Dihydroindole aromatic acid ether derivatives, processes for their preparation and uses thereof

Abstract

The application discloses a kind of dihydroindole aromatic acid ether derivatives and preparation method and purposes thereof.The application specifically discloses a kind of dihydroindole aromatic acid ether derivatives shown in formula (I), or its tautomer, cis-trans isomer, isotopically labeled compound and pharmaceutically acceptable salt thereof.The derivatives show anti-platelet aggregation activity in AA and ADP induced platelet aggregation experiment.The compound of the application can be used for preventing and / or treating ischemic stroke, alzheimer's disease, vascular dementia and / or Parkinson's disease and the like diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a class of dihydroindole aromatic acid ether derivatives and the use thereof in treating or preventing diseases related to nerve injury. BACKGROUND

[0002] Ischemic stroke is the most common cerebrovascular disease, accounting for about 80% of all cerebrovascular diseases, and is one of the main causes of morbidity and mortality worldwide. Studies have shown that ischemic stroke mainly has three stages: thrombosis usually caused by vascular injury, triggering platelet aggregation and adhesion to the blood vessel wall; then the continued growth of arterial thrombus, leading to vascular occlusion; finally, due to insufficient blood supply to the brain, inflammation and oxidative stress occur in brain tissue, leading to apoptosis and necrosis of nerve cells. Therefore, the development of new drugs with dual effects of anti-platelet aggregation and neuroprotection is of great significance for the treatment of ischemic stroke.

[0003] Ferulic acid is widely present in Angelica sinensis, Chuanxiong and other plants, and has pharmacological effects such as improving cerebral circulation, anti-inflammation, anti-oxidative stress, and anti-platelet aggregation. However, due to its weak activity, its structure is optimized to enhance the pharmacological activity, which has certain prospects for the development of new drugs. Du Junrong et al. synthesized a series of ferulic acid derivatives (1), and found that the derivatives not only can reduce the inflammatory injury of cells induced by lipopolysaccharide (LPS), but also can reduce the free radical injury of cells induced by H2O2, improve cell viability, and have significant neuroprotective effect [Chinese Invention Patent CN104958287A]. Lei Hai-min et al. synthesized a series of ligustilide-substituted cinnamic acid derivatives, and the results showed that most of the compounds had certain neuroprotective activity, and compound 2 had the strongest neuroprotective activity (EC 50 = 3.68 μM) [Chinese Invention Patent CN106977464A].

[0004] Indole is an active fragment with anti-inflammatory, antioxidant, antitumor and other pharmacological effects, which is widely used in drug design. Indole-3-propionic acid is a naturally occurring compound, which has been shown to scavenge free radicals and protect neuronal cells from oxidative damage caused by beta amyloid protein. Zaikin et al. surprisingly found that the reduction products of indole (such as general formula 4, general formula 5) have stronger anti-inflammatory and antioxidant activities, and show significant protective activity on RAW264.7 macrophages [Shani Z, Tehilla W, Corina B, et al. Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents [J], J Med Chem, 2018, 61, 4004-4009].

[0005] SUMMARY

[0006] The purpose of the present application is to try to find a drug with anti-platelet aggregation activity and neuroprotective activity by splicing and modifying dihydroindole with anti-inflammatory and antioxidant effects with ferulic acid and its derivatives.

[0007] In one aspect, the present application provides a dihydroindole aromatic acid ether derivative, which is a compound represented by general formula (I)

[0008]

[0009] or tautomers, cis-trans isomers, isotopically labeled compounds and pharmaceutically acceptable salts thereof,

[0010] wherein, R1, R2, X, m, n are as defined herein.

[0011] In another aspect, the present application provides a pharmaceutical composition comprising the compound represented by formula (I) or tautomers, cis-trans isomers, isotopically labeled compounds and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0012] In still another aspect, the present application provides the use of the compound represented by formula (I) or tautomers, cis-trans isomers, isotopically labeled compounds and pharmaceutically acceptable salts thereof and / or the pharmaceutical composition comprising the same in the preparation of a medicament for preventing and / or treating diseases related to nerve damage.

[0013] The compound of the present application shows good anti-platelet aggregation activity in arachidonic acid (AA) and / or adenosine diphosphate (ADP) induced platelet aggregation test, and the compound of the present application also shows significant neuroprotective activity, significantly improves animal neurological score, and reduces cerebral infarction rate. DETAILED DESCRIPTION

[0014] DEFINITIONS

[0015] As used in the present specification, unless the context indicates otherwise, the following words and phrases are generally intended to have the meanings ascribed to them as set forth below.

[0016] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon chain monovalent radical having from 1 to 20 carbon atoms (more typically having from 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms). The term exemplifies, by way of example, the groups such as methyl, ethyl, 1 -propyl (normal propyl), 2-propyl (isopropyl), 1 -butyl (normal butyl), 2-methyl-1 -propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (normal pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -butyl, 2-methyl-1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, and the like.

[0017] As used herein, the term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon chain monovalent radical having from 2 to 20 carbon atoms (more typically having from 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The term exemplifies, by way of example, the groups such as ethenyl (i.e., -CH=CH2), propen-1 -yl (i.e., -CH=CHCH3), propen-3-yl (or allyl, i.e., -CH2CH=CH2), propen-2-yl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and the like.

[0018] As used herein, the term "alkynyl" refers to a straight or branched chain unsaturated hydrocarbon chain monovalent radical having from 2 to 20 carbon atoms (more typically having from 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having a carbon-carbon triple bond (e.g., 1, 2, or 3 carbon-carbon triple bonds). The term exemplified is a group such as ethynyl (i.e., -CºCH), propynyl (i.e., -CH2CºCH), propargyl (i.e., -CºCCH3), and the like.

[0019] As used herein, the term "aryl" refers to an aromatic carbocyclic radical of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple fused (fused together) rings (e.g., naphthyl, fluorenyl, and anthryl). The term exemplified is a group such as phenyl, fluorenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene (if the point of attachment is through the aryl group), and the like.

[0020] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0021] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. The term exemplified is a group such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, and the like.

[0022] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein. The term exemplified is a group such as trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, and the like.

[0023] As used herein, the terms "carbocyclic", "carbocyclic group" refer to a 3- to 8-membered monocyclic or multiple fused (fused together) rings or bridged or spirocyclic monovalent saturated or partially unsaturated radical having 3 to 14 carbon atoms as ring atoms. The carbocyclic or carbocyclic group can be saturated or partially unsaturated and can be fused with another saturated, partially unsaturated, or aromatic ring, provided that the ring atom to which the target molecule is attached is not an aromatic carbon. Examples of carbocyclic or carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, and the like.

[0024] As used herein, the terms "heteroaromatic ring," "heteroaryl," refer to a monocyclic or a multiple fused (fused) ring (e.g., containing 2 or 3 rings) aromatic ring radical containing 5 to 14 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms contain at least one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur. If the ring is aromatic, the sulfur and nitrogen atoms can also be in oxidized forms. A multiple fused (fused) ring heteroaryl is a monocyclic heteroaryl radical as defined above fused with one or more rings selected from heteroaryl (to form, e.g., a naphthridinyl radical such as 1,8-naphthridinyl), heterocyclo (e.g., to form a 1,2,3,4-tetrahydronaphthridinyl radical such as 1,2,3,4-tetrahydro-1,8-naphthridinyl), carbocyclo (to form, e.g., a 5,6,7,8-tetrahydroquinolinyl radical), and aryl (to form, e.g., an indazolyl radical). Such multiple fused ring systems can optionally be substituted on the carbocyclic or heterocyclic portion of the fused ring with one or more (e.g., 1, 2, 3, or 4) oxo groups. When valency permits, the rings of the multiple fused ring system can be connected to one another by fused, spiro, and bridged linkages. It will be appreciated that the individual rings of the multiple fused ring system can be connected relative to one another in any order. It will also be appreciated that the point of attachment of the multiple fused ring system can be at any location of the multiple fused ring system, including the heteroaryl, heterocyclo, aryl, or carbocyclo portion of the multiple fused system. It will also be appreciated that the point of attachment of the heteroaryl radical can be on any suitable atom of the heteroaryl radical, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to: pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzo[d][l,3]dioxolyl, benzimidazolyl, thionaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-lH-indazolyl, and 3b,4,4a,5-tetrahydro-lH-cyclopropane[3,4]cyclopentane[l,2-c]pyrazolyl.

[0025] As used herein, the terms "heterocycle," "heterocyclyl" refer to a 3- to 8-membered monocyclic or multiple fused (fused) or bridged ring monocyclic saturated or partially unsaturated radical having 3 to 14 ring atoms in the ring, wherein in addition to carbon atoms, the ring atoms include at least one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur. Examples of heterocyclyl groups include, but are not limited to, aziridine ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, azepane ring, azocane ring, oxirane ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, oxepane ring, oxocane ring, thiirane ring, thietane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thiepane ring, thiepane ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydroisoxazole ring, tetrahydrothiazole ring, tetrahydroisothiazole ring, piperazine ring, morpholine ring, dioxane ring, thioxane ring, dithiane ring, dihydropyridyl, 4,5,6,7-tetrahydro-lH-benzo[d]imidazole, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine, and the like.

[0026] As used herein, the term "cis-trans isomer" refers to isomers that arise due to the different spatial arrangement of individual groups in a compound molecule due to the presence of a restriction factor for free rotation such as a C=C double bond, C=N double bond, C=S double bond, N=N double bond, or an alicyclic ring. Organic molecules containing such isomers such as alkenes, azo compounds, alicyclic hydrocarbons, and the like are considered cis-trans isomers and are named according to the "cis-trans isomer nomenclature" or "Z-E nomenclature".

[0027] As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and distribution of an active atom or atoms, such as keto-enol tautomers.

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the given compound and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be acid addition salts and / or base addition salts. Acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromic, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, and the like; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, lactate, nicotinate, laurylsulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucaronate, oleate, palmitate, stearate, pamoate, trifluoroacetate, and the like. Base addition salts can be formed with inorganic and organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts and the like; salts derived from organic bases include salts of various primary, secondary, and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperizine, piperidine, morpholine, tromethamine, choline, and the like.

[0029] As used herein, the term "pharmaceutically acceptable" means the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation and / or the mammal to which it is administered.

[0030] Any formula or structure given herein, including Formula I or any formula disclosed herein, is also intended to represent unlabelled forms as well as isotopically label forms of the compounds. These isotopically labeled compounds can also be called "isotopically labeled" or "isotopically enriched" analogs. Isotopically labeled compounds have structures depicted by the formulas as depicted herein, except that one or more atoms are replaced by an atom having the selected atomic mass or mass number. Examples of isotopes that can be enco 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36Cl、 123 I and 125 I. Various isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as3H and11C are 3 H、 13 C and 14 C) are included. Such compounds can be synthesized using techniques known to those skilled in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by a radioactive isotope.

[0031] compound

[0032] In one embodiment, the present application provides a compound of formula (I)

[0033]

[0034] or tautomers, cis and trans isomers, isotopically labeled forms, and pharmaceutically acceptable salts thereof, wherein

[0035] R1is selected from hydrogen, C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C1-C 20 haloalkyl, C1-C 20 alkoxy, C1-C 20 alkanoyl, C1-C 20 alkanoyloxy, C1-C 20 alkoxycarbonyl, halogen, hydroxyl, cyano, nitro, carboxyl;

[0036] R2is selected from hydrogen, C1-C 20 alkyl;

[0037] X is selected from C6-C 14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or C3-C 14 carbocyclyl, optionally substituted with one or more groups selected from halogen, oxo, C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C1-C 20 haloalkyl, C1-C 20 alkoxy, C1-C 20 alkanoyl, C1-C 20 alkanoyloxy, C1-C 20 alkoxycarbonyl, C1-C 20 alkoxycarbonyloxy, hydroxyl, cyano, nitro, carboxyl;

[0038] m is selected from 0 or 1;

[0039] n is selected from an integer between 0-4.

[0040] In one embodiment, in the compound of formula (I) provided by the present application, X is selected from C6-C 14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or C3-C 14 carbocyclyl, optionally substituted with one or more groups selected from halogen, oxo, C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C1-C 20 haloalkyl, C1-C 20 alkoxy, C1-C 20 alkanoyl, C1-C 20 alkanoyloxy, C1-C 20 alkoxycarbonyl, C1-C 20 alkoxycarbonyloxy, hydroxy, cyano, nitro, carboxy; preferably, X is selected from C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or C3-C8carbocyclyl, optionally substituted with one or more groups selected from halogen, C1-C 20 alkyl, C1-C 20 haloalkyl, C1-C 20 alkoxy, C1-C 20 alkanoyl, C1-C 20 alkanoyloxy, C1-C 20 alkoxycarbonyl, C1-C 20 alkoxycarbonyloxy, hydroxy, cyano, nitro, carboxy; more preferably, X is selected from C6-C 10aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl or C3-C8carbocyclyl, optionally substituted by one or more radicals selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkanoyl, C1-C6alkanoyloxy, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonyloxy, hydroxy, cyano, nitro, carboxyl; further preferably, X is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzo[d][l,3]dioxolyl, benzimidazolyl, thianaphthalenyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-lH-indazolyl and 3b,4,4a,5-tetrahydro-lH-cyclopropane[3,4]cyclopentane[l,2-c]pyrazolyl, aziridine ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, azepane ring, azocane ring, oxirane ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, oxepane ring, oxecane ring, thiirane ring, thietane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thiepane ring, thieocane ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydroisoxazole ring, tetrahydrothiazole ring, tetrahydroisothiazole ring, piperazine ring, morpholine ring, dioxane ring, thioxane ring, dithiane ring, dihydropyridyl, 4,5,6,7-tetrahydro-lH-benzo[d]imidazole, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, optionally substituted by one or more radicals selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkanoyl, C1-C6alkanoyloxy, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonyloxy, hydroxy, cyano, nitro, carboxyl; further preferably, X is selected from phenyl, furanyl, thienyl, benzo[d][l,3]dioxol, benzofuranyl, pyridyl, optionally substituted by one or more radicals selected from halogen, methyl, trifluoromethyl, methoxy, cyano, nitro; most preferably, X is selected from phenyl, optionally substituted by one or more radicals selected from methoxy.

[0041] In one embodiment, in the compounds of formula (I) provided by the present application, n is an integer between 0 and 4; preferably, n is 0 or 1 or 2 or 3; more preferably, n is 0 or 1 or 2; most preferably, n is 0 or 1.

[0042] In one embodiment, in the compound represented by formula (I) provided by the present invention, each R1 is independently selected from hydrogen, C1-C1, C2-C3, C4-C5, C6-C6-C5-C6 ... 20 Alkyl, C2-C 20 alkenyl, C2-C 20 Alkyne group, C1-C 20 Haloalkyl, C1-C 20 Alkoxy, C1-C 20 Alkyl group, C1-C 20 Alkyloxy, halogen, hydroxyl, cyano, nitro, carboxyl; preferably, each R1 is independently selected from hydrogen, C1-C1, C2-C4, C3-C4, C4-C4, C5-C6, C6-C6, C7 ... 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Alkoxy, halogen, hydroxy, cyano, nitro, carboxyl; more preferably, each R1 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen; most preferably, each R1 is independently selected from hydrogen, methoxy.

[0043] In one embodiment, in the compound represented by formula (I) provided by the present invention, R2 is selected from hydrogen, C1-C2, and C2-C2. 20 Alkyl; preferably, R2 is selected from hydrogen, C1-C6 alkyl; more preferably, each R2 is selected from hydrogen, C1-C3 alkyl; most preferably, R2 is selected from hydrogen, methyl, ethyl.

[0044] In one embodiment, in the compounds provided by the present invention, each R3 is independently selected from hydrogen, halogen, oxo group, C1-C... 20 Alkyl, C2-C 20 alkenyl, C2-C 20 Alkyne group, C1-C 20 Haloalkyl, C1-C 20 Alkoxy, C1-C 20 Alkyl group, C1-C 20 Alkyloxy, C1-C 20 Alkoxycarbonyl, C1-C 20 Alkoxy, carbonyl, hydroxyl, cyano, nitro, carboxyl; preferably, each R3 is independently selected from hydrogen, C1-C1, C2-C4, C3 ... 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Alkoxy, halogen, hydroxyl, cyano, nitro, carboxyl; more preferably, each R3 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; most preferably, each R3 is independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy.

[0045] In one embodiment, the present application provides a compound represented by Formula (II):

[0046]

[0047] or tautomers, cis and trans isomers, isotopically labeled forms, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, m, n, p are as defined herein.

[0048] In one embodiment, the present application provides a compound represented by Formula (II):

[0049]

[0050] or tautomers, cis and trans isomers, isotopically labeled forms, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, n, m, p are as defined herein.

[0051] In one embodiment, the present application provides a compound represented by Formula (II):

[0052] 4-(3-(2,3-dihydroindol-l-yl)propoxy)-3-methoxybenzoic acid;

[0053] (E)-3-(4-(3-(2,3-dihydroindol-l-yl)propoxy)-3-methoxyphenyl)acrylic acid;

[0054] (E)-3-(4-(3-(2,3-dihydroindol-l-yl)propoxy)phenyl)acrylic acid;

[0055] (E)-3-(4-(2-(2,3-dihydroindol-l-yl)ethoxy)-3-methoxyphenyl)acrylic acid;

[0056] 4-(3-(2,3-dihydroindol-l-yl)propoxy)benzoic acid;

[0057] (E)-3-(3-methoxy-4-(2-(5-methoxy-2,3-dihydroindol-l-yl)ethoxy)phenyl)acrylic acid;

[0058] 4-(3-(2,3-dihydroindol-l-yl)propoxy)-3,5-dimethoxybenzoic acid;

[0059] (E)-3-(3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l-yl)propoxy)phenyl)acrylic acid;

[0060] 3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l-yl)propoxy)benzoic acid;

[0061] (E)-3-(4-(2-(2,3-dihydroindol-l-yl)ethoxy)phenyl)acrylic acid;

[0062] or tautomers, cis-trans isomers, isotopically labeled, and pharmaceutically acceptable salts thereof.

[0063] Pharmaceutical compositions and administration

[0064] The pharmaceutical composition provided by the present application comprises the compound of the present application or its stereoisomer, tautomer, solvate, prodrug, isotopically labeled, pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is known to those skilled in the art, including diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, colorants, flavorings, sweeteners, etc. According to the different routes of administration of the drug, such as oral administration, parenteral administration and rectal administration, etc., the pharmaceutical composition of the present application can be made into solid form (including but not limited to tablets, capsules, pills, granules, powders, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present application is in solid form, the pharmaceutically acceptable carrier usually includes one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium silicate, gelatinized starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants, e.g. ascorbic acid; f) glidants, such as silicon dioxide; g) flavorings, such as peppermint, methyl salicylate; sweeteners, such as sucrose, saccharin. When the pharmaceutical composition of the present application is in liquid form, the pharmaceutically acceptable carrier usually includes one or more of the following: a) diluents, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) antioxidants, such as ascorbic acid or sodium bisulfite; c) buffers, such as acetate, phosphate, etc.

[0065] The effective dosage of the compounds of the present application depends on the nature of the condition being treated, the severity of the disease, the method of delivery and the pharmaceutical dosage form, and will be ultimately at the discretion of the physician. It is expected that about 0.0001 to about 100 mg per kilogram of body weight per day; typically about 0.01 to about 10 mg per kilogram of body weight per day; more typically about 0.01 to about 5 mg per kilogram of body weight per day; and most typically about 0.05 to about 0.5 mg per kilogram of body weight per day will be administered. For example, a candidate daily dosage for an average adult human of about 70 kg body weight can be in the range from 1 mg to 1000 mg, preferably in the range from 5 mg to 500 mg, and can be given in a single dose or in divided doses.

[0066] Indications

[0067] The compounds of the present application have significant anticoagulant and neuroprotective activities, and can be used for treating or preventing neurologic injury related diseases. Including ischemic stroke, posterior circulation cerebral ischemia, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, Alzheimer's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, primary lateral sclerosis peripheral neuropathy, diabetic neuropathy.

[0068] General synthetic methods

[0069] The compounds of the present application can be prepared using the methods disclosed herein and modifications thereof, as well as methods well known in the art. Typical embodiments of the compounds according to the present application can be synthesized using the general reaction schemes below. As will be apparent to one of ordinary skill in the art, modifications to the methodologies can be made without departing from the spirit of the present application. Reaction materials not readily available from commercial sources can be prepared using methods described herein or known to those skilled in the art.

[0070] Reaction schemes

[0071]

[0072] Step 1, compound 1 is subjected to a reduction reaction to obtain intermediate 2;

[0073] Step 2, intermediate 2 is subjected to a nucleophilic substitution reaction with reagent 2a to obtain intermediate 3;

[0074] Step 3, intermediate 3 is subjected to a substitution reaction with reagent 3a to obtain intermediate 4;

[0075] Step 4, intermediate 4 is subjected to a hydrolysis and acidification reaction to obtain compound 5.

[0076] wherein R1, R2, R3, m, n and p are as defined herein.

[0077] In a preferred embodiment, in step 1, compound 1 is dissolved in acetic acid, sodium cyanoborohydride is added portionwise slowly, the reaction is stirred at room temperature for 1 h to obtain intermediate 2;

[0078] In a preferred embodiment, in step 2, intermediate 2 and reagent 2a are dissolved in N,N-dimethylformamide, then potassium carbonate is added, the reaction is stirred at 70 °C for 4 h to obtain intermediate 3;

[0079] In a preferred embodiment, in step 3, intermediate 3 and reagent 3a are dissolved in acetonitrile, then potassium carbonate is added, the reaction is stirred at 50 °C for 4 h to obtain intermediate 4;

[0080] In a preferred embodiment, in step 4, intermediate 4 is dissolved in methanol, 10% NaOH solution is added, the reaction is stirred at 60 °C for 1 h to obtain compound 5.

[0081] Example 1 Synthesis of (E)-3-(3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l- yl)propoxy)phenyl)acrylic acid (compound 5h)

[0082] Step 1: Synthesis of 5-methoxyindoline (intermediate 2a)

[0083]

[0084] In a 100 mL single-necked flask, 5-methoxyindole (1.5 g, 10.2 mmol) was added, glacial acetic acid (20 mL) was added, then NaBH3CN (0.77 g, 12.2 mmol) was added portionwise under stirring at 25 °C, the reaction was continued for 1 h, TLC (petroleum ether: ethyl acetate = 3: 1) detection showed that the reaction was substantially complete. 20% NaOH solution was added to the reaction solution to adjust pH = 9-10, ethyl acetate (50 mL x 3) was extracted, the organic phase was washed with water (50 mL x 3), then dried over anhydrous Na2SO4, filtered and concentrated, and the residue was subjected to silica gel column chromatography to obtain intermediate 2a as a light yellow oil in a yield of 91%.

[0085] Step 2: Synthesis of l-(3-bromopropyl)-5-methoxy-2,3-dihydro-lH-indole (intermediate 3a)

[0086]

[0087] In a 100 mL single necked flask was added intermediate 2a (0.6 g, 4.02 mmol), DMF (20 mL), 1,3-dibromopropane (4.87 g, 24.12 mmol), K2CO3(1.1 g, 8.0 mmol), stirred at 70 °C for 4 h, TLC (petroleum ether: ethyl acetate = 5:1) showed the reaction was almost complete. The reaction was diluted with 150 mL water, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with water (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated, the residue was purified by silica gel column chromatography to give intermediate 3a as a yellow oil in 36% yield.

[0088] Step 3: Synthesis of (E)-methyl 3-(3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l- yl)propoxy)phenyl)acrylate (intermediate 4h)

[0089]

[0090] In a 50 mL single necked flask was added intermediate 3a (0.39 g, 1.44 mmol), CH3CN 8 mL, methyl ferulate (0.3 g, 1.44 mmol), K2CO3(0.3 g, 2.16 mmol), stirred at 50 °C for 4 h, TLC (petroleum ether: ethyl acetate = 3:1) showed the reaction was almost complete. The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to give a brown oil, which was purified by silica gel column chromatography to give intermediate 4h as a white solid 0.45 g, m.p. 83.3-85.1 °C in 80.9% yield.

[0091] Step 4: Synthesis of (E)-3-(3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l- yl)propoxy)phenyl)acrylic acid (compound 5h)

[0092]

[0093] In a 50 mL single necked flask was added intermediate 4h (0.40 g, 1.01 mmol), CH3OH (8 mL), 10% NaOH solution (4 mL), heated to 60 °C, stirred for 1 h, TLC (petroleum ether: ethyl acetate = 3:1) showed the reaction was almost complete. The reaction was concentrated under reduced pressure to remove CH3OH, the residue was diluted with 5 mL water, and adjusted to pH 5-6 with 1 mol / L enamine hydrochloric acid, a large amount of white solid precipitated, filtered to give a white solid, which was dried to give 0.30 g of the target compound 5h in 77.7% yield. m.p. 122.2-123.5 °C. ESI-MS [M+H] + : m / z = 384.03, 1H NMR (400 MHz, DMSO-d6) δ: 12.20 (s, 1H, OH), 7.52 (d, J = 15.9 Hz, 1H, =CH), 7.33 (s, 1H, ArH), 7.18 (d, J = 8.4 Hz, 1H, ArH), 6.99 (d, J = 8.3 Hz, 1H, ArH), 6.71 (s, 1H, ArH), 6.56 (d, J = 8.3, 1.9 Hz, 1H, ArH), 6.44 (d, J = 15.9 Hz, 1H, =CH), 4.10 (t, J = 6.2 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.23 (t, J = 8.1 Hz, 2H, NCH2), 3.11 (t, J = 6.9 Hz, 2H, NCH2), 2.84 (t, J = 8.0 Hz, 2H, ArCH2), 2.02 - 1.94 (m, 2H, CH2CH2CH2).

[0094] Synthesis of 4-(3-(2,3-dihydroindol-l-yl)propoxy)-3-methoxybenzoic acid (Compound 5a)

[0095] The compound 5a of Example 2 was prepared according to the synthetic procedure of Reference Example 1 by replacing 5-methoxy-2,3-dihydroindole with dihydroindole and methyl ferulate with methyl vanillate as starting materials. The compound 5a of Example 2 was obtained as a white solid. m.p. 135.6-137.1 °C. ESI-MS [M+H] + : m / z = 328.41. 1 H NMR (400 MHz, DMSO-d6) δ: 12.63 (s, 1H, OH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.46 (s, 1H, ArH), 7.05 (d, J = 8.5 Hz, 1H, ArH), 7.01 (d, J = 7.1 Hz, 1H, ArH), 6.95 (t, J = 7.6 Hz, 1H, ArH), 6.55 (t, J = 7.3 Hz, 1H, ArH), 6.49 (d, J = 7.8 Hz, 1H, ArH), 4.13 (t, J = 6.3 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.32 (t, J = 8.3 Hz, 2H, NCH2), 3.21 (t, J = 7.0 Hz, 2H, ArCH2CH2), 2.88 (t, J = 8.3 Hz, 2H, ArCH2), 2.05 - 1.97 (m, 2H, CH2CH2CH2).

[0096] Synthesis of (E)-3-(4-(3-(2,3-dihydroindol-l-yl)propoxy)-3-methoxyphenyl)acrylic acid (Compound 5b)

[0097] The compound 5b of Example 3 was prepared according to the synthetic procedure of Reference Example 1 by replacing 5-methoxy-2,3-dihydroindole with 2,3-dihydroindole as starting material to give a pale yellow solid. m.p. 128.5-130.1 °C. ESI-MS [M+H] + : m / z = 354.41. 1 H NMR (400 MHz, DMSO-d6) δ: 12.22 (s, 1H, OH), 7.52 (d, J = 15.9 Hz, 1H, =CH), 7.33 (s, 1H, ArH), 7.18 (d, J = 8.3 Hz, 1H, ArH), 7.03-6.92 (m, 3H, ArH), 6.54 (t, J = 7.0 Hz, 1H, ArH), 6.48 (d, J = 8.0 Hz, 1H, ArH), 6.45 (d, J = 15.9 Hz, 1H, =CH), 4.09 (t, J = 6.2 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.31 (t, J = 8.3 Hz, 2H, NCH2), 3.20 (t, J = 7.0 Hz, 2H, ArCH2CH2), 2.88 (t, J = 8.3 Hz, 2H, ArCH2), 2.04-1.94 (m, 2H, CH2CH2CH2).

[0098] Synthesis of (E)-3-(4-(3-(2,3-dihydroindol-l-yl)propoxy)phenyl)acrylic acid (compound 5c) of Example 4

[0099] The compound 5c of Example 4 was prepared according to the synthetic procedure of Reference Example 1 by replacing 5-methoxy-2,3-dihydroindole with 2,3-dihydroindole as starting material and methyl ferulate with methyl trans-coumarate as starting material to give a pale yellow solid. m.p. 135.8-137.9 °C. ESI-MS [M+H] + : m / z = 324.39. 1H NMR (400 MHz, DMSO-d6) δ: 12.23 (s, 1H, OH), 7.63 (d, J = 8.8 Hz, 2H, ArH), 7.54 (d, J = 15.9 Hz, 1H, =CH), 7.03-6.98 (m, 3H, ArH), 6.96 (t, J = 7.0 Hz, 1H, ArH), 6.55 (t, J = 7.0 Hz, 1H, ArH), 6.48 (d, J = 7.8 Hz, 1H, ArH), 6.38 (d, J = 16.0 Hz, 1H, =CH), 4.11 (t, J = 6.2 Hz, 2H, OCH2), 3.31 (t, J = 8.0 Hz, 2H, NCH2), 3.20 (t, J = 7.0 Hz, 2H, ArCHCH2), 2.88 (t, J = 8.3 Hz, 2H, ArCH2), 2.04-1.95 (m, 2H, CH2CH2CH2).

[0100] Example 5 Synthesis of (E)-3-(4-(2-(2,3-dihydroindol-l-yl)ethoxy)-3- methoxyphenyl)acrylic acid (Compound 5d)

[0101] The compound 5d of Example 5 was prepared according to the synthetic procedure of Reference Example 1 by replacing 5-methoxy-2,3-dihydroindole with 2,3- dihydroindole starting material and 1,3-dibromopropane with 1,2-dibromoethane starting material as white solid. m.p. 155.4-157.8 °C. ESI-MS [M+H] + : m / z = 340.39. 1 H NMR (400 MHz, DMSO-d6) δ: 12.23 (s, 1H, OH), 7.63 (d, J = 8.8 Hz, 2H, ArH), 7.54 (d, J = 15.9 Hz, 1H, =CH), 7.03-6.98 (m, 3H, ArH), 6.96 (t, J = 7.0 Hz, 1H, ArH), 6.55 (t, J = 7.0 Hz, 1H, ArH), 6.48 (d, J = 7.8 Hz, 1H, ArH), 6.38 (d, J = 16.0 Hz, 1H, =CH), 4.11 (t, J = 6.2 Hz, 2H, OCH2), 3.31 (t, J = 8.0 Hz, 2H, NCH2), 3.20 (t, J = 7.0 Hz, 2H, ArCHCH2), 2.88 (t, J = 8.3 Hz, 2H, ArCH2), 2.04-1.95 (m, 2H, CH2CH2CH2).

[0102] Example 6 Synthesis of 4-(3-(2,3-dihydroindol-l-yl)propoxy)benzoic acid (Compound 5e)

[0103] The compound 5e of Example 6 was prepared according to the synthetic procedure of Reference Example 1, replacing 5-methoxy-2,3-dihydroindole with 2,3-dihydroindole starting material, and methyl ferulate with methyl p-hydroxybenzoate starting material, as a white solid. m.p. 137.2-138.5 °C. ESI-MS [M+H] + : m / z = 298.35. 1 H NMR (400 MHz, DMSO-d6) δ: 12.64 (s, 1H, OH), 7.89 (d, J = 8.8 Hz, 2H, ArH), 7.04 (d, J = 8.8 Hz, 2H, ArH), 7.02 (d, J = 4.0 Hz, 1H, ArH), 6.95 (t, J = 7.6 Hz, 1H, ArH), 6.55 (t, J = 7.3 Hz, 1H, ArH), 6.48 (d, J = 7.8 Hz, 1H, ArH), 4.14 (t, J = 6.2 Hz, 2H, OCH2), 3.31 (t, J = 8.3 Hz, 2H, NCH2), 3.20 (t, J = 7.0 Hz, 2H, NCH2), 2.88 (t, J = 8.3 Hz, 2H, ArCH2), 2.05-1.97 (m, 2H, CH2CH2CH2).

[0104] Synthesis of (E)-3-(3-methoxy-4-(2-(5-methoxy-2,3-dihydroindol-l- yl)ethoxy)phenyl)acrylic acid (compound 5f) of Example 7

[0105] The compound 5f of Example 7 was prepared according to the synthetic procedure of Reference Example 1, replacing 1,3-dibromopropane with 1,2-dibromoethane starting material, as a yellow solid. m.p. 154.3-155.8 °C. ESI-MS [M+H] + : m / z = 370.36. 1 H NMR (400 MHz, DMSO-d6) δ: 12.24 (s, 1H, OH), 7.53 (d, J = 15.9 Hz, 1H, =CH), 7.33 (s, 1H, ArH), 7.20 (d, J = 8.2 Hz, 1H, ArH), 7.02 (d, J = 8.3 Hz, 1H, ArH), 6.72 (s, 1H, ArH), 6.60 (d, J = 8.3 Hz, 1H, ArH), 6.54 (d, J = 8.5 Hz, 1H, ArH), 6.45 (d, J = 15.9 Hz, 1H, =CH), 4.19 (t, J = 5.6 Hz, 2H, OCH2), 3.81 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.38-3.32 (m, 4H, NCH2), 2.85 (t, J = 8.1 Hz, 2H, ArCH2).

[0106] Synthesis of 4-(3-(2,3-dihydroindol-l-yl)propoxy)-3,5-dimethoxybenzoic acid (Compound 5g)

[0107] The compound 5g of Example 8 was prepared according to the synthetic procedure of Reference Example 1 by replacing 5-methoxy-2,3-dihydroindole with 2,3-dihydroindole starting material and methyl ferulate with methyl syringate starting material as white solid. m.p. 124.4-126.9 °C. ESI-MS [M+H] + : m / z = 358.36. 1 H NMR (400 MHz, DMSO-d6) δ: 12.94 (s, 1H, OH), 7.24 (s, 2H, ArH), 7.01 (d, J = 4.1 Hz, 1H), 6.97 (d, J = 4.2 Hz, 1H, ArH), 6.55 (t, J = 6.9 Hz, 1H, ArH), 6.48 (d, J = 7.8 Hz, 1H, ArH), 4.05 (t, J = 6.0 Hz, 2H, OCH2), 3.83 (s, 6H, (OCH3)2), 3.29 (t, J = 8.3 Hz, 2H, NCH2), 3.24 (t, J = 8.1 Hz, 2H, NCH2), 2.87 (t, J = 8.3 Hz, 2H, ArCH2), 1.91-1.83 (m, 2H, CH2CH2CH2).

[0108] Synthesis of 3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-l-yl)propoxy)benzoic acid (Compound 5i)

[0109] The compound 5i of Example 9 was prepared according to the synthetic procedure of Reference Example 1 by replacing methyl ferulate with methyl vanillate starting material as off-white solid in 72% yield. m.p. 140.3-143.1 °C. ESI-MS [M+H] + : m / z = 358.02. 1HNMR (400 MHz, DMSO-d6) δ: 12.65 (s, 1H, OH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.46 (s, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH), 6.71 (s, 1H, ArH), 6.56 (d, J = 8.4 Hz, 1H, ArH), 6.42 (d, J = 8.4 Hz, 1H, ArH), 4.13 (t, J = 6.2 Hz, 2H, OCH2), 3.83 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.24 (t, J = 8.1 Hz, 2H, NCH2), 3.11 (t, J = 6.9 Hz, 2H, NCH2), 2.84 (t, J = 8.1 Hz, 2H, ArCH2), 2.05-1.96 (m, 2H, CH2CH2CH2).

[0110] Example 10. Synthesis of (E)-3-(4-(2-(2,3-dihydroindol-l- yl)ethoxy)phenyl)acrylic acid (Compound 5j)

[0111] Example 10. Synthesis of (E)-3-(4-(2-(2,3-dihydroindol-l- yl)ethoxy)phenyl)acrylic acid (Compound 5j) + : m / z = 310.32. 1 HNMR (400 MHz, DMSO-d6) δ: 12.22 (s, 1H, OH), 7.63 (d, J = 8.6 Hz, 2H, ArH), 7.54 (d, J = 15.9 Hz, 1H, ArCH=), 7.05-6.96 (m, 4H, ArH), 6.57 (m, 2H ArH), 6.38 (d, J = 16.0 Hz, 1H, =CH), 4.23 (t, J = 5.5 Hz, 2H, OCH2), 3.44 (m, 4H, N(CH2)2), 2.89 (t, J = 8.3 Hz, 2H, ArCH2).

[0112] Biological activity

[0113] I. Anti-platelet aggregation activity test of the compound of the present application

[0114] (1) Experimental method

[0115] Male rabbits (body weight 1.8-2.0 kg) were anesthetized locally with lidocaine, and the carotid artery was cannulated for blood withdrawal, and a 9:1 mixture of sodium citrate solution (0.38 g of sodium citrate was prepared into a 3.8% sodium citrate solution with 10 mL of normal saline) was used at 500-800 r·min -1 The remaining part was centrifuged at 3000 r·min -1 The remaining part was centrifuged at 3000 r·min -1 ADP, 200 μg·mL -1 AA. 10 μL of drugs at different concentrations (1 μM, 10 μM, 100 μM, 1 mM, 10 mM) was added to 180 μL of PRP in each tube, 10 μL of normal saline was added to the PRP in the control group, and incubated for 3 min, then the above-mentioned different concentrations of inducers (10 μg·mL -1 ADP, 200 μg·mL -1 AA) were added, and the platelet aggregation rate was detected, all experiments were repeated 3 times, and the aggregation inhibition rate was calculated according to the average value of the aggregation rate of each group and the average value of the aggregation rate of the blank group: inhibition rate (%) = (average value of maximum aggregation rate of blank control group-average value of maximum aggregation rate of drug group) / average value of maximum aggregation rate of blank control group x 100%.

[0116] (2) Experimental results

[0117] Table 1: Inhibitory effect of dihydroindole aromatic acid ether derivatives on AA-induced platelet aggregation As can be seen from Table 1, compounds 5a-5j inhibited AA-induced platelet aggregation to varying degrees, and the activities of compounds 5c, 5f, 5g, 5h, 5i were all stronger than that of the control compound [3-(2,3-dihydroindol-1-yl) propanol].

[0118] Table 2. Inhibitory effect of dihydroindole aromatic acid ether derivatives on ADP-induced platelet aggregation As can be seen from Table 2, compounds 5a-5j can significantly inhibit ADP-induced platelet aggregation, and the activities of compounds 5a-5j are all stronger than that of the control compound [3-(2,3-dihydroindol-1-yl) propanol] and the positive control drug aspirin.

[0119] II. Protective effect of the compound on hypoxia / reoxygenation (OGD / R) mediated injury of rat cerebral cortex primary neurons

[0120] (1) Test animals

[0121] Clean level SD pregnant rats, body weight 350-400g, female, purchased from Beijing Vantoll Life Science Experimental Animal Technology Co., Ltd., fed in SPF level animal room, indoor temperature controlled at 23±2℃, free drinking and water, day and night time for 12h / 12h.

[0122] (2) Drug grouping:

[0123] Model group (OGD / R); positive control group (butylphthalide); control group (compound Drug group; compound concentration is 0.1 μmol / L, 1 μmol / L, 10 μmol / L, each concentration biological repeat 5 times.

[0124] (3) Test method

[0125] Take SD rat pups (0-1d), fix the head, disinfect the scalp, open the skull and quickly take out the whole brain tissue, put it into a glass culture dish containing D-Hank's liquid on ice, carefully peel off the blood vessels and meninges on the surface of the brain tissue, remove the cerebellum and brain stem, then wash the brain tissue with D-Hank's liquid repeatedly. Take the cerebral cortex, move it into a glass culture dish, cut it, then add trypsin and mix well, place it in a 37℃ constant temperature water bath box for digestion, then add serum-containing medium to terminate digestion, filter through a 200 mesh sieve, centrifuge the filtrate (800rpm, 10min), discard the supernatant, add an appropriate amount of culture solution (neurobasal medium containing penicillin (final concentration 100U / ml), streptomycin (final concentration 100μg / ml), 2% B27 and L-glutamine (final concentration 0.3mg / ml)) to suspend the precipitate, inoculate it in a 6-well plastic culture plate, and place it in a 37℃, 5% CO2 incubator for culture for 36h, then add cytarabine (3μg / ml), and change the medium after 12h. Change the medium every 3 days thereafter, and culture for 7-14 days.

[0126] (4) Preparation of rat cerebral cortex neuron cells oxygen-glucose deprivation and reoxygenation (OGD / R)

[0127] Select cells grown to about 7 days for preparation of in vitro OGD / R model. Adjust the cell density to 4×10 4Cells were seeded in 12-well plates at a cell density of 1 cell / well. After 24 h of conventional culture using DMEM medium containing 1% FBS and corresponding concentrations of drug-containing DMEM medium, respectively, the OGD / R model was prepared. First, the medium was replaced with DMEM medium without glucose and serum, and the cells were placed in a three-gas incubator containing 5% CO2 and 95% N2 for 2 h to complete the hypoxic process; then the cell medium was replaced with complete DMEM medium, and the cells were placed in a 5% CO2 incubator for 24 h to complete the reoxygenation process. 20 μL of MTT solution (5 mg / mL) was added to each well 4 h before the end of incubation. After incubation, the supernatant in each well was discarded, 150 μL of DMSO was added to each well, and the cells were shaken on a cell shaker for 10 min. After the crystalline substance was completely dissolved, the OD 570 .

[0128] (5) Experimental results

[0129] Table 3 Protective effect of compounds on OGD / R model-mediated rat neuron injury

[0130]

[0131]

[0132] Note: Compared with the OGD / R group, * P < 0.05, ** P < 0.01, compared with the equal molar concentration of butylphthalide group, # P < 0.05, ## P < 0.01.

[0133] As can be seen from Table 3, the compounds of the present application exhibit neuron injury protection activity to varying degrees. Among them, compared with the OGD / R model group, the positive drug butylphthalide and compounds 5c, 5d and 5j at various concentrations can significantly improve the cell survival rate; compared with equal concentrations of butylphthalide, compounds 5c, 5d and 5j at various concentrations have no significant difference.

[0134] Three, rat acute focal cerebral ischemia-reperfusion injury protection experiment

[0135] (1) Experimental grouping

[0136] The rats were randomly divided into 7 groups, 8 rats in each group, namely, a sham operation group, a model group, a compound 5b low-dose group (4 mg / kg), a 5b high-dose group (20 mg / kg), a 5j low-dose group (4 mg / kg), a 5j high-dose group (20 mg / kg) and a positive control butylphthalide group (20 mg / kg).

[0137] (2) Drug preparation

[0138] Dilantin and compound 5b, 5j were dissolved in 5% DMSO + 30% PEG400 + 65% medical sodium bicarbonate (25 mL / 1.25 g) to prepare a solution of dilantin with a concentration of 10 mg / mL, and a solution of compound 5b, 5j with a concentration of 2 mg / mL and 10 mg / mL.

[0139] (3) Modeling method

[0140] The middle cerebral artery occlusion (MCAO) reperfusion model was used to induce cerebral ischemic injury. The rats were anesthetized with 2% chloral hydrate (0.2 mL / 10 g, i.p.), the neck muscle tissue was separated, the right common carotid artery (CCA) was exposed and carefully isolated; the accompanying vagus nerve was stripped, the external carotid artery branch (ECA) was ligated and cut off; the internal carotid artery (ICA) was followed forward, and the sphenopalatine artery was separated and ligated near the skull base. The proximal end of the CCA was ligated with surgical thread; the distal end of the ligation thread was cut open with ophthalmic scissors, and the nylon thread (diameter: 0.26 mm) was inserted along the small opening, and when a slight resistance was felt after inserting about 20 mm, it was indicated that the front end of the thread plug had reached the anterior cerebral artery. The success of modeling was determined by Doppler blood flow detector. At this point, the blood supply of the middle cerebral artery (MCA) including the carotid artery and the blood supply from the anterior communicating branch of the circle of Willis had been blocked. The depth of the inserted thread was determined according to the marker. The extravascular part of the thread was ligated and fixed to prevent the thread plug from slipping. After 90 min of right cerebral ischemia, the nylon wire in the intravascular lumen of the internal carotid artery was carefully pulled out, and the internal carotid artery was reperfused by ligation of the broken end. The skin was sutured, and the rats were carefully fed. The same surgical procedure was performed on the sham-operated rats, but the middle cerebral artery was not blocked. 10 min later, the neurological deficit score was performed, and those with obvious neurological deficit were considered as successful modeling. The body temperature of the animals was kept constant at 37±0.5°C during the operation.

[0141] (4) Dosing regimen

[0142] Three days before modeling in rats, the drug was administered once a day through the tail vein. The sham-operated group and the model group were given the same amount of solvent. Two hours after the third administration, the operation to make the ischemic model was started, and after 90 min of ischemia in rats, the nylon wire in the intravascular lumen of the internal carotid artery was carefully pulled out, and the internal carotid artery was reperfused by ligation of the broken end. 24 h after the third administration, the compound group and the positive control (dilantin) group were administered once again through the tail vein, and the sham-operated group and the model group were injected with the same amount of solvent. The volume of administration was 2 mL / kg of body weight, and a total of 4 administrations were performed.

[0143] (5) Detection index

[0144] Neurological deficit score:

[0145] The motor function of the rats was evaluated by Zea-Longa method 24 h after reperfusion, and the evaluation criteria were as follows: the higher the score, the more severe the nerve injury.

[0146] Evaluation criteria:

[0147] 0 points: normal, no nerve function damage; 1 point: incomplete extension of the left forelimb, slight damage to nerve function; 2 points: the rat walked to the paralyzed side, moderate damage to nerve function; 3 points: the rat walked to the paralyzed side, severe damage to nerve function; 4 points: the rat could not walk at all, and consciousness was impaired.

[0148] (6) Experimental method

[0149] The TTC method was used to evaluate the cerebral infarction volume. After 24 h of reperfusion, the rats were anesthetized with 3.5 mL / kg of 10% chloral hydrate and the brain was removed, placed in a-20℃ refrigerator for 30 min, and then removed. Five coronal brain sections with a thickness of about 2 mm were cut from the frontal pole of the forebrain. The brain slices were placed in a 2% TTC solution (pH=7.4) and incubated at 37℃ for about 30 min in the dark. The solution was discarded, and 4% formaldehyde solution was added for 30 min. The brain slices were observed and photographed. Normal brain tissue was bright red, and infarcted brain tissue was pale. After washing with normal saline, the brain slices were quickly arranged in order from front to back, the surface residual water marks were absorbed, and the photographs were taken. ImageJ image analysis software was used to analyze the photographs, and the white ischemic area and total area were circled. The percentage of cerebral infarction area was calculated using the following formula: infarction rate%=ischemic area / total area×100%. The experimental results are shown in Table 4.

[0150] Table 4. Effect of MCAO reperfusion on focal cerebral ischemia neurological behavior and cerebral infarction rate (x±s, n=8)

[0151]

[0152] * P<0.05, ** P<0.01 vs model control group; # P<0.05, ## P<0.01 vs butylphthalide group

[0153] According to the results shown in Table 4: 24h after MCAO reperfusion, compared with the sham operation group, the model control group rats had obvious changes in neurological behavior, and the pale infarction area on the surgical side was very obvious, and the infarction area was large, which indicated that the modeling was successful. After 3 days of prophylactic administration, compared with the model control group, the butylphthalide 20mg / kg dose group, the 5b low high dose group, and the 5j high dose group can significantly improve the animal neurological score and reduce the cerebral infarction rate (P<0.01, P<0.05). Compared with the butylphthalide group, there is no significant difference in the influence of the 5b and 5j dose groups on the rat neurological score and cerebral infarction rate.

[0154] In summary, the compound in the application has significant anti-platelet aggregation activity and neuroprotective activity, showing good research value and pharmaceutical prospects.

Claims

1. The compound shown in formula (II) Or its cis-trans isomers, deuterated markers, and pharmaceutically acceptable salts, wherein R1 is selected from hydrogen, C1-C 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Alkoxy groups, halogens; R2 is selected from hydrogen or C1-C6 alkyl groups; R3 is independently selected from hydrogen, C1-C 20 Alkoxy; m is selected from 0 or 1; n is an integer between 0 and 4; p is selected from 0, 1, 2, 3 or 4; And it does not contain the following compounds: 4-(3-(2,3-dihydroindol-1-yl)propoxy)-benzoic acid; 4-(2-(2,3-dihydroindol-1-yl)ethoxy)-benzoic acid; 4-(2-(2,3-dihydroindol-1-yl)ethoxy)-methyl benzoate; Methyl 4-(2-(5-bromo-2,3-dihydroindol-1-yl)ethoxy)-benzoate.

2. The compound according to claim 1, or its cis-trans isomers, deuterated labels, and pharmaceutically acceptable salts, wherein... R1 is selected from hydrogen or methoxy groups; R2 is selected from hydrogen, methyl, or ethyl; R3 is selected from hydrogen and methoxy groups; n and m are each independently selected from 0 or 1; p is selected from 0, 1, or 2.

3. The compound according to any one of claims 1-2, wherein it is a compound of formula (Ⅲ): Or its cis-trans isomers, deuterated markers, and pharmaceutically acceptable salts, wherein, R1, R2, R3, n, m, p are defined as in any one of claims 1-2.

4. Compounds, selected from: 4-(3-(2,3-dihydroindol-1-yl)propoxy)-3-methoxybenzoic acid; (E)-3-(4-(3-(2,3-dihydroindol-1-yl)propoxy)-3-methoxyphenyl)acrylic acid; (E)-3-(4-(3-(2,3-dihydroindol-1-yl)propoxy)phenyl)acrylic acid; (E)-3-(4-(2-(2,3-dihydroindol-1-yl)ethoxy)-3-methoxyphenyl)acrylic acid; (E)-3-(3-methoxy-4-(2-(5-methoxy-2,3-dihydroindol-1-yl)ethoxy)phenyl)acrylic acid; 4-(3-(2,3-dihydroindol-1-yl)propoxy)-3,5-dimethoxybenzoic acid; (E)-3-(3-methoxy-4-(3-(5-methoxy-2,3-dihydroindol-1-yl)propoxy)phenyl)acrylic acid; 3-Methoxy-4-(3-(5-methoxy-2,3-dihydroindol-1-yl)propoxy)benzoic acid; (E)-3-(4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl)acrylic acid; Or its deuterium-labeled form and pharmaceutically acceptable salts.

5. A pharmaceutical composition comprising the compound or its cis-trans isomer according to any one of claims 1-4, a deuterium label, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

6. Use of the compound or its cis-trans isomer, deuterium label, pharmaceutically acceptable salt, or pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for antiplatelet aggregation.

7. Use of the compound or its cis-trans isomer, deuterium label, pharmaceutically acceptable salt, or pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for the prevention and / or treatment of neuropathic diseases.

8. The use according to claim 7, wherein the neurological injury-related disease is selected from amyotrophic lateral sclerosis, epilepsy, Huntington's disease, Alzheimer's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, primary spinal lateral sclerosis peripheral neuropathy, and diabetic neuropathy.

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