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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group
patent application
methyl
scope
general formula
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TW087102265A
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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
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
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Publication of TW588047B publication Critical patent/TW588047B/zh

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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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