CN88100328A - 利福霉素衍生物盐 - Google Patents
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- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 150000007530 organic bases Chemical class 0.000 claims abstract description 5
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229940062280 rifamycin sodium Drugs 0.000 claims description 6
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
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- 229930182817 methionine Natural products 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 239000000273 veterinary drug Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 4
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 229930195722 L-methionine Natural products 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- -1 1-diethylamino ethylidene Chemical group 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式(I)的利福霉素衍生物盐及其制备方法和在治疗上的用途。式(I)中B代表无毒性的、药理上适宜的无机或有机碱。
Description
已知利福霉素类是一类重要的抗菌素，特别是其中的利福平，因其口口服后具有强抗菌作用及高生物药效率，从而成为治疗分支杆菌属（例如结核杆菌）感染的首选药物。
在我们的意大利专利20278/83及其它专利如美国专利4，562，203中，我们主要介绍并要求专利保护的是一种新的利福霉素衍生物-3-[（1-二乙基氨基亚乙基）连氮甲基]利福霉素SV，其具体结构如下式所示（其中B为氢）：
此衍生物对于多种分支杆菌属菌株及其它革兰氏阳性菌和部分革兰氏阴性菌具有强抗菌作用;这种抗菌作用的平均强度与利福霉素本身相当，或甚至更高一些。
B为氢的式（Ⅰ）化合物的药理动力学特性明显优于利福霉素，因为它在多种动物的血液中都有较长的半寿期，这说明它能随血液循环较长的时间，从而其体内效果更好。
以下药理动力学评价参量，即口服后的最大血液浓度平均看来和利福霉素相似，这证明B为氢的式（Ⅰ）化合物在各种实验动物体内的生物药效率与利福平相近。
我们发现预先使B为氢的式（Ⅰ）化合物成盐而得到B为无毒性的、药理上适宜的无机或有机碱的式（Ⅰ）化合物，可显著改善其生物药效率。
这些盐-本发明的目的物-是到目前为止在临床文献中还未见到的新化合物。
优选的成盐产物是用碱金属碱、氨基酸，或甚至用简单有机胺制得的盐，例如钠盐、赖氨酸盐和三乙胺盐。
所有这些成盐方法已证明都适用于将基本不溶于水的酸式产物（式Ⅰ，B＝H）（因而它易于通过胃肠道而至少有一部分没有改变，只是有限地被吸收）转变为极易溶于水的盐，由此便创造了提高其生物药效率的必要条件。还应考虑到，尽管成盐物质的良好水溶性是必需的，但一般仍不足以保证成盐物质本身在口服后能被充分吸收，这是因为胃酸可以使盐本身分解并使不溶性结晶物形式的相应酸再次析出。所以这些盐的生物药效率得以改善的原因这样解释更加确切：在上述情况下，该酸性物质在胃中沉淀析出后成为无定形的、极细的分散物质，所以进入碱性的肠道环境后更可溶且/或更易于溶解。
撇开上述盐的生物药效率得以大大提高的内在物理化学和生物化学机制不谈，根据对不同种动物以至最后对人所做实验的结果（参见例示性的表1），都表明：在给药剂量相同的情况下，盐形式的利福霉素衍生物在血液中的浓度水平比酸形式产品高得多。
表1
口服300毫克B为Na的式（Ⅰ）的盐以及相应的式（Ⅰ）（B为H）的游离酸后的血液（血清）水平
化合物Ⅰ，B＝Na 浓度 化合物Ⅰ
B＝H
小时 实验对象1 实验对象2 （微克/毫升） 实验对象3
2 8.0 9.6 2.0
4 8.4 8.5 3.1
6 7.9 82 2.9
10 6.6 72 2.5
26 2.9 2.1 2.5
34 1.9 1.0 1.1
50 0.7 0.2 0.3
不言而喻，在应用式（Ⅰ）的新的利福霉素衍生物的水溶性盐时，可将该衍生物配制成可注射的制剂，而未盐化、因而不溶解的产品不可能如此。
式（Ⅰ）的盐按以下方法易于制得：使几乎等摩尔量的酸式式（Ⅰ）化合物（B＝H）和适宜的碱在水或在有机溶剂如乙醇中进行反应。
上述盐的制备还可以选择在少量抗坏血酸或其盐存在下进行，这是为了利用其已知的还原能力防止利福霉素衍生物可能转变成醌的形式。制得的盐易按以下方法分离：在含水介质中进行制备时，可将所得溶液蒸干或冻干;或者用其它适宜的有机溶剂使盐从溶液中沉淀出来。
必要时，可将分离出的产物用结晶或其它常用的方法进一步提纯。
为了更好地说明而非用以限制本发明，现给出以下制备实例。
例1
将5.0克3-[（1-二乙氨基亚乙基）连氮甲基]利福霉素SV（I，B＝H）悬浮于20毫升乙醇中，再加入60毫克溶于1毫升水中的抗坏血酸钠以防止形成少量氧化产物（即醌式的利福霉素）。在搅拌下，向所得悬浮液中加入等摩尔量（323毫克）的甲醇钠，于是该游离酸因转化成相应的钠盐而很快地溶解。滤除少量不溶物（实际上是抗坏血酸钠），在减压降温下蒸干滤液，得到结晶状残余物，其产率几乎是定量的。该残余物即3-[（1-二乙氨基亚乙基）连氮甲基]利福霉素SV的钠盐（I，B＝Na），基本上是纯的。若需要，此产物可用异丙醇（50毫升）结晶而进一步纯化;结晶产率可达90%以上。此化合物为橙红色固体，易溶于水，可溶于甲醇、乙醇、丙酮、乙酸乙酯、氯仿，不易溶于异丙醇，不溶于乙醚及石油醚。加热时，在210℃开始发生碳化，甚至在更高温度下也不熔解，分光光度分析（采用0.1%甲醇溶液，再用pH6的磷酸盐缓冲液稀释至0.02毫克/毫升）表明在231、261、338、485毫微米处有吸收峰。
元素分析（C44H59N4O12Na;分子量858.95）
C、H、N在实验误差范围内（＜0.5%）
Na（用0.02N盐酸滴定）＝99.6%
例2
将5.0克3-[（1-二乙氨基亚乙基）连氮甲基]利福霉素SV（I，B＝H）悬浮在100毫升水中（悬浮液pH＝5.2），再于搅拌并冷却至5～10℃的条件下使之与5.97毫升1N氢氧化钠反应，后者是约用3小时时间小心滴加到悬浮液中的。产物逐渐缓慢地溶解，过滤澄清最后得到的溶液（pH9.9），用冷冻干燥法将其蒸干，得到定量的所要制备的盐（I，B＝Na）;该盐为无定形橙红色粉末，同例1方法制得的产品相似。
例3
把1.0克3-[（1-二乙氨基亚乙基）连氮甲基]利福霉素SV（I，B＝H）悬浮于10毫升水中，再向悬浮液内加入等摩尔量的D，L-赖氨酸（即0.32毫升50%的D，L-赖氨酸水溶液）。上述利福霉素衍生物迅速完全溶解。然后过滤使溶液变清并在减压降温条件下将其蒸干。从而得到所要制备的赖氨酸盐（I，B＝D，L-赖氨酸·H），产率几乎是定量的。该盐为红色结晶状固体。
要是愿意，可用适宜的异丙醇/异丙醚混合液将该产品进一步提纯。
分析：C50H74N6O14（分子量983.17）
C、H、N在实验误差范围内（＜0.5%）
碱测定值（base assay）＝99.4%
Claims (3)
1、制备下式化合物的方法：
式中B代表无毒性的、药理上适宜的无机或有机碱，该方法包括：使3-[(1-二乙氨基亚乙基)连氮甲基]利福霉素SV与等摩尔量的上述适宜的无机或有机碱在水或有机溶剂中反应，此反应也可以选择地抗坏血酸或其盐存在下进行，然后用蒸干或加入沉淀剂的方法分离出生成的盐。
2、根据权利要求1的方法，其中的无机碱是氢氧化钠或甲醇钠。
3、根据权利要求1的方法，其中的有机碱是赖氨酸。
4、下式化合物在制备用于治疗感染性疾病的兽药或供人使用的口服、非肠道或外部使用的药剂方面的用途：
式中B代表有机或无机碱。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19162/87A IT1202424B (it) | 1987-01-26 | 1987-01-26 | Sali di un derivato rifamicinico |
| IT19162A/87 | 1987-01-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN88100328A true CN88100328A (zh) | 1988-09-28 |
| CN1015368B CN1015368B (zh) | 1992-02-05 |
Family
ID=11155406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88100328A Expired CN1015368B (zh) | 1987-01-26 | 1988-01-26 | 制备利福霉素衍生物盐的方法 |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR960006393B1 (zh) |
| CN (1) | CN1015368B (zh) |
| ES (1) | ES2006280A6 (zh) |
| GB (1) | GB2200353B (zh) |
| IN (1) | IN165924B (zh) |
| IT (1) | IT1202424B (zh) |
| PT (1) | PT86621B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107840854A (zh) * | 2012-08-13 | 2018-03-27 | 阿迪帕姆单人股份公司 | 3‑甲酰基利福霉素sv的3‑(4‑肉桂基‑1‑哌嗪基)氨基衍生物的用途和制备方法 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0447813A1 (en) * | 1990-02-28 | 1991-09-25 | GRUPPO LEPETIT S.p.A. | Water soluble salts of purpuromycin and pharmaceutical formulations thereof |
| BG64021B1 (bg) * | 1998-11-04 | 2003-10-31 | КОНСТАНТИНОВА Румяна | Натриева сол на 3-(4-цинамил-1-пиперазинил)-иминометил рифамицин и метод за получаването й |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1201963B (it) * | 1983-03-24 | 1989-02-02 | Prodotti Antibiotici Spa | Derivati delle rifamicine e procedimento per la loro preparazione |
-
1987
- 1987-01-26 IT IT19162/87A patent/IT1202424B/it active
-
1988
- 1988-01-18 IN IN44/CAL/88A patent/IN165924B/en unknown
- 1988-01-25 KR KR1019880000536A patent/KR960006393B1/ko not_active IP Right Cessation
- 1988-01-25 GB GB8801577A patent/GB2200353B/en not_active Expired - Fee Related
- 1988-01-26 PT PT86621A patent/PT86621B/pt not_active IP Right Cessation
- 1988-01-26 ES ES8800204A patent/ES2006280A6/es not_active Expired
- 1988-01-26 CN CN88100328A patent/CN1015368B/zh not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107840854A (zh) * | 2012-08-13 | 2018-03-27 | 阿迪帕姆单人股份公司 | 3‑甲酰基利福霉素sv的3‑(4‑肉桂基‑1‑哌嗪基)氨基衍生物的用途和制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2200353A (en) | 1988-08-03 |
| KR880009026A (ko) | 1988-09-13 |
| GB8801577D0 (en) | 1988-02-24 |
| IT1202424B (it) | 1989-02-09 |
| PT86621B (pt) | 1991-12-31 |
| GB2200353B (en) | 1990-11-28 |
| IN165924B (zh) | 1990-02-10 |
| IT8719162A0 (it) | 1987-01-26 |
| KR960006393B1 (ko) | 1996-05-15 |
| PT86621A (pt) | 1988-02-01 |
| CN1015368B (zh) | 1992-02-05 |
| ES2006280A6 (es) | 1989-04-16 |
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