TWI455715B - ４－（４－氰基－２－硫基芳基）二氫嘧啶酮類及其用途 - Google Patents

４－（４－氰基－２－硫基芳基）二氫嘧啶酮類及其用途 Download PDF

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TWI455715B
TWI455715B TW097149556A TW97149556A TWI455715B TW I455715 B TWI455715 B TW I455715B TW 097149556 A TW097149556 A TW 097149556A TW 97149556 A TW97149556 A TW 97149556A TW I455715 B TWI455715 B TW I455715B
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phenyl
group
cyano
alkyl
trifluoromethyl
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TW200940063A (en
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Franz Nussbaum
Dagmar Karthaus
Sonja Anlauf
Martina Klein
Volkhart Min-Jian Li
Daniel Meibom
Klemens Lustig
Jens Schamberger
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Bayer Ip Gmbh
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Priority claimed from DE102007061766A external-priority patent/DE102007061766A1/de
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Claims (21)

  1. 一種式(I)化合物 其中A及E都代表C-R7 ，其中R7 在各情形下代表氫、氟或氯，Z代表O或S,n代表數字0、1或2,R1 代表(C1 -C6 )-烷基，其可經羥基、(C1 -C4 )-烷氧基、胺基、單-或二-(C1 -C4 )-烷基胺基、羥基羰基、胺基羰基、(C3 -C6 )-環烷基、苯基或5-或6-員雜芳基取代或經氟取代至多五次，或代表(C2 -C6 )-烯基、(C3 -C6 )-環烷基、苯基或5-或6-員雜芳基，其中提到的(C3 -C6 )-環烷基可經選自包括(C1 -C4 )-烷基、羥基及(C1 -C4 )-烷氧基之相同或不同取代基取代至多兩次，且 提到的苯基及雜芳基可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、二氟甲基、三氟甲基、(C1 -C4 )-烷氧基、二氟甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，R2 代表氫、氟或氯，R3 代表氰基或式-C(=O)-R8 、-C(=O)-O-R8 、-C(=O)-NH2 或-C(=O)-NH-R8 之基團，其中R8 代表(C1 -C6 )-烷基、(C3 -C6 )-烯基或(C3 -C6 )-環烷基，其中(C1 -C6 )-烷基及(C3 -C6 )-環烷基本身可經選自包括羥基、(C1 -C4 )-烷氧基、羥基羰基、(C1 -C4 )-烷氧羰基、胺基、單-及二-(C1 -C4 )-烷基胺基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基及(C3 -C6 )-環烷基中在各情形下一個CH2 基可經氧原子代替，如果此導致一個安定的化合物，R4 代表甲基或乙基或R3 及R4 是彼此連結且一起形成下式之稠合基團其中*代表連結至式(I)所示的二氫嘧啶環之5-位置的點，且**代表連結至式(I)所示的二氫嘧啶環之6-位置的點，且R9 代表氫、(C1 -C6 )-烷基或(C3 -C6 )-環烷基， 其中(C1 -C6 )-烷基可經羥基、(C1 -C4 )-烷氧基、胺基羰基、胺基羰基胺基、(C1 -C4 )-醯基胺基或(C3 -C6 )-環烷基取代，R5 代表氫或(C1 -C6 )-烷基，其可經氰基、羥基、(C1 -C4 )-烷氧基、胺基、單-或二-(C1 -C4 )-烷基胺基或(C3 -C6 )-環烷基取代或經氟取代至多三次，或代表苯基、吡啶基或嘧啶基，其中苯基、吡啶基及嘧啶基本身可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、三氟甲基、(C1 -C4 )-烷氧基及三氟甲氧基之相同或不同取代基取代至多兩次，或R5 代表式-C(=O)-O-R10 、-L1 -C(=O)-O-R11 、-L2 -C(=O)-NR12 R13 、-L2 -SO2 -NR12 R13 、-L2 -C(=O)-NR14 -NR12 R13 或-L2 -SO2 -R15 之基團，其中L1 代表(C1 -C6 )-烷二基，L2 代表一個鍵或(C1 -C6 )-烷二基，R10 代表(C1 -C6 )-烷基，其可經(C3 -C6 )-環烷基或苯基取代，R11 代表氫或(C1 -C6 )-烷基，其可經(C3 -C6 )-環烷基或苯基取代，R12 及R13 是相同或不同且彼此獨立地代表氫、(C1 -C6 )-烷基、(C3 -C6 )-環烷基或4-至6-員雜環基，其中(C1 -C6 )-烷基、(C3 -C6 )-環烷基及4-至6-員雜環基本身可經選自包括氟、羥基、(C1 -C4 )-烷氧基、酮基、 胺基、單-或二-(C1 -C4 )-烷基胺基、羥基羰基、(C1 -C4 )-烷氧羰基及胺基羰基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基中的一個CH2 基團可經一個氧原子代替，如果此導致一個安定的化合物，且(C3 -C6 )-環烷基及4-至6-員雜環基可另外經相同或不同的(C1 -C4 )-烷基取代至多兩次，其中(C1 -C4 )-烷基可進一步經羥基、(C1 -C4 )-烷氧基或羥基羰基取代，或R12 及R13 與和其連結之氮原子形成一個4-至6-員雜環基，其可含有選自包括N、O、S、SO及SO2 之其他環雜原子且其可經選自包括(C1 -C4 )-烷基、羥基、(C1 -C4 )-烷氧基、酮基、胺基、單-或二-(C1 -C4 )-烷基胺基、羥基羰基、胺基羰基、(C3 -C6 )-環烷基、4-至6-員雜環基及5-或6-員雜芳基之相同或不同取代基取代至多兩次，其中(C1 -C4 )-烷基本身可經羥基、(C1 -C4 )-烷氧基或羥基羰基取代，R14 代表氫或(C1 -C4 )-烷基，且R15 代表(C1 -C6 )-烷基、(C3 -C6 )-環烷基、苯基或5-或6-員雜芳基， 其中(C1 -C6 )-烷基可經氯、羥基、(C1 -C4 )-烷氧基、單-或二-(C1 -C4 )-烷基胺基、或(C3 -C6 )-環烷基取代或經氟至多取代三次，且苯基或5-或6-員雜芳基本身可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、二氟甲基、三氟甲基、(C1 -C4 )-烷氧基及三氟甲氧基之相同或不同取代基取代至多兩次，且R6 代表氫、氟或氯，或其醫藥上可接受之鹽。
  2. 根據申請專利範圍第1項之式(I)化合物，其中A及E都代表C-R7 ，其中R7 在各情形下代表氫、氟或氯，Z代表O或S,n代表數字0、1或2,R1 代表(C1 -C6 )-烷基，其可經羥基、(C1 -C4 )-烷氧基、胺基、單-或二-(C1 -C4 )-烷基胺基、羥基羰基、胺基羰基、(C3 -C6 )-環烷基或苯基取代，或代表(C2 -C6 )-烯基、(C3 -C6 )-環烷基或苯基，其中提到的(C3 -C6 )-環烷基可經選自包括(C1 -C4 )-烷基、羥基及(C1 -C4 )-烷氧基之相同或不同取代基取代至多兩次，且 提到的苯基可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、二氟甲基、三氟甲基、(C1 -C4 )-烷氧基、二氟甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，R2 代表氫、氟或氯，R3 代表氰基或式-C(=O)-R8 、-C(=O)-O-R8 、-C(=O)-NH2 或-C(=O)-NH-R8 之基團，其中R8 代表(C1 -C6 )-烷基、(C3 -C6 )-烯基或(C3 -C6 )-環烷基，其中(C1 -C6 )-烷基及(C3 -C6 )-環烷基本身可經選自包括羥基、(C1 -C4 )-烷氧基、羥基羰基、(C1 -C4 )-烷氧羰基、胺基、單-及二-(C1 -C4 )-烷基胺基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基及(C3 -C6 )-環烷基中在各情形下一個CH2 基可經氧原子代替，如果此導致一個安定的化合物，R4 代表甲基或乙基或R3 及R4 是彼此連結且一起形成下式之稠合基團其中*代表連結至式(I)所示的二氫嘧啶環之5-位置的點，且**代表連結至式(I)所示的二氫嘧啶環之6-位置的點，且R9 代表氫、(C1 -C6 )-烷基或(C3 -C6 )-環烷基， 其中(C1 -C6 )-烷基可經羥基、(C1 -C4 )-烷氧基、胺基羰基、(C1 -C4 )-醯基胺基或(C3 -C6 )-環烷基取代，R5 代表氫或(C1 -C6 )-烷基，其可經氟取代至多三次，或代表苯基、吡啶基或嘧啶基，其中苯基、吡啶基及嘧啶基本身可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、三氟甲基、(C1 -C4 )-烷氧基及三氟甲氧基之相同或不同取代基取代至多兩次，或R5 代表式-C(=O)-O-R10 、-L1 -C(=O)-O-R11 、-L2 -C(=O)-NR12 R13 、-L2 -SO2 -NR12 R13 、-L2 -C(=O)-NR14 -NR12 R13 或-L2 -SO2 -R15 之基團，其中L1 代表(C1 -C6 )-烷二基，L2 代表一個鍵或(C1 -C6 )-烷二基，R1 代表(C1 -C6 )-烷基，R11 代表氫或(C1 -C6 )-烷基，R12 及R13 是相同或不同且彼此獨立地代表氫、(C1 -C6 )-烷基、(C3 -C6 )-環烷基或4-至6-員雜環基，其中(C1 -C6 )-烷基、(C3 -C6 )-環烷基及4-至6-員雜環基本身可經選自包括氟、羥基、(C1 -C4 )-烷氧基、酮基、胺基、單-或二-(C1 -C4 )-烷基胺基、羥基羰基、(C1 -C4 )-烷氧羰基及胺基羰基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基中的一個CH2 基團可經一個氧原子代替，如果此導致一個安定的化合物，或 R12 及R13 與和其連結之氮原子形成一個4-至6-員雜環基，其可含有選自包括N、O、S、SO及SO2 之其他環雜原子且其可經選自包括(C1 -C4 )-烷基、羥基、(C1 -C4 )-烷氧基、酮基、胺基、單-或二-(C1 -C4 )-烷基胺基之相同或不同取代基取代至多兩次，其中(C1 -C4 )-烷基本身可經羥基或(C1 -C4 )-烷氧基取代，R14 代表氫或(C1 -C4 )-烷基，且R15 代表(C1 -C6 )-烷基、(C3 -C6 )-環烷基、苯基或5-或6-員雜芳基，其中(C1 -C6 )-烷基可經氟、氯、羥基、(C1 -C4 )-烷氧基、單-或二-(C1 -C4 )-烷基胺基取代，且苯基或5-或6-員雜芳基本身可經選自包括氟、氯、氰基、(C1 -C4 )-烷基、三氟甲基、(C1 -C4 )-烷氧基及三氟甲氧基之相同或不同取代基取代至多兩次，且R6 代表氫、氟或氯，或其醫藥上可接受之鹽。
  3. 根據申請專利範圍第1或2項之式(I)化合物，其中A及E都代表CH Z代表O,n代表0或2之數字， R1 代表(C1 -C4 )-烷基，其可經羥基、(C1 -C4 )-烷氧基、羥基羰基、胺基羰基、(C3 -C6 )-環烷基、苯基或5-員雜芳基取代或經氟取代至多三次，或代表(C3 -C6 )-環烷基、苯基或5-員雜芳基，其中提到的苯基及雜芳基可經選自選自包括氟、氯、氰基、甲基、三氟甲基、甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，R2 代表氫，R3 代表氰基、乙醯基或(2-羥基乙氧基)羰基，R4 代表甲基，或R3 及R4 是彼此連結且一起形成下式之稠合基團其中*代表連結至式(I)所示的二氫嘧啶環之5-位置的點，且**代表連結至式(I)所示的二氫嘧啶環之6-位置的點，且R9 代表氫、(C1 -C4 )-烷基或(C3 -C6 )-環烷基，其中(C1 -C4 )-烷基可經羥基或(C1 -C4 )-烷氧基取代，R5 代表氫或(C1 -C4 )-烷基，其可經氰基或二-(C1 -C4 )-烷基胺基取代，或代表式-L2 -C(=O)-NR12 R13 、-L2 -C(=O)-NH-NR12 R13 或-L2 -SO2 -R15 之基團，其中L2 代表一個鍵、-CH2 -、-CH2 CH2 -或-CH(CH3 )-, R12 代表氫或(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，R13 代表氫、(C1 -C6 )-烷基或(C3 -C6 )-環烷基，其中(C1 -C6 )-烷基可經選自包括羥基、(C1 -C4 )-烷氧基、羥基羰基、(C1 -C4 )-烷氧羰基及胺基羰基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基中的一個CH2 基團可經一個氧原子代替，如果此導致一個安定的化合物，或R12 及R13 與和其連結之氮原子形成一個5-或6-員雜環基其可含有選自包括N、O及S之其他環雜原子且其可經(C1 -C4 )-烷基、羥基、(C1 -C4 )-烷氧基、酮基、羥基羰基、胺基羰基、4-至6-員雜環基或5-或6-員雜芳基取代，其中(C1 -C4 )-烷基本身可經羥基、(C1 -C4 )-烷氧基或羥基羰基取代，且R15 代表(C1 -C4 )-烷基、(C3 -C6 )-環烷基或苯基，其中(C1 -C4 )-烷基可經(C3 -C6 )-環烷基取代，且苯基可經選自包括氟、氯、氰基、甲基、三氟甲基、甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，且R6 代表氫或氟， 或其醫藥上可接受之鹽。
  4. 根據申請專利範圍第1或2項之式(I)化合物，其中A及E都代表CH,Z代表O,n代表數字0或2,R1 代表(C1 -C4 )-烷基，其可經羥基、(C1 -C4 )-烷氧基、羥基羰基、胺基羰基、(C3 -C6 )-環烷基或苯基取代，或代表(C3 -C6 )-環烷基或苯基，其中提到的苯基可經選自包括氟、氯、氰基、甲基、三氟甲基、甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，R2 代表氫，R3 代表氰基或乙醯基，R4 代表甲基，或R3 及R4 是彼此連結且一起形成下式之稠合基團其中*代表連結至式(I)所示的二氫嘧啶環之5-位置的點，且**代表連結至式(I)所示的二氫嘧啶環之6-位置的點，且R9 代表氫、(C1 -C4 )-烷基或(C3 -C6 )-環烷基，其中(C1 -C4 )-烷基可經羥基或(C1 -C4 )-烷氧基取代， R5 代表氫、(C1 -C4 )-烷基或式-L2 -C(=O)-NR12 R13 、-L2 -C(=O)-NH-NR12 R13 或-L2 -SO2 -R15 之基團，其中L2 代表一個鍵、-CH2 -、-CH2 CH2 -或-CH(CH3 )-,R12 代表氫或(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，R13 代表氫、(C1 -C6 )-烷基或(C3 -C6 )-環烷基，其中(C1 -C6 )-烷基可經選自包括羥基、(C1 -C4 )-烷氧基、羥基羰基、(C1 -C4 )-烷氧羰基及胺基羰基之相同或不同取代基取代至多兩次，且在(C1 -C6 )-烷基中的一個CH2 基團可經一個氧原子代替，如果此導致一個安定的化合物，或R12 及R13 與和其連結之氮原子形成一個5-或6-員雜環基其可含有選自包括N、O及S之其他環雜原子且其可經(C1 -C4 )-烷基、羥基、(C1 -C4 )-烷氧基或酮基取代，其中(C1 -C4 )-烷基本身可經羥基或(C1 -C4 )-烷氧基取代，且R15 代表(C1 -C4 )-烷基、(C3 -C6 )-環烷基或苯基，其中苯基可經包括氟、氯、氰基、甲基、三氟甲基、甲氧基及三氟甲氧基之相同或不同取代基取代至多兩次，且R6 代表氫或氟，或其醫藥上可接受之鹽。
  5. 根據申請專利範圍第1或2項之式(I)化合物，其中A及E都代表CH Z代表O,n代表數字2,R1 代表(C1 -C4 )-烷基，其可經羥基、(C1 -C4 )-烷氧基、環丙基、環丁基、或苯基取代或經氟取代至多三次，R2 代表氫，R3 代表氰基或(2-羥基乙氧基)羰基，R4 代表甲基，R5 代表氫、(C1 -C4 )-烷基或式-L2 -C(=O)-NH-R13 或-SO2 -R15 之基團，其中L2 代表一個鍵或-CH2 -,R13 代表氫或(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，或(C3 -C6 )-環烷基，且R15 代表(C1 -C4 )-烷基或(C3 -C6 )-環烷基，且R6 代表氫，或其醫藥上可接受之鹽。
  6. 根據申請專利範圍第1或2項之式(I)化合物，其中A及E都代表CH Z代表O,n代表數字2, R1 代表(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，R2 代表氫，R3 代表氰基，R4 代表甲基，R5 代表氫、(C1 -C4 )-烷基或式-CH2 -C(=O)-NH-R13 或-SO2 -R15 之基團，其中R13 代表氫或(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，且R15 代表(C1 -C4 )-烷基或(C3 -C6 )-環烷基，且R6 代表氫，或其醫藥上可接受之鹽。
  7. 根據申請專利範圍第1或2項之式(I)化合物，其在二氫嘧啶環的4-位置上具有式(I-ent )中所示之組態， 其中A及E都代表CH， Z代表O，n代表數字2，R1 代表(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，R2 代表氫，R3 代表氰基，R4 代表甲基，R5 代表氫、(C1 -C4 )-烷基或式-CH2 -C(=O)-NH-R13 或-SO2 -R15 之基團，其中R13 代表氫或(C1 -C4 )-烷基，其可經羥基或(C1 -C4 )-烷氧基取代，且R15 代表(C1 -C4 )-烷基或(C3 -C6 )-環烷基，且R6 代表氫，或其藥學上可接受之鹽。
  8. 根據申請專利範圍第1或2項之式(I)化合物，其係選自下列組成之群組：4-{(4S)-5-乙醯基-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-4-基}-3-(甲基磺醯基)苄腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N-(2-羥基乙基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-醯胺，(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N’,N’- 雙(2-羥基乙基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-肼，(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N-[2-(2-羥基乙氧基)乙基]-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-醯胺，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-{[(3S)-3-羥基吡咯啶-1-基]羰基}-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-{[4-(2-羥基乙基)六氫吡-1-基]-羰基}-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，2-[(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-基]乙醯胺，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(環丙基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3,6-二甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，4-{(4S)-6-甲基-3-(甲基磺醯基)-2,5-二酮基-1-[3-(三氟甲基)苯基]-2,3,4,5,6,7-六氫-1H-吡咯並[3,4-d]嘧啶-4- 基}-3-(甲基磺醯基)苄腈，(4S)-4-[4-氰基-2-(甲基硫烷基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-{4-氰基-2-[(S)-甲基亞磺醯基]苯基}-6-甲基-2-酮基-1-[3-(三氟甲基)-苯基]-1,2,3,4-四氫嘧啶-5-腈，(外消旋性)-1-(2-{4-[4-氰基-2-(甲基磺醯基)苯基]-2,5-二酮基-1-[3-(三氟甲基)苯基]-1,2,3,4,5,7-六氫-6H-吡咯並[3,4-d]嘧啶-6-基}乙基)脲，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-[(3-羥基吖丁啶-1-基)羰基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-3-[(3R)-3-胺基六氫吡啶-1-基]羰基-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-3-{[4-(吡啶-2-基)六氫吡-1-基]羰基}-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N,N-雙(2-羥基丙基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-醯胺，(6S)-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N-(1-羥基-2-甲基丙-2-基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H)-醯胺， (4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-[(4-氟苯基)磺醯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-{[1-(二氟甲基)-5-甲基-1H-吡唑-4-基]磺醯基}-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-[(2-氰基苯基)磺醯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-3-(氰基甲基)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-4-甲基-2-酮基-3-[3-(三氟甲基)-苯基]-3,6-二氫嘧啶-1(2H)-羧酸苄酯，(4S)-4-[4-氰基-2-(乙基磺醯基)苯基]-3,6-二甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(外消旋性)-4-[4-氰基-2-((2-羥基乙基)磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)-苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-{4-氰基-2-[苯基磺醯基]苯基}-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫 嘧啶-5-羧酸2-羥基乙酯，或其藥學上可接受之鹽。
  9. 根據申請專利範圍第1或2項之式(I)化合物，其係選自由下列組成之群組：(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-醯胺，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(6S )-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N-(2-羥基乙基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H )-醯胺，(6S )-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-N ’,N ’-雙(2-羥基乙基)-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H )-肼，2-[(6S )-5-氰基-6-[4-氰基-2-(甲基磺醯基)苯基]-4-甲基-2-酮基-3-[3-(三氟甲基)苯基]-3,6-二氫嘧啶-1(2H )-基]乙醯胺，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-3-[2-酮基-2-(3-酮基六氫吡-1-基)乙基]-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基 -3-{[2-(三氟甲氧基)苯基]磺醯基}-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(乙基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(環丙基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-3,6-二甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，4-{(4S )-6-甲基-3-(甲基磺醯基)-2,5-二酮基-1-[3-(三氟甲基)苯基]-2,3,4,5,6,7-六氫-1H -吡咯並[3,4-d]嘧啶-4-基}-3-(甲基磺醯基)苄腈，(外消旋性)-4-[4-氰基-2-(甲基磺醯基)苯基]-N -(2-羥基乙基)-6-甲基-2,5-二酮基-1-[3-(三氟甲基)苯基]-1,2,4,5,6,7-六氫-3H -吡咯並[3,4-d]嘧啶-3-醯胺，(4S )-4-{4-氰基-2-[(S )-甲基亞磺醯基]苯基}-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3-[(4-氟苯基)磺醯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S-4-[4-氰基-2-(甲基磺醯基)苯基]-3-[(1,2-二甲基-1H-咪唑-4-基)磺醯基]-6-甲基-2-酮基-1-[3-(三氟甲 基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-3-(氰基甲基)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-3-(4-氰基苯基)-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1,3-雙[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，4-(4S )-3,6-二甲基-2,5-二酮基-1-[3-(三氟甲基)苯基]-2,3,4,5,6,7-六氫-1H -吡咯並[3,4-d]嘧啶-4-基-3-(甲基磺醯基)苄腈，(4S )-4-[4-氰基-2-(乙基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(乙基磺醯基)苯基]-3,6-二甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(乙基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈，(4S )-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-羧酸2-羥基乙酯，或其藥學上可接受之鹽。
  10. 根據申請專利範圍第1或2項之式(I)化合物，其具有 (4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-3,6-二甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈之結構，或其藥學上可接受之鹽。
  11. 根據申請專利範圍第1或2項之式(I)化合物，其具有(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-3-(甲基磺醯基)-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈之結構，或其藥學上可接受之鹽。
  12. 根據申請專利範圍第1或2項之式(I)化合物，其具有(4S)-4-[4-氰基-2-(甲基磺醯基)苯基]-6-甲基-2-酮基-1-[3-(三氟甲基)苯基]-1,2,3,4-四氫嘧啶-5-腈之結構，或其藥學上可接受之鹽。
  13. 一種用於製備根據申請專利範圍第1至6項定義的式(I)化合物之方法，其特徵是使式(II)化合物 其中A、E、n、R1 及R2 具有申請專利範圍第1至6項提供之意義，在酸或酸酐存在下，與式(III)化合物 其中R3 及R4 具有申請專利範圍第1至6項提供之意義，及式(IV)化合物 其中Z及R6 具有申請專利範圍第1至6項提供之意義，在3-成份單鍋反應或依序反應而得到式(I-A)化合物 其中A、E、Z、n、R1 、R2 、R3 、R4 及R6 各具有上述之意義，且此化合物在式(I)中的R5 不代表氫之情形下，在鹼存在下與式(V)化合物反應R5A -X (V)，其中R5A 具有申請專利範圍第1至6項中提供R5 之定義，但不代表氫 且X代表一個釋離基，例如鹵基、甲磺酸酯、甲苯磺酸酯或三氟甲基磺酸酯，得到式(I-B)化合物 其中A、E、Z、n、R1 、R2 、R3 、R4 、R5A 及R6 各具有上述之意義，且在此方法中所得的式(I-A)或(I-B)化合物，如果適當時，是經由熟習該項技術者已知的方法分離成其對掌異構物及/或非對掌異構物及/或用合適的(i)溶劑及/或(ii)鹼或酸轉化成其溶劑化物、鹽及/或鹽的溶劑化物。
  14. 根據申請專利範圍第1或2項之化合物，其用於治療及/或預防疾病。
  15. 根據申請專利範圍第1或2項之化合物，其用於治療或預防肺動脈性高血壓(PAH)及其他形式之肺高血壓(PH)、慢性阻塞性肺病(COPD)、急性肺傷害(ALI)、急性呼吸窘迫徵候群(ARDS)、肺氣腫、α-1-抗胰蛋白酵素缺乏症 (AATD)及囊狀纖維化(CF)之方法中。
  16. 根據申請專利範圍第1或2項之化合物，其用於治療或預防支氣管擴張症。
  17. 一種根據申請專利範圍1至6項中任一項定義之化合物之用途，其用於製備供治療或預防肺動脈性高血壓(PAH)及其他形式之肺高血壓(PH)、慢性阻塞性肺病(COPD)、急性肺傷害(ALI)、急性呼吸窘迫徵候群(ARDS)、肺氣腫、α-1-抗胰蛋白酵素缺乏症(AATD)及囊狀纖維化(CF)之藥劑。
  18. 一種藥劑，其包含根據申請專利範圍第1至6項中任一項定義之化合物結合一或多種惰性無毒之藥學上可接受的佐劑。
  19. 一種藥劑，其包含根據申請專利範圍第1至6項中任一項定義之化合物結合一或多種選自包括激酶抑制劑、基質金屬蛋白酶抑制劑、可溶性鳥苷酸環化酶之刺激劑及活化劑、環前列腺素同系物、內皮素受體拮抗劑、磷酸二酯酶抑制劑、β-腎上腺素受體激動劑、抗膽鹼激性藥物及糖皮質激素之其他活性化合物。
  20. 根據申請專利範圍第18或19項之藥劑，其用於治療或預防肺動脈性高血壓(PAH)及其他形式之肺高血壓(PH)、慢性阻塞性肺病(COPD)、急性肺傷害(ALI)、急性呼吸窘迫徵候群(ARDS)、肺氣腫、α-1-抗胰蛋白酵素缺乏症(AATD)及囊狀纖維化(CF)。
  21. 根據申請專利範圍第18或19項之藥劑，其用於治療及/ 或預防支氣管擴張症。
TW097149556A 2007-12-20 2008-12-19 ４－（４－氰基－２－硫基芳基）二氫嘧啶酮類及其用途 TWI455715B (zh)

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