WO2021012698A1 - 二溴苄基衍生物、其立体异构体或其盐及制法和应用 - Google Patents

二溴苄基衍生物、其立体异构体或其盐及制法和应用 Download PDF

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WO2021012698A1
WO2021012698A1 PCT/CN2020/081092 CN2020081092W WO2021012698A1 WO 2021012698 A1 WO2021012698 A1 WO 2021012698A1 CN 2020081092 W CN2020081092 W CN 2020081092W WO 2021012698 A1 WO2021012698 A1 WO 2021012698A1
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dibromobenzyl
amino
derivative
stereoisomer
pharmaceutically acceptable
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PCT/CN2020/081092
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English (en)
French (fr)
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岑国栋
杨茂廷
谭少军
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成都施贝康生物医药科技有限公司
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Priority to US17/629,617 priority Critical patent/US20220251024A1/en
Priority to EP20842969.6A priority patent/EP4001260A4/en
Priority to JP2022505248A priority patent/JP7344607B2/ja
Publication of WO2021012698A1 publication Critical patent/WO2021012698A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • 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
    • 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
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to dibromobenzyl derivatives, their stereoisomers or their pharmaceutically acceptable salts, and preparation methods and applications.
  • Ambroxol is a metabolite of bromhexine, which can promote the secretion of pulmonary surface active substances and the secretion of airway fluid, break the mucopolysaccharide protein fiber in sputum, promote the dissolution of sputum, significantly reduce the viscosity of sputum, and enhance Ciliary movement of the bronchial mucosa promotes the discharge of sputum, which can effectively improve ventilation and dyspnea. Because the expectorant effect of ambroxol is significantly greater than that of bromhexine, it is less toxic and well tolerated, so it has become a commonly used expectorant drug. Ambroxol was used clinically in the form of hydrochloride in 1984.
  • ambroxol hydrochloride has been marketed globally for more than 30 years. It is an older generation expectorant. Although clinically effective, it has been confirmed.
  • ambroxol enters the human body, the hydroxyl group on the cyclohexane will combine with glucuronic acid and become invalid. Therefore, its metabolic stability in the body is reduced. It needs to be administered 2 to 3 times a day, and clinical patients often report that the expectorant effect is not As you wish. Therefore, there is an urgent need for clinical development of a new generation of expectorant drugs with higher effectiveness and better stability in the body.
  • the purpose of the present invention is to solve the above technical problems, and provide dibromobenzyl derivatives, their stereoisomers or their pharmaceutically acceptable salts, preparation methods and applications, and the dibromobenzyl derivatives and their stereoisomers
  • the body is modified by the structural modification of cyclohexane on ambroxol, thereby making it have very good in vivo pharmacokinetic stability and enhanced drug efficacy, and can be used for the preparation of drugs for the treatment of respiratory system, especially expectorants.
  • A is three-membered cycloalkane, four-membered cycloalkane, five-membered cycloalkane, seven-membered cycloalkane or adamantane;
  • B is hydrogen, alkane, hydroxyl, halogen or halogen substituted alkane.
  • the A is a four-membered cycloalkane, a five-membered cycloalkane or adamantane.
  • said A is a five-membered cycloalkane or adamantane;
  • B is a hydrogen, C1-C5 alkane, hydroxyl, halogen or halogen substituted alkane.
  • the B is a C1-C5 alkane, a hydroxyl group, a halogen or a halogen substituted alkane.
  • the structure of the dibromobenzyl derivative and its stereoisomers is selected from any one of the following compounds:
  • the dibromobenzyl derivative is selected from the following compounds:
  • the dibromobenzyl derivative is selected from the following compounds:
  • the pharmaceutically acceptable salt is formed by a dibromobenzyl derivative and an acid.
  • the acid is specifically acetate, bisulfate, ascorbate, benzoate, benzenesulfonate, citrate, fumarate, hydrochloride, hydrobromide, maleate, formate Sulfonate, nitrate, oxalate, phosphate, succinate or sulfate.
  • the preparation method of the dibromobenzyl derivative with the structure shown in formula I according to the present invention involves reacting amino-AB and 2-amino-3,5 dibromobenzaldehyde. After the reaction is complete, a reducing agent is added for reduction, The reaction formula is:
  • the reducing agent is sodium borohydride or potassium borohydride.
  • the preparation method is as follows: put amino-AB, 2-amino-3,5 dibromobenzaldehyde and 100ml tetrahydrofuran into a reaction flask, reflux and react overnight, until the bulk drug disappears, cool to room temperature, add boron After sodium hydride or potassium borohydride, react for 20-40 hours, add 200-300ml of water, extract with 300ml of ethyl acetate, and concentrate under reduced pressure to obtain dibromobenzyl derivatives or their stereoisomers.
  • the present invention also provides the application of the above-mentioned dibromobenzyl derivative, its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for the prevention and treatment of respiratory diseases.
  • the present invention also provides the application of the above-mentioned dibromobenzyl derivative, its stereoisomer or its pharmaceutically acceptable salt in the preparation of expectorant drugs.
  • the present invention also provides a pharmaceutical composition, comprising the above-mentioned dibromobenzyl derivative, its stereoisomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or other substances within the scope of reasonable medical judgment Animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the present invention has the following beneficial effects:
  • the present invention creatively reforms the structure of cyclohexane on ambroxol to obtain the dibromobenzyl derivative and its stereoisomers of the present invention.
  • the present invention surprisingly finds that the dibromobenzyl derivative and its stereoisomers of the present invention have better efficacy and bioavailability than ambroxol hydrochloride. It has passed the rat capillary expectoration test and the mouse The phenol red expectorant test showed that it has excellent expectorant effects. Compared with the positive control group ambroxol hydrochloride, the efficacy has a significant difference, the pharmacokinetic half-life is long, and it has a significant improvement.
  • Compound 1 was prepared according to the method of Example 1. Then (0.018mol) Compound 1 was washed with 100ml saturated sodium chloride, acidified with hydrochloric acid, and concentrated to dryness under reduced pressure to obtain Compound 2. A total of 7.06g, HPLC purity 98.65%, yield 85%.
  • Compound 3 was prepared according to the method of Example 3. Then (0.029 mol) of Compound 3 was washed with 100 ml of saturated sodium chloride, acidified with sulfuric acid, and concentrated to dryness under reduced pressure to obtain Compound 4. A total of 10.60 g, HPLC purity 98.65%, yield The rate is 80%.
  • the prepared compound 12 (0.020 mol) was washed with 100 ml of saturated sodium chloride, acidified with hydrochloric acid, and concentrated to dryness under reduced pressure to obtain compound 13, a total of 7.06 g, HPLC purity 97.60%, yield 78%.
  • test samples can significantly increase the amount of sputum excretion in rats, with statistical differences (P ⁇ 0.01 or P ⁇ 0.05); compared with the ambroxol hydrochloride group, examples Compounds in groups 1, 3, 5, 6, 8, and 12 can significantly increase the tracheal phenol red excretion in mice ( ⁇ P ⁇ 0.05), which is significantly better than ambroxol hydrochloride. Examples 1, 3, 5, and 12 The compound is more prominent.
  • mice 15 minutes after the last administration, the mice were injected subcutaneously with 5% phenol red saline solution (0.5g/kg), The mice were sacrificed 30 minutes later, a section of trachea from under the thyroid cartilage to the branch of the trachea was cut, placed in a test tube containing 1 mL of normal saline, shaken and soaked for 30 minutes, centrifuged for 10 minutes (3000r/min), and the supernatant was transferred to another Add 0.1mL 1M NaOH solution to the test tube, shake well and compare the color at 546nm. The effects of each group on the excretion of phenol red in the trachea of mice were statistically compared, and the experimental results shown in Table 2 below were obtained:
  • the compounds in groups 1, 3, 5, and 12 can significantly increase the tracheal phenol red excretion in mice ( ⁇ P ⁇ 0.05), which is significantly better than ambroxol hydrochloride.
  • phenol red test is a classic expectorant animal model test, after intraperitoneal injection of phenol red in mice, phenol red can be partially excreted from the bronchus.
  • the compounds in groups 1, 3, 5, and 12 can significantly increase phenol in the trachea of mice.
  • the amount of red excretion ( ⁇ P ⁇ 0.05) is significantly better than ambroxol hydrochloride. Therefore, its application in the treatment of respiratory system drugs, especially expectorants, can make it more effective.
  • Example 1 compound group (10 mg/kg, calculated as free base), Example 3 compound group (10 mg/kg, calculated as free base), and implement Example 12: Compound group, ambroxol hydrochloride group (10mg/kg, calculated as free base), 6 rats in each group; corresponding drugs were given by intravenous injection (pH adjusted and dissolved in physiological saline), 15.0min before and after administration , 30.0min, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12.0h and 24.0h, about 0.2mL of blood collected from the jugular vein, placed in a test tube with EDTA-K2, high-speed centrifugation ( 7800 ⁇ g) Plasma was separated after 15 minutes and stored at -15°C ⁇ -35°C.

Abstract

本发明公开了一种结构如式Ⅰ所示的二溴苄基衍生物、其立体异构体或其药学上可接受的盐及制法和应用。本发明的二溴苄基衍生物、其立体异构体具有更好的体内药代稳定性，更优的药效，可用于治疗呼吸系统药物、尤其是祛痰药物的制备。

Description

二溴苄基衍生物、其立体异构体或其盐及制法和应用 技术领域
本发明涉及药物化学领域，具体涉及二溴苄基衍生物、其立体异构体或其药学上可接受的盐及制法和应用。
背景技术
氨溴索(Ambroxol)为溴己新体内代谢产物，能促进肺表面活性物质的分泌及气道液体的分泌，使痰中的黏多糖蛋白纤维断裂，促进黏痰溶解，显著降低痰粘度，增强支气管黏膜纤毛运动，促进痰液排出，可有效改善通气功能和呼吸困难的状况。由于氨溴索的祛痰作用显著超过溴己新，且毒性小，耐受性好，因此成为了目前常用的祛痰药物。氨溴索在1984年以盐酸盐的形式用于临床，适用于伴有痰液分泌不正常、排痰功能不良的急性/慢性肺部疾病，例如慢性支气管炎急性加重、喘息型支气管炎及支气管哮喘的祛痰治疗，手术后肺部并发症的预防性治疗和早产儿及新生儿的婴儿呼吸窘迫综合症(IRDS)的治疗。
国内已经有盐酸氨溴索的冻干粉针、小水针及大输液上市，且盐酸氨溴索已经全球上市30多年了，为老一代的祛痰药，临床上有效性虽然确定，但由于氨溴索进入人体内，其环己烷上的羟基会与葡萄糖醛酸结合而失效，因此，其体内代谢稳定性降低，需要一天给药2～3次，且临床患者常反应祛痰效果不尽如意。因此，临床尚急需要开发有效性更高、体内稳定性更好的新一代祛痰药品。
发明内容
本发明的目的是为了解决上述技术问题，提供二溴苄基衍生物、其立体异构体或其药学上可接受的盐及制法和应用，该二溴苄基衍生物及其立体异构体是通过对氨溴索上环己烷的结构改造，进而使其具有非常好的体内药代稳定性，且药效增强，可用于治疗呼吸系统药物、尤其是祛痰药物的制备。
为实现上述目的，本发明采用的技术方案如下：
一种结构如式Ⅰ所示的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2020081092-appb-000001
其中，A为三元环烷烃、四元环烷烃、五元环烷烃、七元环烷烃或金刚烷；B为氢、烷烃、羟基、卤素或卤素取代的烷烃。
进一步的，所述A为四元环烷烃、五元环烷烃或金刚烷。
进一步的，所述A为五元环烷烃或金刚烷；B为氢、C1-C5烷烃、羟基、卤素或卤素取代的烷烃。
进一步的，所述B为C1-C5烷烃、羟基、卤素或卤素取代的烷烃。
具体地说，所述二溴苄基衍生物、其立体异构体的结构选自以下任意一种化合物：
Figure PCTCN2020081092-appb-000002
Figure PCTCN2020081092-appb-000003
Figure PCTCN2020081092-appb-000004
具体地说，所述的二溴苄基衍生物选自以下化合物：
3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇，
4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇，
(1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇，
(2-氨基-3,5-二溴苄基)-3-甲基-金刚烷-1-胺，
(1R,2S)-2-三氟甲基-((2-氨基-3,5-二溴苄基)氨基)-环戊烷，
(2-氨基-3,5-二溴苄基)-2-氟-金刚烷-1-胺，
(1R,3R)-3-((2-氨基-3,5-二溴苄基)氨基)-环戊醇，
1-((2-氨基-3,5-二溴苄基)氨基)金刚烷-2-醇，
(1S,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇。
优选的，所述二溴苄基衍生物选自以下化合物：
3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇；
4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇
(1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇。
进一步地，所述药学上可接受的盐是由二溴苄基衍生物与酸形成。所述酸具体为乙酸盐、硫酸氢盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、硝酸盐、草酸盐、磷酸盐、琥珀酸盐或硫酸盐。
本发明所述的结构如式Ⅰ所示的二溴苄基衍生物的制备方法，将氨基-A-B、2-氨基-3,5二溴苯甲醛反应，反应完全后，再加入还原剂还原，其反应式为：
Figure PCTCN2020081092-appb-000005
所述还原剂为硼氢化钠或者硼氢化钾。
作为优选，所述制备方法为：将氨基-A-B、2-氨基-3,5二溴苯甲醛及100ml四氢呋喃放入反应瓶中，回流反应过夜，至原料药基本消失，冷却至室温，加入硼氢化钠或硼氢化钾后反应20～40小时，后加水200～300ml，再用300ml乙酸乙酯提取，减压浓缩即可得二溴苄基衍生物或其立体异构体的化合物。
而在此基础上，将上述得到的化合物再通过100ml饱和氯化钠洗涤，再经酸酸化，减压浓缩，得到对应化合物的盐。
本发明还提供了上述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐在制备预防及治疗呼吸系统疾病的药物中的应用。
本发明又提供了上述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐在制备祛痰药物中的应用。
本发明还提供了一种药物组合物，包括上述二溴苄基衍生物、其立体异构体或其药学上可接受的盐和药学上可接受的载体。
所述“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
与现有技术相比，本发明具有以下有益效果：
本发明创造性地对氨溴索上环己烷进行结构改造，得到本发明二溴苄基衍生物及其立体异构体。本发明惊奇地发现，本发明二溴苄基衍生物及其立体异构体相对于盐酸氨溴索而言，具有更好的药效及生物利用度，通过大鼠毛细管排痰试验、小鼠酚红祛痰试验显示发现，其具有优异的祛痰效果，与阳性对照组盐酸氨溴索相比，药效具有显著性差异，药代半衰期长，具有显著的进步。
具体实施方式
下面结合实施例对本发明作进一步说明，本发明的方式包括但不仅限于以下实施例。
以下实施例中，二溴苄基衍生物及其立体异构体的具体结构是通过质谱(MS)或核磁共振(1HNMR)来确定的。其中，核磁共振(1HNMR)位移(δ)以百万分之一(ppm)的单位给出；核磁共振(1HNMR)的测定是用BrukerAVANCE-400核磁仪。本发明实施例中所用的各原料均为市售。
实施例1
本实施例公开了化合物1：3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000006
将3-氨基-1-金刚烷醇3g(0.018mol)、2-氨基-3,5二溴苯甲醛10g(0.036mol)及四氢呋喃(THF)100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，减压浓缩得化合物1，共6.60g，HPLC纯度98.70％，收率86％。
MS m/z(ES):429.01
1H NMR(400MHz,D 2O)δ7.81(d,1H),7.21(d,1H),3.76(s,2H),1.76(s,2H), 1.68-1.66(m,6H),1.46-1.55(m,4H),1.34-1.38(m,4H)。
实施例2
本实施例公开了化合物2：3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇盐酸盐的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000007
按实施例1的方法制得化合物1，再将(0.018mol)化合物1通过100ml饱和氯化钠洗涤，盐酸酸化，减压浓缩至干得化合物2，共7.06g，HPLC纯度98.65％，收率85％。
MS m/z(ES):429.02
1H NMR(400MHz,D 2O)δ7.80(d,1H),7.22(d,1H),3.76(s,2H),1.77(s,2H),1.68-1.67(m,6H),1.46-1.56(m,4H),1.34-1.38(m,4H)。
实施例3
本实施例公开了化合物3：(1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000008
将反式(1R,2R)-2-氨基环戊烷醇3g(0.029mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，减压浓缩得化合物3，共8.90g，HPLC 纯度98.76％，收率86％。
MS m/z(ES):362.95
1H NMR(400MHz,D 2O)δ7.81(d,1H),7.28(d,1H),3.45(s,2H),4.22(m,1H),3.59(m,1H),2.09-2.34(m,2H),1.53-1.72(m,4H)。
实施例4
本实施例公开了化合物4：(1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇硫酸氢盐的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000009
按实施例3的方法制得化合物3，再将(0.029mol)的化合物3通过100ml饱和氯化钠洗涤，硫酸酸化，减压浓缩至干得化合物4，共10.60g，HPLC纯度98.65％，收率80％。
MS m/z(ES):362.97
1H NMR(400MHz,D 2O)δ7.82(d,1H),7.27(d,1H),3.45(s,2H),4.23(m,1H),3.59(m,1H),2.09-2.33(m,2H),1.53-1.73(m,4H)。
实施例5
本实施例公开了化合物5：(2-氨基-3,5-二溴苄基)-3-甲基-金刚烷-1-胺的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000010
将3-甲基-1-金刚烷胺3g(0.018mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol) 及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，有机相减压浓缩至干得化合物5，共6.36g，HPLC纯度98.75％，收率83％。
MS m/z(ES):427.03[M+1]
1H NMR(400MHz,D 2O)δ7.82(d,1H),7.25(d,1H),3.78(s,2H),1.78(s,2H),1.68-1.69(m,6H),1.45-1.57(m,4H),1.34-1.38(m,2H),1.12(s,3H)。
实施例6
本实施例公开了化合物6：(2-氨基-3,5-二溴苄基)-3-三氟甲基-金刚烷-1-胺的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000011
将3--三氟甲基-1-金刚烷胺3g(0.0136mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，有机相减压浓缩至干得化合物6，共5.74g。HPLC纯度99.65％，收率88％。
MS m/z(ES):481.00[M+1]
1H NMR(400MHz,D 2O)δ7.89(d,1H),7.23(d,1H),3.79(s,2H),1.78(s,2H),1.55-1.69(m,6H),1.45-1.50(m,4H),1.34-1.38(m,2H)。
实施例7
本实施例公开了化合物7：(1R,2S)-2-三氟甲基-((2-氨基-3,5-二溴苄基)氨基)-环戊烷的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000012
将(1R,2S)-2-三氟甲基氨基环戊烷3g(0.0196mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，有机相减压浓缩至干得化合物7，共7.08g。HPLC纯度99.56％，收率90％。
MS m/z(ES):414.96[M+1]
1H NMR(400MHz,D 2O)δ7.88(d,1H),7.24(d,1H),3.45(s,2H),3.57(m,1H),2.09-2.23(m,2H),1.53-1.63(m,4H)。
实施例8
本实施例公开了化合物8：(2-氨基-3,5-二溴苄基)-2-氟-金刚烷-1-胺的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000013
将2-氟-1-金刚烷胺3g(0.018mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml,再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，有机相减压浓缩至干得化合物8，共7.00g。HPLC纯度99.36％，收率92％。
MS m/z(ES):431.01[M+1]
1H NMR(400MHz,D 2O)δ7.79(d,1H),7.33(d,1H),3.77(s,2H),3.02(s, 1H),1.55-1.69(m,6H),1.42-1.50(m,4H),1.24-1.34(m,3H)。
实施例9
本实施例公开了化合物9：(1R,3R)-3-((2-氨基-3,5-二溴苄基)氨基)-环戊醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000014
将(1R,3R)-3-氨基环戊醇3g(0.029mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml,再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，有机相减压浓缩至干得化合物9，共8.75g。HPLC纯度98.45％，收率83％。
MS m/z(ES):361.97[M+1]
1H NMR(400MHz,D 2O)δ7.80(d,1H),7.25(d,1H),3.46(s,2H),4.20(m,1H),3.57(m,1H),2.09-2.13(m,2H),1.63-1.73(m,4H)。
实施例10
本实施例公开了化合物10：1-((2-氨基-3,5-二溴苄基)氨基)金刚烷-2-醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000015
将2-氨基-1-金刚烷醇3g(0.018mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TCL监控反应，至原料药基本消 失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml,再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，减压浓缩至干得化合物10，共6.60g，HPLC纯度97.65％，收率86％。
MS m/z(ES):429.01[M+1]
1H NMR(400MHz,D 2O)δ7.81(d,1H),7.24(d,1H),3.77(s,2H),3.50(m,1H)1.77(m,2H),1.68-1.69(m,6H),1.46-1.58(m,4H),1.35-1.38(m,3H)。
实施例11
本实施例公开了化合物11：(1S,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000016
将(1S,2R)-2-氨基环戊醇3g(0.029mol)，2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中，回流反应过夜，TLC监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml,再用乙酸乙酯300ml提取，100ml饱和氯化钠洗涤，减压浓缩至干得化合物11，共8.74g。HPLC纯度97.45％，收率82％。
MS m/z(ES):361.97[M+1]
1H NMR(400MHz,D 2O)δ7.84(d,1H),7.23(d,1H),3.45(s,2H),4.20(m,1H),3.59(m,1H),2.09-2.14(m,2H),1.63-1.78(m,4H)。
实施例12
本实施例公开了化合物12：4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000017
将4-氨基-1-金刚烷醇3g(0.018mol)、2-氨基-3,5二溴苯甲醛10g(0.036mol)及THF100ml加入反应瓶中,回流反应过夜，TCL监控反应，至原料药基本消失，冷却至室温，加入硼氢化钠2.5g(0.066mol)反应24小时，后加水约250ml，再用乙酸乙酯300ml提取，减压浓缩得化合物12，共6.10g，HPLC纯度97.80％，收率80％。
MS m/z(ES):429.01
1H NMR(400MHz,D 2O)δ7.83(d,1H),7.20(d,1H),4.50(s,1H)，3.76(s,2H),1.75(s,2H),1.60-1.66(m,6H),1.46-1.54(m,4H),1.34-1.39(m,4H)。
实施例13
本实施例公开了化合物13：4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇盐酸盐的制备，其结构如下所示：
Figure PCTCN2020081092-appb-000018
按照化合物12的制备方法，制备的化合物12(0.020mol)，通过100ml饱和氯化钠洗涤，盐酸酸化，减压浓缩至干得化合物13，共7.06g，HPLC纯度97.60％，收率78％。
MS m/z(ES):429.02
1H NMR(400MHz,D 2O)δ7.80(d,1H),7.22(d,1H),4.49(s,1H)，3.76(s, 2H),1.77(s,2H),1.68-1.67(m,6H),1.46-1.56(m,4H),1.34-1.38(m,4H)。
为了检测本发明化合物的性能及用途，还做了以下几个试验例对上述实施例得到的各化合物进行检测，具体如下：
试验例1
大鼠毛细管排痰试验
取180～220g的SD大鼠，♀♂兼用，随机分为9组，每组10只；测排痰量前，大鼠禁食不禁水12h，尾静脉给予相应药物(调PH溶解于生理盐水)或生理盐水，给药后30min，腹腔注射乌拉坦生理盐水溶液1g/kg麻醉，仰位固定，剪开颈部皮肤分离气管，在甲状软骨下缘上中两软骨环之间用注射针头扎一小孔，向气管内向心方向插入毛细管(内径0.8mm，长10cm)，调整毛细管与气管之间的角度,收集痰液,用毛细管内液长度(mm)总数作为评价排痰效果，记录90min内大鼠的排痰量,统计分析各组排痰量的多少，得到的结果如表1所示。
表1对大鼠毛细管排痰法排痰量的影响
Figure PCTCN2020081092-appb-000019
Figure PCTCN2020081092-appb-000020
注：与对照组比较：*P<0.05，**P<0.01；与盐酸氨溴索组比较， ▲P<0.05；
从表1可以看出:与对照组比较，受试样品均可显著增加大鼠排痰量，有统 计学差异(P<0.01或P<0.05)；与盐酸氨溴索组比较，实施例1、3、5、6、8、12组化合物均可显著增加小鼠气管酚红排泌量( ▲P<0.05)，显著优于盐酸氨溴索，其中实施例1、3、5、12化合物更为突出。
试验例2
小鼠酚红祛痰试验
实验方法：取72只小鼠，♀♂兼用，随机均分为对照(生理盐水)组、实施例1组(30mg/kg，以游离碱计)、实施例3组(30mg/kg，以游离碱计)、实施例5组(30mg/kg，以游离碱计)、实施例12组(30mg/kg，以游离碱计)、盐酸氨溴索组(30mg/kg，以游离碱计)，每组12只；尾静脉给予相应药物(调PH溶解于生理盐水)或生理盐水，连续2次，末次给药小鼠后15min，皮下注射5％酚红生理盐水溶液(0.5g/kg)，30min后处死小鼠，剪下自甲状软骨下至气管分支处的一段气管，置盛有1mL生理盐水的试管中，震摇浸泡30min后离心10min(3000r/min)，上清液移至另一试管中，加入0.1mL 1M NaOH溶液，摇匀后于546nm处比色。统计比较各组对小鼠气管酚红排泌量的影响，得到如下表2所示的实验结果：
表2，对小鼠气管酚红排泌量的影响
Figure PCTCN2020081092-appb-000021
Figure PCTCN2020081092-appb-000022
注：与对照组比较：*P<0.05；与盐酸氨溴索组比较， ▲P<0.05；
从上表2可以看出：与对照组的小鼠比较，实施例1、3、5、12组化合物及盐酸氨溴索组均可显著增加小鼠气管酚红排泌量(*P<0.05)；
与盐酸氨溴索组比较，实施例1、3、5、12组化合物均可显著增加小鼠气管酚红排泌量( ▲P<0.05)，显著优于盐酸氨溴索。
由于酚红试验为经典的祛痰动物模型试验，小鼠腹腔注射酚红后，酚红可部分地从支气管分泌排出，实施例1、3、5、12组化合物均可显著增加小鼠气管酚红排泌量( ▲P<0.05)，显著优于盐酸氨溴索，因此将其应用于治疗呼吸系统药物、尤其是祛痰药物中，可使其有效性更高。
试验例例3
大鼠药代动力学试验
实验方法：取24只大鼠，♀♂兼用，随机均分为实施例1化合物组(10mg/kg，以游离碱计)、实施例3化合物组(10mg/kg，以游离碱计)、实施例12化合物组、盐酸氨溴索组(10mg/kg，以游离碱计)，每组6只；静脉注射给予相应药物(调PH溶解于生理盐水)，于给药前及给药后15.0min、30.0min、1.0h、2.0h、3.0h、4.0h、6.0h、8.0h、12.0h和24.0h，由颈静脉采血约0.2mL，置于装有EDTA-K2的试管中，高速离心(7800×g)15min后分离血浆，于-15℃～-35℃保存。
通过HPLC/MS/MS上样分析，并对受试化合物的药代动力学行为进行房室模型拟合，并计算主要药代动力学参数，得到如下表3所示的试验结果：
表3药代动力学参数
Figure PCTCN2020081092-appb-000023
与盐酸氨溴索组比较，*P<0.05；
从上表3试验结果可以看出，与盐酸氨溴索组比较，实施例1组、实施例3 组、实施例12组在半衰期(T1/2)、清除率(CL)、滞留时间(MRT)、曲线下面积指标(AUC)上均明显优于盐酸氨溴索组(*P<0.05)，说明本发明实施例制备化合物与盐酸氨溴索相比，体内代谢稳定增强，药代动力学性质明显改善。
上述实施例仅为本发明的优选实施方式，不应当用于限制本发明的保护范围，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围之内。

Claims (13)

  1. 一种结构如式Ⅰ所示的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2020081092-appb-100001
    其中，A为三元环烷烃、四元环烷烃、五元环烷烃、七元环烷烃或金刚烷；B为氢、烷烃、羟基、卤素或卤素取代的烷烃。
  2. 根据权利要求1所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述A为四元环烷烃、五元环烷烃或金刚烷。
  3. 根据权利要求2所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述A为五元环烷烃或金刚烷；B为氢、C1-C5烷烃、羟基、卤素或卤素取代的烷烃。
  4. 根据权利要求3所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述B为C1-C5烷烃、羟基、卤素或卤素取代的烷烃。
  5. 根据权利要求1所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述二溴苄基衍生物、其立体异构体选自以下任意一种化合物：
    Figure PCTCN2020081092-appb-100002
    Figure PCTCN2020081092-appb-100003
    Figure PCTCN2020081092-appb-100004
  6. 根据权利要求5所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述二溴苄基衍生物选自以下化合物：
    3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇，
    4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇，
    (1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇，
    (2-氨基-3,5-二溴苄基)-3-甲基-金刚烷-1-胺，
    (1R,2S)-2-三氟甲基-((2-氨基-3,5-二溴苄基)氨基)-环戊烷，
    (2-氨基-3,5-二溴苄基)-2-氟-金刚烷-1-胺，
    (1R,3R)-3-((2-氨基-3,5-二溴苄基)氨基)-环戊醇，
    1-((2-氨基-3,5-二溴苄基)氨基)金刚烷-2-醇，
    (1S,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇。
  7. 根据权利要求6所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述二溴苄基衍生物选自以下化合物：
    3-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇；
    4-((2-氨基-3,5-二溴苄基)氨基)金刚烷-1-醇；
    (1R,2R)-2-((2-氨基-3,5-二溴苄基)氨基)-环戊醇。
  8. 根据权利要求1所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐，其特征在于，所述药学上可接受的盐由二溴苄基衍生物与酸形成。
  9. 一种权利要求1所述的结构如式Ⅰ所示的二溴苄基衍生物的制备方法，其特征在于，将氨基-A-B、2-氨基-3,5二溴苯甲醛反应，反应完全后，再加入还原剂还原，其反应式为：
    Figure PCTCN2020081092-appb-100005
  10. 根据权利要求8所述的制备方法，其特征在于，所述还原剂为硼氢化钠或者硼氢化钾。
  11. 权利要求1～7任意一项所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐二溴苄基衍生物或其立体异构体或其盐在制备预防及治疗呼吸系统疾病药物中的应用。
  12. 权利要求1～7任意一项所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐在制备祛痰药物中的应用。
  13. 一种药物组合物，包括权利要求1～7任意一项所述的二溴苄基衍生物、其立体异构体或其药学上可接受的盐和药学上可接受的载体。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536713A (en) * 1966-05-10 1970-10-27 Boehringer Sohn Ingelheim N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof
CN101544572A (zh) * 2008-03-26 2009-09-30 连云港恒邦医药科技有限公司 一种氨溴索衍生物及其制备方法
CN105693764A (zh) * 2015-11-30 2016-06-22 成都施贝康生物医药科技有限公司 一种氨溴索衍生物及应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE625022A (zh) * 1961-11-20 1900-01-01
DE2027944A1 (de) * 1970-06-06 1971-12-16 Knoll Ag, Chemische Fabriken, 6700 Ludwigshafen N-substituierte Norcamphanderivate
AT332375B (de) * 1973-04-13 1976-09-27 Thomae Gmbh Dr K Verfahren zur herstellung von neuen aminobenzylaminen sowie deren saureadditionssalzen
CN103012167A (zh) * 2012-12-16 2013-04-03 石药集团中诺药业（石家庄）有限公司 一种盐酸氨溴索的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536713A (en) * 1966-05-10 1970-10-27 Boehringer Sohn Ingelheim N-(hydroxy-cyclohexyl)-aminobenzylamines and the salts thereof
CN101544572A (zh) * 2008-03-26 2009-09-30 连云港恒邦医药科技有限公司 一种氨溴索衍生物及其制备方法
CN105693764A (zh) * 2015-11-30 2016-06-22 成都施贝康生物医药科技有限公司 一种氨溴索衍生物及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 28 February 2016 (2016-02-28), ANONYMOUS: "Benzenemethanamine, 2-amino-3,5-dibromo-N-cyclopentyl- (CA INDEX NAME) OTHER CA INDEX NAMES- 2-Amino-3,5-dibromo-N-cyclopentylbenzenemethanamine", XP055896678, retrieved from STN Database accession no. 1874745-62-6 *

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