TW401403B - Antithrombotic agents - Google Patents

Antithrombotic agents Download PDF

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Publication number
TW401403B
TW401403B TW084102067A TW84102067A TW401403B TW 401403 B TW401403 B TW 401403B TW 084102067 A TW084102067 A TW 084102067A TW 84102067 A TW84102067 A TW 84102067A TW 401403 B TW401403 B TW 401403B
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hydrogen
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TW084102067A
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Aaron Leigh Schacht
Robert Theodore Shuman
Gerald Floyd Smith
Michael Robert Wiley
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Lilly Co Eli
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Description

401403
8 8 8 8 A B c D 申請專利範圍
E \(CH2)k-R .
、(CH2)k-R
S
R
N—R
N-R E-
(CH2)k-R N—D 、(CH2)k-R .
(CH2)k-R 或
(CH2)k-R 其中D及E各自分別為H或CH ;
NOH NH II -C-NH2
為0或1 ;且 NH R 為-呢，-ONH2 , -C-NH2 或 或G為
N-Η或
N-H 及其中
D E、CH2)k-R E-
(CH2)k-R N-D 、(〇H2)k-R . 之芳族或雜芳族環之無取代碳原子之一或全部可帶有一 個氟取代基； 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 401403
8 8 8 8 ABCD 六、申請專利範圍 或其醫藥可接受鹽；或該化合物或其鹽之醫藥可接受 溶劑合物； 但當 G 為-(CH2)S-R或- CH = CH-(CH2)t-R且 R為 C(NH)NH2_-NH-C(NH)NH2)，Y為未經取代脯胺醯基（
Rp為氫），及了為
Z 時非為氫或第三丁氧羰基； 及又當r = l及s = 0時，R非為胺基或胍基；
及又當G為-(CH2) a-R其中R為 NH NH
II II -ONH2 或-NH-C-NH2 ， Y 為 或未經取代腩胺醯基，R’為氫，T為環己基及Q為 -NH-A時，A非為氫，甲基磺_基或-(CH2)«_Rm;
，Y為 Ο
…丨I -N—^—c— 或未經取代脯胺醯基（Rp為氫）* G 為-(CH2)a-R或-CH:CH-(CH2)t：-R 及 R 為-C(NH)HH2 -4 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 401403
8 8 8 8 A B CD 申請專利範圍 或-NH-C(NH)NH2時，A 不為氫 * R”S02-(其中 R，’為 CrU 烷基）或-(CH2)*-C00H ; 及又當G為
,Ν—R 或
Ν—Η
或 Z CO-- ，及Q為-Ν Η - A時 A 非為 R ” S 0 2 -; 及又當X為 Ο R*0
Ml
(CH2) a~C-C-Q z 其中Z為氫，a為1 ，Rf為氫，Q為-NHA，而A為氫 ，Y為未經取代脯胺醯基（RP為氫），Γ為1或2 ，且G為
E (CH2)k-R (其中D及E各自為CH, -(CH2)k-R為對位且k為0 ) 本紙張尺度適用中國國家標準(CNS) A4規格(210 χ 297公釐) 401403
8 8 8 8 ABCD 六、申請專利範圍
- NH
II 時，R不為-朋4-_ 及又當Y代表吖咀-2-羰基或未經取代脯胺醯基 氫）；且 G代表
其中末二基R當K為0或1時代表- C(NH)NH2，或當 !(為 0 時 R 代表-N Η - C (N H ) N Η 2 ;則： (a)當 X 代表 T-(CH2) a-CH (R，）（Q)-C (0 卜·，且 R ’代表Η ; Q 係-NH-A ;而 A代表Η ， R”S〇2-，R”0C(0)-(其中末二個基R”代表Ci-“烷基 )* r”c(0)-(其中 R” 基代表 CfC* 烷基或- (CH2)d-C00H * 其中 d 係 1 或 2)或-(CH2)«C00H ; 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 401403
8 8 8 8 A B c D 申請專利範圍 則T - ( C Η 2 ) a不代表： (i ) Ci-Cs烷基； (ii ) -((^2)^-(：5-(：6環烷基； (iii) -(CH2)a-苯基，其苯基視需要經Ci-%烷基 取代； (iv ) -(CH2)a-苯基，其中a係0或1且苯基係經 羥基或Ci-L烷氧基取代；或 (v )-(CH2)a-萘基，其中a係0或1 ;且 <b) X不代表高脯胺醯基或
此外 ⑻ 當Y代表吖哩-2-羰基、未經取代腩胺醯基（Rp為 H)或4 -羥基腩胺 醯基（”為OH)， X代表 T- (CH2) a- C(R，）（Q) -c (0)-， T代表 環己基， R ’代表Η， G代表 -(CHU i R代表 -C (NH) -NH 2或-NH-C (NH)-NH2 ，及 -(CH2 )r* ~ ( C Η 2 ) s -鐽代表C 2 - C G伸燒 基時， 則 Q不 代表- Ν Η - A，其中A代表Η、 甲基磺醯基或 -(ch2 )*-C00H ; 當Y代 表盯ng - 2 - 辕基、未 經取代脯 胺醯基 (R p為 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 401403 A8 B8 C8 D8 、申請專利範圍 Η)或4-羥基脯胺醯基（Rp為0H)， X代表 T-(CH2)a-C(lT) (Q)-C(O)-， T代表環己基， R ,代表Η , G代表-(CH2)S-R， R代表-NH-C(NH)-NH2，及 -(CH 2 ) · (CH2) 鏈代表（：2-(：6伸 烷基時 $ 則Q 不 代 表 -NH- A *其中A代表R”0C (0)- ，其中 1T 代表 第 三 丁 基； 又 此 外， 式I化合物不為： (i ) N- [4-[(胺基亞胺基甲基） 胺基]丁基]-1 一 [N-(甲基磺醯基）苯基 丙胺醯 基 ]-L- 腩 胺 醯胺，或 (i η N- [[1-(胺基亞胺基甲基） -4 -六氫啦唾] 甲 基 ]-卜D-苯基丙胺醯基]- L-腩胺 Μ 胺。 裝
2. 根據申請專利範圍第1項之式I化合物或其鹽或溶劑合 物，其中 X為高脯胺醯基，
本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 401403
8 8 8 8 A B c D 六、申請專利範圍 C 8焼基 T為C3-C3環烷基 α- 或 ζ
CO a為0或1 ; Q為-OH、Ci-“烷氧基或-ΝΗ-Α; Α 為氫 * R”S〇2-、ITOC(O)-、R”C(0) -或 -(CH2)*-C00H ; g為1、2或3 ; R ’為氫或Ca-C4烷基； nCi-Cd烷基、-(CH2)d-C00H或吲哚基*視需要經 Ci-“烷基取代； d為1、2或3 ； Z為氫、Ca-C4烷基 Y為 〇•NRg—CHr〇 烷氧基或羥基；. 〇II-C— —N—
R*為-(CH2)p-L-(CH2)q-T ’ ；
Rp 為氫、Ci-“ 烷基或- (CH2)P-L-(CH2：U-T·; 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 401403
8 8 8 8 A B c D 申請專利範圍 其中p為0、1或2 ; L為一個鐽或q為0、1或 2 ;及Τ’為苯基；
Ry為-CH2-;及 當與三個毗連碳原子時共同生成5至8個原子 之飽和碳環系環； r為1或2 ;及 G 為-(CH2)s-R，其中 s 為 0-5; -CH = CH-(CH2：U-R， 其中t為0-3 ;
(CH2)k-R
N—R 其中D和E各自分別為N或C Η ; k為0或1 ;且
NH NOH NH
II li II R 為-Nlfe, -C-NH2 , -C-NH2 ,或; 但當 G 為-(CH2)S-R或-CH = CH-(CH2)t-R，且 R為 -C (NH) _2或-NH-C (NH) NH2)，Y為未經取代脯胺醯基（ Rp為氫），及T為
-10 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 401403
A B c D 申請專利範圍 時，A非為氫或第三丁氧羰基，· 及又當r = l及s = 0時，R非為胺基或胍基； 及又當G為-(CH2)S-R其中R為
NH
NH -C-NH2 或-NH-C-NH2 為 N· 〇 或未經取代脯胺醯基 ’為氫，T為環己基及Q為 NH-A時，則A非為氫，甲基磺醢基或-(CH2)e-C00H;
裝 及又當T為環己基或 Y為 訂 .N· 〇II .〇 或未經取代腩胺_基（Rp為氫） G 為-(CH2)s-R 或-CH = CH-(CH2)fR 及 R 為 _C(NH)NH2 或 Cl -NH-C(NH)NH2時，則A不為氫，R”S〇2-(其中R”為 烷·基）或-(CH2) «-C00H ; 及又當G為
N—R
Z 或
-11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 401403
8 8 8 8 A B c D 申請專利範圍 ，及Q為-Ν Η - A時 A 非為 R”S〇2-; 及又當X為
R'O Γ\_ I ii ( >—(CH2)a-C-C-
Z 其中Z為氫，a為1 ，1^’為氫，0為-關^\，而々為氫 Y為未經取代脯胺醯基（Rp為氫），r為1或2 ，且G為
/=D
E (CH2) k-R (其中D及E各自為CH，-(CH2)k-R為對位且k為0 ) ίίΗ
II 時，R 不為-NH-C-NH2 ， 及又當Y代表吖咀-2-羰基或未經取代腩胺醯基（”係 氫）；且 G代表
ΝΗ ΝΗ2 , ΝΗ
-12 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 χ 297公釐） 401403
8 8 8 8 A BCD 六、申請專利範圍 其中當K係0或1時R基代表-C(NH)NH2，或當K係 0 時 R 基代表-N Η - C ( N H ) N Η 2 ;則： (a)當 X 代表 T-(CH2)a-CH(R’）（Q)-C(0)-;且 R ’代表Η ; Q 係-Ν Η - A ;而 A代表Η ， r”s〇2-，lT’0C(0)-(其中末二個基R”代表Ci-“烷基 ), R”C(0)-(其中 R”基代表 Ci-C4 烷基或- (CH2)d-C00H ，其中 d 係 1 或 2)或-(CH2)*C00H ; 則T - (C H 2 ) a不代表： (i ) Ci-Cs焼基； (i i ) - (CH2)e-C5-Cs環烷基； (iii) -(CH2)a-苯基，其苯基視需要經CrL烷基 取代； (iv ) -(CH2)e-苯基，其苯基經羥基或（^-(：4烷氧 基取代；或 (v )-(CH2)e-萘基；且 fc) X不代表高脯胺醯基或
〇 -13 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）
裝 訂 401403 A8 B8 C8 D8 、申請專利範圍 3 ·根據申請專利範圍第1或2項之化合物或其鹽或溶劑合 物，其中 烷基本身或作為另一取代基之一部份表示甲基、乙基 、正丙基、異丙基、正丁基、第三丁基、異丁基或第二 丁基；
Cs-Cs環烧基表環丙基、甲基環丙基、環丁基、環戊 基、環己基、4-甲基環己基或環辛基。 4. 根據申請專利範圍第1或2項之化合物或其鹽或溶劑合 物，其中 裝 ^~^~~ iCH2)a—CH-C—
HN \
A X為 ，高腩胺_基，或1-或 訂 3-Piq，Y為脯胺醯基；A為氫或R”S02 -及R為胍基或 胖基。 5· 根據申請專利範圍第1或2項之化合物或其鹽或溶劑合 物，其中 G為4 -脾基苯基。 6. 根據申請專利範圍第1或2項之化合物或其鹽或溶劑合 物，其中 Ο 〇 (CH2)—CK-C- HN、 為
、A 其中A為氫、R”S〇2-或 (CH2)«-C00H 〇 14 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 401403
A B c D 申請專利範圍 7 . 根據申請專利範圍第6項之化合物或其鹽或溶劑合物， 其中A為R”S〇2-及R”為乙基。 8. 根據申請專利範圍第6項之化合物或其鹽或溶劑合物， 其中 A 為-(CH2) «-C00H及 g 為 1 。 9 . 根據申請專利範圍第1或2項之化合物或其鹽或溶劑合 物，其中Y為（L)-脯胺醯基，（S)-順式-八氫D朵 - 2-羰基，或N-(2-苯基乙基）甘胺醯基。 10.根據申請專利範園第1項之化合物或其II藥可接夸鹽或 溶劑合物，該化合物係選自： a) 式I a化合物
X 0 II •UI。——NH-CH2
la 1
N 其中苯甲脒環未經取代或可帶有一或二個氟取代基 b ) 式I b化合物
NH2 lb 及 C ) 式I c化合物
••»»11C* — NH * CH2
-D-C
Ic -15 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 401403 A8 B8 C8 _ D8 六、申請專利範圍 其中D為N或CH ; 而X具有如申請專利範圍第卜4和6_8項所述任一值 〇 11·根據申請專利範圍第10項之化合物或其鹽或溶劑合物， 其係式I a化合物，其中苯甲脒環未經取代。 12·根據申請專利範圍第1〇或11項之化合物或其琴或溶劑合 物，其中 ♦ 0 T-(CH2)—CH-C—
、A X為 其中T為環己基或苯基而A為氫、乙基磺醯基或羧甲 基。 13.根據申請專利範圍第1項之化合物或其鹽或溶劑合物， 該化合物係選自 * d) (SH頓式）-N-[ [4-(胺基亞胺基甲基）苯基]甲基 ]-1- [N -(乙基磺醯基）苯基甘胺醯基]-1H-吲卩朵-2-羧 醯胺， e) (S-順式）[ [4-(胺基亞胺基甲基）苯基]甲基 (乙基磺醯基）-D-苯基丙胺醯基]-1H-吲D朵-2-羧 醯胺， h) (S-順式）[ [4-(胺基亞胺基甲基）苯基]甲基 ]-1-[Ν-(羧甲基）環己基丙胺醯基]羧醯 胺， -16- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 401403 A8 B8 C8 D8 六 、申請專利範圍 Π N-(羧甲基）-D-環己基丙胺醯基-N-[ [5-(胺基亞 胺基甲基）噻吩-2-基]甲基]脯胺薩胺， in) N-(羧甲基）環己基丙胺醯基- N-[[5-(胺基亞 胺基甲基）吡啶-2-基]甲基]-L-脯胺醯胺， ο) H-(羧甲基）環己基丙胺醯基- N-[[6-(胺基亞 胺基甲基）嗒哄-3-基]甲基]腩胺醯胺， P) (羧甲基）-D-環己基丙胺醯基- N-[[l-(胺基亞 胺基甲基）-1,2,3,6-四氫吡啶-4-基]甲’基卜L-脯胺醯 胺， q) N-(羧甲基）環己基丙胺醯基-N- [ [4 -(胺基亞 胺基甲基）-2-氟苯基]甲基]脯胺醯胺， r) (羧甲基）-D-環己基丙胺醯基- N-[[4-(胺基亞 胺基甲基）-2,6-二氟苯基]甲基]-L-腦胺_胺，及 w) N-(甲基磺醯基乙醯基）-1^環己基丙胺醯基- N-[[4-(胺基亞胺基甲基）苯基]甲基]脯胺_胺。 14.根據申請專利範圍第1項之化合物或其鹽或溶劑合物， 該化合物係選自 i) (SH頓式）-N-[[4-(胺基亞胺基甲基）苯基]甲基 ]-1-[Ν-(乙基磺醯基）-D-苯基甘胺醯基]-1H-吲跺-2-羧 _胺， v) (羧甲基）環己基丙胺_基-1[[5-(胺基亞 胺基甲基）噻吩-2-基]甲基]脯胺_胺， vii) N-(羧甲基）-D-環己基丙胺醯基- N-[[4-(胺基亞 胺基甲基）-2-氟苯基]甲基]-L-脯胺醯胺，及 vffi) N-(羧甲基）-D-環己基丙胺醯基U[4-(胺基亞 -17 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 401403 A8 B8 C8 D8 六、申請專利範圍 胺基甲基）-2,6-二氟苯基]甲基]-L-脯胺醯胺。 15.根據申請專利範圍第2項之化合物或其鹽或溶劑合物， 該化合物為N-(羧甲基）環己基丙胺藤基- N-[[5-(胺 基亞胺基甲基）噻吩-2-基]甲基卜L-脯胺醯胺。 16· —種作為抗血栓劑之醫藥組合物，包括如申請專利範圍 第1、2、13及14項中任一項之式I 、la、lb、或Ic化合 物或其醫藥可接受鹽或溶劑合物，與醫藥可接受性載劑 、稀釋劑或賦形劑。 17. —種製備如申請專利範圍第1或2項具有式I之化合物 之方法，
X-Y-NH- (CH2) I 該方法包括
a) 同時或依序去除對應式I化合物之保護基P (P)X-Y-NH (CH山-G(P) II 其中（P)X表示帶有一或多個保護基p分別選自其中X含 鹼性部份之式I化合物之胺基保護基p及其中X含羧 基殘基之式I化合物之羧基保護基P ，及G(P)表示帶有 一或多個分別選自胺基官能基P之基團G ;或 b ) 至於其中R為
NH NOH
II _H _C—NH2之式I化合物，係經由氫解其中R為—NH2 之對應式I化合物；及隨後當需要式1化合物之鹽時， 生成與醫藥可接受性酸之鹽。 -18 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)
裝 訂
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AU675981B2 (en) * 1992-12-02 1997-02-27 Bristol-Myers Squibb Company Guanidinyl-substituted heterocyclic thrombin inhibitors
SE9301916D0 (sv) 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
AU1025795A (en) 1994-01-27 1995-08-03 Mitsubishi Chemical Corporation Prolineamide derivatives

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SI0672658T1 (en) 2004-02-29
UA67715C2 (en) 2004-07-15
PE41696A1 (es) 1996-10-12
BR9506979A (pt) 1997-11-18
PL320637A1 (en) 1997-10-13
NO963684L (no) 1996-10-28
CN1515550A (zh) 2004-07-28
PL181306B1 (en) 2001-07-31
CN1134264C (zh) 2004-01-14
EP0672658A1 (en) 1995-09-20
CN100491348C (zh) 2009-05-27
FI963451A (fi) 1996-09-03
NO309034B1 (no) 2000-12-04
EP1361212A1 (en) 2003-11-12
KR100337271B1 (ko) 2002-11-30
IL112795A0 (en) 1995-05-26
HU9602408D0 (en) 1996-11-28
AU684918B2 (en) 1998-01-08
JP4081138B2 (ja) 2008-04-23
ATE250028T1 (de) 2003-10-15
DE69531753T2 (de) 2004-10-21
HUT76330A (en) 1997-08-28
FI963451A0 (fi) 1996-09-03
AU1975295A (en) 1995-09-18
ES2206479T3 (es) 2004-05-16
DK0672658T3 (da) 2004-01-12
AU684918C (en) 2003-05-08
ZA951617B (en) 1997-02-27
CZ258496A3 (en) 1997-06-11
RU2148585C1 (ru) 2000-05-10
WO1995023609A1 (en) 1995-09-08
DE69531753D1 (de) 2003-10-23
NZ282588A (en) 1997-12-19
NO963684D0 (no) 1996-09-03
MY119987A (en) 2005-08-30
CN1147205A (zh) 1997-04-09
IL112795A (en) 2001-01-28
EP0672658B1 (en) 2003-09-17
CZ294674B6 (cs) 2005-02-16
JPH09509937A (ja) 1997-10-07
HU227356B1 (en) 2011-04-28
MX9603831A (es) 1997-03-29
KR970701693A (ko) 1997-04-12
CA2183464A1 (en) 1995-08-09
PT672658E (pt) 2004-02-27

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