WO2022100487A1 - 氨基康普立停衍生物及其应用 - Google Patents

氨基康普立停衍生物及其应用 Download PDF

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WO2022100487A1
WO2022100487A1 PCT/CN2021/128275 CN2021128275W WO2022100487A1 WO 2022100487 A1 WO2022100487 A1 WO 2022100487A1 CN 2021128275 W CN2021128275 W CN 2021128275W WO 2022100487 A1 WO2022100487 A1 WO 2022100487A1
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pharmaceutically acceptable
acceptable salt
trimethoxyphenyl
amino
hydrate
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PCT/CN2021/128275
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English (en)
French (fr)
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王建平
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义乌市华耀医药科技有限公司
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Priority to KR1020237012257A priority Critical patent/KR20230088358A/ko
Priority to AU2021378005A priority patent/AU2021378005A1/en
Priority to EP21891014.9A priority patent/EP4245750A1/en
Priority to CA3196777A priority patent/CA3196777A1/en
Priority to JP2023522350A priority patent/JP2023545151A/ja
Publication of WO2022100487A1 publication Critical patent/WO2022100487A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Definitions

  • the invention belongs to the field of synthesis and preparation of pharmaceutical compounds, in particular to the synthesis and preparation of anti-cancer pharmaceutical compounds, and more particularly to aminocompridine derivatives and a synthesis method and application thereof.
  • Combretastatins series compounds were originally extracted and isolated from the trunk of Combretumcaffrum in South Africa, and the series of compounds have a cis-1,2-stilbene structure.
  • CombretastatinA-4 namely CA-4 (cis-1-(3,4,5-trimethoxy)phenyl-2-(3'-hydroxy-4'-methoxy)phenylethylene) has the most Strong inhibition of microtubule polymerization.
  • T.Hatanaka et al. of Ajinomoto Co., Ltd. of Japan discovered that the anticancer activity was greatly improved by transforming the hydroxyl group at the 3' position of CA-4 into an amino group.
  • the structural formula of aminocomprolizine was further modified, so as to reduce the molecular toxicity, improve the tolerance, and ensure the efficacy of the drug under the premise of meeting the water solubility requirements of different preparations, especially the water solubility requirements of oral preparations. , is a key problem and a technical problem that needs to be solved urgently for those skilled in the art, especially in the research field of comprolizumab.
  • the technical problem to be solved by the present invention is how to improve the water solubility of aminocomprolizine, and at the same time ensure better clinically acceptable drug toxicity and tolerance.
  • the present invention provides the compound represented by the general formula (I), its pharmaceutically acceptable salt, its hydrate, the hydrate of its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt
  • Solvates of acceptable salts, as well as isomers thereof, of the general formula (I) are as follows:
  • R 1 is selected from C1-C3 alkyl or C1-C3 haloalkyl
  • R 2 and R 3 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alcohol.
  • the R 1 is selected from methyl, ethyl, difluoromethyl or trifluoroethyl.
  • the R 2 and R 3 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, propenyl, propyne base.
  • both R 2 and R 3 are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, propenyl or propynyl.
  • the present invention also discloses that the compound is preferably, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl) )amino)propionamide)-4-ethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl) (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-) Butyl)amino)propionamide)-4-ethoxyphenyl)ethylene, or (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2) -n-Butyl)amino)propionamide)-4-methoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis( 2-Ethyl)amino)propionamide)-4-ethoxypheny
  • the pharmaceutically acceptable salts mentioned in the present invention refer to the salts formed by one or more basic salt-forming groups and an acid.
  • the acid may be an organic acid or an inorganic acid.
  • the more preferred scheme is with hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, trifluoroacetic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, oxalic acid, amino acid, benzoic acid, Salicylic acid, 4-aminosalicylic acid, mandelic acid, cinnamic acid, niacin, isonicotinic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluene
  • solvates mentioned in the present invention include organic solvates and inorganic solvates.
  • the present invention includes different physical forms such as solvates, hydrates and unsolvates or unhydrates of the compounds represented by the general formula (I) and their pharmaceutically acceptable salts.
  • Isomers can be in the form of mixtures or in pure forms.
  • the isomers mentioned in the present invention include both the stereoisomers in the form of mixtures and the stereoisomers in pure forms, that is, they contain all possible stereoisomers. structures and mixtures thereof.
  • the isomer here refers to an optical isomer with a specific activity, usually a separable optical isomer with a racemic form.
  • reaction equation is as follows:
  • VI is obtained by brominating the compound, reacting with triphenylphosphine, and then obtaining the cis compound V through the Wittig reaction.
  • Dibromodioctyl bipyridine and metal samarium powder are used as reducing agents to reduce the nitro group in compound V to amino group to obtain aminocomprolizine A-4.
  • aminocompridin A-4 as a raw material, under the catalysis of DMTMM, 2-bromopropionic acid was added to obtain compound III.
  • Compound II is obtained by reacting compound III with an amine compound at high temperature.
  • the compound II is further salted with an acid to form a pharmaceutically acceptable salt product.
  • the separation of optical isomers is also included, and the optical isomers of compound II are separated by physical methods, or separated in the salt-forming step.
  • physical methods reference may be made to the separation methods of optical isomers in the prior art, such as fractional crystallization, separation of diastereomeric derivatives, or separation by chiral chromatographic columns.
  • resolution in the salt-forming step reference can be made to the existing salt-forming resolution methods, for example, the use of an optically active acid to form a salt, followed by crystallization, to obtain the individual optical isomers from the racemate.
  • the present invention also provides the compound represented by the general formula (I), its pharmaceutically acceptable salt, its hydrate or its pharmaceutically acceptable salt hydrate, and its solvate or its pharmaceutically acceptable salt Solvates of salts, and pharmaceuticals or pharmaceutical compositions prepared from isomers thereof.
  • the medicament or pharmaceutical composition is in the form of topical, enteral or parenteral administration.
  • the term of preparations When it is prepared in the form of preparations, it can be inorganic or organic, and it can be either solid or liquid.
  • it when used for oral administration, it can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, and can also be prepared into common liquid preparations, such as oral liquid solvents, oral suspensions, syrups, etc. .
  • isotonic aqueous solutions or emulsions are preferred, such as in the case of lyophilized compositions consisting only of the active ingredient and a carrier, such solutions can be used before preparation.
  • These pharmaceutical compositions may be sterile, or contain excipients, or solubilizers, osmotic pressure-adjusting salts.
  • the present invention discloses the compound represented by the general formula (I), its pharmaceutically acceptable salt, its hydrate or its pharmaceutically acceptable salt hydrate, and its solvate or its pharmaceutically acceptable salt
  • the solvates of the salts, and their isomers are prepared into tablets or capsules.
  • tablets or capsules When tablets or capsules are prepared, such tablets or capsules contain the active ingredient together with a diluent (eg lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol), lubricant (eg talc, stearate), polyethylene glycol.
  • a diluent eg lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol
  • lubricant eg talc, stearate
  • polyethylene glycol e.g lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol
  • lubricant eg talc, stearate
  • polyethylene glycol e.glycerol
  • Tablets contain binders, starch, gelatin, methylcellulose, carboxymethylcellulose and polyvinylpyrrolidone, and if necessary, dis
  • the present invention also discloses the compound represented by the general formula (I), its pharmaceutically acceptable salts, its hydrates or the hydrates of its pharmaceutically acceptable salts, and its solvates or its pharmaceutically acceptable salts.
  • Diseases that have been proven to be caused by abnormal new blood vessels include lung cancer, small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophagus cancer, breast cancer, kidney cancer, bile duct cancer, prostate cancer, testicular cancer, colon cancer, Bladder cancer, cervical cancer, bronchial cancer, melanoma, adenocarcinoma, sweat gland carcinoma, papillary carcinoma, papillary adenocarcinoma, squamous cell carcinoma, basal cell carcinoma, cystic adenocarcinoma, glial cell carcinoma, astrocytoma , neuroblastoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, oligodendroglioma, meningioma, neurofibroma, fibrosarcoma, Fibrocytoma, Fibromatosis, Myxosarcoma,
  • the present invention also discloses the compound represented by the general formula (I), its pharmaceutically acceptable salt, its hydrate or the hydrate of its pharmaceutically acceptable salt, and its solvate or its pharmaceutically acceptable salt.
  • alkyl refers to a straight-chain or branched unsubstituted hydrocarbon group having 1-20 carbon atoms, preferably 1-6 carbon atoms, especially methyl, ethyl, propyl (n- propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), etc.
  • alkenyl refers to an alkene having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, maleic butene, transbutene, and the like.
  • alkynyl refers to an alkyne having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, and the like.
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • hydroxyl refers to the group -OH.
  • carboxyl refers to the group -COOH.
  • amino refers to the group -NH2 .
  • nitro refers to the group -NO2 .
  • alkoxy refers to the group -OR4 , wherein R4 refers to an alkyl group.
  • cyano refers to the group -CN.
  • thiol refers to the group -SH.
  • Substituted means that the subsequently described group may be replaced by some of the usual groups (such as hydrogen, halogen, hydroxyl, amino, mercapto, nitro, cyano, aryl, heterocyclyl, heterocycloalkyl, carboxyl, amide, etc.) substitution.
  • pharmaceutically acceptable carrier includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Such media and agents are well known in the art for use with pharmaceutically active substances. Unless any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Step 2 Synthesis of (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-ethoxyphenyl)ethene
  • Step 3 Synthesis of (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-bromopropionamide)-4-ethoxyphenyl)ethene
  • Step 4 (Z)-1-(3,4,5-Trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-ethoxybenzene base) ethylene synthesis
  • the obtained white filter cake is (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propane) after freeze-drying amide)-4-ethoxyphenyl)ethylene hydrochloride.
  • Step 2 Synthesis of (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyphenyl)ethene
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-bromopropionamide)-4-ethoxyphenyl according to the method shown in Example 1 ) ethylene.
  • Step 2 (Z)-1-(3,4,5-Trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-ethoxybenzene base) ethylene synthesis
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-bromopropionamide)-4-methoxyphenyl according to the method shown in Example 3 ) ethylene.
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-trifluoroethoxyphenyl) according to the method shown in Example 1 vinyl.
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-difluoromethoxyphenyl) according to the method shown in Example 3 vinyl.
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-trifluoroethoxyphenyl) according to the method shown in Example 1 vinyl.
  • Step 1 Synthesize (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-difluoromethoxyphenyl) according to the method shown in Example 3 vinyl.
  • Step 1 According to the method shown in Example 1, (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-ethoxyphenyl)ethylene was synthesized.
  • Step 1 According to the method shown in Example 3, (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyphenyl)ethylene was synthesized.
  • Step 1 According to the method shown in Example 1, (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-ethoxyphenyl)ethylene was synthesized.
  • Step 1 According to the method shown in Example 1, (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-ethoxyphenyl)ethylene was synthesized.
  • the invention provides several drug combination formulations for diseases related to abnormal neovascularization, and the drug combinations mainly include oral preparations such as tablets and capsules.
  • the following "active compound” is the compound represented by the general formula (I) described in the present invention, its pharmaceutically acceptable salt, its hydrate or its pharmaceutically acceptable salt's hydrate, and its solvate or solvates of its pharmaceutically acceptable salts, and isomers thereof.
  • ICR mice were selected, with a body weight of 23 ⁇ 2g, clean grade, male.
  • the route of administration is by gavage (ig), which is consistent with the oral route intended for clinical use.
  • mice were randomly divided into 8 groups according to their body weight: blank control group, Example 1 group, Example 5 group, Example 11 group, Example 12 group, Example 13 group, Example 14 group and control group, respectively.
  • the reference substance group used aminocomprolidine serine amide hydrochloride as the reference substance (hereinafter referred to as the reference substance).
  • mice 48 above-mentioned mice were taken, fasted for 12 hours before the experiment, and randomly divided into groups according to body weight, 10 mice in each group. Each drug group was given 0.25ml/10g body weight of mice by intragastric administration once, and the water control group was intragastrically administered with an equal volume of distilled water. The LD 100 value (100% death), LD 0 (0 death) and the corresponding dose group distance r value were found, and the LD 50 was determined.
  • mice 160 mice were selected and randomly divided into 8 groups according to their body weight, with 20 mice in each group. After fasting for 12 hours before the experiment, each administration group was given 0.3ml/10g mouse body weight by intragastric administration once, and no death occurred after 12 hours, so the second administration was performed, and the control group was intragastrically administered with an equal volume of water . The daily dose of each group was calculated; the control group was given an equal volume of water to observe the acute toxicity test and recorded the daily body weight of the mice within 14 days. Through calculation, the oral LD 50 calculation results of each drug are shown in Table 1:
  • Example 1 hydrochloride 1200
  • Example 3 hydrochloride 1000
  • Example 4 hydrochloride 1100
  • Example 5 hydrochloride 1200
  • Example 6 hydrochloride 900
  • Example 7 hydrochloride 1200
  • Example 8 hydrochloride 1100
  • Example 9 hydrochloride 1000
  • Example 10 Hydrochloride 900
  • Example 11 Hydrochloride 1100
  • Example 12 Hydrochloride 1100
  • Example 13 Hydrochloride 1000
  • Example 14 Hydrochloride 1000 control 200
  • mice The results show that the LD50 of mice is increased by 5-6 times after the amino side chain of the compound shown in the present invention is improved, indicating that the compound shown in the present invention can significantly reduce the acute toxicity, and has good safety for clinical use. Significantly improved.
  • BALB/cA-nude nude mice 6-7 weeks, ⁇ , were purchased from Shanghai Slack Laboratory Animal Co., Ltd. Nude mice were inoculated subcutaneously with human liver cancer Bel-7402 cells, colon cancer HT-29 cells, gastric cancer SGC-7901 cells and non-small cell lung cancer A549 cells, and when the tumors grew to 100-250 mm, the animals were randomly divided into groups (d0). . The tumor volume was measured 2-3 times a week, the mice were weighed, and the data were recorded. The tumor volume (V) was calculated as:
  • T/C(%) (TT 0 )/(CC 0 ) ⁇ 100
  • T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.
  • Example 2 All tested samples were diluted with 50% PEG400 distilled water to the desired concentration. The medication was administered once a day, 50 mg/kg mice were administered by gavage, and the control substance was 50 mg/kg mice for 21 days.
  • the compounds shown in the present invention can significantly inhibit the growth of human liver cancer Bel-7402, colon cancer HT-29 cells, gastric cancer SGC-7901 cells and non-small cell lung cancer A549 cells in nude mice under the condition of oral administration. , and its inhibition rate was significantly higher than that of the reference substance.

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Abstract

本发明公开了氨基康普立停衍生物，具体是通式(I)所示的化合物，及其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体，所述的通式(I)，其中，R 1选自C1-C3烷基或C1-C3卤代烷基；R 2，R 3分别独立地选自C1-C6烷基、C1-C6卤代烷基、或者C1-C6醇基。本发明还涉及这些化合物在制备治疗由非正常新生血管引起的疾病的药物和微管蛋白聚集抑制剂中的应用。

Description

氨基康普立停衍生物及其应用 技术领域
本发明属于药物化合物的合成制备领域，特别是涉及抗癌类药物化合物的合成、制备，更为具体的说是涉及氨基康普立停衍生物及其合成方法和应用。
背景技术
Combretastatins系列化合物最初是从南非Combretumcaffrum树干中提取分离得到的，该系列化合物具有顺式1,2-二苯乙烯结构。其中CombretastatinA-4，即CA-4(顺式-1-(3,4,5-三甲氧基)苯基-2-(3’-羟基-4’-甲氧基)苯基乙烯)具有最强的抑制微管聚合作用。1997年日本味之素株式会社(AjinomotoCo.)T.Hatanaka等人发现把CA-4的3′位的羟基改造成氨基，其抗癌活性大大提高。但是，Combretastatins系列化合物的水溶性很差，特别是将CA-4的3’位改造为氨基后，其水溶性进一步降低。日本味之素株式会社将氨基CA-4用氨基酸进行了修饰，增加了其水溶性，使其成为针剂能对癌症病人使用。但是研究表明，氨基CA-4用氨基酸进行了修饰后，其分子的毒性会大大增加，人体耐受量降低，不适于临床使用。
因此，对氨基康普立停结构式进行进一步改造，从而在满足不同制剂的水溶性要求，特别是口服制剂类药物剂型的水溶性要求的前提下，降低分子毒性，提高耐受量，保证药物疗效，是本领域技术人员，特别是针对康普立停的研究领域中技术人员关注的重点问题和亟待解决的技术难题。
发明内容
本发明所要解决的技术问题是如何能够改善氨基康普立停的水溶性，并且同时保证提供较好的临床可接受的药物毒性和耐受量。
为了解决上述技术问题，本发明提供了通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体，所述的通式(I)结构式如下：
Figure PCTCN2021128275-appb-000001
其中，R 1选自C1-C3烷基或C1-C3卤代烷基；
R 2，R 3分别独立地选自C1-C6烷基、C1-C6卤代烷基、或者C1-C6醇基。
进一步优选的，所述R 1选自甲基、乙基、二氟甲基或三氟乙基。
在一个优选的技术方案中，所述R 2，R 3分别独立地选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基、丙炔基。
在一个优选的技术方案中，所述R 2，R 3均为甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基或丙炔基。
进一步优选的，本发明还公开了所述的化合物优选为，(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯，或(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5- 三甲氧基苯基)-2-((3-(2，2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。
本发明所说的药学上可接受的盐是指一个或者一个以上的碱性成盐基团与酸形成的盐。所述的酸可以为有机酸也可以为无机酸。其中较为优选的方案是与盐酸、硫酸、磷酸、乙酸、丙酸三氟乙酸、乙醇酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、草酸、氨基酸、苯甲酸、水杨酸、4-氨基水杨酸、扁桃酸肉桂酸、烟酸、异烟酸、甲磺酸、三氟甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、2-萘磺酸中的一种或者几种成盐。进一步优选的技术方案是所述的药学上可接受的盐为盐酸盐，硫酸盐，磷酸盐，柠檬酸盐或者酒石酸盐。
需要说明的是，本发明中所说的溶剂化物包括有机溶剂化物和无机溶剂化物。本发明包含通式(I)所示化合物及其药学上可接受的盐的溶剂化物、水合物以及非溶剂化物或非水合物等不同物理形式。
异构体有混合物形式或者纯形式的异构体，本发明中所说的异构体既包括混合物形式的立体异构体也包括纯形式的立体异构体，即包含有所有可能的立体异构体及其混合物。进一步优选的，这里的异构体指具有特定活性的光学异构体，通常为可分离的具有外消旋形式的光学异构体。
同时，在本发明中还进一步公开了通式(I)所示化合物的合成方法，反应方程式如下：
Figure PCTCN2021128275-appb-000002
本发明所述的合成方法通过化合物溴代、与三苯基膦反应后得到VI，再通过维蒂希反应得到顺式的化合物V。再用二溴二辛基联吡啶和金属钐粉作为还原剂将化合物V中的硝基还原成氨基，得到氨基康普立停A-4。然后以氨基康普立停A-4为原料，在DMTMM催化下接2-溴丙酸，得到化合物III。将化合物III与胺类化合物在高温下反应即得化合物II。
进一步优选的是，所述化合物II进一步与酸成盐，形成药学上可接受的盐产物。
进一步优选的是，还包括有光学异构体分离，将化合物II的光学异构体通过物理方法进行拆分，或者在成盐步骤中进行拆分。具体的物理方法可以参考现有技术中的光学异构体拆分方法，譬如对非对映异构体衍生物进行分级结晶、分离或者通过手性色谱柱进行分离。在成盐步骤中拆分可以参考现有的成盐拆分方法，譬如利用具有光学活性的酸成盐，接着通过结晶的方式，从外消旋体得到单独的光学异构体。
本发明还提供了通式(I)所示的化合物，其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体所制备得到的药物或药物组合物。
优选的，所述药物或药物组合物为局部、肠内或肠外给药剂型。
在制备成制剂形式时，可以是无机的，也可以是有机的，可以是固态的，也可以是液态的。譬如，当用于口服时，可以制备成常规的固体制剂，比如片剂、胶囊剂、丸剂、颗粒剂，也可以制备成常见的液体制剂，比如口服液溶剂、口服混悬液、糖浆剂等。又譬如，以肠胃外给药形式或者以针剂形式被适用时，优选等渗水溶液或乳液，如在仅由活性成分和一种载体组成的冻干组合物的情况下，此类溶液可以在使用前制备。这些药物组合物可以式无菌的，或包含赋形剂的，或加溶剂、调节渗透压的盐。
优选的，本发明公开通式(I)所示的化合物，其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体所制备得到的片剂或叫胶囊剂。
当制备片剂或者胶囊剂时，这种片剂或胶囊包含活性成分和稀释剂(如乳糖、葡萄糖、蔗糖、甘露醇糖、山梨醇、纤维素、丙三醇)、润滑剂(如滑石、硬脂酸盐)，聚乙二醇。片剂包含粘合剂、淀粉、明胶、甲基纤维素、羧甲基纤维素和聚乙烯吡咯烷酮，必要时还可以包含粉碎剂(如淀粉、琼脂、藻酸及其盐)，泡腾混合物或吸附剂、染料、调味剂、增填剂。
进一步的，在本发明中还公开了通式(I)所示的化合物，其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体在制备用于治疗由非正常新生血管引起的疾病的药物中的应用。
目前已经证实的由非正常新生血管引起的疾病包括肺癌、小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、肾癌、胆管癌、前列腺癌、睾丸癌、结肠癌、膀胱癌、子宫颈癌、支气管癌、黑色素瘤、腺癌、汗腺癌、乳头状癌、乳头状腺癌、鳞状细胞癌、基底细胞癌、囊性腺癌、胶质细胞癌、星形细胞瘤、成神经细胞瘤、成神经细胞管瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、 少突神经胶质瘤、脑膜瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、粘液肉瘤、粘液囊瘤、脂肪瘤、脂肪腺瘤、软骨肉瘤、软骨癌、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛血管瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、破骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、股囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管瘤、血管肉瘤、淋巴管肉瘤、淋巴管瘤、淋巴瘤、内皮瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、横纹肌瘤、横纹肌肉瘤、急性淋巴性白血病、急性骨髓性白血病、慢性白血病、红细胞增多症、多发性骨髓瘤在内的各种肿瘤，风湿性关节炎、糖尿病视网膜病、早熟视网膜病、视网膜静脉闭塞、牛皮癣、红斑痤疮、卡波济肉瘤、特异性反应性角膜炎、流行性角膜结膜炎、新生血管性青光眼、细菌性溃疡、真菌性溃疡、单纯性疱疹感染、带状疱疹感染、原生动物感染、分枝杆菌感染、多动脉炎、肉样瘤、巩膜炎、潮红、口干眼燥、关节炎综合症、全身性红斑狼疮、艾滋病综合症、梅毒等。
同时，本发明还公开了通式(I)所示的化合物，其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体在制备微管蛋白聚集抑制剂中的应用。
具体实施方式
下面将详细描述本发明的示例性实施方案。这些实施方案仅为说明目的，并不旨在限制本发明的范围。
以下是本说明书中使用的术语的定义。
除非另有说明，本专利就基团或术语而言提供的初始定义适用于在说明书通篇中的所述基团或者术语，不论是单独使用还是作为另一基团部分使用。
术语“烷基”是指直链的或支链的未取代的烃基，其具有1-20个碳原子，优选的是1-6个碳原子，尤其指甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)等。
术语“烯基”是指具有一个或多个碳碳双键的烯烃，如乙烯基、丙烯基、1，3-丁二烯、顺丁烯、反丁烯等。
术语“炔基”是指具有一个或多个碳碳三键的炔烃，如乙炔基、丙炔基等。
术语“卤素”或“卤代”是指氟、氯、溴、碘。
术语羟基是指基团-OH。
术语羧基是指基团-COOH。
术语氨基是指基团-NH 2。
术语硝基是指基团-NO 2。
术语烷氧基是指基团-OR 4,其中R 4指烷基。
术语氨甲酰基是指基团R 5C(＝O)NH 2,其中R 5指烷基。
术语氰基是指基团-CN。
术语酰胺基是指基团-C(＝O)NH-。
术语烷氧羰基是指基团-C(＝O)OR 6,其中R 6指烷基。
术语酰氧基是指基团-OC(＝O)R7,其中R 7指烷基。
术语巯基是指基团-SH。
“取代的”意味着随后描述的基团可以被一些常见的基团(如氢、卤素、羟基、氨基、巯基、硝基、氰基、芳基、杂环基、杂环烷基、羧基、酰胺基等)取代。
“可选的”意味着随后描述的事件或情况可以发生或者不发生，所描述的包括其中所述事件或者情况发生的例子和其中不发生的例子。
本文所用的“药学可接受的载体”包括全部的溶剂、分散介质、包衣、抗细菌和抗真菌药剂、等渗和吸收延迟剂等。这样的介质和药剂用于药学活性物质在本领域是众所周知的。除非任何常规介质或者药剂与活性成分不相容，其在治疗组合物中的应用可预期的。补充的活性成分也可并入组合物中。
实施例1
(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
Figure PCTCN2021128275-appb-000003
步骤1：溴化三甲氧基苄基三苯基膦的合成
将3,4,5-三甲氧基苄醇320g溶于2L甲苯，搅拌溶解后降温到-5到0℃，恒压滴液漏斗滴加100ml溴化磷，保持反应温度-5到0℃。滴加完毕后，继续低温 反应2h，再恢复室温，反应过夜。
加纯化水1.4L淬灭反应，搅拌30min，静置分液。取上层有机相用饱和碳酸氢钠溶液洗涤pH值至7.5-8，加无水硫酸镁干燥并过滤，得到三甲氧基苄溴的甲苯溶液。
在此溶液中加入三苯基磷0.56kg，搅拌48h以上，有固体析出，过滤即得粗产物。再用无水乙醇重结晶。
步骤2：(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯的合成
在反应釜中，通入氩气保护，将溴化三甲氧基苯基亚甲基三苯膦15g溶于300ml无水THF，冷却至-15℃左右，滴入1.6mol/L的正丁基锂环己烷溶液22ml，反应1h。然后将5.7g 3-硝基-4-乙氧基苯甲醛的24mlTHF溶液缓慢滴加入反应液。反应温度逐渐升至室温，搅拌过夜，TLC点板跟踪。反应结束后将反应降温至-5℃，加入饱和食盐水淬灭反应。分液，将有机层浓缩干，硅胶过柱(正己烷：乙酸乙酯＝4：1)分离得到6.5g浅黄色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-乙氧基苯基)乙烯，产率50％到60％。
在干燥的1L四颈瓶中通氩气保护，加入700ml无水异丙醇，后小心加入二溴二锌基联吡啶10g和金属钐粉24g，最后加入(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-乙氧基苯基)乙烯10g，搅拌加热回流，TLC点板跟踪反应直至反应结束。反应结束后，抽滤并将滤液浓缩，硅胶柱过柱(石油醚：乙酸乙酯＝4：1)。收率30％到40％。
步骤3：(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯的合成
将10g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯溶于无水乙醇，加入20g DMTMM，溶清后再加入5.58g溴丙酸。室温反应，TLC点板跟踪。反应结束后迅速低温浓缩干，加乙酸乙酯溶解并用水洗涤。洗涤后合并有机相，浓缩干后用乙酸乙酯和石油醚＝1：4重结晶，得到白色或者米黄色固体，收率60％到70％。
步骤4：(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中，加入0.53g二丙胺和2ml三乙胺，升温至60℃搅拌反应。TLC点板跟踪。反应结束后，浓缩干，乙酸乙酯：石油醚＝1：6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯，收率80％左右。MS(m/Z)＝484.30。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.18(q,2H,-CH 2)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.43(m,4H,-CH 2-)；1.33(t,3H,-CH 3)；0.96(t,6H,-CH 3)。
实施例2
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯盐酸盐的制备
将1g(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯溶于10ml甲醇，加入0.2ml盐酸，加热至35℃搅拌1h。冷却后浓缩干加入10ml水搅拌10min后静置过夜。抽滤，所得白色滤饼冷冻干燥后即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯盐酸盐。
实施例3
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000004
步骤1：溴化三甲氧基苄基三苯基膦的合成
将3,4,5-三甲氧基苄醇320g溶于2L甲苯，搅拌溶解后降温到-5到0℃，恒压滴液漏斗滴加100ml溴化磷，保持反应温度-5到0℃。滴加完毕后，继续低温 反应2h，再恢复室温，反应过夜。
加纯化水1.4L淬灭反应，搅拌30min，静置分液。取上层有机相用饱和碳酸氢钠溶液洗涤pH值至7.5-8，加无水硫酸镁干燥并过滤，得到三甲氧基苄溴的甲苯溶液。
在此溶液中加入三苯基磷0.56kg，搅拌48h以上，有固体析出，过滤即得粗产物。再用无水乙醇重结晶。
步骤2：(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-甲氧基苯基)乙烯的合成
在反应釜中，通入氩气保护，将溴化三甲氧基苯基亚甲基三苯膦15g溶于300ml无水THF，冷却至-15℃左右，滴入1.6mol/L的正丁基锂环己烷溶液22ml，反应1h。然后将5.5g 3-硝基-4-甲氧基苯甲醛24mlTHF溶液缓慢滴加入反应液。搅拌过夜，反应温度逐渐升至室温，TLC点板跟踪。次日，将反应降温至-5℃，加入饱和食盐水淬灭反应。分液，将有机层浓缩干，硅胶过柱(正己烷：乙酸乙酯＝4：1)分离得到6.0g浅黄色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-甲氧基苯基)乙烯，产率50％到60％。
在干燥的1L四颈瓶中，通氩气保护，加入700ml无水异丙醇，后小心加入二溴二锌基联吡啶10g和金属钐粉24g，最后加入(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-甲氧基苯基)乙烯10g，搅拌加热回流，TLC点板跟踪反应直至反应结束。反应结束后，抽滤并将滤液浓缩，硅胶柱过柱(石油醚：乙酸乙酯＝4：1)。收率30％到40％。
步骤3.按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)＝470.28。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.86(s,3H,4-OCH 3)；3.73(s,3H,-OCH 3)；3.70(s,6H,3,5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.43(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例4
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4- 乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000005
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯。
步骤2：(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中，加入0.56g二乙胺和2ml三乙胺，升温至60℃搅拌反应。TLC点板跟踪。反应结束后，浓缩干，乙酸乙酯：石油醚＝1：6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯，收率80％左右。MS(m/Z)＝456.26。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.18(q,2H,-CH 2)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；3.68(t,2H,-CH 2N＝)；3.01(dt,4H,-NCH 2-)；2.55(t,2H,-COCH 2)；1.33(t,3H,-CH 3)；1.15(t,6H,-CH 3)。
实施例5
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000006
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3- 溴丙酰胺)-4-乙氧基苯基)乙烯。
步骤2：(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中，加入0.56g二丁胺和2ml三乙胺，升温至60℃搅拌反应。TLC点板跟踪。反应结束后，浓缩干，乙酸乙酯：石油醚＝1：6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯，收率80％左右。MS(m/Z)＝512.33。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.18(q,2H,-CH 2)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.40(m,4H,-CH 2-)；1.35(m,4H,-CH 2-)；1.33(t,3H,-CH 3)；0.96(t,6H,-CH 3)。
实施例6
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000007
步骤1：按照实施例3所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-甲氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)＝498.31。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.86(s,3H,4-OCH 3)；3.73(s,3H,-OCH 3)；3.70(s,6H,3,5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.4 0(m,4H,-CH 2-)；1.33(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例7
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000008
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-三氟乙氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯。MS(m/Z)＝538.27。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.46(d,2H,-OCH 2CF 3)；3.86(s,9H,3，4，5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.40(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例8
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000009
步骤1：按照实施例3所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-二氟甲氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2- ((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯。MS(m/Z)＝506.26。 1HNMR(ppm)δ：7.36(d,1H,-CHF 2)；7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.73(s,9H,3，4，5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.43(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例9
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000010
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-三氟乙氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯。MS(m/Z)＝566.30。 1HNMR(ppm)δ：7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.46(d,2H,-OCH 2CF 3)；3.86(s,9H,3，4，5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.40(m,4H,-CH 2-)；1.33(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例10
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000011
步骤1：按照实施例3所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-二氟甲氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯。MS(m/Z)＝534.29。 1HNMR(ppm)δ：7.36(d,1H,-CHF 2)；7.08(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.73(s,9H,3，4，5-OCH 3)；2.74(t,2H,-CH 2)；2.36(dt,4H,-NCH 2-)；2.33(t,2H,-COCH 2)；1.39(m,4H,-CH 2-)；1.33(m,4H,-CH 2-)；0.96(t,6H,-CH 3)。
实施例11
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000012
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)＝488.25。 1HNMR(ppm)δ：7.68(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.98(-OCH 2-)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；3.63(q,4H,-CH 2OH)；2.74(q,2H,-CH 2N-)；2.55(dt,4H,-NCH 2-)；2.33(q,2H,-COCH 2-)；1.33(q,3H,-CH 3)。
实施例12
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000013
步骤1：按照实施例3所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-甲氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)＝474.24。 1HNMR(ppm)δ：7.68(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；3.86(s,3H,4-OCH 3)；3.70(s,9H,3,3’，5-OCH 3)；3.63(q,4H,-CH 2OH)；2.74(q,2H,-CH 2N-)；2.55(dt,4H,-NCH 2-)；2.33(q,2H,-COCH 2-)。
实施例13
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000014
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)＝464.21。 1HNMR(ppm)δ：7.68(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；5.39(t，1H，-CHF 2)；3.98(q,2H,-OCH 2)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；2.93(m,2H,-CH 2-)；2.91(t,2H,-NCH 2-)；2.35(t,2H,-COCH 2)；1.33(t,3H,-CH 3)。
实施例14
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
Figure PCTCN2021128275-appb-000015
步骤1：按照实施例1所示的方法，合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2：按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)＝488.25。 1HNMR(ppm)δ：7.68(d,1H,2’-H)；6.92(d,1H,6’-H)；6.76(d,1H,5’-H)；6.62(s,2H,2,6’-H)；6.49(d,1H,J＝12.2Hz,1a-H)；6.43(d,1H,J＝12.2Hz,1a’-H)；4.43(t，1H，-CH-)；3.98(q,2H,-OCH 2-)；3.86(s,3H,4-OCH 3)；3.70(s,6H,3,5-OCH 3)；3.24(s,6H,-OCH 3)；2.93(t,2H,-NCH 2-)；2.85(t,2H,-CH 2-)；2.35(t,2H,-COCH 2)；1.33(t,3H,-CH 3)。
实施例15 药物制剂配方
本发明提供了几种与新生血管异常增生相关疾病的药物组合配方，其药物组合主要有片剂，胶囊等口服制剂。以下“活性化合物”即为本发明中所述的通式(I)所示化合物，其药学上可接受的盐，以及其水合物或其药学上可接受的盐的水合物，和其溶剂化物或其药学上可接受的盐的溶剂化物，以及其异构体。
Figure PCTCN2021128275-appb-000016
Figure PCTCN2021128275-appb-000017
实施例16 动物急性毒性试验
选取ICR小鼠，体重23±2g清洁级，雄性。给药途径采用灌胃(ig)给药，这与临床拟用口服途径一致。
小鼠按体重随机分为8组：分别为空白对照组、实施例1组、实施例5组、实施例11组、实施例12组、实施例13组、实施例14组及对照品组，其中对照品组采用氨基康普立停丝氨酰胺盐酸盐作为对照品(以下称对照品)。
实施例组中所用药物的制备：按照实施例2中公开的盐酸盐的方法，将实施例1、实施例3、实施例4、实施例5、实施例6、实施例7、实施例8、实施例9、实施例10、实施例11、实施例12、实施例13、实施例14中得到化合物制备成盐酸盐产物。
对照品的制备：以氨基乙氧基康普立停(即本专利实施例1步骤2所得产物)为原料，通过以下方法制备：
(1)将氨基乙氧基康普立停、Fmoc-丝氨酸以及DCC和HOBt溶于DMF中。在搅拌下，反应混合物室温反应5小时，TLC跟踪。反应完成后，冷却，加入乙酸乙酯稀释，混合均匀。过滤，经无水硫酸镁干燥，减压浓缩。然后，经快速柱层析分离得到白色泡沫状物质。
(2)取上述得到的(Z)-1-(3，4，5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)- 乙烯-Fmoc-丝氨酰胺溶于甲醇和二氯甲烷混合溶剂中。在搅拌下，加入2N氢氧化钠溶液，室温反应24小时，TLC跟踪。反应完成后，冷却，加入饱和氯化钠溶液，混合均匀。用二氯甲烷萃取3次，有机层经无水硫酸镁干燥，减压浓缩。然后，经常压柱层析分离得到无色泡沫状物质，即得。
预实验：取上述小鼠48只，实验前禁食不禁水12h，按体重随机分组，每组10只。各药物组按0.25ml/10g小鼠体重灌胃给药1次，水对照组灌胃等体积的蒸馏水。找出LD 100值(100％死亡量)、LD 0(0死亡量)和相应的剂量组间距r值，进行LD 50的测定。
正式实验：取上述小鼠160只，按体重随机分为8组,每组20只。实验前禁食不禁水12h后，各给药组按照0.3ml/10g小鼠体重灌胃给药1次，12h后无死亡情况发生，故进行第二次给药，对照组灌胃等体积水。计算各组一日内给药量；对照组灌胃等体积的水，进行急性毒性实验反应观察并记录14d内小鼠每日体重。通过计算，各药物的经口LD 50计算结果如表1所示：
表1：
药物 LD50(mg/Kg)
实施例1盐酸盐 1200
实施例3盐酸盐 1000
实施例4盐酸盐 1100
实施例5盐酸盐 1200
实施例6盐酸盐 900
实施例7盐酸盐 1200
实施例8盐酸盐 1100
实施例9盐酸盐 1000
实施例10盐酸盐 900
实施例11盐酸盐 1100
实施例12盐酸盐 1100
实施例13盐酸盐 1000
实施例14盐酸盐 1000
对照品 200
结果表明，本发明所示化合物在氨基康普立停的氨基侧链改进后，小鼠LD50提高5-6倍，表明本发明所示的化合物可以显著降低急性毒性，对于临床使用的安全性有明显提升。
实施例17 裸小鼠移植瘤的疗效实验
BALB/cA-nude裸小鼠，6-7周，♀，购自上海斯莱克实验动物有限责任公司。裸小鼠皮下分别接种人肝癌Bel-7402细胞、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞，待肿瘤生长至100-250mm 3后，将动物随机分组(d0)。每周测2－3次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：
V＝1/2×a×b 2
T/C(％)＝(T-T 0)/(C-C 0)×100
其中a、b分别表示长、宽；T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
将所试样品均用50％PEG400蒸馏水稀释成所需浓度。用药方式为每天给药1次，50mg/kg小鼠灌胃给药，对照品为50mg/kg小鼠连用21天。分别将实施例1、3、4、5、6、7、8、9、10、11、12、13、14、对照品中得到的化合物参考实施例2公开的方法制备形成对应化合物的盐酸盐作为给药药物，考察其对人肝癌Bel-7402、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞的裸小鼠移植瘤的疗效，并与对照品(制备方法同实施例16)进行比较。结果如表2所示。
表2：
Figure PCTCN2021128275-appb-000018
Figure PCTCN2021128275-appb-000019
结论：本发明所示化合物可以在灌胃给药的条件下明显抑制人肝癌Bel-7402、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞裸小鼠移植瘤的生长，且其抑制率比对照品有显著地提高。
以上所述是本发明的具体实施方式。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，这些改进和润饰也视为本发明的保护范围。

Claims (9)

  1. 通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体，所述的通式(I)结构式如下：
    Figure PCTCN2021128275-appb-100001
    其中，R 1选自C1-C3烷基或C1-C3卤代烷基；
    R 2，R 3分别独立地选自C1-C6烷基、C1-C6卤代烷基、或者C1-C6醇基。
  2. 根据权利要求1所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体，其特征是：
    所述R 1选自甲基、乙基、二氟甲基或三氟乙基；
    所述R 2，R 3分别独立地选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基、丙炔基；特别优选的是，所述R 2＝R 3，进一步优选的是R 2，R 3同时选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基或丙炔基中的一种。
  3. 根据权利要求1所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体，其特征是，所述的化合物为：
    (Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯，或(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙 烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2，2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。
  4. 根据权利要求1所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体，其特征是：所述药学上可接受的盐是指一个或者一个以上的碱性成盐基团与酸形成的盐，所述的酸为有机酸和/或无机酸。
  5. 权利要求1至4中任意一项所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体所制备得到的药物或药物组合物。
  6. 根据权利要求5所述的药物或药物组合物，其特征是，所述药物或药物组合物为局部、肠内或肠外给药剂型.
  7. 根据权利要求6所述的药物或药物组合物，其特征是，通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体所制备得到药物或药物组合物为片剂或胶囊剂。
  8. 权利要求1至4中任意一项所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可 接受的盐的溶剂化物，以及其异构体在制备用于治疗由非正常新生血管引起的疾病的药物中的应用。
  9. 权利要求1至4中任意一项所述的通式(I)所示的化合物，其药学上可接受的盐，其水合物、其药学上可接受的盐的水合物，其溶剂化物、其药学上可接受的盐的溶剂化物，以及其异构体在制备微管蛋白聚集抑制剂中的应用。
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