CN1263532A - 13－二氢－3'－氮丙啶基蒽环素类 - Google Patents
13－二氢－3'－氮丙啶基蒽环素类 Download PDFInfo
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- CN1263532A CN1263532A CN99800548A CN99800548A CN1263532A CN 1263532 A CN1263532 A CN 1263532A CN 99800548 A CN99800548 A CN 99800548A CN 99800548 A CN99800548 A CN 99800548A CN 1263532 A CN1263532 A CN 1263532A
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Abstract
适用作抗肿瘤剂的式(Ⅰ)的蒽环素苷类或其混合物,其中波状线表示13位的羟基可在α或β位。
Description
本发明涉及蒽环素苷类，涉及它们的制备方法，并且涉及含它们的药物组合物。
本发明提供了具有式I结构的蒽环素苷类或其混合物：
其中波状线表示13位的羟基可在α或β位。
式I的化合物包括这样的衍生物：其中13位的羟基具有构型13(S)、13(R)、或者13(R)和13(S)非对映异构体的混合物，即：
4-脱甲氧基-13(S/R)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ia)，
4-脱甲氧基-13(S)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ib)和
4-脱甲氧基-13(R)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ic)。
更优选地，本发明提供了具有上面定义的式I结构的蒽环素苷类，其特征在于，它的13-碳原子是S，即4-脱甲氧基-13(S)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ib)。
式I的化合物可这样制备：还原式II的蒽环素，即，在还原剂(例如硼氢化钠)存在下，在有机溶剂混合物(例如二氯甲烷和甲醇)中，优选在低于50℃的温度下、更优选在-70℃下进行还原，并且，如果希望和必要的话，将生成的13(R)和13(S)化合物的混合物分离成单纯的非对映异构体。例如，单纯的13-二氢非对映异构体可通过用高压液相色谱法(HPLC)分离所述混合物而获得。具体地说，该HPLC分离可在反相柱上进行，应用磷酸盐缓冲剂(例如10mMK2HPO4)与85％H3PO4的混合物调节至pH7.0，并且以有机溶剂(例如四氢呋喃或乙腈)作流动相。
用于制备所述新蒽环素苷类的原料是4-脱甲氧基-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(II)，它被描述于US-A-5,532,218中。
本发明进一步提供了一种药物组合物，它包括与药物上可接受的稀释剂或载体掺和的式I的蒽环素苷类。可应用常规载体和稀释剂。该组合物可按常规方法配制和施用。
本发明的化合物适用于通过疗法治疗人或动物体的方法中。它们适用作抗肿瘤剂。它们适用于治疗白血病和实体瘤，例如结肠、结肠-直肠的、卵巢的、乳房的、前列腺的、肺、肾以及还有黑素瘤肿瘤。所以人可通过这种方法治疗，即对人施用治疗上有效量的本发明的化合物。人患者的状况因而可得以改善。应给予的剂量可应用蒽环素领域中已知的剂量范围确定，通过参考本发明的化合物在体外和体内抗肿瘤试验中表现的活性改变。合适的剂量通常在1～200mg/m2体表面积的范围内，优选为1～100mg/m2，它取决于待治疗的疾病性质和严重程度，并取决于患者的一般健康状况。
式I的化合物是在体外对一组鼠和人肿瘤细胞系以及在体内对弥散性P388/DX鼠白血病测试和发现活性的。
Ia的体外和体内活性
对一组鼠和人肿瘤细胞系，Ia表现高的细胞毒性，如表1的IC50值所示。Ia对弥散性P388/DX鼠白血病的体内试验结果示于表2中。
表1：Ia的体外细胞毒性
| 细胞系1 | IaIC2 50ng/mL平均值±标准误差 |
| L12103 | 3.76±0.13 |
| JURKAT3 | 4.87±0.7 |
| CEM3 | 5.86±0.4 |
| LoVo4 | 20.3±2 |
1)细胞与该化合物保温1小时。
2)50％抑制浓度表示得自至少两次实验的剂量-反应曲线的平均值±标准误差。
3)通过计数存活细胞而确定的生长抑制。
4)通过SRB比色分析而确定的生长抑制。
表2：Ia对弥散性P388/DX的体内抗肿瘤活性
| 化合物 | 剂量2(mg/kg/天) | ILS％3 | Tox4 | LTS5 |
| Ia | 2.93.8 | 80102 | 0/204/17 | 0/200/17 |
1)在第0天静脉注射P388/DX Johnson白血病细胞(105个/小鼠)
2)在肿瘤移植(第0天)后的第1天给予静脉内治疗。将Ia溶于[Cremophor/乙醇＝6.5∶3.5]/[生理盐水]＝20/80v/v中。
3)生活期限的增大：[(治疗过的小鼠平均存活时间/对比组的平均存活时间)×100]-100
4)中毒死亡数/小鼠数
5)在实验结束时的长期存活者(＞60天)。
如下实施例阐述了本发明。
实施例1
13(R/S)-二氢-4-脱甲氧基-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ia)
将4-脱甲氧基-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(II，600mg，1mmol)溶于二氯甲烷(50ml)并在-70℃下冷却。在该溶液中滴加硼氢化钠(120mg，3.2mmol)溶于甲醇(5ml)的溶液。15分钟后，添加丙酮(10ml)，然后让该反应混合物暖至室温，添加二氯甲烷(500ml)，用水(2×200ml)洗涤。分离有机相，浓缩至少量，在硅胶上应用甲苯和丙酮(8∶2的体积比)的混合物进行急骤色谱处理。合并含标题化合物的级分，浓缩至少量，用己烷与乙醚(85∶5的体积比)的混合物沉淀，得13(R/S)-二氢-4-脱甲氧基-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素(Ia，400mg)。
在Kieselgel板(Merck)上应用甲苯和丙酮(80∶20的体积比)的混合物作为洗脱剂进行TLC处理，Rf＝0.3
1H＝NMR(400Mhz，CDCl3)δ：1.14，1.23，1.72(m，CH2CH2氮丙啶，Ia+Ib)；1.27(d，J＝6.3Hz，CH3-13，Ib)；1.32(d，J＝6.3Hz，CH3-13，Ia)；1.38(d，J＝6.5Hz，CH3-5＇，Ia+Ib)；1.47(ddd，J＝2.6，4.5，12.5Hz，CH3-3＇，Ia+Ib)；1.78(m，H-2＇ax，Ia+Ib；H-8ax，Ia)；1.87(dd，J＝4.1，15.0Hz，H-8ax，Ib)；2.07(dd，J＝4.0，13.4Hz，H-2＇eq，Ia)；2.10(dd，J＝4.0，13.4Hz，H-2＇eq，Ib)；2.12(d，J＝7.8Hz，OH-13，Ia)；2.35(ddd，J＝1.7，2.6，15.0Hz，H-8eq，Ib)；2.40(d，J＝3.8Hz，OH-13，Ib)；2.54(ddd，J＝1.7，2.6，15.0Hz，H-8eq，Ia)；2.61(d，J＝19.1Hz，H-10ax，Ia)；2.65(d，J＝19.1Hz，H-10ax，Ib)；3.20(dd，J＝1.9，19.1Hz，H-10eq，Ia+Ib)；3.21(s，SO2CH3)；3.67(m，CH-13，Ia)；3.82(m，CH-13，Ib)；4.11(m，H-5＇，Ia+Ib)；4.22(s，OH-9，Ia)；4.36(s，OH-9，Ib)；4.74(m，H-4＇，Ia+Ib)；5.27(dd，J＝2.6，4.4Hz，H-7，Ia)；5.29(dd，J＝2.6，4.4Hz，H-7，Ib)；5.55(d，J＝3.8Hz，H-1＇，Ia+Ib)；7.84(m，H-2+H-3，Ia+Ib)；8.36(m，H-1+H-4，Ia+Ib)；13.38(s，OH-11，Ia)；13.39(s，OH-11，Ib)；13.59(s，OH-6，Ia)；！3.60(s，OH-6，Ib).FAB-MS(+)m/z：604[MH]+。
Claims (10)
1.一种式I的蒽环素苷类或其混合物
其中波状线表示13位的羟基可在α或β位。
2.权利要求1的化合物，它是4-脱甲氧基-13(S/R)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素、4-脱甲氧基-13(S)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素或4-脱甲氧基-13(R)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素。
3.权利要求1的化合物，它是4-脱甲氧基-13(S)-3’-脱氨基-3’-吖丙啶基-4’-甲磺酰柔红霉素。
4.一种制备权利要求1定义的式(I)的蒽环素苷类的方法，该方法包括在还原剂存在下、在有机溶剂混合物中还原式II的蒽环素，并且，如果希望和必要的话，将生成的13(R)和13(S)化合物的混合物分离成单纯的非对映异构体。
5.权利要求4的方法，其中所述还原剂是硼氢化钠。
6.权利要求4或5的方法，其中所述还原作用是在低于50℃的温度下进行的。
7.权利要求6的方法，其中所述还原作用是在-70℃的温度下进行的。
8.一种药物组合物，它包括权利要求1定义的式(I)的蒽环素苷类，以及药物上可接受的载体或稀释剂。
9.用于通过疗法治疗人或动物体的方法中的权利要求1或2的化合物。
10.用作抗肿瘤剂的权利要求9的化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9808027.8 | 1998-04-15 | ||
| GBGB9808027.8A GB9808027D0 (en) | 1998-04-15 | 1998-04-15 | 13-dihydro-3' aziridino anthracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1263532A true CN1263532A (zh) | 2000-08-16 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99800548A Pending CN1263532A (zh) | 1998-04-15 | 1999-04-09 | 13－二氢－3'－氮丙啶基蒽环素类 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US6258786B1 (zh) |
| EP (1) | EP0989989B1 (zh) |
| JP (1) | JP2002505691A (zh) |
| KR (1) | KR20010013772A (zh) |
| CN (1) | CN1263532A (zh) |
| AR (1) | AR019046A1 (zh) |
| AT (1) | ATE230411T1 (zh) |
| AU (1) | AU749578B2 (zh) |
| BR (1) | BR9906305A (zh) |
| CA (1) | CA2293453A1 (zh) |
| CZ (1) | CZ292718B6 (zh) |
| DE (1) | DE69904682T2 (zh) |
| DK (1) | DK0989989T3 (zh) |
| EA (1) | EA002161B1 (zh) |
| ES (1) | ES2191430T3 (zh) |
| GB (1) | GB9808027D0 (zh) |
| HU (1) | HUP0003802A3 (zh) |
| ID (1) | ID23006A (zh) |
| IL (1) | IL133114A0 (zh) |
| MY (1) | MY115486A (zh) |
| NO (1) | NO314148B1 (zh) |
| NZ (1) | NZ501931A (zh) |
| PL (1) | PL337368A1 (zh) |
| TW (1) | TW454012B (zh) |
| UA (1) | UA45493C2 (zh) |
| WO (1) | WO1999052921A1 (zh) |
| ZA (1) | ZA997793B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0006601D0 (en) * | 2000-03-17 | 2000-05-10 | Pharmacia & Upjohn Spa | Crystalline alkycycline derivative |
| AU2016229807B2 (en) * | 2015-03-09 | 2020-10-29 | Hidrate, Inc. | Wireless drink container for monitoring hydration |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4604381A (en) * | 1982-07-16 | 1986-08-05 | Farmitalia Carlo Erba S.P.A. | 4-demethoxy-13-dihydrodaunorubicin and use thereof |
| JPS59212499A (ja) * | 1983-05-13 | 1984-12-01 | アドリヤ・ラボラトリ−ズ・インコ−ポレ−テツド | 抗腫瘍性抗生物質アントラサイクリンの４−デメトキシ−３′−デアミノ−３′（４−モリホリニル）誘導体 |
| GB8614323D0 (en) * | 1986-06-12 | 1986-07-16 | Erba Farmitalia | Anthracyclines |
| GB9325417D0 (en) * | 1993-12-13 | 1994-02-16 | Erba Carlo Spa | 3'- aziridino-anthracycline derivatives |
-
1998
- 1998-04-15 GB GBGB9808027.8A patent/GB9808027D0/en not_active Ceased
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1999
- 1999-03-22 TW TW088104459A patent/TW454012B/zh not_active IP Right Cessation
- 1999-04-09 WO PCT/EP1999/002567 patent/WO1999052921A1/en not_active Application Discontinuation
- 1999-04-09 EP EP99920684A patent/EP0989989B1/en not_active Expired - Lifetime
- 1999-04-09 BR BR9906305-0A patent/BR9906305A/pt not_active Application Discontinuation
- 1999-04-09 IL IL13311499A patent/IL133114A0/xx unknown
- 1999-04-09 KR KR1019997011789A patent/KR20010013772A/ko not_active Application Discontinuation
- 1999-04-09 DK DK99920684T patent/DK0989989T3/da active
- 1999-04-09 HU HU0003802A patent/HUP0003802A3/hu unknown
- 1999-04-09 NZ NZ501931A patent/NZ501931A/en unknown
- 1999-04-09 ID IDW991599A patent/ID23006A/id unknown
- 1999-04-09 US US09/445,443 patent/US6258786B1/en not_active Expired - Fee Related
- 1999-04-09 PL PL99337368A patent/PL337368A1/xx unknown
- 1999-04-09 AU AU38174/99A patent/AU749578B2/en not_active Ceased
- 1999-04-09 DE DE69904682T patent/DE69904682T2/de not_active Expired - Fee Related
- 1999-04-09 CA CA002293453A patent/CA2293453A1/en not_active Abandoned
- 1999-04-09 EA EA200000025A patent/EA002161B1/ru not_active IP Right Cessation
- 1999-04-09 ES ES99920684T patent/ES2191430T3/es not_active Expired - Lifetime
- 1999-04-09 CN CN99800548A patent/CN1263532A/zh active Pending
- 1999-04-09 JP JP55119799A patent/JP2002505691A/ja not_active Withdrawn
- 1999-04-09 UA UA2000010233A patent/UA45493C2/uk unknown
- 1999-04-09 CZ CZ19994512A patent/CZ292718B6/cs not_active IP Right Cessation
- 1999-04-09 AT AT99920684T patent/ATE230411T1/de not_active IP Right Cessation
- 1999-04-12 AR ARP990101663A patent/AR019046A1/es unknown
- 1999-04-13 MY MYPI99001422A patent/MY115486A/en unknown
- 1999-12-10 NO NO19996127A patent/NO314148B1/no unknown
- 1999-12-21 ZA ZA9907793A patent/ZA997793B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE230411T1 (de) | 2003-01-15 |
| MY115486A (en) | 2003-06-30 |
| IL133114A0 (en) | 2001-03-19 |
| HUP0003802A3 (en) | 2003-05-28 |
| AR019046A1 (es) | 2001-12-26 |
| EA002161B1 (ru) | 2001-12-24 |
| AU749578B2 (en) | 2002-06-27 |
| HUP0003802A2 (hu) | 2001-04-28 |
| EP0989989B1 (en) | 2003-01-02 |
| AU3817499A (en) | 1999-11-01 |
| UA45493C2 (uk) | 2002-04-15 |
| NO996127L (no) | 1999-12-10 |
| GB9808027D0 (en) | 1998-06-17 |
| CZ451299A3 (cs) | 2000-05-17 |
| TW454012B (en) | 2001-09-11 |
| BR9906305A (pt) | 2000-06-20 |
| JP2002505691A (ja) | 2002-02-19 |
| NO996127D0 (no) | 1999-12-10 |
| DK0989989T3 (da) | 2003-05-05 |
| NZ501931A (en) | 2001-08-31 |
| PL337368A1 (en) | 2000-08-14 |
| DE69904682D1 (de) | 2003-02-06 |
| ZA997793B (en) | 2000-08-02 |
| CA2293453A1 (en) | 1999-10-21 |
| ID23006A (id) | 1999-12-30 |
| EP0989989A1 (en) | 2000-04-05 |
| ES2191430T3 (es) | 2003-09-01 |
| DE69904682T2 (de) | 2003-11-13 |
| US6258786B1 (en) | 2001-07-10 |
| CZ292718B6 (cs) | 2003-12-17 |
| NO314148B1 (no) | 2003-02-03 |
| EA200000025A1 (ru) | 2000-08-28 |
| KR20010013772A (ko) | 2001-02-26 |
| WO1999052921A1 (en) | 1999-10-21 |
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