Novel 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salts

Abstract

The present invention provides a 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt having a structure represented by Formula I, a process for preparing the same, a pharmaceutical composition containing the compound as an active ingredient, and use of the compound in the treatment and / or prevention of ischemic heart / cerebrovascular disease, particularly mild, moderate, and severe acute ischemic stroke. JPEG2026508699000035.jpg39164

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a novel 2-(1-hydroxypentyl)benzoate salt, a process for preparing the same, a pharmaceutical composition containing the compound as an active ingredient, and its use in the treatment and / or prevention of ischemic cardio / cerebrovascular diseases, particularly mild, moderate, and severe acute ischemic stroke. [Background technology]

[0002] Acute ischemic stroke, cerebral thrombosis, cerebral embolism, coronary heart disease, angina pectoris, myocardial infarction, etc. are all common ischemic heart / cerebrovascular diseases, which are diseases of ischemic damage caused by thrombus formation induced by various factors. In particular, ischemic cerebrovascular diseases occur when blood vessels are blocked due to severe cerebrovascular stenosis or diseases such as cerebral infarction and / or cerebral thrombosis, resulting in insufficient blood supply to the brain and causing damage and necrosis of brain cells. While such diseases cause great pain and even life-threatening suffering to patients, drug research in this field is also at the forefront and the focus of scientists' attention.

[0003] Butylphthalide is a type I new drug for ischemic cerebrovascular disease developed in China in recent years, and the only preparations currently on the market are butylphthalide soft capsules and butylphthalide sodium chloride injection, whose main mechanism of action is to improve microcirculation in cerebral ischemic areas, promote angiogenesis in ischemic areas, and increase cerebral blood flow in ischemic areas.Butylphthalide itself is a lipophilic compound, and is an oily liquid at room temperature, with poor water solubility and low solubility in the body.Due to its unfavorable physicochemical properties, its manufacturing process is difficult, its utilization rate in the body is low, and its efficacy is insufficient.Therefore, butylphthalide does not have a high comprehensive therapeutic effect in clinical use, and usually needs to be combined with other drugs to enhance the therapeutic effect, which limits its application range in the clinical treatment of ischemic diseases.

[0004] Chinese Patent CN1382682A is the first to disclose the preparation and use of 2-(α-hydroxypentyl)benzoate salts using DL-3-n-butylphthalide as a lead, and relates to salts of monovalent metal ions, divalent metal ions, and organic bases, specifically salts of potassium, sodium, calcium, magnesium, zinc, aniline, benzylamine, morpholine, and diethylamine. The specification also discloses, in a section on pharmaceutical efficacy, the effects of the potassium salt on cerebral infarction size in rats with focal cerebral ischemia, on rat platelet aggregation, and on the protective effect against in vitro cardiac ischemia-reperfusion arrhythmias in rats, demonstrating that the potassium salt plays a beneficial role in the above experiments. Chinese Patent CN1523003A comprehensively compares various metal salts and organic amine / inorganic ammonium salts of 2-(α-hydroxypentyl)benzoic acid, and finds that potassium salt is highly hygroscopic, unstable, and toxic, tert-butylamine salt and benzylamine salt are highly toxic, while N,N'-dibenzylethylenediamine salt has low toxicity, but its efficacy is only comparable to that of potassium salt, and its molecular weight is large, making it difficult to absorb, and the single-dose requirement is large, resulting in poor patient compliance. Therefore, the current market, including those under development, lacks butylphthalide ring-opening derivative drugs that are highly safe, have significant efficacy, and are suitable for formulation.

[0005] Therefore, the development of a therapeutic drug for ischemic heart / cerebrovascular disease, particularly a drug suitable for the treatment of ischemic cerebrovascular disease, which has a more effective and stable solid form and is suitable for intravenous injection, is currently a serious clinical problem that needs to be solved. Summary of the Invention

[0006] In order to overcome the technical problems in the prior art and further develop novel 2-(1-hydroxypentyl)benzoic acid salts, the present invention provides novel 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salts and their preparation and use. The novel 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salts provided by the present invention have good solid form and remarkable medicinal efficacy.

[0007] In one aspect, the present invention provides a 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt having a structure represented by Formula I or an isomer thereof. [ka]

[0008] Here, ring A is selected from adamantane or a 3- to 7-membered cycloalkane, and R1 is independently 1 to 3 selected from hydrogen, an alkyl group, a hydroxy group, a halogen, or a haloalkyl group.

[0009] In some embodiments, the ring A is selected from adamantane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or bicyclo[2,2,1]heptane.

[0010] In some embodiments, the R1 is independently 1 to 3 selected from hydrogen, a C1 to C6 alkyl group, a hydroxy group, a halogen, or a halo C1 to C6 alkyl group.

[0011] In some embodiments, the ring A is selected from adamantane, or / and the R1 is independently 1 to 3 selected from hydrogen, a C1 to C6 alkyl group, a hydroxy group, a halogen, or a halo C1 to C6 alkyl group.

[0012] In some embodiments, the C1-C6 alkyl group includes, but is not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, or an n-hexyl group; and / or the halogen includes, but is not limited to, a fluorine group, a chlorine group, or a bromine group; and / or the halo C1-C6 alkyl group includes, but is not limited to, a trifluoromethyl group or a difluoromethyl group.

[0013] In some embodiments, the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomer includes the following compound: [ka] [ka] [ka]

[0014] If the structure of a compound of the present invention contradicts the nomenclature and cannot be rationally interpreted, the structure shall prevail.

[0015] In some embodiments, hydrogen in the above compounds may be replaced with one or more deuterium atoms.

[0016] In another aspect, the present invention provides a method for producing the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or an isomer thereof, which comprises a step of subjecting compound a and compound b to a salt-forming reaction in the presence of an organic solvent to produce the compound of formula I. [ka] Here, the definitions of ring A and R1 are the same as any of the corresponding definitions above.

[0017] In some embodiments, the organic solvent includes, but is not limited to, an ether or an ester, preferably, the ether solvent includes, but is not limited to, diethyl ether or methyl tert-butyl ether, and the ester solvent includes, but is not limited to, ethyl acetate, isopropyl acetate, or butyl acetate; and / or the temperature for salt formation is 0 to 50°C, preferably 10 to 30°C.

[0018] In a third aspect, the present invention also provides a pharmaceutical composition comprising any of the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salts or isomers thereof, which further comprises a pharmaceutically acceptable carrier.

[0019] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle that is suitable for administration with an active ingredient and for contact with the tissues of human beings and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment.

[0020] In some embodiments, the pharmaceutical composition includes, but is not limited to, a tablet, a capsule, a large volume injectable, a small volume injectable, a lyophilized powder injectable, or a granule.

[0021] In a fourth aspect, the present invention also provides use of the above-mentioned 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or an isomer thereof in the manufacture of a medicament for treating and / or preventing ischemic heart / cerebrovascular disease.

[0022] In some embodiments, the ischemic heart / cerebrovascular disease includes, but is not limited to, mild, moderate, or severe acute ischemic stroke, cerebral thrombosis, cerebral embolism, coronary heart disease, angina pectoris, or myocardial infarction, preferably moderate or severe acute ischemic stroke, more preferably neurological function deficits in patients with acute ischemic stroke.

[0023] Beneficial Effects: The 2-(1-hydroxypentyl)benzoic acid cycloalkylamine of the present invention has at least one of the following technical effects: (1) It has a good solid form and is produced by a simple method, making it suitable for industrial scale-up production. (2) It has a strong antiplatelet aggregation effect, a strong neurological symptom-improving effect, and an effect of suppressing the extent of cerebral infarction, indicating that the compound of the present invention has pharmacological effects such as preventing and / or treating cardiac / cerebral arterial occlusion and improving cardiac / cerebral microcirculation, and is suitable for the prevention and / or treatment of cardiac / cerebral ischemic diseases. (3) It has a wide therapeutic window and is safe for medicinal use. (4) It has good solubility and high stability, making it suitable for formulation, and has potential, particularly for the development of intravenous injections. DETAILED DESCRIPTION OF THE INVENTION

[0024] The following examples will illustrate the technical solutions of the present invention. Those skilled in the art should understand that the following examples are merely illustrative of the present invention and do not limit the scope of the present invention. Unless specific techniques or conditions are specified in the examples, they will be carried out in accordance with the techniques or conditions described in the literature in the field or in accordance with the product instructions. Reagents or equipment used without a manufacturer's name are all commercially available general products.

[0025] The structure of the compound is identified by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography mass spectrometry (LC-MS).

[0026] The liquid chromatography mass spectrometer (LC-MS) was an Agilent G6120B (used with an Agilent 1260 liquid chromatograph). The nuclear magnetic resonance (H NMR) spectrometer was a Bruker AVANCE-400 or Bruker AVANCE-800. Nuclear magnetic resonance (H NMR) shifts (δ) are given in parts per million (ppm), the measurement solvent was DMSO, and the internal standard was tetramethylsilane (TMS).

[0027] In the present invention, the term "room temperature" refers to a temperature of 10 to 30° C. Unless otherwise specified, the reagents and compounds used in the present invention are commercially available.

[0028] The term "xxx group" used in each test example of the present invention indicates that the drug used in the group is "xxx." For example, "compound 1 group" indicates that the drug used in the group is "compound 1."

[0029] Example 1: Preparation of amantadine 2-(1-hydroxypentyl)benzoate [ka]

[0030] Preparation method: 10.00 g of compound a (2-(1-hydroxypentyl)benzoic acid) was dissolved in 40 ml of methyl tert-butyl ether, and the reaction solution was stirred at room temperature. 7.26 g of amantadine (compound b-1) was taken and dissolved in 30 ml of methyl tert-butyl ether, and the amantadine methyl tert-butyl ether solution was added dropwise to the reaction system at room temperature. After the addition was completed, the reaction system was cooled to -5 to 20°C and suction filtered. The resulting solid was placed in a vacuum drying box to dry, yielding 16.50 g of the title compound with a yield of 90% and a purity of 99.2%.

[0031] ESI-MS: Positive ion mode m / z = 152.1 (amantadine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0032] 1H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.05 (3 H, s), 1.81 (6 H, d), 1.63 - 1.73 (5 H, m), 1.55 - 1.60 (3 H, m), 1.30 - 1.39 (1 H, m), 1.20 - 1.29 (2 H, m), 1.09 - 1.18 (1 H, m), 0.82 (3 H, t).

[0033] Example 2: Preparation of 3-methyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0034] The preparation method was the same as in Example 1, except that adamantane was replaced with an equimolar amount of 3-methyladamantan-1-amine and the organic solvent was replaced with ethyl acetate to obtain 15.25 g of the title compound as a solid, with a yield of 85% and a purity of 99.3%.

[0035] ESI-MS: Positive ion mode m / z = 166.2 (3-methyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0036] 1 H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.05 (3 H, s), 1.81 (6 H, d), 1.63 - 1.73 (5 H, m), 1.55 - 1.63 (2 H, m), 1.09 - 1.39 (4 H, m), 0.81 - 0.83 (6 H, m).

[0037] Example 3: Preparation of 2-methyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0038] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 2-methyladamantan-1-amine and the organic solvent was replaced with butyl acetate to obtain 15.73 g of the title compound as a solid, with a yield of 88% and a purity of 99.3%.

[0039] ESI-MS: Positive ion mode m / z = 166.2 (2-methyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0040] 1 H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.05 (3 H, s), 1.81 (6 H, d), 1.63 - 1.73 (5 H, m), 1.55 - 1.63 (2 H, m), 1.09 - 1.39 (4 H, m), 0.81 - 0.83 (6 H, m).

[0041] Example 4: Preparation of 3,5-dimethyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0042] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 3,5-dimethyladamantan-1-amine to obtain 15.82 g of the title compound as a solid, with a yield of 85% and a purity of 99.5%.

[0043] ESI-MS: Positive ion mode m / z = 180.1 (3,5-dimethyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0044] 1 H NMR (400 MHz, DMSO-d6) :8.16 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 1.80 - 2.07 (9 H, m), 1.62 - 1.73 (4 H, m), 1.54 - 1.60 (2 H, m), 1.07 - 1.38 (4 H, m), 0.81 -0.84 (9 H, m).

[0045] Example 5: Preparation of 3,4,6-trimethyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0046] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 3,4,6-trimethyladamantan-1-amine to obtain 15.63 g of the title compound as a solid, with a yield of 84% and a purity of 99.0%.

[0047] ESI-MS: Positive ion mode m / z = 194.3 (3,4,6-trimethyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0048] 1H NMR (400 MHz, DMSO-d6) :8.18 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 1.81 - 2.07 (9 H, m), 1.62 - 1.73 (4 H, m), 1.07 - 1.61 (5 H, m), 0.81 -0.84 (12 H, m).

[0049] Example 6: Preparation of 3-n-propyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0050] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 3-n-propyladamantan-1-amine to obtain 16.58 g of the title compound as a solid, with a yield of 86% and a purity of 99.1%.

[0051] ESI-MS: Positive ion mode m / z = 194.3 (3-n-propyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0052] 1 H NMR (400 MHz, DMSO-d6) :8.18 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 1.79 - 2.07 (9 H, m), 1.63 - 1.73 (4 H, m), 1.43 - 1.62 (7 H, m), 1.07 - 1.38 (4 H, m), 0.80 -0.85 (6 H, m).

[0053] Example 7: Preparation of 4-fluoroadamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0054] The preparation method was the same as in Example 1, except that amantadine was replaced with equimolar 4-fluoroadamantan-1-amine to obtain 16.13 g of the title compound as a solid, with a yield of 89% and a purity of 99.3%.

[0055] ESI-MS: Positive ion mode m / z = 170.2 (4-fluoroadamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0056] 1 H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.06 (3 H, s), 1.07 - 1.83 (17 H, m), 0.82 (3H, t).

[0057] Example 8: Preparation of 4-trifluoromethyladamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0058] The preparation method was the same as in Example 1, except that amantadine was replaced with equimolar 4-trifluoromethyladamantan-1-amine to obtain 17.86 g of the title compound as a solid, with a yield of 87% and a purity of 99.2%.

[0059] ESI-MS: Positive ion mode m / z = 220.2 (4-trifluoromethyladamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0060] 1 H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.06 (3 H, s), 1.07 - 1.83 (17 H, m), 0.82 (3H, t).

[0061] Example 9: Preparation of 3-bromoadamantan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0062] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 3-bromoadamantan-1-amine to obtain 18.95 g of the title compound as a solid, with a yield of 90% and a purity of 99.5%.

[0063] ESI-MS: Positive ion mode m / z = 231.1 (3-bromoadamantan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0064] 1 H NMR (400 MHz, DMSO-d6) :8.17 (3 H, s), 7.62 - 7.64 (1 H, m), 7.13 - 7.23 (3 H, m), 4.53 - 4.56(1 H, m), 2.05 (3 H, s), 1.09 - 1.81 (17 H, m), 0.82 (3H, t).

[0065] Example 10: Preparation of trans-1-hydroxyadamantan-4-amine 2-(1-hydroxypentyl)benzoate [ka]

[0066] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar 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%.

[0067] ESI-MS: Positive ion mode m / z = 168.1 (trans-1-hydroxyadamantan-4-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0068] 1 H NMR (400 MHz, 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).

[0069] Example 11: Preparation of cis-1-hydroxyadamantan-4-amine 2-(1-hydroxypentyl)benzoate [ka]

[0070] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar 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%.

[0071] ESI-MS: Positive ion mode m / z = 168.1 (cis-1-hydroxyadamantan-4-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0072] 1H NMR (400 MHz, 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).

[0073] Example 12: Preparation of 4-hydroxyadamantan-2-amine 2-(1-hydroxypentyl)benzoate [ka]

[0074] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar 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%.

[0075] ESI-MS: Positive ion mode m / z = 168.1 (4-hydroxyadamantan-2-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0076] 1 H NMR (400 MHz, 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).

[0077] Example 13: Preparation of 4-hydroxycyclohexan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0078] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 4-hydroxycyclohexane-1-amine to obtain 14.74 g of the title compound as a solid, with a yield of 95% and a purity of 99.2%.

[0079] ESI-MS: Positive ion mode m / z = 116.1 (4-hydroxycyclohexan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0080] 1 H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.51 - 3.54 (2H, m), 1.25 - 2.37 (14H, m) 0.81 (3H, t).

[0081] Example 14: Preparation of 3-chlorocyclopentan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0082] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 3-chlorocyclopentan-1-amine to obtain 14.01 g of the title compound as a solid, with a yield of 89% and a purity of 99.0%.

[0083] ESI-MS: Positive ion mode m / z = 120.1 (3-chlorocyclopentan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0084] 1H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.53 - 3.57 (2H, m), 1.23 - 2.42 (12H, m) 0.81 (3H, t).

[0085] Example 15: Preparation of 2-methylcyclopropan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0086] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 2-methylcyclopropan-1-amine to obtain 11.54 g of the title compound as a solid, with a yield of 86% and a purity of 98.8%.

[0087] ESI-MS: Positive ion mode m / z = 72.1 (2-methylcyclopropan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0088] 1 H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.43 - 3.55 (2H, m), 1.23 - 2.42 (6H, m), 0.81 -0.84 (6 H, m), 0.37 -0.62 (2 H, m).

[0089] Example 16: Preparation of bicyclo[2,2,1]heptan-2-amine 2-(1-hydroxypentyl)benzoate [ka]

[0090] The preparation method was the same as in Example 1, except that amantadine was replaced with equimolar bicyclo[2,2,1]heptan-2-amine to obtain 13.87 g of the title compound as a solid, with a yield of 90% and a purity of 98.2%.

[0091] ESI-MS: Positive ion mode m / z = 112.2 (bicyclo[2,2,1]heptan-2-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0092] 1 H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.52 - 3.56 (1H, m), 1.25 - 2.37 (16H, m) 0.81 (3H, t).

[0093] Example 17: Preparation of cycloheptylamine 2-(1-hydroxypentyl)benzoate [ka]

[0094] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of cycloheptylamine to obtain 12.87 g of the title compound as a solid, with a yield of 83% and a purity of 99.0%.

[0095] ESI-MS: Positive ion mode m / z = 114.2 (cycloheptylamine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0096] 1H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.52 - 3.56 (1H, m), 1.25 - 2.37 (18H, m) 0.82 (3H, t).

[0097] Example 18: Preparation of 2-hydroxycyclobutan-1-amine 2-(1-hydroxypentyl)benzoate [ka]

[0098] The preparation method was the same as in Example 1, except that amantadine was replaced with an equimolar amount of 2-hydroxycyclobutan-1-amine to obtain 12.06 g of the title compound as a solid, with a yield of 85% and a purity of 99.2%.

[0099] ESI-MS: Positive ion mode m / z = 88.1 (2-hydroxycyclobutan-1-amine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0100] 1 H NMR (400 MHz, DMSO-d6) :8.23 (3 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.50 - 3.55 (2H, m), 1.24 - 2.36 (10H, m) 0.812 (3H, t).

[0101] Comparative Example 1: 2-(1-hydroxypentyl)benzoic acid potassium salt (abbreviated as "potassium salt") prepared according to Chinese patent CN1382682A, with a purity of 99.7%.

[0102] Comparative Example 2: 2-(1-hydroxypentyl)benzoic acid tert-butylamine salt (abbreviated as "tert-butylamine salt") prepared according to Chinese Patent CN1523003A, with a purity of 99.8%.

[0103] Comparative Example 3: Preparation of 2-(1-hydroxypentyl)benzoic acid diisopropylamine salt (abbreviated as "diisopropylamine salt") [ka]

[0104] Prepared according to the method of Example 1, substituting an equimolar amount of diisopropylamine for amantadine, to give 12.2 g of the title compound as a solid, a yield of 82%, and a purity of 99.7%.

[0105] ESI-MS: Positive ion mode m / z = 102.3 (diisopropylamine + H) + , negative ion mode m / z = 207.1 (compound aH) - .

[0106] 1 H NMR (400 MHz, DMSO-d6) :8.15 (2 H, s), 7.61 - 7.63 (1 H, m), 7.13 - 7.21 (3 H, m), 4.53 - 4.56(1 H, m), 3.62 - 3.78 (2H, m), 1.68(12,d)1.24 - 1.55 (6H, m) 0.812 (3H, t).

[0107] Test Example 1: Evaluation of short-term acute efficacy in a rat ischemia-reperfusion stroke model (1) Neurofunctional behavioral scores 1. Grouping and administration: The rats were randomly divided into eight groups: model group, sham operation group, butylphthalide (CAS: 6066-49-5) group, compound 1 group, compound 4 group, compound 10 group, potassium salt (comparison example 1 compound) group, and amantadine (CAS: 768-94-5) group. Administration began after 2 hours of ischemia and reperfusion. The model group and sham operation group were administered an equal volume of 5% glucose injection via tail vein injection, while the other groups received a single dose of the corresponding drug via tail vein injection.

[0108] 2. Modeling Surgery: A rat MCAO model was constructed using the Longa thread embolization method. A nylon thread was cut to a length of 2 cm, and a small amount of molten paraffin was applied to the tip. After cooling, the nylon thread was completely wrapped around the tip and ready for use. Rats were fully anesthetized with 3% sodium pentobarbital (30 mg / kg) and fixed to a surgical plate in a supine position. The neck skin was depilated and disinfected, and a 2 cm incision was made along the midline. The left common carotid artery was isolated by blunt dissection, and the external and internal carotid arteries were separated along the common carotid artery. The distal ends of the common carotid artery and external carotid artery were ligated, and the internal carotid artery was closed with a hemostat. An opening was made in the common carotid artery, and a previously prepared nylon thread embolizer was inserted through the opening. The paraffin-coated end was inserted into the common carotid artery and advanced to the internal carotid artery. The hemostat was released, and advancement was stopped when the paraffin end was 13–16 mm from the opening. The thread embolus was fixed in place, and the neck skin was sutured. After 2 hours of blood flow occlusion, the rats were anesthetized and the thread embolus was removed. In the sham-operated group, rats were fully anesthetized with 3% pentobarbital sodium alone, and the neck skin was depilated and disinfected before being incised. The common carotid artery was isolated by blunt dissection, and the wound was immediately sutured without inserting the thread embolus.

[0109] 3. Neurological function defect score: Score timing: All surviving animals were subjected to improved neurological function scoring using a blinded method before modeling, 2 hours after ischemia, and 24 hours after surgery. The Longa method score criteria are as follows: 0 point: Normal neurological function. 1 point: Mild neurological function defect: When the tail is lifted, the animal's left forelimb flexes. 2 points: Moderate neurological function defect: When the animal is placed on a smooth surface and asked to walk, it turns to the left while walking. 3 points: Moderate neurological defect: When at rest, it leans to the left. 4 points: Decreased consciousness and no spontaneous limb movement. 5 points: Unresponsive to stimulation or death.

[0110] 4. Analysis of results: Behavioral test scores were compared between groups using t-tests, and the results are shown in the table below. [Table 1]

[0111] Note: Compared with the model group, **P<0.01, *P<0.05.

[0112] The results clearly showed that the sham-operated group showed no abnormal behavioral changes, whereas the model, butylphthalide, compound 1, compound 4, compound 10, potassium salt, and amantadine groups all showed hemiplegia at 2 h postoperatively, primarily characterized by forelimb adduction, shoulder joint internal rotation, and decreased forelimb muscle tone on the contralateral side. Compared with the model group, the butylphthalide and potassium salt groups showed significant improvement in neurological symptoms at 24 h postoperatively (P<0.05). The compound 1, compound 4, and compound 10 groups showed highly significant improvement in neurological symptoms (P<0.01). The amantadine group showed no significant improvement in neurological symptoms (P>0.05). The compounds of the present invention have been shown to have a stronger ameliorative effect on neurological symptoms in MCAO rats than the potassium salt at the same molar dose.

[0113] (2) Cerebral infarction volume Twenty-four hours after MCAO-induced ischemia, surviving rats from each group were dissected and cardiac perfusion was performed with pre-chilled PBS. Brain tissue was then collected and stained with 1% tetrazolium red (TTC). The infarct volume percentage was calculated as follows: Cerebral infarct volume percentage = right infarct volume / right cerebral volume × 100%. Between-group comparisons of cerebral infarct volume percentage were performed using a t-test, and the results are shown in the table below. [Table 2]

[0114] Note: Compared with the model group, **P<0.01, *P<0.05.

[0115] As can be seen from the results, 24 hours after the middle cerebral artery infarction in rats, the model group showed significant infarction, while the sham-operated group showed no change. Compared with the model group, the cerebral infarction area of ​​rats in the butylphthalide group was significantly reduced (P<0.05), while the cerebral infarction area of ​​rats in the compound 1 group, compound 4, compound 10 group, and potassium salt group was significantly reduced (P<0.01), while the amantadine group had no significant inhibitory effect (P>0.05). It was demonstrated that the compounds of the present invention have a stronger inhibitory effect on the cerebral infarction area of ​​MCAO rats than butylphthalide and potassium salt at the same molar dose.

[0116] Test Example 2: Effect on platelet aggregation in rats Rats were randomly divided into 14 groups: vehicle control, aspirin, butylphthalide, compound 1, compound 3, compound 4, compound 6, compound 7, compound 10, compound 13, compound 15, compound 16, potassium salt, and N,N'-dibenzylethylenediamine salt. Each group received oral or intragastric administration on the same day. Three hours after administration, blood was collected from the abdominal aorta to collect platelet-rich plasma. Platelet aggregation was induced with 20 μM ADP, and the maximum platelet aggregation rate in the platelet-rich plasma was measured using an aggregometer to evaluate and compare the effects on platelet aggregation in rats.

[0117] [Table 3]

[0118] Note: *P<0.05, **P<0.01 compared with the solvent control group. N,N'-Dibenzylethylenediamine salt was prepared according to Chinese patent CN1523003A with a purity of 99.3%.

[0119] The results show that at the same dose, the rat platelet aggregation rate in the butylphthalide group was significantly different from that in the solvent control group (P<0.05), and the rat platelet aggregation rate in the aspirin group, each example compound group, potassium salt group, and N,N'-dibenzylethylenediamine salt group was significantly different from that in the solvent control group (P<0.01).Here, the rat platelet aggregation rate in each example compound group was far lower than that in the butylphthalide group, potassium salt group, and N,N'-dibenzylethylenediamine salt group, proving that the compounds of the present invention have good anti-platelet aggregation effect.

[0120] Test Example 3: Repeated dose toxicity test in rats Healthy adult SD rats were randomly divided into eight groups (10 rats per group, half male and half female): blank group, vehicle control group, compound 1 low dose group, compound 1 medium dose group, compound 1 high dose group, compound 4 low dose group, compound 4 medium dose group, and compound 4 high dose group. The blank group received an equal volume of 5% glucose injection via tail vein injection, the vehicle control group received an equal volume of the drug preparation solvent via tail vein injection, and the rats in the treatment groups received the corresponding drug concentrations via tail vein injection once daily for 14 consecutive days. The rats were observed and recorded for toxic reactions (e.g., tail vein irritation) daily, and the mortality rate of rats in each group was recorded and statistically analyzed.

[0121] [Table 4]

[0122] As is clear from the results, the compounds of the present invention did not cause any toxic events when used at low, medium, or high doses, proving that the compounds of the present invention are safe as pharmaceuticals, have a high safety margin, and can ensure safe administration.

[0123] Test Example 4: Stability Considerations Test drugs: Compound 1, Compound 4, potassium salt (Comparative Example 1 compound), tert-butylamine salt (Comparative Example 2 compound), diisopropylamine salt (Comparative Example 3 compound).

[0124] An appropriate amount of each test compound was taken and subjected to an influence factor test in accordance with the Chinese Pharmacopoeia 2020, Part 4 General Rule 9001. The appearance of each compound and the content of the main decomposition product, butylphthalide, were measured on days 0 and 30. Here, butylphthalide was detected by high-performance liquid chromatography using octadecylsilane-bonded silica gel as the column packing and methanol-water (65:35) as the mobile phase.

[0125] [Table 5]

[0126] As is clear from the results, the properties of the compounds of the present invention remained unchanged under high-humidity conditions for 30 days, and the main peak and the content of the main decomposition impurity, butylphthalide, remained almost unchanged, demonstrating high humidity stability. Furthermore, when compounds 1 and 4 of the present invention were examined under open, high-temperature, and light irradiation conditions for 30 days, the properties of each compound remained unchanged, and the main peak and the content of butylphthalide remained almost unchanged. Therefore, the compounds of the present invention have high stability. Furthermore, the compounds of the present invention have a simple manufacturing process and are suitable for industrial scale-up production.

[0127] Test Example 5: Solubility test An appropriate amount of compound 1 and compound 4 was taken, and the solubility of each compound in different solvents was measured according to the solubility measurement method in the Fourth Part Notes section of the 2020 edition of the Chinese Pharmacopoeia.

[0128] [Table 6]

[0129] As can be seen from the results, the compounds of the present invention have good water solubility and are suitable for the preparation of intravenous injections, which can provide more reliable options for clinical treatment.

[0130] The above description is merely a preferred embodiment of the present invention, and those skilled in the art can make various modifications to these examples without departing from the technical idea of ​​the present invention, and these modifications should also be considered to fall within the protection scope of the present invention.

Claims

1. 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt having the structure represented by Formula I or an isomer thereof. 【Chemistry 1】 wherein ring A is selected from adamantane or a 3- to 7-membered cycloalkane; R 1 are independently 1 to 3 selected from hydrogen, an alkyl group, a hydroxy group, a halogen, or a haloalkyl group.

2. wherein ring A is selected from adamantane, or / and R 1 are independently 1 to 3 selected from hydrogen, a C1 to C6 alkyl group, a hydroxy group, a halogen, or a halo C1 to C6 alkyl group; 2. The 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomer according to claim 1.

3. The C1-C6 alkyl group includes, but is not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, or an n-hexyl group; and / or The halogen includes, but is not limited to, fluorine, chlorine or bromine; and / or The halo C1-C6 alkyl group includes, but is not limited to, a trifluoromethyl group or a difluoromethyl group.

3. The 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomer according to claim 2.

4. 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt according to claim 1, characterized in that the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt comprises the following compound or an isomer thereof: 【Chemistry 2】

5. 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or an isomer thereof according to any one of claims 1 to 4, wherein hydrogen in the compound may be substituted with one or more deuterium atoms.

6. A method for producing the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or an isomer thereof according to any one of claims 1 to 5, comprising: A production method comprising a step of reacting compound a with compound b to form a salt in the presence of an organic solvent to produce a compound of formula I. 【Transformation 3】 (wherein rings A and R 1 The definitions of are the same as those in claim 1.)

7. 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 solvents include, but are not limited to, ethyl acetate, isopropyl acetate, or butyl acetate; and / or The temperature for the salt formation is 0 to 50°C, preferably 10 to 30°C. The manufacturing method according to claim 6.

8. A pharmaceutical composition comprising the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or an isomer thereof according to any one of claims 1 to 5, A pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

9. Use of the 2-(1-hydroxypentyl)benzoic acid cycloalkylamine salt or its isomer according to any one of claims 1 to 5 in the manufacture of a drug for treating and / or preventing ischemic heart / cerebrovascular disease.

10. The ischemic heart / cerebrovascular disease includes, but is not limited to, mild, moderate, or severe acute ischemic stroke, cerebral thrombosis, cerebral embolism, coronary heart disease, angina pectoris, or myocardial infarction; The ischemic heart / cerebrovascular disease is preferably moderate or severe acute ischemic stroke, more preferably neurological dysfunction in patients with acute ischemic stroke.

10. Use according to claim 9, characterized in that

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