)化合物係已知者或可由式(VII)化合物,於第一步驟中,與還原劑反應,於第二步驟中,於碳酸衍生物之存在下,與式(III)化合物反應,或於第二步驟中,與式(IV)化合物反應。
該反應係依製法[A]與[B]之說明進行。
式(III)、(IV)、(VI)與(VIII)化合物係已知者或可依已知方法,由適當起始物製備。
根據本發明式(I)化合物具有意外且驚人之活性範圍。其對疱疹病毒科之代表性病毒(疱疹病毒),尤指巨細胞病毒(CMV),特定言之人類巨細胞病毒(HCMV)具有抗病毒效果。因此其適用於治療與預防疾病,尤指病毒感染,特定言之如上述病毒感染,及由其引起之感染性疾病。下文中,咸了解,病毒感染係指感染病毒及因感染病毒所引起之疾病。
基於通式(I)化合物之特殊性質,其可用於製備適合預防與/或治療疾病,特定言之病毒感染之醫藥。
適應症之範圍可述反之實例為;1)治療與預防AIDS患者之HCMV感染(視網膜炎、肺炎、胃腸道感染)。
2)治療與預防骨髓與器官移植患者經常發展成危害生命之HCMV肺炎或腦炎之巨細胞病毒感染,及胃腸道與全身性HCMV感染。
3)治療與預防新生兒與嬰兒之HCMV感染。
4)治療孕婦急性HCMV感染。
5)治療與癌症及癌症療法有關之免疫壓抑患者之HCMV感染。
6)治療HCMV-陽性癌症患者,以降低HCMV-所媒介腫瘤發展(參見J.Cinatl等人之FEMS Microbiology Reviews 2004,28,59-77)。
根據本發明化合物較適用於製備適合預防與/或治療疱疹病毒科之代表性病毒,特定言之巨細胞病毒,尤指人類巨細胞病毒之感染。
基於根據本發明化合物之醫藥性質,其可單獨使用或若需要時,可與其他其他活性化合物組合使用,特定言之抗病毒活性化合物,如,例如:甘昔洛飛(gancyclovir)或阿昔洛飛(acyclovir),用於治療與/或預防病毒感染,特定言之HCMV感染。
本發明進一步提供以根據本發明化合物於治療與/或預防疾病上之用途,較佳為用於病毒感染,特定言之人類巨細胞病毒(HCMV)或疱疹病毒科之另一種代表性病毒之感染。
本發明進一步提供根據本發明化合物於治療與/或預防疾病,特定言之如上述疾病上之用途。
本發明進一步提供以根據本發明化合物於製造醫藥,供治療與/或預防疾病,尤指如上述疾病上之用途。
本發明進一步提供一種治療與/或預防疾病,特定言之如上述疾病之方法,其係使用抗病毒有效量之根據本發明化合物。
根據本發明化合物可全身與/或局部作用。為了此目的,其可依適當方式投藥,如,例如:經口、非經腸式、肺、鼻、舌下、舌、頰、直腸、皮膚、穿皮式、結膜或耳朵途徑,或呈植入物或人工支架。
本發明化合物可依適合此等途徑之投藥型式投藥。
適合經口投藥之型式可依據先前技藝產生功能,以迅速與/或改良之方式傳送本發明化合物,其中包含結晶型與/或非晶型與/或溶解型之本發明化合物,如,例如:錠劑(無包衣或有包衣錠劑,例如:包覆腸溶性包衣或不可溶解或延緩溶解並控制釋出本發明化合物之包衣);可於口中迅速崩解之錠劑,或膜衣/扁片、膜衣/冷凍乾燥物、膠囊(例如:硬性或軟性明膠囊)、糖衣錠、粒劑、丸劑、粉劑、乳液、懸浮液、氣霧劑或溶液。
非經腸式投藥法可避開吸收步驟(例如:靜脈內、動脈內、心臟內、脊柱內、或腰內)或包括吸收步驟(例如:肌內、皮下、皮內、經皮膚或腹膜內)。適合非經腸式之投藥型式特別為注射用與輸液用之溶液、懸浮液、乳液、冷凍乾燥物或無菌粉末等製劑。
適合其他投藥途徑之實例為例如:吸入用劑型(特別指粉末吸入劑、霧化劑)、鼻用滴液/溶液/噴液;舌、舌下或頰內投藥用錠劑、膜衣/扁片或膠囊、栓劑、眼或耳用製劑、陰道用膠囊、水性懸浮液(洗液、搖溶性混合物)、親脂性懸浮液、油膏、乳霜、穿皮式醫療系統、乳液、糊劑、泡沫狀物、細粉劑、植入物或人工支架。
根據本發明化合物可轉化成上述投藥型。其可依本身已知方式,與惰性、無毒性之醫藥上可接受之輔劑混合。此等輔劑特別包括載劑(例如:微晶纖維素、乳糖、甘露糖醇)、溶劑(例如:液態聚乙二醇)、乳化劑與勻散劑或濕化劑(例如:十二烷基硫酸鈉、聚氧山梨糖醇酐油酸酯)、結合劑(例如:聚乙烯吡咯啶酮)、合成與天然聚合物(例如:白蛋白)、安定劑(例如:抗氧化劑如,例如:抗壞血酸)、著色劑(例如:無機色素如,例如:氧化鐵)與味道與/或氣味遮蔽劑。
本發明進一步提供一種醫藥,其包含至少一種本發明化合物,通常與一種或多種惰性、無毒性醫藥上可接受之輔劑共同使用,並有關其於上述目的之用法。
通常已證實有利之投藥法為經靜脈內投與劑量約0.001至10毫克/公斤體重,較佳約0.01至5毫克/公斤體重,以達到有效結果,且口服劑量為約0.01至25毫克/公斤體重,較佳為0.1至10毫克/公斤體重。
然而若適當時,可能有必要隨體重、投藥途徑、對活性成分之個別反應、製劑之模式及進行投藥之時間或間隔等偏離上述劑量。因此,有時候低於上述最低劑量可能即已足夠,而其他時候則可能必需超過上述上限。若投與較大劑量時,建議分成幾個較小劑量在一天中投藥。
下列試驗與實例中數據百分比,除非另有說明,否則百分比以重量計;份量比以重量計。液體/液體溶液中之溶劑比例、稀釋比例與濃度數據分別以體積計。
所採用之縮寫BINAP 2,2’-雙(二苯基膦基)-1,1’-聯萘Ex. 實例CD3
CN 氘乙腈TLC 薄層層析法DCI 直接化學離子化(MS)DCM 二氯甲烷DIEA N,N-二異丙基乙胺(亨尼氏鹼)DMAP 4-N,N-二甲基胺基吡啶DMF N,N-二甲基甲醯胺DMSO 二甲亞碸EDCIx HCl N’-(3-二甲基胺基丙基)-N-乙基碳化二亞胺鹽酸鹽EA 乙酸乙酯EI 電子撞擊離子化(MS)ESI 電噴灑離子化(MS)m.p. 熔點sat. 飽和h 小時HATU O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽HBTU O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽HPLC 高壓高效液相層析法conc. 濃縮LC-MS 與液相層析法偶合之質譜LDA 二異丙基胺化鋰lit. (參考)文獻sol. 溶液MS 質譜NMR 核磁共振光譜RP-HPLC 逆相HPLC RT 室溫Rt 滯留時間(HPLC)TBTU O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓四氟硼酸鹽THF 四氫呋喃dil. 稀釋aqu. 水溶液
方法1(LC-MS)
:儀器:Micromass Platform LCZ加裝HPLC Agilent系列1100;管柱:Thermo HyPURITY Aquastar 3μ50 mm x 2.1 mm;移動相A:1升水+0.5毫升50%濃度之甲酸,移動相B:1升乙腈+0.5毫升50%濃度之甲酸;梯度:0.0分鐘100%A→0.2分鐘100%A→2.9分鐘30%A→3.1分鐘10%A→5.5分鐘10%A;烘箱:50℃;流速:0.8毫升/分鐘;UV檢測:210 nm
方法2(LC-MS)
:儀器:Micromass Quattro LCZ加裝HPLC Agilent系列1100;管柱:Phenomenex Synergi 2μHydro-RP Mercury 20 mm x 4 mm;移動相A:1升水+0.5毫升50%濃度之甲酸,移動相B:1升乙腈+0.5毫升50%濃度之甲酸;梯度:0.0分鐘90%A→2.5分鐘30%A→3.0分鐘5%A→4.5分鐘5%A;流速:0.0分鐘1毫升/分鐘,2.5分鐘/3.0分鐘/4.5分鐘2毫升/分鐘;烘箱:50℃;UV檢測:208-400 nm
方法3(LC-MS)
:儀器:Micromass Platform LCZ加裝HPLC Agilent系列1100;管柱:Phenomenex Synergi 2μHydro-RP Mercury 20 mm x 4 mm;移動相A:1升水+0.5毫升50%濃度之甲酸,移動相B:1升乙腈+0.5毫升50%濃度之甲酸;梯度:0.0分鐘90%A→2.5分鐘30%A→3.0分鐘5%A→4.5分鐘5%A;流速:0.0分鐘1毫升/分鐘,2.5分鐘/3.0分鐘/4.5分鐘2毫升/分鐘;烘箱:50℃;UV檢測:210 nm
方法4(LC-MS)
:MS儀器機型:Micromass ZQ;HPLC儀器機型:Waters Alliance 2795;管柱:Phenomenex Synergi 2μHydro-RP Mercury 20 mm x 4 mm;移動相A:1升水+0.5毫升50%濃度之甲酸,移動相B:1升乙腈+0.5毫升50%濃度之甲酸;梯度:0.0分鐘90%A→2.5分鐘30%A→3.0分鐘5%A→4.5分鐘5%A;流速:0.0分鐘1毫升/分鐘,2.5分鐘/3.0分鐘/4.5分鐘2毫升/分鐘;烘箱:50℃;UV檢測:210nm
方法5(LC-MS)
:MS儀器機型:Micromass ZQ;HPLC儀器機型:HP 1100系列;UV DAD;管柱:Phenomenex Synergi 2μHydro-RP Mercury 20 mm x 4 mm;移動相A:1升水+0.5毫升50%濃度之甲酸,移動相B:1升乙腈+0.5毫升50%濃度之甲酸;梯度:0.0分鐘90%A→2.5分鐘30%A→3.0分鐘5%A→4.5分鐘5%A;流速:0.0分鐘1毫升/分鐘,2.5分鐘/3.0分鐘/4.5分鐘。2毫升/分鐘;烘箱:50℃;UV檢測:210 nm
方法6(LC-MS)
:MS儀器機型:Micromass ZQ;HPLC儀器機型:HP 1100系列;UV DAD;管柱:Grom-Sil 120 ODS-4 HE 50 mm x 2 mm,3.0 μm移動相A:水+500微升50%濃度之甲酸/升,移動相B:乙腈+500微升50%濃度之甲酸/升;梯度:0.0分鐘0%B→2.9分鐘70%B→3.1分鐘90%B→4.5分鐘90%B;烘箱:50℃;流速:0.8毫升/分鐘;UV檢測:210 nm
方法7(LC-MS)
:MS儀器機型:Micromass ZQ;HPLC儀器機型:Waters Alliance 2795;管柱:Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 mm;移動相A:水+500微升50%濃度之甲酸/升;移動相B:乙腈+500微升50%濃度之甲酸/升;梯度:0.0分鐘10%B→3.0分鐘95%B→4.0分鐘95%B;烘箱:35℃;流速:0.0分鐘1.0毫升/分鐘→3.0分鐘3.0毫升/分鐘→4.0分鐘3.0毫升/分鐘;UV檢測:210 nm
方法8(LC-MS)
:儀器:Micromass Quattro LCZ,加裝HPLC Agilent系列1100;管柱:Grom-SIL120 ODS-4 HE,50 mm x 2.0 mm,3 μm;移動相A:1升水+1毫升50%濃度之甲酸,移動相B:1升乙腈+1毫升50%濃度之甲酸;梯度:0.0分鐘100%A→0.2分鐘100%A→2.9分鐘30%A→3.1分鐘10%A→4.5分鐘10%A;烘箱:55℃;流速:0.8毫升/分鐘;UV檢測:208-400 nm
方法9(GC-MS)
:儀器:Micromass GCT,GC6890;管柱:Restek RTX-35MS,30 m x 250 μm x 0.25 μm;恆定氦氣流速:0.88毫升/分鐘;烘箱:60℃;入口:250℃;梯度:60℃(維持0.30分鐘),50℃/分鐘→120℃,16℃/分鐘→250℃,30℃/分鐘→300℃(維持1.7分鐘)
方法10(分析級HPLC)
:管柱:Kromasil 100 RP-18,60 mm x 2.1 mm,3.5μm;移動相A:水+0.5%過氯酸(70%濃度),移動相B:乙腈;梯度:0分鐘2%B,0.5分鐘2%B,4.5分鐘90%B,9分鐘90%B,9.2分鐘2%B,10分鐘2%B;流速:0.75毫升/分鐘;管柱溫度:30℃;檢測:UV 210 nm
實例1A
1-苯甲基-1H-咪唑-2-羧酸乙酯
取148克(936毫莫耳)1-苯甲基-1H-咪唑懸浮於480毫升乙腈中,於-20℃下添加120毫升(87.1克;860毫莫耳)三乙基胺。以15分鐘時間,滴加211.2毫升(239克;2208毫莫耳)氯甲酸乙酯。反應混合物於-20℃下攪拌10分鐘。回升至15至20℃後,攪拌反應混合物18小時後,減壓濃縮。添加水、飽和氯化鈉溶液與飽和碳酸氫鈉溶液至殘質中,以乙酸乙酯萃取3次。合併之有機相經飽和氯化鈉溶液洗滌,經硫酸鎂脫水後,減壓濃縮,殘質於高度真空下分餾(沸點=173至181℃,壓力=1.7至1.2毫巴)。
收量:122.6克(理論值之46%)LC-MS(方法4):Rt
=1.71分鐘。
MS(ESI+
):m/z=231[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=7.6(s,1H),7.4-7.1(m,6H),5.2(s,2H),4.25(q,2H),1.25(tr,3H)ppm。
實例2A
咪唑-2-羧酸乙酯
取34.7克(150.9毫莫耳)1-苯甲基-1H-咪唑-2-羧酸乙酯溶於1005毫升乙醇中,添加34克甲酸銨。反應混合物於回流下加熱約6小時。分少量添加共8克10%鈀-碳與18克甲酸銨。冷卻,濾出觸媒,濾液減壓濃縮。產物於此操作期間結晶析出,與80毫升冰-水磨製,抽吸過濾。
收量:15.9克(理論值之75%)
MS(ESI+
):m/z=141[M+H]+
1
H-NMR(200MHz,DMSO-d6
):δ=13.3(s寬,1H),7.4(s,1H),7.15(s,1H),4.3(q,2H),1.3(tr,3H)ppm。
實例3A
4-硝基-1H-咪唑-2-羧酸乙酯
於冰冷卻下,取16.08克(114.7毫莫耳)咪唑-2-羧酸乙酯溶於71.7毫升濃硫酸中。然後滴加71.7毫升100%濃度發煙硝酸。反應溶液於50至60℃下攪拌3小時後,冷卻,倒至800毫升冰/水混合物上。抽吸過濾沉澱晶體,以1500毫升冰-水洗滌。
收量:15克(理論值之70%)
MS(ESI+
):m/z=186[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=14.5(s寬,1H),8.5(s,1H),4.4(q,2H),1.35(tr,3H),ppm。
實例4A
4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1-(環丙基甲基)-1H-咪唑-2-羧酸
步驟1
1-(環丙基甲基)-4-硝基-1H-咪唑-2-羧酸乙酯
於氬氣下,由15克(81毫莫耳)4-硝基-1H-咪唑-2-羧酸乙酯與13.13克(97.2毫莫耳)環丙基甲基溴化物及22.4克(162毫莫耳)碳酸鉀於165毫升DMF中,於80℃下攪拌1小時。冷卻後,反應混合物加水稀釋,以乙酸乙酯萃取4次。合併之有機相以水洗滌一次,以飽和氯化鈉溶液洗滌3次,經硫酸鎂脫水後,減壓濃縮。結晶之殘質直接用於下一個反應。
收量:17.59克(理論值之70%)LC-MS(方法2):Rt
=2.02分鐘。
MS(ESI+
):m/z=240[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.2(s,1H),4.4(q,2H),4.3(d,2H),1.4(m,4H),0.55(q,2H),0.45(q,2H)ppm。
步驟2
4-胺基-1-(環丙基甲基)-1H-咪唑-2-羧酸乙酯
取3.89克(16.26毫莫耳)1-(環丙基甲基)-4-硝基-1H-咪唑-2-羧酸乙酯溶於50毫升THF中,添加藥匙匙尖量之阮來鎳。於氫化器中,反應混合物使用氫氣,於室溫下氫化。濾出觸媒,濾液減壓濃縮。蒸發後之殘質直接用於下一個反應。
收量:3.46克(理論值之100%)LC-MS(方法3):Rt
=1.21分鐘。
MS(ESI+
):m/z=210[M+H]+
1
H-NMR(300MHz,DMSO-d6):δ=6.55(s,1H),4.55(s,2H),4.2(q,2H),4.1(d,2H),1.25(tr,3H),1.2(m,1H),0.5(q,2H),0.3(q,2H)ppm。
步驟3
4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1-(環丙基甲基)-1H-咪唑-2-羧酸乙酯
於氬氣下,添加6克(35.8毫莫耳)異氰酸3-氯-4-苯基酯至含7.49克(35.8毫莫耳)4-胺基-1-(環丙基甲基)-1H-咪唑-2-羧酸乙酯之18毫升THF溶液中,於室溫下攪拌混合物4小時。反應混合物減壓濃縮,產物自混合物中結晶,與40毫升乙酸乙酯磨製及抽吸過濾。
收量:11.1克(理論值之82%)LC-MS(方法2):Rt
=2.66分鐘。
MS(ESI+
):m/z=376[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.45(s,1H),8.0(d,1H),7.35(s,1H),7.3(d,1H),7.2(dd,1H),4.3(q,2H),4.25(d,2H),2.25(s,3H),1.3(tr,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm。
步驟4
4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1-(環丙基甲基)-1H-咪唑-2-羧酸
取10.6克(28.1毫莫耳)4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1-(環丙基甲基)-1H-咪唑-2-羧酸乙酯懸浮於158毫升乙醇中。在冰冷卻下,添加16.4毫升水與6毫升(112毫莫耳)50%濃度氫氧化鈉水溶液。於室溫下攪拌反應混合物1小時後,減壓濃縮。殘質溶於100毫升異丙醇中,於冰冷卻下添加100毫升1N鹽酸。抽吸過濾結晶,於40℃下減壓乾燥。
收量:9.85克(理論值之100%)LC-MS(方法4):Rt
=1.74分鐘。
MS(ESI+
):m/z=349[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=9.4(s,1H),8.0(d,1H),7.3(s,1H),7.25(d,1H),7.2(dd,1H),4.25(d,2H),2.25(s,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm。
實例5A
1-(環丙基甲基)-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
其製法係類似實例4A之方法進行。
收量:10.2克(理論值之93%)LC-MS(方法4):Rt
=1.87分鐘。
MS(ESI+
):m/z=385[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.6(s,1H),8.4(s,1H),7.55(d,2H),7.4(s,1H),7.25(d,2H),4.25(d,2H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm。
實例6A
1-丁基-4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1H-咪唑-2-羧酸
其製法係類似實例4A之方法進行。
收量:2.2克(理論值之93%)LC-MS(方法4):Rt
=1.83分鐘
MS(ESI+):m/z=351[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.35(s,1H),8.0(d,1H),7.3(s,1H),7.25(d,1H),7.2(dd,1H),4.35(tr,2H),2.25(s,3H),1.7(quintet,2H),1.25(sextet,2H),0.9(tr,3H)ppm。
實例7A
1-丁基-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
其製法係類似實例4A之方法進行。
收量:2.05克(理論值之96%)LC-MS(方法4):Rt
=1.96分鐘。
MS(ESI+
):m/z=387[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.0(s,1H),8.9(s,1H),7.55(d,2H),7.3(s,1H),7.25(d,1H),4.35(tr,2H),1.7(quintet,2H),1.25(sextet,2H),0.9(tr,3H)ppm。
實例8A
4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1-[4-(三氟甲基)苯甲基]-1H-咪唑-2-羧酸
類似實例4A之方法製備。
收量:15.2克(理論值之100%)LC-MS(方法2):Rt
=2.46分鐘。
MS(ESI+
):m/z=489[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.15(s,1H),9.05(s,1H),7.75(d,2H),7.55(d,2H),7.45(s,1H),7.35(d,2H),7.25(d,2H),5.7(s,2H)ppm。
實例9A
4-({[(4-氯-2-甲基苯基)胺基]羰基}胺基)-1-[4-(三氟甲基)苯甲基]-1H-咪唑-2-羧酸
類似實例4A之方法製備。
收量:15.6克(理論值之100%)LC-MS(方法4):Rt
=2.23分鐘。
MS(ESI+
):m/z=453[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.5(s,1H),7.95(d,1H),7.75(d,2H),7.4(d,2H),7.35(s,1H),7.25(s,1H),7.15(d,1H),5.75(s,2H),2.25(s,3H)ppm。
實例10A
1-甲基-4-硝基-1H-咪唑-2-羧酸乙酯
取6.80克(36.7毫莫耳)4-硝基-1H-咪唑-2-羧酸乙酯溶於140毫升丙酮中,添加11.2克(80.8毫莫耳)碳酸鉀與4.57毫升(73.5毫莫耳)碘甲烷。混合物於60℃攪拌4小時。依據TLC(環己烷/乙酸乙酯2:1),起始物已完全轉化。冷卻後,過濾混合物,殘質經二氯甲烷洗滌,排除濾液之溶劑。所得固體減壓乾燥。
收量:7.0克(理論值之95%)LC-MS(方法5):Rt
=1.40分鐘。
MS(ESI+
):m/z=200[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.64(s,1H),4.35(q,2H),3.99(s,3H),1.34(t,3H)
實例11A
4-胺基-1-甲基-1H-咪唑-2-羧酸乙酯
取0.50克(2.5毫莫耳)1-甲基-4-硝基-1H-咪唑-2-羧酸乙酯溶於7.5毫升乙醇中,添加0.13克(0.13毫莫耳)鈀-碳(10%),混合物於3巴下氫化12小時。反應溶液經矽藻土過濾,濾液濃縮。殘質減壓乾燥,其未再純化即用於下一個反應。
收量:0.42克(理論值之99%)LC-MS(方法1):Rt
=1.59分鐘。
MS(ESI+
):m/z=170[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=6.47(s,1H),4.55(bs,2H),4.19(q,2H),3.80(s,3H),1.28(t,3H)。
實例12A
1-甲基-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸乙酯
於氬氣下,添加1.46克(7.21毫莫耳)4-(三氟甲氧基)苯基異氰酸酯至含1.22克(3.61毫莫耳)4-胺基-1-甲基-1H-咪唑-2-羧酸乙酯(類似實例4A步驟3,或依據Tetrahedron Lett.2003,44,1607與其中文獻說明之方法合成)之50毫升THF中,於室溫下攪拌混合物一夜。反應混合物過濾,濾液減壓濃縮,經層析法純化。
收量:860毫克(理論值之62%)LC-MS(方法5):Rt
=2.41分鐘。
MS(ESI+
):m/z=373[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.98(bs,2H),7.55(m,2H),7.36(s,1H),7.29(m,2H),4.28(q,2H),3.91(s,3H),1.30(t,3H)。
實例13A
1-甲基-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
取835毫克(2.13毫莫耳)1-甲基-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸乙酯懸浮於5毫升乙醇與12毫升四氫呋喃中。在冰冷卻下,添加2毫升(25毫莫耳)50%濃度氫氧化鈉水溶液。於室溫下攪拌反應混合物一夜後,以冰冷卻,以1N鹽酸酸化。溶液經二氯甲烷萃取。有機相減壓濃縮。殘質經製備性HPLC純化。
收量:346毫克(理論值之44%)LC-MS(方法4):Rt
=1.62分鐘。
MS(ESI+
):m/z=345[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=9.33(bs,1H),8.98(bs,1H),7.55(m,2H),7.30(s,1H),7.28(m,2H),3.90(s,3H),。
實例14A
1-(5-甲基吡啶-2-基)哌
步驟1
1-(第三丁基氧羰基)-4-(5-甲基吡啶-2-基)哌
在氬蒙氣下,取2.50克(19.6毫莫耳)2-甲基-5-氯吡啶與4.38克(23.5毫莫耳)N-(第三丁基氧羰基)哌溶於50毫升無水甲苯中。添加2.26克(23.5毫莫耳)第三丁醇鈉、0.37克(0.59毫莫耳)BINAP與0.36克(0.39毫莫耳)參(二亞苯甲基丙酮)二鈀。混合物於70℃下加熱12小時。冷卻後,添加乙醚至反應混合物中,混合物經飽和氯化鈉溶液洗滌3次,經硫酸鈉脫水,減壓排除溶劑。殘質經急層析法純化(環己烷/乙酸乙酯9:1)。
收量:5.27克(理論值之97%)。
LC-MS(方法4):Rt
=1.26分鐘。
MS(ESI+
):m/z=278[M+H]+
1
H-NMR(300MHz,CDCl3
):δ=8.02(d,1H),7.34(dd,1H),6.59(d,1H),3.55(m,4H),3.45(m,4H),2.21(s,3H),1.49(s,9H)。
步驟2
1-(5-甲基吡啶-2-基)哌
取3.47克(12.5毫莫耳)1-(第三丁基氧羰基)-4-(5-甲基吡啶-2-基)哌溶於10毫升二烷中,添加31毫升(125毫莫耳)鹽酸之二烷溶液(4莫耳濃度)。於室溫下攪拌混合物2小時。混合物濃縮及殘質經1M氫氧化鈉水溶液調成鹼性後,以二氯甲烷重覆萃取。合併之有機相經硫酸鈉脫水,濃縮與減壓乾燥。
收量:2.18克(理論值之98%)。
LC-MS(方法5):Rt
=0.38分鐘。
MS(ESI+
):m/z=177[M+H]+
1
H-NMR(300MHz,CDCl3
):δ=8.02(d,1H),7.32(dd,1H),6.59(d,1H),3.45(m,4H),3.00(m,4H),2.20(s,3H)。
實例15A
1-乙基-4-[({[4-(三氟甲氧基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
類似實例13A之方法進行製備。
收量:425毫克(理論值之91%)LC-MS(方法5):Rt
=1.94分鐘。
MS(ESI+
):m/z=359[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=10.3(bs,1H),7.67(m,2H),7.24(s,1H),7.20(m,2H),4.45(q,2H),1.33(t,3H)。
實例16A
1-丁基-4-[({[4-(三氟甲基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
類似實例13A之方法製備。
收量:1.71克(理論值之90%)LC-MS(方法2):Rt
=2.13分鐘。
MS(ESI+
):m/z=371[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=9.30(bs,1H),9.03(bs,1H),7.64(m,4H),7.36(s,1H),4.35(t,2H),1.68(quintet,2H),1.26(sextet,2H),0.89(t,3H)。
實例17A
1-(5-氟吡啶-2-基)哌
取500毫克(2.84毫莫耳)2-溴-5-氟吡啶與1.22克(14.2毫莫耳)哌於150℃下攪拌加熱24小時。冷卻後,減壓蒸餾排除過量哌(球管蒸餾,1.5毫巴,120℃)。殘質經急驟層析法純化(二氯甲烷/乙醇/濃氨水溶液,30:1:0.1)。
收量:267毫克(理論值之52%)LC-MS(方法9):Rt
=8.07分鐘。
MS(DCI):m/z=182[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.07(d,1H),7.48(td,1H),6.82(dd,1H),3.32(t,4H),2.78(t,4H)。
實例18A
1-(5-溴吡啶-2-基)哌
類似實例17A之方法製備。
收量:827毫克(理論值之81%)LC-MS(方法1):Rt
=2.02分鐘。
MS(ESI+
):m/z=242[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.15(d,1H),7.65(dd,1H),6.79(d,1H),3.38(m,4H),2.74(m,4H)。
實例19A
1-(5-甲氧基吡啶-2-基)哌
類似實例14A之方法製備。
收量:91毫克(理論值之90%)
1
H-NMR(400MHz,CDCl3
):δ=7.94(d,1H),7.15(dd,1H),6.64(d,1H),3.80(s,3H),3.48(m,4H),3.00(m,4H)。
實例20A
4-[({[4-(二氟甲氧基)苯基]胺基}羰基)胺基]-1-甲基-1H-咪唑-2-羧酸
類似實例13A之方法製備。
收量:964毫克(理論值之81%)HPLC(方法10):Rt
=3.57分鐘。
MS(ESI+
):m/z=327[M+H]+
1
H-NMR(400MHz,CDCl3
):δ=8.9(s,1H),8.8(s,1H),7.5(d,2H),7.3(s,2H),7.1(t,1H),7.09(d,2H),3.9(s,3H)。
實例21A
1-[(1-乙基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌
取含1.23克(5.06毫莫耳)1-乙基-4-硝基-1H-咪唑-2-羧酸乙酯(類似實例10A之方法製備)與2.48克(15.2毫莫耳)N-(吡啶-2-基)哌之混合物於100℃下攪拌一夜。操作時,所得粗產物混合物經製備性HPLC純化。得到0.724克(理論值之43%)產物。
HPLC(方法10):Rt
=3.19分鐘。
MS(ESI+
):m/z=331[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.7(s,1H),8.1(m,1H),7.55(m,1H),6.9(d,1H),6.65(dd,1H),4.2(q,2H),3.8(m,4H),3.65(m,2H),3.55(m,2H),1.4(t,3H)。
實例22A
4-[({[4-(二氟甲氧基)苯基]胺基}羰基)胺基]-1-丁基-1H-咪唑-2-羧酸
類似實例13A之方法製備。
收量:1.06克(理論值之71%)HPLC(方法10):Rt
=4.046分鐘。
MS(ESI+
):m/z=369[M+H]+
1
H-NMR(400MHz,CDCl3
):δ=11.1(s,1H),7.7(d,2H),7.1(t,1H),7.05(m,3H),4.5(t,2H),1.7(m,2H),1.3(m,2H),0.9(t,3H)。
實例23A
1-[(1-甲基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌
類似實例21A之方法製備。
收量:4克(理論值之72%)HPLC(方法10):Rt
=2.99分鐘。
MS(ESI+
):m/z=317[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.6(s,1H),8.15(m,1H),7.55(m,1H),6.9(d,1H),6.7(dd,1H),3.9(m,5H),3.8(m,2H),3.7-3.5(m,4H)。
實例24A
1-甲基-4-[({[4-(三氟甲基)苯基]胺基}羰基)胺基]-1H-咪唑-2-羧酸
類似實例13A之方法製備。
收量:168毫克(理論值之99%)HPLC(方法4):Rt
=1.57分鐘。
MS(ESI+):m/z=329[M+H]+
1
H-NMR(400MHz,CDCl3
):δ=9.80(bs,1H),9.18(bs,1H),7.65(m,4H),7.48(s,1H),3.92(s,3H)。
實例1
N-{1-甲基-2-[(4-吡啶-2-基哌-1-基)羰基]-1H-咪唑-4-基}-N'-[4-(三氟甲氧基)苯基]脲
取1.50克(4.36毫莫耳)實例13A溶於30毫升DMF中,添加1.82克(5.66毫莫耳)O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸鹽(TBTU)與266毫克(2.18毫莫耳)4-二甲基胺基吡啶。添加925毫克(5.66毫莫耳)1-(吡啶-2-基)哌後,於室溫下攪拌混合物4小時。反應混合物經RP-HPLC純化。
收量:1.79克(理論值之83%)LC-MS(方法2):Rt
=1.83分鐘。
MS(ESI+
):m/z=490[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.89(bs,2H),8.12(d,1H),7.55(m,3H),7.29(m,2H),7.20(s,1H),6.88(d,1H),6.68(dd,1H),4.02(bs,2H),3.77(s,3H),3.71(bs,2H),3.58(bs,4H)。
實例2
N-(1-甲基-2-{[4-(5-甲基吡啶-2-基)哌-1-基]羰基}-1H-咪唑-4-基)-N'-[4-(三氟甲氧基)苯基]脲
取100毫克(0.29毫莫耳)實例13A溶於2毫升DMF 中,添加139毫克(0.44毫莫耳)O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸鹽(TBTU)與53毫克(0.44毫莫耳)4-二甲基胺基吡啶。添加103毫克(0.58毫莫耳)實例14A後,於室溫下攪拌混合物4小時。反應混合物經RP-HPLC純化。
收量:103毫克(理論值之70%)。
LC-MS(方法5):Rt
=2.01分鐘。
MS(ESI+
):m/z=504[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.92(bs,2H),7.99(d,1H),7.54(m,2H),7.42(dd,1H),7.28(m,2H),7.20(s,1H),6.80(d,1H),4.00(bs,2H),3.77(s,3H),3.72(bs,2H),3.51(bs,4H),2.16(s,3H)。
實例3
N-(2-{[4-(5-氯吡啶-2-基)哌-1-基]羰基}-1-乙基-1H-咪唑-4-基)-N'-[4-(三氟甲氧基)苯基]脲
類似實例2之方法製備。
收量:55毫克(理論值之68%)。
LC-MS(方法5):Rt
=2.76分鐘。
MS(ESI+
):m/z=538[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.97(bs,1H),8.92(bs,1H),8.14(d,1H),7.65(dd,1H),7.54(m,2H),7.28(m,2H),7.24(s,1H),6.92(d,1H),4.16(q,2H),3.97(bs,2H),3.72(bs,2H),3.59(bs,4H),1.32(t,3H)。
實例4
N-(2-{[4-(4-甲氧基苯基)哌-1-基]羰基}-1-甲基-1H-咪唑-4-基)-N'-[4-(三氟甲氧基)苯基]脲
類似實例2之方法製備。
收量:35毫克(理論值之58%)。
LC-MS(方法4):Rt
=2.24分鐘。
MS(ESI+
):m/z=519[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.89(bs,2H),7.53(m,2H),7.28(m,2H),7.19(s,1H),6.92(m,2H),6.84(m,2H),4.05(bs,2H),3.75(m,5H),3.69(s,3H),3.08(bs,4H)。
實例5
N-[4-(二氟甲氧基)苯基]-N'-(1-甲基-2-{[4-(5-甲基吡啶-2-基)哌-1-基]-羰基}-1H-咪唑-4-基)脲
類似實例2之方法,使用實例20A作為起始物製備。
收量:17毫克(理論值之29%)。
LC-MS(方法5):Rt
=1.70分鐘
MS(ESI+
):m/z=486[M+H]+
1
H-NMR(400MHz,DMSO-d6
):δ=8.84(bs,1H),8.77(bs,1H),7.98(d,1H),7.47(m,2H),7.42(dd,1H),7.18(s,1H),7.11(t,1H),7.10(m,2H),6.80(d,1H),4.01(bs,2H),3.77(s,3H),3.71(bs,2H),3.50(bs,4H),2.16(s,3H)。
表1之實例係類似實例2之方法製備。
實例40
N-{1-(環丙基甲基)-2-[(4-吡啶-2-基哌-1-基)-羰基}-1H-咪唑-4-基]-N’-[4-(三氟甲氧基)苯基]脲
取57.6毫克(0.15毫莫耳)實例5A溶於0.5毫升DMF中,添加59.5毫克(0.15毫莫耳)O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽(HBTU)與15毫克(0.15毫莫耳)三乙基胺。添加49毫克(0.3毫莫耳)N-(2-吡啶基)-哌後,於室溫下攪拌混合物16小時。反應混合物經RP-HPLC純化。
收量:46毫克(理論值之58%)LC-MS(方法5):Rt
=2.08分鐘
MS(ESI+
):m/z=530[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.9(s,2H),8.15(d,1H),7.6-7.5(m,3H),7.25(m,3H),6.85(d,1H),6.7(dd,1H),4.05(d,2H),4.00(bs,2H),3.75(bs,2H).3.6-3.5(m,4H),1.75(m,1H),0.5(q,2H),0.35(q,2H)。
表2之實例係類似實例40之方法製備。
實例52
N-(3,5-二氟苯基)-N'-{1-乙基-2-[(4-吡啶-2-基哌-1-基)羰基]-1H-咪唑-4-基}脲
首先,依序添加一藥匙匙尖端量之阮來鎳與11毫克(0.23毫莫耳)肼水合物至含50毫克(0.15毫莫耳)l-[(1-乙基-4-硝基-1H-咪唑-2-基)羰基]-4-(吡啶-2-基)哌之6毫升無水THF中,攪拌混合物1小時。添加硫酸鈉至粗產物溶液中,經矽藻土過濾,濾塊經二氯甲烷洗滌。濾液減壓濃縮,再次溶於6毫升THF中,添加28毫克(0.18毫莫耳)異氰酸二氟苯基酯與2毫克1,4-重氮雙環[2.2.2]辛烷,於室溫下攪拌混合物。1小時後,使用旋轉蒸發器排除溶劑,殘質經製備性HPLC純化。產生20毫克(理論值之29%)產物。
HPLC(方法10):Rt
=3.94分鐘
MS(ESI+
):m/z=456[M+H]+
1
H-NMR(300MHz,DMSO-d6
):δ=8.5(2s,2H),8.1(m,1H),7.55(m,1H),7.25(s,1H),7.15(m,2H),6.9-6.65(m,3H),4.2(q,2H),3.9(m,2H),3.7(m,2H),3.55(m,4H),1.3(t3H)。
表3之實例係類似實例52之方法製備,但實例57則類似實例2之方法製備。
本發明化合物之活體外效應可利用下列分析法證實:抗-HCMV(抗人類巨細胞病毒)細胞致病性試驗
所使用之試驗化合物為含於二甲亞碸(DMSO)之50毫莫耳濃度(mM)溶液。採用甘昔洛飛(ganciclovir)、弗斯卡美(foscamet)與希得飛(cidofovir)作為參考化合物。分別添加2微升50、5、0.5與0.05 mM DMSO母液至第2排A-H中每份98微升細胞培養基中,進行二重覆測定,以50微升培養基稀釋1:2直到96孔分析板之第11排。第1與12排之孔中分別包含50微升培養基。然後吸取150微升1 x 104
個細胞懸浮液(人類包皮纖維母細胞[NHDF])至各孔中(第1排=細胞對照組),第2-12排為感染HCMV之細胞與未感染NHDF之細胞混合物(M.O.I.=0.001-0.002),亦即每1000個未感染細胞包含1-2個感染細胞。第12排(無藥物)作為病毒對照組。最終試驗濃度為250-0.0005μM。分析板於37℃/5%CO下培養6天,亦即直到病毒對照組中所有細胞均感染為止(100%細胞致病效應[CPE])。然後固定凹孔,添加福馬林與奇馬賽氏染料(Giemsa's dye)之混合物進行染色(30分鐘),以雙蒸餾水洗滌,於50℃烘箱中乾燥。然後使用懸掛式顯微鏡(Plaque Multiplier,Technomara公司)目視分析。自試驗分析板取得下列數據。
CC50
(NHDF)=與未處理細胞對照組比較時,細胞未出現可見之細胞停滯效應時之最高藥物濃度μM;EC50
(HCMV)=與未處理病毒對照組比較時,抑制CPE(細胞致病效應)達50%時之藥物濃度nM;SI(選擇性指數)=CC50
(NHDF)/EC50
(HCMV)
本發明化合物之代表性活體外數據示於表A:
本發明化合物治療HCMV感染之適當性可由下列動物模式證實:
HCMV異種移植Gelfoam®模式
動物
自育種公司(Bomholtgaard,Jackasn)購得3-4週大之雌性免疫缺乏症小白鼠(16-18克)。Fox Chase SCID或Fox Chase SCID-NOD或SCID米色。動物單獨置於無菌條件(包括鋪墊與飼料)下。
病毒生長:
使人類巨細胞病毒(HCMV)Davis品系於活體外,在人類胚胎包皮纖維母細胞(NHDF細胞)上生長。5-7天後,當NHDF細胞之感染倍數(M.O.I.)達0.01後,即收集感染病毒之細胞,保存在-40℃下,最基本培養基(MEM)中(含10%胎牛血清(FCS)與10% DMSO)。一系列10倍稀釋感染病毒之細胞後,以中性紅(Neutral Red)進行活體染色或固定後,以福馬林/奇馬賽(Giemsa)混合物(如上述)染色,於24孔分析板上測定融合之NHDF細胞之效價。
海綿之製法、移植、處理與分析
取膠原海綿1x1x1公分規格(Gelfoam,來自Peasel & Lorey,訂購編號407534;K.T.Chong等人說明於”第39屆抗細菌劑與化療法科學交流會議摘要(Abstracts of 39th Interscience Conference on Antimicrobial Agents and Chemotherapy),1999,p.439;P.M.Kraemer等人之Cancer Research 1983,(43):4822-4827)先經磷酸鹽緩衝之生理食鹽水(PBS)沾濕,脫氣以排除其中所含汽泡,然後保存在MEM+10% FCS中。感染3小時後,剝離1x106
個感染病毒之NHDF細胞(感染HCMV Davis M.O.I.=0.01),添加一滴20微升MEM,10% FCS至濕海綿上。12-13小時後,感染之海綿可視需要與25微升PBS/0.1% BSA/1 mM DTT(含5毫微克/微升鹼性纖維母細胞生長因子(bFGF))培養。移植時,以阿弗丁(avertin)或賽拉(xylazine)/亞奇普辛(azepromazine)與氯胺酮(ketamine)之混合物麻醉免疫缺乏症小白鼠,使用刮刀剃除背上毛,打開上皮1-2公分,在無壓力下,將濕海綿移至背部皮膚下。以組合膠密合手術傷口。移植後24小時,小白鼠在連續8天內,經口服接受藥物處理,一天3次(7.00 h與14.00 h與19.00 h),一天2次(8.00 h與17.00 h)或一天一次(14.00 h)。劑量為3或10或30或100毫克/公斤體重,投藥體積為10毫升/公斤體重。藥物調配物成0.5%濃度之泰樂斯(Tylose)懸浮液(可視需要包含2%DMSO)。移植9天後及最後一次投藥後16小時,動物在無痛下殺死後,取出海綿。以膠原酶分解(330 U/1.5毫升),自海綿中釋出感染病毒之細胞,保存在-140℃之MEM下(含10%胎牛血清,10% DMSO)。一系列10倍稀釋感染病毒之細胞後,以中性紅(Neutral Red)進行活體染色或固定後,以福馬林/奇馬賽(Giemsa)混合物(如上述)染色,於24孔分析板上測定融合之NHDF細胞之效價。
與安慰劑處理之對照組比較,測定藥物處理後之感染性病毒粒子數量。
本發明化合物可依下列方式轉化成醫藥製劑:錠劑:組成:
100毫克實例1化合物、50毫克乳糖(單水合物)、50毫克玉米澱粉(未改質)、10毫克聚乙烯吡咯啶酮(PVP 25)(德國(Ludwigshafen市)BASF藥廠)與2毫克硬脂酸鎂。
錠劑重量212毫克。直徑8毫米,彎曲半徑12毫米。
製法:
取含活性成分、乳糖與澱粉之混合物與5%(m/m)PVP水溶液製成顆粒。顆粒乾燥,然後與硬脂酸鎂混合5分鐘。此混合物使用一般壓錠機壓縮(參見上述錠劑規格)。一般指定壓縮力為15kN。
口服用懸浮液:組成:
1000毫克實例1化合物、1000毫克乙醇(96%)、400毫克Rhodigel(黃原膠,來自美國賓州FMC藥廠)與99克水。
10毫升口服懸浮液相當於單一劑量100毫克本發明化合物。
製法:
取Rhodigel黃原膠懸浮於乙醇中,添加活性化合物至懸浮液中。攪拌添加水。攪拌混合物約6小時,至Rhodigel黃原膠完全膨脹為止。
經靜脈內投藥之溶液:組成:
1毫克實例1化合物、15克聚乙二醇400與250克注射用水。
製法:
取實例1化合物與聚乙二醇400共同攪拌溶於水中。溶液經過濾殺菌(孔徑0.22微米),於無菌條件下填裝至經加熱殺菌之輸液瓶中。然後加上輸液瓶塞與旋轉蓋。
Claims (14)
- 一種如下式化合物
- 根據申請專利範圍1項之化合物,其特徵在於R1 代表如下式基團:
- 根據申請專利範圍第1或2項之化合物,其特徵在於R1 代表如下式基團:
- 根據申請專利範圍第1或2項之化合物,其係用於治療或預防病毒感染引起之疾病。
- 一種製備根據申請專利範圍第1項之式(I)化合物之方法,其特徵在於:依據製法[A],由如下式化合物
- 一種醫藥品,其包含根據申請專利範圍第1至3項中任一項之化合物,與至少一種惰性之無毒性,醫藥上可接受之輔劑組合。
- 根據申請專利範圍第6項之醫藥品,其係用於治療或預防病毒感染。
- 根據申請專利範圍第7項之醫藥品,其係用於治療或預防疱疹病毒之病毒感染。
- 根據申請專利範圍第7項之醫藥品,其中該疱疹病毒係人類巨細胞病毒。
- 一種根據申請專利範圍第1至3項中任一項之化合物之用途,係用於於製備治療或預防病毒感染之醫藥品。
- 根據申請專利範圍第10項之用途,其特徵在於該病毒感染係感染人類巨細胞病毒(HCMV)或疱疹病毒科之另一種代表性病毒。
- 根據申請專利範圍第11項之用途,其特徵在於該病毒感染係疱疹病毒感染。
- 根據申請專利範圍第11項之用途,其特徵在於該疱疹病毒係人類巨細胞病毒。
- 一種抗病毒有效量之至少一種根據申請專利範圍第1至3項中任一項之化合物、根據申請專利範圍第6項之醫藥品或根據申請專利範圍第10或11項所得之醫藥品之用途,其係用於製造用於控制人類與動物之病毒感染之醫藥品。
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