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WO2018133670A1 - 丁苯酞-替米沙坦杂合物及其制备方法和用途 - Google Patents

丁苯酞-替米沙坦杂合物及其制备方法和用途 Download PDF

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WO2018133670A1
WO2018133670A1 PCT/CN2018/071308 CN2018071308W WO2018133670A1 WO 2018133670 A1 WO2018133670 A1 WO 2018133670A1 CN 2018071308 W CN2018071308 W CN 2018071308W WO 2018133670 A1 WO2018133670 A1 WO 2018133670A1
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compound
group
pentyl
telmisartan
reaction
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黄张建
庞涛
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China Pharmaceutical University
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China Pharmaceutical University
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Priority to CA3049604A priority Critical patent/CA3049604C/en
Priority to EP18741580.7A priority patent/EP3572404B1/en
Priority to JP2019551260A priority patent/JP6688437B1/ja
Priority to US16/478,400 priority patent/US11028073B2/en
Priority to MYPI2019004140A priority patent/MY189740A/en
Publication of WO2018133670A1 publication Critical patent/WO2018133670A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a butylphthalide-telmisartan hybrid, and more particularly to an optically active ring-opened butylphthalide-telmisartan hybrid or a pharmaceutically acceptable salt or ester thereof, which Preparation methods, pharmaceutical compositions containing these compounds, and their medical use, particularly in the prevention and treatment of diseases associated with neuroinflammation, including ischemic stroke, Alzheimer's disease, brain trauma, Parkinson's disease
  • the application of multiple sclerosis and depression belongs to the field of pharmaceutical technology.
  • Microglia in the central nervous system play a key role in mediating various immune-related functional diseases, which are divided into pro-inflammatory (M1 classical) and anti-inflammatory (M2 alternative activated).
  • M1 type microglia highly express oxidative metabolites (such as superoxide and nitric oxide) and pro-inflammatory cytokines (such as TNF- ⁇ , IL-1 ⁇ , IL-6, IL-18). These substances can produce cytotoxic effects on neurons and glial cells.
  • M2 type microglia secrete neurotrophic factors (such as Arginase 1, CD206, IL-10, TGF- ⁇ 1), which can regulate immune response and promote tissue function repair and remodeling.
  • Telmisartan is a novel non-peptide angiotensin II (Ang II) AT1 receptor antagonist, which can competitively block the binding of AngII to AT1, thereby antagonizing the effects of AngII-induced vasoconstriction, sympathetic excitation, and increased aldosterone secretion. Therefore, it can be used for the treatment of hypertension.
  • Ang II angiotensin II
  • studies have shown that telmisartan can inhibit the formation of M1 microglia, promote the transformation of microglia to M2, can effectively reduce the occurrence of neuroinflammation, and thus play a neuroprotective role.
  • Telmisartan also activates peroxisome proliferator-activated receptor gamma (PPAR ⁇ ) and regulates blood glucose, lipogenesis, and insulin sensitivity-related gene expression and inhibition of inflammatory cytokine production, and thus can be used to improve the heart. Reconstruction and functional treatment also have a certain effect on abnormal glucose and lipid metabolism and complications of diabetes.
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • Butylphthalide (trade name "Enbpu”) is the first new drug with independent intellectual property rights in the field of cerebrovascular disease treatment in China. It was approved for marketing in November 2004 for mild to moderate ischemic stroke. Treatment. Clinical studies have shown that butylphthalide can improve the central nervous system damage in patients with acute ischemic stroke and can promote functional recovery. Animal pharmacodynamics studies suggest that butylphthalide can block multiple pathological aspects of brain injury caused by ischemic stroke, and has strong anti-cerebral ischemia and brain protection effects, especially to significantly improve ischemic mice.
  • Intracerebral ATP and phosphocreatine levels significantly reduce infarct size in rats with focal cerebral ischemia, reduce brain edema, improve brain energy metabolism and microcirculation and blood flow in ischemic brain regions, inhibit neuronal apoptosis, and have certain Anti-cerebral thrombosis and anti-platelet aggregation (J. Neurol. Sci., 2007, 260, 106).
  • Another literature has shown that butylphthalide can inhibit microalangiogenesis, inhibit platelet aggregation and inhibit thromboxane A2 by affecting the metabolism of arachidonic acid (AA) and selectively inhibiting various pathophysiological processes mediated by AA and its metabolites.
  • AA arachidonic acid
  • PHPB butylphthalide ring-opening derivative 2-( ⁇ -hydroxy-n-pentyl)benzoic acid potassium salt
  • PHPB oral the bioavailability of in vivo conversion to NBP is nearly double that of direct oral NBP, completely overcoming the shortcomings of poor water solubility in NBP.
  • pharmacological studies have found that PHPB can significantly improve regional cerebral blood flow after ischemia, inhibit platelet hyper-aggregation and thrombosis, and can prevent mitochondrial dysfunction caused by ischemia-reperfusion through various mechanisms, especially to protect mitochondrial energy metabolism and Reducing the activation of the mitochondrial apoptotic pathway is a promising anti-ischemic drug (J Pharmacol Exp Ther., 2006, 317, 973).
  • the invention designs and synthesizes an optically active butylphthalide ring-opened butylphthalide-telmisartan hybrid according to the principle of prodrug splicing.
  • a compound of the invention such as an optically active butylphthalide-telmisartan complex of formula I or an optical isomer, enantiomer, diastereomer, racemate or racemic thereof a mixture, or a pharmaceutically acceptable salt thereof:
  • R represents a hydrogen atom H, a C1-C10 linear or branched alkyl group, (C1-C10 linear or branched alkylene)-Q, wherein Q represents a hydroxyl group or a halogen;
  • n 1-20;
  • X represents an oxygen atom, a nitrogen atom or a sulfur atom
  • Y represents an oxygen atom, a nitrogen atom or a sulfur atom
  • the chiral center* is in the S configuration or the R configuration.
  • the compound of Formula I or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R represents hydrogen Atom, dimethylamino, diethylamino, pyrrolyl, piperidinyl, morphinolyl, imidazolyl, N-methylpiperazinyl or N-hydroxyethylpiperazinyl.
  • the compound of Formula I or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X represents oxygen Atom or nitrogen atom.
  • the compound of Formula I or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y represents oxygen Atom or nitrogen atom.
  • a compound of the invention or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound includes, but is not limited to:
  • Nitrile benzoyl octylamine telmisartanamide (I 11 )
  • the enantiomers and diastereomers of preferred compounds of the invention, as well as the addition salts thereof with pharmaceutically acceptable acids form an integral part of the invention; among the pharmaceutically acceptable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. , acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid and the like.
  • addition salts of pharmaceutically acceptable acids of the compounds of formula I are preferably selected from the following compounds:
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula I according to the invention, characterized in that it is:
  • (S)- or (R)-butylphthalide is saponified and acidified to obtain lactone ring-opening compound III.
  • Compound III is esterified with acid chloride compound (RCOCl) to obtain ester compound IV, IV and different carbon chain length.
  • the diol (or diamine, etc.) is subjected to a condensation reaction to obtain the intermediate V, and the intermediate V is further condensed with telmisartan to obtain the target compound I; or the telmisartan is first mixed with a diol (or a diamine having a different carbon chain length).
  • the condensation reaction is carried out to obtain the intermediate VI, and then the intermediate VI is further condensed with the ester compound IV to obtain the target compound I; the synthesis route is as follows:
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane.
  • the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, pyridine, 4-methylaminopyridine, triethylamine, N,N-diisopropylmethylamine;
  • the reaction temperature is -20 ° C to reflux.
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane.
  • the condensing agent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxyl Benzotriazole, N-hydroxysuccinimide; base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, N,N-diisopropylmethylamine; reaction temperature from -20 ° C to reflux.
  • the solvent is selected from dichloromethane
  • the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the base is selected to be 4-methylaminopyridine
  • the reaction temperature is room temperature.
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane.
  • the condensing agent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxyl Benzotriazole, N-hydroxysuccinimide; base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, N,N-diisopropylmethylamine; reaction temperature from -20 ° C to reflux.
  • the solvent is selected from dichloromethane
  • the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the base is selected to be 4-methylaminopyridine
  • the reaction temperature is room temperature.
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane.
  • the condensing agent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1 -hydroxybenzotriazole, N-hydroxysuccinimide; base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, N,N-diisopropylmethylamine; reaction temperature from -20 ° C to reflux.
  • the solvent is selected from dichloromethane
  • the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the base is selected to be 4-methylaminopyridine
  • the reaction temperature is room temperature.
  • the solvent is selected from the group consisting of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane.
  • the condensing agent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N-hydroxysuccinimide; base selected from the group consisting of pyridine, 4-methylaminopyridine, triethylamine, N,N-diisopropylmethylamine; reaction temperature -20 ° C to reflux .
  • the solvent is selected from dichloromethane
  • the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the base is selected to be 4-methylaminopyridine
  • the reaction temperature is room temperature.
  • These intermediates or target compounds can be purified according to conventional separation techniques, and if desired, can be separated into their isomers by conventional separation techniques, and converted to a pharmaceutically acceptable acid or base addition salt as needed.
  • Another object of the present invention is to provide a process for the preparation of the compound of the formula II of the present invention:
  • the solvent is selected from one or more of acetonitrile, dichloromethane, chloroform, ethyl acetate, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or dioxane; the reaction temperature is - 20 ° C to reflux.
  • the characteristics of II were prepared by I, the solvent was selected to ethyl acetate, and the reaction temperature was room temperature.
  • a further object of the present invention is to provide an effective amount of a compound of formula I or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable thereof
  • a pharmaceutical composition of a salt and a pharmaceutically acceptable carrier is provided.
  • a further object of the present invention is to provide the use of the compound of the general formula I of the present invention for the preparation of a medicament for preventing or treating a disease associated with neuroinflammation, in particular for the preparation of a medicament for the prevention and treatment of ischemic stroke, Alzheimer's disease, Brain trauma, Parkinson's disease, multiple sclerosis and depression.
  • the compound of the formula I, and pharmaceutically acceptable salts thereof, and solvates of these compounds may be used alone or, preferably, according to specifications. Method It is used in combination with a pharmaceutically acceptable carrier or diluent.
  • the mode of administration can be by various routes including oral, parenteral or topical administration. Parenteral administration as referred to herein includes, but is not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and transdermal administration.
  • 1.1 In vitro inflammatory screening model Primary mouse microglia were extracted from mouse brain, and 1 ⁇ M or 5 ⁇ M drug was pre-administered for 3h, then stimulated with 100ng/mL lipopolysaccharide (LPS) for 5h, and the cell culture supernatant was extracted. The expression level of TNF- ⁇ in the supernatant was determined by ELISA. As can be seen from Fig. 1, I3 can significantly inhibit the increase of TNF- ⁇ produced by LPS-induced mouse primary microglia.
  • LPS lipopolysaccharide
  • Nrf2 in vitro activation screening model BV2 cells were transfected with Neh2-Luciferase reporter plasmid for 6h, cultured in normal medium for 24h, then incubated with drug for 24h, treated with Reporter Lysis Buffer for 20min, and Reporter Lysis Buffer was added to 96. Plates were assayed for luciferase activity. Nrf2 positive drug Oltipraz can significantly promote the activation of Nrf2, compared to 1 ⁇ M and 10 ⁇ M I3, 10 ⁇ M I7, 10 ⁇ M I8 can significantly activate intracellular Nrf2 activity.
  • mice 75 SD male rats weighing 300 ⁇ 20 g were used for experiment after raising for 1 week at 25 ° C and relative humidity of 60-75%. Rats were randomly divided into 5 groups: sham, vehicle, ischemia 24h, administration group after ischemia for 6h, group after ischemia for 4h, group 15 only.
  • tMCAO rat middle cerebral artery occlusion model
  • the mode of administration was administered after surgery, and the concentration was 1 mg/kg.
  • 4h after ischemia administration 4h after ischemia, once again after 24h; 6h after ischemia: administration 6h after ischemia, once again after 24h; 24h after ischemia
  • Drug-administered group administered once every 24 hours after ischemia.
  • TTC staining 48 hours after ischemia-reperfusion, rats were anesthetized with sodium pentobarbital, and the brain was quickly decapitated to remove the olfactory bulb, cerebellum and lower brain stem. The coronary cut was 6 pieces. Then, the brain piece was placed in a solution containing 4% TTC and 1 mol/L of K 2 HPO 4 , protected from light, and incubated at 37 ° C for 30 min, during which time it was flipped every 7-8 min. After TTC staining, the normal brain tissue was reddish red and the infarcted tissue was white. The images were taken after staining and the infarct size was calculated using computer image analysis software. The formula for calculating the percentage of cerebral infarction area is: infarct area/whole brain area ⁇ 100%.
  • Neurological function score Neurobehavioral function scores were obtained 48 h after ischemia-reperfusion in rats. The scoring standard is: 0 points, no symptoms of nerve damage; 1 point, can not fully extend the healthy front paw; 2 points, turn to the healthy side; 3 points, dump to the healthy side; 4 points, can not be self-issued, loss of consciousness.
  • Infarct size test results of rat brain tissue As shown in Fig. 2, compared with the vehicle group, the administration of each time point can significantly reduce the infarct size of rat brain tissue, and the inhibition effect of the 4h administration group is the most. Strong. Compared with NBP, Telm and NBP+Telm, I3 has a more effective effect in reducing the area of cerebral infarction, and has the same effect as the edaravone group. As shown in Table 1.
  • Surgical method such as the above-mentioned tMCAO operation method
  • the line plug was left in the rat brain and was not pulled out.
  • the behavior of the rod was measured every day. After 72 hours of infarction, the infarct size and neurobehavioral score were determined.
  • the operation of the rod behavior the rat was placed on a rotating rod, and the speed was accelerated from 4 rpm, and the maximum speed reached 40 rpm for 5 minutes.
  • the rats were trained for 3-7 days before model establishment, and the behavior of the rods was measured 1, 2, and 3 days after pMCAO, and the time of rat drop was recorded.
  • the experimental method was as described in 2, 30 min before I3, the rats were intraperitoneally injected with 20 mg/kg of AMPK inhibitor Compound C, and the infarct size and behavioral score were determined 48 h after ischemia.
  • the content of AMPK phosphorylation (p-AMPK) in the infarcted cerebral cortex was determined by Western blot in ischemic brain tissue. It was found that pre-administration of Compound C significantly inhibited the neuroprotective effect of I3 on transient ischemic stroke and inhibited the increase of AMPK activity induced by I3.
  • the present invention designs and synthesizes a butylphthalide-telmisartan hybrid, and its in vitro activity study shows that it has dual Nrf2 and AMPK agonistic activities.
  • the hybrid showed stronger anti-ischemic activity than butylphthalide combined with telmisartan and also showed stronger anti-ischemic activity than Edaravone.
  • Pharmaceutical compositions containing these compounds and their medical use, particularly in the prevention and treatment of diseases associated with neuroinflammation, including ischemic stroke, Alzheimer's disease, brain trauma, Parkinson's disease, multiple sclerosis And depression and other aspects have a good application prospects.
  • a and B were pre-incubated with 1 ⁇ M or 5 ⁇ M test compound for 3 h in mouse primary glia, followed by LPS stimulation for 5 h, and the protein content of pro-inflammatory cytokine TNF- ⁇ was determined by ELISA; The activation of Nrf2 by a compound was tested using a luciferase reporter assay.
  • Fig. 2 male rats of 260-280 g were subjected to tMCAO modeling (the rat was removed after 2 h of ischemia, resulting in reperfusion), and intravenous injection of I3 compound (1 mg/kg) 4 h after ischemia, ischemia After 24 hours, intravenous injection, 48 hours after ischemia, the brain tissue was cut into 6 pieces and stained by 2,3,5-triphenyltetrazolium chloride (TTC) to determine the infarct area (white area).
  • TTC 2,3,5-triphenyltetrazolium chloride
  • the neurobehavioral behavior is determined by the Longa test method, the total score is 4 points: 0 points: no abnormal behavior is; 1 point: the left front paw cannot be fully extended, indicating Mild neurological impairment; 2 points: Rats circled to the left during walking, indicating moderate neurological impairment; 3 points: Rats left or paralyzed during walking, indicating severe neurological impairment; 4 points: Can not be released from the issue, there is loss of consciousness;
  • Figure 3 is a graph showing the neuroprotective effect of Compound I3 of the present invention on permanent ischemic stroke (pMCAO);
  • Fig. 3 male rats of 260-280 g were subjected to pMCAO modeling (the cord was not pulled out, resulting in permanent ischemia).
  • the administration method was the same as that in Fig. 2, and the infarct size and neurobehavioral behavior were measured 72 hours after ischemia.
  • the rotarod test is as described above;
  • Figure 4 is the effect of the AMPK pathway on the neuroprotective effect of the present compound I3;
  • AMPK inhibitor Compound C (20 mg/kg) was intraperitoneally injected 3.5 h after ischemia, and I3 compound (1 mg/kg) was injected intravenously 4 h after ischemia. Cerebral infarct size and neurobehavioral behavior were measured 48 h after ischemia. .
  • telmisartan (2.57 g, 5.0 mmol) was dissolved in anhydrous dichloromethane (200 mL), EDAC (1.15 g, 6.0 mmol) and catalytic DMAP were added, stirred at room temperature for 0.5 h, then octanediamine (1.44) was added. g, 10.0 mmol), stirred at rt EtOAc EtOAc (EtOAc) Mp: 113 ° C. MS (ESI): m/z 64 ⁇ /RTI> [M+H] + .
  • the p-methylbenzoyl chloride (1.55 g, 10.0 mmol) was dissolved in anhydrous dichloromethane (50 mL), and triethylamine (2.88 g, 20.0 mmol) was added to the catalytic amount of DMAP, stirred at room temperature for 0.5 h, and then added
  • the amine (1.44 g, 10.0 mmol), EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • the monosubstituted intermediate (1.47 g, 5.0 mmol) obtained by the reaction of p-nitrobenzoic acid and octanediamine was dissolved in anhydrous dichloromethane (30 mL), and then added to EDAC (1.15 g, 6.0). Methyl) and a catalytic amount of DMAP, stirred at room temperature for 0.5 h, then added telmisartan (3.86 g, 7.5 mmol), stirred at room temperature overnight, filtered, and concentrated under reduced pressure.

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Abstract

一种丁苯酞-替米沙坦杂合物及其制备方法和用途，具体涉及一种式I所示的光学活性的开环型丁苯酞-替米沙坦杂合物或其药学上可接受的盐或酯，它们的制备方法、含有这些化合物的药用组合物以及它们的医药用途，特别是在预防和治疗与神经炎症相关的疾病，包括缺血性脑卒中、阿尔兹海默病、脑外伤、帕金森病、多发性硬化症和抑郁症等方面的应用。

Description

丁苯酞-替米沙坦杂合物及其制备方法和用途 技术领域
本发明涉及一种丁苯酞-替米沙坦杂合物，具体涉及一种光学活性的开环型丁苯酞-替米沙坦杂合物或其药学上可接受的盐或酯，它们的制备方法、含有这些化合物的药用组合物以及它们的医药用途，特别是在预防和治疗与神经炎症相关的疾病，包括缺血性脑卒中、阿尔兹海默病、脑外伤、帕金森病、多发性硬化症和抑郁症等方面的应用，属于药学技术领域。
背景技术
中枢神经系统(CNS)中的小胶质细胞在介导各种免疫相关功能疾病中起关键作用，其分为促炎型(M1经典型)以及抗炎型(M2另类活化型)。M1型小胶质细胞高表达氧化代谢产物(例如超氧化物和一氧化氮)及促炎症细胞因子(例如TNF-α、IL-1β、IL-6、IL-18)。这些物质可对神经元和胶质细胞产生细胞毒作用。M2型小胶质细胞分泌神经营养因子(例如Arginase 1、CD206、IL-10、TGF-β1)，这些物质可调节免疫反应，促进组织功能修复和重塑。
替米沙坦是新型非肽类血管紧张素II(AngⅡ)的AT1受体拮抗剂，可以竞争性阻断AngⅡ与AT1结合，从而拮抗AngⅡ引起的血管收缩、交感兴奋、醛固酮分泌增多等作用，因此可用于高血压的治疗。此外，有研究表明，替米沙坦可以抑制M1型小胶质细胞的生成，促进小胶质细胞向M2转型，能够有效的减轻神经炎症的发生，从而起到神经保护的作用。替米沙坦还有激活过氧化物酶体增殖物活化受体γ(PPARγ)，以及调控血糖、脂肪生成代谢和胰岛素敏感性相关基因表达与抑制炎症因子产生的作用，因此还可用于改善心脏重构和功能的治疗，对糖、脂代谢异常及糖尿病并发症也有一定的作用。
丁苯酞(商品名为“恩必普”)是我国脑血管病治疗领域第一个拥有自主知识产权的一类新药，于2004年11月批准上市用于轻、中度缺血性脑卒中的治疗。临床研究结果表明，丁苯酞对急性缺血性脑卒中患者的中枢神经功能的损伤有改善作用，可促进患者功能恢复。动物药效学研究提示，丁苯酞可阻断缺血性脑卒中所致脑损伤的多个病理环节，具有较强的抗脑缺血和脑保护作用，尤其是能够明显提高缺血小鼠脑内ATP和磷酸肌酸水平，明显缩小大鼠局部脑缺血的梗塞面积，减轻脑水肿，改善脑能量代谢和缺血脑区的微循环 和血流量，抑制神经细胞凋亡，并具有一定的抗脑血栓形成和抗血小板聚集作用(J.Neurol.Sci.,2007,260,106)。另有文献表明，丁基苯酞通过影响花生四烯酸(AA)代谢，选择性抑制AA及其代谢产物介导的多种病理生理过程，可以解除微血管痉挛，抑制血小板聚，抑制血栓烷A2的合成，清除自由基等，从而通过多途径，多环节阻断脑缺血引起的病理生理发展过程，保护神经元，修复神经功能(J.Cardiovasc.Pharmacol.,2004,43,876；ActaPharmacol.Sin.,1998,19,117)。
研究表明，丁苯酞开环衍生物2-(α-羟正戊基)苯甲酸钾盐(PHPB)，是一种水溶性NBP前药，无论口服或静脉注射，在体内经酶或化学作用可迅速、完全地转变成NBP而发挥药效。前药PHPB静脉给药后，体内转化为NBP的药代动力学特征，及主要代谢产物和排泄途径均与直接静脉给予NBP的极为相似(Patent PCT/CN02/00320.2002)。且PHPB口服，体内转化为NBP的生物利用度较直接口服NBP提高近一倍，完全克服了NBP所存在的水溶性差的缺点。另外，药理研究发现PHPB可以显著改善缺血后的局部脑血流，抑制血小板过度聚集和血栓形成，并可以通过多种机制避免缺血再灌注造成的线粒体功能损伤，特别是保护线粒体能量代谢以及减少线粒体凋亡通路的激活，是一个具有良好开发前景的抗脑缺血药物(J PharmacolExpTher.,2006,317,973)。
本发明依据前药拼合原理，设计合成了一种光学活性的丁苯酞开环型丁苯酞-替米沙坦杂合物。
发明内容
本发明的目的在于提供一种光学活性的丁苯酞开环型丁苯酞-替米沙坦杂合物、其制备方法及医药用途。
为解决上述技术问题，本发明采用的技术方案如下：
本发明的化合物，如通式I所示的光学活性的丁苯酞-替米沙坦杂合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐：
Figure PCTCN2018071308-appb-000001
其中：
R代表氢原子H、C1-C10直链或支链烷基、(C1-C10直链或支链亚烷基)-Q，其中Q代表羟基或卤素；
n代表1-20；
X代表氧原子、氮原子或硫原子；
Y代表氧原子、氮原子或硫原子；
手性中心*为S构型或R构型。
药理实验证明，本发明的化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，具有降低LPS引起的原代小胶质细胞的促炎因子TNF-α的升高、抑制M1型促炎因子TNF-α和IL-1β和M2型抗炎因子CD206和YM1/2的升高的作用，此外该类化合物还能显著降低脑梗死面积、改善神经行为学、保护神经元。因此，它们可用于预防和治疗与神经炎症相关的疾病，这类疾病包括但不限于缺血性脑卒中、阿尔兹海默病、脑外伤、帕金森病、多发性硬化症和抑郁症等。
在一种技术方案中，通式I化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其中R代表氢原子、二甲胺基、二乙胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、N-甲基哌嗪基或N-羟乙基哌嗪基。
在一种技术方案中，通式I化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其中X代表氧原子或氮原子。
在一种技术方案中，通式I化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其中Y代表氧原子或氮原子。
本发明所涉及化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其中化合物包括但不限于：
2-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}乙二醇替米沙坦酯(I 1)
Figure PCTCN2018071308-appb-000002
4-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二醇替米沙坦酯(I 2)
Figure PCTCN2018071308-appb-000003
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺(I 3)
Figure PCTCN2018071308-appb-000004
5-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}戊二醇替米沙坦酯(I 4)
Figure PCTCN2018071308-appb-000005
6-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二醇替米沙坦酯(I 5)
Figure PCTCN2018071308-appb-000006
8-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二醇替米沙坦酯(I 6)
Figure PCTCN2018071308-appb-000007
6-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二胺替米沙坦酰胺(I 7)
Figure PCTCN2018071308-appb-000008
4-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二胺替米沙坦酰胺(I 8)
Figure PCTCN2018071308-appb-000009
对甲基苯甲酰基辛二胺替米沙坦酰胺(I 9)
Figure PCTCN2018071308-appb-000010
3,5-二氯苯甲酰基辛二胺替米沙坦酰胺(I 10)
Figure PCTCN2018071308-appb-000011
对腈基苯甲酰基辛二胺替米沙坦酰胺(I 11)
Figure PCTCN2018071308-appb-000012
对硝基苯甲酰基辛二胺替米沙坦酰胺(I 12)
Figure PCTCN2018071308-appb-000013
间甲氧基苯甲酰基辛二胺替米沙坦酰胺(I 13)
Figure PCTCN2018071308-appb-000014
邻羟基苯甲酰基辛二胺替米沙坦酰胺(I 14)
Figure PCTCN2018071308-appb-000015
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺坎地沙坦酰胺(I 15)
Figure PCTCN2018071308-appb-000016
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺缬沙坦酰胺(I 16)
Figure PCTCN2018071308-appb-000017
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺氯沙坦酰胺(I 17)；
Figure PCTCN2018071308-appb-000018
本发明优选化合物的对映体和非对映异构体以及其与可药用酸的加合盐构成了本发明的完整部分；在可药用酸中有盐酸，氢溴酸，硫酸，磷酸，乙酸，三氟乙酸，乳酸，丙酮酸，丙二酸，琥珀酸，戊二酸，富马酸，酒石酸，马来酸，柠檬酸，抗坏血酸，甲磺酸，樟脑酸，草酸等。
具体来说，通式I所示化合物的可药用酸的加合盐优选自下列化合物：
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺盐酸盐(II)
Figure PCTCN2018071308-appb-000019
下面药理实验中化合物的代号等同于此处代号所对应的化合物。
本发明的另一目的在于提供本发明通式I化合物的制备方法，其特征在于：
(S)-或(R)-丁苯酞经皂化、酸化反应制得内酯开环物III，化合物III与酰氯类化合物(RCOCl)成酯得到酯类化合物IV，IV与不同碳链长度的二醇(或二胺等)进行缩合反应得到中间体V，中间体V再与替米沙坦进行缩合得到目标化合物I；或者替米沙坦先与不同碳链长度的二醇(或二胺等)进行缩合反应得到中间体VI，然后中间体VI再与酯类化合物IV进行缩合得到目标化合物I；合成路线如下：
Figure PCTCN2018071308-appb-000020
其中，R定义如前所述。
本发明式I化合物的制备方法中各反应步骤的具体条件如下：
由化合物III制备化合物IV的步骤中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；碱选自碳酸钾，碳酸钠，碳酸氢钠，氢氧化钠，氢氧化钾，吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。
由化合物IV制备化合物V的步骤中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。作为更优选，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温。
由化合物V制备化合物I的步骤中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。作为更优选，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温。
由替米沙坦制备化合物VI的步骤中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。作为更优选，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温。
由化合物IV和化合物VI制备化合物I的步骤中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。作为更优选，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温。
这些中间体或目标化合物均可按照常规分离技术加以纯化，如果需要可按常规分离技术分离成它们的异构体，并且根据需要将其转化为与可药用酸或碱的加成盐。
本发明的另一目的在于提供本发明通式II化合物的制备方法：
将化合物I 3溶于溶剂中，加入氯化氢饱和的该溶液，搅拌，得到化合物II；合成路线如下：
Figure PCTCN2018071308-appb-000021
溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；反应温度为-20℃至回流。
由I制备II的特征，溶剂选择乙酸乙酯，反应温度为室温。
本发明的进一步目的在于提供一种含有效量的通式I化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐及可药用的载体的药物组合物。
本发明的再一目的是提供本发明通式I化合物在制备预防或治疗与神经炎症有关的疾病的药物中的应用，尤其可用于制备预防和治疗缺血性脑中风、阿尔兹海默病、脑外伤、帕金森病、多发性硬化和抑郁症等。
本发明中，在给予哺乳动物通式I化合物及其药学上可接受的盐，以及这些化合物的溶剂化物(这里统称为“治疗药物”)时，可以单独使用，或者最好是按照规范的制药方法将其与适于药用的载体或稀释剂配合后使用。给药方式可以经各种途径，包括口服、非胃肠道给药或局部给药。这里所指的非胃肠道给药包括但并不限于静脉注射、肌肉注射、腹腔注射、皮下注射和透皮给药。
下面是本发明的代表化合物的部分药理试验及结果：
1、体外抗炎药物筛选模型及Nrf2激活作用筛选模型
1.1、体外炎症筛选模型：提取小鼠脑部原代小胶质细胞进行体外培养，1μM或5μM药物预给予3h，之后用100ng/mL的脂多糖(LPS)刺激5h，提取细胞培养上清，用ELISA的方法测定上清中TNF-α的表达量。从图1可以看出，I3可以显著地抑制LPS引起小鼠原代小胶质细胞产生的TNF-α的升高。
1.2、Nrf2体外激活作用筛选模型：利用Neh2-Luciferase报告基因质粒转染BV2细胞6h，换有血清正常培养基培养24h，再用药物孵育24h，Reporter Lysis Buffer处理细胞 20min,将Reporter Lysis Buffer加入96孔板，测定荧光素酶的活性。Nrf2的阳性药Oltipraz可以显著地促进Nrf2的激活，于此相比，1μM和10μM的I3，10μM的I7，10μM的I8都可以显著性地激活细胞内Nrf2活性.
2、I3对短暂型缺血性脑中风(tMCAO)的神经保护作用的研究
实验方法：75只SD雄性大鼠，体重300±20g，于25℃、相对湿度60～75％条件下饲养1周后用于实验。大鼠随机分成5组，分别为假手术组(sham)、模型组(vehicle)、缺血24h后给药组，缺血6h后给药组，缺血4h后给药组，每组动物15只。
大鼠大脑中动脉阻断模型(tMCAO)的建立:大鼠腹腔注射水合氯醛麻醉，仰卧于手术台上，四肢用线绳固定。颈部正中切口，切开皮肤及皮下组织暴露二腹肌肌腹，分离右侧颈动脉(CCA)并结扎其近心端，向上分离右侧颈外动脉(ECA)和颈内动脉(ICA)；分离、结扎并剪断甲状腺上动脉和枕动脉。结扎并剪断ECA，用动脉夹夹闭ICA远心端，然后在ECA和ICA交叉靠近ECA处剪一小口。将一端涂有石蜡的尼龙线从剪开的小口处插入，经颈内、颈外动脉交叉处插入颈内动脉并继续深入大脑前动脉近端，以阻断该侧大脑中动脉的供血。脑缺血120分钟后，抽出尼龙线至颈外动脉切口处实现大脑中动脉再灌注。手术中室温控制在25-27℃。
给药方式采取手术后给药，给药浓度为1mg/kg。缺血后4h给药组：在缺血后4h给药，24h后再给药一次；缺血后6h给药组：在缺血后6h给药，24h后再给药一次；缺血后24h给药组：在缺血后24h给药一次。
在确定I3的给药时间窗后，选择缺血后4h给药作为后面的测试时间点。95只SD雄性大鼠被随机分为7组，分别为：手术组，模型组，NBP组，Telm组，NBP+Telm组，I3组和依达拉奉组。手术过程如上，在缺血后4h分别给与NBP(1mg/kg),Telm(1mg/kg),NBP(1mg/kg)+Telm(1mg/kg)，I3(1mg/kg)以及edaravone(3mg/kg)，24h后再给药一次。缺血48h后测定脑梗死面积和神经行为学评分。
2.1、脑组织梗死面积的测定(TTC染色):大鼠缺血再灌注48小时后用戊巴比妥钠麻醉，快速断头取脑，去除嗅球、小脑和低位脑干，冠状切为6片，然后将脑片置于含有4％TTC及1mol/L的K 2HPO 4的溶液中，避光，37℃温孵30min，其间每隔7-8min翻动一次。经TTC染色后，正常脑组织呈玫瑰红色，梗死组织呈白色。染色后拍照，并用计算机图像分析软件计算梗死面积。脑梗死面积百分比的计算公式为：梗死部分面积/全脑剖面面积×100％。
2.2、神经功能评分：大鼠缺血再灌注48h后进行神经行为功能评分。评分标准为：0 分，无神经损伤症状；1分，不能完全伸展健侧前爪；2分，向健侧转圈；3分，向健侧倾倒；4分，不能自发行走、意识丧失。
实验结果：
2.1、大鼠脑组织梗死面积测试结果：如图2所示，与vehicle组相比，各时间点给药，均可以显著地减少大鼠脑组织梗死面积，其中4h给药组的抑制作用最强。并且与NBP，Telm和NBP+Telm相比较，I3减少脑梗死面积的效果更明显，与依达拉奉组有相同的作用。如表1所示。
表1 I3及其组成化合物和Edaravone对短暂缺血性脑中风脑梗死面积的减少作用
Figure PCTCN2018071308-appb-000022
2.2、神经功能评分测试结果：如图2所示，与vehicle组相比，各时间点给药，均可以显著地降低I/R大鼠的神经行为学评分，即能显著改善动物的神经行为学功能。并且与NBP，Telm和NBP+Telm相比较，I3改善神经行为学功能的效果更明显，与依达拉奉组有相同的作用。如表2所示
表2 I3及其组成化合物和Edaravone对改善神经行为学的作用
Figure PCTCN2018071308-appb-000023
3、I3对永久型缺血性脑中风(pMCAO)的保护作用的研究
实验方法：手术方法如上述tMCAO的操作方法，线栓留在大鼠脑内不拔出，每天测定转棒行为学，梗死72h后取脑测定梗死面积和神经行为学评分。其中转棒行为学的操作过程：将大鼠放在转棒上，使速度从4rpm开始加速，最大速度达到40rpm，时间5min。在大鼠造模前进行3-7天的训练，在pMCAO后的1，2，3天分别测定转棒行为学，并记录大鼠掉落的时间。
结果显示：I3对永久缺血性脑中风引起的脑梗死面积和神经行为学缺失有显著的改善作用，并且在改善行为学上比Edaravone有更出色的效果。如表3，4，5所示
表3 I3和Edaravone对永久缺血性脑中风梗死面积的减少作用
Figure PCTCN2018071308-appb-000024
表4 I3和Edaravone对永久缺血性脑中风后的神经行为学的改善的作用
Figure PCTCN2018071308-appb-000025
表5 I3和Edaravone转棒行为学的结果
Figure PCTCN2018071308-appb-000026
4、AMPK通路对I3神经保护作用的影响
实验方法如2所述，在给I3之前30min，大鼠腹腔注射20mg/kg的AMPK抑制剂Compound C，缺血48h后测定梗死面积和行为学评分。缺血脑组织进行Western blot测定梗死侧脑皮层的AMPK磷酸化(p-AMPK)的含量。结果发现，预给予Compound C可以显著地抑制I3对短暂缺血性脑中风的神经保护作用，并抑制I3引起的AMPK活性的增强。
表6 预给药Compound C(CC)抑制I3对短暂缺血性脑中风梗死面积的减少作用
Figure PCTCN2018071308-appb-000027
Figure PCTCN2018071308-appb-000028
表7 预给药Compound C(CC)抑制I3对短暂缺血性脑中风神经行为学恢复的作用
Figure PCTCN2018071308-appb-000029
有益效果：本发明设计、合成了丁苯酞-替米沙坦杂合物，体外活性研究表明其具有双重的Nrf2和AMPK激动活性。在多个体内模型中，杂合物显示比丁苯酞联合替米沙坦更强的抗脑缺血活性，也显示了比Edaravone更强的抗脑缺血活性。含有这些化合物的药用组合物以及它们的医药用途，特别是在预防和治疗与神经炎症相关的疾病，包括缺血性脑中风、阿尔兹海默病、脑外伤、帕金森病、多发性硬化和抑郁症等方面具有良好的应用前景。
附图说明
图1是对本发明中的化合物对脂多糖(LPS)引起的炎症因子TNF-α的抑制作用和Nrf2的体外激活作用的筛选实验结果；
图1中，A和B是采用1μM或5μM的测试化合物预孵育小鼠原代小胶质3h，之后采用LPS刺激5h，采用ELISA的方法测定促炎细胞因子TNF-α的蛋白含量；图C是采用荧光素酶报告基因检测方法测试化合物对Nrf2的激活作用。
图2是本发明代表化合物I3对短暂缺血性脑中风(tMCAO)的神经保护作用；
图2中，260～280g的雄性大鼠进行tMCAO造模(大鼠缺血2h后将线栓拔出，造成复灌)，在缺血后4h静脉注射I3化合物(1mg/kg)，缺血后24h再次静脉注射，缺血后48h，将脑组织切成均匀的6片，通过2，3，5-氯化三苯基四氮唑(TTC)的方法进行染色，测定梗死面积(白色区域表示缺血区域，红色区域表示非缺血区)；神经行为学采用Longa test的方法测定，总分数为4分：0分：无异常行为为；1分：左侧前爪不能完全伸展，表示有轻度神经功能损伤；2分：大鼠在行走过程中向左侧转圈，表示有中度神经功能损伤；3分：大鼠在行走过程中身体左倾或瘫痪，表示有重度神经功能损伤；4分： 不能自发行走，存在意识丧失；
图3是本发明代表化合物I3对永久缺血性脑中风(pMCAO)的神经保护作用；
图3中，260～280g的雄性大鼠进行pMCAO造模(线栓不拔出，造成永久缺血)，给药方式与图2相同，缺血后72h测定脑梗死面积及神经行为学，转棒行为学(rotarod test)如上文中所述；
图4是AMPK通路对本化合物I3神经保护作用的影响；
图4中，AMPK的抑制剂Compound C(20mg/kg)在缺血后3.5h腹腔注射，缺血后4h静脉注射I3化合物(1mg/kg)，缺血后48h测定脑梗死面积及神经行为学。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
2-(1-羟基正戊基)苯甲酸(III)的合成：
将1.24g(6.5mmol)NBP溶于10mL甲醇中，加入10mL 2M NaOH溶液，回流搅拌0.5h，减压蒸除甲醇，加10mL蒸馏水稀释，冷却至-5℃，剧烈搅拌下用5％稀盐酸酸化至pH 2-3，乙醚(15mL×3)萃取，未经任何纯化直接投入下一步反应。
实施例2
2-(1-乙酰基正戊基)苯甲酸(IV)的合成：
将上述含有III的乙醚溶液用200mL二氯甲烷稀释，分别加入2.7mL(19.6mmol)三乙胺，0.5g DMAP，-10℃下滴加1.4mL(19.6mmol)乙酰氯，滴毕于-10℃下搅拌5h，加入10mL水，室温搅拌0.5h，分出有机层，Na 2SO 4干燥，过滤，浓缩得腊状固体，正己烷重结晶，得白色针状晶体1.06g，收率65％。mp 65-66℃.MS(ESI):m/z 249.1[M-H]-. 1H NMR(300MHz,CDCl 3):δ0.93(t,3H,CH 3,J＝8.5Hz),1.37–1.42(m,4H,2×CH 2),1.88–1.91(m,2H,CH 2),2.13–2.33(m,3H,COCH 3),6.61–6.72(m,1H,OCHCH 2),7.37–7.40(m,1H,ArH),7.56–7.62(m,2H,ArH),8.05(d,1H,ArH,J＝8.1Hz),10.98(brs,1H,COOH). 13C NMR(75MHz,CDCl 3):δ172.0,166.5,140.8,133.1,130.3,130.0,127.1,125.7,74.8,41.0,36.3,27.8,22.4,13.8。
实施例3
2-(1-乙酰基正戊基)苯甲酸的基础上偶联二醇的一个代表性中间体V 1的合成：
将2-(1-乙酰基正戊基)苯甲酸(2.50g,10.0mmol)溶于无水二氯甲烷(50mL)中，加入EDAC(2.29g,12.0mmol)和催化量DMAP，室温搅拌0.5h，再加入乙二醇(0.62g,10.0mmol),室温搅拌5h，过滤，减压浓缩，经柱层析[石油醚:乙酸乙酯(v:v)＝30:1]得油状物1.71g，收率58％。MS(ESI):m/z 317.1[M+Na] +. 1H NMR(300MHz,CDCl 3):δ0.807(t,3H,CH 3,J＝7.0Hz),1.181-1.356(m,4H,2×CH 2),1.730-1.777(m,2H,CH 2),1.965(s,3H,COCH 3),3.823-3.862(m,2H,CH 2),4.269-4.474(m,2H,CH 2),5.206(s,1H,OH),6.452(t,1H,COOCH,J＝6.7Hz),7.197-7.265(m,1H,ArH),7.441-7.444(m,2H,ArH),7.750-7.777(m,1H,ArH). 13C NMR(75MHz,CDCl 3):δ170.90,167.51,142.37,132.15,129.94,129.34,127.39,126.46,72.79,67.05,60.88,36.32,27.90,22.42,21.18,13.92。
实施例4
2-(1-乙酰基正戊基)苯甲酸的基础上偶联二胺的代表性中间体V 3的合成：
将2-(1-乙酰基正戊基)苯甲酸(2.50g,10.0mmol)溶于无水二氯甲烷(50mL)中，加入EDAC(2.29g,12.0mmol)和催化量DMAP，室温搅拌0.5h，再加入辛二胺(1.44g,10.0mmol),室温搅拌8h，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝10:1]得油状物1.92g，收率51％。
实施例5
替米沙坦偶联二胺的一个代表性中间体VI 3的合成：
将替米沙坦(2.57g,5.0mmol)溶于无水二氯甲烷(200mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入辛二胺(1.44g,10.0mmol),室温搅拌5h，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝30:1]得白色固体1.48g，收率46％。mp:113℃.MS(ESI):m/z641.4[M+H] +. 1H NMR(300MHz,CDCl 3):δ0.799(t,3H,CH 3,J＝6.8Hz),0.943-1.058(m,8H,4×CH 2),1.506(m,4H,2×CH 2),1.728-1.798(m,2H,CH 2),2.374(s,3H,CH 3),2.731(t,2H,NH 2CH 2,J＝7.2Hz),2.839(t,2H,CH 2,J＝7.7Hz),3.137(t,2H,NHCH 2,J＝6.1Hz),3.728(s,3H,NCH 3),5.398(s,2H,NCH 2),7.015(s,1H,ArH),7.041(s,1H,ArH),7.204(m,4H,ArH),7.251-7.312(m,6H,ArH),7.405(m,1H,NH),7.468-7.491(m,1H,ArH),7.670-7.698(m,1H,ArH). 13C NMR(75MHz,CDCl 3):169.59,159.58,154.56,143.08,142.47,140.04,138.58,136.45,136.05,135.33,135.08,130.12,129.99,129.44,129.31,128.42,127.69,126.40,123.69,122.71,122.52,119.29,109.63,109.02,56.14,43.98,39.66,35.15,31.90,31.81,29.70,29.33,26.41,26.36,22.66,16.94,14.08。
实施例6
2-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}乙二醇替米沙坦酯(I 1)的合成：
将上述中间体V 1(1.47g,5.0mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(2.57g,5.0mmol)，室温搅拌8h，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝50:1]得白色固体1.69g，收率43％。mp:82-83℃.MS(ESI):m/z 791.4[M+H]+,813.4[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.772(m,3H,CH 3),0.989(m,3H,CH 3),1.181(m,4H,2×CH 2),1.712(m,2H,CH 2),1.808(m,2H,CH 2),1.973(s,3H,ArCH 3),2.691(s,3H,COCH 3),2.871(m,2H,NCNCH 2),3.716(s,3H,NCH 3),3.973-4.310(m,4H,2×OCH 2),5.369(s,2H,NCH 2),6.478(m,1H,OCH),6.948(s,1H,ArH),7.023(s,1H,ArH),7.120-7.302(m,7H,ArH),7.323-7.423(m,5H,ArH),7.722-7.796(m,3H,ArH). 13C NMR(75MHz,CDCl 3):δ169.19,167.27,165.83,156.09,154.24,143.63,142.67,142.37,141.70,140.76,136.14,134.49,132.12,131.09,130.26,130.01,129.73,129.58,128.97,128.49,126.94,126.65,125.60,125.32,123.44,121.97,121.80,119.02,109.04,108.53,72.35,62.25,61.78,46.50,36.10,31.29,29.29,27.57,21.98,21.45,20.68,16.41,13.59,13.50
实施例7
4-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二醇替米沙坦酯(I 2)的合成：
参照实施例6的方法，将2-(1-乙酰基正戊基)苯甲酸和丁二醇反应得到的单取代中间体(1.61g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.84g，收率45％。mp:83℃.MS(ESI):m/z 819.5[M+H]+，841.4[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.779(t,2H,CH 3,J＝6.9Hz),0.855(t,1H,CH 3,J＝7.1Hz),0.963(t,3H,CH 3,J＝7.3Hz),1.160-1.304(m,4H,2×CH 2),1.495(m,2H,CH 2),1.725-1.826(m,4H,2×CH 2),1.952(s,3H,ArCH 3),2.676(s,3H,COCH 3),2.847(t,2H,NCNCH 2,J＝7.8Hz),3.671(s,3H,NCH 3),3.926-4.078(m,4H,2×OCH 2),5.339(s,2H,NCH 2),6.438(q,1H,OCH,J＝4.9Hz),7.011(m,2H,ArH),7.149-7.413(m,14H,ArH),7.695-7.741(m,3H,ArH). 13C NMR(75MHz,CDCl 3):δ156.49,143.71,141.73,141.29,136.64,134.99,134.87,132.30,131.36,131.25,130.76,130.63,130.13,129.93,129.85,129.46,129.07,127.41,127.11,126.15,126.02,125.83,123.90,122.51,122.33,119.49,109.55,108.98,72.86,64.44,64.38,47.04,36.60,31.80,29.81,28.08,25.19,25.08,22.49,21.87,21.18,16.91,14.10,14.01
实施例8
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺(I 3)的合成：
将中间体V 3(1.88g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色 固体1.78g，收率41％。mp:94-95℃.MS(ESI):m/z 873.6[M+H]+，895.6[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.723(t,3H,CH 3,J＝7.2Hz),0.917(t,3H,CH 3,J＝7.3Hz),1.130(m,8H,4×CH 2),1.157(m,4H,2×CH 2),1.212(m,2H,CH 2),1.414-1.459(m,2H,CH 2),1.670-1.775(m,4H,2×CH 2),1.912(s,3H,ArCH 3),2.636(s,3H,COCH 3),2.786(t,2H,NCNCH 2,J＝7.8Hz),2.956(q,2H,NHCH 2,J＝6.6Hz),3.266(q,2H,NHCH 2,J＝6.8Hz),3.666(s,3H,NCH 3),5.302(s,2H,NCH 2),5.710(q,1H,OCH,J＝5.7Hz),6.954(s,1H,ArH),6.981(s,1H,ArH),7.134-7.157(m,5H,ArH),7.210-7.263(m,9H,ArH),7.289(m,1H,NH),7.340(m,1H,NH),7.433-7.458(m,1H,ArH),7.603-7.632(m,1H,ArH). 13C NMR(75MHz,CDCl 3):δ171.16,169.02,168.61,155.93,154.05,142.60,142.16,139.55,138.00,137.87,136.06,135.62,135.58,134.72,134.53,129.56,129.49,128.93,128.82,127.97,127.40,127.20,127.16,125.85,125.25,123.33,122.10,121.89,118.88,109.09,108.48,73.78,46.49,39.40,39.26,36.26,31.42,31.33,30.93,29.68,29.29,29.19,28.86,28.59,28.51,27.17,26.39,26.12,21.82,21.33,20.72,16.44,13.60,13.38.
实施例9
5-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}戊二醇替米沙坦酯(I 4)的合成：
参照实施例6的方法，将2-(1-乙酰基正戊基)苯甲酸和戊二醇反应得到的单取代中间体(1.68g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.98g，收率48％。mp:78-79℃.MS(ESI):m/z 833.5[M+H]+,855.5[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.786(t,3H,CH 3,J＝6.9Hz),0.964(t,3H,CH 3,J＝7.4Hz),1.223-1.256(m,6H,3×CH 2),1.345-1.393(m,2H,CH 2),1.571(t,2H,CH 2,J＝7.4Hz),1.707-1.802(m,4H,2×CH 2),1.955(s,3H,ArCH),32.681(s,3H,COCH 3),2.849(t,2H,NCNCH 2,J＝7.8Hz),3.686(s,3H,NCH 3),3.958(t,2H,OCH 2,J＝6.5Hz),4.132(t,2H,OCH 2,J＝6.6Hz),5.356(s,2H,NCH 2),6.448(q,1H,OCH,J＝4.7Hz),6.995(s,1H,ArH),7.022(s,1H,ArH),7.140-7.205(m,6H,ArH),7.240-7.314(m,2H,ArH),7.349-7.416(m,5H,ArH),7.696-7.754(m,3H,ArH). 13C NMR(75MHz,CDCl 3):δ169.82,167.74,166.41,155.98,154.16,143.15,142.63,142.31,141.25,140.78,136.13,134.50,134.28,131.74,130.82,130.27,129.65,129.40,128.95,128.57,126.90,126.59,125.64,125.47,125.33,123.37,123.33,122.03,121.85,119.00,109.05,108.49,72.38,64.34,64.21,46.56,36.12,31.32,29.32,27.68,27.58,27.48,22.00,21.93,21.37,20.69,16.42,13.61,13.52.
实施例10
6-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二醇替米沙坦酯(I 5)的合成：
参照实施例6的方法，将2-(1-乙酰基正戊基)苯甲酸和己二醇反应得到的单取代中间体(1.75g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.82g，收率43％。mp:82-83℃.MS(ESI):m/z 847.5[M+H]+，869.5[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.796(m,3H,CH 3),0.973(t,3H,CH 3,J＝7.2Hz),1.176-1.256(m,10H,5×CH 2),1.600(m,2H,CH 2),1.757-1.806(m,4H,2×CH 2),1.966(s,3H,ArCH 3),2.687(s,3H,COCH 3),2.849(t,2H,NCNCH 2,J＝7.7Hz),3.702(s,3H,NCH 3),3.939-3.961(m,2H,OCH 2),4.169(m,2H,OCH 2),5.349(s,2H,NCH 2),6.443(q,1H,OCH),7.001-7.026(m,2H,ArH),7.154-7.203(m,8H,ArH),7.302-7.405(m,5H,ArH),7.720-7.775(m,3H,ArH). 13C NMR(75MHz,CDCl 3):δ169.81,167.77,166.47,155.97,154.15,143.08,142.64,142.30,141.25,140.80,136.13,134.52,134.22,131.68,130.79,130.35,130.25,129.66,129.38,128.96,128.58,126.90,126.59,125.61,125.42,123.35,122.04,121.86,119.01,109.04,108.49,72.42,64.55,64.37,46.56,36.14,31.34,29.24,28.03,27.73,27.59,25.12,25.05,22.01,21.37,20.69,16.42,13.61,13.52.
实施例11
8-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二醇替米沙坦酯(I 6)的合成：
参照实施例5的方法，将2-(1-乙酰基正戊基)苯甲酸和辛二醇反应得到的单取代中间体(1.89g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.96g，收率45％。mp:83-84℃.MS(ESI):m/z 875.6[M+H]+,897.5[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.806(t,3H,CH 3,J＝6.8Hz),0.981(t,3H,CH 3,J＝7.3Hz),1.179-1.237(m,8H,4×CH 2),1.452-1.474(m,6H,3×CH 2),1.627-1.695(m,2H,CH 2),1.722-1.843(m,4H,2×CH 2),1.980(s,3H,ArCH 3),2.692(s,3H,COCH 3),2.861(t,2H,NCNCH 2,J＝7.8Hz),3.712(s,3H,NCH 3),3.931(t,2H,OCH 2,J＝6.4Hz),4.204(t,2H,OCH 2,J＝6.6Hz),5.364(s,2H,NCH 2),6.455(q,1H,OCH,J＝4.6Hz),7.001-7.027(m,2H,ArH),7.158-7.286(m,8H,ArH),7.337-7.418(m,5H,ArH),7.703-7.797(m,3H,ArH). 13C NMR(75MHz,CDCl 3):δ169.81,167.79,166.55,155.97,154.15,143.12,142.60,141.24,140.81,136.11,134.51,134.16,131.63,130.77,130.40,130.24,129.69,129.37,128.95,128.59,126.89,126.58,125.59,125.38,123.39,122.04,121.86,119.02,109.02,108.50,72.47,64.75,64.54,62.40,46.59,36.15,32.24,31.33,29.33,28.85,28.63,28.55,25.45,25.17,22.02,21.37,20.70,16.42,13.61,13.52.
实施例12
6-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二胺替米沙坦酰胺(I 7)的合成：
参照实施例8的方法，将2-(1-乙酰基正戊基)苯甲酸和己二胺反应得到的单取代中间体(1.74g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.69g，收率40％。mp:96-98℃.MS(ESI):m/z 845.6[M+H]+，867.5[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.768(m,3H,CH 3),0.970(t,3H,CH 3,J＝7.2Hz),1.181(m,10H,5×CH 2),1.417(m,2H,CH 2),1.776-1.801(m,4H,2×CH 2),1.936(s,3H,ArCH 3),2.645(s,3H,COCH 3),2.843(t,2H,NCNCH 2,J＝7.6Hz),3.013-3.032(m,2H,NHCH 2),3.259-3.279(m,2H,NHCH 2),3.751(s,3H,NCH 3),5.365(s,2H,NCH 2),5.749(m,1H,OCH),7.022-7.046(m,2H,ArH),7.195-7.218(m,6H,ArH),7.299-7.328(m,9H,ArH),7.423(m,1H,NH),7.501-7.524(m,1H,NH),7.4674(m,1H,ArH). 13C NMR(75MHz,CDCl 3):δ171.17,169.04,168.62,155.97,154.09,142.63,142.17,139.57,137.94,136.08,135.64,135.52,134.78,134.58,129.62,129.51,128.95,128.84,127.98,127.39,127.23,127.12,125.89,125.29,123.29,122.11,121.92,118.92,109.09,108.50,73.75,46.50,39.17,39.04,36.28,31.37,29.19,28.79,28.43,27.17,25.87,25.68,21.83,21.33,20.69,16.44,13.60,13.38.
实施例13
4-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二胺替米沙坦酰胺(I 8)的合成：
参照实施例8的方法，将2-(1-乙酰基正戊基)苯甲酸和丁二胺反应得到的单取代中间体(1.60g,5.0mmol)和替米沙坦(2.57g,5.0mmol)反应，经柱层析得到白色固体1.88g，收率46％。mp:97-99℃.MS(ESI):m/z 817.5[M+H]+,839.5[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.743-0.766(m,3H,CH 3),0.974(t,3H,CH 3,J＝7.3Hz),1.834-1.260(m,12H,6×CH 2),1.835(s,3H,ArCH 3),2.696(s,3H,COCH 3),2.856(t,2H,NCNCH 2,J＝7.7Hz),3.097(m,4H,2×NHCH 2),3.748(s,3H,NCH 3),5.382(s,2H,NCH 2),5.903(m,1H,OCH),6.998-7.024(m,2H,ArH),7.191-7.215(m,6H,ArH),7.280(m,9H,ArH),7.474(m,2H,2×NH),7.638(m,1H,ArH). 13C NMR(75MHz,CDCl 3):δ170.96,169.22,168.62,156.16,153.91,142.70,139.66,138.30,138.08,135.84,135.30,134.74,129.57,129.33,129.03,128.89,127.87,127.25,127.10,126.84,125.78,125.46,123.27,122.29,121.15,118.69,109.14,108.70,73.52,46.47,38.76,38.52,36.16,31.35,29.16,27.14,26.21,25.69,21.78,21.27,20.52,16.38,13.54,13.31.
实施例14
对甲基苯甲酰基辛二胺替米沙坦酰胺(I 9)的合成：
将对甲基苯甲酰氯(1.55g,10.0mmol)溶于无水二氯甲烷(50mL)中，加入三乙胺(2.88g，20.0mmol)催化量DMAP，室温搅拌0.5h，再加入辛二胺(1.44g,10.0mmol),室温搅拌3h，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝20:1]得单取代中间体，白色固体1.52g，收率58％。将所得中间体(1.52g,5.8mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(5.96g,11.6mmol)，室温搅拌过夜，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝50:1]得白色固体2.15g，收率49％。MS(ESI):m/z 759.4[M+H]+,781.4[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.854(t,3H,CH 3,J＝7.6Hz),1.25(m,8H,4×CH 2),1.535(m,4H,2×CH 2),1.856(m,2H,CH 2),2.342(s,3H,ArCH 3),2.756(s,3H,ArCH 3),2.881(t,2H,CH 2,J＝6.7Hz),3.088(q,2H,NHCH 2,J＝6.6Hz),3.404(q,2H,NHCH 2,J＝6.8Hz)，3.831(s,3H,NCH 3),5.398(s,2H,NCH 2),7.116(m,4H,ArH),7.287-7.421(m,8H,ArH),7.493(s,1H,ArH),7.583-7.767(m,5H,ArH).
实施例15
3,5-二氯苯甲酰基辛二胺替米沙坦酰胺(I 10)的合成：
参照实施例14的方法，将3,5-二氯苯甲酸和辛二胺反应所得的单取代的中间体(1.59g,5.0mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(3.86g,7.5mmol)，室温搅拌过夜，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝50:1]得白色固体1.71g，收率42％.MS(ESI):m/z 813.4[M+H] +,835.4[M+Na] +. 1H NMR(300MHz,CDCl 3):δ0.946(t,3H,CH 3,J＝7.3Hz),1.124(m,8H,4×CH 2),1.337(m,4H,2×CH 2),1.488(m,2H,CH 2),2.666(s,3H,ArCH 3),2.709(t,2H,CH 2,J＝6.7Hz),3.023(q,4H,2×NHCH 2,J＝6.7Hz),3.795(s,3H,NCH 3),5.301(s,2H,NCH 2),7.023(m,2H,ArH),7.195-7.327(m,10H,ArH),7.419(s,1H,ArH),7.507(s,1H,ArH),7.565(d,1H,ArH),7.654(d,1H,ArH),7.806(s,1H,ArH).
实施例16
对腈基苯甲酰基辛二胺替米沙坦酰胺(I 11)的合成：
参照实施例14的方法，将对腈基苯甲酸和辛二胺反应得到的单取代中间体(1.37g,5.0mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(3.86g,7.5mmol)，室温搅拌过夜，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝40:1]得白色固体1.84g，收率48％.MS(ESI):m/z 770.4[M+H]+,792.4[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.959(t,3H,CH3,J＝7.3Hz),1.183(m,4H, 2×CH 2),1.518(m,2H,CH 2),1.759(m,8H,4×CH 2),2.678(s,3H,ArCH 3),2.789(t,2H,CH 2,J＝6.8Hz),3.03(q,2H,NHCH 2,J＝6.5Hz),3.385(q,2H,NHCH 2,J＝6.7Hz),3.792(s,3H,NCH 3),5.306(s,2H,NCH 2),7.035(m,2H,ArH),7.194-7.425(m,11H,ArH),7.509(d,1H,ArH,J＝3.6Hz),7.636(d,1H,ArH,J＝3.4Hz),7.751(d,2H,ArH,J＝4.1Hz),7.891(s,1H,ArH).
实施例17
对硝基苯甲酰基辛二胺替米沙坦酰胺(I 12)的合成：
参照实施例14的方法，将对硝基苯甲酸和辛二胺反应得到的单取代中间体(1.47g,5.0mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(3.86g,7.5mmol)，室温搅拌过夜，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝40:1]得淡黄色固体2.01g，MS(ESI):m/z 790.4[M+H]+,812.4[M+Na]+. 1H NMR(300MHz,CDCl 3):δ0.836(t,3H,CH 3,J＝7.3Hz),1.103(m,8H,4×CH 2),1.213(m,4H,2×CH 2),1.533(m,2H,CH 2),2.652(s,3H,ArCH 3),2.771(t,2H,CH 2,J＝7.7Hz),3.033(q,2H,NHCH 2,J＝6.3Hz),3.342(q,2H,NHCH 2,J＝6.5Hz),3.769(s,3H,NCH 3),5.282(s,2H,NCH 2),7.032(m,2H,ArH),7.192-7.408(m,9H,ArH),7.511(d,1H,ArH,J＝3.6Hz),7.638(d,1H,ArH,J＝3.6Hz),7.789(d,1H,ArH,J＝4.3Hz),7.922(d,1H,ArH,J＝4.3Hz),8.145(s,1H,ArH).
实施例18
间甲氧基苯甲酰基辛二胺替米沙坦酰胺(I 13)的合成
参照实施例14的方法，将间甲氧基苯甲酸和辛二胺反应得到的单取代中间体(1.39g,5.0mmol)溶于无水二氯甲烷(30mL)中，加入EDAC(1.15g,6.0mmol)和催化量DMAP，室温搅拌0.5h，再加入替米沙坦(3.86g,7.5mmol)，室温搅拌过夜，过滤，减压浓缩，经柱层析[二氯甲烷:甲醇(v:v)＝40:1]得淡黄色固体1.74g，收率45％。MS(ESI):m/z775.4[M+H]+,797.4[M+Na]+.1H NMR(300MHz,CDCl3):δ0.784(t,3H,CH3,J＝7.3Hz),1.012(m,8H,4×CH2),1.079(m,4H,2×CH2),1.469(m,2H,CH2),2.683(s,3H,ArCH3),2.819(t,2H,CH2,J＝7.7Hz),3.033(q,2H,NHCH2,J＝6.5Hz),3.342(q,2H,NHCH2,J＝6.5Hz),3.711(s,3H,OCH3),3.767(s,3H,NCH3),5.336(s,2H,NCH2),6.733(s,1H,ArH),6.893(d,1H,ArH,J＝4.0Hz),7.035(d,2H,ArH,J＝3.8Hz),7.212(M,6H,ArH),7.301(M,5H,ArH),7.436(S,1H,ArH),7.529(d,1H,ArH,J＝3.9Hz),7.689(d,1H,ArH,J＝3.2Hz)
实施例19
邻羟基苯甲酰基辛二胺替米沙坦酰胺(I 14)的合成：
参照实施例14的方法，将邻羟基苯甲酸(1.38g,10mmol)溶于无水二氯甲烷(50mL)中，加入EDAC(2.29g,12.0mmol)和催化量DMAP，室温搅拌0.5h，再加入辛二胺(1.44g,10.0mmol),室温搅拌5h，过滤，减压浓缩，经柱层析[石油醚:乙酸乙酯(v:v)＝30:1]得油状物1.32g，收率50％。再将该中间体(1.06g,4.0mmol)和替米沙坦(2.06g,4.0mmol)反应，经柱层析得到白色固体1.34g，收率44％。MS(ESI):m/z 783.5[M+Na]+,759.4[M-H] _. 1H NMR(300MHz,CDCl 3):δ0.919-0.967(m,7H,CH3,2×CH 2),0.967-1.096(m,4H,2×CH 2),1.111-1.243(m,6H,3×CH 2),1.422-1.444(m,2H,CH 2),1.742-1.766(m,2H,CH 2),2.662(s,3H,ArCH 3),2.786(t,2H,CH 2,J＝7.5Hz),2.996-3.015(m,2H,NHCH 2),3.309-3.330(m,2H,NHCH 2),3.771(s,3H,NCH 3),5.278(s,2H,NCH 2),6.554(t,1H,ArH,J＝7.5Hz),6.777-6.804(m,1H,ArH),6.998-7.021(m,2H,ArH),7.122-7.353(m,11H,ArH),7.417(s,1H,NH),7.486-7.549(m,2H,ArH),7.647-7.672(m,1H,ArH),7.863(m,1H,NH)，12.664(s,1H,OH).
实施例20
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺坎地沙坦酰胺(I 15)的合成
参照实施例8的方法，将中间体V 3(1.88g,5.0mmol)和坎地沙坦(2.20g,5.0mmol)反应，经柱层析得到白色固体2.20g，收率55％。MS(ESI):m/z 821.5[M+Na]+,797.4[M-H]_. 1H NMR(300MHz,CDCl 3):δ0.752(t,3H,CH 3,J＝6.9Hz),1.153-1.254(m,16H,8×CH 2),1.346(t,4H,2×CH 2,J＝6.9Hz),1.975(s,3H,OCH 3),2.975-2.995(m,2H,NCH 2),3.282-3.300(m,2H,NCH 2),4.309(q,2H,OCH 2,J＝6.6Hz),5.331(s,2H,CH 2),5.754(t,1H,OCH,J＝6.9Hz),6.087(s,1H,NH),6.642-6.668(m,2H,ArH,),6.741-6.767(m,2H,ArH),6.833-6.884(m,1H,ArH),6.973-7.018(m,2H,ArH),7.184-7.248(m,2H,ArH),7.314-7.330(m,3H,ArH),7.409-7.483(m,2H,ArH,NH),7.652-7.676(m,1H,NH).
实施例21
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺缬沙坦酰胺(I 16)的合成：
参照实施例8的方法，将中间体V 3(1.88g,5.0mmol)和缬沙坦(2.66g,5.0mmol)反应，经柱层析得到白色固体2.06g，收率52％。MS(ESI):m/z 816.5[M+Na]+,792.4[M-H] _. 1H NMR(300MHz,CDCl 3):δ0.755-0.881(m,12H,4×CH 3),1.183-1.302(m,22H,11×CH 2),1.613-1.635(m,2H,CH 2),1.984(s,3H,OCH 3),2.399-2.449(m,2H,NCH 2),2.953-2.996(m,2H,NCH 2),3.307(s,2H,NCH),5.734(t,1H,OCH,J＝6.6Hz),7.194-7.239(m,4H,ArH), 7.284-7.354(m,5H,ArH),7.448-7.537(m,4H,ArH,NH),7.999-8.025(m,1H,NH).
实施例22
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺氯沙坦酰胺(I 17)的合成：
参照实施例8的方法，将中间体V 3(1.60g,5.0mmol)和氯沙坦(2.08g,5.0mmol)反应，经柱层析得到白色固体1.88g，收率49％。mp:197-199℃.MS(ESI):m/z 775[M+H] +。
实施例23
8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺盐酸盐(II)的合成：
取化合物I 3(873mg,1.0mmol)溶于乙酸乙酯中，滴入适量HCl饱和的乙酸乙酯溶液，搅拌，析出固体，蒸干溶剂，得白色固体870mg，收率96％。mp:227-229℃.MS(ESI):m/z907.4[M-H]-.
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种化合物，为通式I所示的光学活性的丁苯酞-替米沙坦杂合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐：
    Figure PCTCN2018071308-appb-100001
    其中：
    R代表氢原子H、C1-C10直链或支链烷基、(C1-C10直链或支链亚烷基)-Q，其中Q代表羟基或卤素；
    n代表1-20；
    X代表氧原子、氮原子或硫原子；
    Y代表氧原子、氮原子或硫原子；
    手性中心*为S构型或R构型。
  2. 根据权利要求1所述的化合物，或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其特征在于：R代表氢原子H、二甲胺基、二乙胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、N-甲基哌嗪基或N-羟乙基哌嗪基；
    X代表氧原子或氮原子；
    Y代表氧原子或氮原子。
  3. 根据权利要求1所述的化合物，或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其特征在于：所述化合物选自：
    2-O-{2-[(1-乙酰氧基)正戊基]苯甲酸}己二醇替米沙坦酯；
    4-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二醇替米沙坦酯；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺；
    5-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}戊二醇替米沙坦酯；
    6-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二醇替米沙坦酯；
    8-O-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二醇替米沙坦酯；
    6-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}己二胺替米沙坦酰胺；
    4-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}丁二胺替米沙坦酰胺；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺替米沙坦酰胺盐酸盐。
  4. 一种化合物，或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，其特征在于：所述化合物选自：
    对甲基苯甲酰基辛二胺替米沙坦酰胺；
    3,5-二氯苯甲酰基辛二胺替米沙坦酰胺；
    对腈基苯甲酰基辛二胺替米沙坦酰胺；
    对硝基苯甲酰基辛二胺替米沙坦酰胺；
    间甲氧基苯甲酰基辛二胺替米沙坦酰胺；
    邻羟基苯甲酰基辛二胺替米沙坦酰胺；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺坎地沙坦酰胺；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺缬沙坦酰胺；
    8-N-{2-[(1-乙酰氧基)正戊基]苯甲酰基}辛二胺氯沙坦酰胺。
  5. 权利要求1所述通式I化合物的制备方法，其特征在于：包括以下步骤：
    (S)-或(R)-丁苯酞经皂化、酸化反应制得内酯开环物III，化合物III与酰氯类化合物成酯得到酯类化合物IV，Ⅳ与不同碳链长度的二醇或二胺进行缩合反应得到中间体V，中间体V再与替米沙坦进行缩合得到目标化合物I；或者替米沙坦先与不同碳链长度的二醇或二胺进行缩合反应得到中间体VI，然后中间体VI再与酯类化合物IV进行缩合得到目标化合物I；合成路线如下：
    Figure PCTCN2018071308-appb-100002
  6. 根据权利要求5所述通式I化合物的制备方法，其特征在于：
    从化合物III制备化合物IV的反应中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；碱选自碳酸钾，碳酸钠，碳酸氢钠，氢氧化钠，氢氧化钾，吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流；和/或，
    从化合物IV制备化合物V的反应中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流；和/或，
    从化合物V制备化合物I的反应中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流；和/或，
    从替米沙坦制备化合物VI的反应中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应 温度为-20℃至回流；和/或，
    化合物IV和化合物VI制备化合物I的反应中，溶剂选自乙腈，二氯甲烷，氯仿，乙酸乙酯，丙酮，四氢呋喃，N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种；缩合剂选自N,N'-二环己基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑，N-羟基琥珀酰亚胺；碱选自吡啶，4-甲氨基吡啶，三乙胺，N,N-二异丙基甲胺；反应温度为-20℃至回流。
  7. 根据权利要求6所述通式I化合物的制备方法，其特征在于：
    从化合物III制备化合物IV的反应中，溶剂选择二氯甲烷，碱选择三乙胺，反应温度为-20℃；和/或，
    从化合物IV制备化合物V的反应中，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温；和/或，
    从化合物V制备化合物I的反应中，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温；和/或，
    从替米沙坦制备化合物VI的反应中，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温；和/或，
    化合物IV和化合物VI制备化合物I的反应中，溶剂选择二氯甲烷，缩合剂选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，碱选择4-甲氨基吡啶，反应温度为室温。
  8. 一种药物组合物，其特征在于：其中含有治疗有效量的权利要求1所述的通式I化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐及可药用的载体、佐剂或媒剂。
  9. 权利要求1-3任一项所述的化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐，在制备预防或治疗与神经炎症有关的疾病的药物中的应用。
  10. 根据权利要求9所述的用途，其特征在于：神经炎症有关的疾病包括缺血性脑卒中、阿尔兹海默病、脑外伤、帕金森病、多发性硬化症和抑郁症。
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