WO2022193369A1 - 反式金刚烷氨衍生物或其盐的用途 - Google Patents

反式金刚烷氨衍生物或其盐的用途 Download PDF

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WO2022193369A1
WO2022193369A1 PCT/CN2021/084409 CN2021084409W WO2022193369A1 WO 2022193369 A1 WO2022193369 A1 WO 2022193369A1 CN 2021084409 W CN2021084409 W CN 2021084409W WO 2022193369 A1 WO2022193369 A1 WO 2022193369A1
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amino
trans
formula
compound
acid
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PCT/CN2021/084409
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English (en)
French (fr)
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牟霞
董波
张海
曾燕群
徐霞
江杰
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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 EP21930957.2A priority Critical patent/EP4310070A1/en
Publication of WO2022193369A1 publication Critical patent/WO2022193369A1/zh

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • 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
    • A61P11/14—Antitussive agents
    • 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 technical field of medicine, in particular to the use of a trans-adamantanamine derivative or a pharmaceutically acceptable salt thereof.
  • Lung injury is the damage of lung parenchyma caused by different traumatic factors, which can be manifested as lung laceration, lung contusion and lung blast injury.
  • the most common is pulmonary contusion, which occurs in 30% to 75% of blunt chest injuries and has a mortality rate of 14% to 40%.
  • Pulmonary trauma, lung surgery, lung infection, pulmonary embolism, etc. can also lead to lung damage.
  • the rate of lung injury in the world continues to rise, and there are no effective drugs, mainly analgesics and anti-infectives. Therefore, there is an urgent need for safe and effective drugs for the treatment of lung injury, especially for the treatment of acute lung injury.
  • Coughing is one of the biological defense responses to exhalation of phlegm and foreign bodies in the airways, but if persistently excessive, it can lead to a decrease in quality of life (QOL). Cough is common clinically, especially chronic cough lasting > 8 weeks, accounting for more than 1/3 of the outpatient department of respiratory department, which seriously affects the work and daily life of patients. The increased cough sensitivity caused by airway neurogenic inflammation is an important mechanism. .
  • Ambroxol has been approved in many countries for acute and chronic lung diseases associated with abnormal sputum secretion and poor expectoration. Therefore, the main effect of ambroxol is to remove nitrogen, and its treatment effect on lung injury, especially acute lung injury, is not good. At the same time, Japan has also approved ambroxol for the treatment of cough.
  • Patent CN201910671508.7 discloses dibromobenzyl derivatives, stereoisomers or salts thereof, and preparation methods and applications.
  • the disclosed dibromobenzyl derivatives are obtained by structural modification of cyclohexane on ambroxol. Compared with ambroxol hydrochloride, the disclosed dibromobenzyl derivative has better bioavailability and better expectorant effect.
  • trans-adamantanidine derivatives for the prevention and treatment of lung injury and cough, especially for acute lung injury and refractory cough.
  • the purpose of the present invention is to provide the use of a trans-adamantaneamine derivative as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or/and treating respiratory diseases.
  • the structure of the present invention is as shown in the use of the trans-adamantane amino derivative or its pharmaceutically acceptable salt in the preparation of a medicament for preventing or/and treating respiratory diseases, as shown in formula I,
  • Some embodiments of the present invention include use in the manufacture of a medicament for preventing or/and treating lung injury.
  • Some embodiments of the present invention include use in the manufacture of a medicament for preventing or/and treating cough.
  • Some embodiments of the present invention include use in the preparation of a preventive or/and therapeutic expectorant.
  • the pharmaceutically acceptable salt is formed from a trans-adamantanamine derivative and an acid.
  • the acid is a pharmaceutically acceptable inorganic acid or organic acid, wherein the inorganic acid is selected from hydrochloric acid, hydrosulfuric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid; the organic acid is selected from formic acid, acetic acid , acetic anhydride, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid , glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, metatartaric acid, ascorbic acid, gallic acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, acid,
  • the pharmaceutically acceptable salts include acetate, bisulfate, ascorbate, benzoate, benzenesulfonate, citrate, fumarate, hydrochloride, hydrobromide , maleate, mesylate, nitrate, oxalate, phosphate, succinate or sulfate.
  • the pharmaceutically acceptable salt is selected from,
  • the pharmaceutically acceptable salt is a hydrochloride having the structure shown in formula V,
  • the structure of the present invention is as the preparation method of trans-adamantane ammonia derivative shown in formula I, including two-step reaction:
  • Step 1 using the compound of formula III, the compound of formula IV or a salt thereof as the starting material, the compound of formula II is prepared by condensation reaction;
  • step 2 the compound of formula II is subjected to a reduction reaction with a reducing agent to obtain the trans-adamantanylamine derivative represented by formula I;
  • step 3 the salt of the compound of formula I is prepared by reacting the compound of formula I with an acid to form a salt, and the reaction formula is:
  • the reducing agent includes, but is not limited to, sodium borohydride or potassium borohydride.
  • salts of compounds of formula IV include, but are not limited to, hydrochloride, sulfate, and hydrobromide.
  • the reaction solvent, the compound of formula III, the compound of formula IV or its salt, an acid binding agent and a desiccant are added into the reaction kettle, and the reaction is heated and stirred to prepare the compound of formula II.
  • the molar ratio of the starting material of the compound of formula III to the compound of formula IV is 1:0.8-1:2.0, preferably 1:1-1:1.5.
  • the acid binding agent is selected from inorganic bases or/and organic bases; preferably, the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, hydrogen Any one or more in potassium oxide, lithium hydroxide or sodium hydride;
  • the organic base includes but is not limited to any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, diethylamine, diisopropylamine, N,N-diisopropylethylamine or several.
  • the molar ratio of the compound of formula III to the acid binding agent is 1:1-1:5.0, preferably 1:1-1:1.5.
  • the reaction solvent includes but is not limited to ethanol, methanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, Any one or more in dimethyl sulfoxide, acetonitrile, tetrahydrofuran;
  • the mass volume ratio of the compound of formula III (2-amino-3,5-dibromobenzaldehyde) to the reaction solvent is 1:3 to 1:20, preferably 1:12 to 1:16, wherein the mass unit When it is kg, the unit of volume is L.
  • the desiccant includes, but is not limited to, any one or more of magnesium sulfate, sodium sulfate, calcium sulfate, molecular sieve, and calcium chloride; preferably, the compound of formula III (2-amino-3,5-dibromobenzene)
  • the molar ratio of formaldehyde) and desiccant is 1:0.5-1:5, preferably 1:0.8-1:1.5.
  • the reaction temperature is 50°C-120°C, preferably 70°C-80°C;
  • the step 1 also includes a post-processing step, in which the reaction solution is filtered, concentrated, crystallized, and dried to obtain the compound of formula II.
  • the solvent for recrystallization includes, but is not limited to, any one or more of methanol, ethanol, isopropanol, and n-propanol; the weight-volume ratio of the compound of formula III to the solvent for recrystallization is: 1:4 ⁇ 1:25, preferably: 1:9 ⁇ 1:11; when the unit of weight and volume is kg, the unit of volume is L.
  • the reaction solvent in the step 2 includes, but is not limited to, one or both of dichloromethane and methanol; the mass-volume ratio of the compound of formula II to the reaction solvent is 1:3-50 ; preferably 1:29, wherein, when the mass unit is kg, the volume unit is L.
  • the reaction temperature is 0°C-10°C
  • the molar ratio of the compound of formula II to the reducing agent is 1:1.1-1:2.5.
  • the reaction solvent in the step 3 is not limited to any one or more of ethanol, acetone and methanol; the mass-volume ratio of the compound of formula I to the reaction solvent is 1:3-70 ; preferably 1:12 or 1:14 or 1:29; wherein, when the mass unit is kg, the volume unit is L.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the trans-adamantaneamine derivative represented by formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the "pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or other tissues of animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the present invention has the following beneficial effects:
  • the present invention creatively carries out structural transformation on cyclohexane on ambroxol to obtain the trans-adamantane ammonia derivative shown in formula I.
  • the present invention finds that the trans-adamantaneamine derivatives and their hydrochloride salts of the present invention have better properties than ambroxol hydrochloride and adamantaneamine hydrochloride derivative mixtures (isomer mixtures).
  • Efficacy Through the mouse acute lung injury test and the ammonia water-induced cough model in mice, it was found that it has an excellent effect on the treatment of lung injury and cough, and its effect is better than that of ambroxol hydrochloride and amantadine hydrochloride derivative mixture. Statistical significance.
  • the trans-amantadine derivative and its hydrochloride of the present invention can significantly increase the amount of sputum in rats, and can significantly increase the amount of phenol red excretion in mice, and its effect is better than that of ambroxol hydrochloride And and amantadine hydrochloride derivative mixture.
  • Figure 7 is the 1 H-NMR spectrum of the compound of formula V trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride (DMSO-d6) ;
  • Figure 8 is the 13 C-NMR spectrum of the compound of formula V trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride (DMSO-d6) ;
  • Figure 10 is the single crystal diffraction pattern of the compound of formula V trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride.
  • Examples 1-17 disclose the preparation of intermediates of the present invention.
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • MS formula C 17 H 20 Br 2 N 2 O Theoretical M is 428.17.
  • the mass spectrum molecular ion peak m/z 429.33 is [M+H] + peak; the mass spectrum molecular ion peak m/z 427.31 is [MH] - peak, which is consistent with the structural formula.
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • This embodiment discloses the preparation method of the intermediate trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol of the present invention, which specifically includes the following steps:
  • Examples 17-20 disclose the preparation methods of trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol and salts thereof.
  • This embodiment discloses the preparation of compound trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol of formula I, and the reaction formula is:
  • the specific preparation method is:
  • Step 1 Preparation of trans-4-[(2-amino-3,5-dibromophenylidene)amino]-adamantan-1-ol (compound of formula II)
  • This embodiment discloses the preparation of trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride (compound of formula V), and the reaction formula is:
  • the specific preparation method is as follows: put 21.50 g (0.05 mol) of the compound of formula I prepared by the method in Example 17 and 300 mL of absolute ethanol into a reaction flask, and heat to 75° C. until the solid dissolves. 40 mL of 15% hydrogen chloride (ethanol) solution was added dropwise to the substrate, and after the addition was completed within 0.5 h, the heating was stopped, and the temperature was naturally cooled for about 3 h. It was filtered to obtain 19.8 g of trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride (compound of formula V).
  • the present application also provides the infrared absorption spectrum of the compound of formula V to confirm its structure (as shown in FIG. 9 ).
  • the application also carried out single crystal cultivation of the compound of formula V of the invention, and carried out a single crystal diffraction experiment (as shown in Figure 10), which further confirmed the 4-[(2-amino-3,5- Dibromobenzyl)amino]adamantane-1-ol is a trans structure, and the trans 4-[(2-amino-3,5-dibromobenzyl)amino]adamantane-1-ol of the present invention was clarified The ratio of alcohol to HCl salt is 1:1.
  • This embodiment discloses the preparation of trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrogen sulfate, and the specific preparation method is as follows:
  • This embodiment discloses the preparation of trans-4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrobromide, and the specific preparation method is as follows:
  • the present invention uses the following test examples to illustrate the medicinal effects of the compounds obtained in the above examples, as follows:
  • This test example discloses the acute lung injury test of the compound of formula I and the compound of formula V in mice.
  • mice Take KM mice with a body weight of 18-22g, 66 males, and randomly divided into groups, namely normal control group, model control group, formula I compound group (40mg/kg, calculated as free base), formula V compound group (40mg/kg) kg, calculated as free base), the control group (40 mg/kg, calculated as free base) and the ambroxol hydrochloride group (40 mg/kg, calculated as free base), 11 in each group, each group was administered iv ( Adjust pH and dissolve in normal saline or directly dissolve in normal saline), once a day, administered 4 times, and the model control group and the normal control group were given the same amount of normal saline.
  • iv Adjust pH and dissolve in normal saline or directly dissolve in normal saline
  • mice 30min after the last administration, except for the normal control group, the other mice were given 300 mg/kg of oleic acid iv (prepared with sterile normal saline containing 0.1% fetal bovine serum to make the required concentration before use), and the blank control group was given Equal volume of 0.1% BSA saline. Mice were sacrificed 4 hours after the last administration, and the right lobe lungs were taken out and fixed in 10% formaldehyde solution. After routine dehydration, paraffin embedding, sectioning, HE staining, the pathological changes of lung tissue were observed under a microscope, and histological grading standards See Table 1 and Table 2 for the results. Wherein, the drug used in the comparative example group was 4-[(2-amino-3,5-dibromobenzyl)amino]adamantan-1-ol hydrochloride (mixture) prepared in Comparative Example 1.
  • the compound of formula I and the compound of formula V have protective effect on oleic acid-induced acute lung injury in mice, and their effect is better than that of ambroxol hydrochloride and the compounds of the comparative example.
  • This test example discloses the effect test of the compounds of formula I and V on the cough response of mice induced by ammonia water.
  • mice Take KM mice, weighing 18-22 g, 50, both male and female. Randomly divided into 5 groups, namely model control group, formula I compound group (15mg/kg, in free base), formula V compound group (15mg/kg, in free base), control group (15mg/kg, with free base) and ambroxol hydrochloride group (15mg/kg, calculated as free base), 10 mice in each group, iv administration (adjust pH to be dissolved in normal saline or directly dissolved in normal saline), 30 minutes after administration, the The mice were placed in an inverted beaker with a volume of 500ml with a cotton ball inside, and the time was started when 0.2ml of concentrated ammonia water was added to the cotton ball, and the number of coughs of each animal within 3min was observed and recorded.
  • model control group formula I compound group (15mg/kg, in free base
  • formula V compound group (15mg/kg, in free base
  • control group 15mg/kg, with free base
  • model control group 41.7 ⁇ 8.76
  • Group of compounds of formula I 15 19.2 ⁇ 5.98**
  • Group of compounds of formula V 15 19.5 ⁇ 6.50**
  • Comparative group 15 25.7 ⁇ 6.40**
  • Ambroxol hydrochloride group 15 32.7 ⁇ 8.55*
  • This test example discloses the rat capillary expectoration test of the compound of formula I and the compound of formula V.
  • the test sample can significantly increase the amount of rat sputum, and there is a statistical difference (P ⁇ 0.05);
  • the compound of formula I, formula Compound V and the compound of the comparative example can both significantly increase the amount of sputum in rats (P ⁇ 0.05), which is significantly better than that of ambroxol hydrochloride; the compound of formula I and compound V are also significantly better than the control group in increasing the amount of sputum in rats Compounds, with significant difference (P ⁇ 0.05).
  • the compound of formula I and the compound of formula V can significantly increase the amount of sputum in rats, and its effect is better than that of ambroxol hydrochloride and the compounds of the comparative example.
  • This test example discloses the murine phenol red expectorant test of the compound of formula I and the compound of formula V.
  • mice both male and female, were randomly divided into control (physiological saline) group, formula I compound group (30mg/kg, calculated as free base), formula V compound group (30mg/kg, free base) ), the control group (30mg/kg, based on free base) and ambroxol hydrochloride (30mg/kg, based on free base), 12 in each group; the tail vein was given corresponding drugs (adjust pH to dissolve in normal saline or Dissolved in physiological saline directly), 2 times in a row, 15 minutes after the last administration, mice were subcutaneously injected with 5% phenol red physiological saline solution (0.5 g/kg), the mice were sacrificed 30 minutes later, and the branch from the thyroid cartilage to the trachea was cut off.
  • control physiological saline
  • formula I compound group (30mg/kg, calculated as free base
  • formula V compound group (30mg/kg, free base)
  • ambroxol hydrochloride 30mg/kg, based on free
  • the test samples can significantly increase the excretion of phenol red in mice, with a statistical difference (P ⁇ 0.05); compared with the ambroxol hydrochloride group , the compound of formula I, the compound of formula V and the compound of the comparative example can significantly increase the excretion of phenol red (P ⁇ 0.05), which is significantly better than that of ambroxol hydrochloride; the compound of formula I and the compound of formula V also significantly increase the excretion of phenol red. Better than the control group, with significant difference (P ⁇ 0.05).
  • the compound of formula I and the compound of formula V can significantly increase the excretion of phenol red, and its effect is better than that of ambroxol hydrochloride and the compound of the comparative example.
  • the compounds of formula I and V have an antitussive effect on the ammonia-induced cough model in mice, and their effect is better than that of ambroxol hydrochloride and the comparative compounds; the compounds of formula I and V can significantly increase the phenolic Red excretion, its effect is better than ambroxol hydrochloride and comparative compounds.

Abstract

本发明属于药物化学技术领域，公开结构如式I所示的反式金刚烷氨衍生物或其药学上可接受的盐在制备预防或/和治疗呼吸系统疾病的药物中的用途。本发明的反式金刚烷氨衍生物及其盐相对于盐酸氨溴索、盐酸金刚烷氨衍生物混旋体(异构体混合物)而言，具有更好的药效。通过小鼠急性肺损伤试验和氨水致小鼠咳嗽模型显示发现，其具有优异的治疗肺损伤和咳嗽的效果，其效果优于盐酸氨溴索及盐酸金刚烷氨衍生物混旋体，且具有统计学意义。本发明的反式金刚烷氨衍生物及其盐酸盐相对于盐酸氨溴索可显著增加大鼠排痰量，并可显著增加小鼠酚红排泌量，其效果优于盐酸氨溴索及及盐酸金刚烷氨衍生物混旋体。

Description

反式金刚烷氨衍生物或其盐的用途 技术领域
本发明涉及药物技术领域，具体涉及反式金刚烷氨衍生物或其药学上可接受的盐的用途。
背景技术
肺损伤是由不同致伤因素导致的肺实质的损伤，可表现为肺裂伤、肺挫伤和肺爆震伤。最常见的是肺挫伤，其发生率为钝性胸部伤的30％～75％，病死率为14％～40％。肺部外伤、肺部手术、肺部感染、肺栓塞等也可导致肺损伤。肺损伤在全球范围内的比率不断攀升，无特效性的药物，主要为镇痛药物、抗感染药物。因此，临床急需安全、有效的可治疗肺损伤的药物，尤其是治疗急性肺损伤的药物。
咳嗽是呼出气道中的痰和异物的生物防御反应之一，但是如果持续过度，则会导致生活质量(QOL)下降。咳嗽临床常见，尤其是持续时间＞8周的慢性咳嗽，占呼吸科门诊1/3以上，严重影响了患者的工作和日常生活，气道神经源性炎症导致的咳嗽敏感性增高是其重要机制。欧美各国的问卷调查显示高达9～33％的人员存在不同程度的咳嗽；在日本，慢性咳嗽的发生率根据报告而有所不同，但大约为2％～10％；2006年，中国广州地区1087名大学生调查显示，咳嗽发生率为10.9％，其中慢性咳嗽发生率为3.3％，推测社区人群将更高。目前没有批准用于治疗慢性咳嗽的药物。常用镇咳治疗剂有可待因，右美沙芬等，但中枢镇咳药经常发生便秘和嗜睡等副作用。因此，临床急需安全、有效的可治疗咳嗽的药物，尤其是治疗慢性咳嗽的药物。
氨溴索在多国批准了伴有痰液分泌不正常及排痰功能不良的急性、慢性肺部疾病。因此，氨溴索的主要功效为祛氮，其对肺损伤，尤其是急性肺损伤的治疗效果不佳，同时日本还批准了氨溴索用于咳嗽的治疗。
专利CN201910671508.7公开了二溴苄基衍生物、其立体异构体或其盐及制法和应用，所公开二溴苄基衍生物是对氨溴索上环己烷进行结构改造所得。其公开的二溴苄基衍生物相对于盐酸氨溴索而言，具有更好生物利用度和更优的祛痰效果。目前，未见任何关于反式金刚烷氨衍生物用于预防和治疗肺损伤和咳嗽方面的相关报道，特别是对急性肺损伤和难治性咳嗽相关的报道。
发明内容
本发明的目的在于，提供一种如式I所示的反式金刚烷氨衍生物或其药学上可接受的盐在制备预防或/和治疗呼吸系统疾病的药物中的用途。
为实现上述目的，本发明采用的技术方案如下：
本发明所述的结构如式I所示的反式金刚烷氨衍生物或其药学上可接受的盐在制备预防或/和治疗呼吸系统疾病的药物中的用途，
Figure PCTCN2021084409-appb-000001
本发明的部分实施方案中，包括在制备预防或/和治疗肺损伤的药物中的用途。
进一步地，包括在制备预防或/和治疗急性肺损伤的药物中的用途。
进一步地，包括在制备预防或/和治疗由肺损伤引起的急性呼吸窘迫综合征药物中的用途。
本发明的部分实施方案中，包括在制备预防或/和治疗咳嗽的药物中的用途。
进一步地，包括在制备预防或/和治疗慢性咳嗽或难治性咳嗽药物中的用途。
本发明的部分实施方案中，包括在制备预防或/和治疗祛痰药物中的用途。
本发明的部分实施方案中，所述药学上可接受的盐由反式金刚烷氨衍生物与酸形成。
所述酸为药学上可接受的无机酸或有机酸，其中无机酸选自盐酸、氢硫酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸；所述有机酸选自甲酸、醋酸、乙酸酐、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、偏酒石酸、抗坏血酸、没食子酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、植酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1，5-萘二磺酸、2-萘二磺酸、樟脑磺酸、氢基磺酸、谷氨酸、天冬氨酸、葡萄酸、葡糖醛酸；优选地，所述药学上可接受的酸为盐酸、氢硫酸、氢溴酸、硫酸、磷酸、醋酸、乳酸、苹果酸、酒石酸、富马酸。
优选地，所述药学上可接受的盐包括乙酸盐、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。
优选地，所述药学上可接受的盐选自，
反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐，
反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇硫酸氢盐，
或反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇氢溴酸盐。
优选地，所述药学上可接受的盐为结构如式V所示的盐酸盐，
Figure PCTCN2021084409-appb-000002
本发明所述的结构如式I所示反式金刚烷氨衍生物的制备方法，包括两步反应：
步骤1，以式Ⅲ化合物、式Ⅳ化合物或其盐为起始原料，经缩合反应制得式Ⅱ化合物；
步骤2，将式Ⅱ化合物与还原剂发生还原反应得到式Ⅰ所示反式金刚烷氨衍生物；
其反应式为：
Figure PCTCN2021084409-appb-000003
本发明的部分实施方案中，还包括步骤3，将式I化合物与酸发生成盐反应制得式I化合物的盐，其反应式为：
Figure PCTCN2021084409-appb-000004
本发明的部分实施方案中，所述还原剂包括但不限局于硼氢化钠或者硼氢化钾。
本发明的部分实施方案中，式Ⅳ化合物的盐包括但不限局于盐酸盐、硫酸盐、氢溴酸盐。
所述步骤1中，包括将反应溶剂、式Ⅲ化合物、式Ⅳ化合物或其盐、缚酸剂、干燥剂加入到反应釜中，加热搅拌反应，制得式Ⅱ化合物。
起始原料式Ⅲ化合物与式Ⅳ化合物的摩尔比为1:0.8～1:2.0，优选为1:1～1:1.5。
所述缚酸剂包括选自无机碱或/和有机碱；优选地，所述无机碱包括但不限局于碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂或氢化钠中的任意一种或几种；
优选地，所述有机碱包括但不限局于甲醇钠、乙醇钠、叔丁醇钾、三乙胺、二乙胺、二异丙胺、N，N-二异丙基乙胺中的任意一种或几种。
式Ⅲ化合物与缚酸剂的摩尔比为1:1～1:5.0，优选为1:1～1:1.5。
所述反应溶剂包括但不限局于乙醇、甲醇、异丙醇、正丙醇、乙酸乙酯、乙酸异丙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙腈、四氢呋喃中的任意一种或几种；
优选地，式Ⅲ化合物(2-氨基-3,5-二溴苯甲醛)和反应溶剂的质量体积比为1:3～1:20，优选为1:12～1:16，其中，质量单位为kg时，体积单位为L。
所述干燥剂包括但不限局于硫酸镁、硫酸钠、硫酸钙、分子筛、氯化钙中的任意一种或几种；优选地，式Ⅲ化合物(2-氨基-3,5-二溴苯甲醛)和干燥剂的摩尔比为1:0.5-1:5，优选为1:0.8～1:1.5。
所述步骤1中反应温度为50℃-120℃，优选为70℃-80℃；
所述步骤1中还包括后处理步骤，将反应液过滤，浓缩、结晶，干燥，得到式Ⅱ化合物。
采用重结晶纯化式Ⅱ化合物时，重结晶的溶剂包括但不限局于甲醇、乙醇、异丙醇、正丙醇中的任意一种或几种；式Ⅲ化合物与重结晶溶剂的重量体积比为1:4～1:25，优选：1:9～1:11；重量体积单位为kg时，体积单位为L。
本发明的部分实施方案中，所述步骤2中的反应溶剂包括但不限局于二氯甲烷、甲醇中的一种或两种；式Ⅱ化合物与反应溶剂的质量体积比为1：3～50；优选为1：29，其中，质量单位为kg时，体积单位为L。
所述步骤2中反应温度为0℃-10℃，式Ⅱ化合物与还原剂的用量摩尔比1:1.1～1:2.5。
本发明的部分实施方案中，所述步骤3中的反应溶剂但不限局于乙醇、丙酮、甲醇中的任意一种或几种；式I化合物与反应溶剂的质量体积比为1：3～70；优选为1：12或1：14或1：29；其中，质量单位为kg时，体积单位为L。
本发明还提供了一种药物组合物，包括式I所示反式金刚烷氨衍生物或其药学上可接受的盐，以及一种或多种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，得到式I所示的反式金刚烷氨衍生物。本发明惊奇地发现，本发明的反式金刚烷氨衍生物及其盐酸盐相对于盐酸氨溴索、盐酸金刚烷氨衍生物混旋体(异构体混合物)而言，具有更好的药效。通过小鼠急性肺损伤试验和氨水致小鼠咳嗽模型显示发现，其具有优异的治疗肺损伤和咳嗽的效果，其效果优于盐酸氨溴索及盐酸金刚烷氨衍生物混旋体，且具有统计学意义。本发明的反式金刚烷氨衍生物及其盐酸盐相对于盐酸氨溴索可显著增加大鼠排痰量，并可显著增加小鼠酚红排泌量，其效果优于盐酸氨溴索及及盐酸金刚烷氨衍生物混旋体。
附图说明
附图1为式Ⅱ化合物反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的 1H-NMR谱图(DMSO-d6)；
附图2为式Ⅱ化合物反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的 13C-NMR谱图(DMSO-d6)；
附图3为式Ⅱ化合物反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的质谱谱图；
附图4为式I化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇的 1H-NMR谱图(DMSO-d6)；
附图5为式I化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇MS谱图；
附图6为式V化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐的HPLC谱图；
附图7为式V化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐的 1H-NMR谱图(DMSO-d6)；
附图8为式V化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐的 13C-NMR谱图(DMSO-d6)；
附图9为式V化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐的红外吸收光谱谱图；
附图10为式V化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐单晶衍射谱图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
以下实施例中，化合物的具体结构是通过质谱(MS)、核磁共振( 1H NMR和 13C NMR)来确定的。其中，核磁共振( 1H NMR和 13C NMR)位移(δ)以百万分之一(ppm)的单位给出；核磁共振( 1H NMR)的测定是用Bruker AVANCE-400核磁仪。本发明实施例中所用的各原料均为市售。
实施例1-17公开了本发明的中间体的制备方法。
实施例1
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
Figure PCTCN2021084409-appb-000005
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、16.3g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.3L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末19.9g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为58.0％，纯度99.1％。
1H-NMR(600MHz，DMSO-d 6)：δppm8.438(d，J＝1.8Hz，1H)，7.678(s，2H)，7.63-7.623(t，J＝2.5Hz，1H)，7.532(t，J＝2.2Hz，1H)，4.468(s，1H)，3.389-3.344(d，J＝3.3Hz，1H)，2.092(q，J＝3.3Hz，1H)，2.059-2.038(dd，J＝12.8，3.2Hz，2H)，1.846(m，2H)，1.771-1.752(d，J＝11.8Hz，2H)，1.700-1.679(dd，J＝13.0，3.0Hz，4H)，1.409-1.388(d，J＝12.3Hz，2H)与结构式相符。
13C-NMR(150MHz，DMSO-d 6)：δppm161.04，145.52，135.37，135.32，119.89，109.47，105.15，73.48，65.99，46.03，44.70，37.31，31.11，30.31与结构式相符。
MS分子式C 17H 20Br 2N 2O理论值M为428.17。质谱分子离子峰m/z 429.33，为[M+H] +峰；质谱分子离子峰m/z 427.31，为[M-H] -峰，与结构式相符。
实施例2
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、20.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末32.9g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为76.8％，纯度98.9％。
实施例3
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、30.5g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末36.4g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为85.0％，纯度98.6％。
实施例4
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、40.7g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末34.7g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为81.0％，纯度99.7％。
实施例5
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、22.4g 反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末39.6g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为92.5％，纯度99.6％。
实施例6
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、22.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、20.7g无水碳酸钾、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末31.2g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为72.9％，纯度98.1％。
实施例7
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇和四氢呋喃混合溶剂(1:1)加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末30.1g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为70.3％，纯度98.5％。
实施例8
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L四氢呋喃加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、10.8g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.3L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末27.8g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为64.9％，纯度99.5％。
实施例9
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.4L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、22.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、10.5g无水碳酸钠、7.1g无水硫酸钠，加热至50℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.25L无水甲醇，加热重结晶。过滤，干燥得到淡黄色粉末30.5g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为71.2％，纯度99.4％。
实施例10
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.15L DMF加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、4.0g氢氧化钠、9.6g无水硫酸镁，加热至90℃反 应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.3L无水甲醇，加热重结晶。过滤，干燥得到淡黄色粉末27.9g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为65.2％，纯度98.5％。
实施例11
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.45L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、5.6氢氧化钾、10.8g无水硫酸镁，加热至70℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.3L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末33.0g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为77.1％，纯度97.5％。
实施例12
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.35L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、15.9g无水碳酸钠、18.1g无水硫酸镁，回流反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.1L无水甲醇，加热重结晶。过滤，干燥得到淡黄色粉末36.8g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为85.9％，纯度92.2％。
实施例13
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.55L异丙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、48.8g无水碳酸铯、24.0g无水硫酸镁，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.4L异丙醇，加热重结晶。过滤，干燥得到淡黄色粉末35.0g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为81.7％，纯度98.8％。
实施例14
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.1L DMSO加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、12.6g无水碳酸氢钠、5.6g氯化钙，加热至120℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.4L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末32.1g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为75.0％，纯度98.7％。
实施例15
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将0.2L无水乙醇加入到反应瓶中，搅拌下加入27.9g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、24.4g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、82mL N，N-二异丙基乙胺、10.8g无水硫酸钙，加热至75℃反应5小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入0.7 L正丙醇，加热重结晶。过滤，干燥得到淡黄色粉末26.1g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为61.0％，纯度99.1％。
实施例16
本实施例公开了本发明的中间体反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇的制备方法，具体包括以下步骤：
将15L无水乙醇加入到反应釜中，搅拌下加入995.8g 2-氨基-3,5-二溴苯甲醛(式Ⅲ化合物)、800.0g反式-4-氨基-1-羟基金刚烷盐酸盐(式Ⅳ化合物)、567.6g无水碳酸钠、400.0g无水硫酸镁，加热，保温75±5℃反应10小时以上。TLC监控至反应完毕，常压蒸馏除去反应溶剂。后向残留物中加入2L无水乙醇，加热重结晶。过滤，干燥得到淡黄色粉末1381.9g反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇，实际收率为90.0％，纯度99.6％。
实施例17-20公开了反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇及其盐的制备方法。
实施例17
本实施例公开了式I化合物反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇的制备，反应式为：
Figure PCTCN2021084409-appb-000006
具体制备方法为：
步骤1：反式-4-[(2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇(式Ⅱ化合物)的制备
将反式-4-氨基-1-羟基金刚烷盐酸盐20.4g(0.1mol)、2-氨基-3,5二溴苯甲醛55.6g(0.36mol)及无水乙醇(EtOH)500mL加入反应瓶中，另加入10g分子筛，回流反应10h，TCL监控反应至反应完全，常压蒸馏除去反应溶剂。向残留物中加入250mL无水乙醇，加热重结晶，冷却过滤得到反式-4-[2-氨基-3,5-二溴苯亚基)氨基]-金刚烷-1-醇36.4g，收率85％，纯度98.5％。
步骤2：反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇(式I化合物)的制备
将中间体式Ⅱ化合物34.3g(0.08mol)、二氯甲烷500mL、无水甲醇500mL投入反应瓶中，搅拌溶解，加入3.71g(0.098mol)硼氢化钠，加毕后，维持5℃反应10小时以上。TLC监控至反应完成。减压浓缩除去反应溶剂后，向残留物中加入100mL饮用水和300mL二氯甲烷，搅拌溶解后分液，无水硫酸钠干燥，过滤，旋干，得到式I化合物31.36g，收率91％，纯度98.9％。
1H NMR(400MHz,DMSO-d 6):δ7.47(d,J＝2.00,1H),7.24(d,J＝2.40,1H),5.76-5.72(m,2H)，4.32(s,1H)，3.64(m,2H)，2.52-2.50(m,1H)，2.19(m,1H)，1.89-1.96(m,5H),1.58(m,6H),1.23-1.26(m,2H)。
MS m/z(ES):431.18[M+H] +、429.02[M-H] -。
实施例18
本实施例公开了反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(式V化合物)的制备，反应式为：
Figure PCTCN2021084409-appb-000007
具体制备方法为：将按实施例17方法制得的式I化合物21.50g(0.05mol)、无水乙醇300mL投入反应瓶中，加热到75℃，至固体溶清。向底物中滴加15％氯化氢(乙醇)溶液40mL，0.5h内加毕后，停止加热，自然降温析晶约3h。过滤得到反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(式V化合物)19.8g。
HPLC纯度99.89％，收率85％。
1H NMR(400MHz,DMSO-d 6):δ9.15(s,2H)，7.70(d,J＝2.24,1H),7.58(d,J＝2.25,1H),5.79(s,2H)，4.61(s,1H)，4.16(m,2H)，3.35(s,1H)，2.39(m,2H)，2.12-2.15(m,2H),2.0(m,1H),1.60-1.64(m,6H),1.31-1.34(m,2H)。
13C NMR(400MHz,DMSO-d 6):δ28.64，28.64，28.64，28.80，30.43，30.43，43.87，44.91，44.96，61.71，65.33，106.33，109.72，119.01，134.25，134.46，144.14。
元素分析，实测值：43.73％(C)、4.87％(H)、6.14％(N)；理论值:43.76％(C)、4.97％(H)、6.0％(N)。
另外，本申请还提供了式V化合物的红外吸收光谱谱图以确证其结构(如附图9所示)。同时本申请还对发明的式V化合物进行了单晶培养，开展了单晶衍射实验(如附图10所示)，进一步地确证了本发明的4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇为反式结构，且明确了本发明的反式4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇与HCl成盐的比例为1:1。
实施例19
本实施例公开了反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇硫酸氢盐的制备，具体制备方法为：
将按实施例17方法制得的式I化合物4.3g(0.01mol)、丙酮50mL投入反应瓶中，并冷却至约10℃，搅拌下，滴加浓硫酸的丙酮溶液(2mL浓硫酸溶于10mL丙酮)，并将温度保持在10℃继续搅拌2小时然后过滤，得到反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇硫酸氢盐4.6g。
HPLC纯度99.89％，收率87％。
1H NMR(400MHz,DMSO-d 6):δ9.10(s,2H)，7.69(d,J＝2.24,1H),7.57(d,J＝2.25,1H),5.78(s,2H)，4.61(s,1H)，4.16(m,2H)，3.35(s,1H)，2.39(m,2H)，2.12-2.15(m,2H),2.0(m,1H),1.60-1.64(m,6H),1.31-1.34(m,2H)。
元素分析，实测值：38.79％(C)、4.35％(H)、5.37％(N)；理论值:38.73％(C)、4.40％(H)、5.31％(N)。
实施例20
本实施例公开了反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇氢溴酸盐的制备，具体制备方法为：
将按实施例17方法制得的式I化合物4.3g(0.01mol)、无水乙醇300mL投入反应瓶中，加热到75℃，至固体溶清。向底物中滴加40％溴化氢溶液4mL，0.5h内加毕后，停止加热，自然降温 析晶约3h。过滤得到反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇氢溴酸盐4.4g。
HPLC纯度99.89％，收率86％。
1H NMR(400MHz,DMSO-d 6):δ9.12(s,2H)，7.70(d,J＝2.24,1H),7.58(d,J＝2.25,1H),5.79(s,2H)，4.61(s,1H)，4.16(m,2H)，3.35(s,1H)，2.39(m,2H)，2.12-2.15(m,2H),2.0(m,1H),1.60-1.64(m,6H),1.31-1.33(m,2H)。
元素分析，实测值：39.99％(C)、4.43％(H)、5.57％(N)；理论值:39.95％(C)、4.54％(H)、5.48％(N)。
对比例1
4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)的制备
根据专利CN201910671508.7中实施例13公开的制备方法合成4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)。
为了明确本发明化合物的性能及用途，本发明以下面几个试验例对上述实施例得到的各化合物的药效进行阐述，具体如下：
试验例1
本试验例公开了式I化合物、式V化合物的小鼠急性肺损伤试验。
取KM小鼠，体重为18～22g，全雄66只，随机分组，即正常对照组、模型对照组、式I化合物组(40mg/kg，以游离碱计)、式V化合物组(40mg/kg，以游离碱计)，对比例组(40mg/kg，以游离碱计)及盐酸氨溴索组(40mg/kg，以游离碱计)，每组11只，各组均iv给药(调PH溶解于生理盐水或直接溶于生理盐水)，每天1次，给予4次，模型对照组和正常对照组给予等量生理盐水。末次给药后30min，除正常对照组外，其余小鼠均iv给予油酸300mg/kg(临用前用含0.1％胎牛血清的无菌生理盐水配成所需浓度)，空白对照组给予等体积的0.1％BSA生理盐水。于末次给药4h后处死小鼠，取右叶肺脏置10％甲醛溶液中固定，经常规脱水、石蜡包埋、切片，HE染色，于显微镜下观察肺组织的病理学改变，组织学分级标准见表1，结果见表2。其中，对比例组所用药物为对比例1制得的4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)。
表1.肺损伤组织学分级标准
Figure PCTCN2021084409-appb-000008
Figure PCTCN2021084409-appb-000009
上述指标，根据病变性质的重要性，乘以不同的加权数(肺泡壁增厚×1，炎细胞浸润×1，肺组织坏死×3)，最后相加，即为肺病变总积分。
表2.各组肺病理检测结果
Figure PCTCN2021084409-appb-000010
注：与模型对照组比较：*P<0.05，**P<0.01；与盐酸氨溴索组比较： ▲P<0.05。
从上表2可以看出：和模型组对照组比较，式I化合物、式V化合物、对比例化合物对油酸致小鼠急性肺损伤的具有明确的保护作用(P<0.05或P<0.01)；式I化合物组、式V化合物组病变总积分与盐酸氨溴索组比较显著减少，有统计学差异(P<0.05)，说明式I化合物、式V化合物对肺的保护作用显著优于盐酸氨溴索；其效果也优于对比例化合物。
综上所述，式I化合物、式V化合物对油酸致小鼠急性肺损伤有保护作用，其效果优于盐酸氨溴索及对比例化合物。
试验例2
本试验例公开了式I化合物、式V化合物对氨水致小鼠咳嗽反应的影响试验。
取KM小鼠，体重为18～22g，50只，雌雄兼用。随机分为5组，即模型对照组、式I化合物组(15mg/kg，以游离碱计)、式V化合物组(15mg/kg，以游离碱计)，对比例组(15mg/kg、以游离碱计)及盐酸氨溴索组(15mg/kg，以游离碱计)，每组10只，iv给药(调PH溶解于生理盐水或直接溶于生理盐水)，给药后30min，将小鼠置于一倒置的容积为500ml内置一棉球的烧杯中，在向棉球上加浓氨水0.2ml/只时开始记时，观察并记录3min内各动物的咳嗽次数，结果用t′检验，结果见表3。其中，对比例组所用药物为对比例1制得的4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)。
表3对氨水致小鼠咳嗽反应的影响(
Figure PCTCN2021084409-appb-000011
n＝10)
组别 剂量(mg/kg) 咳嗽次数(次)
     
模型对照组 — 41.7±8.76
式I化合物组 15 19.2±5.98** ▲▲
式V化合物组 15 19.5±6.50** ▲▲
对比例组 15 25.7±6.40** ▲
盐酸氨溴索组 15 32.7±8.55*
注：与模型对照组比较：*P<0.05，**P<0.01；与盐酸氨溴索组比较： ▲P<0.05， ▲▲P<0.01。
从表3可以看出：与模型对照组比较，式I化合物、式V化合物、对比例化合物及盐酸氨溴索均可显著减少咳嗽次数(P<0.05或P<0.01)；式I化合物组、式V化合物组减少咳嗽次数与盐酸氨溴索组比较，有统计学差异(P<0.01)；式I化合物组、式V化合物组减少咳嗽次数与对比例组比较，有统计学差异(P<0.05)，说明式I化合物、式V化合物的止咳作用显著优于盐酸氨溴索及对比例化合物。
试验例3
本试验例公开了式I化合物、式V化合物的大鼠毛细管排痰试验。
取180～220g的SD大鼠，雌雄兼用，随机分组，每组10只，即空白对照组、式I化合物组(15mg/kg，以游离碱计)、式V化合物组(15mg/kg，以游离碱计)，对比例组(15mg/kg，以游离碱计)及盐酸氨溴索(15mg/kg，以游离碱计)；测排痰量前，大鼠禁食不禁水12h，尾静脉给予相应药物(调PH溶解于生理盐水或直接溶于生理盐水)，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4所示。其中，对比例组所用药物为对比例1制得的4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)。
表4对大鼠毛细管排痰法排痰量的影响
Figure PCTCN2021084409-appb-000012
结果表
组别 受试药物 剂量(mg/kg) 动物数 90min排痰量(mm)
空白对照组 生理盐水 — 10 22.7±4.41
式I化合物组 式I化合物 15 10 45.9±6.79* ▲
式V化合物组 式V化合物 15 10 45.1±5.39* ▲
对比例组 对比例化合物 15 10 39.9±5.43*
盐酸氨溴索组 盐酸氨溴索 15 10 30.1±4.95*
注：与对照组比较：*P<0.05；与对比例比较， ▲P<0.05；
从表4可以看出:与空白对照组比较，受试样品均可显著增加大鼠排痰量，有统计学差异(P<0.05)；与盐酸氨溴索组比较，式I化合物、式V化合物及制备对比例化合物均可显著增加大鼠 排痰量(P<0.05)，显著优于盐酸氨溴索；式I化合物、式V化合物增加大鼠排痰量也显著优于对比例组化合物，具有显著性差异(P<0.05)。
综上所述，式I化合物、式V化合物对可显著增加大鼠排痰量，其效果优于盐酸氨溴索及对比例化合物。
试验例4
本试验例公开了式I化合物、式V化合物的小鼠酚红祛痰试验。
实验方法：取60只小鼠，雌雄兼用，随机均分为对照(生理盐水)组、式I化合物组(30mg/kg，以游离碱计)、式V化合物组(30mg/kg，以游离碱计)，对比例组(30mg/kg，以游离碱计)及盐酸氨溴索(30mg/kg，以游离碱计)，每组12只；尾静脉给予相应药物(调PH溶解于生理盐水或直接溶于生理盐水)，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5所示的实验结果：其中，对比例组所用药物为对比例1制得的4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐(混旋体)。
表5，对小鼠气管酚红排泌量的影响
Figure PCTCN2021084409-appb-000013
Figure PCTCN2021084409-appb-000014
注：与对照组比较：*P<0.05；与对比例组比较， ▲P<0.05；
从上表5可以看出：与对照组(生理盐水)比较，受试样品均可显著增加小鼠酚红排泌量，有统计学差异(P<0.05)；与盐酸氨溴索组比较，式I化合物、式V化合物及对比例化合物均可显著增加酚红排泌量(P<0.05)，显著优于盐酸氨溴索；式I化合物、式V化合物增加酚红排泌量也显著优于对比例组，具有显著性差异(P<0.05)。
综上所述，式I化合物、式V化合物对可显著增加酚红排泌量，其效果优于盐酸氨溴索及对比例化合物。
综上所述，式I化合物、式V化合物对氨水致小鼠咳嗽模型有止咳作用，其效果优于盐酸氨溴索及对比例化合物；式I化合物、式V化合物对可显著增加小鼠酚红排泌量，其效果优于盐酸氨溴索及对比例化合物。
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 (10)

  1. 一种结构如式I所示的反式金刚烷氨衍生物或其药学上可接受的盐在制备预防或/和治疗呼吸系统疾病的药物中的用途，
    Figure PCTCN2021084409-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，包括在制备预防或/和治疗肺损伤的药物中的用途。
  3. 根据权利要求2所述的用途，其特征在于，包括在制备预防或/和治疗急性肺损伤的药物中的用途。
  4. 根据权利要求2所述的用途，其特征在于，包括在制备预防或/和治疗由肺损伤引起的急性呼吸窘迫综合征药物中的用途。
  5. 根据权利要求1所述的用途，其特征在于，包括在制备预防或/和治疗咳嗽的药物中的用途。
  6. 根据权利要求5所述的用途，其特征在于，包括在制备预防或/和治疗慢性咳嗽或难治性咳嗽药物中的用途。
  7. 根据权利要求1所述的用途，其特征在于，包括在制备预防或/和治疗祛痰药物中的用途。
  8. 根据权利要求1-7任意一项所述的用途，其特征在于，所述药学上可接受的盐由反式金刚烷氨衍生物与酸形成。
  9. 根据权利要求5所述的用途，其特征在于，所述药学上可接受的盐包括乙酸盐、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。
  10. 根据权利要求9所述的用途，其特征在于，所述药学上可接受的盐选自，
    反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇盐酸盐，
    反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇硫酸氢盐，
    或反式-4-[(2-氨基-3,5-二溴苄基)氨基]金刚烷-1-醇氢溴酸盐；
    优选为结构如式V所示的盐酸盐，
    Figure PCTCN2021084409-appb-100002
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