TW588047B - Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions - Google Patents

Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions Download PDF

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TW588047B
TW588047B TW087102265A TW87102265A TW588047B TW 588047 B TW588047 B TW 588047B TW 087102265 A TW087102265 A TW 087102265A TW 87102265 A TW87102265 A TW 87102265A TW 588047 B TW588047 B TW 588047B
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Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean Marie Stassen
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Boehringer Ingelheim Pharma
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Priority claimed from DE19706229A external-priority patent/DE19706229A1/de
Priority claimed from DE1997151939 external-priority patent/DE19751939A1/de
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Description

588047 A8 B8 C8 D8 六、申請專利範圍 轰基’苄基氧基羰基,苯甲酸基,p-Cy燒基苯甲 酿基或菸醯基,同時上述(:卜9_烷氧基羰基上2-位的 乙氧基可又以烷基磺醯基或·3_烷氧基)_乙 基取代的, A r指1,4 ·伸苯基,其未經或經氯原子或以甲基,乙 基’或甲氧基取代,或指2,5 -伸。塞吩基,
Het指1-甲基-2,5-苯并伸咪唑基,1 -環丙基-2,5-苯并伸 咪峻基’ 2,5_苯并伸噻唑基,丨-甲基-2,5-伸啕哚基,l 甲基-2,5-咪唑并[4,5-b]伸吡啶基,3-甲基-2,7-咪唑并 [l,2-a]伸吡啶基或丨_甲基-2,5-噻吩并[2,3-d]伸咪唑基, 及 R a指R2NR3-基團,其中 以2是c i·3·烷基(其可以羧基取代),c 1β6-烷基氧基羰 基’苄基氧基羰基,甲基磺醯基胺基羰基,或1Η-四 唑-5 -基, 以藉基取代的(:2_3·烷基,芊基氧基,羧基-Cl-3-烷基 胺基,Cw烷氧基羰基_Ci_3-烷基胺基,n_(Ci3-烷 基)-羧基-C丨烷基胺基或N-(C w烷基)-C ^烷氧 基羰基-C丨·3·烷基胺基,在上述基團中於鄰近氮原子 的α -位的碳原子可以是未經取代的,及 R3指玦丙基,其中不飽和的部分可不直接聯於R2NR3 基團的氮原子上,未經或經氟或氯原子或甲基或甲 氧基取代的苯基,或指吡啶基, 其互變異構物及其鹽。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐).
、申請專利範圍 3.根據申請專利範圍第1項之通式I二取代雙環雜環,其中 A指聯於H e t基團上的苯或噻吩部分上的羰基, B指伸乙基,其中聯於a r基團上的亞甲基可係經-NRi基 團取代的,其中
Ri指氫原子或甲基, E指RbNH-C(=NH)-基團,其中
Rb指氫原子,羥基,Crr烷氧基羰基,環己基氧基 羰基,芊基菸氧基羰基,苯甲醯基,p-C ^3-烷基苯 甲醯基或菸醯基,同時上述Ci-9-烷氧基羰基上2-位 的乙氧基可以是又以曱基磺醯基或2 -乙氧基乙基取 代的, A r指1,4 -伸苯基,其未經或經甲氧基取代,或指2,5-伸屬吩基,
Het指1-甲基-2,5-苯并伸咪唑基,2,5·苯并伸噻唑基, 1-甲基-2,5-伸吲哚基,或1-曱基-2,5-嘍吩并[2,3-(1]伸 咪峻基,及 RJR2NR3-基團,其中 R2是以羧基取代的(:10-烷基,C!_6-烷基氧基羰基, 芊基氧基羰基,甲基磺醯基胺基羰基,或ΙΗ-四唑-5-基, 以羥基取代的C2_3-烷基,苄基氧基,羧基CN3-烷基 胺基’ Ci-3_说氧基談基- Ci-3-坑基胺基’N - ( C 1 _ 3 燒 基)-羧基-c 1-3-烷基胺基或N-(C 1β3·烷基)-C w烷氧 基羰基-C卜3-烷基胺基,在上述基團中於鄰近氮原子 588047 A8 B8 C8 D8 申請專利範園 的α -位的碳原子可以是未經取代的,及 R 3指經或未經氟原子取代的+基或和2 - ρ比唉基, 其' 互變異構物及其鹽。 4·根據申請專利範圍第1項之通式1二取代雙環雜環,其係 選自下列化合物: (a) 2-[N-(4-脒基苯基胺基甲基]•苯并p塞峻-5-幾 酸-N-苯基-N-(2-羧基乙基)-醯胺, (b) 2-[N-(4-脒基苯基)-N-甲基-胺基甲基]•苯并嚷 峻-5-基·幾酸-N-苯基-N-(2-每基談基乙基)-酸胺, U) 1-甲基-2·[Ν-(4-脒基苯基)-胺基甲基]-苯并味 唑-5 -基-羧酸-Ν-苯基-Ν-(2-羥基羰基乙基)·醯胺, (d) 1 -甲基-2- [Ν-(4·脒基苯基)-胺基甲基]-苯并味 唆-5-基-羧酸-Ν-苯基-Ν-(3-羥基羰基丙基)-醯胺, U) 1 -甲基- 2-[Ν-(4_脒基苯基)-胺基甲基]-苯幷味 嗤_5 -基-羧酸-Ν-(2·吡啶基)-Ν-(羥基碳基甲基μ酿 胺, (f) 1 -甲基- 2-[2-(2-脒基苯硫-5 -基)-乙基]-苯并味 唑·5-基-羧酸·Ν-(2-吡啶基)-Ν·(2-羥基羰基乙基)_酸 胺, (g) 1-甲基-2-[N-(4-脒基苯基)·胺基甲基]-苯并味 咬-5-基羧酸-N-(2-吡啶基)·Ν-(2-羥基羰基乙基μ酿 胺, (h) 1 -曱基- 2-[2·(4-脒基苯基)乙基]-苯并咪唑_5_ 基羧酸-Ν-(2-吡啶基)-Ν-(2·羥基羰基乙基)_醯胺, -5- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐). ' -^ 588047 έβ C8 D8 六、申請專利範圍 (i) 1 -甲基- 2-[2-(4·脒基苯基)乙基]-苯并咪唑- 5· 基-羧酸-Ν-苯基-Ν-( 2 -·經基羰基乙基)-醯胺, (j) 1 -甲基- 2-[2-(4-脒基苯基)乙基]-苯并咪唑- 5-基-羧酸-N-苯基-Ν-[2-(1Η-四唑-5-基)乙基]-醯胺, (k) 1 -甲基- 2-[N-(4-脒基苯基)-胺基曱基]-苯并咪 唑-5-基羧酸-N-苯基-Ν-[2-(1Η-四唑-5-基)乙基]-醯 胺, (l) 1-甲基-2-[N-(4-脒基苯基)-N-甲基-胺基甲基]-苯并咪唑-5 -基-羧酸-N-(2-吡啶基)-N-(2 -羥基羰基乙 基)-醯胺, (m) 1-甲基_2-[N-(4-脒基苯基)-Ν·甲基-胺基甲基]-苯并咪唑-5 -基-羧酸-Ν-(3-吡啶基)-N-(2-羥基羰基乙 基)-醯胺, (η) 1-甲基-2-[Ν-(4·脒基苯基)_Ν -甲基-胺基甲基卜 苯并咪唑5 -基-羧酸苯基-Ν-(2-羥基羰基乙基)-醯 胺, (ο) 1 -甲基- 2-[Ν-(4-脒基苯基)-胺基甲基]-苯并咪 唑-5-基羧酸苯基-Ν-[(Ν-羥基羰基乙基-Ν-甲基)-2 -胺基乙基]-酿胺, (ρ) 1 -甲基- 2-[Ν-(4-脒基苯基)-胺基甲基]-苯并咪 唑-5-基-羧酸-Ν-(3 -氟苯基)-Ν-(2-羥基羰基乙基)-醯 胺, (q) 1 -甲基- 2-[N-(4-脒基苯基)-胺基甲基]-苯并咪 唑-5 -基-羧酸-N- (4·氟苯基)-N - ( 2 -羥基羰基乙基)-醯 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 588047 A8 B8 C8
胺, ^甲基β2-[Ν-(4·脒基甲氧基_苯基)·胺基甲 '"并米坐基-&故苯基-N-( 2 -幾基羰基乙 基)-酸胺, (S) ―1·甲基.2-[N-(4-脒基-2·甲氧基·苯基卜胺基甲 ]笨并米嗅· 5 -基-叛酸-N_ (2-p比咬基)-N - (2 -幾基羰 基乙基)-醯胺, (t)丨-甲基·2-[Ν-(4-脒基苯基)胺基甲基卜吲哚_5_ 基·幾酸苯基_Ν•(八甲氧基羰基乙基)_醯胺,及— U)丨-甲基·ΜΝ-(4-脒基苯基)胺基甲基卜噻吩并 [2,3-d]咪唑_5_基羧酸苯基·ν_(2_羥基羰基乙基 醯胺, 土广 其互變異構物及其鹽。 5.根據申請專利範圍第1.項之通式I二取代雙環雜環,其係 1_甲基-2-[ν_(4-脒基苯基)-胺基甲基μ苯并咪唾_5_ 基酸-Ν-苯基_Ν-(2_羥基羰基乙基)_醯胺,及其 鹽0 6·根據申請專利範圍第1項之通式I二取代雙環雜環,其係 1_甲基-2-[Ν-(4-脒基苯基)-胺基甲基μ苯并咪唑_5_ 基-羧酸-Ν-(2-吡啶基)-Ν-(羥基羰基乙基)-醯胺,及 其鹽。 7.根據申請專利範圍第1項之通式I二取代雙環雜環,其係 1-甲基-2-[Ν-(4-脒基-2 -甲氧基-苯基胺基甲基卜苯 并咪唑-5 -基-羧酸-Ν - ( 2 -吡啶基)-Ν ·( 2 -羥基羰基乙 本紙張尺度適用中國國家標準(CNS) Α4規格(210Χ 297公釐). 六、申請專利範圍 基)-酸胺,及其鹽。 8. 根據申請專利範圍第1項之通式I二取代雙環雜環,其係 1-甲基-2-[N-(4-(N_正己基氧基羰基脒基卜苯基)胺基 甲基]-苯并咪唑-5-基-羧酸·Ν-(2-吡啶基)-N-(2 -乙氧 基羰基乙基)_酸胺,及其鹽。 9. 根據申請專利範圍第丨至8項中任一項之通式〗二取代雙 %雜% ’其係生理上可接受的鹽,其中E指RbNH-C(=NH)-基團。 10. 種具有延長凝血酶時間效果、抑制凝血酶效果或對相 關的絲胺酸蛋白酶有抑制效果之醫藥組合物,其包含根 據申請專利範圍第丨至8項中任一項之化合物,其中£指 RbNH-C(=NH)-基團,或根據申請專利範圍第9項之鹽, 其不含或含一或多種惰性載劑及/或稀釋劑。
U·根據申請專利範圍第1至8項中任一項之化合物,其中E 扣RbNH-C(=NH)-基團,或根據申請專利範圍第9項之 鹽,其係用於製備醫藥組合物,此醫藥組合物具有延長 叛血酶時間的效$ ’抑㈣凝血酶效果及對相關的絲胺酸 蛋白酶有抑制效果。 12· —種製備根據申請專利範圍第〗項之化合物及其生理上 可接受的鹽的方法,其特徵在於 a.要製備通式j化合物,其中£指尺以卜基團, 其中Rb是氫原子,羥基*Cl-3_烷基,時 以如下通式之化合物
Ra - A - Het - B - Ar - C(=NH) . Zl ,⑴) 588047 έ88 C8 ________D8_ 六、申請專利範園 此化合物可在反應混合物中生成的, 其中 A,B,Ar,Het,及113之定義如申請專利範圍第五至7項 所述’及Z 1指烷氧基或芳烷氧基,烷基硫基或芳烷基 硫基, 與如下通式的胺反應 H2N - Rb’ ,(III) 其中 - Rbf指氫原子或藉基或C 烷基,或 b ·要製備通式I化合物,其中Ra_A_基團及e之定義如 申請專利範圍第1至8項所述,先決條件是Ra_A-基團含 有叛基及E之定義如申請專利範圍第1至8項所述,或是 Ra_A-基團之定義如申請專利範圍第1至8項之所述而e 指NH-C(=NH)-基團,.或Ra_A-基團含有羧基而e指NH-C(=NH)-基團,時: 將如下通式之化合物
Ra丨-A - Het - B - Ar - C - E* ,(IV) 其中 A,B,Ar及Het之定義如申請專利範圍第1至7項所述,
Ra - A-基團及E ’之定義如申請專利範圍第1至8項給Ra-A-基團及E所下的定義,先決條件是rj _A-基團含有可 藉水解、酸或鹼處理、熱分解或加氫分解轉化成羧基的 基團,E之定義如申請專利範圍第1至8項所述,或E,指 可藉水解、酸或鹼處理、熱分解或加氫分解轉化成NHr _ -9- ^紙張尺度適用中國國家標準(CNS) A4規格(21〇χ 297公釐)· ------ 588047 Λβ B8 C8 ---— ___D8 六、申請專利範圍 --- c卜NH)-基團的基團,Ra’_冬基團之定義如申請專利範 圍第1至8項給Ra-A-基團所下的定義,或是R:A_基團 §有可藉水解、敗或驗處理、熱分解或加氫分解轉化成 羧基的基團,E’指可藉水解、酸或鹼處理、熱分解或加 氫分解轉化成NH2_C(=NH)-基團的基團, 藉水解、酸或驗處理、熱分解或加氫分解轉化成通式I 化a物’其中Ra_A_基團之定義如申請專利範圍第1至8 項所述,先決條件是Ra_冬基團含有羧基,而E之定義 如申請專利範圍第1至8項所述,或是Ra_A_基團之定義 如申請專利範圍第!至8項所述,而E指nh^c卜nh>基 團’或是Ra-A-基團含有羧基而e指NH2-C(=NH)_基團, 或 c ·要製備通式I化合物,其中Ra_A_基團含申請專利範 圍第1至7項所述Ra-A-基團的一種酯,時 以如下通式化合物
Ra,f - A - Het - B - Ar - Ε ,(λ〇 其中 B ’ E ’ Ar及Het之定義如申請專利範圍第1至8項所述, Ran-A-基團之定義如申請專利範圍第1至8項給Ra_A-所 下的定義,先決條件是基團含有羧基或可用醇轉 化成對應的酯的基團,與下式的醇反應 HO R7 ,( VI) 其中 R7是如申請專利範圍第1至8項所述可於活體内裂解的 -10· 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) 588047 A8 B8 C8 D8 申請專利範圍 基團的烷基邵分,但不能用R4-CO-〇_(r5CR6)_基團產生 羧基,或與其甲醯胺乙縮醛反應, 或與如下通式的化合物反應 Z2 _ R8 ,(VII) 其中 R8指申請專利範圍第1至7項所述可於活體内裂解的基 團的fe基部分’但不能用R4-CO-〇-(r5cR6)_基團產生幾 基,及Z 2指離去基,或 d .要製備通式I化合物,其中R b指可於活體内裂解的基 團,時 以如下通式之化合物
Ra - A - Het _ B _ Ar - C(=NH) _ 簡2 ,( VIII) 其中
Ra,A,Het,B及A r之定義如申請專利範園第1至7項所 述,與如下通式之化合物反應 z2 - r7 ,(IX) 其中 R 7指可於活體内裂解的基團’ Z2指離核離去基’或 e·要製備通式I化合物,其中B指伸乙基,其中亞曱基 是以亞磺醯基或磺醯基所取代’時 將如下通式之化合物氧化
Ra - A - Het - Bf - Ar - E ,(X) 其中 A,E,Ar,Het及R a之定義如申請專利範圍第1至7項所 -11- 588047
六、申請專利範園 述,及 B,指伸乙基’其中亞甲基是以亞續酸基或績醢基所取 代,或 f.要製備通式1之化合物’其中E是氰基,B是伸乙 基,其中聯於H e t或A Γ上的亞甲基係由氧或硫原子,或 由亞磺醯基’磺醯基’談基或-NR「基團所取代,時 用如下通式之化合物
Ra A - Het - U ,(XI) 與如下通式之化合物反應 V - Ar - CN > (XII) 其中
Ra,A,Ar及Het之定義如申請專利範圍第1至8項所 述, U或 V基團之一是 HO-,HS_,HOSO-,H0S02-或 HNRr 基團,另一基團是Z3CH2_,其中Ri之定義如申請專利 範圍第1至8項所述,Z3是離核離去基,或 g·要製備通式I之化合物’其中E是氰基,RjR2NR3_ 基團,時 用如下通式之化合物 Η - A - Het - B - Ar - CN ,(XIII) 其中 A,B,H e t及A r之定義如申請專利範圍第i至8項所 述,與如下通式之胺反應 •12- 588047
8 8 8 8 A BCD
六、申請專利範園
R Η — N: ,(XIV)
R 其中 R2及R3之定義如申請專利範圍第1至8項所述’或與其 可反應的衍生物反應,或 h·要製備通式I之苯并咪唑基,苯并嘧唑基或苯并%唑 基化合物’其中B是伸乙基,時 以如下通式化合物 ,(XV) -cr
YH 其中
Ra,A及Y之定義如申請專利範圍第1至8項所述’與如 下通式之化合物反應. HO - CO - CH2CH2 - Ar - E , (XVI) 其中 A r及E之定義如申請專利範圍第1至8項所述,或與其 易反應的衍生物反應,及 i ·要製備通式之喳喏啉-2 -酮化合物時, 用如下通式之化合物 ,(XVI!> NR, Η -13-本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 8 5
具中
Ra,Rl及A之定義如申請專利範圍第項所述,1 如下通式之化合物反應, H〇-C〇.C〇CH2- Ar.E ,(XVlH) 其中 ,或與
Ar及E之定義如申請專利範圍第丨至8項所述 易反應的衍生物反應,或 綠基 j·要製備通式I之化合物,其中R2是經以燒基磺 基羰基取代的C ! y燒基,時 以如下通式之化合物 ,(IXX)
N - A - Het - B - Ar - E 其中 R3,A,B,E,及net之定義如申請專利範圍第i至8 所述,R2’是經羧基取代的^广烷基,或其易反應的 生物,與如下通式.化合物的鹽反應
Ci.3 .烷基 _ s〇2 - NH2 (XX)· 並且,如有必要,裂解反應中用以保護易反應的基團 保護基及/或 將所製通式Z化合物轉化成其鹽,特別是用無機或有 酸或鹼轉化成其供醫藥用途的生理上可接受的鹽。 -14-
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI391382B (zh) * 2005-12-21 2013-04-01 Boehringer Ingelheim Int 製備4-(苯并咪唑基甲基胺)-苯甲脒及其鹽類之改良方法

Families Citing this family (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1608399A (en) * 1997-11-26 1999-06-15 Axys Pharmaceuticals, Inc. Substituted amidinoaryl derivatives and their use as anticoagulants
EP1060166A1 (de) * 1998-02-03 2000-12-20 Boehringer Ingelheim Pharma KG 5-gliedrige benzokondensierte heterocyclen als antithrombotika
US6114532A (en) * 1998-02-03 2000-09-05 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals
CA2321025A1 (en) * 1998-02-09 1999-08-12 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines as protease inhibitors, in particular as urokinase inhibitors
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
US6248770B1 (en) 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
PL351767A1 (en) * 1999-02-09 2003-06-16 Dimensional Pharmaceuticals 3 Heteroaryl amidines, methylamidines and guanidines as protease inhibitors
DE19907813A1 (de) * 1999-02-24 2000-08-31 Boehringer Ingelheim Pharma Substituierte bicyclische Heterocyclen, deren Herstellung und deren Verwendung als Arzneimittel
AR023510A1 (es) 1999-04-21 2002-09-04 Astrazeneca Ab Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina.
DE19939463A1 (de) * 1999-08-20 2001-02-22 Boehringer Ingelheim Pharma Aminocarbonyl-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US6512000B1 (en) 1999-08-20 2003-01-28 Boehringer Ingelheim Pharma Kg Aminocarbonyl-substituted benzimidazoles having tryptase-inhibitory activity
DK1220844T3 (da) * 1999-09-24 2003-07-28 Boehringer Ingelheim Pharma Arylsulfonamid-substituerede benzimidazolderivater og deres anvendelse som tryptase-inhibitorer
DE19945787A1 (de) 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma Arylsulfonamid-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE19945810A1 (de) * 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma Substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US6413990B1 (en) 1999-09-24 2002-07-02 Boehringer Ingelheim Pharma Kg Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
US6407130B1 (en) 1999-11-10 2002-06-18 Boehringer Ingelheim Pharma Kg Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
US6451832B2 (en) 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
EP1614680B1 (en) * 2001-04-19 2011-12-21 Eisai R&D Management Co., Ltd. Process for preparing 2-iminopyrrolidine derivatives
DE10133786A1 (de) * 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Verwendung von Thrombin-Inhibitoren zur Behandlung von Arthritis
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
CA2476054C (en) * 2002-03-07 2011-11-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical composition for the oral administration of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino)-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino)-propionic acid ethyl ester and the salts thereof
DE10235639A1 (de) * 2002-08-02 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Prodrugs von 1-Methyl-2-(4-amidinophenylaminomethyl)-benzimidazol-5-yl-carbonsäure-(N-2-pyridyl-N-2-hydroxycarbonylethyl)-amid, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2004014844A2 (en) 2002-08-09 2004-02-19 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
PE20040804A1 (es) 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa
DE10260730A1 (de) 2002-12-23 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte stickstoffhaltige Heterobicyclen, deren Herstellung und deren Verwendung als Arzneimittel
US7429597B2 (en) 2002-12-23 2008-09-30 Boehringer Ingelheim Pharma Gmbh & Co., Kg Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions
CN100439336C (zh) 2003-02-19 2008-12-03 卫材R&D管理有限公司 制备环状苯甲脒衍生物的方法
DE10310278A1 (de) * 2003-03-10 2004-09-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue aromatische Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel
MXPA05011432A (es) * 2003-04-24 2006-03-21 Boehringer Ingelheim Int Uso de dipiridamol o mopidamol para tratamiento y prevencion de enfermedades trombo-embolicas y desordenes originados por formacion excesiva de trombina y/o por expresion elevada de receptores de trombina.
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
JP2007501844A (ja) 2003-08-08 2007-02-01 トランス テック ファーマ,インコーポレイテッド アリール及びヘテロアリール化合物、組成物並びに使用方法
DE10337697A1 (de) * 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablette enthaltend 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenyl-amino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester oder dessen Salze
DE10339862A1 (de) 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel
DE10341043A1 (de) * 2003-09-03 2005-03-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue oral zu applizierende Darreichungsform für 3-[(2-{[4-Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester und dessen Salze
EP1609784A1 (de) * 2004-06-25 2005-12-28 Boehringer Ingelheim Pharma GmbH & Co.KG Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen
US20060222640A1 (en) * 2005-03-29 2006-10-05 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of thrombosis
DE102005020002A1 (de) * 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Physiologisch verträgliche Salze von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester
DE102005025728A1 (de) 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphe von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-Propionsäure-ethylester
DE602006017694D1 (de) 2005-06-27 2010-12-02 Bristol Myers Squibb Co C-verknüpfte zyklische antagonisten des p2y1-rezeptors mit eignung bei der behandlung thrombotischer leiden
DE102005061624A1 (de) 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von Salzen von 4-(Benzimidazolylmethylamino)-Benzamidinen
US8044242B2 (en) 2006-03-09 2011-10-25 Bristol-Myers Squibb Company 2-(aryloxy) acetamide factor VIIa inhibitors useful as anticoagulants
US8222453B2 (en) 2006-06-08 2012-07-17 Bristol-Myers Squibb Company Benzamide factor VIIa inhibitors useful as anticoagulants
CA2657269A1 (en) * 2006-07-17 2008-01-24 Boehringer Ingelheim International Gmbh New indications for direct thrombin inhibitors
CA2657266A1 (en) * 2006-07-17 2008-01-24 Boehringer Ingelheim International Gmbh New indications for direct thrombin inhibitors in the cardiovascular field
WO2008043759A1 (en) * 2006-10-10 2008-04-17 Boehringer Ingelheim International Gmbh Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
EP2102189B1 (en) 2006-12-15 2015-07-29 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors
PE20081775A1 (es) 2006-12-20 2008-12-18 Bristol Myers Squibb Co Compuestos macrociclicos como inhibidores del factor viia
EP1956018A1 (de) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Verfahren zur Herstellung eines Benzimidazolderivats
KR20100015886A (ko) 2007-04-23 2010-02-12 사노피-아벤티스 P2y12 길항제로서의 퀴놀린-카복스아미드 유도체
EP2178849A1 (en) 2007-07-31 2010-04-28 Mallinckrodt Inc. Integrated photoactive agents and uses thereof
WO2009080226A2 (en) 2007-12-26 2009-07-02 Sanofis-Aventis Heterocyclic pyrazole-carboxamides as p2y12 antagonists
CZ305085B6 (cs) * 2008-03-14 2015-04-29 Zentiva, K.S. Způsob přípravy dabigatranu
TWI436994B (zh) * 2008-07-14 2014-05-11 Boehringer Ingelheim Int 製備含有達比加群(dabigatran)之藥物組合物的新穎方法
US20110190352A1 (en) * 2008-08-19 2011-08-04 Boehringer Ingelheim International Gmbh Use of dabigatranetexilate for treating patients with pulmonary hypertension
CZ2008669A3 (cs) * 2008-10-24 2010-05-05 Zentiva, A. S. Zpusob prípravy dabigatranu a jeho meziprodukty
EP2391893B1 (en) 2009-02-02 2014-09-03 Boehringer Ingelheim International GmbH Lyophilised dabigatran
EP2429520A1 (en) 2009-05-14 2012-03-21 Boehringer Ingelheim International GmbH New combination therapy in treatment of oncological and fibrotic diseases
BR112012004169A2 (pt) 2009-08-24 2016-03-29 Boehringer Ingelheim Int intervenções de emergência com carvão vegetal ativado em superdosagem de etexilato de dabigatran
CN102050815B (zh) * 2009-11-06 2014-04-02 北京美倍他药物研究有限公司 作为前药的达比加群的酯衍生物
CN102050814B (zh) * 2009-11-06 2014-05-28 北京美倍他药物研究有限公司 达比加群的酯衍生物
US8399678B2 (en) 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
AR079944A1 (es) 2010-01-20 2012-02-29 Boehringer Ingelheim Int Anticuerpo neutralizante de la actividad de un anticoagulante
HUP1000069A2 (en) 2010-02-02 2012-05-02 Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag New salts for the preparation of pharmaceutical composition
TWI577665B (zh) 2010-02-11 2017-04-11 必治妥美雅史谷比公司 作為因子xia抑制劑之巨環類
EP2542224B1 (en) 2010-03-01 2014-08-13 Ratiopharm GmbH Dabigatran etexilate-containing oral pharmaceutical composition
CA2792273A1 (en) 2010-03-08 2011-09-15 Ratiopharm Gmbh Dabigatran etexilate-containing pharmaceutical composition
ES2631980T3 (es) 2010-07-01 2017-09-07 Krka, Tovarna Zdravil, D.D., Novo Mesto Formas de dosificación orales farmacéuticas que comprenden dabigatrán etexilato y sus sales farmacéuticamente aceptables
EP2937343A1 (en) 2010-07-09 2015-10-28 Esteve Química, S.A. Process of preparing a thrombin specific inhibitor
WO2012004397A1 (en) 2010-07-09 2012-01-12 Esteve Química, S.A. Intermediates and process for preparing a thrombin specific inhibitor
WO2012027543A1 (en) 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
WO2012077136A2 (en) 2010-12-06 2012-06-14 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
US9000186B2 (en) 2011-02-01 2015-04-07 Kyowa Hakko Kirin Co., Ltd. Ring-fused heterocyclic derivative
EP2691156A1 (en) 2011-03-30 2014-02-05 Boehringer Ingelheim International GmbH Anticoagulant antidotes
HUP1100244A2 (hu) 2011-05-11 2012-11-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Gyógyszeripari intermedierek és eljárás elõállításukra
CN102250099B (zh) * 2011-05-16 2013-10-16 中国药科大学 一类非肽类抗凝血酶抑制剂、其制法以及医药用途
CN102838588B (zh) * 2011-06-24 2014-03-19 中国药科大学 一类可用于口服的凝血酶抑制剂、其制法以及医药用途
ES2611610T3 (es) * 2011-07-25 2017-05-09 Develco Pharma Schweiz Ag Ésteres de ácidos amidoxima-carboxílicos de dabigatrán como profármacos y su utilización como un medicamento
TW201311689A (zh) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 作為因子xia抑制劑之新穎巨環化合物
TW201319068A (zh) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 作為xia因子抑制劑之環狀p1接合劑
WO2013024394A1 (en) * 2011-08-12 2013-02-21 Alembic Pharmaceuticals Limited Novel reference markers of dabigatran etexilate
CN102993175B (zh) * 2011-09-08 2014-08-13 天津药物研究院 达比加群的酯衍生物及其制备方法和用途
CN102993174A (zh) * 2011-09-08 2013-03-27 天津药物研究院 作为前药的达比加群的酯衍生物
CN103987696B (zh) 2011-10-14 2016-12-21 百时美施贵宝公司 作为因子xia抑制剂的取代的四氢异喹啉化合物
PL2766346T3 (pl) 2011-10-14 2017-09-29 Bristol-Myers Squibb Company Podstawione związki tetrahydroizochinoliny jako inhibitory czynnika XIA
ES2699226T3 (es) 2011-10-14 2019-02-08 Bristol Myers Squibb Co Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIa
JP2015500853A (ja) 2011-12-22 2015-01-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 即時放出マルチユニットペレットシステム
US9212166B2 (en) 2012-01-20 2015-12-15 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
WO2013110567A1 (en) 2012-01-24 2013-08-01 Boehringer Ingelheim International Gmbh Novel orally administered dabigatran formulation
JP6215239B2 (ja) 2012-02-21 2017-10-18 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ ダビガトランエテキシラートの経口医薬組成物
EP2631234A1 (en) 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
WO2013144971A1 (en) 2012-03-27 2013-10-03 Cadila Healthcare Limited New solid forms of dabigatran etexilate bisulfate and mesylate and processes to prepare them
EP2834224B1 (en) 2012-04-02 2018-06-06 MSN Laboratories Limited Process for the preparation of benzimidazole derivatives and salts thereof
CN103387566B (zh) * 2012-05-09 2015-09-09 上海医药工业研究院 制备3-[[[2-[[(4-氰基苯基)氨基]甲基]-1-甲基-1h-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯的方法
CN103420980A (zh) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 达比加群衍生物
WO2014001220A1 (en) 2012-06-25 2014-01-03 Boehringer Ingelheim International Gmbh Method for prevention of stroke
JP2015522596A (ja) * 2012-07-16 2015-08-06 インテルキム、ソシエダッド アノニマ ダビガトランエテキシラートの合成のための中間体を調製する方法及び該中間体の結晶形
CN102766134B (zh) * 2012-07-19 2014-06-25 北京普禄德医药科技有限公司 达比加群的酯衍生物及其制备方法和用途
WO2014021383A1 (ja) * 2012-07-31 2014-02-06 協和発酵キリン株式会社 縮環複素環化合物
CN108250199B (zh) 2012-08-03 2021-07-16 百时美施贵宝公司 二氢吡啶酮p1作为凝血因子xia抑制剂
UY34959A (es) 2012-08-03 2014-01-31 Bristol Myers Squibb Company Una Corporación Del Estado De Delaware Dihidropiridona p1 como inhibidores del factor xia
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
WO2014060561A1 (en) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Oral pharmaceutical formulations comprising dabigatran
WO2014060545A1 (en) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions of dabigatran free base
US9399616B2 (en) 2012-10-22 2016-07-26 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
WO2014068587A2 (en) * 2012-10-29 2014-05-08 Biophore India Pharmaceuticals Pvt. Ltd. An improved process for the synthesis of dabigatran and its intermediates
CN102977077A (zh) * 2012-11-28 2013-03-20 浙江燎原药业有限公司 一种达比加群酯中间体的制备方法
EP2740471B1 (en) 2012-12-07 2015-05-27 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
CN103044404A (zh) * 2013-01-14 2013-04-17 中国药科大学 达比加群衍生物、其制法及抗血栓用途
EP2978751B1 (en) 2013-03-25 2018-12-05 Bristol-Myers Squibb Company Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors
CN103224469A (zh) * 2013-05-16 2013-07-31 上海应用技术学院 一种以含氟基团修饰的苯环为中心的达比加群酯类似物及其合成方法
WO2014195230A1 (de) 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Substituierte benzoxazole
UY35592A (es) * 2013-06-03 2014-12-31 Bayer Pharma AG Benzoxazoles sustituidos
CN103288744A (zh) * 2013-06-04 2013-09-11 上海应用技术学院 一种含氟基团修饰的达比加群酯类似物及其合成方法
EP2853260A1 (en) 2013-09-27 2015-04-01 ratiopharm GmbH Pharmaceutical preparation comprising dabigatran etexilate bismesylate
HUE040226T2 (hu) 2014-01-31 2019-02-28 Bristol Myers Squibb Co Makrociklusok heterociklusos P2' csoportokkal XIA faktor inhibitorokként
NO2760821T3 (zh) 2014-01-31 2018-03-10
WO2015128875A2 (en) 2014-02-26 2015-09-03 Megafine Pharma (P) Ltd. A process for preparation of dabigatran etexilate mesylate and intermediates thereof
WO2015137680A1 (ko) * 2014-03-10 2015-09-17 동아에스티 주식회사 뇌졸중 및 전신색전증 치료 또는 예방용 약학적 조성물
WO2015145462A1 (en) 2014-03-26 2015-10-01 Cadila Healthcare Limited Pharmaceutical compositions of dabigatran
WO2015155281A1 (en) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations of dabigatran and proton pump inhibitors
WO2015155297A1 (en) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
CN104230888A (zh) * 2014-06-03 2014-12-24 长春工业大学 一种苯并咪唑化合物的制备方法
CN105218519A (zh) * 2014-06-04 2016-01-06 天津药物研究院 一种达比加群酯中间体的制备方法
CN104003977B (zh) * 2014-06-05 2016-04-13 雅本化学股份有限公司 N-(2-氯甲基-1-甲基-1h-苯并咪唑-5-酰基)-n-(吡啶-2-基) -3-氨基丙酸乙酯的制备方法
DE102014108210A1 (de) 2014-06-11 2015-12-17 Dietrich Gulba Rodentizid
CN104045628B (zh) * 2014-06-13 2019-04-09 深圳翰宇药业股份有限公司 苯并咪唑衍生物的纯化方法
CN105315257A (zh) * 2014-06-24 2016-02-10 华仁药业股份有限公司 一种达比加群酯的合成及纯化方法
WO2016019849A1 (zh) * 2014-08-06 2016-02-11 四川海思科制药有限公司 一种达比加群烷酯衍生物及其制备方法和在药学上的用途
WO2016019848A1 (zh) * 2014-08-06 2016-02-11 四川海思科制药有限公司 一种达比加群硫酯衍生物及其制备方法和在药学上的用途
NO2721243T3 (zh) 2014-10-01 2018-10-20
US10675276B2 (en) 2014-11-03 2020-06-09 Hangzhou Solipharma Co., Ltd. Dosing preparation of dabigatran etexilate or a salt thereof and a preparation method thereof
CN104592204B (zh) * 2014-12-26 2017-05-17 华润赛科药业有限责任公司 达比加群衍生物及其制备方法和用途
CN104650037A (zh) * 2014-12-30 2015-05-27 青岛黄海制药有限责任公司 一种达比加群酯的合成方法
TR201502223A2 (tr) 2015-02-25 2016-09-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dronedaron ve dabigatranın farmasötik kombinasyonları.
CN104628733A (zh) * 2015-03-02 2015-05-20 中国药科大学 四氢苯并[4,5]咪唑并[1,2-a]吡嗪类凝血酶抑制剂
EP3310777B1 (en) 2015-06-19 2019-10-09 Bristol-Myers Squibb Company Diamide macrocycles as factor xia inhibitors
CN104987323B (zh) * 2015-07-10 2017-08-22 浙江美诺华药物化学有限公司 一种达比加群酯的制备方法
WO2017013106A1 (en) 2015-07-20 2017-01-26 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical formulations of dabigatran free base
ES2937156T3 (es) 2015-07-29 2023-03-24 Bristol Myers Squibb Co Inhibidores macrocíclicos del factor XIa que llevan un grupo P2' no aromático
JP6785838B2 (ja) 2015-08-05 2020-11-18 ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company 新規な置換グリシン誘導のfxia阻害剤
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
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WO2017111637A1 (en) 2015-12-23 2017-06-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof
CN105566297A (zh) * 2015-12-31 2016-05-11 哈药集团技术中心 一种达比加群酯甲磺酸盐的制备方法
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EP3332771A1 (en) 2016-12-07 2018-06-13 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayered tablet compositions of dabigatran
TR201617984A2 (tr) 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dabi̇gatranin farmasöti̇k kompozi̇syonlari
JP2018184375A (ja) 2017-04-27 2018-11-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ダビガトランエテキシラート又は医薬的に許容されるその塩を含む錠剤及びその製造方法
WO2019004980A2 (en) 2017-05-10 2019-01-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN DEXILATE
TR201706848A2 (tr) 2017-05-10 2018-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dabigatran eteksi̇lat i̇çeren kati oral farmasöti̇k kompozi̇syonlar
CN109010249A (zh) * 2017-06-08 2018-12-18 上海美悦生物科技发展有限公司 注射用达比加群酯药物组合物及其制备方法和用途
KR20190036857A (ko) 2017-09-28 2019-04-05 한미약품 주식회사 다비가트란 이텍실레이트를 포함하는 복합 캡슐제
TR201722186A2 (tr) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dabi̇gatranin farmasöti̇k kompozi̇syonlari
TR201722323A2 (tr) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dabi̇gatranin oral farmasöti̇k kompozi̇syonlari
TR201722630A2 (zh) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
CN111954532A (zh) * 2018-04-13 2020-11-17 上海交通大学医学院附属瑞金医院 杂芳基酰胺类化合物的抗肿瘤多药耐药性、治疗癌症的用途和蛋白质-药物分子复合物
CN108864047A (zh) * 2018-07-02 2018-11-23 河南师范大学 一种非肽类凝血酶抑制剂达比加群酯的制备方法
EP3771465A1 (en) 2019-08-01 2021-02-03 Zaklady Farmaceutyczne Polpharma SA Pharmaceutical composition comprising dabigatran etexilate
CN111606885A (zh) * 2020-06-18 2020-09-01 安徽鼎旺医药有限公司 一种达比加群酯甲磺酸盐及其制备方法
CN113929661A (zh) * 2020-06-29 2022-01-14 石药集团恩必普药业有限公司 一种达比加群酯中间体及其制备方法
EP4070658A1 (de) 2021-04-06 2022-10-12 BIORoxx GmbH Verwendung von blutgerinnungshemmenden verbindungen als rodentizide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
DE4129603A1 (de) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K Kondensierte 5-gliedrige heterocyclen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
ZA928276B (en) * 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
CA2134192A1 (en) * 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI391382B (zh) * 2005-12-21 2013-04-01 Boehringer Ingelheim Int 製備4-(苯并咪唑基甲基胺)-苯甲脒及其鹽類之改良方法

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