TWI381841B - An immunosuppressive agent and an antitumor agent containing a heterocyclic compound as an active ingredient - Google Patents
An immunosuppressive agent and an antitumor agent containing a heterocyclic compound as an active ingredient Download PDFInfo
- Publication number
- TWI381841B TWI381841B TW095108509A TW95108509A TWI381841B TW I381841 B TWI381841 B TW I381841B TW 095108509 A TW095108509 A TW 095108509A TW 95108509 A TW95108509 A TW 95108509A TW I381841 B TWI381841 B TW I381841B
- Authority
- TW
- Taiwan
- Prior art keywords
- difluoromethylbenzimidazol
- morpholinyl
- dimethylmorpholinyl
- piperazin
- difluoromethyl
- Prior art date
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title claims description 31
- 239000003018 immunosuppressive agent Substances 0.000 title claims description 26
- 229940125721 immunosuppressive agent Drugs 0.000 title claims description 18
- 239000004480 active ingredient Substances 0.000 title claims description 8
- 239000002246 antineoplastic agent Substances 0.000 title claims description 5
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 89
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 74
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 31
- 150000001412 amines Chemical class 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 25
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 24
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 21
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- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
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- DCRYNQTXGUTACA-UHFFFAOYSA-N 1-ethenylpiperazine Chemical compound C=CN1CCNCC1 DCRYNQTXGUTACA-UHFFFAOYSA-N 0.000 claims description 6
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- VEGLQCYQXRHREW-UHFFFAOYSA-N 1-(4,6-dimorpholin-4-ylpyrimidin-2-yl)benzimidazol-2-amine Chemical compound NC1=NC2=CC=CC=C2N1C(N=1)=NC(N2CCOCC2)=CC=1N1CCOCC1 VEGLQCYQXRHREW-UHFFFAOYSA-N 0.000 claims description 3
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Description
本發明與新穎的免疫抑制劑相關,更詳細言之,係關於以特定構造之雜環式化合物為有效成份之免疫抑制劑。又本發明與上述雜環式化合物中的新穎化合物相關,進而亦關於作為其新穎化合物之抗腫瘤劑之用途。
一般而言,使用免疫抑制劑的疾病方面,可例舉臟器或組織移植時的排斥反應,骨髓移植時的移植物抗宿主病,潰瘍性大腸炎或孔羅氏病等之炎症性腸疾病,乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病,慢性阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病,風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭氏修格蘭症候群等的自身免疫疾病等之多種自身免疫疾病。又,環磷醯胺(cyclophosphamide)或胺基甲基葉酸(methotrexate)等的免疫抑制劑亦使用於多發性骨髓瘤,惡性淋巴瘤,白血病等血液腫瘤的治療。進而,對於伴隨有敗血症等感染之以免疫機能亢進為特徵之疾病的治療時,亦有免疫抑制劑與抗生物質併用的情形(非專利文獻1)。
此種情況下,現在,臨床上使用了多種的免疫抑制劑作為前述疾病的治療劑,但是並無法獲得充分的治療效果,而且出現了不被期待的副作用,現況必須改善的問題點頗多。
習知免疫反應顯現時,肇始於T細胞及B細胞的兩淋巴細胞(lymphocyte),與各種細胞及因子有複雜之關連性,現在,臟器移植等所使用的cyclosporin或tacrolimus,其作用僅限於T細胞,更能廣泛的作用於免疫機構的藥劑方面,臨床應用上,副作用少,而且與干預疾病之各種細胞可同時作用的免疫抑制劑被尋求著。
在此,「所謂與疾病相關連之各種細胞」係指免疫細胞,亦即不限定於T細胞,B細胞,單球,巨噬細胞(macrophage),NK細胞,NKT細胞,樹狀細胞,嗜中性球,嗜鹼性球,嗜酸性球,肥大細胞等,亦包含自免疫細胞所釋放出的液性因子,或因免疫細胞上的細胞膜受容體而機能亢進(hyperactive)的血小板,血管內皮細胞,滑液膜細胞(synovial cell),破骨細胞(osteoclast),骨芽細胞,軟骨細胞,氣管上皮細胞等之細胞。又,液性因子為自己的抗體(autoantibody)時,成為標的的抗原亦含有存在的細胞。
關於本發明人等用以取代苯并咪唑環之s-三[1,3,5-三衍生物],嘧啶衍生物,與習知相較,其對固形腫瘤的細胞***抑制作用頗受矚目,與多數化合物的合成,抗腫瘤活性與化學構造的關係之確認一直在進行著(參照專利文獻1,2,3,4及5)。
特別是在苯并咪唑環的第2位具有特定取代基之s-三衍生物及嘧啶衍生物上,發現了能增強對固形腫瘤細胞***抑制作用的方法(參照專利文獻3,4及5)。其衍生
物的製造方法於該等的專利文獻中有詳細的記載,但並不僅限定於其方法,亦可以使用於最終物進而進行各種反應,例如烷基化,烷基羰化等為最終化合物。
[非專利文獻1]T. Munster et. al. Clin. Exp. Rheumatol., 17 (Suppl. 18): S29-S36 (1999)
[專利文獻1]國際公開第99/05138號摘要(pamphlet)
[專利文獻2]國際公開第00/43385號摘要(pamphlet)
[專利文獻3]國際公開第02/088112號摘要(pamphlet)
[專利文獻4]國際公開第2004/037812號摘要(pamphlet)
[專利文獻5]國際公開第2005/095389號摘要(pamphlet)
本發明者使在上述的化合物上,具有抑制磷脂醯肌醇(phosphatidylinositol)3激酶(kinase)(PI3K)之特別的作用明確化(非專利文獻2)。PI3K係為將細胞膜上的磷脂醯肌醇(PI)予以磷酸化的酵素,根據基質特異性分類成3種的亞科(subfamily)。其中,本發明係可特別地(spicifically)抑制(inhibit)等級(class)I的PI3K。
等級I的PI3K生成PI,磷脂醯肌醇4磷酸,磷脂醯肌醇4,5,二磷酸予以磷酸化,磷脂醯肌醇3磷酸,磷脂醯肌醇3,4,二磷酸,磷脂醯肌醇3,4,5,三磷酸予以
生成。所生成的磷脂醯肌醇3,4,5,三磷酸以細胞內第二信使(second messenger)作用。等級I的PI3K出現於各種細胞內,廣泛地作用於細胞的增殖,細胞的生存,葡萄糖輸送,細胞骨架的調節等。明顯可知在PI3K遺傳因子受到毀壞(knock out)的動物上,B細胞,T細胞等的發育(development),訊息轉導(signal transduction)也會有所障礙。又,肥大細胞(mast cell)的脫顆粒或白血球的遷移(migration)亦有障礙為自明(非專利文獻3)。
周知係在脂多糖(lipopolysaccharide:LPS)或抗IgM抗體上,以PI3K抑制劑的Wortmannin或LY294002抑制B細胞的增殖(非專利文獻4)。又,Wortmannin係抑制由抗CD3抗體與抗CD28抗體而引起的T細胞增殖(非專利文獻5)。
血液腫瘤具有由免疫系細胞自發的細胞***之亢進及抑制細胞自毀(apoptosis)的特徵,但是血液腫瘤中亦有脫磷酸化磷脂醯肌醇3,4,5,三磷酸之PTEN蛋白質的減少或Akt的磷酸化亢進等PI3K串聯(cascade)異常的報告(非專利文獻6)。又,吾人可知,以抑制PI3來抑制各種血液腫瘤細胞的***,誘導了細胞的自毀(例如非專利文獻7)。
風濕性關節炎係以免疫異常與滑液膜組織肥大為特徵之疾病。可知滑液膜(synovial membrane)組織的肥大係由於滑液膜細胞的增殖與細胞自毀的抑制所致。風濕性關
節炎患者的炎症滑液膜組織中,因PI3K的活性化導致磷酸化Akt增加(非專利文獻8),又,在試管內(試管內)的實驗中,以抑制PI3K可使滑液膜(synovial membrane)細胞的增殖或細胞自毀的的抑制正常化亦為自明(非專利文獻9)。
但是,Wortmannin或LY294002因具有毒性,在臨床上不被應用。
又,現在,利用PI3K之抑制性質,正進行開發以炎症,癌為始之廣泛疾病的治療藥,但並無臨床應用。因此,使干預免疫系疾病之各種細胞的PI3K機能亢進正常化,對生體無毒性的免疫抑制劑有迫切的必要。
[非專利文獻2]S. Yaguchi et al., 96th Annual Meeting of the AACR, Anaheim, CA, USA. April16-20, 2005, #1691.
[非專利文獻3]R. Wetzker and C. Rommel, Current Pharmaceutical Design, 2004, 10, 1915-1922
[非專利文獻4]A. C. Donahue and D. A. Fruman, J. Immunol. 2003, 170, 5851-5860
[非專利文獻5]S. G. Ward et al., Eur J Immununol. 1995, 25, 526-532
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鑑於上述事情,本發明人等,考慮到關於專利文獻1,2,3,4及5的雜環式化合物,對於使用免疫抑制劑之自身免疫(autoimmune)疾病,臟器移植,過敏性疾病,血液腫瘤,敗血症等的疾病,亦有成為有用化合物之可能性,經戮力研究的結果,首先發現以下一般式(I)所示之雜環式化合物為有效,於是完成本發明。
因此,本發明的一態樣係提供以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;
R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽為有效成份之免疫抑制劑。
在此,一實施態樣係提供,式(I)中,R1,R2任意為羥基之免疫抑制劑。其他的實施態樣提供,式(I)中,R1,R2任意為羥基,R3為二氟甲基之免疫抑制劑。更進一步的實施態樣提供,式(I)中,R1,R2均為氫,R3為二氟甲基之免疫抑制劑。再者,亦提供式(I)中,R6為4-乙醯基哌嗪之免疫抑制劑。
上述中,對象疾病為排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病(obstructive pulmonary disease)或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭氏乾燥症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,慢性白血病,急性白血病,骨髓性白
血病等的血液腫瘤;敗血症,急性肝炎等。
在此,一實施態樣提供式(I)中,R1,R2任意為羥基之PI3K抑制劑。其他的實施態樣提供式(I)中,R1,R2任意為羥基,R3為二氟甲基之PI3K抑制劑。更進一步的實施態樣提供式(I)中,R1,R2均為氫,R3為二氟甲基之PI3K抑制劑。再者亦提供式(I)中,R6為4-乙醯基哌嗪之PI3K抑制劑。
上述中,對象疾病為排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭氏乾燥症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,急性白血病等的血液腫瘤;敗血症,急性肝炎等。
關於上述本發明免疫抑制劑中所使用的式(I)之雜環式化合物中,其一些(several)構造為新穎。因此,本發明其他的態樣提供以一般式(II)
[式中,n為0~2;X為氮原子或CH;Y表示(CH2)n1-,n為1~2;R1,R2同為或任意為氫原子,羥基,鹵素,胺
基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基,R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基,R4,R5為氫原子,C1-C6烷基;R7為氫原子,C1-C6烷基,甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基]所示之雜環式化合物或其藥學上可容許的鹽。
在此,上述式(II)中,R7為氫原子,C1-C6烷基;R6為氫原子,C1-C6烷基。例如,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-4-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-4-基)-6-(反式-2,3-二甲基嗎啉基)
嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三,2-(2-羥甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑4-基)-4-
[4-(N,N-二甲基胺甲醯基哌嗪)4-基]6-(反式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)嘧啶,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶,2-(2-羥甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1.3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,4-[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲
基嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)嘧啶,2-(2-二氟甲基4羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶,4[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯
并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑4-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-羥甲基苯并咪唑-1-基)4嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4(2,2-二甲基嗎
啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-羥甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-4-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二
甲基嗎啉基)嘧啶,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-4-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶,2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)4[4-(3-羥基丙基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]6-(2,2-二甲基嗎啉基-1,3,5-三,2-(2-二氟甲基4羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三,2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪4-基]-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6(2,2-二甲基嗎啉基嘧啶,2-(
2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基-1.3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基-1,3,5-三,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-(2,2-二甲基嗎啉基)嘧啶,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧
啶,2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基嘧啶,2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基嘧啶,2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-6-(3,5-二側氧基哌嗪-1-基)-4-嗎啉基-1,3,5-三。
進而本發明人等亦首先發現對上述式(II)所示之新規化合物可更進一步作為抗腫瘤劑之新用途。因此,更進一步的實施態樣亦關於以式(II)化合物為有效成份之抗腫瘤劑。對像疾病並無特別的限定,可例舉肺癌,***癌,乳癌,結腸癌,胃癌,胰臟癌,肝臟癌,食道癌,腦腫瘤,卵巢癌,子宮癌,惡性黑色素瘤,腎臟癌,頭頸部癌,皮膚癌,膀胱癌,骨肉瘤(osteosarcoma),膽道癌,外陰癌,***腫瘤,陰莖癌,直腸癌,縱隔腫瘤,尿路上皮癌,絨毛癌,骨肉瘤(Musculoskeletal Sarcoma),甲狀腺癌,副甲狀腺癌,副腎癌,惡性褐色細胞瘤,胚細胞腫瘤等。
進而,本發明亦關於下列之各種實施態樣。本發明係關於以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽[之治療的有效量投藥予哺乳動物所成的免疫抑制方法。
在此,一實施態樣,式(I)中,R1,R2任意為羥基,其他的實施態樣,式(I)中,R1,R2任意為羥基,R3為二氟甲基。更進一步的實施態樣,式(I)中,R1,R2
均為氫,R3為二氟甲基。再者,式(I)中,R6為4-乙醯基哌嗪。
又,對象疾病方面,可例舉排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,急性白血病等的血液腫瘤;敗血症,急性肝炎等。
再者,其他的實施態樣係關於含有以一般式(II)
[式中,n為0~2;X為氮原子或CH;Y表示(CH2)n1-,n為1~2;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基,R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R7為氫原子,C1-C6烷基,甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基]所示之雜環式化合物或其藥學上可容許的鹽之治療的有效量投藥於患者所成之治療腫瘤的方法。
再者,其他的態樣中,本發明係關於以一般式(II)
[式中,n為0~2;X為氮原子或CH;Y表示(CH2)n1-,n為1~2;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基,R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R7為氫原子,C1-C6烷基,甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基]所示之含有治療的有效量之雜環式化合物或其藥學上可容許的鹽與藥學上容許的載體之免疫抑制組成物。再者,其他的實施態樣係關於以一般式(II)所示之含有治療的有效量之雜環式化合物或其藥學上可容許的鹽與藥學上容許的載體之組成物,特別是藥學的組成物,更佳為抗腫瘤組成物。
進而,本發明亦關於下列之各種實施態樣。本發明係關於含有以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽之治療的有效量對哺乳動物投藥之PI3K抑制法。
在此,一實施態樣,式(I)中,R1,R2任意為羥基,其他的實施態樣,式(I)中,R1,R2任意為羥基,R3為二氟甲基。更進一步的實施態樣,式(I)中,R1,R2
均為氫,R3為二氟甲基。再者,式(I)中,R6為4-乙醯基哌嗪。
又,對象疾病方面,可例舉排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,急性白血病等的血液腫瘤;敗血症,急性肝炎等。
再者,其他的態樣中,本發明係關於以含有一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1
~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之治療有效量之雜環式化合物或其藥學上可容許的載體[容許的之PI3K抑制組成物。再者,其他的實施態樣係關於以一般式(II)所示之含有治療的有效量之雜環式化合物或其藥學上可容許的鹽與藥學上所容許的載體組成物,特別是藥學的組成物,更佳為PI3K抑制組成物。
進而,本發明係關於以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6
烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子’4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽之,[關於供作免疫疾病治療之醫藥製造之使用或作為免疫抑制劑之使用。
在此,一實施態樣,式(I)中,R1,R2任意為羥基,其他的實施態樣,式(I)中,R1,R2任意為羥基,R3為二氟甲基。更進一步的實施態樣,式(I)中,R1,R2均為氫,R3為二氟甲基。再者,式(I)中,R6為4-乙醯基哌嗪。
又,對象疾病方面,可例舉排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,急性白血病等
的血液腫瘤;敗血症,急性肝炎等。
進而,其他的實施態樣係關於以一般式(II)
[式中,n為0~2;X為氮原子或CH;Y表示(CH2)n1-,n為1~2;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基,R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R7為氫原子,C1-C6烷基,甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基]所示之雜環式化合物或其藥學上可容許的鹽之,使用於腫瘤治療組成物的製造。
進而其他的實施態樣係關於以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽之,[供作抑制PI3K之醫藥製造之使用或作為PI3K抑制劑之使用。
在此,一實施態樣,式(I)中,R1,R2任意為羥基,其他的實施態樣,式(I)中,R1,R2任意為羥基,R3為二氟甲基。更進一步的實施態樣,式(I)中,R1,R2均為氫,R3為二氟甲基。進而,式(I)中,R6為4-乙醯基哌嗪。
又,對象疾病方面,可例舉排斥反應或移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;阻塞
性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎,全身性紅斑性狼瘡,硬皮病,修格蘭症候群等的自身免疫疾病;惡性淋巴瘤,多發性骨髓瘤,急性白血病等的血液腫瘤;敗血症,急性肝炎等。
本發明之更進一步的其他實施態樣,實施形態,特徵,若對照以下的詳細說明的話,對熟悉該項技藝人士亦應該可以明瞭。
本發明中所使用的雜環式化合物係以一般式(I)
[式中,X為氮原子或CH;R1,R2同為或任意為氫原子,羥基,鹵素,胺基,C1-C6烷胺基,C1-C6烷氧基,C1-C6烷基,氰基;R3為氫原子,二氟甲基,胺基,C1-C6烷胺基,甲基,羥甲基;R4,R5為氫原子,C1-C6烷基;R6為嗎啉基(亦可以1~2個的C1-C6烷基取代),吡咯啶基(亦可以羥基C1-C6烷基取代),哌啶基(亦可以1~2個的氧原子,羥基,甲醯基,C1-C6烷基取代),哌
嗪基(1~2個的氧原子,4位的氮亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代),1,4-二氮雜革基(1~2個的氧原子,4位的氮,亦可以選自甲醯基,C1-C6羥烷基,C1-C6烷氧羰基,C1-C6側氧烷基,芳香族羰基,苄基羰基,取代胺甲醯基所成群之取代基取代)]所示之雜環式化合物或其藥學上可容許的鹽。。
上述式中,「C1-C6」若沒有限定的話,係為具有碳數1~6個之基之意。「C1-C6烷基」方面,可例舉甲基,乙基,正丙基,異丙基,正丁基,三級丁基,正戊基,正己基等之直鏈或分支鏈狀的烷基。「C1-C6烷氧基」方面,可例舉甲氧基,乙氧基,正丙氧基,異丙氧基,正丁氧基,三級丁氧基,二級丁氧基,正戊基氧基,正己基氧基等之直鏈或分支鏈狀的烷氧基。「羥基C1-C6烷基」,係表示在上述「C1-C6烷基」所定義之基的任一碳原子有羥基鍵結之基。
上述式中,「C1-C6」若沒有限定的話,係為具有碳數1~6個基之意。「C1-C6烷基」方面,可例舉甲基,乙基,正丙基,異丙基,正丁基,三級丁基,正戊基,正己基等之直鏈或分支鏈狀的烷基。「C1-C6烷氧基」方面,可例舉甲氧基,乙氧基,正丙氧基,異丙氧基,正丁氧基,三級丁氧基,二級丁氧基,正戊氧基,正己氧基等之直鏈或分支鏈狀的烷氧基。「羥基C1-C6烷基」,係表示在上述「
C1-C6烷基」所定義之基的任一碳原子有羥基鍵結之基。
上述雜環式化合物,在其構造中具有不對稱的碳原子時,雖然存在有來自不對稱碳原子之異構體及其混合物(消旋物(racemate)),但是其任一個亦視為含有本發明的化合物。
又,本發明之有效成份所使用的雜環式化合物亦可為藥學上容許的鹽之酸加成鹽的型態。適當的酸加成鹽方面,在無機酸鹽方面,可使用例如鹽酸鹽,硫酸鹽,氫溴酸鹽,硝酸鹽,磷酸鹽等,有機酸鹽方面,可使用例如乙酸鹽,草酸鹽,丙酸鹽,乙醇酸鹽,乳酸鹽,丙酮酸鹽,丙二酸鹽,琥珀酸鹽,順丁烯二酸鹽,反丁烯二酸鹽,蘋果酸鹽,酒石酸鹽,檸檬酸鹽,苯甲酸鹽,桂皮酸鹽,甲烷磺酸鹽,苯磺酸鹽,對甲苯磺酸鹽,水楊酸鹽等。
本發明有效成份之可利用的化合物方面,可例舉如,以下的雜環式化合物,但是本發明並非限定於此。
.2-(2-甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物1)
.2-(苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物2)
.4,6-二嗎啉基-2-(2-羥甲基苯并咪唑-1-基)-1,3,5-三(化合物3)
.2-(2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物4)
.2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基嘧啶(
化合物5)
.2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物6)
.2-(2-二氟甲基苯并咪唑-1-基)-4-哌啶基(piperidino)-6-嗎啉基-1,3,5-三(化合物7)
.2-(6-胺基-2-二氟甲基苯并咪唑-1-基)-4-(順式-2.2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物8)
.2-(2-二氟甲基-6-乙氧基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物9)
.2-(2-二氟甲基-4-甲基-苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物10)
.2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(2,6-二甲基嗎啉基)嘧啶(化合物11)
.2-(2-二氟甲基-5-羥基苯并咪唑-1-基)-4,6-二嗎啉基)-1,3,5-三(化合物12)
.2-(6-胺基-2-二氟甲基苯并咪唑-1-基)-4-(2.2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物13)
.2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物14)
.2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物15)
2-(2-二氟甲基-6-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物16)
2-(5-胺基-2-二氟甲基苯并咪唑-1-基)-4,6-二(2,6-二甲基嗎啉基)嘧啶(化合物17)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4,6-二嗎啉基-嘧啶(化合物18)
2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物19)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基-1,3,5-三(化合物20)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物21)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(3,3-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物22)
2-(2-二氟甲基-5-甲氧基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物23)
2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(順式-2,6-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物24)
2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革(diazepam)-1-基)-1,3,5-三(化合物25)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-羥基哌啶-1-基)-6-嗎啉基-1,3,5-三(化合物26)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-(2-羥基乙基)哌嗪-1-基)-6-嗎啉基-1,3,5-三(化合物27)
4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基(morpholino)-1,3,5-三(化合物28)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-苄基羰基哌嗪-1-基)-6-嗎啉基-1,3,5。三(化合物29)
4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三(化合物30)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三(化合物31)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三(化合物32)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪基-1-基)-6-嗎啉基-1,3,5-三(化合物33)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪基-1-基6-嗎啉基-1,3,5-三(化合物34)
2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三(化合物35)
2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物36)
2-(2-二氟甲基4甲氧基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物37)
2-(2-二氟甲基-4-乙氧基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物38)
本發明的藥劑,係如後述實施例的實証,由於藉由Con A,LPS,抗IgM抗體,抗CD3抗體+抗CD28抗體之抑制T細胞及B細胞的反應,發揮了免疫系細胞中PI3K的抑制作用為自明。亦即,本發明的藥物可以使用於基於PI3K的機能亢進而致的免疫系疾病的治療或預防。由PI3K機能亢進而致的免疫疾病方面,可例舉風濕性關節炎,全身性紅斑性狼瘡,修格蘭氏乾燥症候群等的自身免疫疾病;葡萄膜炎(uveitis),腎小球腎炎,甲狀腺炎,胰臟炎(pancreatitis),折骨術(osteoclasis)等伴隨自身免疫疾病的障礙;組織移植時的排斥反應,骨髓移植時的移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;慢性阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;過敏性的結膜炎或鼻炎;B淋巴瘤,T淋巴瘤,骨髓性白血病等起源於免疫系細胞的血液腫瘤;感染革蘭氏陰性菌或冠狀病毒(coronavirus)等而致的敗血症,重症急性呼吸器症候群,急性肝炎等的疾病等。
接著,本發明的藥劑雖然可適用於人類,狗,貓,兔,倉鼠(hamster),田鼠(rat),老鼠(mouse)等的哺乳動物,但是在此特別說明適用於人類時的投藥方法,劑型,投藥量。
本發明的藥劑可以經口或非經口的投藥,經口投藥的劑型方面,可使用錠劑,膜衣錠(coated tablet)劑,散劑,顆粒劑,膠囊劑,微膠囊劑,糖漿劑等,又非經口投
藥的劑型方面,可使用點眼劑,吸入劑,注射劑(包含使用時溶解而使用的注射用凍結乾燥劑),坐劑,濕布等。該等劑型的調製可以使用藥學上可容許的稀釋劑(diluents),黏結劑(binder),潤滑劑,崩壞劑,懸濁化劑,乳化劑,防腐劑,穩定化劑及分散劑,例如乳糖,白糖,澱粉,糊精(dextrin),結晶纖維素,高嶺土,碳酸鈣,滑石,硬脂酸鎂,蒸餾水或生理食鹽水而進行。
使用經口劑時,有效成份的投藥量依患者的症狀,年齡,體重等而異,以體重60kg的成人來說,可將一日量10~500mg分成2~3次投藥。又,點眼劑,肺或鼻腔的吸入,以炎症關節腔的注射為目的時,亦依照患者的症狀而變化,對成人來說,可以將一日量1~100μg分為2~3次投藥。
本發明的藥劑對於自身免疫疾病,臟器移植,過敏性或炎症性疾病,血液腫瘤,敗血症等與PI3K相關連的疾病之預防或治療及腫瘤的治療深具效果。
使用專利文獻3,4及5的實施例之方法而製造者,在此例示以一般式(I)所示之雜環式化合物的幾個例子
。
參照專利文獻1~3而合成者。
製造例1)
2-(2-甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物1)
熔點:218-20℃(分解)
NMR(CDCl3)δ:3.03(3H,s),3.7-3.9(16H,m),7.2-7.4(2H,m),7.7-7.8(1H,m),8.1-8.3(1H,m)
MS m/z:381(M+)
製造例2)
2-(苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物2)
熔點:147-150℃
NMR(CDCl3)δ:1.1-1.5(6H,m),2.7-3.0(1H,m),3.4-3.6(1H,m),3.7-4.0(8H,m),4.1-4.3(1H,m),4.4-4.7(2H,m),7.3-7.4(2H,m),7.7-7.9(1H,m),8.3-8.4(1H,m),8.98(1H,s)
製造例3)
.4,6-二嗎啉基-2-(2-羥甲基苯并咪唑-1-基)-1,3,5-三(化合物3)
.熔點:208-210℃(分解)
NMR(CDCl3)δ:3.7-3.9(16H,m),4.59(1H,t,J=6Hz),5.15(2H,d,J=7Hz),7.2-7.4(2H,m),7.7-7.8(1H,m),8.3-8.4(1H,m)
MS m/z:397(M+)
實施例4)
2-(2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物4)
熔點:211-214℃
NMR(CDCl3)δ:3.79(8H,t,J=4Hz),3.88(8H,t,J=4Hz),7.3-7.4(2H,m),7.56(1H,t,J=53Hz),7.88(1H,d,J=7Hz),8.32(1H,d,J=7Hz)
MS m/z:417(M+)
製造例5)
2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基嘧啶(化合物5)
熔點:237-239℃
NMR(CDCl3)δ:3.59(8H,t,J=5Hz),3.84(8H,t,J=5Hz),5.46(1H,s),6.65(2H,brs),7.06(1H,t,J=7Hz),7.18(1H,t,J=7Hz),7.37(1H,d,J=7Hz),8.1(1H,d,7Hz)
MS m/z:381(M+)
製造例6)
.2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物6)
熔點:298-300℃(分解)
NMR(CDCl3)δ:3.7-3.9(16H,m),6.74(2H,brs),7.05(1H,t,J=7Hz),7.20(1H,t,J=7Hz),7.39(1H,d,J=7Hz),8.20(1H,d,7Hz)
MS m/z:382(M+)
製造例7)
2-(2-二氟甲基苯并咪唑-1-基)-4-哌啶基-6-嗎啉基-1,3,5-三(化合物7)
熔點:190-192℃
NMR(CDCl3)δ:1.5-1.8(6H,m),3.7-3.9(12H,m),7.3-7.5(2H,m),7.61(1H,t,J=54Hz),7.90(1H,d,J=8Hz),8.34(1H,d,8Hz)
MS m/z:415(M+)
實施例8)
2-(6-胺基-2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物8)
熔點:220-222℃(分解)
NMR(CDCl3)δ:1.22(3H,d,J=9Hz),1.26(3H,d
,J=9Hz),3.1-3.4(1H,m),3.5-4.1(11H,m),4.3-4.5(1H,m),4.5-4.7(1H,m),6.77(1H,dd,J=2Hz,J=9Hz),7.49(1H,t,J=54Hz),7.62(1H,d,J=9Hz),7.64(1H,d,J=2Hz)
MS m/z:460(M+)
製造例9)
.2-(2-二氟甲基-6-乙氧基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物9)
熔點:222-224℃
NMR(CDCl3)δ:1.46(3H,t,J=7Hz),3.7-3.9(16H,m),4.08(2H,q,J=7Hz),7.00(1H,dd,J=9Hz,3Hz),7.52(1H,t,J=54Hz),7.74(1H,d,J=9Hz),7.89(1H,d,J=3Hz)
MS m/z:461(M+)
製造例10)
.2-(2-二氟甲基-4-甲基-苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物10)
熔點259-260℃
NMR(CDCl3)δ:2.72(3H,s),3.7-3.9(16H,m),7.1-7.5(2H,m),7.56(1H,t,J=54Hz),8.15(1H,d,8Hz)
MS m/z:431(M+)
製造例11)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(2,6-二甲基嗎啉基)嘧啶(化合物11)
熔點:265-267℃
1HNMR(CDCl3)d:3.7-3.9(16H,m),3.86(3H,s),7.02(1H,dd,J=3,9Hz,),7.52(1H,t,J=53Hz,),7.75(1H,d,J=9Hz,),7.91(1H,d,J=3Hz,)
MS m/z:447(M+)
製造例12)
.2-(2-二氟甲基-5-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物12)
熔點:272-274℃
NMR(CDCl3)δ:3.7-3.9(16H,m),7.26-7.29(2H,m),7.54(1H,t,J=54Hz),8.20(1H,d,8Hz)
MS m/z:433(M+)
實施例13
2-(6-胺基-2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物13)
熔點:226-227℃(分解)
NMR(CDCl3)δ:1.28(6H,s),3.6-3.8(14H,m),
6.7-6.8(1H,m),7.2-7.7(3H,m)
MS m/z:460(M+)
實施例14)
2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物14)
熔點:214-216℃(分解)
NMR(CDCl3)δ:3.7-3.9(16H,m),4.48(2H,brs),6.63(1H,d,J=BHz),7.21(1H,t,J=8Hz),7.55(1H,t,J=54Hz),7.64(1H,d,J=8Hz)
MS m/z:432(M+)
製造例15)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物15)
熔點:>250℃
NMR(DMSO-d6)δ:3.70-3.90(16H,m),6.76(1H,d,J=8Hz),7.73(1H,t,J=8Hz),7.70(1H,t,J=54Hz),7.74(1H,d,8Hz),10.24(1H,brs)
MS m/z:433
製造例16)
2-(2-二氟甲基-6-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物16)
熔點>250℃
NMR(DMSO-d6)δ:3.70-3.90(16H,m),6.86(1H,d,J=8Hz),7.61(1H,d,J=8Hz),7.70(1H,t,J=54Hz),7.73(1H,s),9.81(1H,brs)
MS m/z:433
製造例17)
.2-(5-胺基-2-二氟甲基苯并咪唑-1-基)-4,6-二(2,6-二甲基嗎啉基)嘧啶(化合物17)
熔點:157-160℃
NMR(CDCl3)δ:1.30(6H,d,J=9Hz),2.6-2.8(4H,m),3.6-4.2(8H,m),5.45(1H,s),6.7-6.8(1H,m),7.5-7.7(2H,m),7.42(1H,t,J=53Hz)
MS m/z:487(M+)
製造例18)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4,6-二嗎啉基-嘧啶(化合物18)
熔點>250℃
NMR(DMSO-d6)δ:3.60-3.80(16H,m),5.98(1H,s),6.72(1H,d,J=8Hz),7.22(1H,t,J=8Hz),7.62(1H,d,J=8Hz),7.65(1H,t,J=54Hz),10.17(1H,brs)
MS m/z:432
製造例19)
2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三(化合物19)
(1)將6-胺基-4-氯-2-二氟甲基苯并咪唑500mg(2.3mmol)溶解於丙酮(50ml)中,在-15℃加入2,4-二氯-6-嗎啉基-1,3,5-三542mg(2.3mmol),進而加入碳酸鉀500mg。慢慢地昇溫至室溫止後,在室溫攪拌5小時。減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=1:4)精製,獲得2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-氯-6-嗎啉基-1,3,5-三272mg(收率28%)。
(2)將所得之2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-氯-6-嗎啉基-1,3,5-三150mg(0.36mmol)溶解於DMF(6ml),在-15℃加入2,2-二甲基嗎啉基鹽酸鹽150mg(1.0mmol)進而加入碳酸鉀500mg。在室溫攪拌1晚後,於反應液中加入水,以乙酸乙酯經數回萃取,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=1:2)精製,獲得為無色結晶的標記化合物130mg(收率73%)。
熔點238℃(分解)
NMR(CDCl3)δ:1.27(6H,s),3.68(2H,s),3.7-3.9(12H,m),6.82(1H,d,J=2.3Hz),7.42(1H,
dt,1=9.6Hz,J=53Hz),7.50(1H,d,J=2.3Hz)
MS m/z:494(M+)
實施例20)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶基-1-基)-6-嗎啉基-1,3,5-三(化合物20)
熔點:245℃(分解)
NMR(CDCI3)δ:1.9-2.1(4H,m),3.5-4.0(12H,m),4.7-4.8(1H,m),5.1-5.3(1H,m),6.89(1H,d,J=9Hz),7.30(1H,t,J=9Hz),7.50(1H,brs),7.55(1H,t,J=54Hz),7.83(1H,d,J=9Hz).
MS m/z:447(M+)
製造例21)
.2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物21)
熔點:185-187℃
NMR(CDCl3)δ:1.29(6H,s),3.48(2H,s),3.59-3.64(6H,m),3.81-3.87(6H,m),5.47(1H,s),6.86(1H,m),7.26-7.32(1H,m),7.49(1H,t,J=53Hz),7.72(1H,d,8Hz)
MS m/z:460(M+)
製造例22)
.2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(3,3-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物22)
熔點:204-206℃
NMR(CDCl3)δ:1.48(6H,s),3.50(2H,s),3.6-3.8(6H,m),3.8-4.0(6H,m),5.76(1H,s),6.68(1H,d,J=7Hz),7.29(1H,d,J=7Hz),7.49(1H,t,J=54Hz),7.66(1H,d,7Hz)
MS m/z:460(M+)
製造例23)
2-(2-二氟甲基-5-甲氧基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(化合物23)
熔點:206-207℃
NMR((CD3)2CO)δ:1.17(6H,d,J=6Hz),2.5-2.8(4H,m),3.6-4.4(10H,m),5.95(1H,s),6.77(1H,d,J=8Hz),7.23(1H,t,J=8Hz),7.66(1H,t,J=53Hz),7.75(1H,d,J=8Hz),8.9(1H,S)
MS m/z:460(M+)
製造例24)
2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(順式-2,6-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物24)
(1)將2-二氟甲基-4-甲氧基苯并咪唑9.03g(45.6mmol)溶解於DMF(100ml)中,加入60% NaH1.82g
(45.6mmol),攪拌30分鐘。將其反應溶液於冰冷下添加使2,4,6-三氯嘧啶15.7g(92.1mmol)溶解於DMF(100ml)的溶液,在冰浴中30分鐘進而在室溫攪拌2小時。加水至反應液中,濾出析出的結晶,以己烷,醚完全洗淨後風乾,獲得2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4,6-二氯嘧啶12.3g(收率78%)。
(2)將所得之2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4,6-二氯嘧啶12.3g(35.7mmol)溶解於DMF(150ml),於室溫加入順式-2,6-二甲基嗎啉基6.63ml(53.7mmol),進而加入碳酸鉀7.35g。在室溫下攪拌30分鐘後,加水至反應液,以乙酸乙酯萃取數回,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。減壓下餾除溶劑,將殘渣以己烷,醚完全洗淨後風乾,獲得4-氯-2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-6-(順式-2,6-二甲基嗎啉基)嘧啶14.4g(收率95%)。
(3)在所得之4-氯-2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-6-(順式-2,6-二甲基嗎啉基)嘧啶14.4g(34mmol)加入嗎福林275ml(3.15mol),室溫下30分鐘進而以80℃攪拌30分鐘。加水至反應液中,濾出(filtering)析出的結晶,以己烷,醚,乙酸乙酯完全洗淨後風乾,獲得2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(順式-2,6-二甲基嗎啉基)-6-嗎啉基嘧啶13.7g(收率86%)。
熔點:180-181℃
NMR(CDCl3)δ:1.28(6H,d,J=6Hz),2.6-2.7(2H,m),3.6-3.7(6H,m),3.80-3.86(4H,m),4.04(3H,s),4.10-4.14(2H,m),5.49(1H,s),6.78(1H,d,J=8Hz),7.32(1H,d,J=8Hz),7.41(1H,t,J=52Hz),7.77(1H,d,J=8Hz)
MS m/z:474(M+)
製造例25)
2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)-1,3,5-三(化合物25)
熔點235-37℃
1HNMR(CDCl3)d:2.7-2.8(2H,m),3.4-3.5(2H,m),3.8-4.2(12H,m),5.97(1H,brs),7.2-7.5(2H,m),7.52(1H,t,J=54Hz),7.8-8.0(1H,m)8.2-8.4(1H,m)
MS m/z:444(M+)
製造例26)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-羥基哌啶-1-基)-6-嗎啉基-1,3,5-三(化合物26)
熔點:219-21℃
1HNMR(CDCl3)d:3.4-3.5(2H,m),3.7-4.1(16H,m),7.3-7.5(2H,m),7.59(1H,t,J=50Hz),7.8-8.0(1H,m)8.3-8.4(1H,m)
MS m/z:431(M+)
製造例27)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-(2-羥基乙基)哌嗪-1-基)-6-嗎啉基-1,3,5-三(化合物27)
熔點:174-77℃
1HNMR(CDCl3)d:2.6-2.7(8H,m),3.6-3.9(12H,m),3.91(1H,br)7.3-7.5(2H,m),7.58(1H,t,J=54Hz),7.9-8.0(1H,m)8.3-8.4(1H,m)
MS m/z:460(M+)
參照專利文獻4
製造例28)
2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基嘧啶
947
(1)將4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑1.49g(5.0mmol)溶解於DMF(10ml)中,室溫下加入2,4,6-三氯嘧啶0.91g(5.0mmol)進而加入碳酸鉀0.55g,攪拌5小時。加水至反應液中,以乙酸乙酯萃取數回,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。
減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=8:1)精製,獲得2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4,6-二氯嘧
啶1.12g(收率50%)。
(2)將所得之2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4,6-二氯嘧啶386mg(0.87mmol)溶解於DMF(6ml),室溫下加入2-吡咯啶甲醇0.13ml(1.3mmol),進而加入碳酸鉀179mg。在室溫攪拌30分鐘後,加水至反應液,以乙酸乙酯萃取數回,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=1:1)精製,獲得2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-氯嘧啶291mg(收率64%)。
(3)在所得之2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-氯嘧啶281mg(0.54mmol)加入嗎福林4.4g(50mmol),室溫下攪拌9小時。加水至反應液中,以乙酸乙酯萃取數回,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=2:3)精製,獲得2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基嘧啶216mg(收率72%)。
將2-(4-三級丁基二甲基矽烷基氧-2-二氟甲基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基嘧啶213mg(0.38mmol)溶解於無水THF(7ml),室溫下加入氟化四丁基銨0.4ml(1M THF溶液),攪拌30分鐘。
加水至反應液,以乙酸乙酯萃取數回,以飽和食鹽水水洗後,以無水硫酸鎂乾燥。減壓下餾除溶劑,將殘渣以二氧化矽凝膠柱層析術(正己烷:乙酸乙酯=1:4)精製,獲得為無色結晶的標記化合物101mg(收率60%)。
熔點:195-198℃
NMR(CDCl3)δ:2.0-2.1(4H,m),3.4-4.0(12H,m),4.0-4.1(1H,m),4.3-4.4(1H,m),5.36(1H,s),6.85(1H,d,J=8Hz),7.28(1H,t,J=8Hz),7.58(1H,brs),7.58(1H,t,J=54Hz),7.73(1H,d,J=8Hz).
MS m/z:446(M+)
參照專利文獻4而製造者
製造例29)
2-(5,6-二甲基-2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(ZSTK705)
熔點:217-220℃
1HNMR(CDCl3)d:2.39(3H,s),2.40(3H/s),3.7-3.9(16H,m),7.53(1H,t,J=54Hz),7.62(1H,s)8.12(1H,s)
MS m/z:445(M+)
製造例30)
2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-(2-羥甲
基吡咯啶-1-基)-6-嗎啉基-1,3,5-三(STK922)
熔點:256℃(分解)
NMR(CD3OD-CDCl3(1:1))δ:1.9-2.2(4H,m),3.68(2H,s),3.5-4.0(11H,m),4.39(1H,brs),6.84(1H,d,J=2.1Hz),7.58(1H,t,J=53Hz),7.64(1H,d,J=2.1Hz)
MS m/z:480(M+)
製造例31)
2-(4-氯-2-二氟甲基-5-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三(STK894)
熔點>250℃
NMR(CDCl3)δ:3.7-3.9(16H,m),5.63(1H,s),7.15(1H,d,J=9Hz),7.51(1H,t,J=53Hz),8.14(1H,d,J=9Hz)
MS m/z:467(M+)
製造例32)
將4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-b-嗎啉基-1,3,5-三(化合物28)的合成
將6-氯-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三(3.66g,10mmol),1-乙醯基哌嗪(1.40g,11mmol),碳酸鉀(1.38g,10mmol),DMF(30ml)的混合物,於室溫攪拌16小時。注入反應溶液至水中,以
二氯甲烷萃取。將萃取液以無水硫酸鈉乾燥,減壓濃縮,將殘留物以二氧化矽凝膠柱精製,獲得收率90%,為無色結晶的目的物的4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5三(4.08g,9.0mmol)。
當然,此種具有哌嗪基之三或嘧啶衍生物2亦可如下列方式合成。
例如將6-氯-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三(3.66g,10mmol),哌嗪(3.45g,40mmol),丙酮50ml的混合物於室溫攪拌16小時。將反應溶液注入水中濾出析出的結晶,以甲醇洗淨,獲得收率93%,為無色結晶之2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(哌嗪-1-基)-1,3,5三(3.87g,9.3mmol)。
1HNMR(CDCl3)d:3.8-4.1(16H,m),7.3-7.5(2H,m),7.59(1H,t,J=54Hz),7.9-8.0(1H,m)8.3-8.4(1H,m)
MS m/z:416(M+)
在2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(哌嗪-1-基)-1,3,5三(417mg,1.0mmol),THF10ml的混合物中,滴下乙醯氯(0.14ml,2.0mmol)。將反應混合物於室溫攪拌22小時。將反應溶液注入水中,以二氯甲烷萃取。將萃取液以無水硫酸鈉乾燥,減壓濃縮,將殘留物以二氧化矽凝膠柱精製,獲得收率77%,為無色結
晶的目的物4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-b-嗎啉基-1,3,5三(354mg,7.7mmol)。
熔點:223℃
1HNMR(CDCl3)d:2.18(3H,s),3.6-4.0(16H,m),7.3-7.5(2H,m),7.55(1H,t,J=53.5Hz),7.9-8.0(1H,m)8.3-8.4(1H,m)
MS m/z:458(M+)
以下與製造例34一樣地製造。
製造例33)
2-(2-二氟甲基苯并咪唑-1-基)-6-(4-甲醯基哌嗪-1-基)-4-嗎啉基-1,3,5-三
熔點:228-30℃.
1HNMR(CDCl3)d:3.8-4.1(16H,m),7.2-7.5(2H,m),7.54(1H,t,J=54Hz),7.8-8.0(1H,m),8.17(1H,s),8.3-8.4(1H,m).
MS m/z:444(VI+).
製造例34)
2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)-1,3,5-三
熔點:255-57℃
1H NMR(CDCl3)d:3.5-3.9(14H,m),6.48(1H,
brs),7.2-7.5(2H,m),7.59(1H,t,J=54Hz),7.8-7.9(1H,m)8.2-8.4(1H,m)
MS m/z:430(M+)
製造例35)
2-(2-二氟甲基苯并咪唑-1-基)-6-(3,5-二側氧基哌嗪-1-基)-4-嗎啉基-1,3,5-三
熔點:230-32℃
1H NMR(CDCl3)d:3.5-3.9(12H,m),7.2-7.5(2H,m),7.59(1H,t,J=55Hz),7.9-8.0(1H,m)8.3-8.4(1H,m)
MS m/z:444(M+)
製造例36)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-苄基羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三(化合物29)
(STK1515)
熔點:178-181℃
1H NMR(CDCl3)d:3.81(2H,s),3.5-3.9(16H,m),7.2-7.5(7H,m),7.52(1H,t,J=54Hz,),7.89(1H,d,J=8Hz,),8.30(1H,d,J=8Hz)
MS m/z:534(M+)
製造例37)
4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三(化合物30)(STK01529)
熔點:79-81℃
NMR(CDCl3-d1)δ:2.19(3H,s),2.60(2H,s),3.70-4.00(16H,m),7.30-7.50(2H,m),7.57(1H,t,J=54Hz),7.90(1H,d,J=8Hz),8.33(1H,d,J=8Hz)
MS m/z:472
製造例38)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三(化合物31)(STK01531)
熔點:220-222℃
NMR(CDCl3-d1)δ:3.80-4.00(16H,m),6.53(1H,d,J=2Hz),7.01(1H,d,J=2Hz),7.30-7.60(4H,m),7.80(1H,d,J=8Hz),8.34(1H,d,J=8Hz)
MS m/z:510
製造例39)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]
6-嗎啉基-1,3,5-三(化合物32)(STK01539)
熔點:203-205℃
NMR(CDCl3-d1)δ:2.90(6H,s),3.30-3.40(4H,m),3.80-4.00(12H,m),7.30-7.40(2H,m),7.56(1H,t,J=54Hz),7.89(1H,d,8Hz),8.34(1H,d,8Hz)
MS m/z:487
製造例40)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3.5-三(化合物33)(STK01540)
熔點:72-75℃
NMR(CDCl3-d1)δ:3.46(3H,s),3.60-4.00(16H,s),4.17(2H,s)7.30-7.50(2H,m),7.55(1H,t,J=54Hz),7.90(1H,d,J=8Hz),8.34(1H,d,J=8Hz)
MS m/z:488
製造例41)
2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]6-嗎啉基-1,3,5-三(化合物34)
(STK01541)
NMR(CDCl3-d1)δ:1.17(2H,m),2.60-2.70(4H,m),3.50-4.00(16H,m),4.70(1H,brs)7.30-7.50(2H,m),7.56(1H,t,J=54Hz),7.90(1H,d,
J=8Hz),8.33(1H,d,J=8Hz)
MS m/z:474
製造例42)
2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三(化合物35)(STK01542)
熔點:198-202℃
NMR(CDCl3-d1)δ:1.20(3H,t,J=7Hz),2.42(2H,q,J=7Hz),3.50-4.00(16H,m),7.30-7.50(2H,m),7.56(1H,t,J=54Hz),7.90(1H,d,J=8Hz),8.33(1H,d,J=8Hz)
MS m/z:472
製造例43)
2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基羰哌嗪-1-基)-6-嗎啉基-1,3,5-三(STK01553)
熔點:255-260℃
NMR(CDCl3-d1)δ:3.59(4H,brs),3.76(3H,s),3.70-3.95(12H,s),7.30-7.50(2H,m),7.55(1H,t,J=54Hz),7.90(1H,d,J=8Hz),8.34(1H,d,J=8Hz)
MS m/z:474
以下係與製造例24)同樣地製造。
製造例44
2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物36)
熔點:166-168℃
NMR(CDCl3)δ:1.30(6H,s),3.49(2H,s),3.4-3.9(12H,m),4.05(3H,s),5.47(1H,s),6.79(1H,d,J=8Hz),7.32(1H,t,J=8Hz),7.41(1H,t,J=54Hz),7.78(1H,d,J=8Hz)
MS m/z:474(M+)
製造例45)
2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物37)
熔點:176-178℃
NMR(CDCl3)δ:1.20(3H,d,J=5Hz),1.22(3H,d,J=5Hz),3.6-3.7(1H,m),3.6-4.1(13H,m),4.05(3H,s),5.47(1H,s),6.79(1H,d,J=8Hz),7.32(1H,t,J=8Hz),7.42(1H,t,J=53Hz),7.78(1H,d,J=8Hz)
MS m/z:474(M+)
製造例46
2-(2-二氟甲基-4-乙氧基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶(化合物38)
熔點:114-116℃
NMR(CDCl3)δ:1.56(3H,t,J=7Hz),3.49(2H,s),3.5-3.9(12H,m),4.32(2H,q,J=7Hz),5.47(1H,s),6.78(1H,d,J=8Hz),7.30(1H,t,J=8Hz),7.41(1H.t,J=53Hz),7.76(1H,d,J=8Hz)
MS m/z:488(M+)
藥效分析(assay)
接著,確認一般式(I)所示雜環式化合物的藥理效果及毒性的試驗方法與其結果如以下所示。此外,被驗物質的化合物編號對應於上述雜環式化合物名所附的化合物編號。
試驗例1
對有絲***原(mitogen)反應的抑制作用
將由C57BL/6N系雌性老鼠(8週齡,自Charles River公司購入)調製的脾臟細胞,懸濁於RPMI1640培養皿(含有10%牛胎兒血清,10 mM HEPES,1 mM丙酮酸,4.5g/L葡萄糖,100 units/mL盤尼西林,0.1mg/mL鏈黴素(streptomycin))(2×106cells/mL),在96培養盤(well plate)以每1井(well)0.225mL的容量接種。在各井階段地添加已稀釋的被驗物質,接著添加伴刀豆球蛋白(concanavalin)A(ConA,3μg/mL),脂多糖(LPS,100μg/mL),或抗老鼠IgM抗體(100μg/mL)。然後,在二氧化碳5%,溫度37℃的條件下培養3日。接著,每
150μL Alamar Blue溶液添加50μL,培養1日後,使用激發波長530nm中螢光強度為590nm的Cytoflour 4000(Applied Biosystems公司製)測定。其結果,如表1所示,可知由於Con A,LPS,或抗IgM抗體,使得s-三類似物(analogue)抑制了老鼠脾臟細胞的增殖。
試驗例2)
人類末梢血單核球增殖抑制試驗
將自健康的人所採取的血液4mL放在單聚分離溶液3mL上,離心後,採取單核球(PBMC)分劃。將PBMC以生理食鹽水洗淨後,懸濁於RPMI1640培養皿(含有10%牛胎兒血清,10mMHEPES,1mM丙酮酸,4.5g/L葡萄糖)內(1x105cells/mL)。接著,在懸濁液添加抗CD28抗體(1μg/mL)後,在抗人CD3T細胞活性化小盤(BD Bioscience)中以每1井0.135mL的容量接種。然後,在各井階段地添加已稀釋的被驗物質,在二氧化碳5%,溫度37℃的條件下培養。3日後,每1井的Alamar Blue溶液添加50μL,培養1日後,使用激發波長530nm中螢光強度為590nm的Cytoflour 4000(Applied Biosystems公司製)測定。其結果,如表2所示,可知由於抗CD3抗體及抗CD28抗體使得s-三類似物(analogue)抑制了人類T細胞的增殖。
試驗例3)
人類末梢血單核球活性化抑制試驗
依照試驗例2的方法,自人類末梢血分離PBMC,在RPMI1640培養皿(含有10%牛胎兒血清,10mMHEPES,1mM丙酮酸,4.5g/L葡萄糖)內懸濁(2 x 106cells/mL),在96培養盤以每1井0.225mL的容量接種。添加被驗物質於各井,接著添加抗CD3抗體(2μg/mL)抗CD28抗體(1μg/mL)。然後,在二氧化碳5%,溫度37℃的條件下培養6小時後,以流式細胞儀法(flowcytometry)測定為活性化標記的CD40L及CD69之顯現。其結果為,受到抗CD3抗體,及抗CD28抗體的刺激時,CD40L顯現於14.4%的CD4陽性細胞上,但若預先處理被驗物質時,顯現出CD40L的細胞比率減少了(ZSTK474:4.9%,913:
3.7%,1213:3.6%)。同樣地,CD69顯現於CD4陽性細胞的28.8%及CD4陰性細胞的50.9%,但若預先以ZSTK474,913,1213處理時,顯現出CD69的CD4陽性細胞的比率(ZSTK474:18.8%,913:10.1%,1213:17.7%)及CD4陰性細胞的比率(ZSTK474:17.7%,913:10.5%,1213:22.4%)減少了。在此種情況下,明顯可知s-三類似物(analogue)抑制了淋巴球的活性化(第1圖)。
試驗例4)
佐藥(adjuvant)誘發關節炎的抑制作用
在Lewis系雄性田鼠(7週齡,自Charles River公司購入)的尾根部以弗羅因德(freund)的不完全佐藥懸濁之乳酪分支桿菌(Mycobacterium butyricum)予以皮內投藥,使其誘發佐藥關節炎。接著,自誘發佐藥關節炎的第10日起,將在0.5%羥基丙基纖維素(HPC)懸濁的被驗物質,每日予以經口投藥。又,自關節炎症狀發生後,使用腳底(sole)浮腫容積測定裝置(TK105,Physio-tech公司製)測定田鼠後肢的體積。其結果,被驗物質如第1圖,對於該模型試驗之第14日以後的對照群,可以確認統計學(分散分析,Dunnett檢定)上有意義(P<0.05)的效果。
試驗例5)
膠原蛋白誘發關節炎的抑制作用
在DBA1系雄性老鼠(7週齡,自Charles River公司購入)的尾根部,將以弗羅因德完全佐藥懸濁之牛II型膠原蛋白,於實驗第1日,及第21日,經皮內投藥。接著,對50%產生關節炎的老鼠,於第28日起,每日以在懸濁於0.5%羥基丙基纖維素(HPC)的被驗物質予以經口投藥。此外,以將關節炎分數化來評價藥效。亦即,每肢體1支均無症狀為0,1支關節的發紅,腫脹為1,2處以上的發紅,腫脹為2,全肢體的腫脹,腫脹為3,全肢體的最大發紅,腫脹為4,來評價關節炎的程度。由其結果可知ZSTK474可依照用量抑制膠原蛋白誘發關節炎的進行。對於以50,100mg/kg的投藥群之第30日以後的對照群,可以確認統計學上(Dunnett檢定)有意義(P<0.05)的效果。但是,以50mg/kg的投藥群自第40日起,症狀開始惡化,對於第44日以後的對照群,則有意差(significant difference)消失了(第3圖)。
試驗例6)
兔滑液膜細胞***抑制試驗
將在HAM培養皿(含有10%牛胎兒血清,25mM HEPES,及0.1mg/mL卡那毒素(kanamycin))懸濁的兔滑液膜細胞HIG-82(4×104 cells/mL)於96培養盤以每1井0.135mL的容量接種。接著,於各井階段地添加已稀釋的被驗物質15μL,在二氧化碳5%,溫度37℃的條件下培
養。
接著,在接種當日及培養的第3日於每1井的Alamar Blue溶液添加50μL,培養1日後,使用激發波長530nm中,螢光強度為590nm的Cytoflour 4000(Applied Biosystems公司製)進行測定。如表3所示,可明瞭s-三類似物(analogue)抑制了兔滑液膜細胞***。
試驗例7
同種(allogeneic)淋巴球混合反應
使用由作為刺激細胞(Stimulator cell)之C57BL/6N系雌性老鼠(8~10週齡,自Charles River公司購入)調
製的脾臟細胞,又,由作為應答細胞(Responder cell)之BALB/c系雌性老鼠(8~10週齡,自Charles River公司購入)調製的末梢淋巴結(peripheral lymph node)單核球(mononuclear leukocyte)。將各自的細胞於RPMI1640培養皿(含有10%牛胎兒血清,100 units/mL盤尼西林,0.1mg/mL鏈黴素)內懸濁(2×106 cells/mL)。接著,於應答細胞(100μL)添加已進行mitomycin C處理(50mg/mL,30分)的刺激細胞(50μL)。接著,於各井階段地添加已稀釋的被驗物質,在二氧化碳5%,溫度37℃的條件下培養86小時。最後以BrdU cell增殖組合(Calbiochem)檢查細胞的增殖。其結果如表4所示,可知S-三類似物(analogue)抑制了同種淋巴球混合反應。
試驗例8)
血液腫瘤細胞增殖抑制作用
將在RPMI1640培養皿(含有10%牛胎兒血清,10mMHEPES,1mM丙酮酸,4.5g/L葡萄糖,100units/mL盤尼西林,0.1mg/mL鏈黴素)中懸濁的Daudi細胞(5×105cells/mL),Jurkat細胞(5×105cells/mL),THP-1細胞(5×105cells/mL),U937細胞(5×105cells/mL),HL60細胞(5×105cells/mL),以每井0.135mL的容量接種在96培養盤上。在各井階段地添加已稀釋的被驗物質15μL/well,在二氧化碳5%,溫度37℃的條件下培養3日。接著,添加50μL的Alamar Blue溶液,培養1日後,使用激發波長530nm中,螢光強度為590nm的Cytoflour 4000(Applied Biosystems公司製)進行測定。其結果,如表5所示,可明瞭s-三類似物(analogue)可抑制血液腫瘤細胞的增殖。
試驗例9)
對人類B淋巴瘤移植模型的治療作用
將以RPMI1640培養皿(含有10%牛胎兒血清,10mMHEPES,1mM丙酮酸,4.5g/L葡萄糖,100units/mL盤尼西林,0.1mg/mL鏈黴素)培養的Daudi細胞(1×107細胞)移植於8週齡的NOD/SCID老鼠胸部。當腫瘤增殖,體積達到800mm3左右,自移植後第20日起經口投藥化
合物8(400mg/kg)。其結果為,化合物8如第4圖,在該模型中,抑制了腫瘤體積的增加。
試驗例10
急性肝炎模型
實驗時使用雄BALB/c系雄性老鼠(7週齡,自Charles River公司購入)。將於5%HPC懸濁的被驗物質予以經口投藥後,將Galactosamine(800mg/kg)及LPS(110μg/kg)予以腹腔內投藥。然後,求得投藥後72小時的生存率。其結果如表6所示,被驗化合物改善了由Galactosamine及LPS產生的致死作用。
試驗例11)
單次經口投藥之毒性試驗
使用SD系雄性田鼠(6週齡,體重162~188g)進行代表性的雜環式化合物之單次經口投藥,其結果為即使化合物8為1200mg/kg亦無法斷定死亡例,在化合物
14LD50為600~900mg/kg。
試驗例12)
Ames試驗
使用Salmonella typhimurium TA98,TA100,TA1535,TA1537及Escherichia coli WP2uvrA的5株,就被驗物質(化合物8,化合物10,化合物12及化合物14)的突變之原始誘發性(mutagenesis),藉由預培育(preincubation)法進行試驗。其結果為,即使在5000μg/平板(最大用量)中無關於S-9所致代謝活性化之有無,而由於任一試驗菌之回復突變(reverse mutation)菌落數亦無增加,使得突變之原始誘發性為陰性。因此,可明瞭s-三類似物(analogue)在田鼠佐藥關節炎試驗,老鼠膠原蛋白關節炎試驗,人B淋巴瘤移植模型,急性肝炎抑制試驗,單次經口投藥毒性試驗等的體內試驗,為安全性更高的化合物。
本發明的藥劑由於係藉由Con A,LPS,抗IgM抗體,抗CD3抗體+抗CD28抗體來抑制對T細胞及B細胞的反應,可以發揮免疫系細胞中PI3K的抑制作用為自明。亦即,本發明的藥物可以使用於由PI3K的機能亢進而致的免疫系疾病的治療或預防上。由PI3K機能亢進而致的免疫疾病方面,可例舉風濕性關節炎,全身性紅斑性狼瘡,修格蘭氏乾燥症候群等的自身免疫疾病;葡萄膜炎,腎小球(glomerulus)腎炎,伴隨甲狀腺炎,胰臟炎,折骨
術等自身免疫疾病的臟器障礙;組織移植時的排斥反應,骨髓移植時的移植物抗宿主病;潰瘍性大腸炎或孔羅氏病等的炎症性腸疾病;乾癬或遺傳性過敏症皮膚炎等的炎症性或過敏性皮膚疾病;慢性阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;過敏性結膜炎或鼻炎;起源於B淋巴瘤,T淋巴瘤,骨髓性白血病等免疫系細胞的血液腫瘤;因革蘭氏陰性菌或冠狀病毒等感染而致的敗血症,重症急性呼吸器症候群,急性肝炎等的疾病等。
試驗例13
血中濃度測定試驗
使用6週齡的BDF1系雄性老鼠進行藥物動態試驗。被檢化合物與藥物重量2.5倍量的羥基丙基纖維素(低分子量)[HPC(L)]共同溶解於二氯甲烷後,減壓乾涸之,使藥物濃度成為20mg/mL於蒸餾水中懸濁。以200mg/kg的投藥量將被檢化合物強制經口投藥於絕食16小時的老鼠上。投藥後1小時後,自各2隻老鼠的眼窩(eye socket)採血獲得血清。在所得血清100μL添加內部標準物質及蒸餾水1ml,以二乙基醚萃取,將溶劑減壓餾除後,以溶離液溶解成為HPLC測定試料。HPLC係使用逆相(reverse phase)系柱,溶離液係使用乙腈-磷酸緩衝液(pH2.5)系。使用自標準品所得之回歸(regression)直線(Y=aX+b),算出試料血清中的藥物濃度。其結果如下述表7所示。
由上述試驗結果,在哌嗪環第4位具有醯基的本發明化合物,與周知的比較化合物2,3及9相較,顯示出投藥後1小時血中濃度迅速的提高。
試驗例14)
試管內抗固形腫瘤試驗
在二氧化碳5%,溫度37℃的條件下,於MEM培養皿(含有10%牛胎兒血清,25mMHEPES及0.1mg/ml卡那毒素)使用試驗中繼代(passage)維持之MCF-7人類乳癌細胞。將對數增殖期(logarithmic growth phase)的MCF-7細胞藉由胰蛋白酶(trypsin)/EDTA處理,成為單懸浮細胞(suspended cell),在MEM培養皿(添加10%牛胎兒血清,25mM HEPES,0.1mg/ml卡那毒素),每1ml調整成4×104個的細胞懸濁液。被驗化合物溶解於DMSO後,在RPMI1640培養皿(含有10%牛胎兒血清,25mM HEPES,0.1mg/ml卡那毒素)稀釋,調整濃度為2.0×10-9~2.0×10-4M。
在96培養盤每1井加入細胞懸濁液0.1ml,培養24
小時,使細胞於多孔盤(microplate)黏接後,添加被驗化合物0.1ml,在二氧化碳5%,溫度37℃下培養72小時。自各種試料濃度的增殖抑制度算出50%增殖抑制濃度(GI50μM),其結果如下述表8所示。
此外,使用其他MCF-7以外的細胞時,替代以在MEM培養皿添加10%牛胎兒血清,而使用下述的培養皿,此外,調整成下述的單細胞懸浮液。
PC-3***癌細胞:F12K培養皿內,10%牛胎兒血清,2×104個的單細胞懸浮液
A549肺癌細胞:DMEM培養皿內,10%牛胎兒血清,1.5×104個的單細胞懸浮液
WiDr結腸癌細胞:MEM培養皿內,10%牛胎兒血清,3×104個的單細胞懸浮液
B16F10黑色素瘤細胞:RPMI1640培養皿內,10%牛胎兒血清,1×104個的單細胞懸浮液
本發明的藥劑可以使用於自身免疫疾病,臟器移植,過敏性或炎症性疾病,血液腫瘤,敗血症等與PI3K相關連之免疫系疾病的預防或治療。此外,可以使用於固形腫瘤的治療。進而,可使用於以PI3K為抑制劑之各種疾病的治療。
[第1圖]表示因抗人CD3抗體及抗人CD28抗體所致而對人類末梢血單核球細胞CD69顯現,CD40L顯現之被驗物質的影響之圖。
[第2圖]關於自關節炎發症後之田鼠後肢體積的變化,被驗物質與對照群的比較圖。
[第3圖]關於自關節炎發症後的關節炎分數(score)之變化,被驗物質與對照群的比較圖。
[第4圖]人類B淋巴瘤移植模型中,被驗物質與對照群的比較圖。
Claims (12)
- 一種免疫抑制劑,其特徵為以一般式(I):
- 如申請專利範圍第1項記載的免疫抑制劑,其中R1,R2任意為羥基。
- 如申請專利範圍第1項記載的免疫抑制劑,其中R1,R2任意為羥基,R3為二氟甲基。
- 如申請專利範圍第1項記載的免疫抑制劑,其中R1,R2均為氫,R3為二氟甲基。
- 如申請專利範圍第1項記載之免疫抑制劑,其中R6為4-乙醯基哌嗪。
- 如申請專利範圍第1項記載的免疫抑制劑,其中雜環式化合物為選自2-(2-甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-6-(4-甲醯基哌嗪-1-基)-4-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-6-(3,5-二側氧基哌嗪-1-基)-4-嗎啉基-1.3,5-三、2-(苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-哌啶基-1,3,5-三、2-(6-胺基-2-二 氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基-6-乙氧基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-二氟甲基-4-甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-二氟甲基-5-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(6-胺基-2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基-1,3,5-三、2-(2-甲基苯并咪唑-1-基)-4,6-二嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4,6-二嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-6-(4-甲醯基哌嗪-1-基)-4-嗎啉基嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(3,3-二甲基嗎啉基)-6-嗎啉基嘧啶、2-(2-胺基苯并咪唑-1-基)-4,6-二嗎啉基嘧啶、2-(2-二氟甲基-4-甲氧基苯并咪唑-1-基)-4-(2,6-二甲基嗎啉基)-6-嗎啉基嘧啶或2-(5-胺基-2-二氟甲基苯并咪唑-1-基)-4, 6-二(2,6-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基嘧啶、2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基-1,3,5-三、2-(6-胺基-4-氯-2-二氟甲基苯并咪唑-1-基)-4-[甲基(1-甲基哌啶-4-基)胺基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基-1,3,5-三、2-(4-氯-2-二氟甲基-5-羥基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、2-(5,6-二甲基-2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基 苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基-6-(反式-2,3-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2- (2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基-6-嗎啉基1,3,5-三、4[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1- 基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、4[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶 、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2- (2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4- 甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]6-(順式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1.3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪- 1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟 甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-6-(3,5-二側氧基哌嗪-1-基)-4-嗎啉基-1,3,5-三所成群者。
- 如申請專利範圍第1項記載的免疫抑制劑,其中雜環式化合物為選自2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2-羥甲基吡咯啶-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基)-6-嗎啉基嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(3,3-二甲基嗎啉基)-6-嗎啉基嘧啶所成群者。
- 如申請專利範圍第1項記載的免疫抑制劑,其中雜環式化合物為選自2-(2-二氟甲基苯并咪唑-1-基)-4,6-二嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三所成群者。
- 如申請專利範圍第1至8項中任一項記載之免疫抑制劑,其中對像疾病為排斥反應(rejection)或移植物抗宿主病(graft versus host);潰瘍性大腸炎或孔羅氏病(Crohn disease)等的炎症性腸疾病;乾癬或遺傳性過敏症(atopic)皮膚炎等的炎症性或過敏性皮膚疾病;阻塞性肺疾病或氣喘等炎症性或過敏性呼吸器疾病;風濕性關節炎(articular rheumatism)、全身性紅斑性狼瘡(erythematosus)、硬皮病(scleroderma)、修格蘭氏乾燥症候群(sjogren’s syndrome)等的自身免疫疾病;惡性淋巴瘤(malignant lymphoma)、多發性骨髓瘤(lymphadenia ossea)、白血病;敗血症、急性肝炎(fulminant hepatic failure)等。
- 一種以一般式(II)所示之雜環式化合物或其藥學上可容許的鹽,
- 如申請專利範圍第10項記載的化合物,其中雜環式化合物為4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、4-(4-乙醯基哌嗪-1-基)-2-( 2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-乙醯基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二 甲基胺甲醯基哌嗪)-1-基]-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(N,N-二甲基胺甲醯基哌嗪)-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、4[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶、2- (2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(2-呋喃甲醯基)哌嗪-1-基]-6-嗎啉基嘧啶、4[(2-呋喃甲醯基)哌嗪-1-基]-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基-1,3,5-三、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基苯并咪唑-1-基)-6-(2 ,2-二甲基嗎啉基)嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-6-嗎啉基嘧啶、4-(4-丙酮基哌嗪-1-基)-2-(2-羥甲基苯并咪唑-1-基)-6-嗎啉基嘧啶,2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(順式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(反式-2,3-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(2,2-二甲基嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、 2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-嗎啉基-6-(4-丙醯基哌嗪-1-基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3.5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(4-胺基- 2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧基乙醯基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]6-(2,2-二甲基嗎啉基-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基])-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(順式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(反式-2,3-二甲基嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-(2,2-二甲基嗎啉基嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪 唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-羥甲基苯并咪唑-1-基)-4-[4-(3-羥基丙基)哌嗪-1-基]-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)-1,3,5-三、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-媽啉基-1,3,5-三、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(順式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(反式-2,3-二甲基嗎啉基)嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-(2,2-二甲基嗎啉基)嘧啶、2-(2-二氟甲基-4-羥基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(4-胺基-2-二氟甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧 啶、2-(2-羥甲基苯并咪唑-1-基)-4-(4-甲氧羰基哌嗪-1-基)-6-嗎啉基嘧啶、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(5-側氧基-1,4-二氮雜革-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-4-嗎啉基-6-(3-側氧基哌嗪-1-基)-1,3,5-三、2-(2-二氟甲基苯并咪唑-1-基)-6-(3,5-二側氧基哌嗪-1-基)-4-嗎啉基-1,3,5-三。
- 一種抗腫瘤劑,其特徵為,以如申請專利範圍第10或11項中任一項記載之化合物為有效成份者。
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MA40933A (fr) | 2014-11-11 | 2017-09-19 | Piqur Therapeutics Ag | Difluorométhyl-aminopyridines et difluorométhyl-aminopyrimidines |
US9951040B2 (en) | 2014-11-20 | 2018-04-24 | Council Of Scientific And Industrial Research | 1,3,5 -triazine based PI3K inhibitors as anticancer agents and a process for the preparation thereof |
CN105130960B (zh) * | 2015-07-31 | 2018-07-06 | 沈阳药科大学 | 1,3,5-三嗪类衍生物及其应用 |
RU2637643C1 (ru) * | 2016-09-05 | 2017-12-05 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фундаментальной и клинической иммунологии" (НИИФКИ) | Иммунодепрессант |
TW201815787A (zh) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
TW201813963A (zh) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
TW201825465A (zh) | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
CN110198717A (zh) * | 2017-01-11 | 2019-09-03 | 国立研究开发法人国立癌症研究中心 | 免疫治疗药 |
KR20200009088A (ko) | 2017-05-23 | 2020-01-29 | 메이 파마, 아이엔씨. | 병용 요법 |
KR20200041358A (ko) | 2017-08-14 | 2020-04-21 | 메이 파마, 아이엔씨. | 병용 요법 |
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EP1020462A1 (en) * | 1997-07-24 | 2000-07-19 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compounds and antitumor agent containing the same as active ingredient |
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US2004A (en) * | 1841-03-12 | Improvement in the manner of constructing and propelling steam-vessels | ||
CA1338012C (en) * | 1987-04-27 | 1996-01-30 | John Michael Mccall | Pharmaceutically active amines |
AU665238B2 (en) | 1992-02-28 | 1995-12-21 | Zenyaku Kogyo Kabushiki Kaisha | S-triazine derivative and remedy for estrogen-dependent diseases containing the same as active ingredient |
IL110296A (en) * | 1993-07-16 | 1999-12-31 | Smithkline Beecham Corp | Imidazole compounds process for their preparation and pharmaceutical compositions containing them |
DK0640599T3 (da) * | 1993-08-26 | 1998-09-28 | Ono Pharmaceutical Co | 4-Aminopyrimidin-derivater |
US5656643A (en) | 1993-11-08 | 1997-08-12 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
JPH0948776A (ja) | 1994-09-26 | 1997-02-18 | Dai Ichi Seiyaku Co Ltd | ピリミジニルピラゾール誘導体 |
TW312694B (zh) | 1994-09-26 | 1997-08-11 | Daiichi Seiyaku Co | |
JP4709388B2 (ja) * | 1999-01-25 | 2011-06-22 | 全薬工業株式会社 | 複素環式化合物及びそれを有効成分とする抗腫瘍剤 |
US6777439B2 (en) * | 2000-05-30 | 2004-08-17 | Advanced Research & Technology Institute, Inc. | Compositions and methods for identifying agents which modulate PTEN function and PI-3 kinase pathways |
US7141579B2 (en) | 2001-01-30 | 2006-11-28 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compounds and cerebral function improvers containing the same as the active ingredient |
PT1389617E (pt) * | 2001-04-27 | 2007-04-30 | Zenyaku Kogyo Kk | Composto heterocíclico e agente antitumoral contendo o mesmo como igrediente activo |
AU2003272972A1 (en) | 2002-10-11 | 2004-05-04 | Kowa Co., Ltd. | Method of treatment for cancer |
ES2389253T3 (es) * | 2002-10-25 | 2012-10-24 | Zenyaku Kogyo Kabushiki Kaisha | Compuestos heterocíclicos y agentes antitumorales que comprenden los mismos como ingrediente activo |
CA2508601A1 (en) * | 2002-12-06 | 2004-06-24 | Warner-Lambert Company Llc | Benzoxazin-3-ones and derivatives thereof as inhibitors of pi3k |
CA2561406C (en) * | 2004-03-31 | 2012-07-03 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compound and anti-malignant-tumor agent comprising the same as effective component |
US20070244110A1 (en) | 2006-04-14 | 2007-10-18 | Zenyaku Kogyo Kabushiki Kaisha | Treatment of prostate cancer, melanoma or hepatic cancer |
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EP1020462A1 (en) * | 1997-07-24 | 2000-07-19 | Zenyaku Kogyo Kabushiki Kaisha | Heterocyclic compounds and antitumor agent containing the same as active ingredient |
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US7750001B2 (en) | 2010-07-06 |
PL1864665T3 (pl) | 2012-10-31 |
CA2599879A1 (en) | 2006-09-14 |
EP1864665A4 (en) | 2008-06-11 |
RU2007137651A (ru) | 2009-04-20 |
KR101296884B1 (ko) | 2013-08-14 |
AU2006221285A1 (en) | 2006-09-14 |
ES2395196T3 (es) | 2013-02-11 |
US20100267700A1 (en) | 2010-10-21 |
CN101137382A (zh) | 2008-03-05 |
CY1112886T1 (el) | 2016-04-13 |
RU2443441C2 (ru) | 2012-02-27 |
AU2006221285B2 (en) | 2011-03-31 |
EP1864665A1 (en) | 2007-12-12 |
CA2599879C (en) | 2013-07-02 |
JPWO2006095906A1 (ja) | 2008-08-21 |
SI1864665T1 (sl) | 2012-09-28 |
CN101137382B (zh) | 2012-11-21 |
JP5089377B2 (ja) | 2012-12-05 |
TW200642689A (en) | 2006-12-16 |
US8338414B2 (en) | 2012-12-25 |
EP1864665B1 (en) | 2012-05-16 |
HK1118016A1 (en) | 2009-01-30 |
US20080113987A1 (en) | 2008-05-15 |
WO2006095906A1 (ja) | 2006-09-14 |
PT1864665E (pt) | 2012-06-27 |
DK1864665T3 (da) | 2012-07-23 |
BRPI0608291A2 (pt) | 2009-12-22 |
KR20070113285A (ko) | 2007-11-28 |
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