WO2024193721A1 - 一种新的2-(1-羟基戊基)苯甲酸环烷胺盐 - Google Patents

一种新的2-(1-羟基戊基)苯甲酸环烷胺盐 Download PDF

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WO2024193721A1
WO2024193721A1 PCT/CN2024/090342 CN2024090342W WO2024193721A1 WO 2024193721 A1 WO2024193721 A1 WO 2024193721A1 CN 2024090342 W CN2024090342 W CN 2024090342W WO 2024193721 A1 WO2024193721 A1 WO 2024193721A1
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hydroxypentyl
compound
benzoic acid
salt
group
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French (fr)
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王晓宇
张俐
付海霞
牟霞
江杰
李连明
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Chengdu Shibeikang Biomedical Technology Co Ltd
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Chengdu Shibeikang Biomedical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • 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
    • 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

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and specifically relates to a novel 2-(1-hydroxypentyl)benzoate and a preparation method thereof, a pharmaceutical composition with the compound as an active ingredient, and applications in the treatment and/or prevention of ischemic cardiovascular and cerebrovascular diseases, especially mild, moderate and severe acute ischemic stroke, etc.
  • Acute ischemic stroke, cerebral thrombosis, cerebral embolism, coronary heart disease, angina pectoris, myocardial infarction, etc. are all common ischemic cardiovascular and cerebrovascular diseases, which are diseases of ischemic damage caused by thrombosis induced by various factors.
  • ischemic cerebrovascular disease due to severe cerebral vascular stenosis, or cerebral infarction and/or cerebral thrombosis and other diseases leading to blood vessel blockage, leads to insufficient blood supply to the brain, causing damage and necrosis of brain cells. This type of disease brings great pain and even life-threatening to patients, and drug research in this field has always been the forefront and hot spot of scientists' attention.
  • Butylphthalide is a new type I drug developed in China in recent years for the treatment of ischemic cerebrovascular disease.
  • Butylphthalide Soft Capsules and Butylphthalide Sodium Chloride Injection are available on the market. Its main mechanism of action is to improve microcirculation in the ischemic area of the brain, promote angiogenesis in the ischemic area, and increase cerebral blood flow in the ischemic area.
  • Butylphthalide itself is a fat-soluble compound, it is an oily liquid at room temperature, has poor water solubility, and has low solubility in the body. Its unfavorable physical and chemical properties inevitably lead to difficulties in its preparation process and low utilization rate in the body, and its efficacy is insufficient. Therefore, the overall efficacy of Butylphthalide in clinical applications is not high, and it often needs to be used in combination with other drugs to enhance the efficacy, which limits its application range in the clinical treatment of ischemic diseases.
  • Patent CN1382682A discloses for the first time the preparation of 2-( ⁇ -hydroxypentyl)benzoate using DL-3-n-butylphthalide as a precursor and its use, and involves salts of monovalent metal ions, divalent metal ions and organic bases, specifically disclosing salts of potassium, sodium, calcium, magnesium, zinc, aniline, benzylamine, morpholine and diethylamine; the efficacy section of its specification also discloses the effect of potassium salt on the cerebral infarction area of rats with local cerebral ischemia, the effect on rat platelet aggregation, and the protective effect of isolated rat heart ischemia-reperfusion arrhythmia, proving that potassium salt played a beneficial role in the above experiments.
  • Patent CN1523003A comprehensively compares various metal salts and organic amine/inorganic ammonium salts of 2-( ⁇ -hydroxypentyl)benzoic acid, among which potassium salt is highly hygroscopic, unstable and highly toxic, tert-butylamine salt and benzylamine salt are highly toxic; and N'N-dibenzylethylenediamine salt is less toxic, but its potency is only comparable to potassium salt, and its molecular weight is large, which is not conducive to absorption on the one hand, and the single dose specification is large on the other hand, and patient compliance is also poor. Therefore, the current market, including the projects under research, lacks butylphthalide open-ring derivative drugs with high safety, significant efficacy and suitable for drug formulation.
  • the present invention provides a new 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt and its preparation and application.
  • the new 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt provided by the present invention has a good solid form and significant drug efficacy.
  • the present invention provides a 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or a Isomers:
  • ring A is selected from adamantane or a 3- to 7-membered cycloalkane
  • R 1 is independently selected from 1 to 3: hydrogen, alkyl, hydroxyl, halogen or halogenated alkyl.
  • the ring A is selected from adamantane, propacycloethane, butacycloethane, pentacycloethane, hexacycloethane, heptacycloethane or bicyclo[2,2,1]heptane.
  • R 1 is independently selected from 1 to 3: hydrogen, C1-C6 alkyl, hydroxyl, halogen or halogenated C1-C6 alkyl.
  • the ring A is selected from adamantane; or/and the R 1 is independently selected from 1 to 3: hydrogen, C1-C6 alkyl, hydroxyl, halogen or halogenated C1-C6 alkyl.
  • the above-mentioned C1 ⁇ C6 alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl; or/and the above-mentioned halogen includes but is not limited to fluorine, chlorine or bromine; or/and the above-mentioned halogenated C1 ⁇ C6 alkyl includes but is not limited to trifluoromethyl or difluoromethyl.
  • the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomers include the following compounds:
  • the hydrogen in the above compounds may be replaced by one or more deuterium.
  • the present invention provides a method for preparing the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomer, comprising the following steps:
  • the organic solvent includes but is not limited to ethers or esters; preferably, the ether solvent includes but is not limited to diethyl ether or methyl tert-butyl ether; the ester solvent includes but is not limited to ethyl acetate, isopropyl acetate or butyl acetate; or/and the salt formation temperature is 0 to 50°C, preferably 10 to 30°C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salts or isomers thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with the active ingredient and is suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit/risk ratio within the scope of reasonable medical judgment.
  • the pharmaceutical compositions include but are not limited to tablets, capsules, large infusions, small injections, lyophilized powder injections or granules.
  • the present invention also provides the use of the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomers in the preparation of drugs for treating and/or preventing ischemic cardiovascular and cerebrovascular diseases.
  • the above-mentioned ischemic cardiovascular and cerebrovascular diseases include, but are not limited to, mild, moderate, and severe acute ischemic stroke, cerebral thrombosis, cerebral embolism, coronary heart disease, angina pectoris, or myocardial infarction; preferably, moderate to severe acute ischemic stroke; more preferably, improvement of neurological deficits in patients with acute ischemic stroke.
  • the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt of the present invention has at least any of the following technical effects: (1) good solid form, simple preparation method, suitable for industrial scale-up production; (2) strong antiplatelet aggregation effect, strong improvement of neurological symptoms and inhibition of cerebral infarction range, indicating that the compound of the present invention has pharmacological effects such as prevention and/or treatment of cardiac and cerebral artery obstruction, improvement of cardiac and cerebral microcirculation, and is suitable for prevention and/or treatment of cardiac and cerebral ischemic diseases; (3) high toxic dose and safe for pharmaceutical use; (4) good solubility and high stability, suitable for drug preparation, especially with the potential to be developed into intravenous injection.
  • the liquid spectrometer-mass spectrometer was Agilent G6120B (used with Agilent 1260 liquid phase); the nuclear magnetic resonance instrument (1H NMR) was Bruker AVANCE-400 or Bruker AVANCE-800.
  • the measurement solvent was DMSO and the internal standard was tetramethylsilane (TMS).
  • room temperature in the present invention refers to a temperature between 10 and 30°C.
  • the reagents and compounds used in the present invention have no special Unless otherwise specified, the products were commercially available.
  • xxx group used in each test example of the present invention means that the drug used in this group is “xxx”.
  • compound 1 group means that the drug used in this group is “compound 1”.
  • Preparation method Dissolve 10.00g of compound a (2-(1-hydroxypentyl)benzoic acid) in 40ml of methyl tert-butyl ether, stir the reaction solution at room temperature, take 7.26g of adamantane amine (compound b-1) and dissolve it in 30ml of methyl tert-butyl ether, add the methyl tert-butyl ether solution of adamantane amine dropwise to the reaction system at room temperature, after the addition is completed, cool the reaction system to -5 to 20°C, filter, and dry the obtained solid in a vacuum drying oven to obtain 16.50g of the title compound, with a yield of 90% and a purity of 99.2%.
  • the preparation method was the same as that of Example 1, except that adamantane was replaced with an equal mole of 3-methyladamantan-1-amine and the organic solvent was replaced with ethyl acetate to obtain 15.25 g of the solid title compound with a yield of 85% and a purity of 99.3%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 2-methyladamantan-1-amine and the organic solvent was replaced with butyl acetate to obtain 15.73 g of the solid title compound with a yield of 88% and a purity of 99.3%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 3,5-dimethyladamantan-1-amine to obtain 15.82 g of the solid title compound with a yield of 85% and a purity of 99.5%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 3,4,6-trimethyladamantan-1-amine to obtain 15.63 g of the solid title compound with a yield of 84% and a purity of 99.0%.
  • the preparation method is the same as that of Example 1, except that adamantane amine is replaced with an equal molar amount of 3-n-propyl adamantane-1-amine to obtain 16.58 g of the solid title compound with a yield of 86% and a purity of 99.1%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 4-fluoroadamantan-1-amine to obtain 16.13 g of the solid title compound with a yield of 89% and a purity of 99.3%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 4-trifluoromethyladamantan-1-amine to obtain 17.86 g of the solid title compound with a yield of 87% and a purity of 99.2%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal mole of 3-bromoadamantan-1-amine to obtain 18.95 g of the solid title compound with a yield of 90% and a purity of 99.5%.
  • Preparation method The preparation method is the same as that of Example 1, except that adamantane amine is replaced with an equal molar amount of trans-1-hydroxyadamantan-4-amine to obtain 16.59 g of the solid title compound with a yield of 92% and a purity of 99.5%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of cis-1-hydroxyadamantan-4-amine to obtain 16.59 g of the solid title compound with a yield of 92% and a purity of 99.0%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of 4-hydroxyadamantan-2-amine to obtain 16.23 g of the solid title compound with a yield of 90% and a purity of 99.2%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of 4-hydroxycyclohexane-1-amine to obtain 14.74 g of the solid title compound with a yield of 95% and a purity of 99.2%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of 3-chlorocyclopentane-1-amine to obtain 14.01 g of the solid title compound with a yield of 89% and a purity of 99.0%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of 2-methylcyclopropane-1-amine to obtain 11.54 g of the solid title compound with a yield of 86% and a purity of 98.8%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of bicyclo[2,2,1]heptane-2-amine to obtain 13.87 g of the solid title compound with a yield of 90% and a purity of 98.2%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of cycloheptane amine to obtain 12.87 g of the solid title compound with a yield of 83% and a purity of 99.0%.
  • the preparation method was the same as that of Example 1, except that adamantane amine was replaced with an equal molar amount of 2-hydroxycyclobutane-1-amine to obtain 12.06 g of the solid title compound with a yield of 85% and a purity of 99.2%.
  • the rats were randomly divided into 8 groups, namely, model group, sham operation group, butylphthalide (CAS: 6066-49-5) group, compound 1 group, compound 4 group, compound 10 group, potassium salt (compound of comparative example 1) group, and amantadine (CAS: 768-94-5) group.
  • Administration was started 2 hours after ischemia and reperfusion.
  • the model group and the sham operation group were injected with an equal volume of 5% glucose injection by tail vein, and the other groups were injected with corresponding drugs by tail vein, and the administration was single.
  • the rat MCAO model was constructed by referring to the Longa suture occlusion method.
  • the nylon thread was cut into 2 cm lengths, and a small amount of molten paraffin was dipped on the top. After cooling, the nylon thread was completely wrapped for later use.
  • the rat was completely anesthetized with 3% sodium pentobarbital. (30mg/kg), fix the rats on the operating board in the supine position. Prepare and disinfect the neck skin, cut 2cm along the midline, bluntly separate the left common carotid artery, and separate the external carotid artery and internal carotid artery along the common carotid artery.
  • Neurological deficit scoring Scoring time: A blind modified neurological score was performed on all surviving animals before modeling, 2 hours after ischemia, and 24 hours after surgery.
  • the Longa’s method scoring criteria are as follows: 0 points: normal neurological function; 1 point: mild neurological deficit: the left forelimb of the animal is flexed when the tail is lifted; 2 points: moderate neurological deficit: the animal is placed on a smooth surface and walks, turning to the left while walking; 3 points: moderate neurological deficit: in a static state, it tilts to the left; 4 points: decreased consciousness, no spontaneous limb movement; 5 points: no response to stimulation or death.
  • Test results The t-test was used to compare the scores of the behavioral tests between the groups. The results are shown in the following table:
  • the rats in the model group, butylphthalide group, compound 1 group, compound 4 group, compound 10 group, potassium salt group, and amantadine group all showed hemiplegia-like symptoms 2 hours after surgery, mainly manifested as adduction of the forelimbs on the surgical side, internal rotation of the shoulder, and decreased forelimb muscle tension.
  • the neurological symptoms of the rats in the butylphthalide group and potassium salt group were significantly improved 24 hours after surgery (P ⁇ 0.05); the neurological symptoms of the rats in the compound 1 group, compound 4 group, and compound 10 group were extremely significantly improved (P ⁇ 0.01); the neurological symptoms of the rats in the amantadine group were not significantly improved (P>0.05). It was proved that at the same molar dose, the compounds of the present invention have a stronger effect on improving the neurological symptoms of MCAO rats than potassium salt.
  • Test Example 2 Effect on platelet aggregation in rats
  • Rats were randomly divided into 14 groups: solvent control group, aspirin group, butylphthalide group, compound 1 group, compound 3 group, compound 4 group, compound 6 group, compound 7 group, compound 10 group, compound 13 group, compound 15 group, compound 16 group, potassium salt group, and N'N-dibenzylethylenediamine salt group.
  • solvent control group aspirin group, butylphthalide group
  • compound 1 group compound 3 group
  • compound 4 group compound 6 group
  • compound 7 group compound 10 group
  • compound 13 group compound 15 group
  • compound 16 group potassium salt group
  • N'N-dibenzylethylenediamine salt group N'N-dibenzylethylenediamine salt group.
  • N'N-dibenzylethylenediamine salt was prepared according to patent CN1523003A, with a purity of 99.3%.
  • the platelet aggregation rate of rats in the butylphthalide group was significantly different from that in the solvent control group (P ⁇ 0.05); the platelet aggregation rates of rats in the aspirin group, the compound groups of each embodiment, the potassium salt group, and the N'N-dibenzylethylenediamine salt group were extremely significantly different from those in the solvent control group (P ⁇ 0.01).
  • the platelet aggregation rates of rats in the compound groups of each embodiment were much lower than those in the butylphthalide group, the potassium salt group, and the N'N-dibenzylethylenediamine salt group, proving that the compounds of the present invention have a good antiplatelet aggregation effect.
  • Test Example 3 Repeated administration toxicity test in rats
  • Healthy adult SD rats were randomly divided into 8 groups, 10 rats in each group, half of which were male and half were female, and were divided into blank group, vehicle control group, low-dose group of compound 1, medium-dose group of compound 1, high-dose group of compound 1, low-dose group of compound 4, medium-dose group of compound 4, and high-dose group of compound 4.
  • the blank group was injected with an equal volume of 5% glucose injection solution through the tail vein
  • the vehicle control group was injected with an equal volume of the solvent used to prepare the drug through the tail vein
  • the drug-treated group was injected with the corresponding concentration of drug through the tail vein, once a day, for 14 consecutive days, and the toxic reactions of the rats (such as irritation to the tail vein) were observed and recorded every day, and the death of rats in each group was counted and statistically analyzed.
  • Drugs to be tested Compound 1, Compound 4, potassium salt (Comparative Example 1 compound), tert-butylamine salt (Comparative Example 2 compound), diisopropylamine salt (Comparative Example 3 compound).
  • the results show that the properties of the compounds of the present invention remain unchanged under high humidity conditions for 30 days, and the contents of the main peak and the main degradation impurity butylphthalide remain basically unchanged, showing high high humidity stability; at the same time, after the compounds 1 and 4 of the present invention were tested under open high temperature and light conditions for 30 days, the properties of the compounds remained unchanged, and the main peak and butylphthalide content remained basically unchanged.
  • the compound has high stability.
  • the preparation process of the compound of the present invention is simple and suitable for industrial scale-up production.

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Abstract

一种结构如式I所示的2-(1-羟基戊基)苯甲酸环烷胺盐及其制法，和该化合物为活性成分的药物组合物，以及该化合物在治疗和/或预防缺血性心、脑血管病，尤其轻、中、重度急性缺血性脑卒中等方面的应用。

Description

一种新的2-(1-羟基戊基)苯甲酸环烷胺盐 技术领域
本发明属于药物技术领域，具体涉及一种新的2-(1-羟基戊基)苯甲酸盐及其制法，和以该化合物为活性成分的药物组合物，以及在治疗和/或预防缺血性心、脑血管疾病，尤其轻、中、重度急性缺血性脑卒中等方面的应用。
背景技术
急性缺血性脑卒中、脑血栓、脑栓塞、冠心病、心绞痛、心肌梗死等均属于常见的缺血性心、脑血管疾病，是由于各种因素诱发血栓形成所导致的缺血性损伤的疾病。尤其缺血性脑血管疾病，由于严重的脑血管狭窄，或者脑梗塞和/或脑血栓形成等疾病导致血管堵塞，继而导致脑部的血液供应不足，引起脑细胞的损伤坏死。该类疾病给病人带来极大的痛苦甚至生命危险，而该领域的药物研究也一直是科学家们关注的前沿和热点。
丁苯酞是近年国内开发的用于抗缺血性脑血管病的Ⅰ类新药，目前上市的制剂只有丁苯酞软胶囊和丁苯酞氯化钠注射液，主要作用机制为改善脑缺血区微循环，促进缺血区血管新生，增加缺血区脑血流。由于丁苯酞本身为脂溶性化合物，常温下为油状液体，水溶性较差，在体内溶解度较低，其不利的理化性质不可避免地导致其制备工艺困难和体内利用率低，且药效强度不足，因此丁苯酞在临床应用中总体疗效并不高，常需与其他药物联用以增强疗效，限制了其在缺血性疾病临床治疗中的应用范围。
专利CN1382682A首次公开了以DL-3-正丁基苯酞为先导物制备2-(α-羟基戊基)苯甲酸盐及其用途，涉及一价金属离子、二价金属离子和有机碱基的盐，具体公开了钾、钠、钙、镁、锌、苯胺、苄胺、吗啉、二乙胺的盐；其说明书药效部分还公开了钾盐对局部脑缺血大鼠脑梗塞面积的影响，对大鼠血小板聚集的影响，以及大鼠离体心脏缺血-再灌注心率失常的保护作用，证明钾盐在上述实验中发挥了有益作用。专利CN1523003A全面对比了2-(α-羟基戊基)苯甲酸的各种金属盐和有机胺/无机氨盐，其中钾盐吸湿性大不稳定且毒性较大，叔丁胺盐、苄胺盐毒性大；而N’N-二苄基乙二胺盐虽然毒性较小，但药效强度仅与钾盐相当，且分子量较大，一方面不利于吸收，另一方面单剂量规格较大，患者顺应性也较差。因此，目前市场上包括在研的项目均缺少安全性高、药效显著且适于成药的丁苯酞开环衍生药物。
因此，进一步开发药效更好、且有稳定固体形态的、适合静脉注射用的治疗缺血性心、脑血管疾病药物，尤其适于治疗缺血性脑血管疾病药物，为当前临床亟待解决的重大难题。
发明内容
为了进一步开发一种新的2-(1-羟基戊基)苯甲酸盐以克服现有技术存在的技术问题，本发明提供了一种新的2-(1-羟基戊基)苯甲酸环烷胺盐及其制备和应用。本发明所提供的新的2-(1-羟基戊基)苯甲酸环烷胺盐具备较好的固体形态且药效显著。
一方面，本发明提供一种结构如式I所示的2-(1-羟基戊基)苯甲酸环烷胺盐或其 异构体：
其中，环A选自金刚烷或3～7元环烷烃，R1独立地选自1～3个：氢、烷基、羟基、卤素或卤代烷基。
在某些实施例中，上述环A选自金刚烷、丙环烷、丁环烷、戊环烷、己环烷、庚环烷或双环[2,2,1]庚烷。
在某些实施例中，上述R1独立地选自1～3个：氢、C1～C6烷基、羟基、卤素或卤代C1～C6烷基。
在某些实施例中，上述环A选自金刚烷；或/和上述R1独立地选自1～3个：氢、C1～C6烷基、羟基、卤素或卤代C1～C6烷基。
在某些实施例中，上述C1～C6烷基包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊烷基或正己烷基；或/和上述卤素包括但不限于氟、氯或溴；或/和上述卤代C1～C6烷基包括但不限于三氟甲基或二氟甲基。
在某些实施例中，上述2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体包括如下化合物：


当本发明化合物结构与命名发生冲突且无法合理解释时，以结构为准。
在某些实施例中，上述化合物中的氢可被一个或多个氘取代。
另一方面，本发明提供上述2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体的制备方法，包括如下步骤：
化合物a与化合物b在有机溶剂存在条件下发生成盐反应生成式I化合物；
其中，环A、R1的定义同上述任一相应定义。
在某些实施例中，上述有机溶剂包括但不限于醚类或酯类；优选地，所述醚类溶剂包括但不限于乙醚或甲基叔丁基醚；所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；或/和所述成盐的温度为0～50℃，优选10～30℃。
第三方面，本发明还提供一种药物组合物，包含上述任一的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，还包含药学上可接受载体。
本发明术语“药学上可接受载体”指与活性成分一同给药的稀释剂、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。
在某些实施例中，上述药物组合物包括但不限于片剂、胶囊、大输液、小水针、冻干粉针或颗粒剂。
第四方面，本发明还提供上述2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体在制备治疗和/或预防缺血性心、脑血管疾病的药物中的用途。
在某些实施例中，上述缺血性心、脑血管疾病包括但不限于轻、中、重度急性缺血性脑卒中、脑血栓、脑栓塞、冠心病、心绞痛或心肌梗死；优选中、重度急性缺血性脑卒中；更优选急性缺血性脑卒中患者神经功能缺损的改善。
有益效果：本发明的2-(1-羟基戊基)苯甲酸环烷胺盐至少具有如下任一技术效果：(1)良好的固体形态，且制备方法简单，适合工业化放大生产；(2)较强的抗血小板聚集作用、较强地改善神经症状和抑制脑梗塞范围作用，说明本发明化合物具有预防和/或治疗心、脑动脉阻塞，改善心、脑微循环等药理作用，适合用于预防和/或治疗心、脑缺血性疾病；(3)毒性剂量高，药用安全；(4)较好的溶解度和较高的稳定性，适于成药，尤其具备开发成静脉注射剂潜力。
实施方式
下面将结合实例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明的具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为通过市购获得的常规产品。
化合物的结构通过核磁共振(1HNMR)或液质联用(LC-MS)来确定。
液质联用仪(LC-MS)为安捷伦G6120B(与液相Agilent 1260配用)；核磁共振仪(1H NMR)为Bruker AVANCE-400或Bruker AVANCE-800，核磁共振(1H NMR)位移(δ)以百万分之一(ppm)的单位给出，测定溶剂为DMSO，内标为四甲基硅烷(TMS)。
本发明术语“室温”是指温度处于10～30℃之间。本发明所用试剂、化合物没有特 别说明情况下指通过市购获得。
本发明各试验例所用术语“xxx组”代表该组所用药物为“xxx”。示例性如“化合物1组”代表该组所用药物为“化合物1”。
实施例1：金刚烷胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法：将10.00g化合物a(2-(1-羟基戊基)苯甲酸)溶于40ml的甲基叔丁醚中，室温搅拌反应液，取7.26g金刚烷胺(化合物b-1)溶于30ml甲基叔丁基醚中，将金刚烷胺的甲基叔丁基醚溶液室温滴加入反应体系中，滴加结束后将反应体系降温至-5～20℃，抽滤，将所得固体置于真空干燥箱中干燥，得标题化合物16.50g，收率90％，纯度99.2％。
ESI-MS：正离子模式m/z＝152.1(金刚烷胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.05(3H,s),1.81(6H,d),1.63–1.73(5H,m),1.55–1.60(3H,m),1.30–1.39(1H,m),1.20–1.29(2H,m),1.09–1.18(1H,m),0.82(3H,t)。
实施例2：3-甲基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷换成等摩尔3-甲基金刚烷-1-胺，有机溶剂换成乙酸乙酯，获得固体标题化合物15.25g，收率85％，纯度99.3％。
ESI-MS：正离子模式m/z＝166.2(3-甲基金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.05(3H,s),1.81(6H,d),1.63–1.73(5H,m),1.55–1.63(2H,m),1.09–1.39(4H,m),0.81–0.83(6H,m)。
实施例3：2-甲基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔2-甲基金刚烷-1-胺，有机溶剂换成乙酸丁酯，获得固体标题化合物15.73g，收率88％，纯度99.3％。
ESI-MS：正离子模式m/z＝166.2(2-甲基金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.05(3H,s),1.81(6H,d),1.63–1.73(5H,m),1.55–1.63(2H,m),1.09–1.39(4H,m),0.81–0.83(6H,m)。
实施例4：3,5-二甲基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的3,5-二甲基金刚烷-1-胺，获得固体标题化合物15.82g，收率85％，纯度99.5％。
ESI-MS：正离子模式m/z＝180.1(3,5-二甲基金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.16(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),1.80–2.0 7(9H,m),1.62–1.73(4H,m),1.54–1.60(2H,m),1.07–1.38(4H,m),0.81–0.84(9H,m)。
实施例5：3,4,6-三甲基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔3,4,6-三甲基金刚烷-1-胺，获得固体标题化合物15.63g，收率84％，纯度99.0％。
ESI-MS：正离子模式m/z＝194.3(3,4,6-三甲基金刚烷-1-胺+H)+，负离子模式mz＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.18(3H,s),7.62–7.64(1H,m),7.13 –7.23(3H,m),4.53–4.56(1H,m),1.81–2.07(9H,m),1.62–1.73(4H,m),1.07–1.61(5H,m),0.81–0.84(12H,m)。
实施例6：3-正丙基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔3-正丙基金刚烷-1-胺，获得固体标题化合物16.58g，收率86％，纯度99.1％。
ESI-MS：正离子模式m/z＝194.3(3-正丙基金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.18(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),1.79–2.07(9H,m),1.63–1.73(4H,m),1.43–1.62(7H,m),1.07–1.38(4H,m),0.80–0.85(6H,m)。
实施例7：4-氟金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔4-氟金刚烷-1-胺，获得固体标题化合物16.13g，收率89％，纯度99.3％。
ESI-MS：正离子模式m/z＝170.2(4-氟金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.06(3H,s),1.07–1.83(17H,m),0.82(3H,t)。
实施例8：4-三氟甲基金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔4-三氟甲基金刚烷-1-胺，获得固体标题化合物17.86g，收率87％，纯度99.2％。
ESI-MS：正离子模式m/z＝220.2(4-三氟甲基金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.06(3H,s),1.07–1.83(17H,m),0.82(3H,t)。
实施例9：3-溴金刚烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔3-溴金刚烷-1-胺，获得固体标题化合物18.95g，收率90％，纯度99.5％。
ESI-MS：正离子模式m/z＝231.1(3-溴金刚烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.17(3H,s),7.62–7.64(1H,m),7.13–7.23(3H,m),4.53–4.56(1H,m),2.05(3H,s),1.09–1.81(17H,m),0.82(3H,t)。
实施例10：反式-1-羟基金刚烷-4-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法：制备方法同实施例1，将金刚烷胺换成等摩尔的反式-1-羟基金刚烷-4-胺，获得固体标题化物16.59g，收率92％，纯度99.5％。
ESI-MS：正离子模式m/z＝168.1(反式-1-羟基金刚烷-4-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),2.11–0.91(20H,m),0.81(3H,t)。
实施例11：顺式-1-羟基金刚烷-4-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的顺式-1-羟基金刚烷-4-胺，获得固体标题化物16.59g，收率92％，纯度99.0％。
ESI-MS：正离子模式m/z＝168.1(顺式-1-羟基金刚烷-4-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13 –7.21(3H,m),4.53–4.56(1H,m),2.09–0.91(20H,m),0.81(3H,t)。
实施例12：4-羟基金刚烷-2-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的4-羟基金刚烷-2-胺，获得固体标题化物16.23g，收率90％，纯度99.2％。
ESI-MS：正离子模式m/z＝168.1(4-羟基金刚烷-2-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),2.08–0.90(20H,m),0.82(3H,t)。
实施例13：4-羟基环己烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的4-羟基环己烷-1-胺，获得固体标题化合物14.74g，收率95％，纯度99.2％。
ESI-MS：正离子模式m/z＝116.1(4-羟基环己烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.51–3.54(2H,m),1.25–2.37(14H,m)0.81(3H,t)。
实施例14：3-氯环戊烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的3-氯环戊烷-1-胺，获得固体标题化合物14.01g，收率89％，纯度99.0％。
ESI-MS：正离子模式m/z＝120.1(3-氯环戊烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.53–3.57(2H,m),1.23–2.42(12H,m)0.81(3H,t)。
实施例15：2-甲基环丙烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的2-甲基环丙烷-1-胺，获得固体标题化合物11.54g，收率86％，纯度98.8％。
ESI-MS：正离子模式m/z＝72.1(2-甲基环丙烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.43–3.55(2H,m),1.23–2.42(6H,m),0.81–0.84(6H,m),0.37–0.62(2H,m)。
实施例16：双环[2,2,1]庚烷-2-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的双环[2,2,1]庚烷-2-胺，获得固体标题化合物13.87g，收率90％，纯度98.2％。
ESI-MS：正离子模式m/z＝112.2(双环[2,2,1]庚烷-2-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.52–3.56(1H,m),1.25–2.37(16H,m)0.81(3H,t)。
实施例17：环庚烷胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的环庚烷胺，获得固体标题化合物12.87g，收率83％，纯度99.0％。
ESI-MS：正离子模式m/z＝114.2(环庚烷胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.52–3.56(1H,m),1.25–2.37(18H,m)0.82(3H,t)。
实施例18：2-羟基环丁烷-1-胺2-(1-羟基戊基)苯甲酸盐的制备
制备方法同实施例1，将金刚烷胺换成等摩尔的2-羟基环丁烷-1-胺，获得固体标题化合物12.06g，收率85％，纯度99.2％。
ESI-MS：正离子模式m/z＝88.1(2-羟基环丁烷-1-胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.23(3H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.50–3.55(2H,m),1.24–2.36(10H,m)0.812(3H,t)。
对比例1：2-(1-羟基戊基)苯甲酸钾盐(简称“钾盐”)，按照专利CN1382682A制备，纯度99.7％。
对比例2：2-(1-羟基戊基)苯甲酸叔丁胺盐(简称“叔丁胺盐”)，按照专利CN1523003A制备，纯度99.8％。
对比例3：2-(1-羟基戊基)苯甲酸二异丙基胺盐(简称“二异丙基胺盐”)的制备：
按照实施例1方法制备，将金刚烷胺换成等摩尔的二异丙基胺，获得固体的标题化合物12.2g，收率82％，纯度99.7％。
ESI-MS：正离子模式m/z＝102.3(二异丙基胺+H)+，负离子模式m/z＝207.1(化合物a-H)-。
1H NMR(400MHz,DMSO-d6)：8.15(2H,s),7.61–7.63(1H,m),7.13–7.21(3H,m),4.53–4.56(1H,m),3.62–3.78(2H,m),1.68(12，d)1.24–1.55(6H,m)0.812(3H,t)。
试验例1：大鼠缺血再灌注脑卒中模型短期急性药效评价
(一)神经功能行为学评分
1、分组和给药：将大鼠随机分为8组，即模型组、假手术组、丁苯酞(CAS:6066-49-5)组、化合物1组、化合物4组、化合物10组、钾盐(对比例1化合物)组、金刚烷胺(CAS:768-94-5)组，缺血2h再灌注后开始给药，模型组和假手术组尾静脉注射给予等体积5％葡萄糖注射液，其余各组尾静脉注射给予相应药物，单次给药。
2、实施造模手术：参考Longa线栓阻塞法构建大鼠MCAO模型。将尼龙线剪成2cm长，顶端蘸取微量熔融石蜡，冷却后完全包裹住尼龙线头备用。3％戊巴比妥钠完全麻醉大鼠 (30mg/kg)，仰卧位将大鼠固定于手术板上。颈部皮肤备皮消毒，沿中线剪开2cm，钝性分离出左侧颈总动脉，沿颈总动脉分离出颈外动脉与颈内动脉。结扎颈总动脉与颈外动脉远端，止血钳封闭颈内动脉。颈总动脉开口，自开口处插入准备好的尼龙线栓。蜡头一段插入颈总动脉并向颈内动脉推进，打开止血钳，待蜡头距离开口13～16mm时停止前进。固定线栓，缝合颈部皮肤。待血流阻断2h时后麻醉大鼠，取出线栓。假手术组仅用3％戊巴比妥钠完全麻醉大鼠，颈部皮肤备皮消毒后打开，钝性分离出颈总动脉，随即缝合伤口，不插入线栓。
3、神经功能缺陷评分：评分时间：于造模前、缺血后2h、术后24h采用盲法对所有存活动物进行改良神经功能评分；Longa’s method评分标准如下：0分：神经功能正常；1分：轻度神经功能缺损：提尾时，动物的左前肢屈曲；2分：中度神经功能缺损：将动物置于光滑平面上行走，行走时向左侧转圈；3分：中度神经缺损：静止状态下，向左侧倾斜；4分；意识减退，肢体无自发活动；5分：对刺激无应答或死亡。
4、试验结果：采用t检验对行为检测分值进行组间比较，结果见下表：
表1各化合物对MCAO大鼠神经症状的改善统计结果
注：与模型组比较，**P<0.01，*P<0.05。
结果表明，假手术组行为未见异常改变，模型组、丁苯酞组、化合物1组、化合物4组、化合物10组、钾盐组、金刚烷胺组大鼠术后2h均出现偏瘫样症状，主要表现为手术对测前肢内收，肩内旋，前肢肌张力降低。与模型组相比，术后24h丁苯酞组、钾盐组大鼠的神经症状均显著改善(P<0.05)；化合物1组、化合物4组和化合物10组大鼠的神经症状均极显著改善(P<0.01)；金刚烷胺组大鼠神经症状均无显著改善(P>0.05)。证明在相同摩尔剂量下，本发明化合物对MCAO大鼠神经症状的改善作用强于钾盐。
(二)脑梗死体积
MCAO缺血后24h，解剖各组存活大鼠，预冷的PBS灌注心脏，取脑组织，使用1％红四氮唑(TTC)进行染色，计算梗死体积百分比。脑梗死体积百分比＝右侧梗死体积/右侧大脑体积×100％。采用t检验对脑梗死体积百分比进行组间比较，结果见下表：
表2各化合物组的MCAO大鼠脑梗死体积统计结果
注：与模型组比较，**P<0.01，*P<0.05。
结果表明，大鼠大脑中动脉梗塞24h后模型组大鼠出现了明显的梗塞灶，假手术组无任何改变。与模型组比较，丁苯酞组大鼠的脑梗塞范围均显著减轻(P<0.05)；化合物1组、化合物4、化合物10组、钾盐组大鼠的脑梗塞范围极显著减轻(P<0.01)；金刚烷胺组大鼠均无显著抑制作用(P>0.05)。证明等摩尔剂量下，本发明化合物对MCAO大鼠脑梗塞范围的抑制作用强于丁苯酞和钾盐。
试验例2：对大鼠血小板聚集的影响
将大鼠随机分为14组：即溶剂对照组、阿司匹林组、丁苯酞组、化合物1组、化合物3组、化合物4组、化合物6组、化合物7组、化合物10组、化合物13组、化合物15组、化合物16组、钾盐组、N’N二苄基乙二胺盐组，各组当天口服灌胃给药3h后，腹主动脉取血收集富血小板血浆；20μM ADP诱导血小板聚集，血小板聚集仪测定富血小板血浆中血小板最大聚集率，评价并比较大鼠血小板聚集的影响。
表3各化合物的血小板聚集作用统计结果
注：与溶剂对照组比较，*P＜0.05，**P＜0.01。N’N二苄基乙二胺盐按照专利CN1523003A制备，纯度99.3％。
结果表明，相同剂量下，丁苯酞组大鼠的血小板聚集率与溶剂对照组相比有显著差异(P<0.05)；阿司匹林组、各实施例化合物组、钾盐组、N’N二苄基乙二胺盐组大鼠的血小板聚集率与溶剂对照组相比均极显著差异(P<0.01)。其中各实施例化合物组大鼠的血小板聚集率均远低于丁苯酞组、钾盐组和N’N二苄基乙二胺盐组，证明本发明化合物具备较好的抗血小板聚集作用。
试验例3：大鼠重复给药毒性试验
取健康成年SD大鼠，随机分为8组，每组10只大鼠，雌雄各半，分为空白组、溶媒对照组、化合物1低剂量组、化合物1中剂量组、化合物1高剂量组、化合物4低剂量组、化合物4中剂量组、化合物4高剂量组。空白组尾静脉注射给予等体积5％葡萄糖注射液，溶媒对照组尾静脉注射给予等体积的配置药物所用的溶媒，给药组大鼠尾静脉注射给予相应浓度药物，每天一次，连续给药14天，每天观察大鼠毒性反应(如对尾静脉的刺激性)情况并记录，统计各组大鼠死亡情况，并统计分析。
表4各化合物毒性试验结果
结果表明，本发明化合物在低、中、高剂量使用时均无毒性事件发生，证明本发明化合物药用安全且具有较高安全窗，能够保证用药安全。
试验例4：稳定性考察
待测药物：化合物1、化合物4、钾盐(对比例1化合物)、叔丁胺盐(对比例2化合物)、二异丙胺盐(对比例3化合物)。
取各待测化合物适量，照中国药典2020版四部通则9001进行影响因素试验考察，分别于0天、30天检测各化合物外观性状和主要降解产物丁苯酞的含量。其中丁苯酞的检测采用高效液相色谱法，色谱柱以十八烷基硅烷键合硅胶为填充剂，甲醇-水(65:35)为流动相。
表5各化合物高湿影响因素考察结果
结果表明，本发明化合物在30天高湿条件下性状不变、主峰和主要降解杂质丁苯酞的含量均基本不变，具有较高的高湿稳定性；同时，本发明化合物1和4经敞口高温、光照试验条件30天考察后，各化合物性状不变，主峰和丁苯酞含量均基本不变。因此，本发明化 合物具备较高的稳定性。且本发明化合物制备工艺简单，适合工业化放大生产。
试验例5：溶解度试验
分别取化合物1和化合物4适量，照中国药典2020版四部凡例项下溶解度测定法测定各化合物在不同溶剂中的溶解性。
表6各化合物溶解度试验结果
结果表明，本发明化合物具备较好的水溶解性，适合用于制备成静脉注射液，可为临床治疗提供更多可靠选择。
以上所述仅是本发明的优选实施方式，应当指出，对于使本技术领域的专业技术人员，在不脱离本发明技术原理的前提下，是能够实现对这些实施例的多种修改的，而这些修改也应视为本发明应该保护的范围。

Claims (10)

  1. 一种结构如式I所示的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体：
    其中，环A选自金刚烷或3～7元环烷烃，R1独立地选自1～3个：氢、烷基、羟基、卤素或卤代烷基。
  2. 根据权利要求1所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，其特征在于，所述环A选自金刚烷；或/和所述R1独立地选自1～3个：氢、C1～C6烷基、羟基、卤素或卤代C1～C6烷基。
  3. 根据权利要求2所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，其特征在于，所述C1～C6烷基包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊烷基或正己烷基；或/和所述卤素包括但不限于氟、氯或溴；或/和所述卤代C1～C6烷基包括但不限于三氟甲基或二氟甲基。
  4. 根据权利要求1所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，其特征在于，所述2-(1-羟基戊基)苯甲酸环烷胺盐包括如下化合物：

  5. 根据权利要求1～4任一所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，其特征在于，所述化合物中的氢可被一个或多个氘取代。
  6. 权利要求1～5任一所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体的制备方法，其特征在于，包括如下步骤：
    化合物a与化合物b在有机溶剂存在条件下发生成盐反应生成式I化合物；
    其中，环A、R1的定义同权利要求1。
  7. 根据权利要求6所述的制备方法，其特征在于，所述有机溶剂包括但不限于醚类或酯类；优选地，所述醚类溶剂包括但不限于乙醚或甲基叔丁基醚；所述酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯或乙酸丁酯；或/和所述成盐的温度为0～50℃，优选10～30℃。
  8. 一种药物组合物，包含权利要求1～5任一所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体，其特征在于，所述药物组合物还包含药学上可接受载体。
  9. 权利要求1～5任一所述的2-(1-羟基戊基)苯甲酸环烷胺盐或其异构体在制备治疗和/或预防缺血性心、脑血管疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述缺血性心、脑血管疾病包括但不限于轻、中、重度急性缺血性脑卒中、脑血栓、脑栓塞、冠心病、心绞痛或心肌梗死；优选中、重度急性缺血性脑卒中；更优选急性缺血性脑卒中患者神经功能缺损的改善。
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