CN109568304A - Application of 2,2- (the 4- carboxyl decoyl amido) methyl benzoate in preparation treatment diseases associated with inflammation drug - Google Patents

Application of 2,2- (the 4- carboxyl decoyl amido) methyl benzoate in preparation treatment diseases associated with inflammation drug Download PDF

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CN109568304A
CN109568304A CN201811507809.8A CN201811507809A CN109568304A CN 109568304 A CN109568304 A CN 109568304A CN 201811507809 A CN201811507809 A CN 201811507809A CN 109568304 A CN109568304 A CN 109568304A
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carboxyl
methyl benzoate
receptor
inflammation
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CN109568304B (en
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胡庆华
李环球
周梦泽
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Jingzhou Jinfeng Pharmaceutical Development Co.,Ltd.
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China Pharmaceutical University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Abstract

The invention discloses the application of 2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt in preparation treatment diseases associated with inflammation drug.Compared with the existing technology, present invention firstly discovers that compound 2,2- (4- carboxyl decoyl amido) methyl benzoate have P2Y14The function of acceptor inhibitor, to P2Y14Receptor related inflammation significantly inhibits, and may be used as the anti-inflammatory drug that preparation acts on P2Y14 receptor.

Description

2,2- (4- carboxyl decoyl amido) methyl benzoate treats diseases associated with inflammation medicine in preparation Application in object
Technical field
The invention belongs to compound new application technical fields, and in particular to 2,2- (4- carboxyl decoyl amido) methyl benzoates Or application of its pharmaceutical salt in preparation treatment diseases associated with inflammation drug.
Background technique
G protein coupled receptor (GPCRs) is divided into three classes according to the G-protein type that downstream is coupled: GsAlbumen, GiAlbumen, GqEgg White and G12/13Four kinds of albumen, different signals is mediated to transmit respectively.G protein coupled receptor is found to exist only in eukaryon life at present In object.It can include neurotransmitter, telergone, polypeptide and small molecule compound etc. in conjunction with the ligand of g protein coupled receptor. G protein coupled receptor takes part in the occurrence and development of many diseases, therefore is important drug targets, reports existing market according to statistics Upper about 30% drug is using g protein coupled receptor as target spot.Gq/GiThe subfamily that there are many coupled receptors, comprising: (1) purinoceptor family (Purinergic Receptor), member has P1, P2；(2) adenosine receptor family (Adenosine Receptor), member has A1, A2A, A2B and A3.Purinoceptor family is adjusting myocardial oxygen consumption, coronary flow, is resisting Inflammation, vascular reactivity, Apoptosis, cytokine secretion etc. play an important role.
P2Subtribe can divide 5 hypotypes: P2X, P2Y, P2Z, P2U and P2T according to Tissue distribution and pharmacological characteristic again.Wherein P2X, P2Z belong to ion channel receptor；P2Y, P2U and P2T belong to g protein coupled receptor.It has been reported that G-protein coupling by The P2Y receptor family of body includes 8 kinds of hypotype (P2Y1、2、4、6、11、12、13、14), it is distributed widely in various cells and tissue, and Tetraploid rice is low between each hypotype, therefore different hypotypes has very high selectivity to ligand.Wherein P2Y1、2、4、6Receptor In conjunction with GqAnd activate PLC approach；P2Y12、13、14Receptor combination GiInhibit the activity of adenyl cyclase；P2Y4Coupled receptors Gq/Gi Two kinds of G-proteins；P2Y11Coupled receptors Gq/GsTwo kinds of G-proteins.The receptor-mediated immunological regulation of P2Y, platelet aggregation, smooth muscle are thin A series of biological effects such as born of the same parents' proliferation.P2Y14Receptor is primarily present in heart, placenta, adipose tissue, gastrointestinal tract and periphery In immunocyte, it can be improved the hypersensitivity of microglia cell, the mobility of neutrophil leucocyte；Increase mast cell to release Medium and kidney intercalary cells inflammation are put, and is able to suppress astroglia release matrix metallo-proteinase in central nervous system And tumor necrosis factor.It has recently been demonstrated that in P2In the mouse that Y14 acceptor gene knocks out, P2Y14The antagonism of receptor Have the function of potentially treating diabetes.Also it has been reported that UDP and UDP-glu is as ligand activation P2Y14Receptor and inflammation, The diseases such as asthma have much relations.At present to P2Y14The research of acceptor inhibitor only reports the compound of 3 kinds of structure types (pyrimido piperidines, 2- naphthoic acid class and 3- substituted benzoyl acids), but also all in the preclinical study stage.Wherein activity and selection Property it is highest be 2- naphthoic acid class, however that there are dissolubilities is poor, oral bio is sharp for the inhibitor for the 2- naphthoic acid class formation reported at present The defects of expenditure is low, synthesizing and purifying difficulty is big, to further discussing structure-activity relationship and biological assessment brings bigger difficulty. Therefore the P2Y of new construction type is found14Receptor antagonist improves the problems such as druggability existing for 2- naphthalene acid inhibitors is poor, at For the P2Y that discovery activity is strong, selectivity is good14The new strategy of acceptor inhibitor.
Summary of the invention
Goal of the invention: in view of the above technical problems, the present invention provides 2,2- (4- carboxyl decoyl amido) methyl benzoates Or application of its pharmaceutical salt in preparation treatment diseases associated with inflammation drug.
Technical solution: in order to achieve the above object of the invention, the technical solution adopted in the present invention is as follows:
2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt are in preparation treatment diseases associated with inflammation drug In application, chemical structural formula is as follows:
It is preferred that:
The pharmaceutical salt includes hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzene sulphur Hydrochlorate, toluenesulfonate, fumarate or tartrate.
The diseases associated with inflammation is P2Y14The relevant disease of receptor.
The diseases associated with inflammation is acute gouty arthritis, rheumatoid arthritis, Osteoarthritis, Atherosclerosis Change, septicemia or pneumonia etc..
2,2- (the 4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt are able to suppress P2Y14Receptor.
2,2- (the 4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt are able to suppress macrophage inflammatory Reaction.
The present invention also provides the combinations containing 2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt Application of the object in preparation treatment diseases associated with inflammation drug.
It is preferred that the composition is with 2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt as work Property ingredient, in addition drug made by pharmaceutically acceptable auxiliary material.
2,2- (4- carboxyl decoyl amido) methyl benzoate of the present invention or its pharmaceutical salt are treating inflammatory disease It when sick, can be used alone, can also cooperate with other drugs and use simultaneously, or compound preparation is made together with other drugs It uses, can achieve the purpose that treat diseases associated with inflammation.
Pharmaceutically acceptable auxiliary material of the present invention refers to that the various routines needed for being added when preparing different dosage forms are auxiliary Material, such as diluent, binder, disintegrating agent, glidant, lubricant, corrigent, inclusion material, adsorbent material etc. are with routine Formulation method is prepared into any common oral preparation, for example, can be granule, powder, tablet, capsule, pill, Oral solution, decoction, pill etc..
Present invention firstly discovers that 2,2- (4- carboxyl decoyl amido) methyl benzoate not only has stronger P2Y14Receptor Inhibitory activity, moreover it is possible to significantly inhibit the THP-1 Cellular inflammatory reaction of urate crystals (MSU) induction, while be effectively improved the pass MSU The rat acute urarthritis that chamber injection induces is saved, synovial tissue is lowered and plants P2Y14The expression of receptor reduces serum and cunning The level of inflammatory factor in membrane tissue.These effects show that 2,2- (4- carboxyl decoyl amido) methyl benzoate has for acute The potentiality of the inflammatory diseases such as urarthritis are expected to preparation and act on P2Y14The anti-inflammatory drug of receptor.
Technical effect: compared with the existing technology, present invention firstly discovers that compound 2,2- (4- carboxyl decoyl amido) benzene Methyl formate has P2Y14The function of acceptor inhibitor, to P2Y14Receptor related inflammation significantly inhibits, Ke Yiyong Make the anti-inflammatory drug that preparation acts on P2Y14 receptor.
Detailed description of the invention
P2Y in the THP-1 cell that Fig. 1 induces MSU for 2,2- (4- carboxyl decoyl amido) methyl benzoate14Receptor protein The influence of overexpression, wherein data are THP-1 cell P2Y14The mean+SD (n=4) of receptor protein relative expression is used One-way anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * represents the P compared with model control group < 0.05, * * represent the P < 0.01 compared with model control group, and * * * represents the P < 0.001 compared with model control group)；
Fig. 2 is that 2,2- (4- carboxyl decoyl amido) methyl benzoate excessively discharges IL-1 β to the THP-1 cell that MSU is induced Influence, wherein data are the mean+SDs of IL-1 β level in THP-1 cell culture medium supernatant, use one-way Anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * represents P < 0.05, * * compared with model control group The P < 0.01 compared with model control group is represented, * * * represents the P < 0.001 compared with model control group)；
Fig. 3 is 2,2- (4- carboxyl decoyl amido) methyl benzoate in acute gouty arthritis synovial cells in rats P2Y14The influence that receptor protein is overexpressed, wherein data are 4 synovial cells in rats P2Y14Receptor protein relative expression's is averaged Value ± standard deviation, carrying out variance analysis with one-way anova, (### represents the P < 0.001 compared with normal group, and * * is represented and mould Type control group compares P < 0.01, and * * * represents the P < 0.001 compared with model control group)；
Fig. 4 is 2,2- (4- carboxyl decoyl amido) methyl benzoate to acute gouty arthritis rat blood serum IL-1 β water Increased influence is put down, wherein data are the mean+SDs of 10 rat blood serum IL-1 β levels, with one-way anova Carrying out variance analysis, (### represents the P < 0.001 compared with normal group, and * represents the P < 0.05 compared with model control group, and * * is represented The P < 0.01 compared with model control group, * * * represent the P < 0.001 compared with model control group)；
Fig. 5 is 2,2- (4- carboxyl decoyl amido) methyl benzoate to acute gouty arthritis synovial cells in rats IL-1 The horizontal increased influence of β, wherein data are the mean+SDs of 10 synovial cells in rats IL-1 β levels, use one-way Anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * represents P < 0.05, * * compared with model control group The P < 0.01 compared with model control group is represented, * * * represents the P < 0.001 compared with model control group)
Specific embodiment
Embodiment 1
Compound is as P2Y14The inhibitory activity evaluation experimental method of acceptor inhibitor:
Surely turn P2Y14The HEK293 cell strain of receptor is incubated in DMEM culture medium (green containing 10% fetal calf serum, 100U/ml Mycin and 100 μ g/ml streptomysins), it is seeded to culture plate before experiment, uses serum free medium instead, inoculum density is 1 × 105It is a Cells/well, cell is in 37 DEG C, 95%O2, 5%CO2Under the conditions of cultivate.IBMX is added and inhibits PDEs activity, to guarantee cAMP one In a higher level.The generation of cell cAMP is stimulated using (30 μM) of adenyl cyclase (AC) agonist Forskolin, in advance The test-compound (0.01,0.1,1,10,100nm) of various concentration is first added, using PPTN as positive control.1 μ is then added The P2Y of M14CAMP Glo is used after receptor stimulating agent UDPG, 4hTMAssay kit (PROMEGA Co.Ltd, the U.S.) detection The content of intracellular cAMP.IC is calculated according to the inhibiting rate to cAMP content50Value.
Embodiment 2
Test-compound inhibits the pharmacological research experimental method of the macrophage inflammatory reaction of urate crystals induction:
Human THP-1 cells are incubated in RPMI-1640 culture medium (containing 10% fetal calf serum, 100U/ml penicillin and 100 μ G/ml streptomysin), culture plate is seeded to before experiment, inoculum density is 1 × 105A cells/well, cell is in 37 DEG C, 95%O2, 5% CO2It is cultivated under damp condition.It is that macrophage is thin that every hole, which is added 100ng/ml PMA and is incubated for induction THP-1 cell differentiation for 24 hours, before experiment Born of the same parents.Test-compound (2.5,5,10 μM), PPTN (5 μM) and dexamethasone (5 μM) are added into culture medium in advance to be intervened, The urate crystals (MSU) of final concentration of 500 μ g/ml are added after 1h into cell, measure following index: Western after 6h Blot method detects P2Y in cell14The protein expression of receptor；Cell culture is detected by ELISA kit (Shenzhen Xin Bosheng) method The level of IL-1 β in base supernatant.
Embodiment 3
Test-compound is in whole animal level to the pharmacological experiment study side of the therapeutic effect of acute gouty arthritis Method:
Male cleaning grade SD rat, 200 ± 20g of weight, Free water food, daily 12h illumination, environment temperature is 25 ± 2 DEG C. Animal is divided into several groups: Normal group, model control group, administration group (test-compound, PPTN and dexamethasone), using one Secondary property joint cavity injection MSU induces acute gouty arthritis model, and Normal group and normal administration each group use equivalent Physiological saline enter articular cavity.Each administration group by joint cavity injection give test-compound (5,10,20mg/kg), PPTN (10mg/kg) and dexamethasone (10mg/kg).Using thread method detect rat articular Zhou Jing, minute point select 0h, 2h, 4h, 8h, 12h, for 24 hours, for 24 hours after, for 24 hours after rat eye rear vein beard take blood, be centrifuged under 10000 × g centrifugal condition 5min takes serum, is placed in 4 DEG C and saves backup.Then the neck that breaks puts to death animal, the quick Fen Qu synovial tissue of joint on ice platform, inspection Survey following index: Western Blot method detects P2Y in synovial tissue14The protein expression of receptor；By ELISA kit (Shenzhen Xin Bosheng) method detection serum, in synovial tissue IL-1 β level.
Experimental result
The compound of various concentration carries out P2Y14The inhibitory activity of receptor is tested, it is found that the compound has and inhibited to live well Property, half-inhibitory concentration IC50For 2.46nM.
Data are THP-1 cell P2Y in Fig. 114The mean+SD (n=4) of receptor protein relative expression, uses one- Way anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * represents the P < compared with model control group 0.05, * * represents the P < 0.01 compared with model control group, and * * * represents the P < 0.001 compared with model control group).As seen from the figure: MSU causes THP-1 cell P2Y14Receptor protein expression is significant to be increased, and modeling success is prompted；Various dose test composition can Different degrees of downward P2Y14Receptor protein expression, embodies significant difference compared with model control group；PPTN also embodies Expected effect is gone out, has shown that experimental result is genuine and believable.Dexamethasone is not shown to P2Y14The regulation of expression of receptor is made With.
Data are the mean+SDs of IL-1 β level in THP-1 cell culture medium supernatant in Fig. 2, use one-way Anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * represents P < 0.05, * * compared with model control group The P < 0.01 compared with model control group is represented, * * * represents the P < 0.001 compared with model control group).As seen from the figure: MSU is caused The horizontal significant raising of IL-1 β, prompts modeling success in THP-1 cell culture medium supernatant；Various dose test composition can IL-1 β is horizontal in different degrees of downward cell culture medium supernatant, and significant difference is embodied compared with model control group； PPTN and dexamethasone have also embodied expected effect, show that experimental result is genuine and believable.
Data are the mean+SDs of 10 rat different time points joint Zhou Jing in table 1, with one-way anova Carrying out variance analysis, (# represents the P < 0.05 compared with normal group, and ### represents the P < 0.001 compared with normal group, and * is represented and model Control group compares P < 0.05, and * * represents the P < 0.01 compared with model control group, and * * * represents the P < compared with model control group 0.001).As seen from the figure: MSU causes rat articular swelling, in 4h, 8h, 12h, shows significant difference for 24 hours, prompts modeling Success；Various dose test composition can be different degrees of alleviation MSU caused by rat articular week diameter increase, with model comparison Group more embodies significant difference；PPTN and dexamethasone have also embodied expected effect, show that experimental result is true It is credible.
Table 1: influence (cm) of the compound to acute gouty arthritis rat articular Zhou Jing
Data are 4 synovial cells in rats P2Y in Fig. 314The mean+SD of receptor protein relative expression, uses one- Way anova carries out variance analysis, and (### represents the P < 0.001 compared with normal group, and * * represents the P < compared with model control group 0.01, * * * represents the P < 0.001 compared with model control group).As seen from the figure: MSU causes lymphocyte of adjurant arthritis rat P2Y14Receptor protein table It is increased up to significant, prompts modeling success；Various dose test composition can be different degrees of downward synovial membrane P2Y14Receptor protein Expression, embodies significant difference compared with model control group；PPTN has also embodied expected effect, shows experimental result It is genuine and believable.Dexamethasone is not shown to P2Y14The regulating and controlling effect of expression of receptor.
Data are the mean+SDs of 10 rat blood serum IL-1 β levels in Fig. 4, are carried out with one-way anova (### represents the P < 0.001 compared with normal group, and * represents the P < 0.05 compared with model control group, and * * is represented and mould for variance analysis Type control group compares P < 0.01, and * * * represents the P < 0.001 compared with model control group).As seen from the figure: MSU causes rat blood serum The horizontal significant raising of IL-1 β, prompts modeling success；Various dose test composition can be different degrees of -1 β of downward serum IL Level embodies significant difference compared with model control group；PPTN and dexamethasone have also embodied expected effect, table Bright experimental result is genuine and believable.
Data are the mean+SDs of 10 synovial cells in rats IL-1 β levels in Fig. 5, with one-way anova Carrying out variance analysis, (### represents the P < 0.001 compared with normal group, and * represents the P < 0.05 compared with model control group, and * * is represented The P < 0.01 compared with model control group, * * * represent the P < 0.001 compared with model control group).As seen from the figure: MSU causes rat The horizontal significant raising of synovial tissue IL-1 β, prompts modeling success；Various dose test composition can be different degrees of downward it is sliding Membrane tissue IL-1 β is horizontal, and significant difference is embodied compared with model control group；PPTN and dexamethasone have also embodied pre- The effect of phase shows that experimental result is genuine and believable.

Claims (8)

1.2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt are in preparation treatment diseases associated with inflammation drug Application.
2. application according to claim 1, which is characterized in that the pharmaceutical salt includes hydrochloride, phosphate, sulfuric acid Salt, acetate, maleate, citrate, benzene sulfonate, toluenesulfonate, fumarate or tartrate.
3. application according to claim 1, which is characterized in that the diseases associated with inflammation is P2Y14The relevant disease of receptor.
4. application according to claim 1, which is characterized in that the diseases associated with inflammation is acute gouty arthritis, class Rheumatic arthritis, Osteoarthritis, atherosclerosis, septicemia or pneumonia.
5. application according to claim 1, which is characterized in that 2,2- (the 4- carboxyl decoyl amido) methyl benzoate or Its pharmaceutical salt is able to suppress P2Y14Receptor.
6. application according to claim 1, which is characterized in that 2,2- (the 4- carboxyl decoyl amido) methyl benzoate or Its pharmaceutical salt is able to suppress macrophage inflammatory reaction.
7. the composition containing 2,2- (4- carboxyl decoyl amido) methyl benzoate or its pharmaceutical salt treats inflammation in preparation Application in property disease medicament.
8. application according to claim 7, which is characterized in that the composition is with 2,2- (4- carboxyl decoyl amido) benzene Methyl formate or its pharmaceutical salt are as active constituent, in addition drug made by pharmaceutically acceptable auxiliary material.
CN201811507809.8A 2018-12-11 2018-12-11 Application of 2,2- (4-carboxyoctylamido) methyl benzoate in preparation of medicines for treating inflammatory diseases Active CN109568304B (en)

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YU J: "Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

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