伊曲康唑杂质40 | 219923-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 伊曲康唑杂质40
• 英文名称: N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea
• 英文别名: [4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]urea
• CAS: 219923-93-0
• 化学式: C₁₈H₂₂N₄O₂
• 分子量: 326.398
• InChiKey: XRKCQBAPGILDOG-UHFFFAOYSA-N

物化性质

• 沸点：
  541.3±50.0 °C(Predicted)
• 密度：
  1.249±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  70.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  伊曲康唑杂质40 在 sodium hydride 作用下， 以 环丁砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.5h， 生成 1-ethyl-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione
  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：

  potassium cyanate 、 1-(4-氨基苯基)-4-(4-甲氧基苯基)哌嗪 在 盐酸 作用下， 反应 4.0h， 以100%的产率得到伊曲康唑杂质40
  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

• 2,4,4-trisubstituted-1,3-dioxolane antifungals
  申请人：——

  公开号：US06387906B1

  公开（公告）日：2002-05-14

  The present invention concerns novel compounds of formula a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein n is zero, 1, 2 or 3; X is N or CH; each R1 independently is halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl; R2 is hydrogen; C3-7alkenyl; C3-7alkynyl, aryl; C3-7cycloalkyl; optionally substituted C1-6alkyl R3 and R4 each independently are hydrogen, C1-6alkyl, C3-7cycloalkyl or aryl; or R3 and R4 taken together form a bivalent radical —R3—R4— of formula: wherein R5a, R5b, R5c, R5d each independently are hydrogen, C1-6alkyl or aryl; and aryl is optionally substituted phenyl; as antifungals; their preparation, compositions containing them and their use as a medicine.

  本发明涉及公式a的新化合物的N-氧化物形式，药学上可接受的酸盐或其立体化异构形式，其中n为零、1、2或3；X为N或CH；每个R1独立地为卤素、硝基、氰基、氨基、羟基、C1-4烷基、C1-4烷氧基或三氟甲基；R2为氢；C3-7烯基；C3-7炔基、芳基；C3-7环烷基；可选择取代的C1-6烷基R3和R4各自独立地为氢、C1-6烷基、C3-7环烷基或芳基；或R3和R4一起形成一个二价基团-R3-R4-的公式：其中R5a、R5b、R5c、R5d各自独立地为氢、C1-6烷基或芳基；芳基为可选择取代的苯基；作为抗真菌剂；它们的制备、含有它们的组合物以及它们作为药物的用途。
• [EN] 2,4,4-TRISUBSTITUTED-1,3-DIOXOLANE ANTIFUNGALS<br/>[FR] ANTIFONGIQUES 1,3-DIOXOLANE TRISUBSTITUES EN 2,4,4
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：WO1999002523A1

  公开（公告）日：1999-01-21

  (EN) The present invention concerns novel compounds of formula (I), a $i(N)-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein n is zero, 1, 2 or 3; X is N or CH; each R1 independently is halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl; R2 is hydrogen; C3-7alkenyl; C3-7alkynyl, aryl; C3-7cycloalkyl; optionally substituted C1-6alkyl; R3 and R4 each independently are hydrogen, C1-6 alkyl, C3-7cycloalkyl or aryl; or R3 and R4 taken together form a bivalent radical -R3-R4- of formula (a), (b), (c), (d), or (e), wherein R5a, R5b, R5c, R5d each independently are hydrogen, C1-6alkyl or aryl; and aryl is optionally substituted phenyl; as antifungals; their preparation, compositions containing them and their use as a medicine.(FR) L'invention concerne de nouveaux composés représentés par la formule (I), une forme $i(N)-oxyde, un sel d'addition acide pharmaceutiquement acceptable ou une forme stéréochimiquement isomérique de ces composés. Dans la formule (I) n est zéro, 1, 2 ou 3; X est N ou CH; chaque R1 est indépendamment halo, nitro, cyano, amino, hydroxy, alkyle C1-4, alcoxy C1-4 ou trifluorométhyle; R2 est l'hydrogène, alcényle C3-7, alcynyle C3-7; aryle, cycloalkyle C3-7, alkyle C1-6 éventuellement substitué; R3 et R4 sont chacun indépendamment l'un de l'autre l'hydrogène, l'alkyle C1-6, cycloalkyle C3-7 ou aryle; ou R3 et R4 forment ensemble un radical bivalent -R3-R4- représenté par les formules (a), (b), (c), (d) ou (e) dans laquelle R5a, R5b, R5c, R5d sont chacun indépendamment les uns des autres l'hydrogène, l'alkyle C1-6 ou l'aryle; et l'aryle est éventuellement le phényle substitué. Ces composés sont utilisés comme antifongiques. L'invention concerne en outre la préparation ce ces composés, des compositions contenant ces composés et l'utilisation de ces composés comme médicament.

  本发明涉及一种新的化合物，其化学式为(I)，包括$ i(N)-氧化物形式、药学上可接受的酸加成盐或其立体化学异构体，其中n为0、1、2或3；X为N或CH；每个R1独立地为卤素、硝基、氰基、氨基、羟基、C1-4烷基、C1-4烷氧基或三氟甲基；R2为氢、C3-7烯基、C3-7炔基、芳基、C3-7环烷基、可选取代的C1-6烷基；R3和R4各自独立地为氢、C1-6烷基、C3-7环烷基或芳基；或R3和R4共同形成一个二价基团-R3-R4-，其化学式为(a)、(b)、(c)、(d)或(e)，其中R5a、R5b、R5c、R5d各自独立地为氢、C1-6烷基或芳基；芳基为可选取代的苯基。这些化合物用作抗真菌药物，其制备、含有它们的组合物以及它们的用途作为药品也属于本发明的范畴。
• Antifungal 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]triazolones and imidazolones
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP0402989A2

  公开（公告）日：1990-12-19

  4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]methoxy]­phenyl]-1-piperazinyl]phenyl]triazolones and imidazolones of formula wherein Q is CH or N; Y is a radical of formula R¹ is C₅₋₇cycloalkyl or mono-, di-, tri-, tetra- or pentahaloC₁₋₄alkyl; and R² is C₁₋₆alkyl, C₅₋₇cycloalkyl or mono-, di-, tri-, tetra- or pentahaloC₁₋₄alkyl, the acid addition salts and stereoisomeric forms thereof; said compounds having antifungal properties. Pharmaceutical compositions containing such compounds as an active ingredient; methods of preparing said compounds and pharmaceutical compositions.

  式中的 4-[4-[4-[4-[[2-(2,4-二氟苯基)-2-(1H-偶氮啉甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]-1-哌嗪基]苯基]三唑酮和咪唑啉酮 其中 Q 是 CH 或 N； Y 是式中的基团 R¹ 是 C₅₋₇环烷基或单、二、三、四或五卤 C₁₋₄烷基；以及 R² 是 C₁₋₆烷基、C₅₋₇环烷基或单、二、三、四或五卤 C₁₋₄烷基、 酸加成盐及其立体异构形式；所述化合物具有抗真菌特性。含有此类化合物作为活性成分的药物组合物；制备所述化合物和药物组合物的方法。
• [EN] ANTIFUNGAL WATER-SOLUBLE PRODRUG AND PREPARATION METHOD THEREFOR<br/>[FR] PROMÉDICAMENT ANTIFONGIQUE SOLUBLE DANS L'EAU ET SON PROCÉDÉ DE PRÉPARATION<br/>[ZH] 抗真菌水溶性前药及其制备方法
  申请人：SHANGHAI YINGNUOFUCHENG BIOTECHNOLOGY CO LTD

  公开号：WO2021129723A1

  公开（公告）日：2021-07-01

  本发明提供一种抗真菌水溶性前药及其制备方法。其结构式如式(Ⅰ)所示：式(Ⅰ)中，n为0时，R1为甲基，R2为H；n为1-4的整数时，R1为H、-CH3或-C2H5，R2为H或NH2。本发明实施例1-6化合物具有较好的溶解性，在pH5-6时的溶解度能够满足制备注射液的要求，在pH5-6时化合物1-6配制的溶液在2-8℃时较室温更稳定，所制备的溶液在血浆中能够部分通过酶的孵育转化成羟基伊曲康唑，说明化合物1-6可以成为式（1）所示化合物的前体药物，由化合物1-6所制备的溶液无刺激性、溶血性，适于制备成注射液。
• 2,4,4-TRISUBSTITUTED-1,3-DIOXOLANE ANTIFUNGALS
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP1068200A1

  公开（公告）日：2001-01-17