CN1182739A - N-苄基唑鎓衍生物 - Google Patents
N-苄基唑鎓衍生物 Download PDFInfo
- Publication number
- CN1182739A CN1182739A CN97118228A CN97118228A CN1182739A CN 1182739 A CN1182739 A CN 1182739A CN 97118228 A CN97118228 A CN 97118228A CN 97118228 A CN97118228 A CN 97118228A CN 1182739 A CN1182739 A CN 1182739A
- Authority
- CN
- China
- Prior art keywords
- triazole
- bromide
- phenyl
- benzyl
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- -1 azole compound Chemical class 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims abstract description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 5
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 55
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
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- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 2
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- 239000012871 anti-fungal composition Substances 0.000 claims description 2
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- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
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- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 claims description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
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Abstract
通式(Ⅰ)的N-苄基唑鎓衍生物,其中Q是具有抗真菌活性的式Ⅱ唑系化合物的剩余部分,Z是氮或次甲基;R1和R2彼此独立地是氢原子或-OY基团[其中Y是生理条件下易于水解的基团];R3和R4彼此独立地是氢或卤原子、低级烷基、低级烷氧基、低级烷硫基、(低级烷基羰基)硫甲基、羧基或甲氧羰基;并且X是可药用的阴离子,以及通式(Ⅰ)化合物的盐、水合物或溶剂化物,具有抗真菌特性。
Description
尽管目前有许多唑系化合物被应用于全身性真菌病,但对大部分全身性真菌病(包括播散性曲霉病)的效果,安全性、以及可以制成口服或非肠道制剂,它们之中没有一种完全符合必需的临床需要。具体地讲,为了治疗严重的全身性真菌病,对于唑系化合物非肠道给药的需求正在增加。在市场上销售以及正在开发的大部分唑系化合物是高亲脂性分子,从而很难制成非肠道制剂。
本发明涉及新的水溶性唑系化合物,该化合物可用于全身性真菌病的治疗并适合于口服和非肠道给药,本发明还涉及这些化合物的制备方法、含有它们的抗真菌组合物以及治疗真菌病的方法。
更具体地讲,本发明涉及通式(I)所代表的新的唑系化合物:其中
Q是具有抗真菌活生的式II唑系化合物的剩余部分:Z 是氮或次甲基;R1和R2 彼此独立地是氢原子或-OY基团[其中Y是生理条
件下易于水解的基团];
R3和R4 彼此独立地是氢或卤原子、低级烷基、低级烷氧
基、低级烷硫基、(低级烷基羰基)硫甲基、羧
基或甲氧羰基;并且
X- 是可药用的阴离子,以及通式(I)化合物的盐、水合物或溶剂化物。
-(其中A为氢原子或直链或支链C1-C5烷基,B为直链或支链C1-
C4亚烷基,-CH2-CONH-CH2或-CH2CH2CH2-CH(NH2)-);
R3和R4各自独立为氢或卤原子或低级烷氧基,
Z、Q和X-定义如上。
在上述式I和I′的唑化合物中尤其优选的是其中Q为下式组的那些化合物或其中D为低级烷酰基或下式基团R7为卤原子,R8为直链或支链C1-C4烷基。以下将对以上所定义的通式(I)中的各基团进行详细说明:式II的唑系化合物的例子是:
d1-1-[2-(2,4-二氯苯基)-2-[(2,4-二氯苯基)甲氧基]乙基]-1H-咪唑,
d1-顺-1-乙酰基-4-[4-[2-(2,4-二氯苯基)-2-(咪唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]哌嗪,
d1-2-[(RS)-仲丁基]-4-[4-[4-[4-[(2R,4S)-2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基-1-哌嗪基]苯基-3H-[1,2,4]三唑-3-酮,
2-[(1R,2R)-2-(2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基]-4-[4-(2,2,3,3-四氟丙氧基)苯基]-3(2H,4H,)-1,2,4-三唑酮,
(+)-2-(2,4-二氟苯基)-3-甲基-1-(1H-1,2,4-三唑-1-基)-3-(6-(1H-1,2,4-三唑-1-基)哌嗪-3-基硫)丁-2-醇,
(2R)-2-(2,4-二氟苯基)-1-[3-[(E)-4-(2,2,3,3-四氟丙氧基)苯乙烯基]-(1,2,4-三唑-1-基)-3-(1,2,4-三唑-1-基)]丙-2-醇,
d1-苏-2-(2,4-二氟苯基)-3-甲基-磺酰基-1-(1H-1,2,4-三唑-1-基)-丁-2-醇,
(-)-4-[4-[4-[4-[[5-(2,4-二氯苯基)-5-(1H-1,2,4-三唑-1-基甲基)四氢呋喃-3-基]甲氧基]苯基]哌嗪基]苯基]-2-[(1S,2S)-1-乙基-2-羟丙基]-3H-1,2,4-三唑-3-酮,
(2R,3R)-3-[4-(4-氰基苯基)噻唑-2-基)]-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)-丁-2-醇,
3-甲基-3-甲硫基-1-(1,2,4-三唑-1-基)-2-(三氟甲基苯基)-丁-2-醇,
1[[(1R,2S,6R)-2-甲氧基-3,3-二甲基-6-(2-对甲苯基乙基)环己基]-甲基]-1H-[1,2,4]-三唑,
(5R,6R)-2,2-二甲基-6-[(1H-1,2,4-三唑-1-基)甲基]-5-[[4-(三氟甲氧基)苯氧基]甲基]环己酮O-甲基肟等。
R1和R2彼此独立地是氢原子或-OY基团[其中Y是生理条件下易于水解的基团]。
以上的在生理条件下易于水解的基团Y优选为氨基酸的酰基残基或下式所代表的基团,
R5CO-或(R6O)2PO-
其中R5是氢、低级烷氧基、可选择性带有羧基取代基的低级烷基、氨
基、低级烷氨基、二低级烷氨基或芳基;并且R6是氢或低级烷基。
本说明书中使用的术语“低级烷基”优选指1至4个碳原子的直链或支链烷基链,例如甲基、乙基、正丙基、异丙基、丁基、异丁基、或叔丁基。
术语“低级烷氧基”优选指1至4个碳原子的直链或支链烷氧基链,例如甲氧基、乙氧基、正丙氧基、并丙氧基、正丁氧基、异丁氧基。
术语“芳基”指取代或未取代的芳基基团,例如苯基、甲氧苯基、吡啶基、吡嗪基或呋喃基。优选Y是甲酰基、乙酰基、丙酰基、异丁酰基、新戊酰基、琥珀酰基、苯甲酰基、烟酰基、磷酰基、二甲基磷酰基、氨基乙酰基、3-氨基丙酰基、4-氨基丁酰基、(2-氨基-乙酰氨基)-乙酰、(S)-2,5-二氨基戊酰基、(S)-2-氨基丙酰基、(S)-吡咯烷-2-羰基、(甲氨基)乙酰基、(丙氨基)乙酰基、(S)-2-(甲氨基)丙酰基、3-(甲氨基)丙酰基、(S)-2-氨基-3-甲基丁酰基、(异丙氨基)乙酰基、(2S)-2-(乙氨基)丙酰基、(乙氨基)乙酰基等。
R3和R4彼此独立地是氢或卤原子、低级烷基、低级烷氧基、低级烷硫基、(低级烷基羰基)硫甲基、羧基或甲氧羰基。
术语“卤素”指氟、氯或溴。
术语“低级烷硫基”指1至4个碳原子的直链或支链烷硫基链,例如甲硫基、乙硫基、正丙硫基。
术语“低级烷基”和“低级烷氧基”同上所定义。
优选R3和R4彼此独立地是甲基、甲氧基或氯。
X-是可药用无机酸的阴离子,例如氯离子、溴离子、硫酸根离子;或有机酸,例如脂肪族、芳香族或芳香脂肪族羧酸或磺酸的阴离子,例如乙酸基、三氟乙酸基、甲磺酸基阴离子等。
本发明特别优选的化合物是:
d1-1-(4-乙酰氧基-3,5-二甲基苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲基苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3,5-二甲基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲氧基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-(4-异丁酰氧基-3,5-二甲基苄基)-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-(4-新戊酰氧基-3,5-二甲基苄基)-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-[4-(2,2-二甲基丙酰氧基)苄基]-3H-咪唑-1-鎓溴化物,
d1-4-(4-苯氧基-3,5-二甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-[4-(吡啶-3-羰酰氧基)-3,5-二甲基苄基]-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基-3,5-二甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基-3-甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-1-[4-(4-{4-[4-(1-仲丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}-苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-4-(4-己酰氧基-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓甲磺酸盐,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-{5-氧代-4-[4-(2,2,3,3-四氟丙酰氧基)苯基]-4,5-二氢-[1,2,4]三唑-1-基}丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-甲基-3-(6-[1,2,4]三唑-1-基-哒嗪-3-基硫烷基(sulfanyl))丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-(3-{(Z)-2-[4-(2,2,3,3-四氟丙酰氧基)苯基]乙烯基}-[1,2,4]三唑-1-基}丙基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-甲磺酰基丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
(2R,3R)-4-(4-氨基乙酰氧基-2-羧基苄基)-1-[3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(吡咯烷-2-羰酰氧基)-苄基]-1-[-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-(4-氨基乙酰氧基-3,5-二甲基苄基)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-(3-氨基丙酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-(4-氨基-丁酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-(2-氨基乙酰基)氨基]乙酰氧基]-3,5-二甲基苄基]-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-[(S)-2,5-二氨基戊酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
4-[4-[(S)-2-氨基-丙酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[3,5-二甲基-4-[(甲氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[3,5-二甲基-4-[(丙氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-2-(甲氨基)丙酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基-丁基]-4-[3,5-二甲基-4-[3-(甲氨基)丙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
4-[4-[(S)-2-氨基-3-甲基-丁酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-丁基]-4-[4-(异丙氨基)乙酰氧基]-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(2S)-4-[2-(乙氨基)丙酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-(乙氨基)乙酰氧基]-3,5-二甲基苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[2-羟基-3-甲基-3-甲基硫烷基1-2-(4-三氟甲基苯基)丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(1R,6R)-2-甲氧亚氨基-3,3-二甲基-6-[(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(1R,2S,6R)-2-甲氧基-3,3-二甲基-6-(2-对甲苯基-乙基)环己基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓溴化物盐酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓氯化物盐酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓溴化物氢溴酸盐。
通式(I)所代表的新的唑系化合物及其盐、水合物或溶剂化物可以通过以下方法生产:A)将具有抗真菌活性的通式(II)的唑系化合物与通式(III)的化合物反应其中R1和R2彼此独立地是氢原子或-OY基团[其中Y是生理条件下易
于水解的基团];R3和R4彼此独立地是氢或卤原子、低级烷基、低级
烷氧基、低级烷硫基、(低级烷基羰基)硫甲基、羧基或甲氧羰基;
并且L是离去基团;或者B)将如上所定义的通式(II)的化合物与R1或R2之一是羟基的通式(III)的化合物反应,随后将生成的化合物与式R5COL或(R6O)2POL的化合物反应,其中R5CO是N-保护的氨基酸的酰基残基,或者R5是氢、低级烷氧基、可选择性带有羧基取代基的低级烷基、氨基、带或不带保护基的低级烷氨基、二低级烷氨基或芳基;R6是氢或低级烷基,并且L是离去基团,例如羟基、氯、溴,OCOR5、甲磺酰基、对甲苯磺酰基等。
通式(II)化合物与通式(III)化合物的反应可以在溶剂中进行,所述溶剂是例如二氯甲烷、氯仿、苯、甲苯、乙腈、四氢呋喃、二氧六环或二甲基甲酰胺,优选氯仿、乙腈或二甲基甲酰胺。
上述苄基化反应的反应时间可以在相对宽的范围内变化。反应通常可以在0℃至100℃之间的温度下反应,优选在0℃至50℃之间。
在方法B中,酰化或磷酰化可以通过本领域技术人员公知的方法用游离酸在缩合剂如1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐等的存在下进行;或用酰卤、酸酐、混合酸酐、烷氧羰基卤化物、二烷氧基磷酰氯或磷酰氯在酸的受体(例如三乙胺、吡啶、甲基吡啶、二甲基吡啶、二甲氨基吡啶或碱金属碳酸盐)的存在下进行。
优选将式III化合物的R5中含有的氨基用合适的氨基保护基(如叔丁氧羰基)保护。
随需要,可以在反应结束后通过本领域技术人员公知的方法除去保护基。
式I的化合物可以含有氨基酸酯取代基R1和/或R2,这些取代基可形成酸加成盐。术语“式I化合物的盐”指如下酸加成盐。这些盐可以是由可药用酸生成的,所述酸如以上对符号X-的描述。成盐可以在脱除保护基的同时进行,也可以通过已知的方法专门进行。
水合作用可以在生产过程中进行,也可以通过最初无水产物的吸湿性而逐渐完成。与可药用溶剂如乙醇的溶剂化物可以在例如结晶的过程中得到。
与通式(II)所代表的已知的抗真菌唑系化合物相比,通式(I)所代表的新的唑系化合物及其水合物或溶剂化物在水中的溶解度要大的多(参见表1)。
表1
化合物(实施例号) | 溶解度(mg/ml) | 溶剂* |
1 | 1.0 | b |
2 | 0.4 | b |
3 | 0.4 | b |
4 | >2.0 | a |
5 | >1.0 | a |
6 | 6.5 | a |
7 | >1.0 | a |
8 | 14.0 | a |
9 | >2.0 | a |
10 | >2.0 | a |
11 | 6.0 | a |
12 | 5.0 | a |
13 | 0.5 | b |
*溶剂a=蒸馏水,溶剂b=Mellvaine缓冲液(pH8.02)
另外,新的唑系化合物可以在水溶液中于室温保持化学稳定达三天以上,但在小鼠、大鼠、猴或人血浆中则可以有效地转变为式(II)的化合物。
如表2所示,通式(I)的代表性新唑系化合物在人血浆中分别转变成了酮康唑和伊曲康唑。将式(I)化合物以10μg/ml的浓度与人血浆一起在37℃下保温120分钟。表2.新的唑系化合物在人血浆中向酮康唑(KCZ)和伊曲康唑(ICZ)的转变
表2
实施例号 | 转变半衰期(分钟) | 保温时间(分钟) | 观测值(%) | |
Comp.I<5<519<5 | KCZ891007480 | |||
911410 | <1<18.43.5 | 552010 | ||
1 | 53 | 60 | 47 | ICZ |
28 |
表3给出了本发明化合物的体内效果。用F344/DuCrj品系的雄性Fisher大鼠作为试验性感染模型,例如全身性念珠菌病、全身性曲霉病和肺曲霉病模型。将免疫活性的4周龄大鼠通过用白色念珠菌分生孢子以5×106/只大鼠或用烟曲霉分生孢子以6×105/只大鼠经尾静脉感染引发全身性念珠菌病或全身性曲霉病。对于肺曲霉病模型,先将大鼠用醋酸可的松进行免疫抑制,然后以2×105/只进行气管内感染。对全身性曲霉病和肺曲霉病的治疗,在第一天进行两次,然后在随后的4天内每日一次(Id.i.+4q.d.);对于全身性念珠菌病的大鼠,治疗在感染后的0、4、24和48小时进行(Id.i.d.+2q.d.)。在感染后的第14天测定50%有效量(ED50)。
表3
(μmol/kg)
全身性含球菌病 肺曲霉病 全身性曲霉病
i.v. p.o. i.v. p.o. i.v. p.o.实施例16 3.5 <2.1 17 18 >35 >55实施例23 4.6 4.7 8.0 17 17 19伊曲康唑 n.t. n.t. n.t. n.t. n.t. 17氟可那唑 n.t. >2.9 n.t. n.t. n.t. n.t.
因此,本发明的通式(I)所代表的水溶性唑系抗真菌剂及其盐、水合物或溶剂化物在非常宽的剂量范围内对于小鼠的各种真菌感染(包括曲霉病)口服和非肠道给药均具有很强的抗真菌活性,可用作抗真菌剂。
本发明还涉及含有通式(I)的唑系化合物及其盐、水合物或溶剂化物的药物组合物。
式(I)的唑系化合物及其盐、水合物或溶剂化物是非常有效的抗真菌剂。它们对多种真菌种有效,包括念珠菌属、新隐型球酵母、曲霉属、发癣菌属、小孢子菌属、外瓶柄霉属、皮炎芽生菌和英膜组织胞浆菌。
因此,本发明的化合物可用于动物以及人真菌病的局部和全身性治疗。例如,它们可用于治疗由例如念珠菌、发癣菌或小孢子菌引起的局部和粘膜真菌感染。它们还可用于治疗由例如念珠菌属、新隐型球酵母、曲霉属、副球孢子菌属、孢子丝菌属、外瓶柄霉属、芽生菌属或组织胞浆菌属引起的全身性真菌感染。
为了临床应用,可将式(I)的唑系化合物及其盐、水合物或溶剂化物单独给药,但通常都是以适合于具体应用及所需目的的药物组合物的形式给药,所述药物组合物通过将赋性剂、粘合剂、润滑剂、崩解剂、包衣材料、乳化剂、悬浮剂、溶剂、稳定剂、吸收促进剂和/或软膏基质混合进行配制。该组合物可进行口服、注射、直肠或局部给药。
用于口服给药的药物制剂可以是颗粒剂、片剂、糖衣片、胶囊、丸剂、悬浮剂或乳剂。为了进行非肠道注射(例如静脉内、肌肉内或皮下),可将式(I)的唑系化合物以无菌水溶液形式使用,所述水溶液可含有其它物质如盐或葡萄糖以维持溶液的渗透压。该唑系化合物还可以以栓剂或阴道栓的形式使用,或可以将它们以洗剂、溶液剂、霜剂、软膏或粉剂的形式局部应用。
当以单、双或多剂量通过口服或非肠道途径给药时,式(I)的唑系化合物的每日剂量水平从大约0.1至大约50mg/kg(分剂量)。因此,化合物的片剂或胶囊中可以含有大约5mg至大约0.5g用于给药的活性化合物。在任何情况下,实际剂量均可由医生来确定并可根据年龄、体重和具体患者的反应而改变。
另外,(I)的唑系化合物及其盐、水合物或溶剂化物对多种植物致病真菌有效,所述真菌包括,例如Pyricularia oryza、瓜果腐霉、链格孢属和宛氏拟青霉。
因此,可将它们应用于农业及园艺领域,优选以适合于具体应用及所需目的的组合物的形式给药,例如粉剂、或颗粒剂、拌种、含水溶液剂、分散剂或乳剂、浸剂、喷雾剂或气雾剂。所述组合物中可以含有农业及园艺领域已知并可以接受常规载体、稀释剂或添加剂。也可将具有除草或杀虫剂活性的其它化合物、或其它抗真菌剂掺入组合物中。该化合物及组合物可以以多种方式应用,例如,可将它们直接施用于植物的叶、茎、枝、种子或根,或施用于土壤或其它生长培养基,它们不仅可用于根除疾病,而且还可用于防止植物或种子受到攻击。
以下实施例说明了制备本发明化合物的优选方法,但并不对本发明的范围构成限定。
实施例14-(4-乙酰氧基-3,5-二甲基苄基)-1-[4-(4-(4-[4-(1-(2-丁基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物;
向1g 3,5-二甲基-4-羟基溴化苄的CHCl3-CH3CN(7/3ml)溶液中加入400mg伊曲康唑并在室温下搅拌15小时。真空蒸除溶剂并将残余物在醋酐-吡啶(4/4ml)中于室温下搅拌2小时。将混合物浓缩并进行硅胶柱色谱(200埃,溶剂:CH2Cl2/MeOH=10/1)得到4-(4-乙酰氧基-3,5-二甲基苄基)-1-[4-(4-(4-[4-(1-(2-丁基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基)苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物(507mg,93%,无定形粉末);FAB-MS:m/z881(M-Br)+;1H-NMR(CDCl3)d0.90(3H,t,J=7.3Hz),1.39(3H,d,J=6.9Hz),1.69~1.77(1H,m),1.81~1.87(1H,m),2.02(3H,s),2.10(3H,s),2.32(3H,s),3.22~3.29(2H,m),3.31~3.38(1H,m),3.66~3.74(1H,m),3.85~3.91(1H,m),4.11~4.15(1H,m),4.28~4.33(2H,m),4.35~4.45(1H,m),5.02(1H,d,J=14.2Hz),5.03(1H,d,J=14.5Hz),5.13(1H,d,J=14.5Hz),5.54(1H,d,J=14.2Hz),6.88~7.04(8H,m),7.29(1H,dd,J=2.0,7.3Hz),7.45(1H,d,J=8.9),7.47(1H,d,J=2.0),7.62(1H,s),7.68(1H,d,J=8.2),8.02(1H,s),11.5~11.6(1H,brs).
实施例2-8的下列化合物以与实施例1相似的方式制得。
实施例24-(4-(吡啶-3-羰酰氧基)-3,5-二甲基苄基)-1-[4-(4-{4-[4-(1-(2-丁基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物;外观:无定形粉末; MALDI-TOF-MS:m/z945(M-Br)+;1H-NMR(CD3OD)d0.88(3H,t,J=7.6Hz),1.36(3H,d,J=5.3Hz),1.73(2H,m),2.16(6H,s),3.30(8H,m),3.63~4.44(6H,m),5.18(2H,s),5.48(2H,s),6.84~8.56(18H,m),9.01(1H,s).
实施例34-(4-苯甲酰氧基-3,5-二甲基苄基)-1-[4-(4-{4-[4-(1-(2-丁基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物;外观:无定形粉末;
FAB-MS:m/z943(M-Br)+;1H-NMR(d6-DMSO)d0.80(3H,t,J=7.3Hz),1.29(3H,d,J=6.6Hz),1.67(2H,m),2.11(6H,s),3.40(8H,brs),3.77(2H,m),3.95(2H,m),4.12(1H,m),4.40(1H,m),5.08(2H,s),5.42(2H,s),6.90(2H,brd),7.11~7.80(14H,m),8.17(2H,d,J=7.2Hz),8.35(1H,s),9.40(1H,s),10.4(1H,s).
实施例41-(4-乙酰氧基-3,5-二甲基-苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基-哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-噻唑-1-鎓溴化物;外观:浅棕色油; FAB-MS:m/z707(M-Br)+;1H-NMR(CDCl3)d2.11(6H,s),2.14(3H,s),2.33(3H,s),3.07(4H,m),3.62(2H,m),3.68(1H,dd,J=4.6,10.2Hz),3.77(2H,m),3.89~3.95(2H,m),4.02(1H,dd,J=4.0,11.6Hz),4.37(1H,m),4.85(2H,s),5.08(1H,d,J=14.2Hz),5.48(1H,d,J=14.2Hz),6.81(2H,d,J=8.9Hz),6.91(2H,d,J=8.9Hz),6.99(1H,s),7.05(2H,s),7.18(1H,s),7.31(1H,dd,J=2.0,8.6Hz),7.47(1H,d,J=2.0Hz),7.69(1H,d,J=8.6Hz),10.42(1H,s).
实施例53-[(2R*,4S*)-4-[4-(4-乙酰基-哌嗪-1-基)-苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1-(4-异丁酰氧基-3,5-二甲基-苄基)-3H-咪唑-1-鎓溴化物;外观:透明薄膜;
FAB-MS:m/z735(M-Br)+;1H-NMR(CDCl3)d1.34(6H,d,J=6.9Hz),2.09(6H,s),2.14(3H,s),2.85(1H,sept,J=6.9Hz),3.06(4H,m),3.61(1H,dd,J=4.9,5.2Hz),3.67(1H,dd,J=4.0,10.6Hz),3.97(1H,dd,J=4.9,5.2Hz),3.90(2H,m),3.97(1H,dd,J=4.0,10.6Hz),4.35(1H,m),4.83(2H,s),5.15(1H,d,J=14.5Hz),5.49(1H,d,J=14.5Hz),6.80(2H,d,J=8.9Hz),6.91(2H,d,J=8.9Hz),7.08(2H,s),7.10(1H,d,J=2.0Hz),7.19(1H,brs),7.30(1H,dd,J=2.0,8.3Hz),7.46(1H,d,J=2.0Hz),7.67(1H,d,J=8.3Hz),10.32(1H,brs).
实施例61-(4-乙酰氧基-3,5-二氯-苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基-哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-咪唑-1-鎓溴化物;外观:浅棕色油; FAB-MS:m/z747(M-Br)+;1H-NMR(CDCl3)d2.14(3H,s),2.39(3H,s),3.07(4H,m),3.62(3H,m),3.78(2H,m),3.89(1H,m),3.97(1H,m),4.10(1H,m),4.39(1H,m),4.75(1H,d,J=16.2Hz),4.83(1H,d,J=16.2Hz),5.11(1H,d,J=14.8Hz),5.77(1H,d,J=14.8Hz),6.79(2H,d,J=9.1Hz),6.92(2H,d,J=9.1Hz),7.01(m,s),7.22(1H,s),7.33(1H,dd,J=8.6,2.0Hz),7.42(2H,s),7.48(1H,d,J=2.0Hz),7.68(1H,d,J=8.6Hz),10.52(1H,s).
实施例7d1-1-(4-乙酰氧基-3,5-二氯-苄基)-3-[2-(2,4-二氯-苄氧基)-2-(2,4-二氯-苯基)-乙基]-3H-咪唑-1-鎓溴化物;外观:无定形粉末; FAB-MS:m/z593(M-Br)+;1H-NMR(CD3OD)d 2.15(6H,s),2.35(3H,s),4.41~4.58(4H,m),5.22(1H,dd,J=3.5,7.8Hz),5.32(2H,s),7.16(2H,brs),7.24~7.56(7H,m),7.66(1H,d,J=1.0Hz),9.00(1H,brs).
实施例84-(4-乙酰氧基-3,5-二甲基苄基)-1-[(1R,2S,6R)-2-甲氧基-3,3-二甲基-6-(2-对甲苯基-乙基)环己基甲基]-1H-[1,2,4]三唑-4-鎓溴化物;外观:无色油; MALDI-TOF-MS:m/z518(M-Br)+;1H-NMR(CDCl3)d0.84(3H,s),1.02(3H,s),1.10~1.30(3H,m),1.37~1.42(1H,m),1.45~1.65(1H,m),1.71(1H,m),1.93(2H,m),2.15(6H,s),2.31(3H,s),2.34(3H,s),2.51(1H,m),2.71(1H,m),2.83(1H,d,J=10.9Hz),3.50(3H,s),4.49(1H,d,J=18.9Hz),4.60(1H,dd,J=18.9,5.9Hz),5.58(1H,d,J=14.4Hz),5.66(1H,d,J=14.4Hz),7.08(4H,s),7.21(2H,s),8.31(1H,s),11.64(1H,s).
实施例91-(4-乙酰氧基苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-咪唑-1-鎓溴化物的制备
向28mg 4-乙酰氧基溴化苄的1.5ml CHCl3溶液中加入30mg酮康唑并将该混合物在室温下搅拌16小时。真空蒸除溶剂。经硅胶柱色谱(WakogelC-200,溶剂:CH2Cl2/MeOH=10/1)得到1-(4-乙酰氧基苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-咪唑-1-鎓溴化物(32mg,76%,无色油);
MALDI-TOF-MS:m/z679(M-Br)+;1H-NMR(CDCl3)d2.14(3H,s),2.28(3H,s),3.05(4H,m),3.60~3.89(8H,m),4.33(1H,m),4.80(2H,s),5.37(1H,d,J=14.5Hz),5.61(1H,d,J=14.5Hz),6.78(2H,d,J=9.1Hz),6.92,(2H,d,J=9.1Hz),7.03(2H,d,J=8.6Hz),7.24~7.63(7H,m),10.1(1H,s).
实施例10-13的下列化合物以与实施例9相似的方式制得。
实施例103-[(2R*,4S*)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1-[4-(2,2-二甲基丙酰氧基)苄基]-3H-咪唑-1-鎓溴化物;外观:无定形粉末; MALDI-TOF-MS:m/z721(M-Br)+;1H-NMR(CDCl3)d1.34(9H,s),2.14(3H,s),3.06(4H,m),3.60-4.00(8H,m),4.36,(1H,m),4.81(2H,s),5.29(1H,d,J=14.4Hz),5.62(1H,d,J=14.4Hz),6.80(2H,d,J=9.3Hz),6.92(2H,d,J=9.3Hz),7.02(2H,d,J=8.6Hz),7.15(1H,brs),7.20(1H,brs),7.28(1H,brs),7.43(2H,d,J=8.6Hz),7.46(1H,brs),7.65(1H,d,J=8.3Hz),10.3(1H,s).
实施例111-(4-乙酰氧基-3-甲基-苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-咪唑-1-鎓溴化物;外观:透明薄膜;
FAB-MS:m/z693(M-Br)+;1H-NMR(CDCl3)d2.13(6H,s),2.31(3H,s),3.06(4H,dt,J=5.0Hz),3.62(2H,t,J=5.0Hz),3.66(1H,dd,J=4.6Hz),3.76(2H,t,J=9.0Hz),3.88(2H,m),3.94(1H,dd,J=4.6Hz),4.36(1H,m),4.81(2H,s),5.26(1H,d,J=14.0Hz),5.55(1H,d,J=14.0Hz),6.79(2H,d,J=9.0Hz),6.91(2H,d,J=9.0Hz),6.96(1H,d,J=8.0Hz),7.22(2H,brs),7.23(1H,dd,J=2.0,8.0Hz),7.29(1H,dd,J=2.0,8.0Hz),7.39(1H,brd),7.45(1H,d,J=2.0Hz),7.64(1H,d,J=8.0Hz),10.21(1H,s).
实施例121-(4-乙酰氧基-3-甲氧基-苄基)-3-[(2R*,4S*)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-3H-咪唑-1-鎓溴化物;外观:无定形粉末; MALDI-TOF-MS:m/z709(M-Br)+;1H-NMR(CDCl3)d2.14(3H,s),2.30(3H,s),3.06(4H,m),3.62(2H,m),3.65(1H,dd,J=4.6,10.2Hz),3.77(2H,m),3.86(3H,s),3.88-3.94(2H,m),4.03(1H,dd,J=4.0,11.6Hz),4.36(1H,m),4.80(2H,s),5.12(1H,d,J=14.2Hz),5.54(1H,d,J=14.2Hz),6.80(2H,d,J=8.9Hz),6.81(1H,s),6.92(2H,d,J=8.9Hz),6.95(1H,s),7.07(1H,s),7.17(1H,s),7.31(1H,dd,J=2.0,8.6Hz),7.44(m,d,J=2.0Hz),7.47(1H,J=2.0Hz),7.66(1H,d,J=8.6Hz),10.41(1H,s).
实施例13d1-1-[4-(4-(4-[4-(1-仲丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}-苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-4-(4-己酰氧基-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓甲磺酸盐;外观:无定形粉末; FAB-MS:m/z937(M-MsO)+;1H-NMR(CDCl3)δ0.80~1.00(6H,m),1.42(3H,d,J=6.6Hz),1.20~1.50(6H,m),1.70~2.00(2H,m),2.10(9H,s),2.58(2H,t,J=7.6Hz),3.26(4H,m),3.36(4H,m),3.62~3.70(2H,m),3.75(1H,m),4.10~4.50(3H,m),4.84(1H,d,J=14.2Hz),5.00(1H,d,J=13.8Hz),5.12(1H,d,J=13.8Hz),5.44(1H,d,J=14.2Hz),6.90(2H,d,J=8.9Hz),6.94(2H,s),6.99(2H,d,J=8.9Hz),7.03(2H,d,J=8.9Hz),7.31(1H,dd,J=8.6,2.0Hz),7.43(2H,d,J=8.9Hz),7.48(1H,d,J=2.0Hz),7.62(1H,s),7.71(1H,d,J=8.6Hz),7.90(1H,s),11.30(1H,s).
实施例14(2R,3R)-4-(4-乙酰氧基-3,5-二甲基苄基)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物;外观:无定形粉末; FAB-MS:m/z614(M-Br)+;1H-NMR(CD3OD)d 1.24(3H,d,J=6.9Hz),2.25(6H,s),2.36(3H,s),4.30(1H,q,J=6.9Hz),4.64(1H,d,J=14.2Hz),5.10(1H,d,J=14.2Hz),5.31(2H,s),6.75-7.27(3H,m),7.10(2H,s),7.82(2H,d,J=8.3Hz),8.09(1H,s),8.18(2H,d,J=8.2Hz),8.73(1H,s),9.95(1H,s)
实施例15(2R,3R)-4-(4-氨基乙酰氧基-2-羧基苄基)-1-[3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐:a)3-(叔丁氧羰酰氨基乙酰氧基)-6-(溴甲基)苯甲酸叔丁酯
将200mg 3-羟基-6-(羟甲基)苯甲酸叔丁酯、187mg Boc-甘氨酸、65mg4-二甲氨基吡啶和245mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐在8mL二氯甲烷中的混合物在室温下搅拌15小时,然后用40mL二氯甲烷稀释。将混合物用1N HCl洗涤并用无水Na2SO4干燥。除去溶剂得到180mg 3-(叔丁氧羰酰氨基乙酰氧基)-6-羟甲基苯甲酸叔丁酯。
向650mg 3-(叔丁氧羰酰氨基乙酰氧基)-6-羟甲基苯甲酸叔丁酯和580mg三苯膦的溶液中加入848mg四溴化碳,然后将混合物在室温下搅拌2小时。将混合物用二氯甲烷稀释并用水洗涤。将有机层用无水Na2SO4干燥并真空浓缩。硅胶柱色谱得到322mg无色油状的3-(叔丁氧羰酰氨基乙酰氧基)-6-(溴乙基)苯甲酸叔丁酯;1H NMR(CDCl3)d1.34(9H,s),1.51(9H,s),4.08(2H,br.d,J=5.6Hz),4.80(2H,s),4.95(1H,br.s),7.12(1H,dd,J=8.6,2.6Hz),7.34(1H,d,J=8.6Hz),7.51(1H,d,J=2.6Hz)b)根据与实施例1相似的方法,从(1R,2R)-4-[2-[2-(2,4-二氟-苯基)-2-羟基-1-甲基-3-[1,2,4]三唑-1-基-丙基]-噻唑-4-基]-苄腈和3-(叔丁氧羰酰氨基乙酰氧基)-6-(溴甲基)苯甲酸叔丁酯制得白色固体状(2R,3R)-4-(4-氨基乙酰氧基-2-羧基苄基)-1-[3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐。外观:白色粉末; FAB-MS:m/z645(M-Br)+;1H-NMR(CD3OD)d 1.22(3H,d,J=7.3Hz),4.21(2H,s),4.28(1H,q,J=7.3Hz),4.61(1H,d,J=14.2Hz),5.09(1H,d,J=14.2Hz),5.68(1H,d,J=14.0Hz),5.75(1H,d,J=14.0Hz),6.78-7.28(3H,m),7.55(1H,dd,J=2.3,8.6Hz),7.64(1H,d,J=8.6Hz),7.81(2H,d,J=8.5Hz),8.03(1H,d,J=2.3Hz),8.10(1H,s),8.17(2H,d,J=8.5Hz),8.67(1H,s),9.80(1H,s)
实施例161-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(吡咯烷-2-羰酰氧基)-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐通过下述方法A或B制得;i)方法A:
向3g 3,5-二甲基-4-羟基苄基溴化物的CH3CN(30mL)溶液中加入1.2g(1R,2R)-4-[2-[2-(2,4-二氟-苯基)-2-羟基-1-甲基-3-[1,2,4]三唑-1-基-丙基]-噻唑-4-基]-苄腈并在室温下连续搅拌2小时。滤出沉淀并用乙醚洗涤得到1.37g(81%产率)白色固体状1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-羟基)苄基-1H-[1,2,4]三唑-4-鎓溴化物(Ro09-3846)。
向30g 1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-羟基苄基)-1H-[1,2,4]三唑-4-鎓溴化物、10.9g Boc-(L)-脯氨酸和2.8g N,N-二甲氨基吡啶在1.2L二氯甲烷的混合物中加入17.6g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐并将混合物在室温下搅拌1.5小时,然后真空浓缩。将残余物在硅胶上进行色谱分离(Wakogel C-200,溶剂:CH2Cl2/MeOH=14/1)得到30.9g(79%收率)白色固体状1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(N-叔丁氧羰基吡咯烷-2-羰酰氧基)-苄基]-1H-[1,2,4]三唑-4-鎓溴化物。
将30.9g 1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(N-叔丁氧羰基吡咯烷-2-羰酰氧基)-苄基]-1H-[1,2,4]三唑-4-鎓溴化物于室温下在600mL 10%TFA-二氯甲烷中搅拌5小时,然后真空蒸除溶剂。将残余物用乙醚稀释并用乙醚洗涤沉淀得到白色固体状1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(吡咯烷-2-羰酰氧基)-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐。ii)方法B:
将1.06g(1R,2R)-4-[2-[2-(2,4-二氟-苯基)-2-羟基-1-甲基-3-[1,2,4]三唑-1-基-丙基]-噻唑-4-基]-苄腈和1.1g 3,5-二甲基-4-[(S)-(N-叔丁氧羰基吡咯烷-2-羰酰氧基]苄基溴化物(从3,5-二甲基-4-羟基苯甲醛通过3步制得)在20mL乙腈中的混合物在回流温度下搅拌15小时后浓缩。将残余物在硅胶上进行色谱分离(Wakogel C-200,溶剂:CH2Cl2/MeOH=12/1)得到1.92g(94%收率)白色固体状的1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(N-叔丁氧羰基吡咯烷-2-羰酰氧基)苄基]-1H-[1,2,4]三唑-4-鎓溴化物。
如方法A所述脱除保护基制得1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(吡咯烷-2-羰酰氧基)苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; MALDI-TOF-MS:m/z669(M-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=7.3Hz),2.18-2.25(2H,m),2.21(6H,s),2.36-2.44(1H,m),2.66-2.71(1H,m),3.43-3.50(2H,m),4.30(1H,q,J=7.3Hz),4.65(1H,d,J=14.2Hz),4.88(1H,m),5.12(1H,d,J=14.2Hz),5.33(2H,s),6.73-6.79(1H,m),6.99-7.06(1H,m),7.14(2H,s),7.21-7.30(1H,m),7.82(2H,d,J=8.6Hz),8.10(1H,s),8.18(2H,d,J=8.6Hz),8.74(1H,s),10.00(1H,s)
实施例17-30的下列化合物以与实施例16相似的方式制得。
实施例17(2R,3R)-4-(4-氨基乙酰氧基-3,5-二甲基苄基)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末;FAB-MS:m/z629(M-Br)+;1H-NMR(CD3OD)d1.25(3H,d,J=7.3Hz),2.21(6H,s),4.29(1H,q,J=7.3Hz),4.31(2H,s),4.66(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.34(2H,s),6.72-7.30(3H,m),7.15(2H,s),7.81(2H,d,J=6.6Hz),8.10(1H,s),8.17(2H,d,J=6.6Hz),8.74(1H,s),10.0(1H,s)
实施例18(2R,3R)-4-[4-(3-氨基丙酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z643(M-TFA-Br)+;1H-NMR(CD3OD)d1.24(3H,t,J=7.3Hz),2.19(6H,s),3.09~3.37(4H,m),4.30(1H,q,J=7.3Hz),4.66(1H,d,J=14.2Hz),5.11(1H,d,J=14.2Hz),5.33(2H,br.s),6.73~6.81(1H,m),6.98-7.07(1H,m),7.12(2H,s),7.20-7.33(1H,m),7.81(2H,d,J=6.9Hz),8.10(1H,s),8.18(2H,d,J=6.9Hz),8.74(1H,s),10.00(1H,s).
实施例19(2R,3R)-4-[4-(4-氨基丁酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末;
FAB-MS:m/z657(M-TFA-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=7.26Hz),2.03~2.12(2H,m),2.17(6H,s),2.87(2H,t,J=7.5Hz),3.07(2H,t,J=7.5Hz),4.30(1H,t,J=7.5Hz),4.65(1H,d,J=14.4Hz)5.10(1H,d,J=14.4Hz),5.31(2H,s),6.73~6.80(1H,m),6.98-7.07(1H,m),7.11(2H,s),7.18-7.28(1H,m),7.82(2H,d,J=8.6Hz),8.10(1H,s),8.17(2H,d,J=8.6Hz),8.73(1H,s).
实施例20(2R,3R)-4-[4-[(2-氨基乙酰氨基)乙酰氧基]-3,5-二甲基苄基]-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z686(M-Br)+;1H-NMR(DMSO-d6)d1.18(3H,d,J=6.9Hz),2.08(6H,s),3.67(2H,brs),4.14(1H,q,J=6.9Hz),4.34(2H,d,J=5.6),4.69(1H,d,J=14.2Hz),5.01(1H,d,J=14.2Hz),5.35(2H,s),6.58(1H,s),6.90-6.96(1H,m),7.07(2H,s),7.21-7.37(2H,m),7.94(2H,d,J=7.9Hz),8.07(2H,brs),8.21(2H,d,J=7.9Hz),8.43(1H,s),8.99(1H,t,J=5.6),9.02(1H,s),10.06(1H,s).
实施例211-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-[(S)-2,5-二氨基戊酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末;
FAB-MS:m/z686(M-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=6.9Hz),1.95-2.43(4H,m),2.22(6H,s),3.09(2H,t,J=7.0Hz),4.30(1H,q,J=6.9Hz),4.60(1H,m),4.67(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.34(2H,s),6.76-7.27(3H,m),7.15(2H,s),7.82(2H,d,J=8.2Hz),8.10(1H,s),8.18(2H,d,J=8.2Hz),8.74(1H,s),10.0(1H,s)
实施例224-[4-[(S)-2-氨基丙酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z643(M-Br)+;1H-NMR(CD3OD)d1.23(3H,d,J=6.9Hz),1.79(3H,d,J=6.9Hz),2.20(6H,s),4.29(1H,q,J=6.9Hz),4.57(1H,q,J=6.9Hz),4.67(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.34(2H,s),6.70-7.26(3H,m),7.14(2H,s),7.80(2H,d,J=8.2Hz),8.10(1H,s),8.18(2H,d,J=8.2Hz),8.74(1H,s),10.0(1H,s)
实施例231-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[3,5-二甲基-4-[(甲氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:无定形粉末;
FAB-MS:m/z 643(M-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=7.3Hz),2.21(6H,s),2.84(3H,s),4.30(1H,q,J=7.3Hz),4.45(2H,s),4.65(1H,d,J=14.2Hz),5.11(1H,d,J=14.2Hz),5.33(2H,s),6.76(1H,m),7.02(1H,m),7.14(2H,s),7.24(1H,m),7.82(2H,d,J=8.6Hz),8.10(1H,s),8.18(2H,d,J=8.6Hz),8.74(1H,s),9.99(1H,s).
实施例24(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-[3,5-二甲基-4-[(丙氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z671(M-Br)+;1H-NMR(CD3OD)d1.05(3H,t,J=7.4Hz),1.25(3H,d,J=7.3Hz),1.77(2H,m),2.21(6H,s),3.10(2H,m),4.31(1H,q,J=7.4Hz),4.47(2H,s),4.66(1H,d,J=13.9Hz),5.12(1H,d,J=13.9Hz),5.33(2H,s),6.72-7.29(3H,m),7.14(2H,s),7.82(2H,d,J=8.3Hz),8.09(1H,s),8.18(2H,d,J=8.3Hz),8.74(1H,s),10.0(1H,s)
实施例251-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-[(S)-2-(甲氨基)丙酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z657(M-Br)+;1H-NMR(CD3OD)d1.25(3H,d,J=7.3Hz),1.83(3H,d,J=7.3Hz),2.21(6H,s),2.83(3H,s),4.26(1H,q,J=7.3Hz),4.57(1H,q,J=7.3Hz),4.66(1H,d,J=14.5Hz),5.12(1H,d,J=14.5Hz),5.34(2H,s),6.72-7.26(3H,m),7.15(2H,s),7.82(2H,d,J=8.6Hz),8.11(1H,s),8.18(2H,d,J=8.6Hz),8.75(1H,s)
实施例26(2R,3R)-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-4-[3,5-二甲基-4-[3-(甲氨基)丙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z657(M-TFA-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=6.9Hz),2.19(6H,s),2.78(3H,s),3.21(2H,t,J=6.6Hz),3.42(2H,t,J=6.6Hz),4.30(1H,q,J=6.9Hz),4.66(1H,d,J=14.2Hz),5.11(1H,d,J=14.2Hz),5.33(2H,s),6.73~6.81(1H,m),6.98~7.07(1H,m),7.12(2H,s),7.20-7.30(1H,m),7.82(2H,d,J=8.7Hz),8.10(1H,s),8.18(2H,d,J=8.7Hz),8.73(1H,s),9.98(1H,s)
实施例274-[4-[(S)-2-氨基-3-甲基丁酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z671(M-Br)+;1H-NM(CD3OD)d1.21(3H,d,J=6.9Hz),1.25(3H,d,J=6.9Hz),1.27(3H,d,J=6.9Hz),2.22(6H,s),2.66(1H,m),4.27(1H,q,J=6.9Hz),4.49(1H,d,J=3.6Hz),4.66(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.35(2H,s),6.73-7.30(3H,m),7.15(2H,s),7.82(2H,d,J=8.6Hz),8.10(1H,s),8.18(2H,d,J=8.6Hz),8.75(1H,s),10.0(1H,s)
实施例28(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-丁基]-4-[4-(异丙氨基)乙酰氧基]-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:无定形粉末; FAB-MS:m/z671(M-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=6.9Hz),1.41(6H,d,J=6.6Hz),2.22(6H,s),3.32-3.53(1H,m),4.30(1H,q,J=7.3Hz),4.50(2H,s),4.66(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.34(2H,s),6.73-6.78(1H,m),6.98-7.06(1H,m),7.15(2H,s),7.20-7.29(1H,m),7.82(2H,d,J=8.6Hz),8.11(1H,s),8.18(2H,d,J=8.6Hz),8.74(1H,s).
实施例291-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(2S)-4-[2-(乙氨基)丙酰氧基]-3,5-二甲基苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:无定形粉末; MALDI-TOF-MS:m/z671(M-Br)+;1H-NMR(CD3OD)d1.24(3H,d,J=7.3Hz),1.38(3H,t,J=7.3Hz),1.83(3H,d,J=7.3Hz),2.21(6H,s),3.14~3.25(2H,m),4.30(1H,q,J=7.3Hz),4.63(1H,q,J=7.3Hz),4.66(1H,d,J=14.2Hz),5.12(1H,d,J=14.2Hz),5.35(2H,s),6.74~6.80(1H,m),6.98-7.07(1H,m),7 16(2H,s),7.21-7.30(1H,m),7.82(2H,d,J=8.6Hz),8.11(1H,s),8.18(2H,d,J=8.6Hz),8.75(1H,s),10.00(1H,s).
实施例30(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-(乙氨基)乙酰氧基]-3,5-二甲基苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐;外观:白色粉末; FAB-MS:m/z657(M-Br)+;1H-NMR(CD3OD)d1.25(3H,d,J=7.3Hz),1.38(3H,t,J=7.3Hz),2.22(6H,s).3.22(2H,q,J=7.3Hz),4.27(1H,q,J=7.3Hz),4.48(2H,s),4.67(1H,d,J=14.2Hz).5.12(1H,d,J=14.2Hz),5.35(2H,s),6.73-7.29(3H,m),7.15(2H,s),7.82(2H,d,J=8.6Hz),8.10(1H,s),8.18(2H,d,J=8.6Hz),8.75(1H,s).10.0(1H,s)
实施例31
1-[(2R,3R)-3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓溴化物盐酸盐
4-[4-[(叔丁氧羰基-甲基-氨基)乙酰氧基]-3,5-二甲基-苄基]-1-[(2R,3R)-3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物(1∶1)通过与方法B中所述相似的方法制得。室温及剧烈搅拌下,于30分钟内向4-{4-[(叔丁氧羰基-甲基-氨基)乙酰氧基]-3,5-二甲基-苄基}-1-[(2R,3R)-3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物(1∶1)(198.7g,241mmol)的EtOAc(1000mL)溶液中加入HCl的EtOAc溶液(4N,600mL)。将生成的悬浮液在室温下搅拌3小时。将沉淀收集在玻璃漏斗(3G)上并用乙醚(500mL×10)洗涤,在40℃下真空干燥2天,然后在80℃下真空干燥12小时得到无色粉末状1-[(2R,3R)-3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓溴化物盐酸盐(183.3g,100%)。外观:无定形粉末; FAB-MS:m/z643(M-Br)+;1H-NMR(DMSO-d6)δ1.18(3H,d,J=7.3Hz),2.12(6H,s),2.64(3H,s),4.13(1H,q,J=7.3),4.42(2H,s),4.72(1H,d,J=14.2),5.01(1H,d,J=14.2),5.39(2H,s),6.70(1H,s),6.90-6.94(1H,m),7.13(2H,m),7.26-7.34(2H,m),7.94(2H,d,J=8.3),8.20(2H,d,J=8.3),8.44(1H,s),9.07(1H,s),9.51(2H,brs),.10.17(1H,s)
实施例32
下列化合物可以按照与实施例1或9相似的方式制得:
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-{5-氧代-4-[4-(2,2,3,3-四氟丙酰氧基)苯基]-4,5-二氢-[1,2,4]三唑-1-基}丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-甲基-3-(6-[1,2,4]三唑-1-基-哌嗪-3-基硫烷基)丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-(3-{(Z)-2-[4-(2,2,3,3-四氟丙酰氧基)苯基]乙烯基)-[1,2,4]三唑-1-基)丙基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-甲磺酰基丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧代-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[2-羟基-3-甲基-3-甲基硫烷基-2-(4-三氟甲基苯基)丁基]-1H-[1,2,4]三唑-4-鎓溴化物,和
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(5R,6R)-2-甲氧亚氨基-3,3-二甲基-6-[(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物。
实施例A
用于肌肉内给药的干粉安瓿的生产
以常规方法制备0.5g 4-(4-乙酰氧基-3,5-二甲基-苄基)-1-[[(1R,6R)-2-甲氧亚氨基-3,3-二甲基-6-[(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物的冻干物并填充到安瓿中。在给药前,将冻干物用2.5mL 2%的盐酸利多卡因水溶液处理。
实施例B
以已知的常规方法生产含有以下成分的硬明胶胶囊:4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(5R,6R)-2-甲氧亚氨基-3,3-二甲基-6-[(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物 100mg乳糖 56mg结晶纤维素 30mg硅酸,轻无水物 10mg滑石 3mg硬脂酸镁 1mg共200mg
实施例C
以已知的常规方法生产含有以下成分的片剂:4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(5R,6R)-2-甲氧亚氨基-3,3-二甲基-6-[(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物 100mg乳糖 60mg玉米淀粉 20mg淀粉甘醇酸钠 10mg聚乙烯吡咯烷酮 6mg滑石 3mg硬脂酸镁 1mg共200mg
Claims (12)
2.根据权利要求1的化合物,其中易水解的基团Y是氨基酸的酰基残基或Y是选自以下的基团:
R5CO-、或(R6O)2PO-其中R5是氢、低级烷氧基、可选择性带有羧基取代基的低级烷基、氨基、低级烷氨基、二低级烷氨基或芳基;并且R6是氢或低级烷基。
3.根据权利要求1的化合物,其中
是来自以下一组系化合物:
d1-1-[2-(2,4-二氯苯基)-2-[(2,4-二氯苯基)甲氧基]乙基]-1H-咪唑,
d1-顺-1-乙酰基-4-[4-[2-(2,4-二氯苯基)-2-(咪唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]哌嗪,
d1-2-[(RS)-仲丁基]-4-[4-[4-[4-[(2R,4S)-2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]-1-哌嗪基]苯基-3H-[1,2,4]三唑-3-酮,
2-[(1R,2R)-2-(2,4-二氟苯基)-2-羟基-1-甲基-3-(1H-1,2,4-三唑-1-基)丙基]-4-[4-(2,2,3,3-四氟丙氧基)苯基]-3(2H,4H,)-1,2,4-三唑酮,
(+)-2-(2,4-二氟苯基)-3-甲基-1-(1H-1,2,4-三唑-1-基)-3-(6-(1H-1,2,4-三唑-1-基)哌嗪-3-基硫)丁-2-醇,
(2R)-2-(2,4-二氟苯基)-1-[3-[(E)-4-(2,2,3,3-四氟丙氧基)苯乙烯基]-(1,2,4-三唑-1-基)-3-(1,2,4-三唑-1-基)]丙-2-醇,
d1-苏-2-(2,4-二氟苯基)-3-甲基-磺酰基-1-(1H-1,2,4-三唑-1-基)-丁-2-醇,
(-)-4-[4-[4-[4-[[5-(2,4-二氯苯基)-5-(1H-1,2,4-三唑-1-基甲基)四氢呋喃-3-基]甲氧基]苯基]哌嗪基]苯基]-2-[(1S,2S)-1-乙基-2-羟丙基]-3H-1,2,4-三唑-3-酮,
(2R,3R)-3-[4-(4-氰基苯基)噻唑-2-基)]-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)-丁-2-醇,
3-甲基-3-甲硫基-1-(1,2,4-三唑-1-基)-2-(三氟甲基苯基)-丁-2-醇,
1[[(1R,2S,6R)-2-甲氧基-3,3-二甲基-6-(2-对甲苯基乙基)环己基]-甲基]-1H-[1,2,4]-三唑,和
(5R,6R)-2,2-二甲基-6-[(1H-1,2,4-三唑-1-基)甲基]-5-[[4-(三氟甲氧基)苯氧基]甲基]环己酮O-甲基肟等。
4.根据权利要求1的化合物,所述化合物选自:
d1-1-(4-乙酰氧基-3,5-二甲基苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲基苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧苄基)-3-[2-(2,4-二氯苄氧基)-2-(2,4-二氯苯基)乙基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3,5-二甲基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-1-(4-乙酰氧基-3-甲氧基苄基)-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-(4-异丁酰氧基-3,5-二甲基苄基)-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-(4-新戊酰氧基-3,5-二甲基苄基)-3H-咪唑-1-鎓溴化物,
d1-3-[(2R,4S)-4-[4-(4-乙酰基哌嗪-1-基)苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧杂环己烷-2-基甲基]-1-[4-(2,2-二甲基丙酰氧基)苄基]-3H-咪唑-1-鎓溴化物,
d1-4-(4-苯氧基-3,5-二甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-[4-(吡啶-3-羰酰氧基)-3,5-二甲基苄基]-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基-3,5-二甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基-3-甲基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-4-(4-乙酰氧基苄基)-1-[4-[4-[4-[4-(1-(2-丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基]苯氧甲基]-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
d1-1-[4-(4-{4-[4-(1-仲丁基-5-氧代-1,5-二氢-[1,2,4]三唑-4-基)苯基]哌嗪-1-基}-苯氧甲基)-2-(2,4-二氯苯基)-[1,3]二氧戊环-2-基甲基]-4-(4-己酰氧基-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓甲磺酸盐,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-{5-氧代-4-[4-(2,2,3,3-四氟丙酰氧基)苯基]-4,5-二氢-[1,2,4]三唑-1-基}丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-甲基-3-(6-[1,2,4]三唑-1-基-哒嗪-3-基硫烷基)丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R)-2-(2,4-二氟苯基)-2-羟基-3-(3-((Z)-2-[4-(2,2,3,3-四氟丙酰氧基)苯基]乙烯基}-[1,2,4]三唑-1-基}丙基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-甲磺酰基丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰基苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R-顺)-2-(2,4-二氟苯基)-4-[4-[4-[4-[1-[(1S,2S)-1-乙基-2-羟丙基)-5-氧-1,5-二氢-[1,2,4]三唑-4-基]苯基]哌嗪-1-基]苯氧甲基]四氢呋喃-2-基甲基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-甲基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3-氯苄基)-1-[(2R,3R)-2-(2,4-二氟苯基)-2-羟基-3-[4-(4-氰基苯基)噻唑-2-基]丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[2-羟基-3-甲基-3-甲基硫烷基-2-(4-三氟甲基苯基)丁基]-1H-[1,2,4]三唑-4-鎓溴化物,
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(5R,6R)-2-甲氧亚氨基-3,3-二甲基-6-(4-三氟甲氧基苯氧基)甲基]环己基]甲基]-1H-[1,2,4]三唑-4-鎓溴化物,和
4-(4-乙酰氧基-3,5-二甲基苄基)-1-[[(1R,2S,6R)-2-甲氧基-3,3-二甲基-6-(2-对甲苯基-乙基)环己基甲基]-1H-[1,2,4]三唑-4-鎓溴化物。
5.根据权利要求1的化合物,所述化合物选自:
(2R,3R)-4-(4-氨基乙酰氧基-2-羧基苄基)-1-[3-[4-(4-氰基-苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-3,5-二甲基-4-(吡咯烷-2-羰酰氧基)-苄基]-1-[-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-(4-氨基乙酰氧基-3,5-二甲基苄基)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-(3-氨基丙酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-(4-氨基-丁酰氧基)-3,5-二甲基苄基]-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-4-[4-[[2-(氨基乙酰基)氨基]乙酰氧基]-3,5-二甲基苄基]-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-[(S)-2,5-二氨基戊酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
4-[4-[(S)-2-氨基-丙酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[3,5-二甲基-4-[(甲氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[3,5-二甲基-4-[(丙氨基)乙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(S)-2-(甲氨基)丙酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[4-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-3-甲基-丁基]-4-[3,5-二甲基-4-[3-(甲氨基)丙酰氧基]苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
4-[4-[(S)-2-氨基-3-甲基-丁酰氧基]-3,5-二甲基苄基]-1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基-丁基]-4-[4-(异丙氨基)乙酰氧基]-3,5-二甲基苄基)-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[(2S)-4-[2-(乙氨基)丙酰氧基]-3,5-二甲基-苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,
(2R,3R)-1-[3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-[4-(乙氨基)乙酰氧基]-3,5-二甲基苄基]-1H-[1,2,4]三唑-4-鎓溴化物三氟乙酸盐,尤其是
1-[(2R,3R)-3-[4-(4-氰基苯基)-噻唑-2-基]-2-(2,4-二氟苯基)-2-羟基丁基]-4-(3,5-二甲基-4-甲氨基乙酰氧基-苄基)-1H-[1,2,4]三唑-4-鎓溴化物盐酸盐。
7.如权利要求6所述生产权利要求2的化合物的方法,该方法包括将权利要求6所定义的通式(II)的化合物与其中的R1或R2之一是羟基的权利要求6所定义的通式(III)的化合物反应,随后将生成的化合物与式R5COL或(R6O)2POL的化合物反应,其中R5CO是N-保护的氨基酸的酰基残基,或者R5是氢、低级烷氧基、可选择性带有羧基取代基的低级烷基、氨基、带或不带保护基的低级烷氨基、二低级烷氨基或芳基;R6是氢或低级烷基,并且L是离去基团。
8.含有权利要求1至4中任一权利要求所定义的化合物和载体的抗真菌组合物。
9.治疗真菌感染的方法,包括向感染的组织给予有效量的权利要求1至4中任一权利要求所定义的化合物。
10.权利要求1至4中任一权利要求所定义的化合物在生产用于治疗真菌感染的药物中的用途。
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CN104974143A (zh) * | 2015-05-12 | 2015-10-14 | 深圳致君制药有限公司 | 一种季铵盐类化合物、其制备方法以及用途 |
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WO2000030655A1 (en) * | 1998-11-20 | 2000-06-02 | Bristol-Myers Squibb Company | Water soluble prodrugs of azole compounds |
US6319933B1 (en) | 2000-04-17 | 2001-11-20 | Basilea Pharmaceutica Ag | Azole derivatives |
AU2002351388A1 (en) | 2001-12-14 | 2003-06-30 | The University Of Wyoming | Methods and compositions for controlled release of drugs |
TW200606129A (en) * | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
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CN101391985B (zh) * | 2007-09-18 | 2013-09-11 | 西南大学 | 具抗微生物活性的三唑鎓类化合物及制备方法和医药用途 |
CN104974143A (zh) * | 2015-05-12 | 2015-10-14 | 深圳致君制药有限公司 | 一种季铵盐类化合物、其制备方法以及用途 |
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HUP9701479A2 (hu) | 1999-02-01 |
KR100252433B1 (ko) | 2000-08-01 |
CA2214669A1 (en) | 1998-03-09 |
HUP9701479A3 (en) | 2001-02-28 |
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