TWI357326B - Constrained himbacine analogs as thrombin receptor - Google Patents
Constrained himbacine analogs as thrombin receptor Download PDFInfo
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- TWI357326B TWI357326B TW094117273A TW94117273A TWI357326B TW I357326 B TWI357326 B TW I357326B TW 094117273 A TW094117273 A TW 094117273A TW 94117273 A TW94117273 A TW 94117273A TW I357326 B TWI357326 B TW I357326B
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- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000004018 waxing Methods 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
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Description
九、發明說明: 【發明所屬之技術領域】 本發明揭示一種由下列構造式所代表之化合物
(CH2)ng Het 式1 及其醫藥上可接受之鹽或溶劑化物,其中: R10和R34所連接之環碳間之單虛線:^代表一單鍵或一 雙鍵; X和與Y相連之碳之間之雙虛線二=__=代表一單鍵或無鍵; 當雙虛線代表一單鍵時,x係為_0〃^_nr6_,當雙虛線代 表無鍵時’ X係為H、-0H或-NHR20 且其他參數係如本文中之定義。 本發明亦揭示含有該化合物之醫藥組合物及組合以及其 田作漩血酶受體拮抗劑和大麻鹼受體結合劑之用途。 【先前技術】 各種吾巴辛(himbacine)衍生性化合物及含有此等化合物 之醫藥組合物係揭示於美國專利第M63,847、6,645,987和 6,326,38G號,以及美國專利巾請案1()/271,715、⑽ms 和1〇/412,982卜此等喜巴辛^生物可作為治療與血栓形 成、動脈粥狀硬化、再狹窄、高血壓、心絞痛、心律不整、 101679.doc 1357326 心臟衰竭、腦缺血、中風、神經退化性疾病和癌症有關之 疾病時之凝血酶受體拮抗劑^凝血酶受體拮抗劑亦已知為 蛋白酶致活受體-1 (par-ι)拮抗劑。許多喜巴辛衍生性化合 物亦可結合於大麻鹼受體並可應用於類風溼性關節炎、紅 斑性狼瘡、多發性硬化症、糖尿病、骨質疏鬆症、腎缺血、 腦中風、腦缺血、腎炎、肺及胃腸道之發炎性病變,以及 呼吸道病變’例如:可逆性氣道阻塞、慢性氣喘及支氣管 炎之治療。 ® 已知凝血酶於不同細胞型中具有不同之活性且已知凝血 扭受體係存在於例如:人類血小板、血管平滑肌細胞、内 皮細胞及纖維組織母細胞等細胞型中。凝血酶受體拮抗劑 因而預期可應用於治療血栓、發炎、動脈粥狀硬化和纖維 增生性病變,以及其他之凝血酶與其受體在其中扮演病理 性角色之病變。 凝血酶受體拮抗劑胜肽已可根據涉及凝血酶受體上之胺 基§九取代基之構造·活性研究來加以鑑別。Bernatowicz等 人’ L-Hed. Chem., (1996),ρ· 4879-4887 中,揭示四和五 胜肽為可能之凝血酶受體拮抗劑,例如:Ν_反式-肉桂醯_ 對-氟Phe-對-胍基Phe-Leu-Arg-NHjoN-反式·肉桂醯-對-氟 Phe-對-胍基phe_Leu_Arg_Arg-NH2。胜肽凝血酶受體拮抗劑 亦揭示於1994年2月17日出版之W0 94/03479。 大麻驗受體係屬G-蛋白質偶合受體超家族。其被歸類為 主導性神經元CB,受體及主導性周圍CB2受體。此等受體藉 由調節腺苷酸環化酶及Ca+2和K+流而產生活性。但CB,受體 101679.doc 之,用主要與中極神經系'統有關,cb2受體則咸信具有關於 支軋管阻塞、免疫調結和發炎之周圍神經作用。因此,經 選之CB2受體結合劑預期可於類風溼性關節炎、紅斑性狼 瘡、多發性硬化症、糖尿病、骨質疏鬆症、腎缺血、腦中 風、腦缺血、腎炎、肺及胃腸道之發炎性病變,以及呼吸 道病變,例如:可逆性氣道阻塞、慢性氣喘及支氣管炎相 關疾病之控制上具有醫療應用性。(R. G. pertwee,〇urr 6 (8)、(1999),635)。 喜巴辛,一種下式之哌啶生物鹼,
已被確認為一種毒菌鹼受體拮抗劑。(+)_喜巴辛之總合成係 揭示於 Chackalamannil等人,J. Am. Chem. Π8 (1996),
Ρ. 9812-9813 。 【發明内容】 在某 些方面,本發明係關於式I之凝血酶受體拮抗劑
式1 101679.doc 或其醫藥上可接受之鹽或溶劑化物,其中: R、R34所連接之環制之單虛線―代表-單鍵戍一 雙鍵; 4 — X和與Y㈣之碳之間之雙虛H表—單鍵或無鍵; 當雙虛線代表一單鍵時,x係為-on·,當雙虛 表無鍵時,X係為h、_oh或_nhr2❶; 4代 當雙虛線代表無鍵時,Rl5係為H、[义统基、_nr18r19 或-OR,7;或當當 ΥΑ Ι))1·2 1))1-2 為 或 時,R15係為Η或
CrC6烷基,當雙虛線代表一單鍵時,r1s不存在; 當雙虛線代表一單鍵時’ γ係為(〇)、⑻、(HH、 Η)或(H C, C0燒氧基),當雙虛線代表無鍵時,γ係為(〇)、 (n〇R”)、(h、h)、(h、C)h)、(h、sh)、(h、(^燒 或(H、-NHR45);
Z 係選自-ch2-、_〇·、_SWn4_、-nr30 、 -NC(0)R3。·、NC02R3。-、_NC(〇)NR3〇R3丨、 _NS〇2R3G-、-NS02NHR3。-、-C(〇)-、 c( N〇RG)4〇_cR3GR31_所組成之群; nI,n2,〜及〜係個別為〇_2 ;
R 為1至3個個別選自由下列所組成之群之取 代基.Η、C卜C6烧基、鹵素,經基、胺基、 (C!-^)烷基-胺基、(Ci_C6)二烷基胺基、 (C^Ce)烷氧基、-COR16' _c〇OR17、-SOR16、 -S〇2R16 , -NR16COR,6a . -NR,6COORI6a ^ 101679.doc -9· 1357326 _Nr16conr4r5’氣·(c】_c6)貌基、二氟(C「C6) 烷基、二氟(CrC6)烷基、C3_C6環烷基、q ^ 烯基、芳基(CVC:6)烷基、芳基((VC6)稀基、 雜芳基(CrC6)-烷基、雜芳基(C2_CJ烯基、 羥基(Cl-C6)烷基、胺基(crc6)-烷基、芳基 和硫(c「c6)烷基; R1和R2 係個別選自H、CVC:6烷基、氣(CVC6)烷基、 二iUc「c6)烧基、三敗_(c丨·C6)院基、q q 環烷基、CVC6烯基、芳基(CrC6)烷基、芳 基(G-c:6)烯基、雜芳基(Ci_C6)烷基、雜芳基 (C2-C6)稀基、經基·((:卜〇6)院基' (C1_C6)烷 氧基(crc0)烷基、胺基_(Crc6)烷基、芳基 和硫(CrC6)烷基組成之群;或Ry〇R2共同形 成一 =0基; r3 為 η、羥基、CPC6炫氧基、-nr18r〗9、-S0R16、 -S〇2R17、_c(0)0R17、_C(0)NRl8Rl9、CrC6貌 基、齒素 '氣(cvc6)烧基 '二氟(Ci_c6)烧基、 二lucked烧基、c3-c7環烷基、c2_c6稀基、 芳基(CrC6)烷基、芳基(C2_C6)烯基、雜芳基 (C! C6)烧基、雜芳基(02_(^6)稀基、經基(C!_C6) 烷基、胺基(Cl-C6)烷基、芳基、硫(crc6) 烷基、(crc6)烷氧基(Crc6)烷基或(c〗_c6) 烷基胺基(crc6)烷基、·〇_芳基、n3、n〇2、 C(=NR1)NR,R2 - N^CR^NR^2 ' NR,8COR19 > 101679.doc •10- 1357326 NR18CONR18R19、NR1SC⑼0R19、NRl8s(〇)2Rl9、 nr,8s(〇)2nr,8r19 > nhnr,8r19 , nr18nr,8r19 或nr]8r19 ;
Het
為5至14個原子的單-、雙·或三環雜芳基包含 1至13個碳原子以及1至4個雜原子,其係個 別選自由N,0和S組成之群,其中一環氮可 和C「C4烧基基團形成一 N•氧化物或一四級 基團, 其中該Het基團由1至4部分w所取代,其係個 別選自下列所組成之群:H; Ci_c6烷基;氟 (C丨-C6)烧基,二氟(crc6)貌基,·三氟 _(C1_C6)-烧基;C3_C7環烷基;雜環烷基;由 烧基取代之雜環烧基、稀基、 0H-(<VC6)烧基或=〇 ; c2-c6稀基;R2匕芳基 (CVD 烧基;R21-芳基 _(c2-c6)_ 稀基;r21_ 芳基氧基;R21-芳基-NH ;雜芳基(c「c6)烷 基’雜芳基(C^-C;6)-烯基;雜芳氧基;雜芳 基-NH-,.經基(C〗-C6)院基;二經基(Ci_c6) 院基;胺基(crc6)烷基;(crc6)烷基胺基 _(ci-c6)烧基;二-((Ci-C6)烧基)_ 胺基(Ci_d 烧基;硫(c〆6)燒基;cvc:6貌氧基; 婦基氧基,_ 素,-NR4R5 ; ; _〇Ι·Ι ; -COOR17 ; -COR16 ; -〇s〇2CF3 ; -CH2〇CH2CF3 , (C1-C6)燒基硫; 101679.doc 11 ⑧ -C(0)NR4R5; -OCHR6-苯基;苯氧基 _(CrC6) 烷基;-NHCOR16 ; -NHS02R16 ;二笨基; -OC(R6)2COOR7 ; -0C(R6)2C(0)NR4R5 ; (crc6)烷氧基;-C(=NOR17)R18 ; (c丨-(:6)烷 基取代之CrC6烷氧基、胺基、-OH ' COOR17、-NHCOOR17、-CONR4R5、芳基、 由1至3個部分取代之芳基,其係個別選自卣 素、-CF3、CrC6烷基、CVC6烷氧基和 -COOR17組成之群,芳基,其中鄰近碳原子 和一甲烯二氧基基團-C(〇)NR4R5或雜芳基 形成一環;R21-芳基;芳基,其中鄰近碳原 子和一曱烯二氧基基團形成一環;雜芳 基;和雜芳基,其中鄰近碳原子和一 c,_c 3 5
R4和R 烯基基團或甲烯二氧基基團形成一環; 為個別選自由H、CrC6烷基、苯基、苄基和 q-C7環烷基組成之群,或R4和R5共同為 -(CH2)4-、-(CH2)5-或-(CH2)2NR7-(CH2)2-並與 其相連結的氮共同形成一環; R6 為個別選自由H、c〗-c6烷基、苯基、(C3_C7) %烧基、(c3-c7)環烧基(crc6)烧基、(C〗-C6) 烷氧基(CpC:6)烷基、羥基(CrC:6)烷基和胺基 (Cl-C6)^基組成之群; R? R8、R1 101679.doc 為Η或(c「c6)烧基; 洋R為個別選自R丨和_〇R丨組成之群,當單虛線為
-12· 1357326 R9 一雙鍵,則R1G不存在; 為Η、〇H、CrC6燒氧基、鹵素或鹵(Ci-c6) 院基; ' R16和 R16a 係個別選自由(^-(^低碳烷基、苯基或苄基所 * 組成之群; _ R17、R18和 R】 19係個別選自由Η、(^-(:6烷基、苯基、苄基組 r20 成之群; 為Η、CrC6烷基、苯基、苄基、-C(0)R6或 • -so2r6 ; R2丨 為1至3部分個別選自,H、-CN、-CF3、-0CF3、 • 鹵素、-N〇2、CrC6烷基、(^-(^烷氧基、 (CrCJ-烧基胺基-、二-((Cj-Cg)院基)胺基、 胺基(c「c6)烷基、(cvc6)-烷基胺基(c「c6) 烷基、二-((cvd烷基)胺基(crc6)烧基、羥 基-(Crc6)烧基、-COOR17 、 -COR17 、 -NHCOR】6、-NHS02R16、-NHS02CH2CF3, 雜芳基、-c(=nor17)r18,NR25R26烷基-、羥 - 基-烷基-、-C(0)0R17、-COR17、-NHCOR16、 - _NHS(0)2R16 、 -NHS(0)2CH2CF3 、 -C(0)NR25R26 、 -NR25-C(0)-NR25R26 、 R22 -S(0)R13、-S(0)2R13和-SR13所組成之群; 係選自 Η、Ι124-((ν(:1())烷基、R24-(C2-C1())烯 基、1124-((:2-(:,。)炔基、R27-雜-環烷基、r25_ 方基、R -方基(C〗-C6)烧基、R29-(C3-C7)環
I01679.doc • 13_ <D 1357326 烧基、R29-(C3-C7)環烯基、-OH、-〇C(〇)R30、 -C(0)0R3。、-C(0)R3°、-C(O)NR30R31' >NR3°R31、 -NR30C(O)R31' -NR3°C(0)NR31R32、-NHS02R30、 -OC(O)NR30R31 、R24_(Cl_Cl。)烷氧基、 R24-(C2-C1())-烯氧基、R24_(CVCi())炔氧基、 R -雜環烧氧基、r29-(C3-C7)環貌氧基、 R29-(C3-C7)環-埽氧基、R29_(C3_C7)環烷基
-NH-、-NHS02NHR16和-CH(=NOR17); 或R和R 與其相連之碳共同,個別形成一經R42_取代 之3-10個原子的環碳環,或一經汉42_取代之 4-10個原子之雜環,其中^個環成員係個別 選自由-0-、-NH-和-SOn2-所組成之群,當 R22和R1Q形成一環時,單虛線代表無鍵; R24為1、2或3部分個別選自由下列所組成之群:Ή、齒素、 -OH、(q-CO烷氧基、R35_芳基、
烷基-c(o)-、(c2-c丨。)-烯基-c(o)-、(C2_Ci〇) 炔基-c(〇) ’雜環烷基、r26-(C3-C7)環烷基、 R26-(C3-C7)環烯基、_oc(〇)R3。、{(owyo、 -C(0)R30、-C(〇)NR30R31、-NR3〇R3i、 -NR30C(O)R31 、 -NR3°C(0)NR3lR32 、 -NHSO2R30 > -OC(〇)NR30R31 ' R24-(C2_C] ^ 烯氧基、R24-(C2_C1Q)快氧基、R27-雜環烧氧 基、R29-(C3-C7)-環炫1 氧基、R29_(C3^@_ 烯氧基' r29-(c3-c7)環烷基、Nh_、 101679.doc -14- 1357326 -NHSO2NHR16和-CH(=NOR17); R 為1、2或3部分個別選自由下列所組成之 群:H、雜環烷基、鹵素、_C〇〇r36、_CN、
-C(0)NR37R38. -NR39C(0)R40' -〇R36> (C3-C7) 環烷基、(C3-C7)環烷基-CVC6)烷基、(Cl_c6) 烧基(C3-C7)環烧基-(c丨-C6)烧基、豳基(Cj-cj 烧基(C3-C7)環烧基(c丨-C6)烧基、經基(c丨_c6) 炫基、(CVCe)炫氧基(CVC6)炫基、和r4匕雜 芳基;或兩個相鄰環碳上之R25形成一稠合亞 甲基二氧基基團; 2 6 R 為1、2或3部分個別選自由H、鹵素和 院氧基所組成之群: 2 7 R 為1、2或3部分個別選自由下列所組成之 群:H、R28-(Cl-Cl〇)院基、R28_(C2_C1Q)稀基 和 R28-(C2-C1())炔基; 2 8 R 係為Η、-OH或((VC6)烷氧基; ^29 為1、2或3部分個別選自由下列所組成之 群.Η、(CVC6)烧基、-OH、(CVC6)烧氧基 和鹵素; R 、R和R係個別選自由下列所組成之群:Η、(c丨_c 1 〇)_ 烧基' (Ci-C6)烷氧基(C】-C10)-烷基、尺25_芳 基(c,-c6)-烷基、R33-(C3_C7)環烷基、 R34-(c3-c7)環烷基(c,-c6)烷基、芳基、 雜環烷基、雜芳基、雜環烷基(Ci_C6)烷基和 10J679.doc (¾) -15· 1357326
R 33 R35
R36 R37和 R38 R39和 R40 雜芳基(C^Cd烷基; 係為H、(q-Cd烷基、OHJCVCd烷基或 (CrCe)烷氧基; 當單虛線為一單鍵時,R34係為(H、R3)、(Η、 R43)、(〇)或(NOR17),當單虛線為一雙鍵時, R34 係為 R44 ; 為1至4部分個別選自由下列所組成之群: H、(CVC6)烷基、-OH、自素、-CN,((VC6) 烷氧基、三鹵(C丨-C6)烷氧基、(Ci-Ce)烷基胺 基、二((Ci-CJ烷基)胺基、-〇CF3, ΟΗ-((ν(:6) 烷基、-CHO、烷基胺基、-C(O) 二((C〗-C6)烷基)胺基、-NH2、-NHC^OKCrCe) 烧基和-N((Ci_C;6)烧基)C(0)(C!-C6)烧基; 係為H、(c丨-c6)烷基、鹵(cvc6)烷基、二鹵 (C丨-C6)烷基或三氟(C「C6)烷基; 係個別選自由下列所組成之群:Η、(<^·(:6) 烷基、芳基((VC6)烷基、苯基和(C3-Ci5)環 烧基; 或 R37 和 R38 共同為 _(CH2)4-、-(CH2)5-或 -(CH2)2_NR39-(CH2)2-並與其相連之氮形成 一環; 係個別選自由下列所組成之群:Η、(Ci-CO 烷基、芳基(CVC6)烧基、苯基和(C3-C15)-環 烧基; 101679.doc • 16 - ⑤ 1357326 或-NR39C(0)R40基團中之R39和R40,與其所 相連之碳和氮原子,形成一個5-8員之環内醯 胺;
為1至4部分個別選自由氫、(CrCd烷基、 (CVQ)烷氧基、(CVC6)烷基胺基、二(((VC6) 烷基)胺基,-OCF3,OH-CCVCJ烷基、-CHO 和苯基組成之群; R42 為1至3部分個別選自由氫、-OH、(CVCe)烷 基和(C丨-C6)烷氧基組成之群; r43 為-nr30r31、-nr30c(o)r31、-nr30c(o)nr31r32、 -NHS02R30或-NHCOOR17 ; R 為 Η、CVC6 烷氧基、-SOR16、-S〇2R17、 -C(0)0R17、-C(0)NR18R19、Cl-C6烷基、鹵 素、氟(C「c6)烧基、二氟(c丨-c6)烷基、三氟 (Crc6)烷基、(:3-(:7環烷基、C2-C6烯基、芳 基(cvc6)烷基、芳基(C2_C6)烯基、雜芳基 (CVC6)烧基、雜芳基(c2-c6)烯基、經基(Ci_c6) 烷基、胺基(CrC6)烧基、芳基、硫(c「c6) 虎基' (C】-C6)院氧基(c^-c^)院基或(c「c6) 烧基胺基(C^-Cg)院基;和 R45 為H、CrG烧基、-C00R164_S02。 在某些具體實施例中,Het係為吡啶基且W為苯基。 在另一具體實施例中,w係經氟或_CN取代。 再另一具體實施例中’ Z係為-CH2-、η丨為n2為〇,且〜 10l679.doc -17-
1357326
再另-具體實施例中’Z係為如n丨為l _〇,且h為卜 再另一具體實施例中,Z係為办^為^⑽’且〜為卜 再另一具體實施例中,R1為曱基,且r2、r8、r9、Rl〇、 R11均為H。 再另一具體實施例中,R3為Η。 再另一具體實施例中,R3為_〇Η。 再另一具體實施例中,R22為甲基。 Β 再另一具體實施例中,X和γ均為〇。 再另一具體實施例中,單虛線和雙虛線均為單鍵。 再另一具實施例中,本發明係針對—種醫藥組合物,其 s有治療有效3:之至少一種式〗化合物及一體醫藥上可接 受之載體。 再另具體貫施例中’本發明係針對一種抑制凝血酶受 體之方法,其包含對需要此等治療之哺乳動物投予治療有 鑄效量之至少一種式I化合物。 再另一具體實施例中’本發明係針對一種抑制大麻鹼受 ^方法,其包含對需要此等治療之哺乳動物投予治療有 效量之至少一種式I化合物。 再另具體實摊•例+,本發明係針對一種治療醫療狀況
1 I θ /、L έ對需要此等治療之哺乳動物投予治療有效 里之至少一插·+、Τ 徑式I化合物,其中該醫療狀況係為一心血管或 循環疾病或狀 &况、發炎疾病或狀況、呼吸道疾病或狀況、 癌症、急性腎多· Θ农蝎、腎絲球腎炎、星狀細胞增生、肝、腎、
1〇1679.dOC •18- 1357326 肺或腸道之纖維化病變、阿茲海默症、糖尿病、糖尿病神 經病、類風濕關節炎、神經退化症、神經毒症、系統紅斑 性狼瘡、多發性硬化症、骨質疏鬆症、青光眼、黃斑病變' 牛皮癬、放射線後的纖維化、内皮功能障礙、創傷或脊髓 損傷’或其徵兆或結果。 再另一具體實施例中,本發明係針對一種治療—醫療狀 況之方法’其中該^血管疾病或循環疾病或狀況係為了動 脈粥狀硬化、再狹窄、高血壓、急性冠心症、心絞痛、心 m心肌梗塞' 血栓性或血检检塞 性中風、周圍血管疾病、深部靜脈检塞症、靜脈血检检塞 症、與荷爾蒙替代治療有關之心血管疾病、泛發性血管内 血㈣固症、腎缺血、腦中風、腦缺血、腦梗塞、偏頭痛、 腎管恆定或勃起功能障礙。 再另-具體實施例中,本發明係針對_種治療—醫療狀 況之方法,其中該發炎疾病或狀況係為腸道激躁症、克隆 氏症、腎炎或為照射或化療誘發之冒腊、# ㈣之月腸道、肺、膀胱、胃 腸道或其他器官之增生或發炎性病變。 再另一具體實施例中,本發明係針對_ π θ ϋ β τ耵種治療一醫療狀 況^万法’其中該呼吸道疾病或妝 ^灰7丙飞狀况係為可逆性氣道阻 塞、乳%、慢性氣喘、支㈣炎或慢性氣道疾病。 再另一具體實施例中,本發明係針 'V7 ^ ^ t 種治療一醫療狀 況之方法,其中該癌症係為腎細 病變。 I 飞與血管新生有關之 再另一具體實施例中,本發 療狀 101679.doc •19· 1357326 況之方法,其中該神經退化性疾病係為巴金森氏症、肌萎 縮性側索硬化症、阿兹海默症、亨丁頓氏症或威爾森氏症。 再另一具體實施例中,本發明係針對一種治療一醫療狀 況之方法,其進—步包括投予至少—種治療有效量之可用 以治療下列之藥劑:發炎、風濕症、氣喘、腎絲球腎炎、 骨質疏鬆症'神經病變及/或惡性腫瘤、血管新生相關病 變、癌症、肝、腎或肺之病變、黑色素瘤、腎細胞癌、腎 病、急性腎衰竭、慢性腎衰竭、腎血管恆定、腎絲球腎炎、 慢性氣道疾病、膀胱發炎、神經退化性疾病及/或神經毒疾 病、狀況或傷害、放射線後的纖維化、内皮功能障礙、牙 周病或創傷。 再另一具體實施射,纟發明係、針對一種治療—醫療狀 况之方法,其進一步包括投予至少兩種治療有效量之藥劑。 詳細說明: 本發月係關於以式!表:^之化合物作為凝血酶受體抬抗 籲』之發現。此等化合物和任何包含該等化合物之調配物可 用以,口療各種疾病和狀況,包括但不限於:血检形成、動 脈粥狀硬化、心律不整、心臟衰竭、再狹窄、心絞痛、高 片堅恥缺血、癌症、腦中風、多發性硬化症、糖尿病、 骨質疏鬆症、類風澄性關節炎、系統紅斑性狼瘡、腎缺血 性腎炎、肺及胃腸道之發炎性疾病,以及呼吸道病變’例 士可逆性氣道阻塞、慢性氣喘及支氣管炎。 、在式I中’若與其所連接之氮連結成一環,則所形 成之%為定基、卜㈣基和i•略嗪基,其中該略嗓基 !〇1679^〇〇 1357326 環:可視情況於4_位置之氮上經r7基團取代。 若在下列部份中之單虛線環鍵代表一單鍵,
則R係為(0)或⑼(〇)(R17),或⑻(r3)或⑻化43)。類似 地’若在下列部份中之單虛線環鍵代表一雙鍵,
R34
在上文及本發明文t,除非另有指明,否則下列術語係 具有下列意涵: 患者」包括人類及動物二者。 哺乳類」係指人類及其他哺乳動物。 「燒基」係指-脂肪族碳氫鏈,其可為直鏈或支鍵並於 鏈中包含約1至約20個碳原子。較佳之烧基基團於鏈中包含 約1至約12個碳原子。更佳之烷基基團鏈中包含則至約6 個碳原子。支鏈係指一或多個低碳數烷基基團例如:甲 基、乙基或丙基連接於-線狀貌基n碳數燒基」係指 鏈中具有約i至約6個碳原+之基目,其彳為直鏈或支鍵 狀。術語「經取代之烷基」係指該烷基基團可經一或多個 相同或不同之取代基取代,各個 素、烷基、芳基、環烷基、氰基、 取代基係個別選自由函 羥基、烧氧基、炫硫基、
Wi679.doc -21.
1357326 胺基、-NH(烷基)' -NH(環烷基)、_N(烷基)2、羧基和_c(〇)〇 烷基所組成之群。適當之烷基基團之非限制性實例包括: 甲基,乙基、正丙基、異丙基和第三丁基。 「芳烷氧基」係指芳烷基-〇·基團,其令該芳烷基基團係 如前述。芳烷氧基機團之非限制性實例包括:苄氧基及卜 或2-萘曱氧基。其透過醚氧與母部分結合。 氟烷基、二氟烷基和三氟烷基係指烷基鏈,其中端點之 碳係經1、2或3個氟原子取代,例如·· _Cf3、·εΗ2(^、 -CH2CHF2或-CP^Ci^F。齒烷基係指經1至3個齒原子取代之 烧鏈。 「烯基」係指直鏈或枝鏈狀之碳原子鏈,其鏈中具有一 或多個共|ra或非共輕雙鍵。「炔基」係指—脂肪族烴基團, 其含有至少一個碳-碳三鍵且其可為直鏈或枝鏈狀並於鏈 中含有約2至約15個碳原子。較佳之炔基基團之鏈中具有約 2至約12個碳原子,且更佳者為鏈中具有約2至約4個碳原 子分枝狀係指一或多個低碳數烷基基團,例如:曱基、 乙基或丙基,連接於一線狀炔基鏈。「低碳數炔基」係指鏈 中有約2至約6個碳原子’其可為或枝鏈狀。適當之块基基 團之非限制性實例包括:乙絲、丙缺基、2_丁块基和3_ 曱基丁块基。術語「經取代之炔基」係指該快基基團可經 一或多個相同或不同之取代基取代,各個取代基係個別選 自由烷基、芳基和環烷基所組成之群。 烷基烯基和炔基鏈上之取代係取決於鏈之長度和取代 基之大j及本性。沾習此項技藝者明白較長之鏈可搭載多
J01679.doc -22- 1357326 個取代基,較短之烧基鏈,例如:甲基或乙基,則可㈣ 素多重取代,但其他則除了⑽外只能有-或兩個取代 基。較短之不飽和鏈’例如:乙烯基或乙炔基,通常不經 取代或僅限於經-或兩個基團取代,其端視可用之碳鍵而 定。 「環院基」係、指-非芳香性單.或多環環系統包含約3至 約1〇個碳原子’較佳為約5至約1〇個碳原子。較佳之環烷基 環包含約5至約7個環原子。環燒基視情況可由一或多「環 系統取代基」取代,如上定義,取代基可為相同或不同。 適用之單環環院基之非限制實例包括環丙基、環戍基、環 己基、環庚基及其類似物。適用之多環環 例包括卜十氮蔡基、正获基、金剛烧基及其類似物,= 部份鮮者,例如:氮節基、四氮蔡基及其類似物。 「環伸燒基」係指-相對應之二價環,其中與其他基圓 之連接點包括所有位置及幾何異構物。「環烯基」係指一3 鲁至7個原子並具有一或多個不飽和鍵但不具芳香性之碳環。 「環系取代基」係指-連接於-芳香或非芳香環系之取 代基,其例如:取代環系上之可用H。環系取代基可為相同 或相異’其各個別選自由下列所組成之群··院基、稀基、 炔基、芳基、雜芳基、芳炫基、烧基芳基 '雜芳烧基、雜 芳基烯基、雜芳基块基、烧基雜芳基、經基、經基貌基、 :氧基、芳氧基、芳烷氧基、醯基、芳醯基、豳素、硝基, 亂基、幾基、貌氧幾基、芳氧幾基、芳貌氧幾基、燒基石黃 醯基、芳基石黃醯基、雜芳基石黃醯基、烧硫基、芳硫基,雜 101679.doc
•23- 1357326 芳硫基’芳烷硫基、雜芳烷硫基、環烷基,雜環基、、c (=N-CN)-NH2、-C(=NH)-NH2、-C(=NH)-NH(烷基),γ〗γ2Ν… Ιυ2ν-烷基-、yiY2NC(o)-、YiY2NS〇24〇_s〇2NYiY2,其 中Yi和Y2可為相同或相異且係個別選自由Η、烧基、芳 基、環烷基和芳烷基所組成之群《「環系取代基」亦可代表 一單一部分,其於環系上兩個位於相鄰碳上之可用玛每個 碳上一個Η)上同時取代。此等部分之實例為亞甲基二氧 基、伸乙基二氧基、-C(CH3)2_和類似者,其形成例2下 之部分:
v # D 「雜環絲」係指-5綱鮮環含有心個碳原子和】 或2個雜原子’其係選自由_〇_、_8_和领7'组成之群, 過一碳原子與分子之其他部分捸蛀 、 咐m 卩刀連接。雜環貌基之實例為2_ 各咬基、四氣硫苯_2-基、四氫如夫喃基、4m 2 ㈣基、四氣+比嗔基、2-嗎琳基和2_硫嗎琳基〇 V _ 「鹵素」係指氟、氣、溴或碘基團。 二:ί:Γ6)炫基」係指,鏈,其於兩個不同之 石反原子上經兩個羥基基團取代。 J之 「芳基」係指一芳香性單環或多環系 個碳原子,較佳為約6至約1()個碳原子^ =至㈣ 經-或多個「環系取代Α Μ甘方基基團可視情況 文中之定義。適當之二美」;代’其可相同或相異並如本 之方基基團之非限制性實例包括:苯美、 101679.doc •24· 萘基'茚基、四氫萘基或氫茚基β 「雜芳基」係指-芳錄單環或苯并稠合㈣基團, 含5至1。個原子,其中有2至9個碳原子和】 :、: :個別選自Ν、〇和s組成之群,但該環不包括鄰近氧二: 幵4環氮之Ν-氧化物及環氮由一 c「Ca基 ; =四級胺化合物亦包括其中。單環雜芳基基團之實二 ㈣基,基、異㈣、吟二唾基、㈣、=為 嗟^ ϋ基、㈣基、时基、㈣基、異喧唾基、售 j基、料基和三°坐基。苯并稠合㈣基基團之實例為% :二二基、異喹琳基、二氮雜萘基、苯并°塞吩基(即: =秦基)、v❹基、苯并吱喃基、苯并喔哇基和苯 基^有位置異構物全都涵蓋,例如2_㈣基、H定基和 一疋基w.取代雜芳基係指該基團巾可取代環碳原子具有 二如上述定義之取代基’或其鄰近碳原子和—伸烧基基團或 亞甲基一氧基團形成一環,或在Het環中之氮可用r21_芳基 取代=可視需要由如”所定義之院基取代基所取代。土 何扣Het」經例證為單環及如上定義之苯并稠合雜芳基 基團’以及三環基團,例如苯并㈣基(例如1,4或7,8)或啡 啉基(例如1,7、H0或4,7)。 鄰,厌原子和一伸烷基形成-環之雜芳基基團之實例為 ’衣戊烯吡啶、2,3-環己烯吡啶和2,3-環庚烯吡啶。 列描述中,例如若稱其中的R4和R5為個別選自一取代 基基團,音:lt:r>4e5 . . 思'知R和R係經個別選擇,但R4*R5亦可能出現 在一個分子巾扣 %過一次,該等出現亦經個別選擇。熟習此 101679.doc 1357326 項技藝者將瞭解取代基 之數目。 之大小和性質將影響 存在之取代基 ^經取代」係指在指定之原子上 選自經指定之基團所置換,以二:由 之正常價電子不會過多,且令取^疋原子在現存核境下 取代基及/或可變基團之組合 2化。物 人札「政— 令田e亥組合物為穩定之化 〇?合物」或「穩定結構」係^夠強健以便從 二合物令分離時能存活成為—有用純度之化合物, 並可調配成為一有效治療藥劑。 術語「視料絲代」料㈣料 分選擇性取代。視情況經取 由基次# 代或經取I 取代之原子可如所指明為未經取 物本::之化合物有至少一個不對稱碳原子,其所有異構 ’ ^ .非鏡像異構物和旋轉異構物並因而涵蓋為本發 明之-部份。本發明包括(+)·和(_)_異構物,其可為純物型 式或混合物,包括消旋混合物。異構物可利用傳統之技術, 藉由使光學純化或光學強化之起始物質或藉由分離式!化 合物之異構物而製得。 咸亦應庄意.本文之内文、流程和實例中任何具有未滿 足價數之任何碳原子及雜原子係假設其具有足以滿足價數 之Η原子數。 若稱化合物中之官能基團為「受保護」,此意指該基團為 經修飾型式以防止該化合物進行反應時於經保護位置上之 不欲副反應。適當之保護基團係為熟習此項技藝者所知, 】01679.doc • 26 · 1357326 並可參考標準教科書’例如:τ· w· Greene等人,p論如〜
Groups in organic Synthesis (1991),而^,New 。 本文所使用之術語「組合物」係涵蓋含有特定量之特定 成份之產物,以及任何直街或間接自特定量之特定成份之 組合所產生之產物。 本發明化合物之溶劑化物亦涵蓋在内。「溶劑化物」係指 本發明化合物與一或多種溶劑分子之物理性結合。此等物 理性結合涉及不同程度之離子和共價鍵,包括:氫鍵。在 某些例子中’溶劑化物可被分離,例如:若—或多種溶劑 分子併人於結晶@體之晶格中時。「溶劑化物」涵蓋溶液相 及可分離之溶劑化物。適當之溶劑化物之非限制性實例包 括:乙醇化物、甲醇化物以及類似者。「水合物」係為一溶 劑化物,其中之溶劑分子為H2〇。 「有效量」或「治療有效量」係指可有效抑制凝血酶受 體並因兒產生所欲之治療、緩和、抑制或預防功效之本發 明化合物或組合物之量。 彼等熟習此項技藝者明瞭:對於某些式工化合物,其中一 種異構物之藥理活性會較大於其他異構物。 式I之化合物可形成鹽類,其亦包含於本發明之範圍内。 本文中除非另有指明’否則參照式!之化合物亦包括參日3苴 鹽類。本文所使用之術語「鹽(類)」係指與無機及/或有機 酉复所生成之酸性鹽類,及與無機及/或有機驗所生成之驗性 鹽類。此外’若-^化合物含有驗性部分,例如但不限於: 吡咬和味唾,和一酸性部分,例如但不限於:缓酸’則可 101679.doc -27^ liy/02b 月fci形成兩性離子(「内链>. 「 — 、 皿」)並包括於本文所使用之「鹽(類)」 中醫藥上可接<(例無毒、生理上可接受)之鹽類為較 :者II然其他鹽類議可使用。式!化合物之鹽類之生成可 藉由例如’使式I化合物與一量,例如:當量之酸或鹼在— "質你J如.可使鹽沉澱者或在水性介質中反應,再予以 冷凍乾燥》 酸加成鹽類之示例包括:醋酸鹽、抗壞血酸鹽、苄酸鹽、 苯%酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦 鹽、彳早腦%酸鹽、延胡索酸鹽、鹽酸鹽、溴酸鹽、碘酸鹽、 乳酸鹽、馬來酸鹽、甲磺酸鹽、萘磺酸鹽、硝酸鹽、草酸 鹽、磷酸鹽、丙酸鹽、水楊酸鹽、琥珀酸鹽、、硫酸鹽、 酒石酸鹽、硫氰鹽、甲苯磺酸鹽(亦稱為tosylate)及類似者。 此外,一般認為適用於與鹼性醫藥化合物生成醫藥上有用 之鹽類之酸係例如:由P. Stahl等人討論於Camille G.(編著) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH、S. Berge等人 ’ Journal of Pharmaceutical Sciences (1977) 66⑴ 1-19 ; P. Gould, International J. of Pharmaceutics (1986) 3_3 201-217 ; Anderson 等人,The Practice of Medicinal Chemistry (1996),
Academic Press,New York ;和 The Orange Book (華盛頓, D.C·,Food & Drug Administration之網站)中。此等揭示係 以參照之方式列為本文之參考。 鹼加成鹽類之示例包括:銨鹽、鹼金屬鹽類’例如:鈉、 鋰和鉀鹽、鹼土金屬鹽類’例如:鈣和鎂鹽、具有機鹼基(例 101679.doc • 28- 1357326 如:有機胺類)之鹽類,例如:二環己胺、第三丁胺、和具 胺基酸之鹽類,例如:精胺酸、離胺酸及同類者。鹼性含 氮基團可以試劑,例如:低碳數烷基函化物(例如:甲基, 乙基和丁基氯化物、溴化物及碘化物)、二烷基硫酸鹽(例 如:二甲基、二乙基和二丁基硫酸鹽)、長鏈齒化物(例如: *基月桂基和硬脂酸氯化物、溴化物及蛾化物)、芳烧基 鹵化物(例如.苄基和苯乙基溴化物),及其他者加以四級化。 Φ 所有此等酸性鹽類和鹼性鹽類預料均為本發明範圍内之 醫藥上可接受之鹽類且將所有酸和驗性鹽類視為等同於使 用於本發明目的上之游離型式之相對應化合物。 式I之化合物,及其鹽類、溶劑化物和前藥,可能以其互 變異構物型式存在(例如:為—酿胺或亞胺驗)。所有此等互 變異構物型式於本文中均視之為本發明之一部分。 本發明化合物(包括該化合物之鹽類、溶劑化物和前藥以 及該前藥之鹽類和溶劑化物)之所有立體異構物(例如:幾何 • 異構物、光學異構物和同類者),例如彼等可因各取代基上 不對稱炭而存在者,包括:鏡像異構型式(其無不對稱碳 時仍可存在)、旋轉異構物、阻轉異構物(atr〇pis〇_)和非 鏡像異構型式在本發明之範圍為均視之為位置異構物(例 如:4-。比。定基和3“比。定基)。本發明化合物之個別立體異構 物可能例如為實質上無其他異構物或可能為混合物,例 如··為消旋混合物或具有所有其他,或其他經選之立體異 構物本么明之對掌中心可有S或R構型,如IXJPAC 1 974 汉⑽咖印咖嶋之定義。所使用之術語「鹽類」'「溶劑化 101679.doc •29· 物」、「前藥」和類似者係預料可 之鏡像異構物、立體 k用於本發明化合物 杨里田故 構物、旋轉異構物、互變異魅 位置異構物、消旋混合物 ^異構物、 咸知本發明涵!…鹽、溶劑化物和前藥。 碉本發月㊆盍包含式地合物以及至少 之組合物和至少一遒十τ外入d 種式I化合物 施例。 式化口物之鹽或溶劑化物之具體實 間咸^非另有陳述’否則所有定量測量’例如··時 其名義上陳述之值。 ㊣的變絲圍並不受限於 代表性之式I化合物之合成顯示如下。 在流程i中’以BBr3將異喜巴辛類似物i裂解,再將所得 之酵加以保護以得到醋酸醋2。此類似物之分子間自由基環 化作用產生化合物3,將之以曱醇化K2C〇3處理以得醇4。將 該醇去氧並導入-7a經基基團以得5。其亦被轉化成厢醚 6 〇
101679.doc
-30- 丄力7326
流程1
經雜原子取代之類似物之合成係展示於流程2-4。在流程 2中’將對掌丙炔醇7轉化成第三丁酯8。烯醛u可隨即被製 備出來並藉由標準Horner-Wardsworth-Emmons反應再接著 4化反應該轉化成二烯醇酸^該酸可與醇8偶合以得到酯 13。選擇性炔屬烴還原作用再接著熱環化作用可得到中間 物15,將之轉形成醋酸酯16。將第三丁基基團加以裂解並 101679.doc -31 * 1357326
將該酸轉化成其酸氯化物並以Bu3SnH和鈀催化劑加以還原 以得到盤17a和17b。 流程2
1)(Et0)2P(0)CH2C02Et NaH 2) KOH R·! = OBn orCH2OBn
Hi Lindlar 催 1 劑 P查P林
r2 16 :OAc or CH2〇Ac 1) TFA-DCM 2) (COCl)2, cat. DMF 3) Bu3SnH, Pd cat.
r2 17a, R2 = OAc 17 b, R2 = CH2OAc 在流程3中,將醛17a與磷酸酯18偶合以得中間物19。將 此化合物與曱醇化K2C03迴流時,其可產生環醚20,將其7a-位置羥化以得中間物21。將此中間物與硼酸偶合以得類似 物 2 2 a - d 〇 •32· 101679.doc 1357326 流程3
在流程4中,將醛17b同樣地與磷酸酯23偶合,以得醋酸 酯24和醇25之混合物。以四溴化碳和三苯基膦處理處理該 醇25,可得溴化物26和環醚27之混合物。該溴化物26可置 於自由基條件中以得28。 101679.doc •33· 1357326 流程4
將上列所表現之流程圖徑更詳細說明於下列步驟中。 101679.doc • 34- 1357326 步驟1 :
於溶於6 ml曱苯之2 (110 mg,0.207 mmol)(2之製備請參 見美國專利第6,645,987號)溶液中加入AIBN (7 mg,0.04 mmol,0.2 當量),再加入Bu3SnH (170 μΐ,0.63 1 mmol,3 當量)並將該混合物加熱迴流3小時。將此溶液冷卻、濃縮 並以製備性TLC加以純化以得到69 mg之3。
於溶於 2 ml之MeOH-H2〇混合物(8 : 2 v/v)之3 (50 mg, 0.111 mmol)之溶液中加入 K2CO3 (77 mg,0.557 mmol,5 當 量)並於室溫之下攪拌1小時。以NH4C1水溶液將該混合物稀 釋並以CH2C12萃取3次。以鹽水洗滌合併之有機層、經 MgS04脫水、過濾、濃縮並以製備性TLC加以純化以得到28 mg之 4。HRMS : 410.2134 (MH+)。 101679.doc 35-
1357326 步驟2 :
1) TsCI, Py 2) Nal, CH3CN 3) Bu3SnH, AIBN 4) LHMDS 然接 02
將溶於〇°C之4 ml。比咬之4 (1 30 mg,0.32 mmol)之溶液與 5當量之TsCl於室溫下攪拌至以TLC檢測得知反應已進行。 將吡啶濃縮並於殘留物中加入NaHC03水溶液。以EtOAc萃 取該混合物並以層析法純化該粗產物以得到13 5 mg之曱苯 績酸S旨。 將溶於4 ml CH3CN之甲苯磺酸酯(135 mg,0.24 mmol)溶 液與Nal (3 60 mg,2.4 mmol,10當量)迴流過夜。以30 ml EtOAc將該混合物稀釋並以H20和鹽水洗滌之。經MgS04脫 水、過》慮並》農縮以得到12 0 m g之埃化物。 將此蛾化物(120 mg,0.23 mmol)溶於5 ml苯之溶液與6 當量之Bu3SnH和0.4當量之AIBN迴流3小時。將之冷卻、濃 縮並藉由層析純化以得到80 mg脫碘產物。 於此化合物(80 mg,0.203 mmol)溶於0°C之3 ml THF之溶 液中加入1 Μ之溶於THF之LHMDS溶液(305 μΐ,0.305 mmol,1.5當量)。攪拌20分鐘之後,將反應瓶排空並充填 入氧並攪拌1.5小時,再加入NaHS03水溶液至其中。將THF 濃縮,並以EtOAc萃取水相。將萃出物經MgS〇4脫水、過慮、 101679.doc -36- 1357326 濃縮並以製備性TLC加以純化以得60 mg之5。MS : 410.1 (MH+)。 步驟3 :
於4 (3 2 mg,0.073 mmol)溶於2 ml CH2CI2之溶液中加入 NaHC03 (13 mg,0· 155 mmol,2 當量)和 Dess-Martin過填炫 (38 mg,0.09 mmol,1.2當量)。將該混合物於室溫之下授 拌1.5小時,以Et20稀釋並與Na2S203攪拌至兩層分清楚為 止。分離有機層並以Et20萃取水層兩次。以鹽水洗滌合併 之有機層,經MgS04脫水、過濾、濃縮以得30 mg之醛。
於此酿(30 mg,0.074 mmol)溶於0.75 m卜比0定之溶液中加 入經胺氣化氫(20 mg,0.240 mmol)並於室溫之下撥拌過 夜。將該混合物倒入NH4C1水溶液中並以EtOAc加以萃取。 以鹽水加以洗滌,經MgS04脫水並藉由層析純化以得到26 mg之 6。HRMS : 437.2259 (MH+)。 步驟4 :
OH
1) DHP, PTSA 7
OH 2) BuLi, (Boc)2〇 3) PPTS, EtOH
101679.doc -37- ⑤ 1357326
於0C 之下,於7 (10 ml,127.5 mmol)溶於純 DHP (12·8 14〇.3 mmo卜1·ι當量)之溶液中加入對曱苯磺酸單水合 物(243 mg,1.28 mmol,丄mol %)並移除冰浴。將該混合物 於室溫之下攪拌2小時,以THF (200 ml)稀釋將之冷卻至-78 C並加入溶於己烷之2.5 M BuLi溶液(56.1 ml,140.3 mm〇1 ’ 1,1 當量)。攪拌 1小時,添加(Boc)20 (34.4克,1.2 當量)於30毫升THF中之溶液。將該混合物m_78°c下攪拌1 小時、於Ot之下攪拌3〇分鐘,再加入4〇〇 mi之NH4C1水溶 液終止反應。將THF濃縮並以Et20 (3 X 1 50 ml)萃取該水性漿 狀物’以鹽水洗滌合併之有機層,經MgS〇4脫水、過濾並 濃、&以得3 8 g之油。
將此粗產物溶於500 ml之EtOH中,加入3.2 g PPTS並將 該溶液於55°C下加熱2小時。以400 ml之NaHC03水溶液稀 釋該混合物,將EtOH蒸發並以4χ 100 ml Et20萃取該水性漿 狀物。以鹽水洗滌合併之有機層,經MgS04脫水、過濾、 濃縮並層析純化得20 g之油狀8。4 NMR (400 MHz,CDC13) 4.61 (q, J = 6.8 Hz, 1H), 1.50 (d5 J = 6.8Hz, 3H), 1.50 (s5 9H) 〇 步驟5 :
t 八 _JL PPh3 'OBn 1回流 9 1〇 將已知酸10 (21 g,128 mmol) ’(酸之製備請參見:Barnett 等人,Tetrahedron Lett.,2001,57 (6),9741-9746)和可由市 I0l679.doc -38 - 1357326 售購得·9 μ 1 g ’ 129 mmol ’ 1當量)溶於400 m丨苯之混合物 氹封g中加熱約14小時(浴溫〜85〇c)。將該溶液濃縮並以 層析屯化以得16 4 g之油狀u。丨H nmr (彻MHz,CDCl3) (s> !Η), 7.38-7.30 (m, 5H), 6.56 (tq, J = 7.0, 1.4, 1H), 4'54 (S,2H),3 63 J = 6·^ 3H), 2.66 (qd, J = 6.6, 0.8, 2H),1.77-1.76 (m,3H)。 步驟6 :
1) (Et0)2P(〇)CH2CO2Et NaH__^ 2) KOH '
O
OBn 於室溫之下’於溶於300 ml THF之6〇% NaIi (4 7 g,U8 mm〇l)之懸浮液中加入三乙基膦醋酸酯(24 ml,121 mm〇l) 並將該混合物於室溫之下攪拌2〇分鐘。於其中加入純^ (i6 g ’ 78 mmol)並將該混合物於室溫之下攪拌3〇分鐘再藉由添
加400 ml印0加以冷卻。將THF蒸發並以3χ〗5〇⑹玢2〇萃 取該水性漿狀物。合併之有機層以Η"洗滌兩次再以鹽水洗 一次,經MgS〇4脫水、過濾並濃縮以得到約24 g之粗產物。 將此產物溶於各100 ml之THF和MeOH中並加入溶於100 ml H20之KOH (13.2 g ’ 235 mmol,3當量)溶液並將此混合 物於室溫下授拌3小時。以500 ml HA稀釋該溶液並以2〇〇 ml己烧加以洗滌’之後以1 N HC1將其酸化至〜pH2並再以 3x150 ml EtOAc加以萃取。將合併之有機層以h2〇洗務之後 再以鹽·水洗,經MgS〇4脫水、過濾並濃縮以得到18 6 g之油 狀 12。'H NMR (400 MHz,CDC13) 7.39-7.23 (m, 6H),5.95 (t 101679.doc -39- 1357326 J = 7.2, 1H), 5.77 (d, J = 15.6, 1H), 4.48 (s, 2H), 3.51 (t, J =6.8, 2H)} 2.50 (q> J = 6 8j 2R), 1.76 (d, J = 1.2, 3H) 〇 步驟7 : 〇 〇
於8 (11.7 g ’ 69 mmol)和 12 (18.6 g,76 mmo卜 1.1 當量) # 溶於300 ml CH2C12之溶液中加入DCC (15.6 g,76 mmo卜 1.1當直)並於授拌10分鐘之後,加入DMAP (0.84 g,6.9 mmol,0.1當量)並再持續攪拌1·5小時。以500 ml Et20稀釋 反應混合物並經矽藻土墊過濾以除去沉澱物。將濾液以 2x300 ml 1 N HC1、300 ml NaHC03水溶液和 300 ml鹽水加 以洗滌’經MSs〇4脫水、過濾、濃縮並以10% EtOAc-己烷 加以層析以得到22 g之U油。1H NMR (400 MHz,CDC13) 7.34-7.23 (m, 6H), 5.93 (t, J = 7.0, 1H), 5.76 (d, J = 15.6, ® 1H), 5.58 (q, J = 6.8, 1H), 4.47 (s, 2H), 3.50 (t, J = 6.6, 2H), 2.49 (q, J = 6.8, 2H), 1.74 (d, J = 1.2, 3H), 1.52 (d, J =6_8, 3H), 1.45 (s, 9H)。 步驟8 :
101679.doc 40- 於 13 (22 g ’ 55.2 mmol)和喹啉(1.5 g,11.6 mmo 卜 0.2 當 量)溶於250 ml EtOAc之溶液中加入Lindlar催化劑(2.2 g, 10 wt %)並將該懸浮液於通入Η2之下攪拌並以1hNmR監測 該反應。約攪拌3.5小時之後,將催化劑經矽藻土墊過濾去 除。將有機相以1 N HC1洗3次’再以鹽水洗,經1^^$04脫 水、過濾並濃縮以得~25 g之14。 將此產物溶於約400 ml甲苯中並於經密封之管中加熱6 小時(浴溫〜185°C ),在冷卻至室溫,加以濃縮並以15% EtOAc-己烧層析以得7·2 g之exo加成物。將該exo產物溶於 100 ml CH2C12 中並與 DBU (540 μΐ,3.91 mmol,0.2當量) 攪拌45分鐘再以loo ml Et2〇加以稀釋並以3x5〇 ml丨n HC1 洗條之後再以鹽水洗。將之經MgS〇4脫水、過濾並濃縮以 得 7.0 g之 15。NMR (400 MHz, CDC13) 7.31-7.21 (m,5H), 5.45-5.43 (m, 1H), 4.53-4.47 (m, 1H), 4.43 (dd, J = 12.0, 14.8, 2H),3.41 (td,J = 6.4,1.2, 2H),3.16-3.12 (m,1H), 2.78 (dd, J = 7.6, 4.8, 1H), 2.56-2.51 (m, 1H), 2.46-2.45 (m, 1H), 1.86-1.70 (m, 2H), 1.70 (s, 3H), 1.37 (s, 9H), 1.29 (d, J = 6.4, 3H) 〇 步驟9 :
O^O'Bu 16 於15 (7 g)溶於5〇 ml MeOH之溶液中加入1〇〇/0 Pd-C (700 -41 - 101679.doc 1357326 mg)並將該懸浮液於耐壓容器(par]* vessel)中於50 psi H2之 下振盪過夜。將催化劑濾除並將產物經層析純化再由 TBME-己烧t再結晶以得合併產量為3.26g之醇。 於該醇(1.1 g ’ 3.52 mmol)和 DMAP (43 mg ’ 0.35 mmol, 0.1當量)溶於20 ml 0°C之CH2C12之溶液中加入Ac20 (500 μ 卜 5.29 mmo 卜 1.5 當量),再加入 Et3N (980 μ 卜 7.03 mmol, 2當量)。將該溶液攪拌2小時,以100 ml Et2〇加以稀釋並以 NaHC03水溶液洗蘇兩次再以鹽水洗一次,經MgS〇4脫水、 過滤、濃縮並以20% EtOAc-hex加以層析以得1 · 16 g之16。 !H NMR (400 MHz, CDC13) 4.69 (dq, J = 9.8, 5.8, 1H), 4.11-4.00 (m, 2H), 2.60-2.52 (m, 2H), 2.45-2.39 (m, 1H), 2.00 (s, 3H), 1.91 (ddd, J = 13.4, 6.0, 2.6, 1H), 1.72-1.67 (m, 2H), 1.54-1.38 (m, 2H), 1.43 (s, 9H), 1.31 (d, J = 6.0, 3H),1.24-1.18 (m, 1H),0.99 (d, J = 6.4, 3H)。 步驟10 :
於 16 (1.15 g’3.25 mmol)溶於 l〇 mi CH2Cl2之溶液中加入 10 ml TFA。將該混合物於室溫下攪拌!小時,加以濃縮並 以甲苯加以蒸發以得該酸。 將該酸溶於20 ml CH2C12中並與乙二醯二氣(57〇 μ卜6 53 mmol,2當量)一起攪拌。攪拌丨小時之後,將該 101679.doc • 42-
溶液濃縮並以甲苯加以蒸發以得酸氯化物β 於此酸氯化物溶於20 ml室溫之甲苯之溶液中加入pd (PPh3)4,再加入Bu3SnH (1.8 mi,6 69 mmo卜 2當量)。將 該混合物攪拌30分鐘,再加以濃縮並以4〇% Et〇Ac hex加以 層析以得 760 mg之 17 b。丨H NMR (4〇〇 MHz, CDC13) 9.73 (d, J = 2.4, 1H),4.62 (dq,J = 9.6, 6.0, 1H),4.10-4.00 (m,2H), 2.73 (ddd,J = 10.8,5.6,2.4,ih),2.70-2.63 (m,1H), 2.59-2.53 (m,1H),1.99 (s,3H),ι·96 (ddd,j = 13 8,6 4, 3.0, 1H), 1.77-1.60 (m, 3H), 1.38-1.32 (m, 1H), 1.30 (d, J = 6·4,3H),1.24-1.14 (m,1H),1.02 (d,j = 6.4,3H)。 步驟11 :
使用類似於搭17b之製備步驟來製備經17a ^ NMR (400MHz,CDC13) 9·76 (d,J = 2.4, m),4 61 (dq,】=9 6, 6.0,1H),4.25 (dd,J = 11.6,2.8,旧),4 14 (dd,j = 12 〇, 4.8,1H),2.84 (ddd,J = 10.8’ 5.6,2.4,1H), 2.75-2.68 (m, 1H), 2.66-2.61 (m, 1H), 2.04 (s> 2.04-1.98 (m, 1H), 1.93-1.85 (m,1H),1.52-1.42 (m,m),135 (d,】=6 〇, 3H), 1.40-1.26 (m, 1H),1.07 (d,J = 6.4, 3H)。 101679.doc • 43· 1357326 步驟12 :
17a
LHMDS 11(0^〇4 於填酸醋 18 (720 mg,2.34 mmol,
THF之溶液中加入1 μ LHMDS溶於THF (2.3 ml,2
mmol,2當量)之溶液並將該混合物攪拌2〇分鐘。(18之製備 請參見美國專利第6,645,987號)。對此加入Ti (〇>〇4再加入 17a (330 mg,1.16 mmol)溶於3 ml THF之溶液。移除冰浴 並將該溶液於室溫之下攪拌45分鐘,再以〜70 ml Na-K酒石 酸鹽加以冷卻。將THF蒸發並以3 X30 ml EtOAc萃取水相, 以鹽水洗滌合併之有機層,經Mgs〇4脫水、過濾、濃縮並
經30。/。EtOAc-hex加以層析以得46〇 邮之19。iH NMR (400 MHz,CDC13) 8.58 (d,J = 2.4,1H), 7.75 (dd,J = 8.0,2.4, 1H),7.07 (d,J = 8.4,1H),6.59 (dd,J = 15.6,10.2,1H), 6.43 (d, J = 15.6, 1H), 4.74-4.67 (m,lH), 4.29 (dd, J = 11.6, 3.2,1H),4.01 (dd,J = 11.6,2.4,1H),2.78-2.67 (m,2H), 2.38 (dt,J = 10.0, 6.5, 1H),2.05-2.00 (m,1H),2.02 (s,3H), 1.61-1.55 (m,1H),1.47-1.38 (m,ih),1.40 (d,J = 6.0, 3H), 1·38·1·25 (m,1H),1.04 (d,J = 6.4,3H)。 101679.doc -44- ⑧ 1357326 步驟13 :
將 19 (570 mg,1.35 mmol)和 K2C03 (750 mg,5.43 mmol,
4當量)溶於10 ml MeOH之混合物加熱迴流5小時《將MeOH 加以濃縮並將該混合物與NH4C1水溶液攪拌並以4x30 ml EtOAc加以萃取。將合併之有機層以鹽水洗滌,經MgS04 脫水、過濾、濃縮並經35% EtOAc-hex加以層析以得440 mg 之 20。NMR (400 MHz,CDC13) 8.59 (d,J = 2.4, 1H),7.73 (dd, J = 8.4, 2.6, 1H), 7.17 (d, J = 8.4, 1H), 4.60-4.52 (m, 1H), 4.07-4.02 (m, 2H), 3.39 (dd, J = 10.2, 8.2, 1H). 3.12 (dd, J = 14.0, 3.2, 1H), 2.85 (dd, J = 14.0, 7.6, 1H), 2.70
(dt, J = 12.8, 6.8, 1H), 2.52-2.46 (m, 1H), 2.07 (ddd5 J = 14.0,6.8, 3.2,1H),1.71-1。67 (m,2H),1.44 (dd,J = 6.0, 3H),1.41-1.25 (m,1H),1.19-1。09 (m,1H),0.94 (d,J = 6.4, 3H)。 步驟1 4 :
101679.doc -45- 1357326 於 20 (310 mg,0.815 mmol)溶於 _78eC 之 5 ml THF 之溶液 中加入 1 M LHMDS溶於 THF (0.98 ml,0.98 mmol,1.2 當量) 之溶液並於-78t:下攪拌1 5分鐘、於〇°c之下攪拌15分鐘再 冷卻回-78°C。對此加入(1S)-(+)-(i〇_樟腦磺醯基)啞嗪(280 mg ’ 1·22 mmo卜1.5當量)溶於2.5 ml THF之溶液並將該混 合物攪拌30分鐘’再使之缓缓回至室溫。加入10〇 mi nh4C1 水》谷液使之冷卻並將THF加以蒸發。以3x25 ml EtO Ac萃取 水相並以鹽水洗滌合併之有機層,經MgS〇4脫水、過遽、 濃縮並經層析純化以得150 mg之21。丨H NMR (400 MHz, CDC13) 8.59 (d, J = 2.4, 1H), 7.73 (dd, J = 8.4, 2.4, 1H), 7.17 (d. J = 8.4, 1H), 4.49-4.42 (m, 1H), 4.12-4.02 (m, 2H), 3.45 (dd5 J = 9.6, 8.0, 1H), 3.17 (br s, 1H), 3.10 (dd, J = 14.0, 3.2, 1H), 2.88 (dd, J = 14.0, 7.8, 1H), 2.42 (dd, J = 9.6, 5.2, 1H), 1.93 (td, J = 11.6, 5.2, 1H), 1.85 (d, J = 7.0, 1H), 1.74-1.69 (m, 2H), 1.45 (d, J = 6.0, 3H), 1.32 (dd, J = 14.2, 11·4, 1H), 0.93 (d,J = 6.0, 3H)。 步驟1 5 :
將 21、Pd (PPh3)4 (5 mol %)、K2C03 (4當量)和適當之侧 酸(1.5當量)溶於PhMe-EtOH-H20 (4 : 2 : 1 v/v/v)之混合物 101679.doc • 46- 1357326 於1 00°C下加熱5小時’以H2〇稀釋並以EtOAc加以萃取。以 鹽水洗滌有機層’經Mgs〇4脫水、過濾、蒸發並經製備性 TLC力口以純化以得類似物22a_d (如上列流程3所顯示)。22a 之MS : m/e 412.1 (MH+)。22b之MS : m/e 419.1 (MH+)。22c 之MS : m/e 412.1 (MH+)。22d之MS : m/e 408.1 (MH+)。 步驟16 :
將 18 (2.12 g,6.88 mmol) ' Pd(PPh3)4 (400 mg,0.346 mmol,5 mol %)、(2-氰苯基)硼酸2,2-二曱基丙二醇-1,3-環 酯(1.8 g,8.37 mmol,1.2 當量)和 K2C03 (3.0 g,27·49 mmo卜 4 當量)溶於甲苯(20 ml)-EtOH (10 ml)-H20 (5 ml)混 合物之溶液於密封之管中以l〇〇°C加熱4小時。將該混合物 以150 ml Η20加以稀釋並以3x50 ml EtOAc加以萃取。以鹽 水洗滌合併之有機層,經MgS04脫水、過濾、濃縮並經層 析純化以得 23 (1.82 g)固體。4 NMR (400 MHz,CDC13) 8.66 (d, J = 2.0, 1H), 7.86 (dd, J = 8.0, 2.0, 1H), 7.78-7.75 (m, 1H)} 7.68-7.64 (m, 1H), 7.50-7.45 (m, 3H), 4.08 (dq, J =8.0, 7.2, 4H), 3.46 (d, J = 22, 2H),1.26 (t,6H)。 10l679.doc • 47· 1357326 步驟17 :
於填酸 g 旨 23 (1.33 g,4·03 mmol)溶於 0°C 之 15 ml THF 之 溶液中加入1 M LHMDS溶於THF之溶液並將該混合物攪拌 15分鐘。於其中加入Ti (0卞〇4再加入17b溶於5 ml THF之溶 液並將該混合物攪拌過夜(〇°C至室溫)。將該反應混合物以 100 ml之Na-K-酒石酸鹽水溶液加以稀釋並將THF蒸發。以 3x30 ml之EtOAc萃取該漿狀物並以鹽水洗滌合併之有機 層,經MgS04脫水、過濾、蒸發並以50% EtOAc-hex至100% EtOAc力u以層析以得到420 mg之24和5 10 mg之25。24之
MS : m/e 459.1 (MH+)。25之 MS : m/e 417.1 (MH+)。 步驟1 8 :
於 0°C 之下’於 25 (105 mg’ 0.230 mmol)和 CBr4 (155 mg ’ 101679.doc -48-
1357326 0.467 mmo卜2當量)溶於2.5 ml THF之溶液中加入PPh3並移 除冰浴。攪拌過夜之後,將該混合物濃縮並以矽膠層析法 加以純化以得26 (52 mg)和 27 (19 mg)。26之MS : m/e 481.3 (MH+)。27之 MS : m/e 417.2 (MH+)。 步驟19 :
將 26 (51 mg,0.106 mmol)、BU3SnH (58 μ 卜 0.215 _〇卜 2當量)和ΑΙΒΝ (1.8 mg,o.ou _。卜〇丨當量)溶於2 mi苯 之溶液加熱迴流2小時’冷卻至室i,濃縮並以5㈣
EtOAc-hex 加以層析以得 35 mgi28eMS:m/e 4〇ι 2 (mh+卜 上述製程之起始原料均為可購得、為此項技藝中已知或 者藉由此項技藝中已知之步驟加以製備者。 不參與上述過程之反應性基團於反應期間W慣用 護基團加以保護,其可於反應之後 ’、 1无丹稭由铋準步驟加以去 I0l679.doc -49- 1357326 表A 受保護之基團及保護基團 —COO坑棊,一COO笨甲棊,一COO苯基 〉NCO挽朞二NCO苯甲棊,二NC◦丨苯基 \ \ /NCH2〇CH2CH2Si(CH3)3 NC(0)0C(CH 3)3, \ 、 、v /N-benzyl, /NSi(CH3)3. NSi-C(CH) 3
受保護之基團 -COOH ^NH
-NH2 -OH 〇 ell 3 o CH3 -OCH 3, —OCH 2OCH 3t OSi(CH 3)3,— OSi-C(CH) 3 或一 OCH2苯基 Ch,3 【實施方式】 本發明亦關於含有至少一種本發明之式I化合物和一醫 藥上可接受之載體之醫藥組合物。式I之化合物可以任何慣 用之口服劑型加以投藥,例如為:膠囊、藥錠、粉末、藥 囊、懸浮液或溶液。調配物及醫藥組合物之製備可利用慣 用之醫藥上可接受之賦形劑及添加物和慣用之技術。此等 醫藥上可接受之賦形劑及添加物包括無毒之適用性填充 劑、結合劑、崩解劑、緩衝劑、防腐劑、抗氧化劑、湖滑 劑、調香劑、黏稠劑、色素、乳化劑及同類者。 式I化合物用以治療上列疾病或狀況之每日劑量為每曰 約0.001至約100 mg/kg體重,較佳為約0.001至約10 mg/kg。因平均體重為70 kg,故劑量為每日約0.1至約700 mg 101679.doc -50· 1357326 之藥,分單次或2-4次分開給藥。然而,確實之劑量係由主 治醫師決定並視所投予化合物之效力、患者之年齡、重量、 狀況和反應而定。 下列調配物體現本發明之一些劑型。其中,「活性成份」 係指式I之化合物。 實例A-藥錠 號瑪 成份 毫克/键 毫克/鍵 1 活性成份 100 500 2 乳糖USP 122 113 3 玉米澱粉,食品級,溶於純水之10°/。糊 30 40 4 玉米澱粉,食品級 45 40 5 硬脂酸鎂 3 7 總和 300 700 製造方法 於適當之混拌機中將第1和2項混合10-15分鐘。將該混合 物與第3項顆粒化。視需要將該濕顆粒磨經一粗篩網(例 如:1/4”,0.63 cm)。將該濕顆粒乾燥。視需要將該經乾燥 顆粒過篩並與第4項混合並混拌10-15分鐘。加入第5項並混 合1 -3分鐘。以適當之製錠機將該混合物壓成適當之大小及 重量。 實例B-膠囊 號碼 成份 毫克/鍵 毫克/疑 1 活性成份 100 500 2 乳糖USP 106 123 3 玉米澱粉,食品級 40 70 4 硬脂酸鎂NF 4 7 總和 250 700 101679.doc 51 1357326 製造方法 於適當之混拌器中將第1、2和3項混合10·15分鐘。加入 第4項並混合卜3分鐘。於適當之膠囊化機器上將該混合物 填充至適當之兩件式硬明膠膠囊中。 治療和共調配之方法 美國專利第10/705,282號揭示數種關於凝血酶受體拮抗 劑之其他類群之治療和共調配方法。同樣地,關於本發明二 進一步t具體實施例涵蓋投予至少一種式工之〖合物伴隨 至少-種治療上有效之藥劑。所涵蓋之其他治療有效藥劑 係為不同於由式I之化合物加以補足原子或重排者。可與本 發明之新穎化合物併用之治療上有效之藥劑包括已知且被 用於治療發炎、風濕症 '氣喘、腎絲球腎炎、骨質疏鬆症、 神經病變及/或惡性腫瘤、血管新生相關㈣、癌症、肝、 腎或肺之病變、黑色素瘤、腎細胞癌 '腎病、急性腎衰竭、 慢性腎衰竭、腎血管怪定、腎絲球腎炎、慢性氣道疾病' 膀胱發炎、神經退化性疾病及/或神經毒疾病、狀況或傷 害、放射線後的纖維化、内皮功能障礙、牙周病或創傷之 藥物。可與式I化合物合併投藥之治療有效試劑之進—步實 例包括:腫瘤細胞對抗化療之抗性因子及平滑肌細胞、内 皮細胞、纖維組織母細胞、腎細胞、骨肉瘤細胞、肌細皰、 癌細胞及/或神經膠質細胞之增生抑制劑。治療有效劑可為 心血管藥劑。 可與本發明之新穎化合物併用之心血管藥劑包括具有浐 血拴、抗血小板聚集、抗動脈粥狀硬化、抗再狭窄及/或抗 10i679.doc •52· 1357326 凝血活性之藥物。此等藥物可用以治療血栓相關性疾病, 包括:血栓形成、動脈粥狀硬化、再狹窄、高血壓、心絞 痛、心律不整、心臟衰竭、心肌梗塞、腎絲球腎炎、血拴 性和thr〇mb〇emb〇lic中風、周圍血管疾病、其他心血管疾 病、腦缺血、發炎性病變及癌症,以及凝血酶及其受體於 其中扮演病理學角色之其他病變。適當之心血管藥劑係選 自由下列所組成之群〔血栓素入2生合成抑制劑,例如:阿 斯匹靈;血栓素拮抗劑,例如:塞曲司特(seratrodast)、吡 考他胺(picotamide)和雷馬曲班(ramatr〇ban);腺苷二磷酸 (ADP)抑制劑’例如:克羅匹多(clopidogrel);環氧酶抑制 劑,例如:阿斯匹靈、美洛昔康(meI〇xicam)、羅菲可西保 (rofecoxib)和希樂葆(celec〇xib);血管收縮素拮抗劑,例如: (valsartan)、特米沙坦(telmisartan)、坎第沙坦 (candesartran)、依貝沙、洛沙坦〇〇sartan)和 依普沙坦(epr〇Sartan);内皮素拮抗劑,例如:特洛申坦 φ (tezosentan);磷酸二醋酶抑制劑,例如:米利農(milrinoone ) 和依諾昔酮(enoximone);血管收縮素轉換酶(ACE)抑制 劑,例如:卡托普利(captopril) '依拉普利(enalapril)、依 拉普雷(enaliprilat)、螺普利(spirapril )、奎普利(quinapril)、 派利多普利(permdopril)、拉米普利(ramiprii)、弗西諾普利 (fosinopril )、群多普利(trand〇lapril)、利辛諾普利 (lisinopril)、莫西普利(m〇exiprii)和苯納普利 (benazapril);中性内肽酶抑制劑,例如:坎沙曲(cand〇xatrU) 和依卡曲(ecadotril);抗凝血劑,例如:希美加群 101679.doc •53 ‘
Ϊ357326 (ximelagatran) ' 芳達.帕林(fondaparin)和依諾肝素 (enoxaparin);利尿劑’例如:氣噻嗪(chl〇r〇thiazide)、氫 氯嗟嘻(hydrochlorothiazide)、依他尼酸(ethacrynic acid)、 咳塞米(furosemide)和阿米洛利(amii〇ride);血小板聚集抑 制劑’例如·阿昔單抗(abciximab)和埃替非巴肽 (eptifibatide);以及GPIIb/IIIa拮抗劑。 可與本發明之新穎化合物併用之藥物型式較佳為血栓素 A2生合成抑制劑、環氧酶抑制劑和adp拮抗劑。使用於該 組合中特別較佳者為阿斯匹靈和二硫酸氯吡格雷 (clopidogrel bisulfate) 〇 本發明之進一步具體實施例涵蓋至少一種式〗化合物伴 隨一種以上之其他治療有效藥劑之投藥。於此等具體實施 例中,該等其他治療有效藥劑可能是或不是普遍應用於相 同狀況之/0療者。例如.式I之化合物可伴隨兩種心血管藥 劑投藥。或者, 式I之化合物可伴隨一種心血管藥劑及一種 • 可用於治療發炎之治療有效藥劑投藥。 一種式I化合物及一或多種治療有效
101679.doc 若本發明包含至少 藥劑之組合,則該二 後投藥,或可投予含; 藥劑於一醫藥上π姐 -54- 1357326
同樣地’術語「一或多種 於本說明文中,術語「 一種可與式I之化合物合併投藥之其 y.L ♦.七 ..
凝血酶受體拮抗劑之活體外試驗步爾: 二種不同之式I化合物可 中。較佳為使用一種式I化合物。 心血管藥劑」係指一至三種可盥 φ 式1化合物之活性可藉由下列步驟加以測定。 [3H】haTRAP之製備 將 A(pF-F)R(ChA)(hR)(VY)_NH2 (1 〇3 叫)和 i〇% pd/c (5.07 mg)懸浮於DMF (250 μΐ)和二異丙基乙胺(1〇 μ丨)中。將 容器連接氚氣管,在液態氮中冷凍並加以排空。再將氚氣 (342 mCi)加至反應瓶中,將其於室溫之下攪拌2小時。反應 完成時,將過量之氚去除並以DMF (0·5 ml)稀釋經反應之胜 肽洛液並將催化劑濾除。將收集之粗胜肽之DMF溶液以水 φ 加以稀釋並冷凍乾燥以去除不穩定之氚。將固態胜肽再溶 於水中並重複該冷凍乾燥步驟。將經標定之胜肽 ([11]1^丁11八?);谷於〇.51111之0.1%丁?八水溶液中並以下列條 件進行 HPLC純化:管柱,vydac C18,25 cm><9.4 mm I.D.; 移動相 ’(A)0.1°/〇 TFA溶於水,(B)0.1% TFA溶於CH3CN; 梯度(A/B),30分鐘期間自i〇〇/〇至4〇/60 ;流速,5 ml /min ; 偵測,UV 215 nm。以HPLC分析得[3H]haTRAP之放射化學 純度為99%。得到一批14 9 mCi,其比活性為18.4 Ci/mmol。 血小板膜之製備 10l679.doc •55- ⑧ 1357326 血小板膜係利用Natarajan等人之方法(Natarajan等人,Int. L Peptide Protein Res. 45 : 145-15 1 (1995))加以修改,於收 集48小時内’自20單位之來自North Jersey血液中心(East Orange,NJ)之血小板濃縮物中製得。所有步驟均於4艺下, 於經核可之生物危害安全環境之下進行。於4〇c下將血小板 以1 00 X g濃縮20分鐘以去除紅血球。將上澄液倒出並以 3000 X g離心1 5分鐘以使血小板沉降。將血小板再懸浮於i〇 mM Tris-HCl,pH 7.5,150 mM NaCl,5 mM EDTA中,使總 體積為200 ml並以4400 χ g離心i〇分鐘。將此步驟再重複兩 次。將血小板再懸浮於5 mM Tris-HCl,pH 7.5,5 mM EDTA ’使終體積為約3〇 mi並於Dounce均質機中以20擊加 以均質。以41,000 χ g將膜沉降下來,再懸浮於4〇_5〇 ml 2〇 mM Tris-HCl,pH 7·5,1 mM EDTA,0.1 mM二硫蘇糖醇 中’並分成每份10 ml’於液態氮中冷凍並貯存於_8〇。〇。要 完成膜之製備,需將分裝物解凍、倒在一起並於D〇unce均 質機中以5擊加以均質。將膜沉降下來並於〗0 mM三乙醇胺 -HC1,pH 7.4,5 mM EDTA中洗滌3次並再懸浮於20-25 ml 50 mM Tris-HCl,pH 7.5,10 mM MgCl2,1 mM EGTA和 1% DMSO之中。將膜分裝,於液態氮中冷凍並貯存於_8〇。匚。 膜可安定至少3個月。20單位之血小板濃縮物典型可生產 250 mg之膜蛋白。蛋白質濃度之測定係藉由L〇wry分析 (Lowry 等人’ J. Biol. Chem.. 193 : 265-275 (1951)) 〇 高處理量凝血·酶受體放射配體結合分析 凝血酶受體拮抗劑之篩選係使用經修飾之Ahn等人(Ahn 101679.doc -56· 1357326 等人,Mol. Pharmacol., 5 1 : 350-356 (1997))之凝血酶受體 放射配體結合分析。該分析係於96孔Nunc盤(目錄號碼 269620)中進行,最終分析體積為200 μΐ 〇將血小板膜和 [3H]haTRAP於結合緩衝液(50 mM Tris-HCl,pH 7.5,10 mM MgCl2,1 mM EGTA,0.1% BSA)中分別稀釋至 〇·4 mg/ml和 22·2 nM。將試驗化合物之母液(1 0 mM溶於loo% DMSO)進 一步稀釋於100% DMSO中。除非另有指明,否則在各孔中 均加入1 0 μΐ之經稀釋化合物溶液和90 μΐ之放射配體(終濃 度為10 nM溶於5% DMSO),並藉由加入1〇〇 μΐ之膜(40 pg 蛋白質/孔)使反應開始。其結合並不受5% DMSO顯著抑 制。選用三種化合物濃度(0.1,1和10 μΜ)進行試驗。將該 盤蓋上並於室溫下於一 Lab-Line定量盤震盪器上緩和震盪 1小時。將Packard UniFilter GF/C過遽盤在0.1%聚乙稀亞胺 中浸泡至少一小時。使用 Packard FilterMate Universal Harvester收集經培養之膜,且吾人快速以300 μΐ冰冷之50 mM Tris-HCl,pH 7.5,10 mM MgCl2,1 mM EGTA洗務四 次。在各孔中加入MicroScint 20閃爍雞尾酒(25 μΐ)並將該 盤置於Packard TopCount Microplate閃爍計數器中加以計 數。專一性結合係定義為總結合減去過量(50 μΜ)未經標示 之haTRAP存在下所觀察到之非專一性結合。[3H]haTRAP 化合物結合至凝血酶受體之抑制%係由下列關係式中計算 而得: 101679.doc -57- ⑧ 1357326 抑制%= 總結合-試驗化合物存在下之結合χ 100 總結合-非專一性結合 材料 A(pF-F)R(ChA)(hR)Y-NH2 和 A(pF-F)R(ChA)(hR)(I2-Y)-NH2 係自AnaSpec Inc. (San Jose, CA)訂做合成。此等胜肽之純 度 >95%。氚氣(97%)係購自 EG&G Mound, Miamisburg Ohio。此氣體係隨後裝載並貯存於IN/US Systems Inc. Trisorber。MicroScint 20閃爍雞尾酒(scintillation cocktail) 係來自 Packard Instrument公司。 利用上述之試驗步驟,發現式I之代表性化合物之凝血酶 受體IC5G值(即:50%凝血酶受體抑制時之濃度)為1至1000 nM,較佳為1-100 nM,更佳為1-20 nM。 101679.doc 58-
Claims (1)
1357326 第094117273號專利申請案 中文申請專利範圍替拷本(tew 十、申請專利範圍: 1. 一種由下列構造式所代表之化合物 R34
(CH2)n3 Het 式1 或其醫藥上可接受之鹽或溶劑化物,其中: R1G和R34所連接之環碳間之單虛線rrrrrz代表一單鍵; X和與Y相連之碳之間之雙虛線:::::::代表一單鍵; X為; R15為Η或C「C6烷基; Y為(0); Z係選自-ch2-及-〇-所組成之群; 以為1或2 ; Π·2 為 〇, Π·3 為 1, R為1至3個個別選自由烷基所組成之群之取 代基; R1和R2係個別選自由烷基所組成之群; R3為Η或羥基; 11以為。比咬基, 其中Het基團視需要經W取代,其中W係選自由視 101679-1001021.doc 需要經鹵基、CrC6烷基或CN所取代之芳基所組成之 群; τ>8 ^ 10 1 1 ^ K、R和R係個別為Η ; R為Η或OH ; r17*cvc6 烷基; R係選自H'RMjc^-Cm)烷基及-OH所組成之群; R24 係選自由 Η、-OH、·〇α〇)·(〇νς:6)烷基和 -CH(=NOR17)所組成之群;且 R34為(Η、R3)。
2. 如請求項丨之化合物,其中之W為苯基。 3. 如4求項2之化合物,其中之貿係經氟取代。 4. 如請求項2之化合物,其中之W係經-CN取代》 5_如凊求項1之化合物,其中之Ζ為-CH2-且⑴為1。 6.如凊求項1之化合物,其中之Z為·〇_且〜為1。
7·如請求項1之化合物,其中之Z為-〇-且n丨為 8·如4求項1之化合物,其中之R1為甲基,且R2、R8、r9、 〜丨丨均為Η。 9.如明求項1之化合物’其中之R3為Η。 1〇·如明求項1之化合物,其中之R3為-OH。 如請求項1之化合物,其中之R22為甲基。 如响求項1之化合物,該化合物係選自由下列結構式所代 表之化合物: 101679.100102Ld〇c -2- 1357326
22c
22b •ΛΛ/V άΜβ 22d
或其藥學上可接受性鹽或溶劑化物β 道之纖維化病變、阿茲海默症、糖尿病、糖尿病神經病、 類風濕關節炎、神經退化症、神經毒症、系統紅斑性狼 瘡、多發性硬化症、骨質疏鬆症、青光眼、黃斑病變、 牛皮癬、放射線後的纖維化、内皮功能障礙、創傷或脊 髓損傷,或其徵兆或結果。 14. 一種如請求項1至12中任一項之化合物用於製造醫藥品 之用途’該醫藥品係用於在需要此之哺乳類抑制凝血酶 受體。 15. —種如請求項1至12中任一項之化合物用於製造醫藥品 之用途’該醫藥品係用於在需要此之哺乳類抑制大麻鹼 受體。 16_ —種如請求項1至12中任一項之化合物用於製造醫藥品 之用途’該醫藥品係用於在需要此之哺乳類治療醫療狀 況’其中該醫療狀況係為心血管或循環疾病或狀況、發 炎疾病或狀況、呼吸道疾病或狀況、癌症、急性腎衰竭、 腎絲球腎炎、星狀細胞增生、肝、腎、肺或腸道之纖維 化病變、阿茲海默症、糖尿病、糖尿病神經病、類風濕 關節炎、神經退化症、神經毒症、系統紅斑性狼瘡、多 發性硬化症、骨質疏鬆症、青光眼、黃斑病變、牛皮癖、 放射線後的纖維化、内皮功能障礙、創傷或脊髓損傷, 或其徵兆或結果。 17.如請求項16之用途,其中該心血管疾病或循環疾病或狀 況係為:動脈粥狀硬化、再狹窄、尚血壓、急性冠心症、 心絞痛 '心律不整、心臟病、心衰竭、心肌梗塞、血检 101679-1001021.doc -4· 1357326 性或血栓栓塞性中風、周圍血管疾病、深部靜脈栓塞症、 靜脈血栓栓塞症、與荷爾蒙替代治療有關之心血管疾 病、泛發性血管内血液凝固症、腎缺血、腦中風、腦缺 灰、腦梗塞、偏頭痛、腎管怪定或勃起功能障礙。 18. 如請求項16之用途,其中該發炎疾病或狀況係為腸道激 躁症、克隆氏症、腎炎或為照射或化療誘發之胃腸道、 肺、膀胱、胃腸道或其他器官之增生或發炎性病變。 19. 如請求項16之用途,其中該呼吸道疾病或狀況係為可逆 性氣道阻塞、氣喘、慢性氣喘、支氣管炎或慢性氣道疾 病。 20. 如請求項16之用途,其中該癌症係為腎細胞癌或與血管 新生有關之病變。 21. 如請求項16之用途,其中該神經退化性疾病係為巴金森 氏症、肌萎縮性側索硬化症、阿茲海默症、亨丁頓氏症 或威爾森氏症。 22. 如請求項16之用途,其中該醫藥品進一步包含至少—種 可用以治療下列之藥劑或與用以治療下列之藥劑併用: 發炎、風濕症、氣喘、腎絲球腎炎、骨質疏鬆症、神經 病變及/或惡性腫瘤、血管新生相關病變 '癌症、肝、腎 或肺之病變 '黑色素瘤、腎細胞癌、腎病、急性腎衰竭、 慢性腎衰竭、腎血管恆定、腎絲球腎炎 '慢性氣道疾病、 膀胱發炎、神經退化性疾病及/或神經毒疾病、狀況或傷 害、放射線後的纖維化、内皮功能障礙、牙周病或創傷。 23.如請求項22之用途,其中該醫藥品進一步包含至少兩種 藥劑或與該等藥劑併用。 101679-1001021.doc
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US8022088B2 (en) | 2006-06-29 | 2011-09-20 | Schering Corporation | Substituted bicyclic and tricyclic thrombin receptor antagonists |
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US8227412B2 (en) * | 2007-03-29 | 2012-07-24 | Tsopanoglou Nikos E | Bioactive parstatin peptides and methods of use |
WO2008128038A2 (en) * | 2007-04-13 | 2008-10-23 | The Scripps Research Institute | Methods and compositions for treating cardiac dysfunctions |
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DE602005009355D1 (de) | 2008-10-09 |
US7442712B2 (en) | 2008-10-28 |
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