TWI532739B - 用於合成n-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法 - Google Patents
用於合成n-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法 Download PDFInfo
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- TWI532739B TWI532739B TW101134784A TW101134784A TWI532739B TW I532739 B TWI532739 B TW I532739B TW 101134784 A TW101134784 A TW 101134784A TW 101134784 A TW101134784 A TW 101134784A TW I532739 B TWI532739 B TW I532739B
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- Prior art keywords
- methyl
- phenyl
- thiazol
- pyridyl
- acetamide
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- 238000000034 method Methods 0.000 title claims description 24
- IVZKZONQVYTCKC-UHFFFAOYSA-N bay 57-1293 Chemical compound N=1C(C)=C(S(N)(=O)=O)SC=1N(C)C(=O)CC(C=C1)=CC=C1C1=CC=CC=N1 IVZKZONQVYTCKC-UHFFFAOYSA-N 0.000 title claims description 6
- 230000002194 synthesizing effect Effects 0.000 title 1
- OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 claims description 47
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 43
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
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- 239000000203 mixture Substances 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 2-Benzyl-phenyl Chemical group 0.000 claims description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 15
- DZNBZPKZOBDXEL-UHFFFAOYSA-N dicyclohexyl-(2-dicyclohexylphosphanylphenyl)phosphane Chemical compound C1CCCCC1P(C=1C(=CC=CC=1)P(C1CCCCC1)C1CCCCC1)C1CCCCC1 DZNBZPKZOBDXEL-UHFFFAOYSA-N 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
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- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
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- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
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- 125000004429 atom Chemical group 0.000 claims 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
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Description
本發明關於N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺以及其甲磺酸鹽單水化物鹽之經改良之合成方法,所述合成方法是使用硼酸衍生物或硼雜環戊烷(borolane)試劑進行,同時可避免有毒的有機錫化合物;且關於N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之甲磺酸鹽單水化物鹽,所述鹽顯示增加之長期穩定性以及自醫藥組成物中之釋放動力學(release kinetics)。
自EP 1244641 B1中獲知N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之合成方法,且WO 2006/103011 A1揭示了使用包含甲烷磺酸之酸性組分來調配含有經微米尺寸化之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺的錠劑。
本發明之目標在於提供化合物N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺以及穩定鹽之經改良之合成方法,所述化合物以及穩定鹽展現增加之長期穩定性以及經改良之自醫藥調配物中之釋放動力學,以及包括所述鹽且具有經改良之釋放動力學的醫藥調配物。
本發明之目標藉由以下方法之教示而得以實現。本發明之其他有利特徵、態樣以及細節可由本申請案之發明說明、圖式以及實例顯而易見。
本發明提供用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,所述方法是根據以下步驟進行:
步驟A:
使以下通式A*之化合物A:
其中R1表示離去基,以及R2表示具有1至6個碳原子之烷基殘基或具有3至6個碳原子之環烷基殘基,與硼酸衍生物、硼雜環戊烷、硼雜環己烷(borinane)或二硼酸試劑在消除R1-H或R1-B(OR)2且形成化合物A之中間物硼酸衍生物的條件下反應,其中使所述中間物硼酸衍生物接著與以下通式B*之吡啶化合物B:
其中R3表示離去基,在鹼性條件下反應,以直接獲得(4-吡啶-2-基-苯基)乙酸,接著進行純化。
步驟B:
使由步驟A獲得之(4-吡啶-2-基-苯基)乙酸與4-甲基-2-(甲基胺基)-1,3-噻唑-5-磺醯胺反應:
以獲得下式之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺:
本發明亦提供結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水
化物。
本發明亦提供醫藥組成物,所述醫藥組成物含有如上述之結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑。
本發明關於醫藥活性(pharmaceutically active)化合物N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺以及其甲磺酸鹽之經改良且新穎的合成方法。所述經改良之合成方法以與當前技術下舊的已知合成方法相同的化合物為起始物,但藉由使用硼酸衍生物或硼雜環戊烷試劑而組合三個反應步驟。所述改進因避免了兩個分離並純化步驟而使得更容易完成合成且亦能夠增加產率。
如EP 1244641 B1中第21頁所述之舊的已知合成方法以2-溴吡啶為起始物。在步驟1中,製備2-三甲基錫烷基吡啶(2-trimethylstannanylpyridine),產率為(理論產率之)45%至50%。隨後,使2-三甲基錫烷基吡啶與(4-溴苯基)乙酸乙酯反應,以獲得(4-吡啶-2-基-苯基)乙酸乙酯,產率為75%。在第三步驟中,將(4-吡啶-2-基-苯基)乙酸乙酯皂化成(4-吡啶-2-基-苯基)乙酸,產率為理論產率之約95%。因此,如以下所示之當前技術合成方法:
包括3個步驟,總產率為約34%,所述3個步驟包含兩個分離並純化步驟,這些步驟耗時且涉及使用用於萃取並洗滌所需化合物之溶劑以及用於純化所述化合物之配置(arrangement)。
如以下所示之本發明合成方法:
藉由使用硼酸衍生物或硼雜環戊烷或硼雜環己烷試劑來組合三個個別步驟,由此允許在單一階段中合成關鍵中間物(4-吡啶-2-基-苯基)乙酸,總產率為理論產率之約
40%,從而避免了當前技術合成方法中的兩個分離並純化步驟。
作為附加益處,使用含硼試劑與使用有毒的有機錫化合物相比優點在於可由水溶液洗滌容易地移除所得硼酸副產物。相反,有機錫化合物不僅是製程廢料流中已知的問題,而且亦注意到其不良地污染下游合成之所得產物。(4-吡啶-2-基-苯基)乙酸與4-甲基-2-(甲基胺基)-1,3-噻唑-5-磺醯胺反應,產生最終產物,接著將所述最終產物轉化為如以下所示之明確(definite)的甲磺酸鹽單水化物鹽。
因此,本發明關於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺以及其甲磺酸鹽之方法,所述方法是根據以下步驟進行:
步驟A:使以下通式A*之化合物A:
其中R1表示離去基,以及R2表示具有1至6個碳原子之烷基殘基或具有3至6個碳原子之環烷基殘基,與硼酸衍生物、硼雜環戊烷、硼雜環己烷或二硼酸試劑在消除R1-H或R1-B(OR)2且形成化合物A之中間物硼酸衍生物的條件下反應,其中用於所述反應之較佳催化劑為試劑系統乙酸鈀與三乙胺以及三苯基膦或PdCl2(PPh3)2與三乙胺,其中使中間物硼酸衍生物接著與以下通式B*之吡啶化合物B:
其中R3表示離去基,在鹼性條件下反應,以獲得呈相應羧酸鹽之鹼性溶液形式的(4-吡啶-2-基-苯基)乙酸。
藉由在不同pH值下進行簡單洗滌以及澄清過濾步驟,接著較佳藉由用適量鹼將(4-吡啶-2-基-苯基)乙酸之酸性水溶液的pH值適當地調節至3.5-5.0(較佳為3.8-4.7)以便進行沈澱或結晶來純化所得(4-吡啶-2-基-苯基)乙酸。除簡單洗滌以及過濾步驟以外,無需藉由例如再結晶或層析來進一步純化(4-吡啶-2-基-苯基)乙酸或任何中間物。
步驟B:使由步驟A獲得之(4-吡啶-2-基-苯基)乙酸與4-甲基-2-(甲基胺基)-1,3-噻唑-5-磺醯胺反應
以獲得下式之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺:
此後最佳將N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-
基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺轉化(作為步驟C)為迄今未知的N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲磺酸鹽單水化物。需說明的是,WO 2006/103011 A1中揭示了甲磺酸鹽,但未揭示展現經改良之性質的特定單甲磺酸鹽單水化物鹽。
用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之本發明方法可更包括步驟D,步驟D是關於製備所述甲烷磺酸單水化物鹽之醫藥組成物:步驟D:製備結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑的醫藥組成物。
所述醫藥組成物可藉由將結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑混合或摻合在一起來製備。
本發明之方法可更包括在步驟D之後的步驟E:步驟E:向結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑之醫藥組成物中添加乙醯水楊酸、三氟尿苷(trifluridine)、碘苷、膦甲酸(foscarnet)、西多福韋(cidofovir)、苷昔洛韋(ganciclovir)、阿昔洛韋(aciclovir)、
噴昔洛韋(penciclovir)、伐昔洛韋(valaciclovir)及/或泛昔洛韋(famciclovir)。
因此,在步驟E之後獲得含有乙醯水楊酸、三氟尿苷、碘苷、膦甲酸、西多福韋、苷昔洛韋、阿昔洛韋、噴昔洛韋、伐昔洛韋或泛昔洛韋與結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑之組合的醫藥組成物,或含有乙醯水楊酸以及三氟尿苷、或乙醯水楊酸以及碘苷、或乙醯水楊酸以及膦甲酸、或乙醯水楊酸以及西多福韋、或乙醯水楊酸以及苷昔洛韋、或乙醯水楊酸以及阿昔洛韋、或乙醯水楊酸以及噴昔洛韋、或乙醯水楊酸以及伐昔洛韋、或乙醯水楊酸以及泛昔洛韋與結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑之組合的醫藥組成物。因此,本發明亦關於醫藥組成物,所述醫藥組成物含有乙醯水楊酸或阿昔洛韋或噴昔洛韋或乙醯水楊酸以及阿昔洛韋或乙醯水楊酸以及噴昔洛韋,以及結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑。一些供應商使用名稱艾賽可威(acyclovir)替代阿昔洛韋(aciclovir)。
如本文中所用之術語「離去基」為在異質性鍵裂解時
與一對電子一起離去之分子片段。離去基可為陰離子或中性分子。常用陰離子性離去基為鹵離子,諸如Cl-、Br-以及I-,以及磺酸根,諸如對甲苯磺酸根(「甲苯磺酸根」,TsO-)、三氟甲烷磺酸根(「三氟甲磺酸根」,TfO-、CF3SO2O-)、苯磺酸根(benzenesulfonate)(「苯磺酸根(besylate)」,C6H5SO2O-)或甲烷磺酸根(「甲磺酸根」,MsO-)。
以下所示之通式A*
涵蓋在苯基殘基之4位上具有離去基的所有苯乙酸酯。
因此,R1較佳表示-F、-Cl、-Br、-I、-OMs、-OTf以及-OTs。基團「-OMs」是指-O-甲磺酸酯,基團「-OTf」是指-O-三氟甲磺酸酯且基團「-OTs」是指-O-甲苯磺酸酯。
基團R2表示具有1至6個碳原子之烷基殘基或具有3至6個碳原子之環烷基殘基,且較佳為-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H11、-C6H13、環-C3H5、環-C4H7、環-C5H9、環-C6H11。更佳為-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3以及-C5H11。尤其較佳為-CH3、-C2H5、-C3H7以
及-CH(CH3)2。
本文中揭示之本發明合成方法之步驟A中可使用各種硼雜環戊烷以及硼雜環己烷以及相應二硼酸衍生物。較佳為以下通式之硼雜環戊烷:
其中R'以及R"彼此獨立地為任何經取代或未經取代之具有1至10個碳原子之直鏈或分支鏈烷基或具有3至10個碳原子之環烷基,或R'以及R"亦可與硼原子一起形成雜環,其中R'與R"一起形成經取代或未經取代之具有2至10個碳原子之直鏈或分支鏈伸烷基。較佳R'以及R"彼此獨立地表示-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3以及-C5H11。較佳為環狀硼雜環戊烷。
以下硼雜環戊烷、硼雜環己烷以及二硼酸衍生物較佳:
其中Ra、Rb、Rc、Rd、Re以及Rf彼此獨立地表示經取代或未經取代之具有1至10個碳原子之直鏈或分支鏈烷基或具有3至10個碳原子之環烷基。較佳為具有1至6個碳原子之直鏈烷基殘基,且最佳為-CH3、-C2H5、-C3H7以及-CH(CH3)2。
以上含硼化合物之尤其較佳實例為4,4,5,5-四甲基[1,3,2]二氧雜硼雜環戊烷(頻那醇硼烷(pinacolborane))、[1,3,2]二氧雜硼雜環戊烷、[1,3,2]二氧雜硼雜環己烷、5,5-二甲基[1,3,2]二氧雜硼雜環己烷、4,6,6-三甲基[1,3,2]二氧雜硼雜環己烷、4,4,6,6-四甲基[1,3,2]-二氧雜硼雜環己烷、4,4,5,5,6,6-六甲基[1,3,2]-二氧雜硼雜環己烷、二異丙氧基硼烷、六氫苯并[1,3,2]二氧雜硼雜環戊烯、9,9-二甲基-3,5-二氧雜-4-硼雜-三環[6.1.1.62,6]癸烷、6,9,9-三甲基-3,5-二氧雜-4-硼雜-三環[6.1.1.62,6]癸烷、B2Pin2(雙(頻哪醇根基)二硼烷)、雙(新戊基乙二醇根基)二硼以及兒茶酚硼烷。
在步驟A中,使所述硼酸衍生物、硼雜環戊烷、硼雜環己烷或二硼酸試劑與通式A*之化合物A反應以獲得中間物硼雜環戊烷或硼雜環己烷試劑,其未經分離以及純化。可在存在多種有機鹼以及無機鹼,諸如三乙胺(Et3N)、
NaOAc、KOAc以及K3PO4的情況下使用藉由組合鈀鹽(諸如[Pd(OAc)2]以及PdCl2)與三苯基膦(PPh3)、三-鄰甲苯基膦(P(o-Tol)3)、三環己基膦(PCy3)、三-第三丁基膦、1,4-雙(二苯膦基)-丁烷(dppb)以及1,1'-雙(二苯膦基)-二茂鐵(dppf)現場製備之催化劑或預先形成之催化劑(諸如Pd(PPh3)2Cl2、Pd(PPh3)4、法博凱特(Fibrecat)1032以及Pd(dppf)Cl2)來支持此反應。對於所述反應而言,加熱至70℃至150℃,較佳為80℃至130℃,更佳為90℃至110℃之溫度較佳。此外,使用非質子性且較佳非極性溶劑,且較佳使用芳族溶劑,諸如苯或甲苯或二甲苯。
所述步驟A藉由避免使用有毒的有機錫化合物來改良當前技術合成方法,所述有機錫化合物在廢料流純化以及最終作為人類用藥物之實際反應產物中是一個非常棘手的問題。
隨後,使中間物硼酸試劑與通式B*之吡啶基化合物反應,其中R3表示離去基。因此R3表示-F、-Cl、-Br、-I、-OMs、-OTf以及-OTs,且較佳為-Cl或-Br。
用鹼水溶液現場處理相應(4-吡啶-2-基-苯基)乙酸酯以裂解酯鍵聯。在偶合/皂化步驟期間,宜將反應混合物加熱至中等溫度且較佳加熱至40℃至90℃,更佳為45℃至80℃,甚至更佳為50℃至70℃且最佳為55℃至65℃之溫度。
在純化且分離關鍵中間物(4-吡啶-2-基-苯基)乙酸後,獲得(4-吡啶-2-基-苯基)乙酸,產率為理論產率之至少
40%(僅包含一個分離並純化步驟)。
本發明方法之其他優點為:
‧藉由用有機溶劑(甲苯、MIBK、EtOAc、MeTHF等)連續洗滌鹼性產物水溶液以及酸性產物水溶液來進行純化以及Pd移除。
‧藉由木炭/矽藻土處理清除附加的Pd。
‧可藉由中和作用自鹼性水溶液或酸性水溶液中結晶(較佳在50℃至70℃下)。
此後,使(4-吡啶-2-基-苯基)乙酸與下式之4-甲基-2-(甲基胺基)-1,3-噻唑-5-磺醯胺反應:
以上化合物是根據EP 1244641 B1中所揭示之合成方法而製備,以便獲得下式之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺:
在WO 01/47904 A中,使用含HOBT(1-羥基-1H-苯并三唑水化物)之DMF來描述醯胺偶合反應,含HOBT之DMF由於其爆炸特性而一般在按比例增量(up-scaling)期間造成問題。此外,在最佳化過程中,已偵測到溶劑DMF為多種副產物(來自維爾斯麥爾型甲醯化(Vilsmaier type formylations))的形成原因。
在試圖改良偶合條件時,含EDC×HCl(1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽且不含HOBT)之NMP/THF溶劑組合可被成功使用是令人感到驚訝的。因此,較佳用含EDC×HCl(不含HOBT)作為偶合劑之THF/NMP溶劑混合物(比率為10:1至1:1)進行上述方法中之步驟B。隨後自THF/水中再結晶可清除Pd至小於5ppm。對於偶合以及再結晶,可達成高於80%之總產率。
因此,本發明亦關於根據本文中所揭示之合成方法獲得的化合物N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺。
而後,將所述N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺轉化為當前技術下尚未揭示的結晶甲磺酸鹽單水化物鹽。非化學計量甲磺酸
鹽在當前技術下是已知的,但對於明確且化學計量的單甲磺酸鹽單水化物鹽並非如此,其中所述單甲磺酸鹽單水化物鹽為每莫耳當量N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺恰好具有1莫耳當量水以及1莫耳當量甲磺酸根。
因此,本發明是關於化合物N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物且尤其是關於結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物,以及可根據本文中揭示之合成方法獲得以及根據本文中揭示之合成方法獲得的結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物。N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物實質上是純的(純度高於96重量%,較佳高於98重量%且更佳高於99重量%)且為呈規則結晶結構形式之明確的單水化物,亦即1莫耳N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物含有1莫耳水以及1莫耳甲磺酸根陰離子,如圖2以及圖3中所示。
由N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之過飽和溶液以及甲烷磺酸,藉由在控制條件下進行結晶而形成結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙
醯胺甲磺酸鹽單水化物鹽。較佳結晶條件為在高溫下且較佳在30℃至90℃下,更佳在35℃至80℃下,甚至更佳在40℃至70℃下,甚至更佳在45℃至60℃下且最佳在50℃至55℃下,向含有N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之有機溶劑與水之混合物中添加甲烷磺酸,產生N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲磺酸鹽之過飽和溶液。可與水混溶或共溶之有機溶劑較佳,諸如MeOH、EtOH、n-PrOH、i-PrOH、乙腈、THF、丙酮。此外,較佳亦在高溫(如30℃至90℃,較佳為35℃至80℃,更佳為40℃至70℃,甚至更佳為45℃至60℃且最佳為50℃至55℃)下向所述過飽和混合物中添加N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之晶種。對所述混合物進行中速至緩慢攪拌且使所述混合物緩慢冷卻至室溫亦較佳。此外,較佳在高溫下經5分鐘至15分鐘添加甲烷磺酸且在甲烷磺酸添加完成後,將所得混合物保持在所述高溫下0.5小時至5小時且更佳為1小時至2小時。在1小時至5小時內且較佳在2小時至3小時內冷卻至室溫且此後較佳在室溫下再緩慢攪拌混合物1小時。接著,濾出晶體,用乙醇/水洗滌且較佳在真空下在20℃至60℃之溫度下乾燥(較佳始於20℃且止於60℃)。
結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲磺酸鹽單水化物鹽展現增
加之長期穩定性,尤其醫藥組成物具有理想或經改良之釋放動力學,且因此允許製備長期穩定醫藥組成物。與N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]之游離鹼形式相比,結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺單甲磺酸鹽單水化物鹽之長期穩定性較優越。
此外,結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺單甲磺酸鹽單水化物鹽與游離鹼形式或其他鹽相比亦展現多晶穩定性,如可由表1中顯見。多形現象(Polymorphism)是指固體物質以多於一種晶體結構或固體形式存在之能力。
游離鹼形式以及鹽酸鹽及甲苯磺酸鹽形成具有較低熱量以及較低多晶穩定性之水合物。在適度加熱後(約50℃至60℃),水含量降低,由此使得這些鹽以及游離鹼形式在生產以及調配期間極難處理以及加工。相反,單甲
磺酸鹽之水化物可在顯著遠高於100℃的溫度下熱穩定且多晶穩定,如藉由TGA所判定。
N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼在室溫下以四種多晶形式以及一種非晶形式存在。此外,視溶劑而定,可偵測到游離鹼之若干種溶劑化物。當前可獲得之資料無法鑑別熱力學上最穩定之形式,因為由差示掃描熱量測定顯示根據先前技術合成之所有批料均顯示多於一個熔融峰。已研究並比較多種鹽(鹽酸鹽(HCl)、甲磺酸鹽(MsOH)、甲苯磺酸鹽(TsOH))以及游離鹼之物理-化學性質。
N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼之二鹽酸鹽(2×HCl)、二甲磺酸鹽(2×MsOH)、二甲苯磺酸鹽(2×TsOH)以及苯甲酸鹽(1×PhCOOH)不滿足化學計量準則。此外,單鹽酸鹽水化物在儲存期間顯示結晶度降低。此外,游離鹼以及單甲苯磺酸鹽形成熱穩定性較低之水化物,使其不適於製錠。這些結果揭示於以上表1中,其中論述鹽酸鹽、甲苯磺酸鹽以及游離鹼形式之多晶不穩定性。因此,令人驚訝的是,僅本發明之單甲磺酸鹽展現所需多晶穩定性以及熱穩定性,從而允許進行製造、加工以及調配,尤其是以製藥規模。
用於製備結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之一種可能方法為將鹼溶解於體積為其10倍的乙醇/水(1:1)中,在50℃至55℃下經5分鐘至15分鐘添加1.15
當量甲烷磺酸,用0.5莫耳%最終產物種晶,在50℃下老化1小時至1.5小時,且在2.5小時內冷卻至20℃至25℃。
再攪拌1小時後,藉由過濾來分離結晶甲磺酸鹽單水化物且在真空中乾燥,得到產率>95%。藉由使用此程序,可在產率以及純度方面可再現地製備純度高於99%且含有小於2ppm殘餘Pd的N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物。
再者,可製備呈明確且穩定之多晶形式的結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物,此外,應用此製程避免了可溶性較低之游離鹼形式共沈澱。因此,本發明之結晶甲磺酸鹽單水化物不含或實質上不含游離鹼。
本發明之結晶甲磺酸鹽單水化物鹽更在長期穩定性研究中顯示穩定性(作為純API以及在醫藥調配物中),自醫藥組成物中展現增加之釋放動力學,並且引起經改良之生物可用性。
如由展示N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之單晶X射線結構分析的圖2中顯見,在甲磺酸根與質子化吡啶基環之間形成鹽。此外,恰好1莫耳當量水被併入晶體結構中,其中水分子之氫原子與兩個不同甲磺酸鹽分子之氧原子形成氫橋。晶格中的此界定明確位置(well-defined posiiton)(參見圖3)由水僅在高溫(始於160℃)下自晶
體中釋放的事實驗證。因此,本發明化合物為明確的N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之單甲磺酸鹽以及單水化物。
根據本發明之結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物為用於製備用以治療及/或預防疱疹病毒感染及/或預防疱疹病毒傳染之醫藥組成物的有用化合物。對健康志願者進行單次劑量施用以及多次劑量施用所獲得之藥物動力學資料展現較佳的血漿濃度隨時間變化曲線,表明對於每日一次給藥方案或更低頻率的給藥方案(諸如每週一次)的具有長效半衰期。在人類中的血漿濃度超過了以下兩種濃度:活體內以及活體外實驗中所達到的足以有效治療多種動物模型中之疱疹單純型病毒感染的濃度,以及防止細胞培養物中病毒複製的濃度。
令人驚訝的是,發現結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物針對疱疹病毒以及由疱疹病毒(主要是疱疹單純型病毒)所致之感染具有高活性。因此,本發明之結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物尤其適用於治療及/或預防由疱疹單純型病毒所致之疾病及/或防止疱疹病毒傳染。
根據被疱疹單純型病毒(HSV,亞型I以及亞型II)感染的部位將此感染分類為多種病症中的一種感染形式。
口面疱疹病毒感染(其可見症狀通常稱為唇疱疹(cold sores)或熱病性疱疹(fever blisters))會感染面部以及口胺。口面疱疹為最常見的感染形式。生殖器疱疹為第二常見的疱疹單純型病毒感染形式。儘管在高程度上相信生殖器疱疹是僅由HSV-2所致,但生殖器HSV-1感染正在增加。疱疹單純型病毒亦可導致其他病症,諸如疱疹性指頭炎(herpetic whitlow)、外傷性疱疹、眼部疱疹(角膜炎)、腦部疱疹感染腦炎、莫拉雷氏腦膜炎(Mollaret's meningitis)、新生兒疱疹以及有可能導致的貝爾氏麻痹(Bell's palsy)。
此外,本發明是關於結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與消炎劑之組合。尤其較佳為結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與乙醯水楊酸之組合。
此外,本發明是關於結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與抗病毒劑之組合。所述另一抗病毒劑較佳為抗代謝劑且最佳為核苷鹼基(nucleobase)類似物、核苷酸類似物或核苷類似物藥物。若所述另一抗病毒劑適用於對抗疱疹病毒及/或疱疹病毒傳染且是由包括但不限於以下藥物或由以下藥物構成的藥物族群中選出則更佳:三氟尿苷、碘苷、膦甲酸、西多福韋、苷昔洛韋、阿昔洛韋或噴昔洛韋或伐昔洛韋前藥或泛昔洛韋前藥,則更佳。最佳為
結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與阿昔洛韋或噴昔洛韋或前藥伐昔洛韋以及前藥泛昔洛韋之組合。
結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與另一活性劑(如消炎劑、免疫調節劑或抗病毒劑,例如治療性疫苗、siRNA、反義寡核苷酸、奈米粒子或病毒吸收抑制劑,諸如正二十二醇)之組合可於單一醫藥組成物中或於多於一種醫藥組成物中同時投與,其中各組成物均包括至少一種活性劑。
本發明化合物較佳用於製造醫藥組成物,所述醫藥組成物含有結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑。所用結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物不含或實質上不含N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之游離鹼形式。
可在習知固體或液體載劑或稀釋劑以及習知製藥佐劑中用已知方式以合適劑量濃度製備本發明之醫藥組成物。較佳製劑可適於經口施用。這些投藥形式包含例如丸劑、錠劑、膜錠劑、包衣錠劑、膠囊、脂質體調配物、微米調配物(micro-formulation)以及奈米調配物(nano-formulation)、粉劑以及沈積物。
根據本發明之醫藥組成物較佳包括5重量%至70重量%,更佳為10重量%至30重量%的結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物(所有百分比資料均為以醫藥製劑重量計之重量百分比)。以單一劑量計,醫藥組成物通常包括2毫克至600毫克結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物,較佳為5毫克至500毫克,更佳10毫克至300毫克且尤其較佳為20毫克至200毫克。根據本發明之醫藥組成物視情況包括一或多種填充劑,所述填充劑例如是由以下所構成的族群中選出:微晶纖維素、纖維纖維素、磷酸鈣以及甘露醇。根據本發明,較佳使用微晶纖維素以及甘露醇。醫藥組成物宜包括20%至80%,較佳為40%至80%,尤其較佳為45%至70%的微晶纖維素以及1%至40%,較佳為5%至30%,尤其較佳為10%至20%的甘露醇。根據本發明之醫藥製劑可包括至少一種崩解助劑,所述崩解助劑例如是由以下崩解助劑所構成的族群中選出:澱粉、預糊化澱粉、澱粉羥乙酸鹽、交聯聚乙烯吡咯啶酮、羧甲基纖維素鈉(=交聯羧甲纖維素鈉)以及羧甲基纖維素之其他鹽。亦可使用兩種崩解劑之混合物。根據本發明,較佳使用交聯羧甲纖維素鈉。醫藥組成物宜包括3%至35%,較佳為5%至30%且尤其較佳為5%至10%的崩解助劑。本發明之醫藥製劑可包括至少一種由脂肪酸以及其鹽所構成的族群中選出的潤滑劑。根據本發明,使用硬脂酸鎂尤其較佳。
本發明之醫藥組成物可包括流動劑,其可為膠態無水二氧化矽或滑石粉。根據本發明,使用膠態無水二氧化矽尤其較佳。流動劑之用量宜為0.3%至2.0%,尤其較佳為0.4%至1.5%且最佳為0.5%至1%。
本發明之尤其較佳醫藥組成物包括:5%至30%結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物、5%至10%交聯羧甲纖維素鈉、0.5%至0.7%硬脂酸鎂、40%至70%微晶纖維素、10%至20%甘露醇以及0.5%至1%膠態無水二氧化矽。
根據本發明之醫藥組成物可以約20毫克至750毫克結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之每日一次劑量投與有需要之患者,且每日投與一次。根據本發明之醫藥組成物亦可每日三次、每日兩次、每日一次、每週三次、每週兩次或每週一次投與有需要之患者。基於每週三次、每週兩次或每週一次之投藥較佳,且尤其較佳為每週一次投藥,亦即每週一次投與含有400毫克至600毫克本發明N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之醫藥組成物。此外,較佳以較高起始劑量開始投與本發明之甲磺酸鹽單水化物,例如初始單次劑量為400毫克至800毫克且在治療期間以每天或每週100毫克至150毫克之較低劑量繼續投藥。
此外,本發明亦包含用於較佳非經腸施用之醫藥組成
物。其他投藥方式為經真皮施用、皮內施用、胃內施用、皮膚內施用、血管內施用、靜脈內施用、肌肉內施用、腹膜內施用、鼻內施用、陰道內施用、頰內施用、經皮膚(percutan)施用、直腸施用、皮下施用、舌下施用、局部施用或經皮(transdermal)施用。除了典型媒劑及/或稀釋劑以外,所投與之醫藥組成物亦含有結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物作為活性成分。
更佳為用於經真皮施用或經皮施用之結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之局部調配物。較佳局部調配物為皮膚用乳膏、皮膚用洗液、乳液、凝膠、懸浮液、軟膏、油劑、唇膏以及香膏。
調配物中可添加任何習知載劑、佐劑以及視情況選用之其他成分。較佳助劑來源於包括以下助劑或由以下助劑所構成的族群:防腐劑、抗氧化劑、穩定劑、增溶劑以及氣味劑。
軟膏、糊狀物、乳膏以及凝膠可包含至少一種習知載劑,例如動物以及植物脂肪、蠟、石蠟、澱粉、黃蓍、纖維素衍生物、聚乙二醇、矽酮、皂土、矽酸、滑石以及氧化鋅或這些物質之混合物。溶液以及乳液可包含習知載劑,諸如溶劑、增溶劑以及乳化劑,例如水、乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁基乙二醇、油(特定言之,棉籽油、花生油、
玉米油、橄欖油、蓖麻油以及芝麻油)、甘油脂肪酸酯、聚乙二醇以及脫水山梨糖醇脂肪酸酯或這些物質之混合物。懸浮液可包含習知載劑,諸如液體稀釋劑(例如水、乙醇或丙二醇)、懸浮劑(例如乙氧基化異十八醇、聚環氧乙烷以及聚環氧乙烷脫水山梨糖醇酯)、微晶纖維素、皂土、瓊脂以及黃蓍或這些物質之混合物。
本發明組成物可含有轉運結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之脂質粒子。醫藥組成物之調配物亦可含有此類型組成物中常用之佐劑,諸如增稠劑、潤膚劑、保濕劑、界面活性劑、乳化劑、防腐劑、抗發泡劑、香料、蠟、羊毛脂、推進劑以及染料。
本發明醫藥組成物亦可呈醇性凝膠形式,所述醇性凝膠包括結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物以及一或多種低級醇或低級多元醇(諸如乙醇、丙二醇或甘油)以及增稠劑(諸如矽藻土)。油性-醇性凝膠亦包括天然或合成油或蠟。凝膠亦可含有有機增稠劑(諸如阿拉伯膠(Gum arabic)、三仙膠、褐藻酸鈉、纖維素衍生物,較佳為甲基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素)或無機增稠劑(諸如矽酸鋁(諸如皂土)或聚乙二醇與聚乙二醇硬脂酸酯或聚乙二醇二硬脂酸酯之混合物)。
本發明醫藥組成物可含有以下防腐劑:苯氧乙醇、甲
醛溶液、對羥基苯甲酸酯、戊二醇或山梨酸。
作為可使用之醫藥學上可接受之載劑、賦形劑及/或稀釋劑,載劑較佳諸如為惰性載劑,如乳糖、澱粉、蔗糖、纖維素、硬脂酸鎂、磷酸氫鈣、硫酸鈣、滑石、甘露醇、乙醇(液體填充膠囊(liquid filled capsules));合適黏合劑包含澱粉、明膠、天然糖、玉米甜味劑、天然膠以及合成膠(諸如阿拉伯膠(acacia)、褐藻酸鈉、羧甲基纖維素、聚乙二醇以及蠟)、糖(諸如蔗糖)、澱粉(來源於小麥、玉米、稻以及馬鈴薯)、天然膠(諸如阿拉伯膠、明膠以及黃蓍)、海藻衍生物(諸如褐藻酸、褐藻酸鈉以及褐藻酸銨鈣)、纖維素物質(諸如甲基纖維素、羧甲基纖維素鈉以及羥丙基甲基纖維素)、聚乙烯吡咯啶酮以及無機化合物(諸如矽酸鎂鋁);潤滑劑,諸如硼酸、苯甲酸鈉、乙酸鈉、氯化鈉、硬脂酸鎂、硬脂酸鈣或硬脂酸鉀、硬脂酸、高熔點蠟以及其他水溶性潤滑劑,諸如氯化鈉、苯甲酸鈉、乙酸鈉、油酸鈉、聚乙二醇以及D,L-白胺酸;崩解劑(崩解物),諸如澱粉、甲基纖維素、瓜爾膠(guar gum)、改質澱粉(諸如羧甲基澱粉鈉)、天然膠以及合成膠(諸如槐豆膠、刺梧桐樹膠、瓜爾膠、黃蓍膠以及瓊脂)、纖維素衍生物(諸如甲基纖維素以及羧甲基纖維素鈉)、微晶纖維素以及交聯微晶纖維素(諸如交聯羧甲纖維素鈉)、褐藻酸鹽(諸如褐藻酸以及褐藻酸鈉)、黏土(諸如皂土)以及起泡混合物;著色劑、甜味劑、調味劑、防腐劑;助滑劑為例如二氧化矽以及滑石;合適吸附劑為黏土、氧化鋁;合適稀釋劑為非
經腸注射用水或水/丙二醇溶液、果汁、糖(諸如乳糖、蔗糖、甘露醇以及山梨糖醇)、澱粉(來源於小麥、玉米、稻以及馬鈴薯)以及纖維素(諸如微晶纖維素)。
包括以下實例以顯示本發明之較佳實施例。熟習此項技術者應瞭解,以下實例中揭示之技術表示由發明者發現且在實施本發明時起良好作用之技術,且因此可被視為構成用於實施本發明的較佳模式。然而,根據本發明,熟習此項技術者應瞭解,可在不偏離本發明之精神以及範疇的情況下對所揭示之特定實施例中進行許多變化而仍獲得相似或類似的結果。
鑒於此發明描述,熟習此項技術者將顯而易知本發明之各種態樣的其他修改以及替代性實施例。因此,此發明描述應僅被視為說明性的並且是用於教示熟習此項技術者執行本發明之一般方式的目的。應理解,本文中所展示且描述之本發明形式應被視為實施例之實例。其他要素以及材料可替代本文中所說明以及描述之要素以及材料,部件以及製程可顛倒,且本發明之某些特徵可獨立利用,所有這些在一般熟習此項技術者受益於本發明說明後均將顯而易見。可在不偏離如以下申請專利範圍中所描述之本發明精神以及範疇的情況下,對本文中所描述之要素作出變化。
實例
定義:如本文中所用,術語「1體積」是指1公升每公斤各別起始物質(1體積=1公升/公斤各別物質或起始物質)。
實例1:合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸鹽單水化物
步驟1(鈴木-宮浦偶合(Suzuki-Miyaura coupling)以及皂化)
將雙(三苯基膦)氯化鈀(II)(0.010當量)裝入經惰性化之反應器中並且再惰性化。接著,添加甲苯(1.65體積)。在加熱至40℃後,添加三乙胺(3.00當量)。添加乙基-4-溴苯基乙酸酯(1.00當量)於甲苯(0.82體積)中之溶液。將所得懸浮液加熱至90℃至95℃,隨後經60分鐘至90分鐘投配頻哪醇硼烷(1.30當量)。在90℃至95℃下繼續再攪拌至少2小時,隨後藉由HPLC檢查轉化率。冷卻至10℃後,將2-氯吡啶(1.00當量)裝入反應混合物中。接著,添加30% NaOH(6.00當量),接著加熱至55℃至60℃。在此溫度下繼續攪拌至少4小時,隨後藉由HPLC檢查轉化率。在認為轉化已完成後,在約300毫巴下濃縮反應混合物直至收集0.8體積餾出物。將反應混合物用水(2.72體積)稀釋,冷卻至20℃且分離各相。丟棄有機層,同時藉由在20℃下添加33% HCl將水層之pH值調節至pH 1。添加MIBK(2.30體積)以及矽藻土(165公克/公斤)且在20℃下將所得混合物攪拌至少15分鐘,隨後藉由過濾移除固體。相繼用水沖洗反應器以及濾餅且將所合併之濾液轉移回反應器中。分離各相且用MIBK將水層再洗滌2次。用水稀釋後,將酸性產物水溶液加熱至55℃,並且通
過底部以矽藻土封裝且頂部以活性炭封裝之栓塞進行過濾。將矽藻土/木炭栓塞用預先加熱之水(0.5體積,55℃)再洗滌一次且將所合併之濾液裝回反應器中。在20℃下,藉由添加30% NaOH將pH值調節至約3.0,隨後將產物溶液加熱至60℃。再投配NaOH以將pH值調節至4.1至4.3。在60℃下將所得懸浮液攪拌1小時至1.5小時,隨後冷卻至20℃。在此溫度下再攪拌至少1小時後,過濾產物,用水洗滌兩次,在氮氣流中預乾燥且在真空中在50℃至65℃下進行最終乾燥。典型產率:38%至42%。
步驟2(醯胺偶合)
將步驟1之產物(1.00當量)以及4-甲基-2-(甲基胺基)-1,3-噻唑-5-磺醯胺(1.02當量)裝入反應器中。添加THF(7.08體積)以及NMP(1.11體積)。使所得懸浮液冷卻至0℃,隨後經大於90分鐘之時期添加4等份1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(1.23當量)。在0℃下再過至少2小時後,使反應混合物升溫至20℃。在此溫度下再繼續攪拌2小時,隨後藉由HPLC檢查轉化率。接著,在10℃至15℃下在至少5分鐘內將約2%(0.2體積)反應混合物添加至水(12.3體積)中。在10℃至15℃下將所得稀懸浮液攪拌至少1小時,隨後經大於4小時投配其餘反應混合物整體。在10℃至15℃下繼續攪拌至少0.5小時,隨後濾出固體,用水洗滌且在吸濾器上在穩定氮氣流中乾燥,直至認為足夠乾燥為止(LOD<45%(重量/重量);LOD:乾燥失重)。
將粗產物、THF(8.15體積)以及水(至多1.17體積,視粗產物之LOD而定)裝入進料反應器中。將所得懸浮液加熱至60℃至65℃且在此溫度下攪拌1小時。獲得幾乎澄清之溶液,使用加熱至60℃之可加熱透鏡過濾器對其進行精緻過濾。在60℃至65℃下,相繼用THF(0.44體積)與純水(0.06體積)之混合物沖洗進料反應器、輸送管線以及過濾器。將所合併之濾液收集在單獨的反應器中且加熱至50℃至55℃。經至少30分鐘向反應器內含物中投配水(3.23體積)。在50℃至55℃下繼續攪拌1小時至1.5小時,隨後在2小時內緩慢添加另一份水(8.93體積)。在50℃下攪拌1小時至1.5小時後,使所得懸浮液經2.5小時冷卻至5℃並且再攪拌0.5小時。接著,濾出固體,用水(3次,每次2.96體積)洗滌並且在吸濾器上在穩定氮氣流中預乾燥。使用錐形乾燥器在真空中在50℃至65℃下實現最終乾燥。典型產率:78%至83%。
步驟3(鹽形成)
將得自步驟2之產物(1.00當量)、乙醇(4.96體積)以及水(4.96體積)裝入反應器中。在將所得懸浮液加熱至50℃至55℃後,在小於15分鐘內添加甲烷磺酸(1.15當量)。通常在添加完全結束時觀測到起始物質完全溶解。緊接著在接下來的5分鐘內,將攪拌降低至最小可接受速率且用先前實驗中所製備之呈所需多晶形式之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸鹽單水化物(0.005當量)對反應混合物
進行種晶。在50℃至55℃下繼續緩慢攪拌60分鐘至90分鐘,隨後在大於2.5小時期間冷卻至20℃至25℃。再攪拌1小時後,濾出固體,用乙醇/水5:2(體積/體積)(3.10體積)洗滌,在氮氣流中預乾燥且轉移至錐形乾燥器中以供在真空中在20℃至60℃下進行最終乾燥。
典型產率:>95%。
實例2:
錠劑,包括60毫克根據本發明之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(以游離鹼形式計算)作為經微米尺寸化之活性化合物,活性化合物含量為約59%(以無包衣錠劑計):
實例3:
軟膏,包括30毫克根據本發明之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(以游離鹼形式計算)作為經微米尺寸化之活性化合物
結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物,經微米尺
實例4:
凝膠,包括40毫克根據本發明之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(以游離鹼形式計算)作為經微米尺寸化之活性化合物。
實例5:
凝膠,包括40毫克根據本發明之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(以游離鹼形式計算)作為經微米尺寸化之活性化合物。
結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物,經微米尺
實例6:
錠劑,包括50毫克根據本發明之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(以游離鹼形式計算)作為經微米尺寸化之活性化合物,活性化合物含量為約59%(以無包衣錠劑計):
實例7:
N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物的晶體結構
化學式C19H24N4O7S3,M=516.62,F(000)=540,無色片,尺寸0.02×0.13×0.15立方毫米,三斜狀,間
隔基P-1,Z=2,a=9.4908(7)埃,b=9.5545(7)埃,c=14.4137(9)埃,α=86.130(3)°,β=72.104(3)°,γ=68.253(4)°,V=1153.68(15)立方埃,Dcalc.=1.487毫克/立方公尺。在游標(Nonius)KappaCCD繞射計上,在293K下使用石墨-單色Mo Kα放射線(λ=0.71073埃,θmax=30.065°)來量測晶體。最小/最大透射率0.95/0.99,μ=0.370毫米-1。使用克萊科特(COLLECT)套件進行資料收集以及積分。在總共43492次反射中,6761次是獨立的(合併r=0.026)。在這些獨立的反射中,認為觀測到4955次反射(I>3.0σ(I))且用於修正298個參數。使用程式SIR92藉由直接法來解決結構問題。使用程式克瑞斯特爾(CRYSTALS)對所有非氫原子進行針對F之最小二乘法修正。R=0.0313(觀測資料),wR=0.0432(所有資料),GOF=1.0736。最小/最大殘餘電子密度=-0.28/0.33個電子/立方埃。使用契比雪夫(Chebychev)多項式加權來完成所述修正。
N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之單晶結構參數展示於圖1A中。
由X射線粉末繞射分析獲得的批料BXR3NC1之特徵峰展示於表3中。
表3:由X射線粉末繞射分析(Cu K
α
放射線)獲得的批料BXR3NC1之特徵峰。
由於正態偏差為+/-0.1°,因此2-θ值四捨五入至1位小數位
實例8:
將使用游離鹼N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺(游離鹼)進行之重複劑量13週毒性研究中曝露於N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之大鼠的曝露與使用甲磺酸鹽單水化物進行之26週重複劑量毒性研究中所觀測到的曝露進行比較。在兩項研究中,測試物均以0.5%(重量/體積)泰勒纖維素(tylose)懸浮液形式投與,且針對游離鹼N-[5-(胺磺醯基)-4-甲基-1,3-噻唑
-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之當量調節濃度。
在投與第一個劑量後(第1天,第2天;表4)以及在重複劑量投藥13週後(表5),可比較投與10毫克/公斤/天、50毫克/公斤/天以及250毫克/公斤/天後的曝露。
在10毫克/公斤/天之劑量後,指示可能存在更高曝露。應注意觀測到在50毫克/公斤/天以及250毫克/公斤/天之劑量(針對游離鹼當量加以調節)後,與投與游離鹼後之曝露相比,在投與N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲磺酸鹽單水化物後的曝露更高。曝露程度增加多達2.7倍(對於Cmax)以及4倍(對於AUC)。得出以下結論:與投與等分子劑量(50毫克/公斤/天以及250毫克/公斤/天)之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺游離鹼當量後所觀測到的曝露相比,N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲磺酸鹽單水化物引起更高曝露。因此,曝露程度之此種顯著增加表明,甲磺酸鹽改良物理化學性質,從而引起更有利溶解概況,其中伴有全身曝露相對於投與游離鹼後所觀測者有所增加。
因此,在投與甲磺酸鹽後之所述曝露增強意謂達成了針對活性成分之更高曝露,從而產生更大功效以及更高病毒抗性屏障,兩者均被視作治療病毒感染的必要特徵。功效以及抗性屏障均增強被判定為與甲磺酸鹽調配物相關的
主要特徵。
表5:比較大鼠13週毒性(游離鹼)研究與26週毒性(甲磺酸單水化物鹽)研究中第13週之曝露。M,雄性;F,雌性。Cmax為最大觀測分析物濃度;AUC(0-24)定義為給藥後達24小時分析物濃度相對於時間之曲線下面積;藉由線性上升/自然對數下降求和法進行計算
圖1A展示N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物(批料BXR3NC1)之單晶結構參數。
圖1B展示N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物(批料BXR3NC1)之X射線粉末繞射譜圖(由單晶資料計算)。
圖1C展示批料BXR3NC1之N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之量測X射線粉末繞射譜圖(藍線)與N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物之計算X射線粉末繞射譜圖(紅線)的重疊圖。
圖1D展示批料BXR3NC1之量測X射線粉末圖。
圖2展示具有所指示之氫橋的N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物的X射線結構。據顯示,吡啶基環(右側下方)之氮原子經質子化,且在使吡啶基環氮質子化的氫與甲磺酸根陰離子之一個氧之間形成一個氫橋,並且在甲磺酸根陰離子之另一個氧與水分子之氫之間形成另一個氫橋,而水分子之另一個氫與另一個甲磺酸根陰離子之氧形成一個氫橋。
圖3展示N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物在封裝於晶體內時的單晶X射線結構分析,據顯示,苯基吡啶基環系統定向於彼此平行的平面中。
Claims (7)
- 一種用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,所述方法是根據以下步驟進行:步驟A:使以下通式A*之化合物A
- 如申請專利範圍第1項所述之用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,更包括步驟C:使N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺與甲烷磺酸在有機溶劑與水之混合物中轉化成下式之結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物:
- 如申請專利範圍第1項所述之用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,其中R1以及R3彼此獨立地由-F、-Cl、-Br、-I、-O-甲磺酸酯、-O-三氟甲磺酸酯以及-O-甲苯磺酸酯中選出。
- 如申請專利範圍第1項所述之用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,其中為了製備所述化合物A的所述中間物,使用試劑乙酸鈀、三乙胺以及三苯基膦或PdCl2(PPh3)2以及三乙胺。
- 如申請專利範圍第1項所述之用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,其中以1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽作為偶合劑在四氫呋喃/1-甲基吡咯烷-2-酮溶劑混合物中進行步驟B。
- 如申請專利範圍第2項所述之用於合成N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,其中N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺於有機溶劑以及水中之所述混合物在於高溫下添加甲烷磺酸後產生過飽和溶液,所述N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物在長時間攪拌、種晶或冷卻後自所述過飽和溶液中結晶。
- 如申請專利範圍第2項或第6項所述之用於合成 N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法,更包括步驟D:製備所述結晶N-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-N-甲基-2-[4-(2-吡啶基)苯基]乙醯胺甲烷磺酸單水化物與至少一種醫藥學上可接受之載劑、賦形劑、溶劑及/或稀釋劑之醫藥組成物。
Applications Claiming Priority (1)
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EP11007823A EP2573086A1 (en) | 2011-09-26 | 2011-09-26 | N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
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TW201317234A TW201317234A (zh) | 2013-05-01 |
TWI532739B true TWI532739B (zh) | 2016-05-11 |
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TW105109173A TWI567070B (zh) | 2011-09-26 | 2012-09-21 | 結晶n-﹝5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基﹞-n-甲基-2-﹝4-(2-吡啶基)苯基﹞乙醯胺甲烷磺酸單水化物、其組合物、其用途以及包括其的醫藥組成物 |
TW101134784A TWI532739B (zh) | 2011-09-26 | 2012-09-21 | 用於合成n-[5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基]-n-甲基-2-[4-(2-吡啶基)苯基]乙醯胺之方法 |
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TW105109173A TWI567070B (zh) | 2011-09-26 | 2012-09-21 | 結晶n-﹝5-(胺磺醯基)-4-甲基-1,3-噻唑-2-基﹞-n-甲基-2-﹝4-(2-吡啶基)苯基﹞乙醯胺甲烷磺酸單水化物、其組合物、其用途以及包括其的醫藥組成物 |
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US (1) | US9340535B2 (zh) |
EP (3) | EP2573086A1 (zh) |
JP (2) | JP6161614B2 (zh) |
KR (4) | KR20180088530A (zh) |
CN (2) | CN105541829A (zh) |
AR (3) | AR088043A1 (zh) |
AU (2) | AU2012314536B2 (zh) |
BR (1) | BR112014003245B1 (zh) |
CA (1) | CA2791142C (zh) |
CL (1) | CL2014000149A1 (zh) |
DK (2) | DK2598501T3 (zh) |
ES (2) | ES2466221T3 (zh) |
HK (1) | HK1220978A1 (zh) |
HR (1) | HRP20140351T1 (zh) |
IL (2) | IL230152A (zh) |
IN (1) | IN2014DN01993A (zh) |
JO (2) | JO3037B1 (zh) |
MX (2) | MX371088B (zh) |
MY (2) | MY185063A (zh) |
PE (1) | PE20141148A1 (zh) |
PH (1) | PH12015502801B1 (zh) |
PL (2) | PL2602258T3 (zh) |
PT (1) | PT2598501E (zh) |
RU (2) | RU2669388C1 (zh) |
SG (1) | SG10201407430TA (zh) |
TW (2) | TWI567070B (zh) |
UA (2) | UA115317C2 (zh) |
WO (1) | WO2013045479A1 (zh) |
ZA (2) | ZA201401773B (zh) |
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EP2573086A1 (en) * | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
EP2573085A1 (en) | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(aminosulfonyl)-4methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl] acetamide mesylate monohydrate having a specific particle size distribution range and a specific surface area range |
UA123734C2 (uk) * | 2016-04-06 | 2021-05-26 | Інновейтів Молекьюлз Ґмбх | Похідні амінотіазолу, отримані як противірусні засоби |
HUE054845T2 (hu) | 2016-11-28 | 2021-10-28 | Aicuris Gmbh & Co Kg | Az N-[5-(amino-szulfonil)-4-metil-1,3-tiazol-2-il]-N-metil-2-[4-(2-piridinil)fenil]acetamid szabad bázis maleát sója, gyógyászati készítmények, elõállítási eljárások és Herpes vírusok kezelésére történõ alkalmazások |
EP4201934A1 (en) * | 2016-11-28 | 2023-06-28 | AiCuris GmbH & Co. KG | N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate, methods of manufacture and uses thereof |
WO2018095576A1 (en) * | 2016-11-28 | 2018-05-31 | Aicuris Anti-Infective Cures Gmbh | Topical pharmaceutical formulation comprising n-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide |
KR102335327B1 (ko) | 2017-04-28 | 2021-12-03 | 현대자동차 주식회사 | 수냉식 이지알 쿨러 |
NZ760339A (en) * | 2017-06-28 | 2023-06-30 | Aicuris Gmbh & Co Kg | Intravaginally applicable devices comprising antiviral compounds |
UA126163C2 (uk) | 2017-10-05 | 2022-08-25 | Інновейтів Молекьюлз Ґмбх | Енантіомери серії противірусних сполук |
US11964969B2 (en) | 2018-07-06 | 2024-04-23 | Phaeno Therapeutics Co., Ltd | Crystal forms of thiazole compound and application thereof |
CA3113353A1 (en) * | 2018-09-19 | 2020-03-26 | Modernatx, Inc. | High-purity peg lipids and uses thereof |
TW202038947A (zh) | 2018-11-28 | 2020-11-01 | 德商創新分子有限責任公司 | 在與溶瘤病毒之組合療法中治療癌症的解旋酶引子酶抑制劑 |
WO2024047507A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | A novel crystalline form of pritelivir |
WO2024047508A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | Pharmaceutical compositions for herpes virus |
WO2024047506A1 (en) | 2022-08-29 | 2024-03-07 | Assembly Biosciences, Inc. | A novel crystalline form of pritelivir |
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DOP2000000109A (es) * | 1999-12-23 | 2002-08-30 | Gerald Kleymann | Derivados de tiazolilamida |
DE10129716A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Kombinationspräparate zur Herpes-Behandlung |
DE10129717A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Kombinationspräparate zur Herpes-Behandlung |
DE10129714A1 (de) * | 2001-06-22 | 2003-01-02 | Bayer Ag | Topische Anwendung von Thiazolylamiden |
DE10131128A1 (de) * | 2001-06-28 | 2003-01-16 | Bayer Ag | Sekundäre Sulfonamide |
GB0423653D0 (en) * | 2004-10-25 | 2004-11-24 | Piramed Ltd | Pharmaceutical compounds |
DE102005014248A1 (de) | 2005-03-30 | 2006-10-05 | Aicuris Gmbh & Co. Kg | Pharmazeutische Zubereitung von N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamid |
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EP2573085A1 (en) * | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(aminosulfonyl)-4methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl] acetamide mesylate monohydrate having a specific particle size distribution range and a specific surface area range |
EP2573086A1 (en) * | 2011-09-26 | 2013-03-27 | AiCuris GmbH & Co. KG | N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate |
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