CN114907221A - 一种氘代氨溴索衍生物及其制备和用途 - Google Patents
一种氘代氨溴索衍生物及其制备和用途 Download PDFInfo
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- CN114907221A CN114907221A CN202110164994.0A CN202110164994A CN114907221A CN 114907221 A CN114907221 A CN 114907221A CN 202110164994 A CN202110164994 A CN 202110164994A CN 114907221 A CN114907221 A CN 114907221A
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- Prior art keywords
- deuterated
- pharmaceutically acceptable
- acceptable salt
- ambroxol
- compound
- Prior art date
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- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical class NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 15
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- 229910052805 deuterium Inorganic materials 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 3
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- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
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- WCYWZMWISLQXQU-FIBGUPNXSA-N trideuteriomethane Chemical group [2H][C]([2H])[2H] WCYWZMWISLQXQU-FIBGUPNXSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/12—Mucolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种氘代的氨溴索衍生物及其制备和用途。具体地，本发明公开了一种式（
）所示化合物或其立体化学异构体、溶剂化合物、或药学上可接受的盐。实验结果表明，本发明提供的氘代的氨溴索衍生物具有更好的稳定性和药代动力学，能够用于制备更安全有效的祛痰药，应用前景优良。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一种化合物及其制备和用途。
背景技术
氨溴索又称溴环己基胺醇，为反式-4-[（2-氨基-3，5-二溴苄基）胺基]环己醇，其分子式为C13H18Br2N2O，其结构式为：
氨溴索为溴己新的代谢产物，本品为粘液溶解剂，能增加呼吸道粘膜浆液腺的分泌,减少粘液腺分泌，从而降低痰液粘度；还可促进肺表面活性物质的分泌，增加支气管纤毛运动,使痰液易于咳出。本品从血液至组织的分布快且显著,肺脏为主要靶器管。血浆半衰期为7-12小时，无累积效应。氨溴索主要在肝脏代谢,大约90%经肾脏排除。适用于伴有痰液分泌不正常及排痰功能不良的急性、慢性呼吸道疾病,例如慢性支气管炎急性加重、喘息型支气管炎、支气管扩张及支气管哮喘的祛痰治疗。术后肺部并发症的预防性治疗。早产儿及新生儿婴儿呼吸窘迫综合症(IRDS)的治疗。
4-(6,8-二溴-3,4-二氢喹唑啉-3-基)-环己醇（杂质B）是氨溴索主要的降解杂质。临床滴注氨溴索注射液，关于是否可以用葡萄糖注射液作为溶媒，曾经有过反复的意见。2013年3月，因临床反应，氨溴索注射液用5%葡萄糖注射液稀释，有微粒析出的现象。当时生产氨溴索注射液（商品名，沐舒坦）的勃林格殷格翰（中国）公司做了一个实验，将沐舒坦与来自不同国家不同生产商、不同批次的5%葡萄糖溶液混合，检出了一定数量的降解产物B-是由盐酸氨溴索与葡萄糖溶液中普遍存在的微量甲醛发生反应后形成的。于是该公司发表了关于“盐酸氨溴索注射液与5%葡萄糖注射液不宜混合使用”致经销商/医院的沟通信。同年12月该公司又发布信息：之前公司在进一步毒理学实验尚未完成的情况下，本着严谨科学的态度，建议慎用盐酸氨溴索与5%葡萄糖溶液混合使用。而最新完成的毒理学研究显示，没有发现任何证据表明该降解产物会对患者安全性带来风险。基于目前为止的所有证据，勃林格殷格翰公司确认沐舒坦（盐酸氨溴索注射液）可以安全地与5％葡萄糖溶液配伍使用。在中国现行产品说明书中，盐酸氨溴索注射液（15mg/2ml）被批准可以与溶媒（生理盐水、林格氏液、5％葡萄糖溶液、5％果糖溶液）混合后静脉给药。但是还有可能存在一定的风险。以盐酸氨溴索为起始原料,与甲醛经环合,氧化两步反应合成了此有关物质。
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期会延长。
由于生物系统的代谢过程复杂，药物在生物体内的药代动力学性质受到多方面因素影响，也表现出相应的复杂性。与相应的非氘代药物相比，氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期，反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery andDevelopment，P405-406。)，劣化其药代动力学性质；另一方面，药物分子上某些位置的氢因为空间位阻等原因也不易被氘代，因此，药物的氘代并非随心所欲，可氘代的位点是不可预期的。
本发明人期望通过对氨溴索进行氘代，得到一类稳定性好、祛痰、药代动力学性质良好、降低有毒副作用的代谢产物的氘代药物。
发明内容
本发明的目的在于提供一种具有祛痰生物活性的氘代氨溴索衍生物。
一种式（
）所示氘代氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐：
其中R1和R2分别独立地选自氢和氘、CH3、CD3，且所述R1和R2中至少含有一个D原子。
进一步地，所述的立体化学异构体为（1r，4r）。
进一步地，所述的药学上可接受的盐为盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐；优选为盐酸盐。
进一步地，所述的化合物为：
本发明还提供了上述的氘代氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐在制备祛痰药物中的用途。
一种药物组合物，它是以上述的氘代氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明中，“治疗”也包括复发性(relapse)预防或阶段性(phase)预防，以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗，例如抑制症状。它可以在短期内实现，在中期内调整，或者可以说是长期治疗，例如在维持疗法里面。
所述“预防”包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作；防止对象染上病症、疾病或病况；或降低对象染上病症、疾病或病况的风险的方法。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
除特别标注的外，本发明所用试剂和测试设备均为常规的市售试剂和设备。
实施例1、（1r，4r）-4-（（2-（氨基-D）-3,5-二溴苄基）氨基）环己-1-醇（化合物1）
第一步：合成（1r，4r）-4-（（（（E）-2-（氨基-D）-3,5-二溴亚苄基）氨基）环己-1-醇（1-2）
向干燥洁净的250ml反应瓶中加入2-（一氘代-氨基）-3,5-二溴苯甲醛25g（0.089mol），反式-4-氨基环己醇10.3g(0.089mol)，无水乙醇150ml，启动搅拌，升温至回流，保温反应12小时。TCL监控，反应毕，然后降温至20~30℃，向反应体系中加入纯化水75ml，析出大量固体，过滤，滤饼干燥得浅黄色固体33.5g，收率：99.4%，HPLC纯度97.6%。
第二步：合成（1r，4r）-4-（（2-（氨基-D）-3,5-二溴苄基）氨基）环己-1-醇（化合物1）
向干燥洁净500ml反应瓶中加入中间体
32.5g（0.086mol），无水甲醇130ml，启动搅拌，升温至40~60℃，保温30min，然后降温至20~30℃，向反应液中滴加硼氢化钠水溶液（NaBH4：3.25g 0.086mol；H2O：29.25g配制溶液），滴加完毕后，保温反应3小时，然后加入水，再加入二氯甲烷萃取（3*100ml），有机相合并，减压浓缩后加入丙酮，加入盐酸成盐，析出大量固体，过滤，滤饼干燥得浅黄色至类白色固体（HPLC纯度99.2%）。
本发明的其他化合物可用类似的方法制备得到。
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物的药学稳定性实验
（1）高效照高效波相色谱法测定，用十八烷基硅烷键合硅胶为填充剂，以0.01mol/L磷酸氢二铵溶液（用磷酸调节pH值至7.0）-乙腈（50:50）为流动相，检测波长为248nm。盐酸氨溴索与杂质B（相对保留时间约为0.8）的分离度应大于4.0。
（2）取盐酸氨溴索约5mg,加甲醇0.2ml溶解，再加甲醛溶液（1-100）40μl，摇匀，置60℃水浴中加热5分钟，氮气吹干。残渣加水5ml溶解，再加流动相稀释至20，摇匀。
（3）化合物（
）、化合物（
）和以方法（2）相同方法破坏。
（4）取上述供试品溶液20μl分别注入液相色谱仪，记录色谱图，以归一化法计算杂质B的含量。
体外药学稳定性试验结果见表1。
表1、体外药学稳定性试验结果
| 杂质B | 主峰（%） | |
| 盐酸氨溴索 | 43.8% | 56.2% |
| 实施例1化合物 | 11.6% | 88.4% |
| 实施例2化合物 | 0.05% | 99.5% |
如上表所示，实施例1和实施例2制备的化合物稳定性较盐酸氨溴索好。显示了本发明的氘代化合物都比非氘代的化合物盐酸氨溴索好，表明本发明化合物体外有更好的稳定性和安全性。
试验例2、本发明化合物的大鼠药代动力学
1)实验材料及仪器：
Agilent 1100高效液相色谱系统，API4000三重四极杆质谱仪，配有电喷雾离子化（ESI源），Analyst 1.4(美国ABI公司) 。
高速冷冻离心机，购自Thermo Fisher Scientific
分析天平，购自赛多利斯，SECURA225D-1CN
健康SPF级SD大鼠12只，雄性，动物合格证编号：42000600002461
2)实验方法及结果
将12只SD大鼠（180-250g)分为A、B两组，每组6只，禁食过夜(自由饮水)后，分别灌胃给药56.25mg；于给药前及给药后0.5、1、1.5、2、3、4、6、8、12、24h断尾取血约0.5ml，入放入装有肝素钠的1.5ml的EP管中，4℃离心5min分离血浆，于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。
表2、本发明化合物的大鼠药代动力学参数
从表2可以看出本发明化合物的暴露量(AUC)显著高于贝达喹啉，显示了更好的药代动力学。预期在临床上可以减小使用剂量，成为更安全,病人依从性更好的抗结核病药物。
综上，本发明提供的氘代氨溴索化合物具有更好的代谢稳定性和药代动力学，能够用于制备更安全有效的祛痰治疗的药物。应用前景优良。
Claims (6)
1.一种式（I）所示化合物或其立体化学异构体、溶剂化合物、或药学上可接受的盐：
其中R1和R2分别独立地选自氢和氘、CH3、CD3，且所述R1和R2中至少含有一个D原子。
2.根据权利要求1所述的化合物或其化学立体异构体、溶剂化合物或药学上可接受的盐，所述的化学异构体为（1r，4r）。
3.根据权利要求1所述的化合物或其化学立体异构体、溶剂化合物或药学上可接受的盐，其特征在于：所述的药学上可接受的盐为盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐；优选为盐酸盐。
4.根据权利要求1～3任一项所述的氘代氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐，其特征在于：所述化合物结构为
5.权利要求1～4任一项所述的氘代的氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐在制备黏痰溶解药物中的用途。
6.一种药物组合物，其特征在于：它是以权利要求1～4任一项所述的氘代的氨溴索衍生物或其立体化学异构体、溶剂合物或药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
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