CN101356175A - 吡唑并嘧啶酮衍生物及其制备方法和用途 - Google Patents
吡唑并嘧啶酮衍生物及其制备方法和用途 Download PDFInfo
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- CN101356175A CN101356175A CNA2006800507965A CN200680050796A CN101356175A CN 101356175 A CN101356175 A CN 101356175A CN A2006800507965 A CNA2006800507965 A CN A2006800507965A CN 200680050796 A CN200680050796 A CN 200680050796A CN 101356175 A CN101356175 A CN 101356175A
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- methyl
- phenyl
- amino
- compound
- pyrazolos
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 249
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- 201000010099 disease Diseases 0.000 claims abstract description 11
- 230000004064 dysfunction Effects 0.000 claims abstract description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 217
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 192
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 148
- 239000002585 base Substances 0.000 claims description 123
- -1 pyridine radicals Chemical class 0.000 claims description 108
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 55
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 230000001681 protective effect Effects 0.000 claims description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
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- 239000000203 mixture Substances 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 16
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
Description
Claims (1)
- 利 要 求 书1. 结构式如下式 (1A)和 (IB)的吡唑并嘧啶酮衍生物以及它们的任何前药形式, 或它们的可药 用盐或可药用溶剂化物,其中:R1为 H, -C6烷基, C3-C6环烷基, d-C3卤代垸基, 或被 C3-C6环烷基取代的 Q-C3烷 基;12为02 6垸基, C3-C6环烷基, 卤代烷基, 或被 c3-c6环烷基取代的 cr c3烷基; R3为 C!-C6烷基, ¾-0>环垸基, Cr C3卤代垸基, 被01- 垸氧基取代的 d- C3垸基, 或 被 c3-c6环烷基取代的 d-G烷基; 在式 (1A) 中,m=l-6; n=0-6;p=l-5; q=l-5;Π、 r2、 和 各自独立地为 H, d- C3烷基, 或 Γ Π Ι·2、 r3和 r4与它们相连的碳原子共同 成环;R4和 R5各自独立地为 H, d-C6烷基, (CH2)uAr, (CH2)vHet, COR9, S02R9, 被 d-C3 烷氧基取代的 Ci-Cg烷基, 或被 NR^R11基取代的 d-Cs烷基; 但当 n=0时, R5不为 H; 当 R1为甲基, R2为丙基, R3为乙基, m=l, n=l, p=q=2, r,, r2、 r3和 r4为 H时, R4和 R5不同 时为 H; ' .R9为 d- 垸基(任选被 d- C3垸氧基或被 NR12R13基取代), (CH2)uAr或 (C¾)vHet;R1Q和 R11各自独立地为 H, -C6垸基 (任选被 d- C3垸氧基或被 NR12R13基取代); 或 R1Q、 R11与它们相连的氮原子共同构成 Het;R12和 R13各自独立地为 H, 或 -C6烷基;在式 (1B) 中, t=l -5 ;R^g C!-Q;烷基, -。6环烷基, -C3卤代垸基, d-C3垸氧基, 苯基, 吡啶基, 呋喃基, 哒嗪基, 嘧啶基, 吡嗪基, 咪唑基, 或被羟基、 -C3烷氧基、 乙酰氧基、 苯基、 吡啶基、 呋 喃基、 哒嗪基、 嘧啶基、 吡嗪基、 咪唑基取代的 C C3烷基; 上述苯基, 吡啶基, 呋喃基, 哒嗉基, 嘧啶基, 吡嗪基, 咪唑基可以选择性地被一个或者多个取代基取代, 取代基选自卤 素、 C C3烷基、 CrC3烷氧基;R7、 R8各自独立为 H, C C6烷基, C3-C6环垸基, CrC3卤代垸基, d -C3烷氧基, 被羟 基、 乙酰氧基、 -C3烷氧基取代的 CrC3 '烷基, 或者, 它们与它们相连的氮原子共同构成含 四到八元杂环, 该杂环包括吗啉、 硫吗啉、 哌啶、 吡咯、 哌嗪; 上述杂环可以选择性地被一 个或者多个取代基取代, 取代基选自卤素、 d- C3烷基, C3-C6环烷基, d-Cs卤代烷基、 C,-C3 烷氧基;上述各项中,u, ν=0,1或 2;Ar代表被一个或二个取代基取代的苯基, 取代基选自卤素、 NH2、 CrC3烷基、 d- C3垸 氧基、 CONH2、 CN、 S02NH2 ;Het代表含有 1-4个杂原子的 5和 6元杂环, 杂原子选自 N、 S和 0, 且任选被一个或二 个取代基取代, 取代基选自卤素、 CrC3烷基、 CrC3烷氧基。 。2.根据权利要求 "1所述的吡唑并嘧啶酮衍生物以及它们的任何前药形式,或它们的可药用盐 或可药用溶剂化物, 其特征在于其中! 1为01-04烷基, 或 C3-C6环烷基; 'R2为 C2-C4烷基, 或 C3-C6环烷基;R3为 烷基; 被 d-C3烷氧基取代的 CrC3烷基;其中式 (1A) 中,m=l-2; n=0-2 ;p=2-4; q=2-4;r, > r2、 r3和 r4各自独立地为 H, 甲基;R4和 R5各自独立地为 H, CrC3垸基,苄基,吡啶甲基, 哌啶- 4-基, COR9, 或被 NR10RU 基取代的 - 烷基; 但当 n=0时, R5不为 H; 当 R1为甲基, R2为丙基, R3为乙基, m=l , n=l , p=q=2, 、 r2、 r3和 r4为 H时, R4和 R5不同时为 H;R9为 CrC4烷基,苯基或吡啶基;和 R"各自独立地为 H, CrC3垸基; 或 R'0、 R1 1与它们相连的氮原子共同构成吗啉、 硫吗啉、 哌嗪、 哌啶、 吡咯垸杂环;其中式 (IB ) 中, t=2-3 ;!^为^-^烷基, 苯基, 吡啶基, 苄基, 或被羟基、 d-C ^氧基、 乙酰氧基、 苯基、 吡 啶基取代的 C C3垸基;R7、 R8与它们相连的氨原子共同构成吗啉, 哌啶, 吡咯烷杂环。 '3.根据权利要求 2所述的吡唑并嘧啶酮衍生物以及它们的任何前药形式,或它们的可药用盐 或可药用溶剂化物, 其特征在于-R1为甲基或乙基;R2为乙基或正丙基;R3为乙基、 正丙基或甲氧基乙基;其中式 (1A) 中,m = 1; n = 0-1;p =2-3 ; q = 2-3;ri、 r2、 r3和 i'4为 H;R4和 R5各自独立地为 H, 甲基, 乙基或 COR9; 但当 R1为甲基, R2为丙基, R3为乙基, p=q=2时, R4和 R5不同时为 H;R9为甲基或吡啶基;其中式 (IB ) 中,t=2-3 ;R6为甲基, 乙基, 苄基, 吡啶甲基或者被羟基、 烷氧基、 乙酰氧基取代的 d-C3 焼基; -R7、 Rs与它们相连的氮原子共同构成吗啉, 哌啶, 吡咯烷杂环;4.根据权利要求 1所述的吡唑并嘧啶酮衍生物以及它们的任何前药形式,或它们的可药用盐 或可药用溶剂化物, 其优选自-1 -甲基- 5-{2-丙氧基 -5- [双 (2-乙酰氧基乙基)氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶- 7-酮 (实施例 1化合物)甲基—5— {2-丙氧基— 5— [双 (2-羟乙基)氨基磺酰基]苯基 }_3-丙基 -1,6—二氢— 7H—吡唑并 [4,3-d] 嘧啶 -7-酮 (实施例 2化合物)1-甲基 -5-{2-丙氧基 -5- [双 (2-烟酰氧基乙基)氨基磺酰基]苯基 3-丙基 -1,6-二氢- 7H-吡唑 并 [4,3- d]嘧啶 -7-酮 (实施例 3化合物)1-甲基- 5-{2-乙氧基 -5- [双 (2-乙酰氧基乙基)氨基磺酰基]苯基 }- 3-丙基 -1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶 -7-酮 (实施例 4化合物)1-甲基 -5-{2-乙氧基 -5- [双 (2-烟酰氧基乙基)氯基磺酰基]苯基 }-3-丙基 -1,6-二氢- 7H-吡唑 并 [4,3-d]嘧啶 -7-酮 (实施例 5化合物) I—甲基— 5-{2-乙氧基—5- [双 (2-乙酰氧基乙基)氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶 -7-酮 (实施例 6化合物)1-甲基 -5-{2-乙氧基 -5- [双 (2-烟酰氧基乙基)氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶- 7-酮 (实施例 7化合物)1 -甲基 -5- {2-乙氧基 -5- [双 ( 2-羟乙基) 氨基磺酰基]苯基 }- 3-乙基- 1 ,6-二氢 -7H-吡唑并[4,3-d]嘧啶 -7-?綱 (实施例 8化合物 )1-甲基 -5-{2-甲氧乙氧基 -5- [双 (2-乙酰氧基乙基)氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H- 吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 9化合物)1 -甲基 -5-{2-甲氧乙氧基 -5- [双 (2-羟乙基)氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并[4,3-d]嘧啶 -7-酮 (实施例 10化合物)1—甲基 -5_{2-乙氧基— 5- [1- ( 二乙基氨基乙基) 1- (2-羟乙基) -氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 13化合物)1-甲基 -5- {2-丙氧基 -5- [卜 (2-二乙基氨基乙基) -卜 (2-羟乙基) -氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3- d]嘧啶 -7-酮 (实施例 14化合物)丄—甲基 _5_{2—乙氧基 U- -二乙基氨基乙基) - 1- (2-羟乙氧基乙基) 氨基磺酰基]苯 基 3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 16化合物)1-乙基 -5-{2-乙氧基 -5-{ [卜乙基-卜[2- (1-乙基- 1- (2-乙酰氧基乙基))氨基]乙基]氨基 磺酰基 }苯基 }- 3-乙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 19化合物)1 -甲基 -5- {2-乙氧基 - 5-{ [1-甲基 1 - [2- (卜甲基-卜 (2-轻乙基))氨基]乙基]氨基磺酰基 } 苯基 3-丙基- 1 ,6-二氢 -7Η-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 21化合物)1-甲基 -5-{2-丙氧基 -5-{U-甲基-卜 [2- (1-甲基- 1-〈2-羟乙基))氨基]乙基]氨基磧酰基 } 苯基 }-3-丙基- 1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 23化合物)μ甲基 _ {2-丙氧基 -5-[ [卜苄基-卜 (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6- 二氢 -7Η-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 24化合物)i -甲基 _5_{2—乙氧基 _5— [[1-苄基-卜 (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }— 3_丙基 6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 25化合物)1-甲基 -5-{2-甲氧基 - 5- [[卜苄基- 1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 26化合物)1 -甲基 -5-{2-乙氧基 -5- [[卜苄基- 1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-乙基 4,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 27化合物)1-甲基 -5-{2-乙氧基 -5- [[卜 (2-羟乙氧基乙基 ) -1- (2-吗啉-卜基)乙基]氨基磺酰基]苯 基}-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 28化合物)1-甲基- 5- {2-乙氧基 -5- [[卜 (2 -轻乙基) -卜 (2-哌啶- 1-基)乙基]氨基磺酰基]苯基 }-3-丙 基- 1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 29化合物) 1-甲基 -5-{2-丙氧基 - 5- [ [ l-甲基- 1- (2-羟乙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 31化合物)1-甲基 -5-{2-丙氧基 -5- [ [1-甲基- 1- (2-乙酰氧基乙基)]氨基磺酰基]苯基 }-3-丙基 -1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 33化合物)1 甲基—5— {2-丙氧基 -5- [U-甲基 -I- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 3-乙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 35化合物)1-甲基 _5—{2_乙氧基 _5—[ [1-甲基- 1- (2-吗啉 -1-基)乙基]氨基磺酰基]苯基 }-3-乙基 -1,6-二 氢 -7H-吡吨并 [4,3-d]嘧啶 -7-酮 (实施例 36化合物)1_甲基 _5— {2-丙氧基 _5— [双 (3_羟丙基)氛基磧酰基]苯基 }— 3—乙基— 二氢 -7H-吡唑并 [4,3-d] 嘧啶- 7-酮 (实施例 37化合物)1-甲基 -5-{2-丙氧基 -5- [[1- (2-羟乙基 ) - 1- (3-轻丙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮(实施例 38化合物)i -甲基 -5_{2_丙氧基 _5_[[卜 (2-羟乙氧基乙基) -卜 (3-羟丙基) ]氨基磺酰基]苯基 } -3-丙基 -1,6-二氢 _7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 39化合物)1-甲基- 5-{2-丙氧基 - 5- [[ 乙基- 1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-乙基 _1,6-二 氢 -7H-吡唑并 [4,3 -d]嘧啶 -7-酮(实施例 41化合物)1-甲基 -5- {2-丙氧基 -5- [双 (2-羟丙基)氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑并 [4,3-d] 嘧啶 -7-酮 (实施例 42化合物)1-甲基 -5-{2-乙氧基 -5-[ [ 乙基 -1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-乙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 43化合物)1-甲基 -5- {2-乙氧基 -5- [双 (3-羟丙基)氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑并 [4,3-d] 嘧啶 -7-酮 (实施例 44化合物)1-甲基 -5- {2-乙氧基 -5- [双 (2-羟丙基)氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑并 [4,3-d] 嘧啶 -7-酮 (实施例 45化合物) ·1-甲基 -5-{2-乙氧基 - 5- [[卜 (2-羟乙基) -卜 (3羟丙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 46化合物)1-甲基 -5- {2-乙氧基 -5-[[1- (2-羟乙氧基乙基 ) -1- (3 羟丙基) ]氨基磺酰基]苯基 } -3-丙基 - 1 ,6-二氢 -7H-吡唑并 [4,3 -d]嘧啶 -7-酮(实施例 47化合物)1-甲基 -5-{2-乙氧基 -5- [ [1-乙基 -1- (2-羟乙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H- 吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 51·化合物)1-甲基 {2—乙氧基 _5_ [ [卜乙基- (2-羟乙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H- 吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 52化合物)1-甲基 -5- {2-丙氧基 -5-[[1-甲基-卜 (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 3-乙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 53化合物) 1-甲基 -5-{2-丙氧基 -5-[ [l-乙基- 1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-乙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 54化合物)1-甲基 -5-{2-丙氧基 -5-[ [1- (4-氟苄基 ) - 1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 56化合物)1-甲基 -5-{2-丙氧基 -5-[ - (2-吡啶甲基) -1- (2-吗啉 -1-基)乙基]氨基磺酰基]苯基 }-3-丙 基 -I,6-二氢 _7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 60化合物)1-甲基 -5-{2-乙氧基 - 5-[ [1- (3-吡啶甲基) -1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 61化合物)1-甲基 -5-{2-丙氧基 -5-[[1- (3-吡啶甲基) - 1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }- 3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 _7-酮(实施例 ω化合物)μ甲基— 5— {2_丙氧基 _5— [ [1- (4-吡啶甲基) -1- (2 -吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7Η-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 63化合物)1-甲基 -5-{2-乙氧基 -5-[ [1- (4-吡啶甲基)- 1- (2-吗啉-卜基)乙基]氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 64化合物)1-甲基 -5-{2-丙氧基 -5-[[1-苄基 -1-(3-轻丙基)]氨基磺酰基]苯基 }-3-丙基- 1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶 -7-酮 (实施例 65化合物) '1-甲基 -5-{2-乙氧基 -5-[[1-苄基小(3-羟丙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑 并 [4,3- d]嘧啶 -7-酮(;实施例 66化合物)1-甲基 -5-{2-丙氧基 -5-[[1-苄基 -1- (2-羟乙基)]氨基磺酰基]苯基) -3-丙基 -1,6-二氢 -7H-吡唑 并 [4,3-d]嘧啶 -7-酮(实施例 68化合物)1-甲基 -5-{2-丙氧基 -5- [ [卜乙基- 1- (3-羟丙基) ]氨基磺酰基]苯基 3-丙基 -1,6-二氢 -7H- 吡唑并 [4,3- d]嘧啶 -7-酮(实施例 70化合物)1-甲基 -5-{2-丙氧基 -5-[ [1- (2-呋喃甲基) -1- (2-吗啉- 1-基)乙基]氨基磺酰基]苹基 }- 3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 72化合物)1-甲基 -5-{2-丙氧基 -5-[[卜甲基- 1- (2-哌啶-卜基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 78化合物)1-甲基 -5-{2-乙氧基 -5-[ [1-甲基- 1- (2 哌啶-卜基)乙基]氨基磺酰基]苯基 }-3-丙基- 1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 79化合物)1-甲基 -5-{2-丙氧基 -5-[ [1 -甲基 - 1- (2-吡咯烧 -1-基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 80化合物)1-甲基 -5-{2-乙氧基 - 5- [[卜甲基-卜 (2-吡咯烷 - 1-基)乙基]氨基磺'酰基]苯基 }-3-丙基 1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 81化合物)1 -甲基 -5-{2-乙氧基 -5-[[1-苄基- 1- (2-哌啶- 1-基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6-二 氢- 7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 化合物)1 甲基 _5_{2-丙氧基 -5-[ [1-甲基 -1- (2-哌啶- 1-基)乙基]氨基磺酰基]苯基 3-丙基 -1,6-二 氢 -7H-吡唑并 [4,3- d]嘧啶 -7-酮 (实施例 S3化合物)1-甲基 -5- {2-丙氧基 -5- [ [1-苄基- 1- (2-吡咯烷 -1-基)乙基]氨基磺酰基]苯基卜 3-丙基 -1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 84化合物)1_甲基— 5_{2—乙氧基 - 5- [[卜苄基 -1- (2-吡咯烷 -1-基)乙基]氨基磺酰基]苯基 }- 3-丙基 4,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 85化合物)1-甲基 -5-{2-丙氧基 -5-[[1- (2-吡啶甲基 ) -1 (2-哌啶- 1-基)乙基]氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 87化合物)j—甲基 -5- {2—乙氧基 - (2 -吡啶甲基) -卜 (2-哌啶-卜基)乙基]氨基磺酰基]苯基 }-3-丙 基 -1,6-二氢 -7H-吡唑并 [4 d]嘧啶 -7-酮 (实施例 88化合物)1-甲基 -5-{2-丙氧基 - 5-[[卜(3-吡啶甲基) - 1- (2-吡咯烷 -卜基)乙基]氨基磺酰基]苯基 3- 丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 89化合物)1-甲基- 5-{2-乙氧基 - 5-[[1- (3-吡啶甲基)- 1- (2 -吡咯烷- 1-基)乙基]氨基磺酰基]苯基 }-3- 丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 90化合物)1-甲基 -5-{2-丙氧基 -5-[ [卜(2-乙酰氧基乙基) -卜 (2-羟乙基)〕氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 91化合物)1—甲基 _5-{2_丙氧基—5- [ [1- (3-乙酰氧基丙基 ) -1- (3-羟丙基)〕氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 92化合物)1-甲基 -5-{2-丙氧基 - 5- [双 (3-乙酰氧基丙基)氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 93化合物)1-甲基 -5-{2-丙氧基 -5- [ [1-乙基-卜 (2-乙酰氧基乙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 94化合物)1_甲基 _ {2-丙氧基 -5-[[1-(2-羟乙基)小 (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3-丙基 -1,6- 二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 95化合物)1-甲基 -5- {2-丙氧基 -5-[[1-(2-乙酰氧基乙基 )-1-(2-吗啉 -1-基)乙基]氨基磺酰基]苯基 }-3-丙 基 4,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 96化合物)1-甲基 -5-{2-丙氧基 -5- [ [卜乙基-卜 (3-乙酰氧基丙基) ]氨基磺酰基]苯基 3-丙基 -1,6-二 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 97化合物)1-甲基 -5-{2-丙氧基 -5-[[1-〔2-甲氧基乙基)小(2-吗啉小基)乙基]氨基磺酰基]苯基 3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 98化合物)1-甲基 -5-{2-丙氧基 -5- [ [1- (2-甲氧基乙基) - 1- (3-羟丙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢- 7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 99化合物)1-甲基 -5- {2-乙氧基 -5-[ [1- (2 甲氧基乙基) - 1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3- 丙基 -1 ,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 100化合物). 1-甲基 -5-{2-乙氧基 -5- [ [1- (2-甲氧基乙基) - 1- (2 羟乙基)]氨基磺酰基]苯基 }-3-丙基 - 1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 101化合物)1_甲基 _5_{2-乙氧基 -5- [ [1- (2-甲氧基乙基) - 1- (3-羟丙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 102化合物)1-甲基- 5-{2-丙氧基 -5- [双 (3-甲氧基丙基)氨基磺酰基]苯基 }-3-丙基- 1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 103化合物)1-甲基 -5-{2-丙氧基 -5-[ [1- (2-羟乙氧基乙基)- 1- (2_吗啉 1 基)乙基]氨基磺酰基]苯 基}-3-丙基 -1,6-二氢- 7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 104化合物)1-甲基 -5- {2-丙氧基 - 5-[[卜 (2-甲氧乙氧基乙基) -1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯 基}-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 105化合物)1-甲基 -5-{2-丙氧基 -5- [ [1 - (2-甲氧基乙基) - 1- (2-羟乙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 106化合物)1-甲基 -5-{2-乙氧基 -5- [ [1-甲基-卜 (2 -乙酰氧基乙基) ]氨基磺酰基]苯基 }-3-丙基 -1,6-二 氢— 7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 107化合物)1-甲基 -5- {2-乙氧基 -5- [双 (3-乙酰氧基丙基)氨基磺酰基]苯基 3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 108化合物)1-甲基 -5-{2-丙氧基 -5- [ [1- (3-甲氧基丙基) - 1- (2-羟乙基)]氨基磺酰基]苯基 }-3-丙基 -l,6-: 氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 109化合物)1-甲基 -5-{2-丙氧基 -5-[[1-甲基- 1- (2-二甲基氨基乙基) ]氨基磺酰基]苯基 }- 3-丙基- 1,6-二 氢 -7H—吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 110化合物)1-甲基- 5-{2-丙氧基 -5-[ [1- (2-乙氧基乙基) -卜 (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3- 丙¾-1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 111化合物)1-甲基 -5-{2-丙氧基 -5-[ [1- (2-乙氧基乙基) - 1- (2-吗啉- 1-基)乙基]氨基磺酰基]苯基 }-3-' 丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 112化合物)1-甲基 -5-{2-丙氧基 - 5-[[1-苄基 -1-(2-吗啉 -1-基)丙基]氨基磺酰基]苯基 }-3-乙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮(实施例 113化合物)1-甲基 -5-{2-丙氧基 -5- [ [1- (3-甲氧基丙基) -卜 (2-乙酰氧基乙基) ]氨基磺酰基]苯基 }-3- 丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶- 7-酮 (实施例 114化合物)1_甲基—5-{2—乙氧基 (3—乙酰氧基丙基 )—― (3-羟丙基)]氨基磺酰基]苯基 }-3-丙基 - 1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 115化合物)1-甲基- 5-{2-丙氧基 - 5- [ [1- (3-甲氧基丙基) -卜 (2-羟乙基)]氨基磺酰基]苯基 }-3-丙基 -1,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 116化合物)1-甲基 -5-{2-丙氧基 -5-[[1-苄基 -1-(2-吗啉 -1-基)丁基]氨基磺酰基]苯基 }- 3-乙基 -1 ,6-二氢 -7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 117化合物)1-甲基 -5-{2-丙氧基 -5-[ [1- (3-甲氧基丙基) - 1- (3-乙酰氧基丙基) ]氨基磺酰基]苯基 }-3- 丙基 -1,6-二氢- 7H-吡唑并 [4,3-d]嘧啶 -7-酮 (实施例 118化合物)5. 一种可药用的组合物, 由权利要求 1-4项中任一项的式 (1A)和 (1B)化合物以及它们的任何 前药形式、 或它们的可药用盐或可药用溶剂化物, 以及一种或多种可药用辅料制备而成。6. 权利要求 5所述的组合物, 使用有效剂量为卜 500mg/天, 优选 10~100mg/天。7. 如权利要求 1所述的式 (1A)和 (1B)的吡唑并嘧啶酮衍生物以及它们的任何前药形式, 或它 们的可药用盐或可药用溶剂化物的制备方法, 对于式 (1B)和式 (1A)磺酰胺侧链不含有末端羟 基时 (R4、 R5不为 H), 可由如下步骤制备:步骤一其中 R2、 R3、 R4、 R5、 R6、 R7、 Rs、 r!、 r2、 r3、 r4、 m、 n、 p、 q和 t如权利要 求 1中的定义, 但 R4、 R5不为 H。 第一种, 先用亚硫酰氯、 革酰氯、 氯甲酸乙酯等将式(3A)或(3B)化合物的羧基转化 为酰氯或混合酸酐, 再与式(4)化合物反应得到相应的酰胺(2A)或(2B)。 酰化反应通常 在去酸剂存在下, 在常用溶剂中进行。 优选的去酸剂包括有机碱(优选三乙胺、 二异丙基乙 基胺、 吡啶)和无机碱(优选氢氧化物、 碳酸盐)。 优选的溶剂包括烷烃类(优选石油醚、 正 己烷、 环己烷)、 卤代烃(优选二氯甲烷或氯仿)、 醚(优选四氢呋喃、 二氧六环、 乙醚)、 芳 香类溶剂 (优选甲苯〉、 以及醇类(优选叔丁醇、 异丙醇)。操作方法二, 采用羧酸和胺直接缩合得到酰胺 (2A) 或 (2B)。 反应通常在活化剂或脱水剂 存在下, 在无水惰性溶剂中进行。 优选的活化剂或脱水剂包括 DCC、 EDCI、 EEDQ, CDI、 HOBt等。 优选的溶剂包括卤代烃 (优选二氯甲垸或氯仿)、 醚 (优选四氢呋喃、 二氧六环、 乙醚)、 芳烃 (优选苯、 甲苯)、 醇类 (优选叔丁醇、 异丙醇)、 极性非质子溶剂 (二甲亚砜、 Ν,Ν-二甲基甲酰胺), 或这些溶剂的混合物。步骤二其中 I 1、 R2、 R3、 R4、 R5、 R6、 R7、 R8、 r!、 r2、 r3、 r4、 m、 n、 p、 q和 t'如权利要求 1中的 定义, 但 R4、 R5不为 H。 '该步骤通常在碱的存在下, 在适当的溶剂中进行反应, 温度通常 30-200°C。 优选的碱包 括碱金属烷氧化物(优选叔丁醇钾、 乙醇钠)、碱金属或碱土金属氢化物、 胺(优选三乙胺)、 胺的金属盐、 氢氧化物(优选氢氧化钠)、碳酸盐和碳酸氢盐; 优选的溶剂包括醇(例如叔丁 醇、 乙醇、 甲醇、 异丙醇、 乙二醇、 乙二醇单甲醚)、 芳烃 (例如苯、 甲苯、 氯苯)、 吡啶、 卤代烃、 乙腈、 四氢呋喃、 二氧六环、 二甲亚砜、 Ν,Ν-二甲基甲酰胺、 Ν-甲基吡咯烷 -2-酮。8. 如权利要求 1所述的式 (1A)的吡唑并嘧啶酮衍生物以及它的任何前药形式, 或它们的可药 用盐或可药用溶剂化物的制备方法, 当式 (1A)磺酰胺侧链含有末端羟基时(R4和 R5至少一个 为 H), 可由相应的酯类衍生物的水解反应制备-n、 p和 q如权利要求 1中的定义。9.如权利要求 1所述的吡唑并嘧啶酮衍生物及生理可接受的盐的用途,在治疗或预防勃起功 能障碍、 雌性的性功能障碍、 早产、 痛经、 良性前列腺增生、 膀胱出口梗阻、 失禁、 不稳定 的和变异的 Prinzmetal心绞痛、 高血压、肺动脉高压、 充血性心衰、 肾衰竭、动脉粥样硬化、 中风、 周围血管疾病、 雷诺氏症、 炎症性疾病、 支气管炎、 慢性哮喘、 过敏性哮喘、 过敏性 鼻炎、 青光眼、 以及特征为肠蠕动障碍的疾病中应用。
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CA2235642C (en) * | 1998-05-15 | 2007-11-13 | Torcan Chemical Ltd. | Processes for preparing sildenafil |
GB9823101D0 (en) * | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
KR100353014B1 (ko) * | 1998-11-11 | 2002-09-18 | 동아제약 주식회사 | 발기부전 치료에 효과를 갖는 피라졸로피리미디논 화합물 |
US6225315B1 (en) * | 1998-11-30 | 2001-05-01 | Pfizer Inc | Method of treating nitrate-induced tolerance |
WO2002027848A2 (de) | 2000-09-22 | 2002-04-04 | Siemens Aktiengesellschaft | Verfahren zum überwachen des medienaustritts aus einer brennstoffzelle und brennstoffzellenanlage |
US6548508B2 (en) * | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
DE60222931T2 (de) * | 2001-12-13 | 2008-07-10 | Asubio Pharma Co., Ltd. | Pyrazolopyrimidinonderivate mit pde7-hemmender wirkung |
WO2007113243A2 (en) * | 2006-03-31 | 2007-10-11 | Investigación Y Clínica Andrológicas S.L. | Use of pde 5 inhibitors for the treatment of overactive bladder |
-
2005
- 2005-11-17 CN CNA2005101104850A patent/CN1966506A/zh active Pending
-
2006
- 2006-11-16 EP EP06817839A patent/EP1961753A4/en not_active Withdrawn
- 2006-11-16 CN CN2010100005596A patent/CN102002045B/zh active Active
- 2006-11-16 EP EP10171901A patent/EP2253632B1/en not_active Not-in-force
- 2006-11-16 CN CN200680050796A patent/CN100593542C/zh active Active
- 2006-11-16 US US12/094,071 patent/US20080318949A1/en not_active Abandoned
- 2006-11-16 ES ES10171901T patent/ES2387645T3/es active Active
- 2006-11-16 JP JP2008540434A patent/JP5209486B2/ja not_active Expired - Fee Related
- 2006-11-16 WO PCT/CN2006/003094 patent/WO2007056955A1/zh active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CN100593542C (zh) | 2010-03-10 |
US20080318949A1 (en) | 2008-12-25 |
ES2387645T3 (es) | 2012-09-27 |
EP2253632A1 (en) | 2010-11-24 |
JP5209486B2 (ja) | 2013-06-12 |
EP2253632B1 (en) | 2012-05-23 |
CN102002045A (zh) | 2011-04-06 |
CN102002045B (zh) | 2012-11-28 |
EP1961753A1 (en) | 2008-08-27 |
CN1966506A (zh) | 2007-05-23 |
JP2009515911A (ja) | 2009-04-16 |
WO2007056955A1 (fr) | 2007-05-24 |
EP1961753A4 (en) | 2009-11-25 |
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