(-)-(2S)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate ester | 171764-50-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (-)-(2S)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate ester
• 英文别名: (-)-(2S-cis)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester)；(+)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester)；cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate (ester)；cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester)；[(2S,4S)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate
• CAS: 171764-50-4
• 化学式: C₁₄H₁₅F₂N₃O₅S
• 分子量: 375.353
• InChiKey: PUGQXVLRGZJODD-SMDDNHRTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (-)-(2S)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate ester 、 1-ethyl-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 在 sodium hexamethyldisilazane 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.17h， 以61%的产率得到1-[4-[4-[4-[[(2S,4R)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-3-ethyl-5,5-dimethyl-1,3-diazinane-2,4,6-trione
  参考文献：
  名称：

  Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

  摘要：

  In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in animal models. This panel of azoles was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c) showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine, against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole and terbinafine against 182 dermatophyte isolates and only rare activity against other pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal activity at least three times greater than itraconazole and were superior compared to terbinafine in M. cants infected guinea pigs. In a mouse model infected by T mentagrophytes, again 4c, but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c was effective in both models but less effective than itraconazole in these models. On the basis of these promising results, 4c is currently being clinically investigated for its potential as a novel antifungal agent against dermatophytosis.

  DOI：

  10.1021/jm0494772
• 作为产物：
  描述：

  2'4'-二氟-2-[1-(1H-1,2,4-三唑基)]苯乙酮 、 (2S)-1,2,3-propanetriol 1-(methylsulfonate) ester 在 甲烷磺酸 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以22%的产率得到(-)-(2S)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate ester
  参考文献：
  名称：

  Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

  摘要：

  In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in animal models. This panel of azoles was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c) showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine, against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole and terbinafine against 182 dermatophyte isolates and only rare activity against other pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal activity at least three times greater than itraconazole and were superior compared to terbinafine in M. cants infected guinea pigs. In a mouse model infected by T mentagrophytes, again 4c, but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c was effective in both models but less effective than itraconazole in these models. On the basis of these promising results, 4c is currently being clinically investigated for its potential as a novel antifungal agent against dermatophytosis.

  DOI：

  10.1021/jm0494772

文献信息

• [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-
  申请人：Janssen Pharmaceutica, N.V.

  公开号：US04791111A1

  公开（公告）日：1988-12-13

  Novel [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H -imidazoles and 1H-1,2,4-triazoles, having anti-microbial activity, compositions containing the same, and methods of inhibiting and/or eliminating the development of fungi and bacteria in warm-blooded animals suffering from diseases caused by these fungi and/or bacteria.

  新型[[4-[4-(4-苯基-1-哌嗪基)苯氧甲基]-1,3-二氧杂环戊烷-2-基]甲基]-1H-咪唑和1H-1,2,4-三唑，具有抗微生物活性，含有这些化合物的组合物，以及抑制和/或消除患有由这些真菌和/或细菌引起的疾病的温血动物体内真菌和细菌发展的方法。
• Watersoluble azole antifungals
  申请人：Janssen Pharmaceutica, N.V.

  公开号：US05707977A1

  公开（公告）日：1998-01-13

  A compound of formula (I), ##STR1## an acid or base addition salt thereof or a stereochemically isomeric form thereof, wherein A and B taken together form --N.dbd.CH--, --CH.dbd.N--, --CH.sub.2 --CH.sub.2, CH.dbd.CH--, --C(.dbd.O)--CH.sub.2 --, --CH.sub.2 --C(.dbd.O); D is a radical of formula ##STR2## L is a radical of formula ##STR3## Alk is a C.sub.1-4 alkanediyl radical; R.sup.1 is halo; R.sup.2 is hydrogen or halo; R.sup.3 is hydrogen, C.sub.1-6 alkyl, phenyl or halophenyl; R.sup.4 is hydrogen, C.sub.1-6 alkyl, phenyl or halophenyl; R.sup.5 is hydrogen or C.sub.1-6 alkyl; R.sup.6 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyloxycarbonyl, or R.sup.5 and R.sup.6 taken together with the nitrogen atom to which they are attached form a heterocyclic ring. Active intermediates, compositions and methods of preparing compounds, compositions are described.

  公式（I）的化合物，##STR1## 其酸盐或碱盐加合物，或其立体化学异构体形式，其中A和B共同形成--N.dbd.CH--, --CH.dbd.N--, --CH.sub.2 --CH.sub.2, CH.dbd.CH--, --C(.dbd.O)--CH.sub.2 --, --CH.sub.2 --C(.dbd.O); D是公式##STR2##的基团；L是公式##STR3##的基团；Alk是C.sub.1-4烷二基基团；R.sup.1是卤素；R.sup.2是氢或卤素；R.sup.3是氢，C.sub.1-6烷基，苯基或卤苯基；R.sup.4是氢，C.sub.1-6烷基，苯基或卤苯基；R.sup.5是氢或C.sub.1-6烷基；R.sup.6是氢，C.sub.1-6烷基，C.sub.1-6烷氧羰基，或R.sup.5和R.sup.6与它们连接的氮原子共同形成一个杂环环。描述了活性中间体、组合物和制备化合物、组合物的方法。
• Water soluble azoles as broad-spectrum antifungals
  申请人：——

  公开号：US06384030B1

  公开（公告）日：2002-05-07

  The present invention concerns novel compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein L represent a radical of formula wherein each Alk independently represents an optionally substituted C1-6alkanediyl; is 1, 2 or 3; Y is O, S or NR2; R1 represents hydrogen, aryl, Het1, or an optionally substituted C1-6alkyl; each R2 independently represents hydrogen or C1-6alkyl; or in case R1 and R2 are attached to the same nitrogen atom, they may be taken together to form a heterocyclic radical; or they may be taken together to form an azido radical; each R3 independently represents hydrogen, hydroxy or C1-4alkyloxy; aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each of said aryl groups may optionally be substituted; Het1 represents an optionally substituted monocyclic or bicyclic heterocyclic radical; Het2 is the same as Het1 and may also be piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl; R6 represents hydrogen or C1-4alkyl; R7 represents hydrogen or C1-4alkyl; or R6 and R7 taken together form a bivalent radical of formula —N═CH— (i), —CH═N— (ii), —CH═CH— (iii), —CH2—CH2 (iv), wherein one hydrogen atom in the radicals (i) and (ii) may be replaced with a C1-4alkyl radical and one or more hydrogen atoms in radicals (iii) and (iv) may be replaced by a C1-4alkyl radical; D represents a trisubstituted 1,3-dioxolane derivative; as antifungals; their processes for preparation, compositions containing them and their use as a medicine.

  本发明涉及一种新颖的化合物，其分子式为N-氧化物形式，其中L代表一个基团，其分子式为其中每个Alk独立表示一个可选择取代的C1-6烷二基；n为1、2或3；Y为O、S或NR2；R1表示氢、芳基、Het1或一个可选择取代的C1-6烷基；每个R2独立地表示氢或C1-6烷基；或者当R1和R2连接到同一个氮原子时，它们可以结合形成一个杂环基团；或者它们可以结合形成一个偶氮基团；每个R3独立地表示氢、羟基或C1-4烷氧基；芳基表示苯基、萘基、1,2,3,4-四氢萘基、茚基或茚基；所述的每个芳基基团可以选择性地被取代；Het1表示一个可选择取代的单环或双环杂环基团；Het2与Het1相同，也可以是哌嗪基、环戊哌嗪基、1,4-二氧杂环基、吗啉基、硫吗啉基；R6表示氢或C1-4烷基；R7表示氢或C1-4烷基；或者R6和R7结合在一起形成一个分子式为—N═CH—（i）、—CH═N—（ii）、—CH═CH—（iii）、—CH2—CH2（iv）的二价基团，其中在基团（i）和（ii）中的一个氢原子可以被C1-4烷基基团取代，基团（iii）和（iv）中的一个或多个氢原子可以被C1-4烷基基团取代；D表示三取代的1,3-二氧杂环戊烷衍生物；作为抗真菌药物；它们的制备方法、含有它们的组合物和作为药物的用途。
• 4-[4-[4-[4-[[2-(2,4-difluoro
  申请人：Janssen Pharmacuetica N.V.

  公开号：US04916134A1

  公开（公告）日：1990-04-10

  4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]m ethoxy]phenyl]-1-piperazinyl]phenyl]triazolones, their pharmaceutically acceptable acid addition salts and stereoisomeric forms having improved antimicrobial properties, compositions containing the same, and methods of inhibiting and/or eliminating the development of fungi and bacteria in warm-blooded animals suffering from diseases caused by these fungi and/or bacteria.

  4-[4-[4-[4-[[2-(2,4-二氟苯基)-2-(1H-咪唑甲基)-1,3-二氧杂环戊烷-4-基]甲氧基]苯基]-1-哌嗪基]苯基]三唑酮，其药学上可接受的酸盐和立体异构体形式具有改善的抗微生物特性，含有相同成分的组合物，以及抑制和/或消除温血动物患有由这些真菌和/或细菌引起的疾病的方法。
• Antifungal ethers
  申请人：Janssen Pharmacuetica N.V.

  公开号：US06583136B1

  公开（公告）日：2003-06-24

  The present invention concerns compounds of formula the N-oxide forms, the salts, the quaternary amines and stereochemically isomeric forms thereof, wherein D represents a tetrahydrofuran or dioxolane ring substituted with aryl and azolmethyl; —A—B— represents an optionally substituted bivalent radical of formula —N═CH—, —CH═N—, —CH═CH—, —CH2—CH2; Alk represents C1-6alkanediyl; Y represents optionally substituted C1-6alkanediyl; R1 and R2 represent hydrogen, C1-6alkyl or arylC1-6alkyl; or R1 and R2 may be taken together to form an optionally substituted heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl or phthalimid-1-yl; aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each of said aryl groups may optionally be substituted; having broad-spectrum antifungal activity; their preparation, compositions containing them and their use as a medicine.

  本发明涉及公式的化合物，其中N-氧化物形式、盐、季铵盐和立体化异构体，其中D代表被芳基和氮杂环甲基取代的四氢呋喃或二氧兰环；—A—B—代表公式—N═CH—、—CH═N—、—CH═CH—、—CH2—CH2的可选择取代的二价基团；Alk代表C1-6烷二基；Y代表可选择取代的C1-6烷二基；R1和R2代表氢、C1-6烷基或芳基C1-6烷基；或R1和R2可以结合在一起形成可选择取代的杂环基团，选自吗啡啉基、吡咯啉基、哌啶基、同哌啶基、哌嗪基或邻苯二甲酰亚胺-1-基；芳基代表苯基、萘基、1,2,3,4-四氢萘基、茚基或茚基；每个芳基基团可以可选择地被取代；具有广谱抗真菌活性；它们的制备、含有它们的组合物以及它们作为药物的用途。