CN115504909A - Benzoylguanidine derivative and preparation method and application thereof - Google Patents

Benzoylguanidine derivative and preparation method and application thereof Download PDF

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CN115504909A
CN115504909A CN202210505530.6A CN202210505530A CN115504909A CN 115504909 A CN115504909 A CN 115504909A CN 202210505530 A CN202210505530 A CN 202210505530A CN 115504909 A CN115504909 A CN 115504909A
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substituted
unsubstituted
group
compound
pharmaceutically acceptable
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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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Ocean University of China
Qingdao Marine Biomedical Research Institute Co Ltd
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Ocean University of China
Qingdao Marine Biomedical Research Institute Co Ltd
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Abstract

The invention provides a benzoylguanidine derivative, a preparation method and application thereof, wherein the benzoylguanidine derivative is simple in preparation method, has the effects of obviously inhibiting phosphodiesterase PDEs activity, TNF-alpha release and neutrophilic leukocyte or eosinophilic cytosis, can also protect nerve cells, myocardial cells and vascular endothelial cells, and has good safety, so that the benzoylguanidine derivative has important development significance.

Description

Benzoylguanidine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzoylguanidine derivative, and a preparation method and application thereof.
Background
Phosphodiesterases are a member of the enzyme family, and 11 PDE enzyme families (PDE 1-PDE 11) are known to date, which differ in their substrate specificity (cAMP, cGMP or both) and their dependence on other substrates (e.g. calmodulin). Inhibition of different types of PDE isozymes leads to intracellular accumulation of cAMP and/or cGMP, which can be useful in the treatment of different inflammation-related diseases. PDE4 is mainly distributed in various inflammatory cells, such as mast cells, macrophages, eosinophils, lymphocytes and epithelial cells, and can increase intracellular concentration by inhibiting enzyme activity, which helps to reduce the harm of inflammatory reaction to the body. The major PDE isozymes are also type 4 in cells important for allergic inflammation (lymphocytes, mast cells, eosinophils, macrophages). Therefore, inhibition of PDE4 with suitable inhibitors is considered an important starting point for the treatment of various allergy-induced diseases. PDE4 inhibitors have been developed to date as anti-inflammatory drugs, such as roflumilast, primarily for the treatment of inflammation of the lung, particularly asthma and chronic obstructive pulmonary disease; difamilast is used in the treatment of atopic dermatitis; and apremilast is used in the treatment of psoriatic arthritis.
Meanwhile, an important feature of PDE4 inhibitors is the inhibition of the release of tumor necrosis factor (TNF-. Alpha.) from inflammatory cells. TNF- α is an important proinflammatory cytokine affecting a variety of biological processes, which can be released from activated local cells, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. TNF-alpha itself has an activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, releasing different tissue-destructive mediators. TNF- α causes increased levels of other proinflammatory cytokines such as GM-CSF (granulocyte-macrophage colony stimulating factor) or interleukin-8 in monocytes, macrophages and T lymphocytes. TNF- α plays a key role in a variety of diseases such as respiratory inflammation, joint inflammation, endotoxic shock, tissue rejection, AIDS and a variety of other immune disorders, as TNF- α promotes inflammation and catabolic effects. Therefore, PDE4 inhibitors are also useful in the treatment of TNF- α related diseases.
Obstructive Pulmonary Disease (COPD) is a general term for a group of chronic airflow obstructive diseases that combine different syndromes of chronic bronchitis with productive cough and symptoms of progressive and irreversible lung function deterioration. The course of the disease is episodic and is often complicated by bacterial infections. At present, the western medicines for treating chronic obstructive pulmonary disease mainly comprise bronchodilators including theophylline, beta 2 agonists and anticholinergic medicines, and are matched with oxygen therapy, antibiotics, hormones, auxiliary ventilation and the like for symptomatic treatment. However, the antibiotics are easy to have drug resistance and toxic and side effects after long-term use, and patients with repeated infection often adopt high-grade antibiotics which are expensive and difficult to bear by patients; hormones have strong side effects. New therapeutic approaches to attack inflammatory mediators, proteases or adhesion molecules may be very promising.
Chronic inflammation, dominated by neutrophils, is found in the bronchi independently of bacterial infections that are concurrent with the disease. In addition to this, mediators and enzymes released by neutrophils are responsible for the structural changes observed in the respiratory tract (emphysema). Therefore, inhibition of neutrophil activity is a reasonable starting point for preventing or delaying COPD progression (lung function parameter regression). An important stimulus for the activation of granulocytes is the proinflammatory cytokine TNF- α. TNF- α is currently known to stimulate neutrophil oxygen free radicals. PDE4 inhibitors can be very effective in inhibiting the release of TNF-alpha by a variety of cells and thus inhibit neutrophil activity. The nonspecific PDE inhibitor pentoxifylline is capable of inhibiting the production of oxygen radicals and the ability of neutrophils to phagocytose.
In addition, asthma is also a common respiratory disease, which is a chronic airway inflammation involved by various cells, particularly mast cells, eosinophils and T lymphocytes, and has become a major chronic disease that seriously threatens public health. At present, the western medicine treatment mode of asthma mostly depends on bronchodilators or oxygen inhalation to relieve symptoms, and the treatment is not carried out aiming at the pathogenesis of asthma. The mode of treating symptoms and root causes is easy to cause dependence and repeated attack, has side effects and can seriously affect the normal life of patients.
Although PDE4 inhibitors are known to have shown beneficial pharmacological effects, such inhibitors have adverse effects that cause diarrhea, nausea, and the like. Therefore, the research of novel specific inhibitors to overcome these adverse reactions becomes one of the hot spots of inhibitor drug research. The natural traditional Chinese medicine derivative is a treasury discovered by a lead compound for developing new medicines, a novel inhibitor is searched from the treasury, and the natural traditional Chinese medicine derivative has important significance for developing an inhibitor anti-inflammatory medicine with high curative effect and small side effect.
Disclosure of Invention
The invention provides a new-structure benzoylguanidine derivative, a preparation method and application thereof. The phenylglyoxylic acid derivative has a novel structure, and pharmacological experiments prove that the phenylglyoxylic acid derivative has the effects of inhibiting phosphodiesterase activity and protecting nerve cells, myocardial cells and vascular endothelial cells.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
Figure BDA0003637356330000031
wherein the content of the first and second substances,
a is O or NH;
b is a linking group which is a linear or branched group having a length of 1 to 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 group;
f is absent; or is, straight-chain or branched C 1 -C 6 Alkylene, which may be interrupted by O, NR 5 Or an S atom;
R 1 is H, substituted or unsubstituted C 1 -C 6 An alkyl group; substituted or unsubstituted C 1 -C 6 A carbonyl group;
R 2 、R 3 、R 4 and R 5 Each independently is H, deuterium, halogen, hydroxyl, amine, carboxyl, amide, 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 alkylcarboxyl, substituted or unsubstituted alkyl ester, substituted or unsubstituted alkyl-OH, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl-NH 2 Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl;
the substitution refers to deuterium, halogen, hydroxyl, amine group, carboxyl group, amide group, ester group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylcarboxyl group, substituted or unsubstituted alkyl ester group, substituted or unsubstituted alkyl-OH, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkyl-NH 2 Substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
A compound as described above, or a pharmaceutically acceptable salt thereof, having the structure shown below:
Figure BDA0003637356330000032
a compound as described above, or a pharmaceutically acceptable salt thereof, having the structure shown below:
Figure BDA0003637356330000041
wherein n is an integer from 1 to 8, preferably 2, 3, 4,5, 6, 7.
A compound as described above, or a pharmaceutically acceptable salt thereof, characterized in that: f is absent or- (CH) 2 ) m-, wherein m is an integer from 0 to 6, preferably 0, 1,2, 3, 4 or 5.
A compound as described above, or a pharmaceutically acceptable salt thereof, characterized in that: and E is a substituted or unsubstituted 3-10 membered monocyclic or bicyclic alkyl group.
A compound as described above, or a pharmaceutically acceptable salt thereof, characterized in that: e is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or a substituted or unsubstituted 3-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S.
A compound as described above, or a pharmaceutically acceptable salt thereof, characterized in that: the R is 1 Is substituted or unsubstituted C 1 -C 6 An alkyl group; preferred is C substituted by 1,2 or 3 halogens 1 -C 6 An alkyl group; more preferred halogens are F, cl, br, and/or I.
The compound or pharmaceutically acceptable salt thereof as described above, characterized by being one or more of the following compounds:
Figure BDA0003637356330000051
the invention also provides a preparation method of the compound or the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:
condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentanyloxy-4-alkoxybenzoic acid with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc, and removing the Boc protective group under the action of trifluoroacetic acid to obtain a compound;
or condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentanyloxy-4-alkoxybenzoic acid with Boc-protected 4-guanidino-1-butylamine or 4-guanidino-1-propylamine, and then removing the Boc protecting group in a mixed solution of dichloromethane and trifluoroacetic acid to obtain the compound.
The invention also provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, characterized by its use as phosphodiesterase PDEs and/or TNF- α inhibitors; for the prevention and/or treatment of inflammatory or allergic diseases; inhibiting phosphodiesterase activity; inhibiting the release of TNF- α; inhibiting neutrophilia or eosinophilia; alleviating the symptoms of inflammatory or allergic diseases; preventing and/or treating pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis, sepsis, gastritis, immune inflammation, allergic inflammation, eczema, dermatitis, asthma, lung infiltration, ulcerative conjunctivitis, caused by TNF-alpha release, eosinophilia or neutrophilia, and/or activation of phosphodiesterase PDEs; preventing and/or treating a disease of the nervous system or a disease of the cardiovascular system; inhibition of Abeta aggregates and/or CoCl 2 Induced nerve cell and/or cardiac muscle cell damage; reversing oxidative low density lipoprotein ox-LDL induced vascular endothelial cell damage; protecting neuronal or cardiovascular cells; preferably, the cardiovascular disease comprises arteriosclerosis, heart failure, angina pectoris, ischemic injury caused by myocardial cell or vascular endothelial cell injury; preferably, the neurological disorder comprises alzheimer's disease, memory loss, dementia, stroke, schizophrenia, depression, anxiety, parkinson's disease caused by nerve cell damage.
The invention also provides pharmaceutical use (use for preparing a medicament) of the compound or the pharmaceutically acceptable salt thereof, which is used for preventing and/or treating the use. Also provided is the use of a compound as described above, or a pharmaceutically acceptable salt thereof, for the preparation of an agent which inhibits phosphodiesterase PDEs and/or TNF-alpha, inhibits neutrophilia or eosinophilia.
The present invention also provides a pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof; optionally further comprising a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is a tablet, an oral liquid, an aerosol, a pill, a capsule, a granule, an ointment, a drop pill, a syrup, a powder, a granule, a tincture, a powder injection or an injection.
The invention provides a new-structure benzoylguanidine derivative, which comprises compounds ML-1, ML-2, ML-3, ML-4, ML-5, ML-6, ML-7 and ML-8, and the structural formulas are respectively as follows:
Figure BDA0003637356330000061
the invention also provides a preparation method of the new-structure benzoylguanidine derivative, which is characterized by comprising the following steps:
condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid serving as an initial raw material with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc under the action of diisopropylcarbodiimide, recrystallizing methanol, removing a Boc protecting group under the action of trifluoroacetic acid, dissolving saturated sodium bicarbonate to separate out a solid, filtering, and recrystallizing with ethanol to obtain compounds ML-5 and ML-6;
or 3-cyclopentanyloxy-4-alkoxybenzoic acid is used as a starting material, dissolved in dichloromethane, condensed with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc, added with a condensing agent, filtered after the reaction is completed, vacuum-filtered, distilled under reduced pressure, recrystallized under ice methanol, and then Boc protecting groups are removed under the action of trifluoroacetic acid to obtain compounds ML-1 and ML-2;
or 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentyloxy-4-alkoxybenzoic acid reacts with thionyl chloride in a tetrahydrofuran solvent to obtain an active intermediate, wherein the reaction temperature is 20-120 ℃, and the reaction time is 1-24 hours; and reacting the Boc protected 4-guanidino-1-butylamine (or 4-guanidino-1-propylamine) with sodium hydroxide in a dichloromethane solution to obtain activated amino anions at the reaction temperature of 0-100 ℃ for 1-10 hours, slowly adding an active intermediate into the activated amino anions for 1-24 hours, then removing the Boc protecting group from a dichloromethane and trifluoroacetic acid mixed solution, and recrystallizing the obtained crude product with ethyl acetate to obtain the compounds ML-7, ML-8, ML-3 and ML-4.
Further: the compounds also include pharmaceutically acceptable salts thereof, and can be obtained by a method of neutralizing a base with an inorganic acid or an organic acid.
Further: the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; the organic acid comprises carboxylic acid, thioacid, sulfonic acid, acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic 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, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, or naphthalene-2-sulfonic acid.
Further: the compounds or pharmaceutically acceptable salts thereof also include the D form, L form or D, L-mixtures thereof.
Further: the compounds or pharmaceutically acceptable salts thereof also include stereoisomers thereof, preferably, enantiomers and diastereomers.
The invention also provides application of the new-structure benzoylguanidine derivative in preparing a medicament for preventing and treating inflammatory diseases or allergic diseases.
Further, the compound or a pharmaceutically acceptable salt thereof can alleviate symptoms of inflammatory diseases or allergic diseases by inhibiting phosphodiesterase activity, inhibiting TNF-alpha release, and inhibiting neutrophilia or eosinophilia.
Further: the phosphodiesterase is PDE4, PDE2, PDE3, PDE5 and PDE10.
Preferably, the following components: the phosphodiesterase is PDE4.
Further: the inflammatory or allergic disease comprises pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis, sepsis, gastritis, immune inflammation, allergic inflammation, eczema, dermatitis, asthma, lung infiltration, ulcerative conjunctivitis caused by TNF-alpha release, eosinophilia or neutrophilia and/or activation of phosphodiesterase PDEs.
Further: the inflammatory or allergic disease also includes inflammatory diseases associated with inhibition of TNF- α 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; inflammatory diseases or allergies associated with eosinophilia include bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, gastric ulcers, gouty arthritis, eczema, allergic vasculitis, eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (lung infiltration with eosinophilia), urticaria, crohn's disease, psoriasis and keratosis.
Further: the compounds or pharmaceutically acceptable salts thereof can also be used to treat infections associated with TNF including viral infections, malaria, leishmaniasis, fever from infection, muscle pain from infection, AIDS and cachexia.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for preventing and treating nervous system diseases or cardiovascular system diseases.
And further: the compound or the pharmaceutically acceptable salt thereof can inhibit A beta aggregate and/or CoCl 2 Induced nerve cell and/or myocardial cell injury, or vascular endothelial cell injury induced by effectively reversing oxidized low density lipoprotein ox-LDL, thereby achieving the effect of protecting nerve cells or cardiovascular cells。
Further: the cardiovascular diseases comprise arteriosclerosis, heart failure, angina and ischemic injury caused by myocardial cell or vascular endothelial cell injury; the nervous system diseases include Alzheimer's disease, amnesia, dementia, apoplexy, schizophrenia, depression, anxiety and Parkinson's disease caused by nerve cell injury.
Further: the nervous system disease or cardiovascular system disease further comprises memory loss, intermittent claudication, hyperlipidemia, hyperglycemia, benign prostatic hyperplasia, pollakiuria, nocturia, incontinence, and urinary calculus-induced striated pain and sexual dysfunction.
Further: the medicine can be tablet, oral liquid, aerosol, pill, capsule, granule, unguent, dripping pill, syrup, powder, granule, tincture, powder for injection or injection.
Further: the medicament is administered orally, parenterally, intravenously, transdermally, topically, by inhalation, and intranasally.
Further: the dose of the drug is administered as a single dose once a day, or is divided into two or more doses each of 0.001-500mg per day.
And further: the medicament also comprises at least one of an adjuvant, a carrier and an additive.
Further: the carrier comprises calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methyl cellulose, talc, highly dispersed silicon dioxide, silicone oil, stearic acid, gelatin, agar, vegetable or animal fats and oils, polyethylene glycol.
Further: the adjuvants include sweeteners, flavoring agents, preservatives, stabilizers, wetting agents, osmotic agents, emulsifiers, coating agents, cosolvents, salts for controlling osmotic pressure or for buffering, sugars or sugar alcohols and/or viscosity regulators.
Further: the additive comprises tartrate and citrate buffer, ethanol and complexing agent.
Further: for viscosity control, the additives can also use liquid polyethylene oxide, microcrystalline cellulose, polyvinylpyrrolidone, dextran or gelatin.
And further: oil suspensions for parenteral or topical application may contain synthetic or semi-synthetic oils of vegetable origin, including liquid fatty acid esters thereof having from 8 to 22 carbon atoms in the fatty acid chain, including palmitic, lauric, tridecanoic, margaric, stearic, eicosanoic, myristic, behenic, pentadecanoic, linoleic, elaidic, basilic, erucic or oleic acid, which are esterified with mono-and trihydric alcohols having from 1 to 6 carbon atoms, including methanol, ethanol, propanol, butanol, pentanol or isomers thereof, ethylene glycol or glycerol; the fatty acid ester includes Miglyole, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG-6 decanoic acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, waxy fatty acid esters such as synthetic duck tail gland fat, isopropyl esters of coconut oil fatty acids, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, fatty acid esters of polyhydric alcohols; silicone or fatty alcohols including isotridecanol, 2-octyldodecanol, cetostearyl or oleyl alcohol, oleic acid and vegetable oils including castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil can also be used.
Further: as solvents, gel formers and cosolvents, water or alcohols are used including ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, adipates, propylene glycol, glycerol, dipropylene glycol, tripropylene glycol, waxes, methyl cellosolve, esters, wulin, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydroxypyran, cyclohexanone.
Further: as film forming agents, cellulose ethers which are soluble or swellable in water and organic solvents are used, including hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches, sodium carboxymethylcellulose, polyacrylic acid, polyisobutylene acid and its salts, sodium pullulan hemiglycolate, alginic acid or propylene glycol alginate vinegar as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
Further: as other adjuvants, glycerol, paraffin of different viscosity, triethanolamine, collagen, allantoin, novantisolysure can also be used.
Further: surfactants, emulsifiers or wetting agents can also be included in the medicament, including sodium lauryl sulfate, fatty alcohol ether sulfates, disodium N-lauryl- β -iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate, cetyl alcohol, lecithin, glycerol stearate, polyoxyethylene stearate, alkylphenol polyglycol ether, ethoxylated cetyl trimethylammonium or alkyl or dialkyl polyglycol ether orthophosphoric acid ethanolamine salt; stabilizers include montmorillonite or colloidal silica; antioxidants including tocopherol or butylated hydroxyanisole; preservatives include parabens.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing phosphodiesterase PDEs and/or TNF-alpha inhibitors.
Further: the phosphodiesterases include PDE4, PDE2, PDE3, PDE5 and PDE10.
Preferably: the phosphodiesterase is PDE4.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the novel-structure benzoylguanidine derivative prepared by the invention has a novel structure, and pharmacological experiments prove that the novel-structure benzoylguanidine derivative has good effects of inhibiting phosphodiesterase activity, TNF-alpha release and neutrophilia or eosinophilia, further relieves symptoms of inflammatory diseases or allergy, achieves the effects of preventing and treating the inflammatory diseases or the allergy, and can also inhibit nerve cell damage induced by Abeta aggregates or inhibit CoCl 2 Induced hypoxic damage to nerve cells or cardiac muscle cells, withEffectively reverse ox-LDL damage of vascular endothelial cells, further increase the activity of nerve cells or myocardial cells, avoid the injury of the vascular endothelial cells by oxidized low density lipoprotein, and achieve the effect of protecting the nerve cells or cardiovascular cells. The new-structure benzoyl guanidine derivative has good treatment effect on various diseases, has good safety and has further development value.
The terminology convention:
"stereoisomers" or "optical isomers" are compounds having the same chemical composition but differing arrangements of atoms or groups in space. It includes "diastereoisomers" and "enantiomers"
"diastereoisomers" are stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example: melting point, boiling point, spectral characteristics and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis, crystallization, using, for example, chiral HPLC columns in the presence of resolving agents or chromatography.
"enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. The mixture of 50.
"alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C as used herein 1 -C 6 Alkyl represents an alkyl group having 1 to about 6 carbon atoms. When C is used in combination with another group herein 0 -C n When alkyl, with (phenyl) C 0 -C 4 Alkyl is an example, a group being specified, in which case phenyl is via a single covalent bond (C) 0 ) Either directly bonded or attached through an alkyl chain having the indicated number of carbon atoms (in this case, 1 to about 4 carbon atoms). Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isoPropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
"alkenyl" or "alkenyl" refers to straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, such as: c 2 -C 8 、C 2 -C 6 And C 2 -C 4 An alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.
"cycloalkyl" preferably refers to monocyclic, bicyclic, tricyclic, bridged, spiro cyclic alkyl groups having 3-15 carbon atoms; preferred are cyclopropane, cyclopentane, cyclohexane, and the like.
"alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.
The term "heterocycle" means a 5-to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing from 1 to about 4 heteroatoms selected from N, O and S with the remaining ring atoms being carbon, or a 7-to 11-membered saturated, partially unsaturated, or aromatic heterocyclic system and a 10-to 15-membered tricyclic ring system containing at least 1 heteroatom in a polycyclic ring system selected from N, O and S and up to about 4 heteroatoms independently selected from N, O and S in each ring in the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that it is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on carbon or nitrogen atoms, as long as the resulting compounds are stable. The nitrogen atoms in the heterocycle may optionally be quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not more than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridazinyl (pyridizinyl), pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl (benz [ b ] thiophenyl), isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.
"aryl" or "heteroaryl" means a stable 5-or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S and the remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl group is no greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. The nitrogen atoms in the heterocycle may optionally be quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such 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, thereby forming, for example, [1,3] dioxazolo [4,5-c ] pyridinyl. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples.
Example 1: synthesis of benzoyl guanidine derivative benzyl ester compound
1. Synthesis of the general Compound 4-guanidinobutane-3-cyclopropylmethoxy-4-difluoromethoxybenzyl
Using commercially available 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as starting material, dissolving 35g in 100mL of anhydrous dichloromethane, stirring to dissolve completely, and adding dimethylaminopyridine p-toluenesulfonate in portions60g, after the solution is clarified, adding 32.5g of Boc protected 4-guanidino-1-butanol, stirring to dissolve, then adding 38.5g of diisopropylcarbodiimide, stirring overnight at room temperature, after the TLC detection reaction is finished, firstly filtering off insoluble substances, then distilling under reduced pressure to remove dichloromethane, then adding frozen methanol ice frozen in advance until white crystals are separated out, and filtering to obtain about 25.3g of white powdery crystal precursor. Precursor compound 4.0mM was taken and added to 1:1 in 10mL of a mixed solution of dichloromethane and trifluoroacetic acid, and reacting at room temperature for 5 hours, and then determining whether the reaction is completed by TLC. Distilling under reduced pressure to remove dichloromethane, washing with petroleum ether for 3 times, adding appropriate amount of saturated NaHCO 3 Adjusting the pH of the solution to 8-11, separating out a solid, and then filtering to obtain 4-guanidinobutane-3-cyclopropanyloxy-4-difluoromethoxybenzyl, namely representing a product ML-5, wherein the data of a nuclear magnetic resonance hydrogen spectrum and a carbon spectrum are as follows:
Figure BDA0003637356330000131
compound ML-5 hydrogen spectrum: 1 H 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).
compound ML-5 carbon spectrum: 13 C 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. using the classical acid-alcohol condensation method described above, compounds ML-6, ML-1, ML-2 can be synthesized as follows:
Figure BDA0003637356330000132
compound ML-6 hydrogen spectrum: 1 H 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).
compound ML-6 carbon Spectrum: 13 C 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 BDA0003637356330000133
compound ML-1 hydrogen spectrum: 1 H 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).
compound ML-1 carbon spectrum: 13 C 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 BDA0003637356330000141
compound ML-2 hydrogen spectrum: 1 H 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).
compound ML-2 carbon Spectrum: 13 C 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).
example 2: synthesis of benzoylguanidine derivative benzamide compound
1. Synthesis of the representative Compound 3-Cyclopentyloxy-N-4-guanidinobutane-4-methoxybenzylamine
2.83g NaH was added to 50mL dry tetrahydrofuran, and Boc protected4-guanidino-1-butylamine (78.2 mM) and reacted at room temperature for 1.5 hours for later use; dissolving 3-cyclopentanyloxy-4-methoxybenzoic acid (33.1 mM) in 200mL dry tetrahydrofuran, and slowly adding 8.6mL SOCl dropwise under ice-bath condition 2 After the completion of the addition, the mixture was refluxed for 6 hours, the solvent was distilled off, and the mixture was dissolved in 65mL of anhydrous tetrahydrofuran, and then the mixture was slowly dropped into the above reaction system at room temperature to react at 50 ℃ for 6 hours. Cool to room temperature, add 300mL of water and extract 3 times with 150mL of acetate, dry the combined organic phases over anhydrous sodium sulfate and add 1:1, reacting at room temperature for 6 hours, determining whether the reaction is finished deprotection or not by TLC (thin layer chromatography), then evaporating under reduced pressure to remove the solvent to obtain a crude product, recrystallizing the crude product by ethyl acetate to obtain a representative compound, namely 3-cyclopentanyloxy-N-4-guanidinobutane-4-methoxybenzamide, namely a compound ML-3, wherein the nuclear magnetic hydrogen spectrum and the carbon spectrum of the compound are as follows:
Figure BDA0003637356330000151
compound ML-3 hydrogen spectrum: 1 H 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).
compound ML-3 carbon spectrum: 13 C 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. using the classical acid-amine condensation method described above, compounds ML-7, ML-8, and ML-4 can be synthesized as follows:
Figure BDA0003637356330000152
compound ML-7 hydrogen Spectrum: 1 H 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).
compound ML-7 carbon spectrum: 13 C 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 BDA0003637356330000153
compound ML-8 Hydrogen Spectrum: 1 H 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).
compound ML-8 carbon spectrum: 13 C 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 BDA0003637356330000161
compound ML-4 hydrogen spectrum: 1 H 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).
compound ML-4 carbon spectrum: 13 C 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).
example 3: new structural benzoyl guanidine derivatives inhibit Phosphodiesterase (PDEs)
PDE4 activity was determined in enzyme preparations from rat polymorphonuclear lymphocytes (PMNL) and PDE2, PDE3, PDE5 and PDE10 activity was determined using isolated platelet PDE. Preventing coagulation of the extracted rat blood with citrate; separating the platelet rich plasma from the red blood cells and white blood cells in the supernatant by centrifugation at room temperature; platelets were then lysed by sonication and reserved for use in PDE3, PDE5 and PDE10 assays. For determining PDE2 activity, the cytoplasmic platelet fraction was purified by a NaCl gradient on an anion exchange column, obtaining the PDE2 peak for the determination; after further sedimentation by dextran, PMNL cells for PDE4 assay were isolated by Ficoll gradient centrifugation. After washing the PMNL cells 2 times, residual erythrocytes were removed by lysis for 6 minutes at 4 ℃ by adding 10mL hypotonic lysis buffer. The still intact PMNL cells were washed twice more with PBS and by sonication, centrifuged at high speed for 1h at 4 ℃ and the supernatant obtained contains the PDE4 cytoplasmic fraction for use as starting material for the enzymes in the PDE4, PDE2, PDE3, PDE5 and PDE10 assays described below.
The Activity of each enzyme was determined using a phosphodiesterase Activity Assay kit (purchased from Abcam, inc., cat # ab13940, PDE Activity Assay kit, colorimetric): the operation method is modified appropriately, the protease provided by the kit is replaced by the protease prepared by the method, and other methods are strictly detected according to the operation instruction: adding 20 microliter cAMP substrate, adding 15 microliter determination buffer solution, adding 10 microliter 5' nucleosidase, mixing uniformly, adding test compound with proper concentration, adding extracted and purified PDE enzyme, incubating at 30 ℃ for 30 minutes, adding Green Assay reagent to detect decomposed phosphate ions, mixing for 20 minutes to obtain uniform color, and determining OD620nm to calculate the inhibitory activity of the compound on the PDE enzyme.
Results are shown in Table 1, IC for PDE4 inhibition determined for each compound prepared in example 1 50 Value of 10 -12 -10 -7 M, a factor of 20-10000 for PDE types 2, 3, 5 and 10, indicating that the novel benzoylguanidine derivatives have the effect of inhibiting PDE4 activity and can be used as strong PDE4 inhibitors.
Table 1: IC of compounds for inhibiting PDE4 50 Value of
Compound (I) IC for PDE inhibition 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
Example 4: new structural benzoyl guanidine derivative for inhibiting TNF-alpha release from nasal polyp cell
Nasal polyp tissue was washed with RPMI 1640, then lysed with protease (2.5 mg/mL), collagenase (1.0 mg/mL), hyaluronidase (0.5 mg/mL) and DNase (0.1 mg/mL) for 150 minutes at 37 ℃ (1 g tissue and 4mL of RPMI 1640 containing the enzyme). The resulting mixture of cells (epithelial cells, monocytes, macrophages, lymphocytes, fibroblasts and granulocytes) was filtered, washed by repeated centrifugation in culture solution, passively sensitized by the addition of human IgE, and the cell suspension diluted to a concentration of 2 million cells/mL in RPMI 1640 (supplemented Hang Shengsu, 10% fetal bovine serum, 2mM glutamine and 25mM Hepes). The suspension was dispensed onto 6 well cell culture plates (1 ml/well). Cells were pre-incubated for 30 minutes with varying concentrations of test substance and then stimulated to release TNF- α by addition of anti-IgE, with maximum release into the medium occurring after about 16 hours. During this period, the cells were cultured at 37 ℃ in an incubator containing 5% carbon dioxide. The medium (supernatant) was collected by centrifugation and maintained at-80 ℃ until cytokine determination. TNF- α was measured in the supernatant using an ELISA kit.
Cells not stimulated with anti-IgE produce hardly any TNF- α, whereas stimulated cells secrete large amounts of TNF- α, which can be reduced by PDE4 inhibitors to a dose-dependent extent. IC was calculated from the percent inhibition of different concentrations of compound (TNF-alpha release of cells stimulated with anti-IgE = 100%) 50 (concentration to achieve 50% inhibition). Results IC of the compound prepared in example 1 are shown in Table 2 50 Value of 10 -10 -10 -4 M shows that the new-structure benzoylguanidine derivative has the function of inhibiting TNF-alpha release and can be used as a TNF-alpha inhibitor.
Table 2: results of inhibition of TNF-alpha Release by Compounds
Figure BDA0003637356330000181
Example 5: novel structure of benzoylguanidine derivative for inhibiting eosinophilia in rat allergy model
50mg of V-grade ovalbumin, 100mg of aluminum hydroxide and 6 multiplied by 10 inactivated bordetella pertussis 9 Dissolving in 1ml of normal saline to obtain suspension gel, and proportionally expanding to obtain 12ml of sensitizing solution (for preventing wall-hanging residue loss in 10 injections, preparing multiple preparations)2ml out). Sensitization on day 1: the rats in the blank group are subjected to intraperitoneal injection of 1ml of normal saline, and the rats in the model group are subjected to intraperitoneal injection of 1ml of sensitizing solution for sensitization; challenge started on day 15: two groups of rats are respectively placed in atomization boxes with the same size, 6ml of physiological saline is given to a blank group for atomization excitation, 6ml of 5%V-level ovalbumin solution is given to a model group for atomization excitation, the stimulation is carried out once a day, each time is 30min, and the continuous stimulation is carried out for 10 days. The test compounds were administered intraperitoneally or orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethyl cellulose 2 hours prior to allergen challenge. The control group was treated with vehicle depending on the administration form of the test compound. Fixing four limbs of a rat at the end of an experiment, disinfecting the neck by using 75% alcohol, fully exposing the trachea, inserting a trachea cannula needle (the needle head is slightly ground flat) near the throat, and inserting the needle head into a certain position without exceeding the bifurcation of the trachea; lavage with 2mL precooled PBS was repeated 3 times, alveolar lavage fluid was collected into EP tubes, centrifuged at 1000rpm at 4 ℃ and cells were collected, stained with Reishi Giemsa and counted under microscope for differential cell counting.
The leucocytes are a crucial cell type in the immune process, and the differential cell count can effectively analyze the change of the leucocyte proportion in alveolar lavage fluid BALF. During the pathogenesis, the inflammatory cells that infiltrate their bronchi are mainly lymphocytes and eosinophils. Lymphocytes amplify the inflammatory response of eosinophils in the bronchial mucosa and, as eosinophils increase, they increase their accumulation, activation and interaction with other inflammatory cells, mediators, cytokines in the lung, thus exacerbating the hypersensitivity.
As shown in Table 3, the compound prepared in example 1 effectively inhibited eosinophilia symptoms by 86% -95% after intraperitoneal administration at a dose of 1-5mg/kg, and each compound inhibited eosinophilia symptoms by 81-93% after oral administration at a dose of 10-50 mg/kg. Therefore, the new-structure benzoylguanidine derivatives of the present invention are suitable for the treatment and prevention of diseases associated with eosinophilic activity.
Table 3: results of inhibition of eosinophilia with Compounds
Figure BDA0003637356330000191
Example 6: new structure benzoyl guanidine derivative for inhibiting neutral leucocytosis caused by Lipopolysaccharide (LPS)
The inhibitory effect of the compound prepared in example 1 on lung neutrophil infiltration was tested in male Wistar rats (200 ± 20 g). On the day of the experiment, animals were individually placed in an open 1L plexiglass box that was connected to a head-nose exposure device. Animals were exposed to an aerosol of lipopolysaccharide suspension (LPS 100 μ g/mL dissolved in PBS solution containing 0.1% hydroxylamine) (LPS challenge) for 45 minutes, and standard controls were sprayed with an aerosol of PBS solution containing 0.1% hydroxylamine for 45 minutes. After 6 hours of LPS challenge, a 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-hydroxyethyl cellulose 2 hours prior to LPS challenge. The control group was treated with the vehicle depending on the administration form of the test substance. Fixing four limbs of a rat at the end of an experiment, disinfecting the neck by using 75% alcohol, fully exposing the trachea, inserting a trachea cannula needle (the needle head is slightly ground flat) near the throat, and inserting the needle head into a certain position without exceeding the bifurcation of the trachea; lavage with 2mL precooled PBS was repeated 3 times, alveolar lavage fluid was collected into EP tubes, centrifuged at 1000rpm at 4 ℃ and cells were collected, stained with Reishi Giemsa and counted under microscope for differential cell counting.
The results are shown in Table 4, and the compounds of the present invention inhibited neutrophilia symptoms by 85% -95% after oral administration at a dose of 10-50 mg/kg. Therefore, the new-structure benzoyl guanidine derivative of the present invention is suitable for treating and preventing diseases related to the activity of neutrophils, and the compounds ML-5 and ML-8 have the best effect.
Table 4: results of inhibition of neutrophilia by Compounds
Figure BDA0003637356330000201
Example 7: protective effect of new-structure benzoylguanidine derivative on A beta aggregate-induced nerve cell injury
The inhibition effect of the compound prepared in example 1 on the nerve cell cytotoxicity induced by the Abeta is observed by taking the cell viability without adding the Abeta 1-42 as a negative control, and the specific implementation steps are as follows: inoculating PC12 cells into MEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, adding the A beta protein oligomer, adding the compound solution to each well after 2 hr, adding the same amount of sterile water to the model group, and incubating for 24 hr. After completion, the cell viability was measured by the MTT method. Each time three replicates were performed and the experiment was repeated three times.
The results are shown in table 5, and after treatment at the administration concentration of 10 μmol/L, the compounds of the present invention all have good nerve cell protection effects, and have obvious inhibition effects on A β aggregate induced nerve cell damage. Therefore, the new-structure benzoylguanidine derivatives of the present invention are useful for the treatment and prevention of diseases associated with neuroprotection.
Table 5: results of protecting neuronal cells with Compounds
Group of Cell viability (%)
Model set 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
Example 8: novel structure of benzoylguanidine derivative p-CoCl 2 Protective action for inducing hypoxia injury of nerve cell and cardiac muscle cell
With no addition of CoCl 2 Cell viability of induced nerve cells PC12 and cardiomyocytes H9C2 was negative control, and the compound prepared in example 1 was observed against induced CoCl 2 The specific implementation steps of the generated inhibition effect of the hypoxia injury of the nerve cells and the cardiac muscle cells are as follows: inoculating PC12 and H9C2 cells into MEM or DMEM complete culture solution, culturing in 96-well plate, incubating in constant temperature cell incubator for 24 hr, adding pre-dissolved CoCl-containing solution 2 After 2h, each compound solution was added to each well of each compound group at a concentration of 50. Mu. Mol/L, and the model group was added with an equal amount of sterile water and incubated in the incubator for another 48 hours. After completion, the cell viability was measured by the MTT method. Each time three replicates were performed and the experiment was repeated three times.
As shown in tables 6 and 7, the compounds of the present invention have excellent effects of protecting nerve cells and myocardial cells from hypoxia injury after treatment at a dose concentration of 50. Mu. Mol/l. Therefore, the new-structure benzoyl guanidine derivative of the present invention is suitable for treating and preventing diseases related to damage of nerve cells and cardiovascular system.
Table 6: effect of Compounds on hypoxia-induced nerve injury
Figure BDA0003637356330000211
Figure BDA0003637356330000221
Table 7: protective effect of compound on cardiovascular cells caused by hypoxia
Group of Cell survival rate (%)
Model set 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
Example 9: new-structure phenylguanidine derivative with inhibition effect on oxidative low-density lipoprotein (ox-LDL) -induced vascular endothelial cell damage
HUVEC of vascular endothelial cells are inoculated in MEM complete culture solution, and the protective effect of the compound on vascular endothelial atherosclerosis injury induced by ox-LDL is observed by taking a group of non-oxidized low-density lipoprotein ox-LDL as a negative control. The method comprises the following specific steps: HUVEC cells are inoculated in MEM or DMEM complete culture solution, placed in a 96-well plate for culture, placed in a constant-temperature cell culture box for incubation for 24 hours, and then an induction solution containing ox-LDL dissolved in advance is added, and after 2 hours, 50 mu M of phenylguanide derivative is added into each well, and a group without adding ox-LDL is used as a negative control. After completion, the content of IL-6 inflammatory factor was measured by ELISA.
The results are shown in Table 8, that the benzoyl guanidine derivatives can effectively inhibit the increase of IL-6 in vascular endothelial cells stimulated by oxidative low-density lipoprotein ox-LDL, and that the benzoyl guanidine derivatives with the novel structure are suitable for preventing and treating diseases related to vascular endothelial cell injury.
Table 8: inhibition of ox-LDL induced endothelial cell atheroma
Figure BDA0003637356330000222
Figure BDA0003637356330000231
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or equivalents may be substituted for some of the features thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.

Claims (10)

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure shown below:
Figure FDA0003637356320000011
wherein the content of the first and second substances,
a is O or NH;
b is a linking group which is a linear or branched group having a length of 1 to 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 group;
f is absent; or is, straight-chain or branched C 1 -C 6 Alkylene, which may be interrupted by O, NR 5 Or an S atom;
R 1 is H, substituted or unsubstituted C 1 -C 6 An alkyl group; substituted or unsubstituted C 1 -C 6 A carbonyl group;
R 2 、R 3 、R 4 and R 5 Each independently is H, deuterium, halogen, hydroxyl, amino, carboxyl, amido, ester group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted alkyl groupSubstituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylcarboxyl group, substituted or unsubstituted alkyl ester group, substituted or unsubstituted alkyl-OH group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkyl-NH group 2 Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl;
the substitution refers to deuterium, halogen, hydroxyl, amine group, carboxyl group, amide group, ester group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylcarboxyl group, substituted or unsubstituted alkyl ester group, substituted or unsubstituted alkyl-OH, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkyl-NH 2 Substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure shown below:
Figure FDA0003637356320000021
3. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure shown below:
Figure FDA0003637356320000022
wherein n is an integer from 1 to 8.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: f is absent or- (CH) 2 ) m-, wherein m is an integer of 0 to 6.
5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: and E is a substituted or unsubstituted 3-10 membered monocyclic or bicyclic alkyl group.
6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: e is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or a substituted or unsubstituted 3-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, which is one or more of the following compounds:
Figure FDA0003637356320000031
8. a process for the preparation of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising the steps of:
condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentanyloxy-4-alkoxybenzoic acid with 4-guanidino-1-butanol or 4-guanidino-1-propanol protected by Boc, and removing the Boc protective group under the action of trifluoroacetic acid to obtain a compound;
or condensing 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid or 3-cyclopentyloxy-4-alkoxybenzoic acid with 4-guanidino-1-butylamine or 4-guanidino-1-propylamine protected by Boc, and then removing the Boc protecting group in a mixed solution of dichloromethane and trifluoroacetic acid to obtain the compound.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as phosphodiesterase PDEs and/or TNF- α inhibitors; for preventing and/or treating inflammatory diseasesOr allergic diseases; inhibiting phosphodiesterase activity; inhibiting the release of TNF- α; inhibiting neutrophilia or eosinophilia; alleviating the symptoms of inflammatory or allergic diseases; preventing and/or treating pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis, sepsis, gastritis, immune inflammation, allergic inflammation, eczema, dermatitis, asthma, lung infiltration, ulcerative conjunctivitis, caused by TNF-alpha release, eosinophilia or neutrophilia, and/or activation of phosphodiesterase PDEs; preventing and/or treating a disease of the nervous system or a disease of the cardiovascular system; inhibition of Abeta aggregates and/or CoCl 2 Induced nerve cell and/or cardiomyocyte damage; reversing oxidative low density lipoprotein ox-LDL induced vascular endothelial cell damage; protecting neuronal or cardiovascular cells; preferably, the cardiovascular disease comprises arteriosclerosis, heart failure, angina pectoris, ischemic injury caused by myocardial cell or vascular endothelial cell injury; preferably, the neurological disease includes alzheimer's disease, memory loss, dementia, stroke, schizophrenia, depression, anxiety, parkinson's disease caused by nerve cell damage.
10. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof; optionally further comprising a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is a tablet, an oral liquid, an aerosol, a pill, a capsule, a granule, an ointment, a drop pill, a syrup, a powder, a granule, a tincture, a powder injection or an injection.
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