CN1261885A - 2-取代的4,5-二芳基咪唑 - Google Patents
2-取代的4,5-二芳基咪唑 Download PDFInfo
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- CN1261885A CN1261885A CN98806673A CN98806673A CN1261885A CN 1261885 A CN1261885 A CN 1261885A CN 98806673 A CN98806673 A CN 98806673A CN 98806673 A CN98806673 A CN 98806673A CN 1261885 A CN1261885 A CN 1261885A
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- Prior art keywords
- alkyl
- pyridyl
- imidazoles
- fluorophenyl
- group
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- -1 alkylcycloalkenyl Chemical group 0.000 claims abstract description 49
- 239000002253 acid Substances 0.000 claims abstract description 23
- 150000002148 esters Chemical group 0.000 claims abstract description 17
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 13
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 10
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
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- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
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- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
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- 239000003018 immunosuppressive agent Substances 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- RTEHHLKYFIUUEN-UHFFFAOYSA-N 2-[[4-(4-fluorophenyl)-5-pyridin-4-ylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical class C[Si](C)(C)CCOCN1C=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC=C1 RTEHHLKYFIUUEN-UHFFFAOYSA-N 0.000 claims description 4
- KLHHFYHTAPSQFN-UHFFFAOYSA-N 2-[[5-(4-fluorophenyl)-4-pyridin-4-ylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical class C[Si](C)(C)CCOCN1C=NC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 KLHHFYHTAPSQFN-UHFFFAOYSA-N 0.000 claims description 4
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- JEWOUZJICLJHPM-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]cyclohexan-1-amine Chemical class N=1C(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)NC=1C1(N)CCCCC1 JEWOUZJICLJHPM-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
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- DKNOJZGVJQZILW-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]cyclohexan-1-ol Chemical class N=1C(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)NC=1C1(O)CCCCC1 DKNOJZGVJQZILW-UHFFFAOYSA-N 0.000 claims description 2
- SIQUUVQVHIMYKO-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]-1-methylpiperidin-4-ol Chemical class C1CN(C)CCC1(O)C1=NC(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)N1 SIQUUVQVHIMYKO-UHFFFAOYSA-N 0.000 claims description 2
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- 229910005965 SO 2 Inorganic materials 0.000 claims description 2
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical class [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 2
- CIWPUIAGXFUHHK-UHFFFAOYSA-N 4-[2-(4-butoxy-1-methylpiperidin-4-yl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical class N=1C(C=2C=CC(F)=CC=2)=C(C=2C=CN=CC=2)NC=1C1(OCCCC)CCN(C)CC1 CIWPUIAGXFUHHK-UHFFFAOYSA-N 0.000 claims 1
- BZZSFPHVNZOGOL-UHFFFAOYSA-N 4-[2-(benzenesulfonyl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical class C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)NC(S(=O)(=O)C=2C=CC=CC=2)=N1 BZZSFPHVNZOGOL-UHFFFAOYSA-N 0.000 claims 1
- OIENJEGEDXPCRZ-UHFFFAOYSA-N 4-[2-(cyclohexen-1-yl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical class C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)NC(C=2CCCCC=2)=N1 OIENJEGEDXPCRZ-UHFFFAOYSA-N 0.000 claims 1
- ZOAVMSMTFGCRQW-UHFFFAOYSA-N 4-[2-(cyclopropylmethyl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical class C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)NC(CC2CC2)=N1 ZOAVMSMTFGCRQW-UHFFFAOYSA-N 0.000 claims 1
- JVDIQZGPSNGXBD-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-phenylselanyl-1h-imidazol-5-yl]pyridine Chemical class C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)NC([Se]C=2C=CC=CC=2)=N1 JVDIQZGPSNGXBD-UHFFFAOYSA-N 0.000 claims 1
- ZELGPAUEPBZKBC-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-2-thiophen-2-yl-1h-imidazol-5-yl]pyridine Chemical class C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)NC(C=2SC=CC=2)=N1 ZELGPAUEPBZKBC-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
提供了新颖的2-取代的4,5-二芳基咪唑,其中:i)1位上的氮原子被含有三烷基甲硅烷基的取代基取代,或者ii)2位上的取代基是芳烷基、芳基磺酰基、芳硫基、芳硒基、芳碲基、环烷基、环烯基、烷基环烷基、烷基环烯基、氨基或肼基,或者是单环或二环的N-杂环基,其中的含N环具有六个环原子,特别是式Ⅰ化合物,其中R1、R2、R3和R4是如说明书所定义的,它们以游离形式或药学上可接受的酸加成盐或生理学上可分解的酯形式存在,具有p38MAP激酶(促分裂原活化蛋白激酶)抑制活性。该化合物用作药物,治疗由TNFα和IL-1介导的疾病,例如类风湿性关节炎,和骨代谢疾病,例如骨质疏松症。
Description
本发明涉及2-取代的4,5-二芳基咪唑及其用途,用于治疗由TNFα和IL-1介导的疾病,例如类风湿性关节炎和骨代谢疾病,如骨质疏松症。
因此,本发明提供了新颖的2-取代的4,5-二芳基咪唑,其中:
i)1位上的氮原子被含有三烷基甲硅烷基的取代基取代,或者
ii)2位上的取代基是芳烷基、芳基磺酰基、芳硫基、芳硒基、芳碲基、环烷基、环烯基、烷基环烷基、烷基环烯基、氨基或肼基,或者是单环或二环的N-杂环基,其中的含N环具有六个环原子,其条件是2位上的取代基不是哌啶-4-基、1-羧酸叔丁酯-4-苄基哌啶-4-基、1,4-二甲基哌啶-4-基、4-苄基哌啶-4-基、或只在N原子进一步被取代的哌啶-4-基,
及其药学上可接受的酸加成盐和生理学上可分解的酯。
4-或5-芳基取代基可以是任何本领域中已知的那些,例如WO95/03297和WO 97/12876所述。例如,4-和5-芳基取代基可以是如下对式I的R1和R2所定义的,包括杂芳基取代基。
当1位的氮原子被含有三烷基甲硅烷基的取代基取代时,该取代基适宜为三烷基甲硅烷基烷氧基烷基取代基。
当2位的取代基是芳烷基时,它宜为苯基烷基。
当2位的取代基是芳烷基、芳基磺酰基、芳硫基、芳硒基、芳碲基、环烷基、环烯基、烷基环烷基、烷基环烯基、氨基或肼基,或者是单环或二环的N-杂环基时,它可以进一步被取代,例如被至多6个取代基取代,选自卤、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4硫代烷氧基、硝基、氨基、C1-4烷基亚磺酰基、C1-4烷基磺酰基、羧酸盐或酯。
本说明书的上述和其他内容中,术语卤或卤素指I、Br、Cl或F,优选为F。
其中
R1为4-吡啶基、嘧啶基、喹唑啉-4-基、喹啉基、异喹啉基、1-咪唑基或1-苯并咪唑基,并可选地被一个或两个取代基取代,取代基各自独立地选自
C1-4烷基、卤素、C1-4烷氧基、C1-4烷硫基、NR5R6、或具有5至7个环原子的N-杂环,杂环可选地含有另外一个选自O、S或N的杂原子,
其中R5和R6各自独立为C1-4烷基;
R2为苯基、萘-1-基或萘-2-基,并可选地被至多5个取代基取代;
R3为氢,
杂环基,
杂环基C1-10烷基,
三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基,
可选卤代的C1-10烷基、C2-10烯基、C2-10炔基、C3-7环烷基、C3-7环烷基C1-10烷基、C5-7环烯基、芳基、芳基C1-10烷基、杂芳基、或杂芳基C1-10烷基,
可选一或二C1-4烷基取代的C0-10烷基-氧羰基或-氧硫代羰基,并可选地被C1-10烷基、C3-7环烷基、杂环基、杂环基C1-10烷基、芳基、芳基C1-10烷基、杂芳基、杂芳基C1-10烷基取代,或
可选一或二C1-4烷基取代的C1-10烷基
-氰基,
-硝基,
-羟基、-C1-10烷氧基、-C3-7环烷氧基、-杂环氧基、-杂环基
C1-10烷氧基、-芳氧基、-芳基C1-10烷氧基、-杂芳氧基、-
杂芳基C1-10烷氧基(及其硫氧类似物),
以及可选取代的氨基、羧酸盐、硫代羧酸盐、羰基或硫代羰基、
亚磺酰基或磺酰基;
R4为-C0-4烷基一或二C3-7环烷基,并可选地被-卤、-OH、-C1-4烷基、-C1-4烷氧基、-C1-4硫代烷氧基、-硝基、-氨基、-C1-4烷基亚磺酰基、-C1-4烷基磺酰基、-羧酸盐或-酯取代,
-NR7R8、NHNHR9,
其中R7、R8或R9各自独立为C1-4烷基、C2-4烯基、C2-6炔基,
-X-C5-10芳基(包括杂芳基)
其中X为S、SO2、Se、Te或C1-4烷基,
单环或二环的N-杂环基,其中的含N环具有六个环原子,
或可选被至多4个取代基取代的芳基或杂芳基,
其条件是
当R3不是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基时,
R4不是可选被至多3个取代基取代的芳基或杂芳基,除非R4是单环或二环的N-杂环基,其中的含N环具有六个环原子,和
其条件是
R4不是哌啶-4-基、1-羧酸叔丁酯-4-苄基哌啶-4-基、1,4-二甲基哌啶-4-基、4-苄基哌啶-4-基、或只在N原子进一步被取代的哌啶-4-基,
及其药学上可接受的酸加成盐和生理学上可分解的酯。
R2被至多5个取代基取代,取代基可以是任何本领域中已知的取代基,例如WO 95/03297中所述的R4和WO 97/12876中所述的R。
当R4是-X-C5-10芳基、且X是C1-4烷基时,该C5-10芳基或X可以被至多6个取代基取代,取代基选自卤、OH、C1-4烷基、C1-4烷氧基、C1-4硫代烷氧基、硝基、氨基、C1-4烷基亚磺酰基、C1-4烷基磺酰基、羧酸盐或酯。
当R4是单环或二环的N-杂环基时,其中的含N环具有六个环原子,它可以是饱和或不饱和的,例如芳族的、杂环基。
当R4是可选被至多4个取代基取代的芳基或杂芳基时,R4可以包含常用于本领域的芳基或杂芳基之一;例如WO 93/03297的取代基R3所定义的。
具有2-取代基(例如上文所定义的R4)、并在4位和5位具有芳基取代基(例如上文R1和R2的定义)的咪唑是全新的,其中1位上的氮原子被含有三烷基甲硅烷基的取代基取代。
其中
R3’为三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基,R1、R2和R4是如上所定义的,
及其药学上可接受的酸加成盐和生理学上可分解的酯。
其中R4是H并且R2、R3’和R4如上所定义的式I’化合物是重要的中间体,用于合成其中R3不是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基的其他式I化合物,如下所述。
取代基R1、R2、R3、R3’和R4’独立地具有下列优选的含义。
优选地,R1是4-吡啶基或嘧啶基,尤其是4-吡啶基。
R2优选为苯基,包括取代的苯基
最优选地,R3’是三甲基甲硅烷基乙氧基甲基。
当R3是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基时,R1优选为4-吡啶基。
当R3是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基时,R2优选为4-氟苯基。
当R3是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基时,R4优选为H。
其中R1、R2、R3和X是如上所定义的,R11代表1-4个取代基,它们独立地选自H、卤、OH、C1-4烷基、C1-4烷氧基、C1-4硫代烷氧基、硝基、氨基、C1-4烷基亚磺酰基、C1-4烷基磺酰基、羧酸盐或酯,
及其药学上可接受的酸加成盐和生理学上可分解的酯。
其中R1、R2和R3是如上所定义的,D为C3-7环烷基、C3-7环烯基或单环或二环的N-杂环基,其中的含N环具有六个环原子,X’为一条直接的键或-CR12R13-,
其中R12为H或C1-4烷基,R13为H或可选被C3-7环烷基或C3-7环烯基取代的C1-4烷基,
及其药学上可接受的酸加成盐和生理学上可分解的酯。
式IV中,X’和D可以进一步被例如至多6个取代基取代,取代基选自卤、OH、C1-4烷基、C1-6烷氧基、C1-4硫代烷氧基、硝基、氨基、C1-4烷基亚磺酰基、C1-4烷基磺酰基、羧酸盐或酯。
优选地,D是环己基、环己烯基、环丙基、吡啶基(例如4-吡啶基)、哌啶基(例如哌啶-4-基)、氮杂环己烯基(piperidenyl)(例如氮杂环己烯-4-基)、氮杂二环[3,2,1]辛基、氮杂二环[3,3,1]壬基或莨菪烷基二环N-杂环(以及该二环N-杂环的烯基类似物,例如8-氮杂二环{3.2.1)辛-2-烯-3-基)。在特别优选的实施方式中,-X’-D是1-羟基环己基、1-氨基环己基、1-环己烯基、环丙基甲基、1,2-二环丙基乙基、2,3,5,6-四氟吡啶基、2-氨基-3,5,6-三氟吡啶基、2,6-二氨基-3,5-二氟吡啶基、莨菪烷-3-醇基、4-羟基-1-甲基哌啶基、4-C1-6烷氧基-1-甲基哌啶基(例如4-正丁氧基-1-甲基哌啶基、8-甲基-8-氮杂二环{3.2.1}辛-2-烯-3-基)、1-甲基-4-哌啶基。
当R4是-X-芳基或-X’-D时,R1优选为4-吡啶基。
当R4是-X-芳基或-X’-D时,R2优选为卤代的苯基,尤其是4-氟-苯基。
当R4是-X-芳基或-X’-D时,R3优选为H。
特别优选的式IV化合物是其中X’是一条直接的键,D是可选取代的吡啶基、例如4-吡啶基,或哌啶基、例如哌啶-4-基。
本发明新颖的2-取代的4,5-二芳基咪唑、特别是式I至IV化合物和实施例1-19的具体化合物以下被称为“本发明化合物”。
包含游离羟基的本发明化合物也可以以药学上可接受的、生理学上可分解的酯的形式存在,它们本身包括在本发明的范围内。该药学上可接受的酯优选为前体药物酯衍生物,在生理条件下通过溶剂分解作用或裂解作用可转化为对应的包含游离羟基的本发明化合物。适用的药学上可接受的前体药物酯来源于羧酸、碳酸一酯或氨基甲酸,更有益的酯来源于可选取代的低级链烷酸或芳基羧酸。
本发明化合物也可以以药学上可接受的盐的形式存在,它们本身包括在本发明的范围内。药学上可接受的盐包括与常规的酸所产生的酸加成盐,酸例如无机酸,如盐酸、硫酸或磷酸,或者例如有机酸,如脂族或芳族羧酸或磺酸,如乙酸、丙酸、琥珀酸、乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、富马酸、羟基马来酸、丙酮酸、双羟萘酸、甲磺酸、甲苯磺酸、萘磺酸、磺胺酸或环己基氨基磺酸;以及氨基酸,例如精氨酸和赖氨酸。对具有酸性基团、例如游离羧基的本发明化合物来说,药学上可接受的盐也代表金属或铵盐,例如碱金属盐或碱土金属盐,如钠盐、钾盐、镁盐或钙盐,以及与氨或适当的有机胺所产生的铵盐。
其中R1和R2是如上文所定义的,
与对应的醛、酮、二磺酰胺、二硫化物、二硒化物、二碲化物或卤化物反应,如果需要的话引入所需的R3取代基或进一步转化所得产物,并且可选地回收其游离形式或盐形式。因此例如,在n-BuLi的存在下,例如在冷却(例如-40℃)的THF溶液中,将式VIII化合物用对应的醛、酮、二磺酰胺、二硫化物、二硒化物、二碲化物或卤化物处理。
当式VIII化合物用对应的醛或酮处理时,所得最初产物的R4取代基是1-羟基取代的,例如当酮是环己酮时,则R4是1-羟基环己基。可以得到对应的脱水化合物,例如R4是1-环己烯基,例如是在回流下、在甲苯溶液中用pTsOH处理。
其中R1和R2是如上文所定义的,
与对应的醛、酮、二磺酰胺、二硫化物、二硒化物、二碲化物或卤化物反应,如果需要的话引入所需的R3取代基或进一步转化所得产物,并且可选地以游离或盐形式回收本发明化合物。
制备式VIII化合物的方法可以是例如在双(三甲基甲硅烷基)氨基钾的存在下,在冷却(例如-78℃)的DMF/THF溶液中,用2(三甲基甲硅烷基)乙氧基甲基卤化物(例如氯化物)处理对应的式I的1H-咪唑,即其中R4为H的对应的式I化合物。该过程得到对应的式VIII和IX的1-2(三甲基甲硅烷基)乙氧基甲基咪唑混合物
其中R1和R2是如上文所定义的。
式VIII化合物是新颖的中间体,用于制备其他的本发明化合物,本身也包括在本发明内。式IX化合物是本发明的化合物。
另一种优选的实施方式中,使用烷氧基烷基氮保护基团,例如二烷氧基烷基氮保护基团、尤其是二乙氧基甲基保护基团,来代替三甲基甲硅烷基乙氧基甲基保护基团。引入该烷氧基烷基保护基团的方法可以是用三烷基原甲酸酯、例如三乙基原甲酸酯处理对应的式I的1H-咪唑,即其中R4为H的对应的式I化合物,例如以下实施例所述。
下列实施例进一步描述本发明化合物的合成。
实施例
实施例1和2:4-(4-氟苯基)-5-(4-吡啶基)-1-(2-(三甲基甲硅烷基)乙氧基甲基)咪唑和4-(4-吡啶基)-5-(4-氟苯基)-1-(2-(三甲基甲硅烷基)乙氧基甲基)咪唑
将4-(4-氟苯基)-5-(4-吡啶基)-1H-咪唑(3)(1g,4.18mmol)溶于DMF/THF(50ml/20ml),并冷却至-78℃。在-78℃下加入双(三甲基甲硅烷基)氨基钾(15%甲苯溶液;6.7ml 5mmol),搅拌30分钟,然后加入2-(三甲基甲硅烷基)乙氧基甲基氯,使反应混合物温度升至室温,2小时后倾倒在水上,用乙酸乙酯萃取3次。合并了的有机相经Na2SO4干燥,蒸发至干,用色谱法(SiO2丙酮/己烷4/6至6/4)得到1-(2-(三甲基甲硅烷基)乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑,首先洗脱得到的是白色晶体(218mg,14%),然后是4-(4-吡啶基)-5-(4-氟苯基)-1-(2-(三甲基甲硅烷基)乙氧基甲基)咪唑,为白色晶体(590mg,38%)。用ROESY、HSQC和HMBC光谱测定法得到结构的正确分配。
1H-NMR(360MHz CDCl3);1-(2-(三甲基甲硅烷基)乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑(实施例1):
0.00(s,9H);0.92(t,2H);3.55(t,2H);5.15(s,
2H);6.95(t,2H);7.36(d,2H);7.42(dd,2H);7.72(s,1H);8.68(d,2H)
4-(4-吡啶基)-5-(4-氟苯基)-1-(2-(三甲基甲硅烷基)乙氧基甲基)咪唑(实施例2):
0.00(s,9H);0.90(t,2H);3.48(t,2H);5.10(s,2H);7.20(t,2H);7.35-7.45(m,
4H);7.75(s,1H);8.45(d,2H).
或者,可以将1H-咪唑原料转化为对应的4-(4-氟苯基)-5-(4-吡啶基)-1-(1,1-二乙氧基甲基)咪唑和4-(4-吡啶基)-5-(4-氟苯基)-1-(1,1-二乙氧基甲基)咪唑产物。
将4-(4-氟苯基)-5-(4-吡啶基)咪唑(72.7g;0.304mol)和pTsOH.H2O(1.1g;5mmol)溶于热的三乙基原甲酸酯(770ml),并回流,同时缓慢蒸馏出大约300ml三乙基原甲酸酯和乙醇。2小时后,反应混合物蒸发至于,溶于叔丁基甲基醚(500ml)。缓慢加入己烷(51),滤出沉淀,用叔丁基甲基醚/己烷(1∶9)洗涤。滤液用1N Na2CO3洗涤,经Na2SO4干燥,并蒸发。加入两次二甲苯,并再次蒸发,得到标题化合物,为黄棕色粘性的油(79.3g;76%;-1∶1混合物),使用时无需进一步精制。
实施例3:4-(4-氟苯基)-2-((RS)-1-羟基-4’-氟苄基)-5-(4-吡啶基)咪唑
在-40℃下,向1-(2-(三甲基甲硅烷基)乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑(实施例2;50mg 0.13mmol)的THF(1.4ml)溶液中加入1.6M n-BuLi的己烷溶液(0.085ml 0.13mmol)。在-40℃下15分钟后,向反应混合物中加入4-氟苯甲醛(0.018ml 0.18mmol)的THF(0.4ml)溶液,使温度升至室温,10分钟后倾倒在水上,用乙酸乙酯萃取3次。合并了的有机相经Na2SO4干燥,蒸发至干,得到所需的N-保护的标题化合物(64mg)。为了除去SEM保护基团,将后者物质溶于THF(2ml),在60℃下用Bu4NF(4.3ml;1M THF溶液)处理1小时,倾倒在NaHCO3饱和溶液上,用乙酸乙酯萃取3次。合并了的有机相经Na2SO4干燥,蒸发至干,用色谱法(SiO2甲苯/EtOH/浓NH3 90/10/0.6)得到标题化合物,为白色晶体(32mg 67%,经过2个步骤)。1H-NMR(360 MHz DMSO-d6):5.80(s,1H);6.30(bs,OH);7.15(t,2H);7.20-7.30(bs,1H);7.37(d,2H);7.42-7.48(m,2H);7.52-7.58(m,2H);8.38-8.5 1(bs,2H);12.50-12.60(bs,NH)
在另一种过程中,可以使用如上所述制备的1-(1,1-二乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑和3-(1,1-二乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑代替1-(2-(三甲基甲硅烷基)乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑;例如下述4-(4-氟苯基)-5-(4-吡啶基)-2-(2,3,5,6-四氟吡啶基)咪唑的制备。
4-(4-氟苯基)-5-(4-吡啶基)2-(2,3,5,6-四氟吡啶基)咪唑
在-45℃下,向1-(1,1-二乙氧基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑和1-(1,1-二乙氧基甲基)-5-(4-氟苯基)-4-(4-吡啶基)咪唑(15g;43mmol)的~1∶1混合物的THF(210ml)溶液中加入1.6M nBuLi(66ml;45mmol)。在-45℃下15分钟后,反应混合物冷却至-55℃,快速加入五氟吡啶(5.1ml;47mmol)。除去冷却浴,使反应混合物温度升至-15℃,倾倒在水(1l)上,然后用2N HCl(100ml)酸化。搅拌5分钟后,将混合物与Na2CO3饱和溶液合并,并用乙酸乙酯萃取三次。合并了的有机相经Na2SO4干燥,过滤并蒸发至干,得到标题化合物,为棕色晶体(16.3g)。用色谱法(SiO2;丙酮/己烷1∶1)得到标题化合物以及一些未反应的和未被保护的咪唑原料,用丙酮洗涤可以除去,得到标题化合物(8.7g;52.4%)。1H-NMR(360Mhz CDCl3):7.30-7.40(bt,2H);7.45(d,2H);7.58(bq;2H);8.52(bs,2H).MS(m/z):388.9(MH+)
将实施例7产物2-((1-羟基)环己基)-4-(4-氟苯基)-5-(4-吡啶基)-1H-咪唑(50mg 0.15mmol)溶于甲苯(100ml),并用pTsOH(100mg)回流15分钟。反应混合物倾倒在饱和NaHCO3上,用乙酸乙酯萃取3次。合并了的有机相经Na2SO4干燥,蒸发至干,用色谱法(SiO2丙酮/己烷4/6)得到标题化合物,为白色晶体(38mg 81%)。
1H-NMR(360MHz DMSO-d6),NH-互变异构体的8/2混合物:1.60(m,2H);1.68
(m,2H);2.18(bs,2H);2.50(bs,2H);6.55(bs,0.8H);6.62(bs,0.2H);7.15-7.60(m,
6H);8.40(d,1.6H);8.52(d,0.4H);12.25(bs,0.2H);12.37(bs,0.8H)
注1:使用SOCl2的吡啶溶液代替pTsOH的甲苯溶液。
将实施例10产物、4-(4-氟苯基)-5-(4-吡啶基)2-(2,3,5,6-四氟吡啶基)咪唑(2g;5.15mmol)悬浮在浓NH3(25%;200ml)中,在密封的钢筒中加热至150℃达5小时。蒸发掉水分,残余物用色谱法(SiO2,TBME/MeOH/浓NH3 98/2/0.2)得到标题化合物4-(4-氟苯基)-5-(4-吡啶基)2-(2-氨基-3,5,6-三氟吡啶基)咪唑(880mg;44.4%)和4-(4-氟苯基)-5-(4-吡啶基)2-(2,6-二氨基-3,5-二氟吡啶基)咪唑(650mg;33%),为浅色晶体。
4-(4-氟苯基)-5-(4-吡啶基)2-(2-氨基-3,5,6-三氟吡啶基)咪唑:
1H-NMR(400MHz,DMSO-d6)互变异构体的混合物:6.80(s,2H);7.25(bt,0.6H);
7.38(t,1.4H);7.45(d,2H);7.58(t,2H);8.49(d,1.4H);8.62(bd,0.6H)
MS(m/z):385(M+)
4-(4-氟苯基)-5-(4-吡啶基)2-(2,6-二氨基-3,5-二氟吡啶基)咪唑:
1H-NMR(400MHz,DMSO-d6)互变异构体的混合物:5.75(s,2H);7.22(t,0.6H);
7.33(t,1.4H);7.41-7.47(m,2H);7.52-7.58(m,2H);8.47(d,1.4H);8.58(d,0.6H)
MS(m/z):382(M+)
实施例18:4-(4-氟苯基)-2-((1-氨基)环己基)-5-(4-吡啶基)咪唑
在21℃下,在10分钟内向4-氟苯基-4-吡啶基甲基酮(I.Lantos等《医药化学杂志》1984,27,72-75)(100g;0.46mol)的乙酸(800ml)溶液中加入溴(74.4g;0.46mol)的乙酸(160ml)溶液。滤出黄色晶体,用乙酸、乙醚和己烷洗涤,然后在减压下干燥,得到所需化合物的氢溴化物(250g;72%)。
将1-N-苄酯基-1-环己烷羧酸(E.Didier等《四面体》1992,48(39),8471)(13.9g;50mmol)和碳酸铵(Fluka;4.8g;50mmol)溶于DMF(50ml),并加热至110℃达10分钟,直至气体停止放出。反应烧瓶冷却至60℃,加入固体的1-(4-氟苯基)-2-溴-2-(4-吡啶基)乙酮氢溴化物(3.75g;10mmol),并加热至125℃达2.5小时。反应混合物倾倒在1M Na2CO3上,用乙酸乙酯萃取三次。合并了的有机相用水洗涤,经Na2SO4干燥,蒸发至干,得到粗的标题化合物(4.8g),色谱法(SiO2;乙酸乙酯)后得到纯的标题化合物,为淡黄色晶体(1.4g;30%)。
1H-NMR(400MHz;CDCl3):1.25-2.40(m,10H);5.12(s,2H);7.08-7.16(m,2H);7-
30-7.50(m,9H);8.50(d,2H)
MS(m/z):471.2(MH+)
将4-(4-氟苯基)-2-((1-N-苄酯基)环己基)-5-(4-吡啶基)咪唑(1.6g;4mmol)溶于EtOH(140ml),在Pd/C(10%;0.7g)的存在下,在室温、1大气压下氢化2小时。过滤并蒸发溶剂,然后从乙酸乙酯/乙醚中重结晶,得到所需的胺,为不完全白色的晶体(0.63g;47%)。
1H-NMR(400MHz;DMSO-d6):1.25-1.78(m,8H);1.95-2.10(bt,2H);7.25-7.34
(bt,2H);7.40(d,2H);7.47-7.52(m,2H);8.43(d,2H)
MS(m/z):336(M+)
在加热至40℃下,将实施例12产物、4-(4-氟苯基)-5-(4-吡啶基)2-(4-羟基-1-甲基哌啶-4-基)咪唑(22.2g;63mmol)溶于1-丁醇(1l)。滴加浓H2SO4(27.8g;283mmol),将最初得到的混悬液回流3.5小时,同时蒸馏除去~200ml 1-丁醇。反应混合物冷却至室温,倾倒在Na2CO3饱和溶液(500ml)上。含水相用乙酸乙酯萃取,合并了的有机相经Na2SO4干燥,过滤并蒸发至干。用色谱法纯化(SiO2,TBME/MeOH/浓NH3 96/4/0.4至70/30/1),得到标题化合物,为黄色晶体(15.5g;60.3%)。样本从CH2Cl2/TBME中重结晶,得到无色晶体:熔点177℃。
1H-NMR(400MHz;DMSO-d6):互变异构体混合物,使芳族信号加倍; 0.80(bt,3H);1.25-1.35(m,2H);1.38-1.48(m,2H);2.12(bs,4H);2.18(s,
3H);2.35(m,2H);2.42(m,2H);3.12(t,2H);7.18(t,0.5H);7.32(t,1.5H);7.40(m,
2H);7.48(m,2H);8.40(d,1.5H);8.53(d,0.5H).
MS(m/z):408(M+,20%);351(100%);335(95%).
以游离、药学上可接受的酸加成盐或生理学上可分解的酯形式存在的本发明化合物表现出药理学活性,可用作例如治疗的药物,用于治疗下列疾病和病症,以下称之为本发明试剂。
特别是本发明试剂具有p38 MAP激酶(促分裂原活化蛋白激酶)抑制活性。因此本发明试剂起到抑制炎性细胞因子产生的作用,例如TNF-α和IL-1,还可有效阻滞这些细胞因子对其靶细胞的作用。本发明试剂的这些和其他药理学活性可以在标准试验方法中得到证实,例如下述:
p38 MAP激酶测定
在4℃下,将底物(GST-ATF-2;包含ATF-2的氨基酸1-109和通过在大肠埃希氏杆菌表达得到的GST蛋白质的融合蛋白)涂在微量滴定板的小孔上(50μl/孔;1μg/ml PBS溶液/0.02%叠氮化钠)过夜。第二天,微量滴定板用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次,在37℃下用PBS/2%BSA/0.02%叠氮化钠封闭1小时。滴定板再用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次。然后,以10μl等分试样加入下列反应剂引发激酶级联反应,直至最终的反应体积为50μl。
1.在10倍稀释液或溶剂(DMSO)或H2O中滴定为10至0.001μM的本发明试剂。
2.激酶缓冲液(5x);pH 7.4;125mM Hepes(在1M下储存;Gibco#15630-056),125mM β-甘油磷酸酯(Sigma#G-6251):125mM MgCl2(Merck#5833);0.5mM正钒酸钠(Sigma#5-6508),10mM DTT(Boehringer Mannheim#708992)。(5x)激酶缓冲液必须是在测定当天、从保存在室温下的5x储备溶液新鲜制备的。DTT保存在-20℃下,是最后加入的试剂。
3.His-p38 MAP激酶(10ng/孔;Novartis-包含全长鼠p38 MAP激酶和His标记的融合蛋白,通过在大肠埃希氏杆菌中的表达得到)
4.冷的ATP(最终浓度120μM;Sigma#A-9187)
5.水
在37℃下1小时后,滴定板如上所述洗涤四次以终止激酶反应。然后检测磷酸化的GST-ATF-2,通过加入:
1.PhosphoPlus ATF-2(Thr71)抗体(50μl/孔;在PBS/2%BSA/0.02%叠氮化钠中的最终稀释比为1/1000;New England Biolabs#9221L),室温下90分钟。
2.生物素标记的山羊抗兔IgG(50μl/孔;在PBS/2%BSA/0.02%叠氮化钠中的最终稀释比为1/3000;Sigma#B-9642),室温下90分钟。
3.链霉抗生物素-碱性磷酸酶(50μl/孔;在PBS/2%BSA/0.02%叠氮化钠中的最终稀释比为1/5000;Jackson Immunoresearch#016-050-084),室温下30分钟。
4.底物(100μl/孔;Sigma 104磷酸底物片,5mg/片;#104-105;1mg/ml底物缓冲液溶液,二乙醇胺(97ml/l;Merck#803116)+MgCl2.6H2O(100mg/l;Merck#5833)+叠氮化钠(0.2g/l)+HCl 1M至pH 9.8),室温下30分钟。
经过步骤1、2和3后,微量滴定板用PBS/0.5%吐温20/0.02%叠氮化钠洗涤四次。经过步骤4后,滴定板在Bio-Rad微量滴定板读数器中以双波长方式读数(测量滤波器405nm,参比滤波器490nm)。减去背景值(不含ATP),使用Origin计算机程序(4参数逻辑函数)计算IC50值。
用上述测定测得,本发明试剂通常具有p38 MAP激酶抑制作用的IC50s在约1μM至约10nM或以下的范围内。例如在该测定中,实施例17化合物的IC50约为10nM。
抑制TNF-α从hPBMCS释放的测定
按照Hansell等《免疫方法杂志》(1991)145:105的方法,利用菲科尔-海帕克(ficoll-hypaque)密度分离法,从健康志愿者的外周血液中获得人外周血液单核细胞(hPBMCS),存在于RPMI 1640加10%FCS,使用浓度为105个细胞/孔。细胞用供试化合物系列稀释液在37℃下培养30分钟,然后加入IFNg(100U/ml)和LPS(5mg/ml),随后进一步培养三小时。以1400 RPM离心10分钟终止培养。使用商用ELISA法(Innotest hTNFa,可从Innogenetics N.V.,Zwijnaarde,Belgium得到)测量上清液中的TNF-α。本发明试剂的检测浓度为0至10mM。该测定中,供例证的本发明试剂通常抑制了TNF的释放,该测定测得IC50为约1μM至约10nM或以下。例如该测定测得实施例17化合物的IC50约为90nM。
抑制TNF-α在LPS刺激的小鼠中的产生的测定
注射脂多糖(LPS)诱发可溶性肿瘤坏死因子(TNF-α)快速释放进入外周。该模型用来分析体内TNF释放的预期阻滞剂。
对OF1小鼠(雌性,8周龄)静脉内注射LPS(20mg/kg)。一小时后从动物体内抽血,使用一种抗TNF-α的抗体,通过ELISA法分析血浆中的TNF水平。使用20mg/kg LPS通常诱发至多15ng TNF-α/ml血浆的水平。在LPS注射前1至4小时,将待评价的化合物口服或皮下给药。读出对LPS诱发的TNF释放的抑制作用结果。
上述测定中,当以10mg/kg口服给药时,本发明试剂通常抑制约50%至约90%或以上的TNF产生。例如在该测定中,实施例17化合物抑制约80%的TNF产生。
正如上述测定所示,本发明试剂是有效的TNF-α释放抑制剂。因此,该新颖的化合物具有下列药学应用:
本发明试剂可用于预防和治疗由TNFα和IL-1等细胞因子介导的疾病或病理学状态,例如炎性病症、自体免疫疾病、严重感染、和器官或组织移植排斥,例如用于治疗接受心、肺、联合心肺、肝、肾、胰、皮肤或角膜移植的患者,用于预防移植物对宿主的疾病,如骨髓移植后发生的疾病。
本发明试剂特别可用于治疗、预防或改善自体免疫疾病和炎性病症,特别是病因中包括自体免疫成分的炎性病症,如关节炎(例如,类风湿性关节炎、慢性进育型关节炎(arthritis chronicaprogrediente)和变形性关节炎)和风湿性疾病。本发明试剂适用的具体自体免疫疾病包括自体免疫性血液病(例如包括溶血性贫血、再生障碍性贫血、纯红细胞性贫血和特发性血小板减少)、系统性红斑狼疮、多发性软骨炎、硬化病、韦格内氏肉芽肿病、皮肤肌炎、慢性活动性肝炎、重症肌无力、牛皮癣、斯-约二氏综合征、特发性口炎性腹泻、自体免疫性炎性肠病(例如包括溃疡性结肠炎和克罗恩氏病)、内分泌性眼病、格雷夫斯氏病、肉样瘤病、多发性硬化、原发性胆汁性肝硬变、少年糖尿病(I型糖尿病)、(前及后)眼色素层炎、干性角膜结膜炎和春季角膜结膜炎、间质性肺纤维变性、牛皮癣性关节炎和肾小球性肾炎(有或没有肾病综合征,例如包括特发性肾病综合征或极小改变的肾病(minimal change nephropathy))。
本发明试剂也可用于治疗、预防或改善哮喘、支气管炎、肺尘埃沉着病、肺气肿、和其他气道的阻塞性或炎性疾病。
本发明试剂可用于治疗由TNF介导的、尤其是由TNFα介导的不良的急性和超急性炎性反应,例如急性感染,如脓毒性休克(例如内毒素休克和成人呼吸窘迫综合征)、脑膜炎、肺炎;和严重烧伤;用于治疗感染、癌、或器官机能障碍后继发的与致病性TNF释放有关的恶病质或消瘦综合征,尤其用于治疗与AIDS有关的恶病质,例如与HIV感染有关或HIV感染继发的恶病质。
本发明试剂特别可用于治疗骨代谢疾病,包括骨关节炎、骨质疏松症和其他关节炎症。
对上述指征来说,适当的剂量当然要取决于例如所用的具体本发明试剂、受治疗者、给药方式和所治疗病症的性质与严重性。不过一般来说,在动物体内得到令人满意的结果所需的每日口服剂量为约1至约10mg/kg/天。对大多数哺乳动物来说,例如人,所示每日剂量在约50至约750mg本发明试剂范围内,口服给药一次,或者更适合于分二至四次/天给药。
本发明试剂可以以任何常规途径给药,例如口服方式,例如以口服液、片剂或胶囊剂的剂型,或胃肠外方式,例如以可注射溶液或混悬液的剂型。通常对全身给药来说,口服剂型是优选的,不过在某些情况下,本发明试剂也可以局部给药或经皮给药,例如以皮肤药膏或凝胶的剂型或类似制剂,或者为了眼用,以眼药膏、凝胶的剂型或眼药水制剂;或者可以通过吸入法给药,例如治疗哮喘。适用于口服给药的单位剂型例如每单位剂型包含25至250mg新化合物。
按照上文所述,本发明也进一步提供了系列实施方式:
A.在受治疗者(即哺乳动物,尤其是人)需要接受治疗时抑制可溶性TNF、尤其是TNFα产生或者减少炎症的方法,该方法包括对所述受治疗者给以有效量的本发明试剂,或者治疗任意上述病症的方法,特别是治疗炎性或自体免疫疾病或病症的方法,例如类风湿性关节炎,或者减轻任意上述病症的一种或几种症状的方法。
B.本发明试剂,用作一种药物,例如用作免疫抑制剂或抗炎剂,或者用于预防、改善或治疗任意上述疾病或病症,例如自体免疫或炎性疾病或病症。
C.药物组合物,包含本发明试剂以及药学上可接受的稀释剂或载体,例如用作免疫抑制剂或抗炎剂,或者用于预防、改善或治疗任意上述疾病或病症,例如自体免疫或炎性疾病或病症。
D.本发明试剂在药物制备中的用途,该药物用作免疫抑制剂或抗炎剂,或者用于预防、改善或治疗任意上述疾病或病症,例如自体免疫或炎性疾病或病症。
Claims (11)
1. 2-取代的4,5-二芳基咪唑,其中:
i)1位上的氮原子被含有三烷基甲硅烷基的取代基取代,或者
ii)2位上的取代基是芳烷基、芳基磺酰基、芳硫基、芳硒基、芳碲基、环烷基、环烯基、烷基环烷基、烷基环烯基、氨基或肼基,或者是单环或二环的N-杂环基,其中的含N环具有六个环原子,其条件是2位上的取代基不是哌啶-4-基、1-羧酸叔丁酯-4-苄基哌啶-4-基、1,4-二甲基哌啶-4-基、4-苄基哌啶-4-基、或只在N原子进一步被取代的哌啶-4-基,
它们以游离形式或药学上可接受的酸加成盐或生理学上可分解的酯形式存在。
2.式I化合物
其中
R1为4-吡啶基、嘧啶基、喹唑啉-4-基、喹啉基、异喹啉基、1-咪唑基或1-苯并咪唑基,并可选地被一个或两个取代基取代,取代基各自独立地选自
C1-4烷基、卤素、C1-4烷氧基、C1-4烷硫基、NR5R6、或具有5至7个环原子的N-杂环,杂环可选地含有另外一个选自O、S或N的杂原子,
其中R5和R6各自独立为C1-4烷基;
R2为苯基、萘-1-基或萘-2-基,并可选地被至多5个取代基取代;
R3为氢,
杂环基,
杂环基C1-10烷基,
三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基,
可选卤代的C1-10烷基、C2-10烯基、C2-10炔基、C3-7环烷基、C3-7环烷基C1-10烷基、C5-7环烯基、芳基、芳基C1-10烷基、杂芳基、或杂芳基C1-10烷基,
可选一或二C1-4烷基取代的C0-10烷基-氧羰基或-氧硫代羰基,并可选地被C1-10烷基、C3-7环烷基、杂环基、杂环基C1-10烷基、芳基、芳基C1-10烷基、杂芳基、杂芳基C1-10烷基取代,或
可选一或二C1-4烷基取代的C1-10烷基
-氰基,
-硝基,
-羟基、-C1-10烷氧基、-C3-7环烷氧基、-杂环氧基、-杂环基
C1-10烷氧基、-芳氧基、-芳基C1-10烷氧基、-杂芳氧基、-
杂芳基C1-10烷氧基(及其硫氧类似物),
以及可选取代的氨基、羧酸盐、硫代羧酸盐、羰基或硫代羰基、
亚磺酰基或磺酰基;
R4为-C0-4烷基一或二C3-7环烷基,并可选地被-卤、-OH、-C1-4烷基、-C1-4烷氧基、-C1-4硫代烷氧基、-硝基、-氨基、-C1-4烷基亚磺酰基、-C1-4烷基磺酰基、-羧酸盐或-酯取代,
-NH2、-NR7R8、NHNHR9,
其中R7、R8或R9各自独立为C1-4烷基、C2-4烯基、C2-6炔基,
-X-C5-10芳基(包括杂芳基)
其中X为S、SO2、Se、Te或C1-4烷基,
单环或二环的N-杂环基,其中的含N环具有六个环原子,
或可选被至多4个取代基取代的芳基或杂芳基,
其条件是
当R3不是三C1-4烷基甲硅烷基C1-10烷氧基C1-4烷基时,
R4不是可选被至多4个取代基取代的芳基或杂芳基,除非R4是单环或二环的N-杂环基,其中的含N环具有六个环原子,和
其条件是
R4不是哌啶-4-基、1-羧酸叔丁酯-4-苄基哌啶-4-基、1,4-二甲基哌啶-4-基、4-苄基哌啶-4-基、或只在N原子进一步被取代的哌啶-4-基,
它们以游离形式或药学上可接受的酸加成盐或生理学上可分解的酯形式存在。
5.根据权利要求2的化合物,它为式IV
其中R1、R2和R3是如权利要求2所定义的,D为C3-7环烷基、C3-7环烯基或单环或二环的N-杂环基,其中的含N环具有六个环原子,X’为一条直接的键或-CR12R13-,
其中R12为H或C1-4烷基,R13为H或可选被C3-7环烷基或C3-7环烯基取代的C1-4烷基,
它们以游离形式或药学上可接受的酸加成盐或生理学上可分解的酯形式存在。
6. 4-(4-氟苯基)-5-(4-吡啶基)-1-(2-三甲基甲硅烷基乙氧基甲基)咪唑;
4-(4-吡啶基)-5-(4-氟苯基)-1-(2-三甲基甲硅烷基乙氧基甲基)咪唑;
4-(4-氟苯基)-2-((RS)-1-羟基-4’-氟苄基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-2-(苯磺酰基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-2-(苯硫基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-2-(苯硒基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-2-((1-羟基)环己基)-5-(4-吡啶基)咪唑;
2-(1-环己烯基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑;
2-(1,2-二环丙基乙基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑;
2-(环丙基甲基)-4-(4-氟苯基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(2,3,5,6-四氟吡啶基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(莨菪烷-3α-醇-3β-基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(4-羟基-1-甲基哌啶-4-基)咪唑;
+/-4-(4-氟苯基)-5-(4-吡啶基)2-(8-甲基-8-氮杂二环[3.2.1]辛-2-烯-3-基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(2-氨基-3,5,6-三氟吡啶基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(2,6-二氨基-3,5-二氟吡啶基)咪唑;
4-(4-氟苯基)-2-((1-氨基)环己基)-5-(4-吡啶基)咪唑;
4-(4-氟苯基)-5-(4-吡啶基)2-(4-正丁氧基-1-甲基哌啶-4-基)咪唑,或
4-(4-氟苯基)-5-(4-吡啶基)2-(1-甲基-4-氮杂环己烯基)咪唑,
它们以游离形式或药学上可接受的酸加成盐或生理学上可分解的酯形式存在。
8.对需治疗患者抑制可溶性TNF产生或者减少炎症的方法,该方法包括对所述受治疗者给以有效量的如权利要求1或2所定义的化合物。
9.如权利要求1或2所定义的化合物,用作一种药物,例如用作免疫抑制剂或抗炎剂。
10.药物组合物,包含如权利要求1或2所定义的化合物以及药学上可接受的稀释剂或载体,例如用作免疫抑制剂或抗炎剂。
11.如权利要求1或2所定义的化合物在药物制备中的用途,该药物用作免疫抑制剂或抗炎剂。
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GBGB9713726.9A GB9713726D0 (en) | 1997-06-30 | 1997-06-30 | Organic compounds |
GB9713726.9 | 1997-06-30 |
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-
1997
- 1997-06-30 GB GBGB9713726.9A patent/GB9713726D0/en active Pending
-
1998
- 1998-06-11 TW TW087109301A patent/TW429258B/zh active
- 1998-06-25 CO CO98036362A patent/CO4940462A1/es unknown
- 1998-06-26 PE PE1998000569A patent/PE99999A1/es not_active Application Discontinuation
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100402521C (zh) * | 2001-10-22 | 2008-07-16 | 田边制药株式会社 | 4-咪唑啉-2-酮化合物 |
CN100471856C (zh) * | 2003-07-31 | 2009-03-25 | Irm责任有限公司 | 作为pdf抑制剂的二环化合物和组合物 |
CN100455579C (zh) * | 2003-10-02 | 2009-01-28 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
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