CN109666019B - 一种氘代的氮唑醇类化合物及其制备方法和用途 - Google Patents
一种氘代的氮唑醇类化合物及其制备方法和用途 Download PDFInfo
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- CN109666019B CN109666019B CN201710955700.XA CN201710955700A CN109666019B CN 109666019 B CN109666019 B CN 109666019B CN 201710955700 A CN201710955700 A CN 201710955700A CN 109666019 B CN109666019 B CN 109666019B
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- 150000001875 compounds Chemical class 0.000 claims description 63
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/02—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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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Abstract
本发明公开了如式(I)所示的氘代氮唑醇类化合物及其可药用盐和前药的制备方法和用途。本发明所述的氘代氮唑醇类化合物具有较好的抗真菌活性同时具有较好的代谢稳定性,可用于制备抗真菌药物。
Description
技术领域
本发明涉及抗真菌药物合成,具体涉及一种氘代氮唑醇类化合物及其前药和药学上可接受的盐的制备方法和其在治疗或预防真菌感染方面的应用。
背景技术
深部真菌感染现已成为艾滋病和肿瘤等重大疾病死亡的主要原因,但就目前临床应用的抗真菌药物而言,存在副作用大、抗菌谱窄、易产生耐药性等问题,有效的抗真菌药物特别是抗深部真菌药物十分缺乏,远不能满足治疗需要。VT-1161、VT-1129和VT-1598是由美国VIAMET公司开发的抗真菌药物,目前处于临床前研究阶段,其结构如下所示:
该类化合物主要作用于真菌细胞的CYP51靶点,与以往的三氮唑类抗真菌药物相比具有抗菌谱更广,毒性低,安全性高及选择性好等优点,但是VT-1161、VT-1129和VT-1598在药效和药代动力学性质方面仍有很大的改进空间。
发明内容
本发明的目的是针对现有技术中药效与药代动力学的不足,提供一种氘代氮唑醇类化合物或其可药用盐。
本发明的第二个目的,提供一种药物组合物,所述药物组合物包含第一方面所述的氘代氮唑醇类化合物或其可药用盐。
本发明的第三个目的,提供所述的氘代氮唑醇类化合物或其可药用盐的制备方法。
本发明的第四个目的,本发明提供了如第二方面所述的药物组合物在制备抗真菌感染药物方面的用途。
为实现上述目的,本发明采取的技术方案是:
一种氘代氮唑醇类化合物或其可药用盐,化学结构如式(I)所示:
其中:
R1-R12为氢原子或氘原子;
R13分别选自C1~C6烷基、卤素取代烷基、苯基、吡啶基、C1~6烷基取代的苯基或吡啶基、卤素取代的C1~6烷基取代的苯基或吡啶基、卤素取代的苯基或吡啶基、硝基取代的苯基或吡啶基、氰基取代苯基或吡啶基、三氟甲基取代的苯基或吡啶基;
R14和R15分别选自氘原子、氢原子或、卤素;
R16为氢原子或磷酸基;
X代表N或CH;
Y代表或无取代;
Z代表O或S。
优选地,氘在氘取代位置的氘同位素含量大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
更优选地,所述的氘代氮唑醇类化合物选自式(Ⅱ)或式(Ⅲ)所示化合物:
其中,R1-R12分别选自氢原子或氘原子;
R13选自甲苯、氰基取代苯基、三氟甲基取代苯基、二氟甲基取代苯基、三氟甲氧基取代苯基、卤素取代苯基、氰基取代吡啶,Z为氧原子或硫原子;
其中,R7-R10分别选自氢原子或氘原子,R17为三氟甲基或三氟甲氧基。
上述的化合物中所述的R13基团中的苯基或吡啶基为氘代苯基或氘代吡啶。
所述的化合物包含R型异构体或S型异构体,所述的R型异构体为:
所述S型异构体为:
所述的可药用盐为无机酸盐或有机酸盐;
优选地,所述的无机酸为盐酸、磷酸;所述的有机酸为对甲苯磺酸盐、乙酸、马来酸、富马酸、酒石酸、琥珀酸。
本发明还提供了一种晶型化合物,该晶型化合物为如所述的氘代氮唑醇类化合物或其可药用盐。
本发明还提供了一种药物组合物,所述药物组合物包含有所述的氘代氮唑醇类化合物或其可药用盐。
优选地,所述药物组合物进一步包含:至少一种药学上可接受的载体,或/和至少一种另外的抗真菌化合物。
更优选地,所述的另外的抗真菌化合物包含但并不限于:克霉唑,氟康唑,伏立康唑,泊沙康唑,酮康唑和伊曲康唑,以及上述化合物的可药用盐或酯中任意一种或两种以上。
为实现上述第三个目的,本发明采取的技术方案是:
所述的氘代氮唑醇类化合物或其可药用盐的制备方法,包括以下步骤:
将化合物C溶于有机溶剂中,加入钯催化剂,碱试剂,化合物A或化合物B,在氮气保护下,加热反应得目标产物化合物D。
优选地,所述的有机溶剂为N,N-二甲基甲酰胺,四氢呋喃,二甲基亚砜,甲苯,N-甲基吡咯烷酮,二氧六环。
优选地,所述的钯催化剂为Pd(PPh3)2Cl2,Pd(PPh3)4,Pd(CH3CN)2Cl2,Pd(dppf)Cl2,PdCl2。
优选地,所述的碱试剂为K2CO3,Na2CO3,Cs2CO3,K3PO4,三乙胺,N,N-二异丙基乙胺。
本发明还提供了一种所述的药物组合物在制备抗真菌感染的药物中的用途。
本发明优点在于:本发明合成了一种氘代氮唑醇类化合物,该类化合物对人体致病真菌白色念珠菌具有较好的抑制活性,而且本发明的化合物对人肝微粒体酶的稳定性显著优于对照化合物VT-1598,氘代后使得药物的代谢变得困难,这导致首过效应的降低,药物稳定性显著提高。在这种情况下,可以改变剂量并形成长效制剂,其也可以长效制剂的形式改善适用性。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
本发明所用试剂和原料均市售可得或可按文献方法制备。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。实施例中所用试剂均为市售分析纯。
实施例1:化合物D1的合成
步骤一:将化合物1(5mmol)溶于四氢呋喃中,冰浴条件下加入硼氘化钠(3mmol),待原料反应完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干得化合物2,直接用于下一步。
步骤二:将化合物2(3mmol)溶于二氯甲烷中,冰浴条件下加入三溴化磷(3mmol),反应完全后,倒入冰水中,二氯甲烷萃取3次,1M稀盐酸洗一次,饱和碳酸氢钠洗一次,饱和氯化钠洗一次,干燥,旋干得化合物3,直接用于下一步。
步骤三:将化合物3(2mmol)和4(2mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(4mmol),50度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物5。
步骤四:将化合物5(2mmol),乙炔基三甲基硅烷(4mmol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(10mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物6。
步骤五:将化合物C(1mol)和化合物6(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),氟化钾(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥,旋干后柱层析得终产物D1。
1H NMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.28(s,1H),5.12-5.07(d,J=15.0Hz,1H).
实施例2:化合物D2的合成
步骤一:将化合物7(5mmol)溶于四氢呋喃中,-78度条件下加入氘代氢化锂铝(6mmol)反应,待原料反应完全,按氘代氢化锂铝质量比1(H2O):1(15%NaOH):3(H2O)分次加入,搅拌10分钟,固体过滤,滤液旋干后得化合物8,粗品直接用于下一步。
步骤二:将化合物8(3mmol)溶于二氯甲烷中,冰浴条件下加入三溴化磷(3mmol),反应完全后,倒入冰水中,二氯甲烷萃取3次,1M稀盐酸洗一次,饱和碳酸氢钠洗一次,饱和氯化钠洗一次,干燥,旋干得化合物9,直接用于下一步。
步骤三:将化合物9(2mmol)和10(2mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(4mmol),KI(2mmol),50度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物11。
步骤四:将化合物11(2mmol),乙炔基三甲基硅烷(4mmol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(10mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物12。
步骤五:将化合物12(1mol)和化合物C(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),氟化钾(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥,旋干后柱层析得终产物D2。
1HNMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.12-5.07(d,J=15.0Hz,1H).
实施例3:化合物D3的合成
步骤一:将氘代碘甲烷25g和氘代二甲亚砜(25mL)加热回流条件下反应3天,析出固体过滤得化合物13直接用于下一步。
步骤二:将化合物13(2mmol)溶于无水N,N-二甲基甲酰胺中,-5度条件下加入氢化钠(2mmol)搅拌10分钟,再加入化合物E(2mmol),反应完全后,倒入冰水中,乙酸乙酯取3次,饱和氯化钠洗一次,干燥,旋干后柱层析得化合物14,直接用于下一步。
步骤三:将化合物14(2mmol)和1-H-四氮唑(6mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(6mmol),90度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物15。
步骤四:将化合物15(1mmol)和化合物16(1mmol),CuI(5%mol),KF(1mmol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥旋,干后柱层析得终产物D3。
1H NMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.28(s,2H).
实施例4:化合物D4的合成
将化合物15(1mol)和化合物12(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D4。
1H NMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H).
实施例5:化合物D5的合成
步骤一:将化合物17(2mmol)溶于无水N,N-二甲基甲酰胺中,-5度条件下加入叔丁醇钠(2mmol)搅拌10分钟,再加入化合物E(2mmol),反应完全后,倒入冰水中,乙酸乙酯取3次,饱和氯化钠洗一次,干燥旋干后柱层析得化合物18,直接用于下一步。
步骤二:将钯碳(2g)在氢气中搅拌一个小时,然后加入到重水中,再加入1-H-四氮唑,除氢气后,在100度下搅拌1小时,滤除钯碳后旋干得化合物19,粗品直接用于下一步。
步骤三:将化合物18(2mmol)和19(6mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(6mmol),90度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物20。
步骤四:将化合物20(1mmol)和化合物16(1mmol),CuI(5%mol),KF(1mmol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D5。
1H NMR(300MHz,DMSO)δ8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.28(s,2H),5.12-5.07(d,J=15.0Hz,1H).
实施例6:化合物D6的合成
将化合物15(1mol)和化合物6(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D6。
1H NMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.28(s,1H).
实施例7:化合物D7的合成
将化合物20(1mol)和化合物12(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D7。
1H NMR(300MHz,DMSO)δ8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.12-5.07(d,J=15.0Hz,1H).
实施例8:化合物D8的合成
步骤一:将化合物14(2mmol)和19(6mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(6mmol),90度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物21。
步骤二:将化合物21(1mol)和化合物12(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D8。
1H NMR(300MHz,DMSO)δ8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.58-7.55(d,J=9.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H).
实施例9:化合物D9的合成
步骤一:将化合物22(2mmol)和23(2mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(4mmol),50度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物24。
步骤二:将化合物24(2mmol),乙炔基三甲基硅烷(4mmol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(10mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得化合物25。
步骤三:将化合物C(1mol)和化合物25(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D9。
1H NMR(300MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.89-7.87(d,J=6.0Hz,2H),7.66-7.64(d,J=6.0Hz,2H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.28(s,2H),5.12-5.07(d,J=15.0Hz,1H).
实施例10:化合物D10的合成
将化合物C(1mol)和化合物26(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D10。
1H NMR(500MHz,CDCl3)δ8.75(s,1H),8.62(s,1H),7.86(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.50(d,J=9.0Hz,2H),7.34-7.32(m,4H),6.95(d,J=9.0Hz,2H),6.77-6.75(m,1H),6.67-6.65(m,1H),5.59(d,J=14.0Hz,1H),5.12(d,J=14.0Hz,1H).
实施例11:化合物D21的合成
将化合物15(1mol)和化合物27(1mol),Pd(PPh3)2Cl2(10%mol),K3PO4(2mmol)溶于N,N-二甲基甲酰胺中,80度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D21。
1H NMR(500MHz,CDCl3)δ8.76(s,1H),8.70(s,1H),7.95(d,J=8.0Hz,1H),7.70(s,1H),7.64(d,J=8.5Hz,1H),7.54(d,J=8.5Hz,2H),7.42-7.37(m,1H),7.08(d,J=8.5Hz,2H),6.79-6.75(m,1H),6.69-6.66(m,1H),4.44-4.39(m,2H).
实施例12:化合物D22的合成
将化合物15(1mol)和化合物28(1mol),Pd(PPh3)2Cl2(10%mol),K3PO4(2mmol)溶于N,N-二甲基甲酰胺中,80度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D22。
1H NMR(500MHz,CDCl3)δ8.76(s,1H),8.70(s,1H),7.95(d,J=8.0Hz,1H),7.70(s,1H),7.64(d,J=8.5Hz,1H),7.42-7.37(m,1H),6.79-6.75(m,1H),6.69-6.66(m,1H),4.44-4.39(m,2H).
实施例13:化合物D23的合成
将化合物15(1mol)和化合物29(1mol),Pd(PPh3)2Cl2(10%mol),K3PO4(2mmol)溶于N,N-二甲基甲酰胺中,80度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物H23。
1H NMR(500MHz,CDCl3)δ8.76(s,1H),8.70(s,1H),7.97(dd,J=8.0,2.0Hz,1H),7.68(d,J=8.5Hz,1H),7.60-7.56(m,3H),7.43-7.36(m,3H),6.80-6.76(m,1H),6.70-6.67(m,1H).
实施例14:化合物D24的合成
将化合物C(1mol)和化合物27(1mol),CuI(5%mol),Pd(PPh3)2Cl2(10%mol),N,N-二异丙乙胺(5mol),KF(1mmol)溶于N,N-二甲基甲酰胺中,60度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D24。
1H NMR(500MHz,DMSO)δ9.14(s,1H),8.71-8.70(d,J=3.0Hz,1H),8.07-8.03(dd,J=9.0,3.0Hz,1H),7.49-7.46(d,J=9.0Hz,1H),7.32(s,1H),7.23-7.14(m,2H),7.12-7.09(d,J=9.0Hz,2H),6.92-6.86(td,J=9.0,3.0Hz,1H),5.65-5.60(d,J=15.0Hz,1H),5.28(s,2H),5.12-5.07(d,J=15.0Hz,1H).
实施例15:化合物D25的合成
将化合物15(1mol)和化合物30(1mol),Pd(PPh3)2Cl2(10%mol),K3PO4(2mmol)溶于N,N-二甲基甲酰胺中,80度条件下反应到原料完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后,旋干后柱层析得终产物D25。
1H NMR(500MHz,CDCl3)δ8.72(s,1H),8.16(s,1H),7.92(dd,J=8.5,2.0Hz,1H),7.69(s,1H),7.61(d,J=8.0Hz,1H),7.52-7.47(m,1H),6.77-6.70(m,1H),4.42(q,J=8.0Hz,2H).
实施例16:化合物G的合成
步骤一:将化合物D2(1mmol),1-H-四氮唑(5mmol)溶于二氯甲烷(10mL),再将化合物F(4mmol)的二氯甲烷溶液滴加到体系中,室温下搅拌反应2小时,将反应体系降到-5度,滴加m-CPBA(4mmol)的二氯甲烷溶液,滴毕-5度下反应1小时,再加入二氯甲烷50mL,用5%硫代硫酸钠洗2次,10%碳酸氢钠洗2次,饱和氯化钠水溶液洗两次,无水硫酸钠干燥后旋干,反相制备后真空冻干得化合物31。
步骤二:将化合物31(0.5mmol)溶于四氢呋喃中,冰浴条件下依次加入亚膦酸三苯酯(0.5mmol),四三苯基膦钯(0.05mmol),三乙胺(1mmol),1M乙酸(2.5mmol),加完后室温下反应过夜,滤除固体,滤液旋干后反相制备后真空冻干得G
1H NMR(400MHz,CD3OD)δ9.33(s,1H),8.70(s,1H),7.92(d,J=8.0Hz,1H),7.75(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.51(d,J=8.0Hz,1H),7.45-7.39(m,1H),7.34-7.27(m,1H),7.05(d,J=8.0Hz,2H),6.95-6.89(m,1H),6.83-6.78(m,1H),6.21(d,J=15.2Hz,1H),5.94(d,J=15.2Hz,1H).31P NMR(400MHz,CD3OD)δ-6.98(s).
实施例17:手性化合物33的合成
步骤一:将(R,R)-Co(salen)(0.3mmol)溶于甲苯中,加入醋酸(13mmol),室温下反应30分钟后旋干。化合物14(15mmol)和所形成的催化剂溶于甲苯中,冰浴下滴加水(8mmol),然后室温下反应14个小时,反应液旋干,柱层析得化合物32。
步骤二:将化合物32(2mmol)和1-H-四氮唑(6mmol)溶于N,N-二甲基甲酰胺中,加入碳酸钾(6mmol),90度条件下反应至完全,倒入冰水中,用乙酸乙酯萃取3次,干燥后旋干后柱层析得化合物33。
1H NMR(500MHz,CDCl3)δ8.74(s,1H),8.62(s,1H),7.94(d,J=7.5Hz,1H),7.46(d,J=9.0Hz,1H),7.31-7.26(m,1H),6.88(s,1H),6.78-6.74(m,1H),6.70-6.67(m,1H).
实施例18:化合物D2的对甲苯磺酸盐的合成
将D2(5mmol)溶于乙酸异丙酯,30度条件下,加入对甲苯磺酸一水合物(5mmol),在50-60度条件下反应2小时至有固体析出,在冰浴条件下再搅拌10小时,固体抽滤,滤饼用少量乙酸异丙酯洗,滤饼在真空干燥箱烘干,得D2的对甲苯磺酸盐。
本发明包含的具体氘代氮唑醇类化合物如下:
实验例1:
本发明化合物的体外抑菌实验
(一)实验方法:采用常规的体外抑菌实验方法(详见:Antimicrob AgentsChemother 1995,39(5):1169)。
1.材料与方法
(1)实验菌株
本实验选用的真菌菌株由上海长征医院真菌室(或购自中科院药物所)提供。
白色念珠菌(Candida albicans,标准株SC5314),
(2)试验方法
菌悬液配制:上述真菌经YEPD液体培养基35℃培养16小时,两次活化,用血细胞计数板计数,以RPM1640液体培养基调整菌浓度至1*104~1*105个/mL。
药液配制:取本发明待测化合物溶于二甲亚砜,配成0.8mg/mL的药物储存液,实验前用RPM1640稀释成8μg/mL。
接种:96孔板1号孔加RPM1640 100μL作空白对照;3-12号孔各加菌悬液100μL,2号孔加菌悬液200μL和药液2μL,2-11号孔的药物浓度作10级倍比稀释,各孔药物浓度依次为8、4、2、1、0.5、0.25、0.125、0.0625、0.0313、0.0156μg/mL。12号孔不加药液,作阳性对照。药物对照选用氟康唑。
(二)实验结果
体外抑菌实验结果见表1。
表1目标化合物体外抗真菌最小抑菌浓度值(MIC80,μg/mL)
上述实验结果表明,本发明化合物具有较好的抗真菌活性,体外抑菌活性均显著强于氟康唑,且与VT-1598相比,氘代后体外抗菌活性影响不大。
实验例2:
体外人肝微体酶稳定性实验
(1)化合物信息
(2)微粒体
本实验使用的人的混合肝微粒体均来源于美国Corning公司或其他常用的商业化公司,储存在-90~-60℃条件。
(3)实验步骤
受试化合物将与人肝微粒体在以下条件下(见表)进行共孵育,向孵育管中加入受试化合物作液,混匀后瞬离,置于37℃水浴中。然后加入NADPH的工作液启动反应。在0、5、10、20、40、60min取出部分孵育液并转移至含有内标的乙腈中终止反应。蛋白沉淀后,3,700rpm离心10min,取上清。上清液中的受试化合物由LC-MS/MS方法分析。根据受试化合物在孵育体系中的清除半衰期算出体外内在清除率。咪达唑仑作为阳性对照平行孵育。孵育条件总结如下表(孵育体系有机溶剂的含量不超过1%),均平行孵育2份:
(4)数据分析
分析物/内标峰面积之比(Aanalyte/AIS)将由仪器得出,剩余百分比(%Control)由非零时间点样品与零时刻样品中Aanalyte/AIS之比计算出。将Ln(%Control)对孵育时间作图并进行线性拟合。受试化合物清除常数(k,min-1)、清除半衰期(T1/2,min)以及体外内在清除率(CLint,μL min-1 mg-1proteins)由以下方程式计算得到。
k=-slope
T1/2=0.693/k
CLint=k/Cprotein
Cprotein(mg mL-1)指孵育体系中的微粒体蛋白质浓度。
(5)结果见表2
表2目标化合物对人肝微粒体酶的稳定性测试
从结果可以看出,氘代后的化合物D2对人肝微粒体酶的稳定性显著优于VT-1598,氘代后的VT-1598具有广阔的市场前景。
综上所述,本发明的化合物对人体致病真菌白色念珠菌具有较好的抑制活性,且化合物稳定性显著提高,该类化合物无论在药效学还是药物代谢动力学性质方面均得到较大的改善。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (6)
2.根据权利要求1所述的化合物或其可药用盐,其特征在于,所述的化合物包含R型异构体或S型异构体;所述R型异构体结构式中,OH连接的C的构型为R;所述S型异构体结构式中,OH连接的C的构型为S。
3.根据权利要求2所述的化合物或其可药用盐,其特征在于,所述的可药用盐为无机酸盐或有机酸盐;
所述的无机酸盐为盐酸,所述的有机酸盐对甲苯磺酸盐。
5.一种药物组合物,其特征在于,所述药物组合物含有如权利要求1-3中任意一项所述的氘代氮唑醇类化合物或其可药用盐。
6.一种如权利要求5所述的药物组合物在制备抗真菌感染药物方面的用途。
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