WO2022237798A1 - 一种苯酰胍衍生物及其制备方法和应用 - Google Patents

一种苯酰胍衍生物及其制备方法和应用 Download PDF

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WO2022237798A1
WO2022237798A1 PCT/CN2022/092035 CN2022092035W WO2022237798A1 WO 2022237798 A1 WO2022237798 A1 WO 2022237798A1 CN 2022092035 W CN2022092035 W CN 2022092035W WO 2022237798 A1 WO2022237798 A1 WO 2022237798A1
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substituted
unsubstituted
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/092035
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English (en)
French (fr)
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郝杰杰
于广利
王德
李海花
张彦
李春霞
管华诗
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青岛海洋生物医药研究院
中国海洋大学
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Priority to BR112023023493A priority Critical patent/BR112023023493A2/pt
Publication of WO2022237798A1 publication Critical patent/WO2022237798A1/zh

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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a benzoylguanidine derivative and a preparation method and application thereof.
  • Phosphodiesterases are a member of the enzyme family, and so far there are 11 PDE enzyme families (PDE1-PDE11), which differ in their substrate specificity (cAMP, cGMP, or both) and their sensitivity to other substrates. Dependence (such as calmodulin). Inhibition of different types of PDE isoenzymes leads to intracellular accumulation of cAMP and/or cGMP, which can be used to treat different inflammation-related diseases.
  • PDE4 is mainly distributed in various inflammatory cells, such as mast cells, macrophages, eosinophils, lymphocytes and epithelial cells, etc. It can increase the intracellular concentration by inhibiting the activity of the enzyme, which will help reduce the impact of inflammatory reactions on the body s damage.
  • PDE4 inhibitors have been developed into anti-inflammatory drugs, such as roflumilast, which is mainly used for the treatment of lung inflammation, especially asthma and chronic obstructive pulmonary disease; Difamilast is used for the treatment of atopic dermatitis; Prester is used in the treatment of psoriatic arthritis.
  • TNF- ⁇ tumor necrosis factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • TNF- ⁇ promotes inflammation and catabolism
  • TNF- ⁇ plays a key role in a variety of diseases such as airway inflammation, arthritic inflammation, endotoxic shock, tissue rejection, AIDS and various other immune diseases. Therefore, PDE4 inhibitors are also suitable for treating diseases related to TNF- ⁇ .
  • Obstructive pulmonary disease is a collective term for a group of chronic airflow obstructive diseases that combine the different syndromes of chronic bronchitis with symptoms of productive cough and progressive and irreversible lung function deterioration. The course of the disease is episodic and often complicated by bacterial infection.
  • Western medicines for COPD mainly include bronchodilators including theophylline, ⁇ 2 agonists, and anticholinergic drugs, combined with symptomatic treatment such as oxygen therapy, antibiotics, hormones, and assisted ventilation.
  • symptomatic treatment such as oxygen therapy, antibiotics, hormones, and assisted ventilation.
  • long-term use of antibiotics is prone to drug resistance and side effects, and patients with repeated infections often choose high-grade antibiotics, which are expensive and difficult for patients to bear; hormones have strong side effects.
  • New therapeutic approaches that attack inflammatory mediators, proteases or adhesion molecules could be very promising.
  • a chronic inflammation dominated by neutrophils was found in the bronchi, independent of bacterial infection concurrent with the disease.
  • mediators and enzymes released by neutrophils are responsible for the observed structural changes (emphysema) in the airways. Therefore, inhibition of neutrophil activity is a reasonable starting point to prevent or delay the progression of COPD (deterioration of lung function parameters).
  • An important stimulus for activating granulocytes is the pro-inflammatory cytokine TNF- ⁇ . It is currently known that TNF- ⁇ stimulates neutrophils to form oxygen free radicals.
  • PDE4 inhibitors are very effective in inhibiting the release of TNF- ⁇ from a wide variety of cells, and thus the activity of neutrophils.
  • the non-specific PDE inhibitor pentoxifylline can inhibit the generation of oxygen free radicals and the ability of neutrophils to phagocytize cells.
  • asthma is also a common respiratory disease. It is a chronic airway inflammation involving a variety of cells, especially mast cells, eosinophils and T lymphocytes. It has become a major chronic disease that seriously threatens public health.
  • Western medicine mainly relies on bronchodilators or oxygen inhalation to relieve symptoms of asthma, and does not treat the cause of asthma. This way of treating the symptoms but not the root cause is likely to cause dependence and repeated attacks, and also has side effects, which will seriously affect the normal life of the patient.
  • the invention provides a new structure benzoylguanidine derivative and its preparation method and application.
  • the benzoylguanidine derivative has a novel structure, and pharmacological experiments prove that the benzoylguanidine derivative has the functions of inhibiting the activity of phosphodiesterase and protecting nerve cells, cardiomyocytes and vascular endothelial cells.
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound has the following structure:
  • A is O or NH
  • B is a connecting group, which is a straight chain or a branched group with a length of 1-8 atoms;
  • E is a substituted or unsubstituted 3-10 membered monocyclic or bicyclic alkyl group, a substituted or unsubstituted 3-10 membered monocyclic or bicyclic heterocyclic group, a substituted or unsubstituted 3-10 membered aryl group, or a substituted or Unsubstituted 3-10 membered heteroaryl;
  • F is not present; or, straight chain or branched C 1 -C 6 alkylene, which may be mixed with O, NR 5 or S atoms;
  • R 1 is H, substituted or unsubstituted C 1 -C 6 alkyl; substituted or unsubstituted C 1 -C 6 carbonyl;
  • R 2 , R 3 , R 4 and R 5 are each independently H, deuterium, halogen, hydroxyl, amino, carboxyl, amido, ester, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylcarboxy, substituted or unsubstituted alkane Ester group, substituted or unsubstituted alkyl-OH, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl-NH 2 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl base;
  • substitution refers to deuterium, halogen, hydroxyl, amino, carboxyl, amido, ester, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylcarboxy, substituted or unsubstituted alkyl ester, substituted or unsubstituted alkyl -OH, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl-NH 2 , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, substituted.
  • n is an integer of 1-8, preferably 2, 3, 4, 5, 6, 7.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is characterized in that: said F is absent or -(CH 2 )m-, wherein m is an integer of 0-6, preferably 0, 1, 2, 3, 4 or 5.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is characterized in that: said E is a substituted or unsubstituted 3-10 membered monocyclic or bicyclic alkyl group.
  • the above-mentioned compound or its pharmaceutically acceptable salt is characterized in that: said E is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or a substituted or Unsubstituted 3-8 membered heterocyclic group having 1-3 heteroatoms selected from N, O and S.
  • R 1 is a substituted or unsubstituted C 1 -C 6 alkyl; preferably C substituted by 1, 2 or 3 halogens 1 -C 6 alkyl; more preferred halogen is F, Cl, Br, and/or I.
  • the present invention also provides a preparation method of the above compound or a pharmaceutically acceptable salt thereof, characterized in that the preparation method comprises the following steps:
  • the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, characterized in that it is used as a phosphodiesterase PDEs and/or TNF- ⁇ inhibitor; for the prevention and/or treatment of inflammatory diseases or Allergic diseases; inhibiting the activity of phosphodiesterase; inhibiting the release of TNF- ⁇ ; inhibiting neutrophil increase or eosinophilia; reducing the symptoms of inflammatory diseases or allergic diseases; prevention and/or treatment of TNF- ⁇ Pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis, sepsis, gastritis, immune inflammation, allergic inflammation, eczema, Dermatitis, asthma, pulmonary infiltrates, ulcerative conjunctivitis; prevention and/or treatment of diseases of the nervous system or cardiovascular system; inhibition of A ⁇ aggregates and/or CoCl2 - induced damage to nerve cells and/or cardiomyocytes; reversal of oxidative hypodensity Lipoprotein ox
  • the present invention also provides the pharmaceutical use (use for preparing medicine) of the above-mentioned compound or a pharmaceutically acceptable salt thereof for preventing and/or treating the above-mentioned use. Also provided is the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof for preparing a reagent, which can inhibit phosphodiesterase PDEs and/or TNF- ⁇ , and inhibit neutropenia or eosinophilia.
  • the present invention also provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7; optionally also comprising a pharmaceutically acceptable carrier; preferably, the drug
  • the composition is tablet, oral liquid, aerosol, pill, capsule, granule, ointment, drop pill, syrup, powder, electuary, tincture, powder injection or injection.
  • the present invention provides a new structure of benzoylguanidine derivatives, said new structure of benzoylguanidine derivatives including compounds ML-1, ML-2, ML-3, ML-4, ML-5, ML-6, ML -7 and ML-8, their structural formulas are as follows:
  • the present invention also provides the preparation method of described new structure benzoylguanidine derivative, it is characterized in that, described preparation method comprises the following steps:
  • the compound also includes its pharmaceutically acceptable salt, which can be obtained by neutralizing a base with an inorganic acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid;
  • the organic acid includes carboxylic acid, thioacid, sulfonic acid, acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, malonic acid, Toric acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid , 3-aminosalicylic acid, ascorbic acid, pamoic acid, niacin, isonicotinic acid, oxalic acid, amino acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethyl-1,2-disulfonic acid, benzene Sulfonic acid, 4-
  • the compound or its pharmaceutically acceptable salt also includes its D form, L form or D, L-mixture.
  • the compound or its pharmaceutically acceptable salt also includes its stereoisomers, preferably, enantiomers and diastereomers.
  • the present invention also provides the application of the benzoylguanidine derivative with the new structure in the preparation of medicines for preventing and treating inflammatory diseases or allergic diseases.
  • the compound or a pharmaceutically acceptable salt thereof can alleviate inflammatory diseases or allergic reactions by inhibiting the activity of phosphodiesterase, inhibiting the release of TNF- ⁇ , and inhibiting the increase of neutrophils or eosinophils. Symptoms of disease.
  • phosphodiesterases are PDE4, PDE2, PDE3, PDE5 and PDE10.
  • the phosphodiesterase is PDE4.
  • the inflammatory disease or allergic disease includes pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis caused by TNF- ⁇ release, eosinophilia or neutrophil increase and/or phosphodiesterase PDEs activation , sepsis, gastritis, immune inflammation, allergic inflammation, eczema, dermatitis, asthma, lung infiltration, ulcerative conjunctivitis.
  • the inflammatory diseases or allergic diseases also include inflammatory diseases related to the inhibition of TNF- ⁇ release, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, osteoporosis, sepsis, Septic shock, Gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome, transplant rejection, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus, and chronic demyelination Sheath; inflammatory diseases or allergies associated with eosinophilia including bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, gastric ulcer, gouty arthritis, eczema, allergic vasculitis, eosinophilia Cellular fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltrates with eosinophilia), urticaria, Crohn's disease, ps
  • the compound or a pharmaceutically acceptable salt thereof can also be used to treat TNF-related infections, including viral infections, malaria, leishmaniasis, fever caused by infection, muscle pain caused by infection, AIDS and cachexia .
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for preventing and treating nervous system diseases or cardiovascular system diseases.
  • the compound or a pharmaceutically acceptable salt thereof can inhibit the damage of nerve cells and/or cardiomyocytes induced by A ⁇ aggregates and/or CoCl 2 , or effectively reverse the blood vessel damage induced by oxidized low-density lipoprotein ox-LDL Endothelial cell damage, thereby achieving the effect of protecting nerve cells or cardiovascular cells.
  • the cardiovascular disease includes arteriosclerosis, heart failure, angina pectoris, and ischemic injury caused by myocardial cell or vascular endothelial cell damage;
  • the nervous system disease includes Alzheimer's disease caused by nerve cell damage , memory loss, dementia, stroke, schizophrenia, depression, anxiety, Parkinson's disease.
  • the nervous system disease or cardiovascular system disease also includes memory loss, intermittent claudication, hyperlipidemia, hyperglycemia, benign prostatic hyperplasia, frequent urination, nocturia, incontinence, pain and sexual dysfunction caused by uroliths.
  • the medicine is tablet, oral liquid, aerosol, pill, capsule, granule, ointment, drop pill, syrup, powder, electuary, tincture, powder injection or injection.
  • the medicine is administered orally, parenterally, intravenously, transdermally, locally, inhaled and intranasally.
  • the dose of the drug is a single dose administered once a day, or divided into two or more doses per day, each 0.001-500 mg.
  • the medicine also includes at least one of auxiliary agent, carrier and additive.
  • the carrier includes calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talcum powder , highly dispersed silica, silicone oil, stearic acid, gelatin, agar, vegetable or animal fats and oils, polyethylene glycol.
  • auxiliaries include sweeteners, flavoring agents, preservatives, stabilizers, wetting agents, penetrants, emulsifiers, coating agents, cosolvents, used to control osmotic pressure or used for buffering Salt, Sugar or Sugar Alcohols and/or Viscosity Regulators.
  • the additives include tartrate and citrate buffers, ethanol, and complexing agents.
  • the additive can also use liquid polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone, dextran or gelatin.
  • oily suspensions for parenteral or topical administration may contain synthetic or semi-synthetic oils of plants, including liquid fatty acid esters having 8-22 carbon atoms in the fatty acid chain, including palm Acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, eicosanoic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, bassilic acid , erucic acid or oleic acid, these fatty acids are esterified with monohydric monohydric alcohols having 1-6 carbon atoms, said alcohols include methanol, ethanol, propanol, butanol, pentanol or their isomers, ethylene glycol alcohol or glycerin; the fatty acid alcohols include Miglyole, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG-6 capric acid, cap
  • solvents such as ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, hexane Dioxyester, propylene glycol, glycerin, dipropylene glycol, tripropylene glycol, wax, methyl cellosolve, cellosolve, ester, molin, dioxane, dimethyl sulfoxide, dimethyl formamide , tetrahydrofuran, cyclohexanone.
  • alcohols including ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, hexane Dioxyester, propylene glycol, glycerin, dipropylene glycol, tripropylene glycol, wax, methyl cellosolve, cellosolve, ester, molin, dioxane, dimethyl sulfoxide, dimethyl formamide
  • cellulose ethers that can be dissolved or swelled in water and organic solvents, including hydroxypropyl methylcellulose, methylcellulose, ethylcellulose or soluble starch, carboxymethyl Sodium cellulose, polyacrylic acid, polymethacrylic acid and salts thereof, sodium pullulan hemiglycolate, alginic acid or propylene glycol alginate as sodium salt, acacia, xanthan, guar or carrageenan.
  • organic solvents including hydroxypropyl methylcellulose, methylcellulose, ethylcellulose or soluble starch, carboxymethyl Sodium cellulose, polyacrylic acid, polymethacrylic acid and salts thereof, sodium pullulan hemiglycolate, alginic acid or propylene glycol alginate as sodium salt, acacia, xanthan, guar or carrageenan.
  • glycerin As other preparation auxiliary materials, glycerin, paraffins of different viscosities, triethanolamine, collagen, allantoin, and Novantisolsaure can also be used.
  • the drug can also include surfactants, emulsifiers or wetting agents, including sodium lauryl sulfate, fatty alcohol ether sulfate, disodium N-lauryl- ⁇ -iminodipropionate, polyethylene glycol Oxygenated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate, cetyl alcohol, lecithin, glyceryl-stearate, polyoxyethylene stearate, Alkylphenol polyglycol ether, cetyltrimethylammonium amide or alkyl or dialkyl polyglycol ether orthophosphoethanolamine salt; stabilizers including montmorillonite or colloidal silicon dioxide; antioxidant Includes tocopherol or butylated hydroxyanisole; preservatives include parabens.
  • surfactants including sodium lauryl sulfate, fatty alcohol ether sulfate, disodium N-lauryl- ⁇ -iminodipropionate, poly
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of phosphodiesterase PDEs and/or TNF- ⁇ inhibitors.
  • phosphodiesterases include PDE4, PDE2, PDE3, PDE5 and PDE10.
  • the phosphodiesterase is PDE4.
  • the new structure benzoylguanidine derivatives prepared by the present invention have a novel structure, and pharmacological experiments prove that the new structure benzoylguanidine derivatives have good inhibitory effects on phosphodiesterase activity, release of TNF- ⁇ , and neutrality.
  • Leukocytosis or eosinophilia thereby reducing the symptoms of inflammatory diseases or allergies, achieving the effect of prevention and treatment of inflammatory diseases or allergies, and can also inhibit the nerve cell damage induced by A ⁇ aggregates, or inhibit the induction of CoCl 2 hypoxic injury of nerve cells or cardiomyocytes, and effectively reverse the ox-LDL damage of vascular endothelial cells, thereby increasing the vitality of nerve cells or cardiomyocytes, preventing vascular endothelial cells from being damaged by oxidized low-density lipoprotein, and achieving the protection of nerve cells or The role of cardiovascular cells.
  • the new structure benzoylguanidine derivatives of the present invention can have good therapeutic effect on various diseases, and all have good safety, and have the value of further development.
  • Stepoisomers or “optical isomers” are compounds that have identical chemical composition but differ in the arrangement of the atoms or groups in space. It includes “diastereoisomers” and “enantiomers”
  • Diastereomers are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Mixtures of diastereomers can be separated under high resolution analytical steps such as electrophoresis, crystallization using, for example, chiral HPLC columns in the presence of resolving agents or chromatography.
  • Enantiomers refer to two stereoisomers of a compound that are nonsuperimposable mirror images of each other.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur during chemical reactions or manipulations where there has been no stereoselectivity or stereospecificity.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, generally 1 to about 12 carbon atoms.
  • the term C 1 -C 6 alkyl as used herein denotes an alkyl group having 1 to about 6 carbon atoms.
  • the designated group is exemplified by (phenyl)C 0 -C 4 alkyl, in which case phenyl is obtained by a single co- The valence (C 0 ) is bonded directly or through an alkyl chain having the indicated number of carbon atoms (in this case, 1 to about 4 carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.
  • alkenyl refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain.
  • the alkenyl groups described herein typically have 2 to about 12 carbon atoms.
  • Preferred alkenyl groups are lower alkenyl groups, those having 2 to about 8 carbon atoms, such as: C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkenyl groups.
  • Examples of alkenyl groups include ethenyl, propenyl, and butenyl.
  • Cycloalkyl preferably refers to a monocyclic, bicyclic, tricyclic, bridged ring, spirocyclic cyclic alkyl group with 3-15 carbon atoms; preferably cyclopropane, cyclopentane, cyclohexane, etc. .
  • Alkoxy means an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
  • heterocyclic ring means a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring comprising 1 to about 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, or is a 7- to 11-membered saturated ring, a partially unsaturated ring, or an aromatic heterocyclic ring system and a 10- to 15-membered tricyclic ring system containing at least 1 heteroatom selected from N, O and S polycyclic ring systems And comprising up to about 4 heteroatoms independently selected from N, O and S in each ring in the polycyclic ring system.
  • a heterocyclic ring can be attached to a group where it substitutes at any heteroatom and carbon atom and results in a stable structure.
  • the heterocyclic rings described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable.
  • the nitrogen atoms in the heterocycle can be optionally quaternized.
  • the total number of heteroatoms in the heterocyclyl group is not greater than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not greater than 2, more preferably not greater than 1.
  • heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]thiophenyl (benz[b]thiophenyl), isoquinolyl, quinazolinyl, quinoxalinyl, Thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidine morpholinyl, piperazinyl, piperidinyl, pipe
  • Aryl or “heteroaryl” means a stable 5- or 6-membered monocyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon or polycyclic.
  • the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heteroaryl group is not greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not greater than one.
  • the nitrogen atoms in the heterocycle can be optionally quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups.
  • substitution may include fusion with a 5 to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S, to form, for example, [1,3]dioxin Azolo[4,5-c]pyridyl.
  • heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , and 5,6,7,8-tetrahydroisoquinoline.
  • Embodiment 1 the synthesis of benzoylguanidine derivative benzyl ester compound
  • the insoluble matter was filtered off with suction, and then dichloromethane was removed by distillation under reduced pressure.
  • the body is about 25.3g.
  • Take 4.0 mM of the precursor compound add 10 mL of a 1:1 mixed solution of dichloromethane and trifluoroacetic acid, react at room temperature for 5 h, and then determine whether the reaction is complete by TLC.
  • Embodiment 2 the synthesis of benzoylguanidine derivative benzamide compound
  • PDE4 activity was determined in enzyme preparations of rat polymorphonuclear lymphocytes (PMNL), and PDE2, PDE3, PDE5 and PDE10 activities were determined using the PDE of isolated platelets. Citrate was used to prevent the coagulation of the extracted rat blood; the platelet-rich plasma in the supernatant was separated from the red blood cells and white blood cells by centrifugation at room temperature; used in the PDE10 assay. To measure PDE2 activity, the cytoplasmic platelet fraction was purified by NaCl gradient on an anion-exchange column to obtain the PDE2 peak for the assay; after sedimentation by dextran, PMNL cells were isolated by Ficoll gradient centrifugation for the PDE4 assay .
  • the obtained supernatant contained the cytoplasmic fraction of PDE4 for the following assays of PDE4, PDE2, and PDE3 , PDE5 and PDE10 assay in enzyme raw material.
  • phosphodiesterase activity assay kit purchased from Abcam, Cat. No. ab13940, PDE Activity Assay kit, Colorimetric
  • the protease prepared by separation is enough, and the others are strictly tested according to the operation instructions: first add 20 microliters of cAMP substrate, then add 15 microliters of assay buffer, then add 10 microliters of 5' nucleosidase, mix well and then add appropriate Concentration of the test compound, then add the PDE enzyme that has been extracted and purified, incubate at 30°C for 30 minutes, and finally add Green Assay reagent to detect the decomposed phosphate ions, mix for 20 minutes to achieve uniform color, and calculate the compound by measuring OD620nm Inhibitory activity against PDE enzymes.
  • the results are shown in Table 1.
  • the IC50 values for the inhibition of PDE4 measured by the various compounds prepared in Example 1 are 10-12-10-7 M, and the selectivity to 2, 3, 5 and 10 types of PDE is 20-10000 Factor of , indicating that the novel benzoylguanidine derivatives have the effect of inhibiting the activity of PDE4 and can be used as strong inhibitors of PDE4.
  • Example 4 Novel structural benzoylguanidine derivatives inhibit TNF- ⁇ release from nasal polyp cells
  • the nasal polyp tissue was washed with RPMI 1640, and then treated with protease (2.5mg/ml), collagenase (1.0mg/ml), hyaluronidase (0.5mg/ml) and DNase (0.1mg/ml) at 37°C Lyse for 150 minutes (1 g tissue and 4 mL RPMI 1640 with enzyme).
  • the resulting mixture of cells was filtered, washed by repeated centrifugation in culture solution, passively sensitized by adding human IgE, and the cells were The suspension was diluted to a concentration of 2 million cells/mL in RPMI 1640 (supplemented with antibiotics, 10% fetal bovine serum, 2 mM glutamate and 25 mM Hepes). The suspension was distributed on 6-well cell culture plates (1 ml/well).
  • the IC 50 value of the compound prepared in Example 1 was 10 -10 -10 -4 M, indicating that the new structure of benzoylguanidine derivatives has the effect of inhibiting the release of TNF- ⁇ , and can be used as a TNF- ⁇ inhibitor. agent.
  • Sensitization on the first day Rats in the blank group were given intraperitoneal injection of 1ml of normal saline, while rats in the model group were given intraperitoneal injection of 1ml of sensitizing solution for sensitization; on the 15th day of stimulation: the two groups of rats were placed in the same size atomization box Inside, the blank group was given 6ml of normal saline for stimulation, and the model group was given 6ml of 5% grade V ovalbumin solution for stimulation, once a day, 30min each time, for 10 consecutive days. Test compounds were administered intraperitoneally or orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose 2 hours before allergen challenge.
  • Control groups are treated with vehicle depending on the form of administration of the test compound.
  • fix the limbs of the rat use 75% alcohol to disinfect the neck, fully expose the trachea, insert a tracheal intubation needle (the needle is slightly ground) near the throat, and insert the needle into a certain position, and do not exceed the bifurcation of the trachea;
  • Leukocytes are a crucial type of cells in the immune process, and cell differential counting can effectively analyze the changes in the proportion of leukocytes in alveolar lavage fluid BALF.
  • the inflammatory cells infiltrating the bronchi were mainly lymphocytes and eosinophils. Lymphocytes can expand the inflammatory response of eosinophils on the bronchial mucosa, and with the increase of eosinophils, they will increase their accumulation, activation and interaction with other inflammatory cells, inflammatory mediators and cytokines in the lung, This in turn exacerbates allergies.
  • Example 6 New structure benzoylguanidine derivatives inhibit lipopolysaccharide (LPS)-induced neutropenia
  • the inhibitory effect of the compound prepared in Example 1 on the infiltration of neutrophils in the lung was tested in male Wistar rats (200 ⁇ 20 g).
  • the animals were individually housed in an open 1 L plexiglass box attached to a head-nasal exposure device. Animals were exposed to an aerosol of lipopolysaccharide suspension (LPS 100 ⁇ g/mL dissolved in PBS solution containing 0.1% hydroxylamine) (LPS challenge) for 45 minutes. Aerosol spray of PBS solution for 45 min.
  • LPS challenge lipopolysaccharide suspension
  • a large number of neutrophils migrated into the lungs of the animals.
  • Each compound tested was administered orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose 2 hours before the LPS challenge.
  • the control group was treated with vehicle depending on the form of administration of the test article.
  • fix the limbs of the rat use 75% alcohol to disinfect the neck, fully expose the trachea, insert a tracheal intubation needle (the needle is slightly ground) near the throat, and insert the needle into a certain position, and do not exceed the bifurcation of the trachea;
  • Example 7 The protective effect of new structure benzoylguanidine derivatives on nerve cell damage induced by A ⁇ aggregates
  • the novel structural benzoylguanidine derivatives of the present invention are suitable for the treatment and prevention of diseases related to neuroprotection.
  • Example 8 Protective Effects of New Structure Benzoylguanidine Derivatives on CoCl2 - Induced Hypoxic Injury of Nerve Cells and Cardiomyocytes
  • PC12 and H9C2 cells were inoculated in MEM or DMEM complete culture medium, cultured in 96-well plate, placed in a constant temperature cell incubator and incubated for 24 hours, then added pre-dissolved injury solution containing CoCl 2 , after 2 hours, Add each compound solution to each well of each compound group, the concentration is 50 ⁇ mol/L, add the same amount of sterile water to the model group, and continue to incubate in the incubator for 48 hours. After the end, the cell viability was measured by MTT method. Three parallels were performed each time, and the experiment was repeated three times.
  • the novel structural benzoylguanidine derivatives of the present invention are suitable for the treatment and prevention of diseases related to nerve cells and cardiovascular system damage.
  • Example 9 Inhibitory Effect of New Structure Benzoylguanidine Derivatives on Vascular Endothelial Cell Injury Induced by Oxidized Low Density Lipoprotein (ox-LDL)
  • Vascular endothelial cells HUVEC were inoculated in complete MEM medium, and the group without oxidized low-density lipoprotein ox-LDL was used as a negative control to observe the protective effect of compounds on ox-LDL-induced vascular endothelial atherosclerosis.
  • inoculate HUVEC cells in MEM or DMEM complete culture medium place them in a 96-well plate for culture, put them in a constant temperature cell incubator and incubate for 24 hours, add the induction solution containing ox-LDL dissolved in advance, and then , 50 ⁇ M benzoylguanidine derivatives were added to each well, and the group without ox-LDL was used as a negative control. After the end, ELISA was used to detect the content of IL-6 inflammatory factor.
  • benzoylguanidine derivatives can effectively inhibit the increase of IL-6 in vascular endothelial cells stimulated by oxidized low-density lipoprotein ox-LDL, showing that the new structure benzoylguanidine derivatives of the present invention are suitable for preventing and treating Diseases associated with vascular endothelial cell damage.

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Abstract

本发明提供了一种苯酰胍衍生物及其制备方法和应用，所述的苯酰胍衍生物制备方法简单，具有显著抑制磷酸二酯酶PDEs活性、TNF-α的释放、中性白细胞或嗜酸性细胞增多的作用，还能够保护神经细胞、心肌细胞和血管内皮细胞，其安全性良好，因此具有重要的开发意义。

Description

一种苯酰胍衍生物及其制备方法和应用 技术领域
本发明属于医药技术领域，具体涉及一种苯酰胍衍生物及其制备方法和应用。
背景技术
磷酸二酯酶是酶家族的一员，迄今为止已知有11个PDE酶家族(PDE1-PDE11)，它们的不同在于其底物特异性(cAMP、cGMP或者二者)及其对其它底物的依赖性(例如钙调蛋白)。抑制不同类型的PDE同工酶导致cAMP和/或者cGMP在细胞内聚集，这可用于治疗不同的炎症相关的疾病。PDE4主要分布于各种炎症细胞内，肥大细胞、巨噬细胞、嗜酸粒细胞、淋巴细胞和上皮细胞等，可通过抑制酶的活性来提高细胞内浓度，将有助于减轻炎症反应对机体的伤害。在对于过敏炎症很重要的细胞中(淋巴细胞、肥大细胞、嗜酸性粒细胞、巨噬细胞)，主要的PDE同工酶也是4型。因此，用合适的抑制剂抑制PDE4视为治疗多种变态反应引起的疾病的重要开始。目前，PDE4抑制剂已被开发成抗炎的药物，如罗氟司特主要用于肺部的炎症治疗，尤其是哮喘和慢性阻塞性肺疾病；Difamilast被用于特异性皮炎的治疗；而阿普斯特被用于银屑病关节炎的治疗。
同时，PDE4抑制剂的一个重要特征是抑制肿瘤坏死因子(TNF-α)从炎性细胞中释放。TNF-α是影响多种生物过程的重要的促炎性细胞因子，其能从激活的局势细胞、激活的T淋巴细胞、肥大细胞、嗜碱性粒细胞、成纤维细胞、内皮细胞和脑中的星形细胞释放。TNF-α自身对于中性白细胞、嗜酸性细胞、成纤维细吧和内皮细胞有激活作用，进而释放出不同的组织破坏性介质。在单核细胞、巨噬细胞和T淋巴细胞中，TNF-α导致其他的促炎性细胞因子例如GM-CSF(粒细胞-巨噬细胞集落刺激因子)或白介素-8的含量增加。由于TNF-α促进炎症和分解代谢作用，TNF-α在多种疾病中起着关键作用，这些疾病有例如呼吸道炎症、关节炎症、内毒素性休克、组织排斥、AIDS和多种其它免疫疾病。因此，PDE4抑制剂也是适用于治疗与TNF-α有关的疾病。
性堵塞性肺病(COPD)是一组慢性气流阻塞性疾病的统称，其合并了慢性支气管炎的不同综合征与排痰性咳嗽以及进行性和不可逆肺功能退化的症状。该病 的病程是发作性的，并且通常并发有细菌感染。目前治疗慢阻肺的西药主要有支气管扩张剂包括茶碱类、β2激动剂和抗胆碱能药物，并配合氧疗、抗生素、激素及辅助通气等对症处理。但抗菌素长期使用易出现耐药和毒副反应，而反复感染的患者常选用高档抗菌素，其价格昂贵，病者难以承受；而激素则具有较强的副作用。攻击炎性介质、蛋白酶或粘着分子的新的治疗方法可能非常有前途。
在支气管中发现了通过嗜中性粒细胞支配的慢性炎症，其独立于与该疾病并发的细菌感染。除此之外，由嗜中性粒细胞释放的介质和酶是在呼吸道中观察到的结构性变化(肺气肿)的原因。因此，抑制嗜中性粒细胞的活动是预防或延迟COPD进行(肺功能参数退化)的合理起点。激活粒细胞的一个重要刺激是促炎性细胞因子TNF-α。目前已知TNF-α刺激嗜中性粒细胞形成氧自由基。PDE4抑制剂可非常有效地抑制多种细胞释放TNF-α，并因此抑制嗜中性粒细胞的活动。非特异性PDE抑制剂己酮可可碱能够抑制氧自由基生成以及嗜中性粒细胞噬吞细胞的能力。
此外，哮喘也是一种常见呼吸系统疾病，其是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症，已成为严重威胁公众健康的一种主要慢性疾病。目前西医治疗哮喘的方式多依靠支气管扩张药或吸氧使症状缓解，并没有针对哮喘病的发病原因进行治疗。这种治标不治本的方式容易使人产生依赖性并且反复发作，还具有副作用，会严重影响患者正常生活。
尽管已知PDE4抑制剂已经显示了其有益药理作用，但这类抑制剂存在引起腹泻、恶心等不良作用。因此，研究新型的特异性抑制剂来克服这些不良反应，就成为抑制剂药物研究的热点之一。天然中药衍生物是新药研发先导化合物发现的宝库，从中寻找具有新型抑制剂，对于研发疗效高、副作用小的抑制剂抗炎药物具有重要意义。
发明内容
本发明提供了一种新结构苯酰胍衍生物及其制备方法和应用。所述苯酰胍衍生物结构新颖，并经药理学实验证明，苯酰胍衍生物具有抑制磷酸二酯酶活性以及保护神经细胞、心肌细胞和血管内皮细胞的作用。
为实现上述发明目的，本发明的技术方案如下：
本发明提供了一种化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
Figure PCTCN2022092035-appb-000001
其中，
A为O或NH；
B为连接基团，为具有1-8个原子长度的直链或具有支链的基团；
E为取代或未取代的3-10元单环或双环烷基、取代或未取代的3-10元单环或双环杂环基、取代或未取代的3-10元芳基、或取代或未取代的3-10元杂芳基；
F为不存在；或者为，直链或具有支链的C 1-C 6亚烷基，其中可以杂有O、NR 5或S原子；
R 1为H、取代或未取代的C 1-C 6烷基；取代或未取代的C 1-C 6羰基；
R 2、R 3、R 4和R 5各自独立的为H、氘、卤素、羟基、胺基、羧基、酰胺基、酯基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的烷氧基、取代或未取代的烷基羧基、取代或未取代的烷基酯基、取代或未取代的烷基-OH、取代或未取代的烷氧基、取代或未取代的烷基-NH 2、取代或未取代的芳基、取代或未取代的杂环芳基；
所述取代是指被氘、卤素、羟基、胺基、羧基、酰胺基、酯基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的烷氧基、取代或未取代的烷基羧基、取代或未取代的烷基酯基、取代或未取代的烷基-OH、取代或未取代的烷氧基、取代或未取代的烷基-NH 2、取代或未取代的芳基、或取代或未取代的杂环芳基，所取代。
如上所述的化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
Figure PCTCN2022092035-appb-000002
如上所述的化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
Figure PCTCN2022092035-appb-000003
其中n为1-8的整数，优选的可以为2、3、4、5、6、7。
如上所述的化合物或其药学上可接受的盐，其特征在于：所述F为不存在或-(CH 2)m-，其中m为0-6的整数，优选的可以为0、1、2、3、4或5.
如上所述的化合物或其药学上可接受的盐，其特征在于：所述E为取代或未取代的3-10元单环或双环烷基。
如上所述的化合物或其药学上可接受的盐，其特征在于：所述E为取代或未取代的环丙基、环丁基、环戊基、环己基或环庚基；或者为取代或未取代的具有1-3个杂原子的3-8元杂环基，所述杂原子选自N、O和S。
如上所述的化合物或其药学上可接受的盐，其特征在于：所述R 1为取代或未取代的C 1-C 6烷基；优选的为被1、2或3个卤素取代的C 1-C 6烷基；更优选的卤素为F、Cl、Br、和/或I。
如上所述的所述化合物或其药学上可接受的盐，其特征在于为如下化合物中的一种或多种：
Figure PCTCN2022092035-appb-000004
本发明还提供了如上所述化合物或其药学上可接受的盐的制备方法，其特征在于，所述制备方法包括以下步骤：
由3-环丙甲氧基-4-二氟甲氧基苯甲酸或3-环戊烷氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，在三氟乙酸作用下脱除Boc保护基，得到化合物；
或者由3-环丙甲氧基-4-二氟甲氧基苯甲酸或3-环戊烷氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-丁胺或4-胍基-1-丙胺缩合，然后再在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基得到化合物。
本发明还提供了如上所述化合物或其药学上可接受的盐的用途，其特征在于用作磷酸二酯酶PDEs和/或TNF-α抑制剂；用于预防和/或治疗炎症性疾病或过敏性疾病；抑制磷酸二酯酶的活性；抑制TNF-α的释放；抑制中性白细胞增多或嗜酸性细胞增多；减轻炎症性疾病或过敏性疾病的症状；预防和/或治疗由TNF-α释放、嗜酸粒细胞增多或中性白细胞增多和/或磷酸二酯酶PDEs激活引起的肺纤维化、慢阻肺、关节炎、脓毒症、胃炎、免疫性炎症、过敏性炎症、湿疹、皮炎、哮喘、肺浸润、溃疡性结膜炎；预防和/或治疗神经系统疾病或心血管系统疾病；抑制Aβ聚集体和/或CoCl 2诱导的神经细胞和/或心肌细胞损伤；逆转氧化低密度 脂蛋白ox-LDL诱导的血管内皮细胞损伤；保护神经细胞或心血管细胞；优选的，所述心血管疾病包括由心肌细胞或血管内皮细胞损伤引起的动脉硬化、心力衰竭、心绞痛、缺血性损伤；优选的，所述神经系统疾病包括由神经细胞损伤引起的阿尔茨海默氏症、失忆、痴呆、中风、精神分裂症、抑郁症、焦虑症、帕金森氏病。
本发明还提供了如上所述化合物或其药学上可接受的盐的制药用途(制备药物的用途)，用于预防和/或治疗上述用途。也提供了如上所述化合物或其药学上可接受的盐的制备试剂的用途，所述试剂可以抑制磷酸二酯酶PDEs和/或TNF-α，抑制中性白细胞增多或嗜酸性细胞增多。
本发明还提供了一种药物组合物，包括权利要求1-7任一项所述化合物或其药学上可接受的盐；任选的还包括药学上可接受的载体；优选的，所述药物组合物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
本发明提供了一种新结构苯酰胍衍生物，所述新结构苯酰胍衍生物包括化合物ML-1、ML-2、ML-3、ML-4、ML-5、ML-6、ML-7和ML-8，其结构式分别如下：
Figure PCTCN2022092035-appb-000005
本发明还提供了所述的新结构苯酰胍衍生物的制备方法，其特征在于，所述 制备方法包括以下步骤：
由3-环丙甲氧基-4-二氟甲氧基苯甲酸作为起始原料，在二异丙基碳酰亚胺的作用下，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，甲醇重结晶后，在三氟乙酸作用下脱除Boc保护基，再在饱和碳酸氢钠溶解中析出固体，过滤后经乙醇重结晶得到化合物ML-5、ML-6；
或者由3-环戊烷氧基-4-烷氧基苯甲酸作为起始原料，溶于二氯甲烷后，与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，加入缩合剂反应完全后抽滤，减压蒸馏后于冰甲醇下重晶体，再在三氟乙酸作用下脱除Boc保护基，得到化合物ML-1、ML-2；
或者由3-环丙甲氧基-4-二氟甲氧基苯甲酸或者3-环戊烷氧基-4-烷氧基苯甲酸在四氢呋喃溶剂中与二氯亚砜反应得活性中间体，反应温度为20-120℃，反应时间为1-24小时；再将Boc保护的4-胍基-1-丁胺(或者4-胍基-1-丙胺)在二氯甲烷溶液中与氢氧化钠作用得到活化的氨基负离子，反应温度为0-100℃，反应时间为1-10小时，再缓慢将活性中间体加入到活化的氨基负离子中，反应时间为1-24小时，然后再在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基，所得粗品经乙酸乙酯重结晶，得到化合物ML-7、ML-8、ML-3、ML-4。
进一步的：所述化合物还包括其药学上可接受的盐，并可通过无机酸或有机酸中和碱的方法获得。
进一步的：所述无机酸包括盐酸、硫酸、磷酸或氢溴酸；所述有机酸包括羧酸、硫代酸、磺酸、乙酸、酒石酸、乳酸、丙酸、乙醇酸、丙二酸、马来酸、富马酸、鞣酸、琥珀酸、藻酸、苯甲酸、2-苯氧基苯甲酸、2一乙酰氧基苯甲酸、肉桂酸、扁桃酸、柠檬酸、苹果酸、水杨酸、3-氨基水杨酸、抗坏血酸、扑酸、烟酸、异烟酸、草酸、氨基酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙-1,2一二磺酸、苯磺酸、4-甲基苯磺酸或萘-2-磺酸。
进一步的：所述化合物或其药学上可接受的盐还包括其D型、L型或D,L-混合物。
进一步的：所述化合物或其药学上可接受的盐还包括其立体异构体，优选的，包括对映异构体和非对映异构体。
本发明还提供了所述的新结构苯酰胍衍生物在用于制备预防和治疗炎症性疾病或过敏性疾病的药物中的应用。
进一步的，所述化合物或其药学上可接受的盐能够通过抑制磷酸二酯酶的活性、抑制TNF-α的释放、抑制中性白细胞增多或嗜酸性细胞增多，来减轻炎症性疾病或过敏性疾病的症状。
进一步的：所述磷酸二酯酶为PDE4、PDE2、PDE3、PDE5和PDE10。
优选的：所述磷酸二酯酶为PDE4。
进一步的：所述炎症性疾病或过敏性疾病包括由TNF-α释放、嗜酸粒细胞增多或中性白细胞增多和/或磷酸二酯酶PDEs激活引起的肺纤维化、慢阻肺、关节炎、脓毒症、胃炎、免疫性炎症、过敏性炎症、湿疹、皮炎、哮喘、肺浸润、溃疡性结膜炎。
进一步的：所述炎症性疾病或过敏性疾病还包括与抑制TNF-α释放有关的炎症性疾病包括类风湿性关节炎、类风湿性脊椎炎、骨关节炎、骨质疏松、脓毒症、脓毒性休克、格兰氏阴性脓毒症、中毒性休克综合征、呼吸窘迫综合征、移植排斥反应、多发性硬化、肾小球性肾炎和眼色素层炎、胰岛素依赖性糖尿病和慢性脱髓鞘；与嗜酸性细胞增多相关的炎症性疾病或过敏包括支气管哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、胃溃疡、痛风性关节炎、湿疹、过敏性脉管炎、嗜酸细胞性筋膜炎、嗜酸细胞性肺炎和PIE综合征(嗜酸性细胞增多的肺浸润)、荨麻疹、局限性回肠炎、牛皮癣和角化病。
进一步的：所述化合物或其药学上可接受的盐还能够用于治疗与TNF相关的感染，包括病毒感染、疟疾、利什曼病、感染引起的发烧、感染引起的肌肉疼痛、AIDS和恶病质。
本发明还提供了所述的化合物或其药学上可接受的盐在用于制备预防和治疗神经系统疾病或心血管系统疾病的药物中的应用。
进一步的：所述化合物或其药学上可接受的盐能够通过抑制Aβ聚集体和/或CoCl 2诱导的神经细胞和/或心肌细胞损伤，或者有效逆转氧化低密度脂蛋白ox-LDL诱导的血管内皮细胞损伤，进而达到保护神经细胞或心血管细胞的作用。
进一步的：所述心血管疾病包括由心肌细胞或血管内皮细胞损伤引起的动脉硬化、心力衰竭、心绞痛、缺血性损伤；所述神经系统疾病包括由神经细胞损伤引起的阿尔茨海默氏症、失忆、痴呆、中风、精神分裂症、抑郁症、焦虑症、帕金森氏病。
进一步的：所述神经系统疾病或心血管系统疾病还包括记忆遗失、间歇性跛 行、高血脂、高血糖、良性前列腺增生、频尿、夜尿症、失禁、尿石引起的纹痛和性功能障碍。
进一步的：所述的药物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
进一步的：所述的药物通过口服、非胃肠道、静脉内、透皮、局部、吸入和鼻内给药。
进一步的：所述的药物的剂量为每天施用一次的单一剂量给药，或者每天分成两次或更多次剂量给药，每次为0.001-500mg。
进一步的：所述的药物中还包括辅助剂、载体和添加剂中的至少一种。
进一步的：所述载体包括碳酸钙、磷酸钙、磷酸钠、乳糖、淀粉、甘露醇、藻酸盐、明胶、瓜尔胶、硬脂酸镁、硬脂酸铝、甲基纤维素、滑石粉、高度分散的二氧化硅、硅油、硬脂酸、明胶、琼脂、植物或动物脂肪和油、聚乙二醇。
进一步的：所述辅助剂包括甜味剂、调味剂、防腐剂、稳定剂、润湿剂、渗透剂、乳化剂、涂布剂、助溶剂，用于控制渗透压或用于起缓冲作用的盐、糖或糖醇和/或粘度调节剂。
进一步的：所述添加剂包括酒石酸盐和柠檬酸盐缓冲剂、乙醇、络合剂。
进一步的：为了控制粘度，所述添加剂还能够使用液体聚氧化乙烯、微晶纤维素、聚乙烯吡咯烷酮、葡聚糖或明胶。
进一步的：用于非胃肠道或局部施用的油悬浮液可含有植物的合成或半合成油，包括其在脂肪酸链中具有8-22个碳原子的液体脂肪酸酯，所述脂肪酸包括棕榈酸、月桂酸、十三烷酸、十七烷酸、硬脂酸、二十烷酸、肉豆蔻酸、二十二烷酸、十五烷酸、亚油酸、反油酸、巴西勒酸、芥酸或油酸，这些脂肪酸被具有1-6个碳原子的一元一三元醇酯化，所述醇包括甲醇、乙醇、丙醇、丁醇、戊醇或其异构体，乙二醇或甘油；所述脂肪酸酣包括Miglyole、肉豆蔻酸异丙酯、棕桐酸异丙酯、硬脂酸异丙酯、PEG-6癸酸、饱和脂肪醇的辛酸/癸酸酯、聚氧化乙烯甘油三油酸酯、油酸乙酯、蜡状脂肪酸酯例如合成的鸭尾腺脂肪、椰油脂肪酸的异丙酯、油酸油酯、油酸癸酯、乳酸乙醋、邻苯二甲酸二丁酯、己二酸二异丙酯、多元醇的脂肪酸酯；还能够使用硅油或脂肪醇包括异十三烷醇,2一辛基十二烷醇、鲸蜡基硬脂醇或油醇、油酸以及植物油包括蓖麻油、杏仁油、橄榄油、芝麻油、棉子油、花生油或豆油。
进一步的：作为溶剂、凝胶形成剂和助溶剂，使用水或醇包括乙醇或异丙醇、苯甲醇、2一辛基十二烷醇、聚乙二醇、邻苯二甲酸酯、己二酸酯、丙二醇、甘油、一缩二丙二醇、三丙二醇、蜡、甲基溶纤剂、溶纤剂、酯、呜琳、二氧杂环己烷、二甲亚砜、二甲基甲酰胺、四氢吠喃、环己酮。
进一步的：作为成膜剂，使用可溶解在或膨胀在水和有机溶剂中的纤维素醚，包括羟丙基甲基纤维素、甲基纤维素、乙基纤维素或可溶性淀粉、羧甲基纤维素钠、聚丙烯酸、聚异丁烯酸和其盐、支链淀粉半羟乙酸钠、藻酸或作为钠盐的丙二醇藻酸醋、阿拉伯胶、黄原胶、瓜尔胶或角叉菜胶。
进一步的：作为其它制剂辅料，还能够使用甘油、不同粘度的石蜡、三乙醇胺、胶原、尿囊素、Novantisolsaure。
进一步的：所述药物中还能够包括表面活性剂、乳化剂或润湿剂，包括月桂基硫酸钠、脂肪醇醚硫酸盐、N-月桂基-β-亚氨基二丙酸二钠、聚乙氧基化蓖麻油或脱水山梨醇一油酸醋、脱水山梨醇一硬脂酸酯、聚山梨醇酯、鲸蜡醇、卵磷脂、甘油-硬脂酸酯、聚氧乙烯硬脂酸酯、烷基苯酚聚乙二醇醚、氛化鲸蜡基三甲基铵或烷基或二烷基聚乙二醇醚正磷酸乙醇胺盐；稳定剂包括蒙脱石或胶态二氧化硅；抗氧化剂包括生育酚或丁基羟基茴香醚；防腐剂包括对羟基苯甲酸酯。
本发明还提供了所述的化合物或其药学上可接受的盐在用于制备磷酸二酯酶PDEs和/或TNF-α抑制剂中的应用。
进一步的：所述磷酸二酯酶包括PDE4、PDE2、PDE3、PDE5和PDE10。
优选的：所述磷酸二酯酶为PDE4。
与现有技术相比，本发明的优点和有益效果为：
本发明制备得到的新结构苯酰胍衍生物结构新颖，并通过药理学实验证明，所述新结构苯酰胍衍生物具有很好的抑制磷酸二酯酶活性、TNF-α的释放、中性白细胞增多或嗜酸性细胞增多的作用，进而减轻炎症性疾病或过敏的症状，达到预防和治疗炎症性疾病或过敏的作用，并且还能够抑制Aβ聚集体诱导的神经细胞损伤，或者抑制CoCl 2诱导的神经细胞或心肌细胞缺氧性损伤，并有效逆转血管内皮细胞的ox-LDL损伤，进而增加神经细胞或心肌细胞的活力，避免血管内皮细胞受氧化低密度脂蛋白损伤、达到保护神经细胞或心血管细胞的作用。本发明的新结构苯酰胍衍生物能够对多种疾病具有良好的治疗效果，并且均具有良好的安全性，具有进一步开发的价值。
术语约定：
“立体异构体”或“旋光异构体”是具有相同化学组成但原子或基团在空间中的排布不同的化合物。其包括“非对映异构体”和“对映异构体”
“非对映异构体”是具有两个或更多手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体具有不同物理性能，例如：熔点、沸点、谱特性和反应活性。在拆分剂或色谱存在的情况下，使用诸如手性HPLC柱，可以在诸如电泳、结晶的高分辨分析步骤下分离非对映异构体的混合物。
“对映异构体”指代彼此无重叠镜像的一种化合物的两个立体异构体。对映异构体的50:50的混合称为外消旋混合物或外消旋体，其在化学反应或处理过程中可以出现在已经没有立体选择性或立体定向性的情况下。
“烷基”包括支链和直链饱和脂肪族烃基两者，并具有指定数量的碳原子数量，一般1至约12个碳原子。如在本文中使用的术语C 1-C 6烷基表示具有1至约6个碳原子的烷基。当本文中结合另一基团使用C 0-C n烷基时，以(苯基)C 0-C 4烷基为例，指定的基团，在这种情况下，苯基是通过单个共价键(C 0)直接键合或通过具有指定的碳原子数(在这种情况下，1至约4个碳原子)的烷基链连接。烷基的实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、和仲戊基。
“烯基”或“烯烃基”指包括一个或多个不饱和的碳-碳键的直链和支链烃链，碳-碳键可以出现在沿着链的任一稳定点。本文中所述的烯基通常具有2至约12个碳原子。优选烯基是低级烯基，那些烯基具有2至约8个碳原子，如：C 2-C 8、C 2-C 6、和C 2-C 4烯基。烯基的实例包括乙烯基、丙烯基、和丁烯基。
“环烷基”优选的是指具有3-15个碳原子的单环、双环、三环、桥环、螺环的环状烷基；优选的为环丙烷、环戊烷、环己烷等。
“烷氧基”是指具有通过氧桥连接的指定数量的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、3-己氧基、和3-甲基戊氧基。
术语“杂环”表示5-至8-元饱和环、部分不饱和环、或包含选自N、O和S的1至约4个杂原子且剩余的环原子是碳的芳族环，或是7至11元饱和环、部分不饱和环、或芳族杂环系统和10至15-元三环系统，该系统包含选自N、O和S的多环系统中的至少1个杂原子并且在多环系统中的各环中包含独立地选自N、O和S的至多约4个杂原子。除非另外指明，否则杂环可以连接至它在任何杂原子和碳 原子处取代并且产生稳定结构的基团。当指明时，本文中所述的杂环可以在碳或氮原子上被取代，只要得到的化合物是稳定的。可以可选地季铵化杂环中的氮原子。优选杂环基中杂原子的总数不大于4而且优选杂环基中S和O原子的总数不大于2，更优选不大于1。杂环基的实例包括：吡啶基、吲哚基、嘧啶基、哒嗪基(pyridizinyl)、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基(benz[b]thiophenyl)、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、二氢异吲哚基、5,6,7,8-四氢异喹啉、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡咯烷基、吗啉基、哌嗪基、哌啶基、和吡咯烷基。
“芳基”或“杂芳基”表示包含选自N、O和S的1至4个、或优选1至3个杂原子并且剩余环原子为碳的稳定的5-或6-元单环或多环。当杂芳基中S和O原子的总数超过1时，这些杂原子不彼此邻近。优选杂芳基中S和O原子的总数不大于2。尤其优选杂芳基中S和O原子的总数不大于1。可以可选地季铵化杂环中的氮原子。当指明时，这些杂芳基还可以用碳或非碳原子或基团取代。这种取代可以包括与可选地包含独立地选自N、O和S的1或2个杂原子的5至7-元饱和的环基的稠合，从而形成例如[1,3]二噁唑并[4,5-c]吡啶基。杂芳基的实例包括但不限于：吡啶基、吲哚基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、三唑基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细的说明。
实施例1：苯酰胍衍生物苯甲酯类化合物的合成
1、合成通代表化合物4-胍基丁烷-3-环丙甲氧基-4-二氟甲氧基苯甲酯
将市售可得的3-环丙甲氧基-4-二氟甲氧基苯甲酸为起始原料，取35g溶解在100mL经无水处理的二氯甲烷中，搅拌使充分溶解，并分批加入二甲氨基吡啶对甲苯磺酸盐共60g，待溶液澄清后，加入Boc保护的4-胍基-1-丁醇32.5g，搅拌使溶解，然后加入二异丙基碳酰亚胺38.5g，室温搅拌过夜，TLC检测反应进行完毕，先抽滤掉不溶物，再减压蒸馏，除去二氯甲烷，然后加入事先冷冻的冰甲醇，直至析出白色晶体，抽滤得到白色粉末状晶体前体约25.3g。取前体化 合物4.0mM，加入1：1的二氯甲烷和三氟乙酸的混合溶液10mL，室温反应5h后，TLC测定反应是否完成。减压蒸馏除去二氯甲烷，用石油醚清洗3遍后，加入适量饱和NaHCO 3溶液，调节PH至8-11，析出固体，然后过滤得4-胍基丁烷-3-环丙甲氧基-4-二氟甲氧基苯甲酯，即为代表产物ML-5，核磁共振氢谱和碳谱的数据如下：
Figure PCTCN2022092035-appb-000006
化合物ML-5氢谱： 1H NMR(400MHz,DMSO-d 6)δ8.29(s,1H),7.58(s,2H),7.41(s,2H),7.06(s,2H),6.60(s,4H),6.05(s,2H),4.40(s,2H),4.30(s,2H),3.94(s,4H),3.57(s,2H),1.83(s,2H),1.50(s,2H),1.10(s,1H),0.47(s,2H),0.23(s,2H).
化合物ML-5碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.37(s),156.86(s),153.61(s),149.68(s),125.82(s),124.84(s),124.56(s),119.05(s),118.56(s),74.00(s),66.74(s),41.46(s),27.93(s),27.36(s),10.70(s),7.85(s).
2、使用上述经典的酸醇缩合方法，可合成化合物ML-6、ML-1、ML-2，具体如下：
Figure PCTCN2022092035-appb-000007
化合物ML-6氢谱： 1H NMR(400MHz,DMSO-d 6)δ8.31(s,2H),7.61(s,4H),7.44(s,4H),7.09(s,4H),6.63(s,8H),6.10(s,4H),4.42(s,4H),4.30(s,4H),3.95(s,8H),3.58(s,4H),2.00(s,3H),1.11(s,1H),0.51(s,4H),0.17(s,4H).
化合物ML-6碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.37(s),156.86(s),153.61(s),149.68(s),125.82(s),124.84(s),124.56(s),119.05(s),118.56(s),74.00(s),62.55(s),38.88(s),30.61(s),10.70(s),7.85(s).
Figure PCTCN2022092035-appb-000008
化合物ML-1氢谱： 1H NMR(400MHz,DMSO-d 6)δ7.61(s,1H),7.44(s,1H),6.90(s,1H),6.73(s,1H),6.48(s,2H),4.30(d,J＝15.8Hz,2H),3.83(s,3H),3.68(s,1H),3.58(s,1H),2.05(s,1H),1.84(s,2H),1.78(s,1H),1.71(s,1H),1.61(s,1H),1.51(s,1H).
化合物ML-1碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.37(s),156.86(s),156.67(s),148.08(s),123.16(s),122.49(s),117.64(s),117.01(s),83.94(s),66.74(s),56.83(s),41.46(s),33.43(s),27.93(s),27.36(s),24.08(s).
Figure PCTCN2022092035-appb-000009
化合物ML-2氢谱： 1H NMR(400MHz,DMSO-d 6)δ7.61(s,1H),7.44(s,1H),6.90(s,1H),6.14(s,1H),6.09(s,2H),5.07(s,1H),4.30(s,1H),4.20(s,1H),3.83(s,3H),3.58(s,1H),2.05(s,1H),2.00(s,1H),1.78(s,1H),1.71(s,1H),1.61(s,1H).
化合物ML-2碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.37(s),156.86(s),156.67(s),148.08(s),123.16(s),122.49(s),117.64(s),117.01(s),83.94(s),62.55(s),56.83(s),38.88(s),33.43(s),30.61(s),24.08(s).
实施例2：苯酰胍衍生物苯甲酰胺类化合物的合成
1、合成代表化合物3-环戊烷氧基-N-4-胍基丁烷-4-甲氧基苯甲胺
将2.83g NaH加到50mL干燥的四氢呋喃中，再缓慢加入Boc保护的4-胍基-1-丁胺(78.2mM)，室温下反应1.5小时待用；再取3-环戊烷氧基-4-甲氧基苯甲酸(33.1mM)用200mL干燥的四氢呋喃溶解，冰浴条件下缓慢滴加8.6mL SOCl 2，加完后回流6小时，蒸除溶剂，用65mL无水四氢呋喃溶解后，室温条件下缓慢滴加到上述反应体系中，50℃反应6小时。冷到室温，加入300mL水，并用乙酸酯150mL萃取3次，合并的有机相用无水硫酸钠干燥，后加入1：1的二氯甲烷和三氟乙酸的混合溶液12mL，室温反应6h后，TLC测定反应是否完成脱保护，然后减压蒸除溶剂后得到粗品，粗品经乙酸乙酯重结晶后得到代表化合物3-环戊烷氧基--N-4-胍基丁烷-4-甲氧基苯甲酰胺，即化合物ML-3，其核磁氢谱和碳谱为：
Figure PCTCN2022092035-appb-000010
化合物ML-3氢谱： 1H NMR(400MHz,DMSO-d 6)δ7.61(s,1H),7.49(s,1H),7.02(s,1H),6.63(s,2H),6.15(s,1H),5.94(s,1H),4.46(s,1H),4.36(s,1H),3.83(s,3H),3.58(s,2H),3.30(s,2H),2.06(s,1H),1.78(s,1H),1.71(s,1H),1.61(s,1H),1.55(s,2H),1.49(s,2H).
化合物ML-3碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),83.94(s),56.83(s),41.49(d,J＝7.6Hz),33.43(s),27.39(s),24.08(s).
2、使用上述经典的酸胺缩合方法，可合成化合物ML-7、ML-8、ML-4具体如下：
Figure PCTCN2022092035-appb-000011
化合物ML-7氢谱： 1H NMR(400MHz,DMSO-d 6)δ8.35(s,1H),7.57(s,2H),7.45(s,2H),7.12(s,2H),6.74(s,2H),6.47(s,4H),6.06(s,2H),3.99(s,2H),3.94(s,4H),3.56(s,4H),3.28(s,4H),1.54(s,6H),1.48(s,2H),1.10(s,1H),0.47(s,2H),0.19(s,2H).
化合物ML-7碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.82(s),156.86(s),153.70(s),147.81(s),128.59(s),124.84(s),121.58(s),118.99(s),118.56(s),74.00(s),41.49(d,J＝7.6Hz),27.39(s),10.70(s),7.85(s).
Figure PCTCN2022092035-appb-000012
化合物ML-8氢谱： 1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),7.55(d,J＝60.0Hz,4H),7.16(s,2H),6.63(s,4H),6.10(s,2H),6.00(s,2H),4.45(s,2H),3.96 (s,4H),3.58(s,2H),3.42(s,2H),1.90(s,2H),1.11(s,1H),0.49(s,2H),0.16(s,2H).
化合物ML-8碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.82(s),156.86(s),153.70(s),147.81(s),128.59(s),124.84(s),121.58(s),118.99(s),118.56(s),74.00(s),39.20(s),38.35(s),28.44(s),10.70(s),7.85(s).
Figure PCTCN2022092035-appb-000013
化合物ML-4氢谱： 1H NMR(400MHz,DMSO-d 6)δ7.55(d,J＝60.0Hz,2H),7.02(s,1H),6.32(d,J＝11.6Hz,3H),6.06(s,1H),4.57(s,1H),4.22(s,1H),3.83(s,3H),3.58(s,1H),3.42(s,1H),2.06(s,1H),1.90(s,1H),1.70(t,J＝42.3Hz,6H),1.61(s,3H),1.61(s,1H).
化合物ML-4碳谱： 13C NMR(101MHz,DMSO-d 6)δ166.82(s),156.86(s),153.51(s),148.80(s),128.31(s),122.37(s),116.54(s),113.88(s),83.94(s),56.83(s),39.20(s),38.35(s),33.43(s),28.44(s),24.08(s).
实施例3：新结构苯酰胍衍生物抑制磷酸二酯酶(PDEs)
在大鼠多形核淋巴细胞(PMNL)的酶制备物中测定PDE4活性，用分离的血小板的PDE测定PDE2、PDE3、PDE5和PDE10的活性。用柠檬酸盐防止提取的大鼠血液凝结；通过在室温离心的方法将上清液中的富含血小板的血浆与红细胞和白细胞分离开；再通过超声将血小板裂解，预留在PDE3、PDE5和PDE10测定中使用。为了测定PDE2活性，在阴离子交换柱上通过NaCl梯度纯化胞质血小板级分，获得了用于测定的PDE2峰；再通过葡聚糖沉降后，用Ficoll梯度离心分离出用于PDE4测定的PMNL细胞。将PMNL细胞洗涤2次后，通过加入10mL低渗裂解缓冲液于4℃裂解6分钟以去除残留的红细胞。将仍然完整的PMNL细胞再用PBS洗涤两次，并通过超声裂解，于4℃以高速离心1h，获得的上清液含有PDE4的胞质级分以用于下述测定中PDE4、PDE2、PDE3、PDE5和PDE10测定中酶的原料。
使用磷酸二酯酶活性测定试剂盒(购自Abcam公司，货号ab13940，PDE Activity Assay kit,Colorimetric)来测定各种酶的活性：将操作方法适当修改，把试剂盒提供的蛋白酶替换为如上述方法分离制备的蛋白酶即可，其它的按照操作 说明书进行严格检测：先加入20微升cAMP底物，再加入15微升测定缓冲液，然后加入10微升5’核苷酶，混合均匀后加入适当浓度的测试化合物，然后加入已提取纯化准备好的PDE酶，30℃孵育30分钟后，最后加入Green Assay试剂检测分解出的磷酸根离子，混合20分钟后达到颜色均匀，通过测定OD620nm来计算化合物对PDE酶的抑制活性。
结果如表1所示，实施例1制备得到的各个化合物测定的抑制PDE4的IC 50值为10 -12-10 -7M，对2、3、5和10型PDE的选择性为20-10000的因数，说明新型苯酰胍衍生物具有抑制PDE4活性的作用，可作为PDE4强抑制剂。
表1：化合物的抑制PDE4的IC 50值
化合物 抑制PDE的IC 50(μmol/L)
ML-1 0.00011
ML-2 0.00056
ML-3 0.00016
ML-4 0.00072
ML-5 0.000013
ML-6 0.000035
ML-7 0.000054
ML-8 0.000041
实施例4：新结构苯酰胍衍生物抑制从鼻息肉细胞释放TNF-α
将鼻息肉组织用RPMI 1640洗涤，然后用蛋白酶(2.5mg/ml)、胶原酶(1.0mg/ml)、透明质酸酶(0.5mg/ml)和DNA酶(0.1mg/ml)于37℃溶解150分钟(1g组织和4mL含有酶的RPMI 1640)。将所得细胞(上皮细胞、单核细胞、巨噬细胞、淋巴细胞、成纤维细胞和粒细胞)的混合物过滤，通过在培养溶液中反复离心来洗涤，加入人源IgE来被动致敏，将细胞悬浮液在RPMI 1640(补充杭生素、10％胎牛血清、2mM谷氨酸胺和25mM Hepes)中稀释至2百万个细胞/mL的浓度。将悬浮液分配在6孔细胞培养平板上(1ml/孔)。将细胞与不同浓度的测试物预培养30分钟，然后通过加入抗IgE进行刺激以释放TNF-α，约16小时后发生了向培养基内的最大释放。在该期间，将细胞在37℃和含5％二氧化碳的培养箱中培养。通过离心来收集培养基(上清液)，并在-80℃保持，直至测定细胞因子。用ELISA试剂盒测定上清液中的TNF-α。
未用抗IgE刺激的细胞几乎不产生任何TNF-α，而刺激的细胞分泌大量TNF-α，可通过PDE4抑制剂减少TNF-α的量，减少程度与剂量有关。由不同浓 度的化合物的抑制百分比(用抗IgE刺激的细胞TNF-α释放＝100％)计算IC 50(达到50％抑制的浓度)。结果如表2所示，实施例1制备的化合物的IC 50值为10 -10-10 -4M，说明新结构苯酰胍衍生物具有抑制TNF-α释放的作用，可作为TNF-α抑制剂。
表2：化合物的抑制TNF-α释放的结果
Figure PCTCN2022092035-appb-000014
实施例5：新结构苯酰胍衍生物抑制大鼠过敏模型的嗜酸性细胞增多
将V级卵清蛋白50mg，氢氧化铝100mg和灭活百日咳杆菌6×10 9个溶于生理盐水1ml中，配制成混悬液凝胶，并按此比例扩大配成12ml作为致敏液备用(为防止分10次注射使用时挂壁残留损耗，多配制出2ml)。第1天致敏：空白组大鼠给予腹腔注射1ml生理盐水，而模型组给予腹腔注射1ml致敏液致敏；第15天开始激发：将两组大鼠分别置于相同大小的雾化箱内，空白组给予生理盐水6ml雾化激发，模型组给予5％V级卵清蛋白溶液6ml雾化激发，每天激发一次，每次激发30min，连续激发10天。测试化合物是在变应原攻击前2小时，作为在10％聚乙二醇300和0.5％5-羟基乙基纤维素中的悬浮液腹膜内或口服施用的。对照组是依据测试化合物的施用形式用载体治疗。实验结束时固定大鼠四肢，使用75％酒精对颈部消毒，充分暴露气管，在喉部附近插入气管插管针(针头稍磨平)，针头插入一定位置，切勿超过气管分叉处；用2mL预冷的PBS反复灌洗3次，收集肺泡灌洗液到EP管中，1000rpm、4℃离心，收集细胞，经瑞氏-吉姆萨染色，在显微镜下进行细胞分类计数。
白细胞是免疫进程中至关重要的一类细胞，细胞分类计数可以有效分析肺泡灌洗液BALF中白细胞比例的变化。在发病过程中，浸润其支气管的炎症细胞主要是淋巴细胞和嗜酸性细胞。淋巴细胞能够扩大支气管粘膜上嗜酸性细胞的炎症反应，并且随着嗜酸性粒细胞的增多，会增加其在肺内聚集、活化以及与其它炎 性细胞、炎性介质、细胞因子的相互作用，进而加重过敏。
结果如表3所示，以1-5mg/kg剂量腹膜内施用后，实施例1制备的化合物将嗜酸性细胞增多症状有效抑制了86％-95％，以10-50mg/kg的剂量口服施用后，各化合物将嗜酸性细胞增多症状抑制了81-93％。因此，本发明的新结构苯酰胍衍生物适合用于治疗和预防与嗜酸性细胞活动有关的疾病。
表3：化合物的抑制嗜酸性细胞增多的结果
Figure PCTCN2022092035-appb-000015
实施例6：新结构苯酰胍衍生物抑制脂多糖(LPS)引起的中性白细胞增多
在雄性Wistar大鼠(200±20g)中测试实施例1制备的化合物对肺中性白细胞浸润的抑制作用。在实验的当天，将动物单独置于开口的1L有机玻璃盒子中，该盒子与头鼻暴露装置连接。将动物暴露于脂多糖悬浮液(LPS 100μg/mL溶解于含有0.1％羟基胺的PBS溶液中)的气雾剂中(LPS攻击)，暴露时间是45分钟，标准对照是用含有0.1％羟基胺的PBS溶液的气雾剂喷雾45分钟。LPS攻击6小时后，有大量中性粒细胞迁移到动物的肺内。测试各化合物是在LPS攻击前2 小时，作为在10％聚乙二醇300和0.5％5-羟基乙基纤维素中的悬浮液口服施用的。对照组是依据测试物的施用形式用载体治疗。实验结束时固定大鼠四肢，使用75％酒精对颈部消毒，充分暴露气管，在喉部附近插入气管插管针(针头稍磨平)，针头插入一定位置，切勿超过气管分叉处；用2mL预冷的PBS反复灌洗3次，收集肺泡灌洗液到EP管中，1000rpm、4℃离心，收集细胞，经瑞氏-吉姆萨染色，在显微镜下进行细胞分类计数。
结果如表4所示，以10-50mg/kg的剂量口服施用后，本发明化合物将中性白细胞增多症状抑制了85％-95％。因此，本发明的新结构苯酰胍衍生物适用于治疗好预防与中性白细胞活动有关的疾病，且化合物ML-5和ML-8效果最好。
表4：化合物的抑制中性白细胞增多的结果
Figure PCTCN2022092035-appb-000016
实施例7：新结构苯酰胍衍生物对Aβ聚集体诱导神经细胞损伤的保护作用
以未加Aβ1-42的细胞活力为阴性对照，观察实施例1制备的化合物对Aβ诱导产生的神经细胞毒的抑制作用，具体实施步骤如下：将PC12细胞接种于MEM完全培养液中，置入96孔板中培养，放入恒温细胞培养箱孵育24小时后，加入提前聚集的Aβ蛋白寡聚体，2h后，各化合物组在每孔加入本化合物溶液，浓度为10μmol/L，模型组加入等量的无菌水，培养箱中继续孵育24h。结束后，采用MTT法测定细胞存活率。每次三个平行，实验重复三次。
结果如表5所示，以10μmol/L的给药浓度处理后，本发明化合物均具有较好的保护神经细胞的作用，对Aβ聚集体诱导神经细胞损伤具有明显的抑制作用。因此，本发明的新结构苯酰胍衍生物适用于治疗和预防与神经保护有关的疾病。
表5：化合物的保护神经细胞的结果
组别 细胞存活率(％)
模型组 42±2.8
ML-1 78±2.7
ML-2 82±2.5
ML-3 80±2.3
ML-4 75±2.1
ML-5 93±2.6
ML-6 81±2.9
ML-7 75±2.2
ML-8 91±3.2
实施例8：新结构苯酰胍衍生物对CoCl 2诱导神经细胞和心肌细胞缺氧损伤的保护作用
以未加CoCl 2诱导的神经细胞PC12和心肌细胞H9C2的细胞活力为阴性对照，观察实施例1制备的化合物对诱导CoCl 2产生的神经细胞和心肌细胞缺氧损伤的抑制作用，具体实施步骤如下：将PC12和H9C2细胞接种于MEM或者DMEM完全培养液中，置入96孔板中培养，放入恒温细胞培养箱孵育24小时后，加入提前溶解好的含CoCl 2的损伤液，2h后，各化合物组每孔加入各化合物溶液，浓度为50μmol/L，模型组加入等量的无菌水，培养箱中继续孵育48小时。结束后，采用MTT法测定细胞存活率。每次三个平行，实验重复三次。
结果如表6和7所示，以50μmol/l的给药浓度处理后，本发明化合物均具有较好的保护神经细胞和心肌细胞缺氧损伤的作用。因此，本发明的新结构苯酰胍衍生物适用于治疗和预防与神经细胞和心血管系统损伤有关的疾病。
表6：化合物的对缺氧导致的神经损伤的作用
组别 细胞存活率(％)
模型组 51±1.8
ML-1 70±1.5
ML-2 80±2.0
ML-3 78±1.7
ML-4 85±2.2
ML-5 97±3.4
ML-6 86±2.5
ML-7 90±3.4
ML-8 92±3.6
表7：化合物的对缺氧导致的心血管细胞的保护作用
组别 细胞存活率(％)
模型组 52±3.1
ML-1 74±2.0
ML-2 77±1.7
ML-3 80±2.5
ML-4 85±2.8
ML-5 93±2.2
ML-6 85±2.4
ML-7 90±3.2
ML-8 91±3.4
实施例9：新结构苯酰胍衍生物对氧化性低密度脂蛋白(ox-LDL)诱导的血管内皮细胞损伤的抑制作用
将血管内皮细胞HUVEC接种于MEM完全培养液，以未加氧化性低密度脂蛋白ox-LDL组为阴性对照，观察化合物对ox-LDL诱导产生血管内皮类粥样损伤的保护作用。具体如下：将HUVEC细胞接种于MEM或者DMEM完全培养液中，置入96孔板中培养，放入恒温细胞培养箱孵育24小时后，加入提前溶解好的含ox-LDL的诱导液，2h后，每孔加入50μM苯酰胍衍生物，以未加ox-LDL组为阴性对照。结束后，采用并采用ELISA检测IL-6炎症因子的含量。
结果如表8表明，苯酰胍衍生物可有效抑制氧化性低密度脂蛋白ox-LDL所刺激的血管内皮细胞中IL-6的增加，表明本发明的新结构苯酰胍衍生物适用于防治血管内皮细胞损伤相关的疾病。
表8：化合物对ox-LDL诱导内皮细胞粥样损伤的抑制结果
组别 IL-6释放量(ng/L)
模型组 1122±27.8
ML-1 901±19.5
ML-2 853±17.2
ML-3 806±20.3
ML-4 821±19.1
ML-5 702±23.1
ML-6 740±22.6
ML-7 718±17.9
ML-8 755±21.2
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。

Claims (10)

  1. 化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
    Figure PCTCN2022092035-appb-100001
    其中，
    A为O或NH；
    B为连接基团，为具有1-8个原子长度的直链或具有支链的基团；
    E为取代或未取代的3-10元单环或双环烷基、取代或未取代的3-10元单环或双环杂环基、取代或未取代的3-10元芳基、或取代或未取代的3-10元杂芳基；
    F为不存在；或者为，直链或具有支链的C 1-C 6亚烷基，其中可以杂有O、NR 5或S原子；
    R 1为H、取代或未取代的C 1-C 6烷基；取代或未取代的C 1-C 6羰基；
    R 2、R 3、R 4和R 5各自独立的为H、氘、卤素、羟基、胺基、羧基、酰胺基、酯基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的烷氧基、取代或未取代的烷基羧基、取代或未取代的烷基酯基、取代或未取代的烷基-OH、取代或未取代的烷氧基、取代或未取代的烷基-NH 2、取代或未取代的芳基、取代或未取代的杂环芳基；
    所述取代是指被氘、卤素、羟基、胺基、羧基、酰胺基、酯基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的烷氧基、取代或未取代的烷基羧基、取代或未取代的烷基酯基、取代或未取代的烷基-OH、取代或未取代的烷氧基、取代或未取代的烷基-NH 2、取代或未取代的芳基、或取代或未取代的杂环芳基，所取代。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
    Figure PCTCN2022092035-appb-100002
  3. 如权利要求1所述的化合物或其药学上可接受的盐，所述化合物具有如下所示结构：
    Figure PCTCN2022092035-appb-100003
    其中n为1-8的整数。
  4. 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其特征在于：所述F为不存在或-(CH 2)m-，其中m为0-6的整数。
  5. 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其特征在于：所述E为取代或未取代的3-10元单环或双环烷基。
  6. 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其特征在于：所述E为取代或未取代的环丙基、环丁基、环戊基、环己基或环庚基；或者为取代或未取代的具有1-3个杂原子的3-8元杂环基，所述杂原子选自N、O和S。
  7. 如权利要求1-6任一项所述的所述化合物或其药学上可接受的盐，其特征在于为如下化合物中的一种或多种：
    Figure PCTCN2022092035-appb-100004
  8. 权利要求1-7任一项所述化合物或其药学上可接受的盐的制备方法，其特征在于，所述制备方法包括以下步骤：
    由3-环丙甲氧基-4-二氟甲氧基苯甲酸或3-环戊烷氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-丁醇或4-胍基-1-丙醇缩合，在三氟乙酸作用下脱除Boc保护基，得到化合物；
    或者由3-环丙甲氧基-4-二氟甲氧基苯甲酸或3-环戊烷氧基-4-烷氧基苯甲酸与Boc保护的4-胍基-1-丁胺或4-胍基-1-丙胺缩合，然后再在二氯甲烷和三氟乙酸混合溶液中脱除Boc保护基得到化合物。
  9. 权利要求1-7任一项所述化合物或其药学上可接受的盐的用途，其特征在于用作磷酸二酯酶PDEs和/或TNF-α抑制剂；用于预防和/或治疗炎症性疾病或过敏性疾病；抑制磷酸二酯酶的活性；抑制TNF-α的释放；抑制中性白细胞增多或嗜酸性细胞增多；减轻炎症性疾病或过敏性疾病的症状；预防和/或治疗由TNF-α释放、嗜酸粒细胞增多或中性白细胞增多和/或磷酸二酯酶PDEs激活引起的肺纤维化、慢阻肺、关节炎、脓毒症、胃炎、免疫性炎症、过敏性炎症、湿疹、皮炎、哮喘、肺浸润、溃疡性结膜炎；预防和/或治疗神经系统疾病或心血管系统疾病；抑制Aβ聚集体和/或CoCl 2诱导的神经细胞和/或心肌细胞损伤；逆转氧化低密度 脂蛋白ox-LDL诱导的血管内皮细胞损伤；保护神经细胞或心血管细胞；优选的，所述心血管疾病包括由心肌细胞或血管内皮细胞损伤引起的动脉硬化、心力衰竭、心绞痛、缺血性损伤；优选的，所述神经系统疾病包括由神经细胞损伤引起的阿尔茨海默氏症、失忆、痴呆、中风、精神分裂症、抑郁症、焦虑症、帕金森氏病。
  10. 一种药物组合物，包括权利要求1-7任一项所述化合物或其药学上可接受的盐；任选的还包括药学上可接受的载体；优选的，所述药物组合物为片剂、口服液、气雾剂、丸剂、胶囊剂、颗粒剂、膏剂、滴丸剂、糖浆剂、散剂、冲剂、酊剂、粉针剂或注射液。
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