CN1177858C - 9- 去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β,β-二取代衍生物 - Google Patents
9- 去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β,β-二取代衍生物 Download PDFInfo
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Abstract
本发明涉及9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，即式(I)化合物的新的大环内酯类半合成抗生素。其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，其中R4为C1-C4烷基；涉及它们与无机或有机酸的药用加成盐；涉及它们的制备方法；涉及药物组合物的制备方法以及该药物组合物在治疗细菌感染方面的用途。
Description
本发明涉及9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素(homoerythromycin)A的β，β-二取代衍生物，即一种新的具有抗菌作用的通式(I)大环内酯类半合成抗生素：
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，其中R4为C1-C4烷基；涉及它们与无机或有机酸的药用加成盐；涉及它们的制备方法；涉及药物组合物的制备方法和涉及所得到的药物组合物在治疗细菌感染方面的用途。
9-去氧-9a-氮杂-9a-高红霉素A是一个大环内酯抗生素，该结构的特点在于把氮原子引入14元环而扩环，得到15元的大环内酯，同时它也是第一次从新的半合成大环内酯类通过向氮化(azalide)的14元大环内酯引入氮原子得到的合成化合物。
所述化合物的抗革兰氏阳性菌活性与红霉素A和红霉素肟的活性等同，但是在抗革兰氏阴性菌和临床分离方面优于红霉素A。在酸性介质中的稳定性和急性毒性方面，它们优于红霉素肟，但是比红霉素A要差一些。
在丙酮和水的混合物中，用甲苯磺酰氯直接进行9(E)-肟的贝克曼重排，形成6，9-亚氨基醚，将其还原得到作为中间体的9-去氧-9a-氮杂-9a-高红霉素A(S.Djokic，G.Kobrehel，G.Lazarevski，N.Lopotar，Z.Tambura*ev，B.Kamener，A.Nagl and I.Vickovic，J.Chem.Soc.perkinTrans I，1881，1986)。
为了得到具有更好生物活性的化合物，以9-去氧-9a-氮杂-9a-高红霉素A作为起始化合物制备了许多新的化合物。
通过用羧酸酐选择性地酰基化9-去氧-9a-氮杂-9a-高红霉素A来制备酰基衍生物(S.Djokic，G.Kobrehel和G.Lazarevski，J.Antibiotics，40，1006，1987)。通过改变反应温度和时间可实现选择性酰化。这样，在室温下，通过起始物质的反应得到单、二和三酰基衍生物。在吡啶溶液中，通过起始物质与乙酸酐反应，分离得到二乙酰基衍生物，通过甲醇解起始化合物可得到单乙酰基衍生物，它是去除了2’-O-乙酰基。通过加长反应时间得到三乙酰基衍生物。通过增高反应温度(70℃)，乙酰化9-去氧-9a-氮杂-9a-高红霉素A得到四乙酰基衍生物。
除了这些化合物外，另外还制备了9-去氧-9a-氮杂-9a-高红霉素A的9a-N-甲酰基、9a-N-丙酰基、2’-O，9a-N-二丙酰基和2’-O，9a-N-二甲酰基衍生物。
首先甲基化三重保护(3’，9a)-二-N-2’-O-三-(苄基氯甲酸酯)，然后消除2’和3’位的保护基而去保护(G.Kobrehel，G.Lazarevski，Z.Kelnericand S.Djokic，J.Antibiot.，46，1239，1993)，最后通过还原甲基化相应的3’-des-N-甲基衍生物，在3’位引入甲基制备最终所需化合物，得到O-甲基环状氨基甲酸酯。
在乙二醇二乙酸酯中，通过用碳酸亚乙酯对9-去氧-9a-氮杂-9a-高红霉素A进行酯基转移作用，得到11，12-环状碳酸酯，(S.Djokic，G.Kobrehel，G.Lazarevski，J.Antibiotics，40，1006，1987)。在一系列临床分离实验中，得到的环状碳酸酯显示的体外抗革兰氏阴性菌活性优于红霉素A。
根据Eschweler-Clark反应，通过在9-去氧-9a-氮杂-9a-高红霉素A的9a位上氮的还原甲基化，制备得到9-去氧-9a-甲基-9a-氮杂-9a-高红霉素A-azithromycin(S.Djokic，G.Kobrehel，BE 892 357，1982)，它的特点在于其在酸性介质中的稳定性、显著增强的组织穿透性和延长的生物学意义上的半衰期，它也具有可观的抗革兰氏阳性、革兰氏阴性菌和细胞内致病微生物的活性(G.M.Bright，A.A.Nagel，J.Bordner，K.A..Desai，J.N.Dibrino，J.Nowakowska，L.Vincent，R.M.Watrous，F.C.Sciavolino，A.R.English，J.A..Retsema，M.R.Anderson，L.A，Brenana，R.J.Borovov，C.R.Cimochowski，J.A.Faiella，A.E.Girard，D.Girard，C.Herbert，M.Manousos和R.Mason，J.Antibiot，41，1029，1988)。
根据已知的文献，9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物和其与无机或有机酸的药用加成盐，其制备方法及其药物制剂的制备方法和其用途以前都没有公开过。
我们已经发现，即本发明的主题，9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，其与无机或有机酸的药用加成盐可以通过以下方法制备：使9-去氧-9a-氮杂-9a-高红霉素A与取代的乙氧基亚甲基衍生物反应，以及如有必要，再用所得到的9-去氧-9a-N-乙烯基-9a-氮杂-9a--高红霉素A的β，β-二取代衍生物分别和无机或有机酸反应。
技术方案
已经发现式(I)的9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，以及它们和无机或有机酸的药用加成盐。
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，其中R4为C1-C4烷基。这些化合物及其盐可以通过式(II)9-去氧-9a-氮杂-9a-高红霉素A与式(III)乙氧基亚甲基衍生物反应，
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，R4为C1-C4烷基，反应在温度为20-80℃下，在甲苯、二甲苯或其它的非质子溶剂中进行。
通过使9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物与等摩尔量的合适的无机或有机酸在对反应呈惰性的溶剂中进行反应，得到代表本发明另一个目的药用加成盐，例如盐酸、氢碘酸、硫酸、磷酸、乙酸、三氟乙酸、丙酸、苯甲酸、苯磺酸、甲基磺酸、十二烷基磺酸、硬脂酸、棕榈油酸、丁二酸、乙基丁二酸、乳糖酸、草酸、水杨酸等的盐。
通式(I)的9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，以及它们与无机或有机酸的药用加成盐具有类似于红霉素的体外的活性，因此，它们能够用于相同的目的并以红霉素A相同的方式使用，通过在微型板上稀释的方法(method of dilution on microplates)测定活性，这种方法以临床实验标准的国家委员会协定(NCCL，M7-A2)为依据。
以最小抑制浓度(MIC mcg/ml)表示的结果表明了其潜在的作为例如在室内和医疗器械方面的消毒剂的作用，和作为例如保护木材和墙壁涂料的工业抗菌试剂的作用。
9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物的制备方法用以下的实施例来说明，但无论如何不是限制本发明。
实施例1
9-去氧-9a-N-(β，β-乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A
在100-105℃的温度下，加热9-去氧-9a-氮杂-9a-高红霉素A(7.27克，0.01摩尔)和乙氧基亚甲基丙二酸二乙基酯(10.36克，0.04摩尔)的混合物12小时。然后冷却，过硅胶柱，首先用氯仿，接着用氯仿∶甲醇＝9∶1的混合溶剂洗脱。得到纯的9-去氧-9a-N-(β，β-二乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A。用波谱(NMR、IR和MS)的方法分析，表明为预期所需要的化合物结构。
实施例2
9-去氧-9a-N-(β-氰基-β-乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A
在110-115℃温度下，搅拌9-去氧-9a-氮杂-9a-高红霉素A(7.27克，0.01摩尔)和乙氧基亚甲基氰基乙酸乙酯(2.0克，0.018摩尔)的甲苯(50.0毫升)溶液18小时。混合反应物冷却到室温后，分离树脂状的沉淀物。倾倒出甲苯，首先将树脂状沉淀物溶解在丙酮(15.0毫升)中，然后蒸干溶液。得到粗产品(3.27克)，过硅胶色谱柱，用氯仿∶甲醇＝9∶1的混合溶剂体系洗脱，得到9-去氧-9a-N-(β-氰基-β-乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A.用波谱(NMR、IR和MS)的方法分析，表明为预期所需要的化合物结构。
实施例3
9-去氧-9a-N-(β，β-二氰基乙烯基)-9a-氮杂-9a-高红霉素A
在约70℃温度下，搅拌9-去氧-9a-氮杂-9a-高红霉素A(7.27克，0.01摩尔)和(乙氧基-亚甲基)-丙二腈(1.6克，0.01摩尔)的甲苯(30.0毫升)溶液8小时。将反应混合物冷却到室温后，分离树脂状沉淀物。倾倒出甲苯，首先将树脂状沉淀物溶解在丙酮(15.0毫升)中，然后蒸干溶剂。得到粗产品(3.31克)，过硅胶色谱柱，用氯仿∶甲醇＝9∶3的混合溶剂体系洗脱，得到9-去氧-9a-N-(β，β-二氰基乙烯基)-9a-氮杂-9a-高红霉素A.用波谱(NMR、IR和MS)的方法分析，表明为预期所需要的化合物结构。
实施例4
9-去氧-9a-N-(β-乙酰基-β-乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A
在110-115℃温度下，搅拌9-去氧-9a-氮杂-9a-高红霉素A(7.27克，0.01摩尔)和α-(乙氧基亚甲基)乙酰乙酸乙酯(2.0毫升，0.011摩尔)的甲苯(30.0毫升)溶液6小时。混合反应物冷却到室温后，分离树脂状的沉淀物。减压(2.13×103帕)蒸馏掉甲苯。得到粗产品(4.84克)，过硅胶色谱柱，用氯仿∶甲醇＝9∶1的混合溶剂体系洗脱，得到9-去氧-9a-N-(β-乙酰基-β-乙氧基羰基乙烯基)-9a-氮杂-9a-高红霉素A.用波谱(NMR、IR和MS)的方法分析，表明为预期所需要的化合物结构。
Claims (12)
1、式(I)的9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，及其与无机或有机酸的药用加成盐：
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，其中R4为C1-C4烷基。
2、根据权利要求1的物质，其特征为R1和R2彼此相同并代表式COOR3的羧基，其中R3是C1-C4烷基。
3、根据权利要求2的物质，其特征为R3是乙基。
4、根据权利要求1的物质，其特征为，R1和R2之一为氰基，另一个为式COOR3的羧基，其中R3为C1-C4烷基。
5、根据权利要求4的物质，其特征为R3为乙基。
6、根据权利要求1的物质，其特征为R1和R2相同并代表氰基。
7、根据权利要求1的物质，其特征为R1和R2之一为式COOR3的羧基，另一个为COR4的酮基，其中R3为C1-C4烷基，R4为C1-C4烷基。
8、根据权利要求7的物质，其特征为R3为乙基。
9、根据权利要求7的物质，其特征为R4为甲基。
10、式(I)的9-去氧-9a-N-乙烯基-9a-氮杂-9a-高红霉素A的β，β-二取代衍生物，及其与无机或有机酸的药用加成盐的制备方法，
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基，或式COR4的酮基，其中R4代表C1-C4烷基，其特征为式(II)9-去氧-9a-氮杂-9a-高红霉素A
与式(III)乙氧基亚甲基衍生物反应，
其中R1和R2彼此相同或不同并代表氰基、式COOR3的羧基，其中R3为C1-C4烷基或式COR4的酮基，其中R4为C1-C4烷基，
反应在20-80℃温度下、在甲苯、二甲苯或其它的非质子性溶剂中进行，如有必要，再与无机或有机酸反应。
11、药物组合物，其特征在于包含药学上可接受载体和抗菌有效量的权利要求1的物质。
12、权利要求1到9任一项的物质在制备治疗细菌感染的药物制剂中的应用。
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| HRP970714A | 1997-12-31 | ||
| HR970714A HRP970714B1 (en) | 1997-12-31 | 1997-12-31 | Beta,beta-disubstituted derivatives of 9-deoxo-9a-n-ethenyl-9a-aza-9a-homoerythromycin a |
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| CN1177858C true CN1177858C (zh) | 2004-12-01 |
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| EP (1) | EP0927722B1 (zh) |
| JP (1) | JPH11255793A (zh) |
| CN (1) | CN1177858C (zh) |
| AT (1) | ATE234320T1 (zh) |
| BG (1) | BG63572B1 (zh) |
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| CZ (1) | CZ294878B6 (zh) |
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| HR (1) | HRP970714B1 (zh) |
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| EP1437360A3 (en) * | 1998-08-19 | 2005-04-06 | Pfizer Products Inc. | C11 Carbamates of macrolide antibacterials |
| CN102993250B (zh) * | 2011-07-06 | 2016-02-10 | 洛阳惠中兽药有限公司 | C-3取代的-9-脱氧-9a-氮杂-9a-高红霉素a衍生物 |
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| MX13723A (es) * | 1987-11-10 | 1993-05-01 | Pfizer | Procedimiento para preparar derivados de 9-desoxo-9a-alil- y propargil-9a-aza-9a-homoeritromicina a |
| HRP931480B1 (en) * | 1993-12-08 | 1997-08-31 | Sour Pliva | 9a-N-(N'-CARBAMONYL) and 9a-N-(N'-THIOCARBAMONYL) DERIVATES OF 9-DEOXO-9a-HOMOERYTHROMYCIN A |
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| Publication number | Publication date |
|---|---|
| UA58515C2 (uk) | 2003-08-15 |
| DE69812059T2 (de) | 2004-03-04 |
| HUP9803043A2 (hu) | 1999-08-30 |
| CA2256017A1 (en) | 1999-06-30 |
| JPH11255793A (ja) | 1999-09-21 |
| HUP9803043A3 (en) | 1999-12-28 |
| SK177798A3 (en) | 2000-06-12 |
| ES2195266T3 (es) | 2003-12-01 |
| CZ294878B6 (cs) | 2005-04-13 |
| CN1229085A (zh) | 1999-09-22 |
| RU2205185C2 (ru) | 2003-05-27 |
| PT927722E (pt) | 2003-07-31 |
| CA2256017C (en) | 2004-04-27 |
| ATE234320T1 (de) | 2003-03-15 |
| HRP970714B1 (en) | 2003-08-31 |
| EP0927722B1 (en) | 2003-03-12 |
| US6071886A (en) | 2000-06-06 |
| NO986186L (no) | 1999-07-01 |
| HRP970714A2 (en) | 1999-10-31 |
| BG63572B1 (bg) | 2002-05-31 |
| BG103045A (en) | 1999-09-30 |
| PL187390B1 (pl) | 2004-06-30 |
| EP0927722A1 (en) | 1999-07-07 |
| SK283163B6 (sk) | 2003-03-04 |
| SI0927722T1 (en) | 2003-08-31 |
| CZ431198A3 (cs) | 1999-07-14 |
| HU9803043D0 (en) | 1999-02-01 |
| PL330616A1 (en) | 1999-07-05 |
| DE69812059D1 (de) | 2003-04-17 |
| NO312034B1 (no) | 2002-03-04 |
| DK0927722T3 (da) | 2003-05-19 |
| NO986186D0 (no) | 1998-12-29 |
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