CN101472588A - Application of 5-methyl 1-(substituted phenyl group)-2-(1H) pyridinone compound as anti-inflammatory medicament and alpha-tumor necrosis factor (TNF-alpha) - Google Patents
Application of 5-methyl 1-(substituted phenyl group)-2-(1H) pyridinone compound as anti-inflammatory medicament and alpha-tumor necrosis factor (TNF-alpha) Download PDFInfo
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Abstract
For the preparation of pharmaceutical composition for treatment of tumor necrosis factor-alpha (TNF-alpha ) mediated diseases, 5-methyl-1-(substituted phenyl)-2(1H) pyridones of formula (I), is used. n : 1 or 2;and R : F, Br, I, Cl, nitro, alkyl, alkoxy, or halogenated alkyl group where the relative position of R is ortho, meta or para. Provided that: (1) when n=1, then R is selected from F, Br, I, nitro group, alkyl group, alkoxy group, or halogenated alkyl group; and (2) when n=2, then R is selected from F, Cl, Br, I, alkyl group, alkoxy group, or halogenated alkyl group.
Description
Technical field
The present invention relates to comprise the purposes of the pharmaceutical composition of 5-methyl isophthalic acid-(substituted-phenyl)-2-(1H) pyridine compounds.
Background technology
Inflammation is a kind of common pathological, and many different diseases all can be generalized into inflammation class disease because of similar pathological condition.Inflammation is a very complicated process, has defined a variety of media at present and has participated in inflammatory process.Outstanding especially is, many inflammation class diseases all involve a kind of cytokine of key: α-Zhong Liuhuaisiyinzi (TNF-α), therefore to be known as with α-Zhong Liuhuaisiyinzi again be mesomeric disease to this class inflammation class disease, and rheumatoid arthritis (RA) is the representative of this type of disease.
α-Zhong Liuhuaisiyinzi is a kind of polypeptide compound of many performances, and molecular weight is 17kDa.When infected by microbes or tumor cell invaded tissue or organ, many kinds of cells all can be reacted and be secreted α-Zhong Liuhuaisiyinzi.Although other kind cell, for example T cell, mastocyte, neutrophilic leukocyte, endepidermis cell and spider cell all can be excited to secrete α-Zhong Liuhuaisiyinzi, and the main source of α-Zhong Liuhuaisiyinzi is the macrophage that is activated.A large amount of researchs show, the relation that has of the increase of α-Zhong Liuhuaisiyinzi and a lot of inflammation class diseases, these diseases comprise rheumatoid arthritis (RA), psoriasis, psoriasis arthropathica, asthma, scurvy and Crohn disease (Crohn ' s) etc.
Rheumatoid arthritis (RA) is a kind of systemic disease, it is characterized by the chronic inflammatory reaction of intraarticular synovial membrane.Serious inflammatory reaction can cause the degeneration of cartilage and the erosion of nearly ossa articularia.Mass data has shown that not only α-Zhong Liuhuaisiyinzi is a key in the rheumatoid arthritis pathogenic process, but also is a target of good Drug therapy.In recent ten years, the pharmaceutical control and administration department of the many countries blocker of three kinds of well-known protein-based α-Zhong Liuhuaisiyinzis of having ratified in succession to go on the market: etanercept (Enbrel), inflixmab (Remicade), and adalimumab (Humira).Though the effect of these injection protein drugs is fine, their limitation also little by little displays (Anti-TNF-α therapies:the next generation, Palladino MA.et al, Nat Rev.DrugDel, 2 (9) 736-746,2003).Therefore, many research projects all attempt exploitation micromolecular, can be oral the medicine of anti-α-Zhong Liuhuaisiyinzi.
One big feature of asthma is that the inflammatory cell that oozes out is in a large number arranged on bronchial mucosa, comprises the mastocyte and the T cell that are activated.It is generally acknowledged that the various kinds of cell factor has participated in causing the process of above-mentioned feature, especially interleukin-4, interleukin-5, interleukin-6 and α-Zhong Liuhuaisiyinzi.Wherein α-Zhong Liuhuaisiyinzi is considered to be in many inflammation diseases and a kind of most important medium that influences in immunne response and the air flue inflammatory process that depend on cytokine.Recent studies show that the contact sensitizer is the main cause of asthma, in the world popular in a large amount of contacts to airborne sensitizer cause of asthma.Mastocyte and macrophage that anaphylaxis produces can be secreted α-Zhong Liuhuaisiyinzi in a large number, so the content of the α-Zhong Liuhuaisiyinzi from the juice that the bronchioles of asthma patient washes out is far above healthy people's level.
Vitamin C deficiency claims systemic inflammatory reaction syndrome (SIRS) again, is to the overreaction of bacterial infection and the serious symptom of a kind of danger close that produces by human body.Vitamin C deficiency can cause whole body to fill the air inflammatory reaction and blood coagulation.The inflammatory reaction meeting causes skin rubefaction, whole body heating, a large amount of perspirations, the functional disorder of ache all over the body and organ or depletion.Thereby a large amount of blood coagulation meetings in the vitamin C deficiency process reduce the blood flow of extremity and vitals further causes the depleted downright bad of organ.Result of study to the experimental animal model of vitamin C deficiency shock discloses, and gives the α-Zhong Liuhuaisiyinzi blocker and can obviously reduce the mortality rate of animal, shows that α-Zhong Liuhuaisiyinzi is to cause the scorbutic main inflammatory reaction cytokine in early stage.
Reported have antiinflammatory and the active chemical compound of fibrosis has many.U.S. Pat P3,839,346, USP 4,052,509 and USP 4,042, the 699 reports pyridine compounds of 29 tool general formula Is altogether:
A in the general formula I is an aromatic group.But these chemical compounds have concentration, especially one of them chemical compound of good antiinflammatory and analgesic activity and blood sugar lowering and blood uric acid, and 5-methyl isophthalic acid-phenyl-2-(1H) pyridone has best active and lower toxicity.
U.S. Pat P 5,310, and 562 have reported 5-methyl isophthalic acid-phenyl-2-(1H) pyridone (PIRFENIDONE, fibrosis activity PFD).U.S. Pat P 5,518,729 and USP 5,716,632 subsequently the fibrosis activity is extended to 44 N-and replaces 3 (1H) pyridinone compounds that-2 (1H) pyridones (general structure I) or N-replace.
U.S. Pat P 5,962, and 478 have further set forth the activity of the anti-α-Zhong Liuhuaisiyinzi of 5-methyl isophthalic acid-phenyl-2-(1H) pyridone and 44 similar structures chemical compounds again.
Chinese patent ZL02114190.8 has disclosed many new 5-methyl isophthalic acid-substituted-phenyls-2-(1H) pyridine compounds and synthetic method thereof.These chemical compounds have the structure of general formula I I:
Wherein when n=1, described substituent R can be F, Br, I; When n=2, described substituent R can be F, Cl, Br, I, straight chained alkyl, straight chain alkoxyl or straight chain haloalkyl.The position of described substituent group R on phenyl ring can be ortho position, a position or para-position.
U.S. Pat P 5,716,7 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds of listing among the 632 and USP 5,962,478 be at first by Gadekar at U.S. Pat P4, propose in 042,699.According to the data of being grasped, Gadekar has summed up a structure activity relationship for the chemical compound of " substituted-phenyl ", and this special structure activity relationship instructs non-substituted-phenyl pyridinone compounds that best biological activity is arranged.In a United States Patent (USP) that is awaiting the reply, the enlightenment that we obtain is that with regard to fibrosis, the pyridinone compounds (having general structure II) that is actually substituted-phenyl has better activity.Therefore, a significant research is to determine whether the substituted-phenyl pyridinone compounds with general structure II has the activity of ideal anti-α-Zhong Liuhuaisiyinzi.
Summary of the invention
The invention describes the activity of the anti-α-Zhong Liuhuaisiyinzi of 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds.Chinese patent ZL02114190.8 has disclosed the synthesis technique of a series of representational substituted-phenyl pyridine compounds, and these disclosures are incorporated into herein as a reference.The example of these pyridones has: 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone (AKF-PD), 1-(3 '-bromophenyl)-5-methyl-2-(1H) pyridone (AKF-BR), 1-(3 '-chlorphenyl)-5-methyl-2-(1H) pyridone (AKF-CL), 1-(3 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone (AKF-CH
3) and 1-(3 '-methoxyphenyl)-5-methyl-2-(1H) pyridone (AKF-OCH
3).These chemical compounds were all tested by the macrophage with mice, and wherein AKF-PD is further observed in the animal model experiment of various types of rheumatic arthritis.The result of these tests and observation shows that it is mesomeric disease with α-Zhong Liuhuaisiyinzi that 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds might be used for treating as this class of rheumatoid arthritis as a kind of very hypotoxic medicine.
In a specific embodiments, the present invention set forth one or more structure general formula I I that sign an undertaking pyridinone compounds to be used for the treatment of as this class of rheumatoid arthritis be the purposes of mesomeric disease with α-Zhong Liuhuaisiyinzi.
When n=1, described substituent R can be F, Br, I, nitro, alkyl, alkoxyl or haloalkyl in general formula I I; When n=2, described substituent R can be F, Cl, Br, I, alkyl, alkoxyl or haloalkyl.
The present invention also provides a kind of pharmaceutical composition, it comprises 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds with general structure II, it is mesomeric disease with α-Zhong Liuhuaisiyinzi that this pharmaceutical composition can effectively be treated as this class of rheumatoid arthritis, and described pyridine compounds is present in this pharmaceutical composition with the treatment effective dose.
It is the method for mesomeric disease as this class of rheumatoid arthritis with α-Zhong Liuhuaisiyinzi that the present invention also provides a kind of treatment, comprises to the patient using the pyridinone compounds with general structure II, in this compound structure, n=1, substituent R is F, that is, and and AKF-PD.
The present invention also provides a kind of and has comprised above-mentioned pharmaceutical composition with 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds of general structure II to be used for the treatment of as this class of rheumatoid arthritis be the purposes of mesomeric disease with α-Zhong Liuhuaisiyinzi.
Description of drawings
In conjunction with following accompanying drawing content, the specific descriptions by following preferred embodiment will further disclose above-mentioned and further feature and superiority of the present invention.
Fig. 1: AKF-PD and PFD generate the inhibitory action of TNF-α mRNA to the macrophage of mice.
Fig. 2: AKF-PD is synthetic and excretory inhibitory action to the albumen of the TNF-α of the macrophage of mice.
Fig. 3: five kinds of 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridine compounds is synthetic and excretory inhibitory action to the albumen of the TNF-α of the macrophage of mice.
Fig. 4: AKF-PD is to the reduction of serum TNF-α concentration of arthritis model rat.
Fig. 5: AKF-PD is to the reduction of the TNF-α concentration in the arthritis model rat claw tissue.
Detailed Description Of The Invention
In the elaboration of this paper, term " anti-α-tumornecrosisfactor is the disease of intermediary " means and controls Treat all because of the disease of TNF-α for crucial pathological factor, for example rheumatoid arthritis. Term " anti-inflammatory " means and processes all inflammatory reactions, especially processes local immune response, but gets rid of α-tumornecrosisfactor is the disease of intermediary.
The document of having delivered thinks that all 5-methyl isophthalic acid-phenyl-2-(1H) pyridone (PFD) has ideal Anti-α-tumornecrosisfactor and the compound of anti-inflammatory activity, this viewpoint and Gadekar ' s propose Structure-activity relationship is consistent, that is, the activity of the described pyridinone compounds of non-substituted phenyl is better than gets Pyridinone compounds for phenyl. Therefore, beyond thought result is, the present invention find the 5-methyl isophthalic acid-Substituted-phenyl-2-(1H) pyridone (general structure II), especially AKF-PD have shown and have compared 5-The anti-α that methyl isophthalic acid-(unsubstituted phenyl)-2 (1H) pyridones (PIRFENIDONE) are stronger-swollen Tumor necrosis factor and anti-inflammatory activity, and toxicity is also low many than PFD.
Some representational 5-methyl isophthalic acid-substituted-phenyls-2-(1H) pyridinone compounds all be by in The synthesis technique of describing among the state patent ZL02114190.8 synthesizes, and these descriptions is incorporated into herein done Be reference. These pyridine compounds comprise 1-(3 '-fluorophenyl)-5-methyl-2-(1H) Pyridone (AKF-PD), 1-(3 '-bromophenyl)-5-methyl-2-(1H) pyridone (AKF-BR), 1-(3 '-chlorphenyl)-5-methyl-2-(1H) pyridone (AKF-CL), 1-(3 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone (AKF-CH3) and 1-(3 '-methoxyphenyl)-5-methyl-2-(1H) pyridone (AKF-OCH3). The research table Bright, these 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridones are than PIRFENIDONE, the 5-first Base-1-unsubstituted phenyl-2-(1H) pyridone has better anti-α-tumornecrosisfactor activity. In these compounds, 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone the most effectively (AKF-PD). Moreover, 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone Toxicity can significantly lower. As described herein, 1-(3 '-fluorophenyl)-5-methyl-2-(1H) half of pyridone (AKF-PD) is measured LD till death50, only have PIRFENIDONE's 30%. It is worth mentioning that, resemble this class of rheumatoid arthritis take α-tumornecrosisfactor as intermediary Disease or the skin disease of this class of eczema, generally all be chronic or the disease of recurrence repeatedly. Any controlling The treatment means all will be long process, need long-term medicine intervening acts to guarantee. Therefore, Long term administration is sought after the low TNF alpha antibody of toxicity or anti-inflammatory drug in the clinical use.
Other 5-methyl isophthalic acid-substituted-phenyl-2-(1H) pyridone (general structure II) includes, but are not limited to following institute example:
Work as n=1, R=Br, but compound 1-(2 '-bromophenyl)-5-methyl-2-(1H) pyrrole Pyridine ketone, 1-(3 '-bromophenyl)-5-methyl-2-(1H) pyridone, or 1-4 '-bromophenyl)-5-methyl-2-(1H) pyridone.
Work as n=1, R=F, but compound 1-(2 '-fluorophenyl)-5-methyl-2-(1H) Pyridone, 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone, or 1-(4 '-fluorobenzene Base)-5-methyl-2-(1H) pyridone.
Work as n=1, R=I, but compound 1-(2 '-iodophenyl)-5-methyl-2-(1H) Pyridone, 1-(3 '-iodophenyl)-5-methyl-2-(1H) pyridone, or 1-(4 '-iodobenzene Base)-5-methyl-2-(1H) pyridone.
Work as n=2, R=F, Br or Cl, but chemical compound 1-(2 ', 3 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(3 ', 4 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(3 ', 5 '-dibromo phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 3 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(3 ', 4 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(3 ', 5 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone, 1-(2 ', 3 '-difluorophenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-difluorophenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-difluorophenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-difluorophenyl)-5-methyl-2-(1H) pyridone, 1-(3 ', 4 '-difluorophenyl)-5-methyl-2-(1H) pyridone, or 1-(3 ', 5 '-difluorophenyl)-5-methyl-2-(1H) pyridone.
When n=1 or 2, the R=trifluoromethyl, but chemical compound 1-(2 '-trifluoromethyl)-5-methyl-2-(1H) pyridone, 1-(4 '-trifluoromethyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 3 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(3 ', 4 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone, or 1-(3 ', 5 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone.
When n=1 or 2, the R=methyl, but chemical compound 1-(2 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(3-aminomethyl phenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 3 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone, or 1-(3 ', 4 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone.
When n=1 or 2, the R=methoxyl group, but chemical compound 1-(2 '-methoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(3 '-methoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 3 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 4 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 5 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(2 ', 6 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone, 1-(3 ', 4 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone, or 1-(3 ', 5 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone.
In one embodiment, the present invention proposes a kind of method that α-Zhong Liuhuaisiyinzi is mesomeric disease for the treatment of, this method comprises provides a kind of pharmaceutical composition that one or more have said structure general formula I I chemical compound that comprises.In the described chemical compound, when n=1, described substituent R can be F, Br, I, nitro, alkyl, alkoxyl or alkylhalide group; When n=2, described substituent R can be F, Cl, Br, I, alkyl, alkoxyl or alkylhalide group; And the position of described substituent group R on phenyl ring can be ortho position, a position or para-position etc.Preferably, when n=1, R is F, Br or I; When n=2, R is F, Cl, Br, I, alkyl, alkoxyl or alkylhalide group, and for example, R can be straight chained alkyl, branched alkyl, straight chain alkoxyl or straight chain alkylhalide group.Normal conditions, the carbon number of straight chained alkyl or branched alkyl are 1 to 6, preferred 1 to 4.
According to Therapeutic Method of the present invention, the administration daily dose that contains the pharmaceutical composition of one or more described chemical compounds is about 25 to about 6000 milligrams.Pharmaceutical composition among the present invention can such as oral, be injected with arbitrary conventional way administration, or external.Similarly, the pharmaceutical composition among the present invention can be prepared into any suitable form of administration according to common process, solution for example, tablet, capsule, suppository, inhalant, suspensoid, gel, Emulsion, or ointment.
In another embodiment, the present invention proposes a kind of treatment for example this class of rheumatoid arthritis be the method for mesomeric disease with α-Zhong Liuhuaisiyinzi, this method comprises to the patient uses 5-methyl isophthalic acid-(substituted-phenyl)-2-(1H) pyridinone compounds that contains general molecular formula II, in this compound structure, substituent R is F, and the position is at 3.This pharmaceutical composition can be prepared into various conventional formulations with arbitrary conventional way administration.
The invention allows for that a kind of to be used for the treatment of as this class of rheumatoid arthritis be the pharmaceutical composition of mesomeric disease with α-Zhong Liuhuaisiyinzi, this medicine comprises the chemical compound of 5-methyl isophthalic acid-(substituted-phenyl)-2-(1H) pyridinone for the treatment of effective dose.This 5-methyl isophthalic acid-(substituted-phenyl)-2-(1H) pyridone has said structure general formula I I, and wherein when n=1, described substituent R can be F, Br, I, nitro, alkyl, alkoxyl or alkylhalide group; When n=2, described substituent R can be F, Cl, Br, I, alkyl, alkoxyl or alkylhalide group.The relevant position of described substituent group R on phenyl ring is ortho position, a position or para-position.Ideal structure is that when n=1, R is F, Br or I; When n=2, R is F, Br, I, alkyl, alkoxyl or alkylhalide group, and for example, R can be a straight chained alkyl, branched alkyl, straight chain alkoxyl or straight chain alkylhalide group.Generally, the carbon number of straight chained alkyl or branched alkyl is about 1 to 6, preferred 1 to 4.In a specific embodiments, be used for the treatment of when being mesomeric disease with α-Zhong Liuhuaisiyinzi, the effective dose of said medicine is about 5 to 6000 milligrams of every days.More satisfactory, effective dose was about 50 to 2000 milligrams when treatment was mesomeric disease with α-Zhong Liuhuaisiyinzi.Best dosage is about 100 to 1000 milligrams.
Following example only is in order to help further to understand technological thought described in the invention, just to have comprised the description of some specified scheme of the present invention and specific embodiments, these examples to the present invention without any restriction.
AKF-PD and PD are to the synthetic inhibitory action of TNF-α mRNA of mouse macrophage
Experimental design: with the AKF-PD of variable concentrations or PFD to mouse macrophage, 264.7RAW, pretreatment 4 hours, drug level is: 0,10 μ g/ml, 100 μ g/ml and 500 μ g/ml.And then stimulating this by the mouse macrophage 264.7RAW that AKF-PD or PFD handled with the lipopolysaccharide (LPS, endotoxin) of 5ng/mL concentration, stimulation time is 15-20 hour.Collect the cell that this endotoxin stimulated and isolate mRNA.The expression of TNF-α mRNA is measured with the PCR method of real-time quantitative, and the test kit (TaqMan PCR core reagentkit) of measuring usefulness is available from Applied Biosystems.
Experimental result: as shown in Figure 1, AKF-PD and PFD are subjected to the generation of the post-stimulatory TNF-α of endotoxin mRNA that inhibitory action is arranged to mouse macrophage.When drug dose is 500 μ g/ml, can reach about 50 percent to the inhibition degree of TNF-α mRNA.In Fig. 1, stimulate and the gene expression of the TNF-α of the mouse macrophage of drug treating is 1 without endotoxin, as benchmark.It is long that all relative this benchmark of other data forms multiplication.The gene expression of mice β actin (actin) is as the interior mark of experiment.Each band error target bar diagram represents the average mRNA water gaging of two parallel sample flat ± SD among Fig. 1.The p value that three concentration of all AKF-PD and the statistical analysis of benchmark relatively draw is all less than 0.01 (p＜0.01); And under same condition, have only the PFD (100 and 500 μ g/ml) of two concentration that the p value less than 0.01 is just arranged.The same with PFD, AKF-PD can block the LPS endotoxin effectively stimulates mouse macrophage to cause the increase of TNF-α.
AKF-PD is to the proteic synthetic and excretory inhibitory action of the TNF-α of mouse macrophage
Experimental design: the AKF-PD mouse macrophage strain RAW264.7 that synthetic and excretory influence adopts LPS to stimulate to TNF-α albumen analyzes.With the AKF-PD pair cell pretreatment of variable concentrations 4 hours, drug level was: 0,30 μ g/ml, 100 μ g/ml and 300 μ g/ml.And then further to stimulate RAW264.7 cell, stimulation time with the lipopolysaccharide (LPS, endotoxin) of 100ng/mL concentration be 8 hours.Be prepared into the cell analyte behind the cell harvesting that endotoxin was stimulated.Remaining cell culture fluid (media) is concentrated tenfold.With the enzyme mark analytical reagent special, OptEIA to mice TNF-α
TM(BD Biosciences) is according to producer's explanation analysis of cells analyte and spissated cell culture fluid.
Experimental result: as shown in Figure 2, the secretion of the TNF-α of the cell of handling with the AKF-PD of 100 μ g/ml is subjected to 64% inhibition.When the dosage of AKF-PD was 300 μ g/ml, the excretory inhibition of TNF-α can reach 89% (Fig. 2 A).TNF-alpha levels in the AKF-PD pair cell also has certain inhibitory action, and the AKF-PD of 300 μ g/ml has about 50% inhibition (Fig. 2 B).There is significantly and depend on the inhibitory action of dosage with excretory TNF-α so give RAW264.7 cell AKF-PD in all can pair cell.Among Fig. 2, each has meansigma methods and the standard deviation (SD) thereof of error target bar diagram representative from TNF-α in three parallel tested samples.The secretion level of the cell of handling for AKF-PD, the p value that relatively draws with respect to the statistical analysis of benchmark (reference) in three concentration of all AKF-PD is all less than 0.001; With regard to intracellular TNF-alpha levels, in the p value of the AKF-PD of 100 μ g/ml and 300 μ g/ml dosage respectively all less than 0.01.
Embodiment 3
The chemical compound of multiple 5-methyl isophthalic acid-(substituted-phenyl)-2-(1H) pyridinone is to the proteic synthetic and excretory inhibitory action of the TNF-α of mouse macrophage
Experimental design: the mouse macrophage strain RAW264.7 that stimulates with endotoxin carries out the chemical compound of five kinds of 5-methyl isophthalic acids-(substituted-phenyl)-2-(1H) pyridinone to the proteic synthetic and secretory action effect Analysis of TNF-α.These five kinds of chemical compounds are: 1-(3 '-fluorophenyl)-2-(1H) pyridone (AKF-PD), 1-(3 '-bromophenyl)-5-methyl-2-(1H) pyridone (AKF-BR), 1-(3 '-chlorphenyl)-5-methyl-2-(1H) pyridone (AKF-CL), 1-(3 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone (AKF-CH
3) and 1-(3 '-methoxyphenyl)-5-methyl-2-(1H) pyridone (AKF-OCH
3).With the various AKF chemical compounds of 30 μ g/ml concentration to described cell pretreatment 4 hours.And then further stimulating the 264.7RAW cell of being crossed by the AKF compound treatment with the lipopolysaccharide (LPS, endotoxin) of 100ng/mL concentration, stimulation time is 8 hours.With after removing culture fluid behind the cell and concentrating ten times, with the enzyme mark analytical reagent special, OptEIA to mice TNF-α
TM(BD Biosciences) analyzes spissated cell culture fluid according to manufacturer's operation instruction.
Experimental result: as shown in Figure 3, five kinds of 5-methyl isophthalic acid-substituted-phenyls-2 (1H) pyridinone compounds all stimulates the LPS endotoxin and TNF secretion-alpha levels has inhibitory action.Under 30 μ g/ml concentration, AKF-PD and AKF-OCH
3Inhibitory action the most obvious, oozy TNF-α reduces 56% and 63% respectively.AKF-BR, AKF-CL and AKF-CH
3Also show inhibitory action, but to the inhibitory action of TNF-α secretion level a little less than.Each has meansigma methods and standard deviation (SD) thereof that TNF-α in three parallel tested samples has been represented in the bar diagram of error target among Fig. 3.For the cell of AKF compound treatment, all processing shown with respect to benchmark the p value that relatively draws of statistical analysis all less than 0.001.
Embodiment 4
AKF-PD is to the inhibitory action of the serum levels of the TNF-α of rat arthritis animal model
Experimental design: a kind of modal human rheumatoid arthritis (RA) animal model, the adjuvant-induced arthritis of rat (AIA) are used to estimate the inhibitory action of AKF-PD to TNF-alpha levels in the body.Select big male rat (Lewis rat) of 10 weeks.((Difco Laboratories) is suspended in incomplete Freund formula adjuvant with 7.5mg/ml and makes Freund formula Freund's complete adjuvant (CFA) with heat treated Mycobacteriumbutyricum.0.1ml Freund formula Freund's complete adjuvant emulsion is expelled to the root (Arthritis Rhem 39:1677,1996) of the Mus tail of rat in the mode of intradermal injection, the arthritis that stimulates CFA to bring out.Have three groups of rats altogether: zero matched group (health), adjuvant/conventional normal saline group, adjuvant/AKP-PD group.Every group of 6 rats.Behind the injection adjuvant 2 to 14 days, gave AKF-PD or the normal saline of 500mg/kg to two adjuvant groups in the mode of irritating stomach every day respectively, then with sacrifice of animal.With the special enzyme mark analytical method of TNF-α blood serum sample is analyzed after collecting serum, analytical reagent is available from ChemiKine.
Experimental result: as shown in Figure 4, only the level of serum TNF-α of the TNF-α of the rat of injection adjuvant is than the level high a lot (47.9ng/ml is to 8.1ng/ml) of the serum TNF-α of zero matched group; And the level that the serum TNF-α of arthritic rat after AKF-PD treatment arranged is significantly reduced (12.9ng/ml), the level of this result and the serum TNF-α of zero matched group be more or less the same (8.1ng/ml).Each has level and the standard deviation (SD) thereof of the average serum TNF-α of error target bar diagram representative 6 rats on the same group among Fig. 4.
Embodiment 5
AKF-PD is to the inhibitory action of the TNF-alpha levels in the pawl palm tissue of rat arthritis animal model
Experimental design: the processing of bringing out arthritis process and AKF-PD about CFA all and embodiment 4 identical.Rat is at injection adjuvant and be condemned to death in AKF-PD14 days.With the pawl palm tissue of execution rat and in-80 ℃ of preservations.With the tissue peeling of the pawl palm and the chopping of melting, (100mg wet tissue/5ml buffer) extracted in 4 ℃ of cold urea liquids with 5M in the back of weighing.Then extracting solution is carried out precipitation process with ammonium sulphate.Then that the freezing immediately preservation of partially purified extracting solution is for further analysis.(CA USA) measures protein content in this pawl palm tissue extract for Bio-RadLaboratories, Hercules with Bradford protein determination cover group.
Experimental result: as shown in Figure 5 and determination of serum result similar (Fig. 4), AKF-PD can obviously reduce the level of the TNF-α in the pawl palm tissue, and the 8.1ng/ml from rats with arthritis is reduced to the 3.4ng/ml in the AKF-PD treatment rat.Among Fig. 5, each has meansigma methods and the standard deviation (SD) thereof of error target bar diagram representative 6 rats on the same group.
Embodiment 6
The generation of the inductive rat arthritis of AKF-PD prevention adjuvant
The present invention also adopts the inductive rat arthritis model of adjuvant to verify with the influence of AKF-PD whole body administration to arthritic generation.
Experimental design: the Lewis rat in 10 weeks is handled with good fortune formula Freund's complete adjuvant (CFA) according to the method that embodiment 4 describes.From second day, these rats gave 500mg/kg AKF-PD or normal saline in the mode of irritating stomach every day, until fortnight is put to death then.The rat that CFA handles generally can arthritic symptom (enlargement of the pawl palm) occur at the inoculation adjuvant in latter two week.
Table 1 has been summed up experimental result: after fortnight, and average loss of weight 5 grams of the rat behind the injection adjuvant, and the normal rats of injection adjuvant average weight gain 41 in this fortnight does not restrain.The rat of the rat of having injected adjuvant being used AKF-PD has stoped weight loss and has caused average weight to increase by 37 grams.All control rats (8/8) of only using adjuvant to handle arthritic symptom all occurred after behind the injection adjuvant 10 to 14 days, and in adjuvant+AKD-PD group, do not have a rat (0/8) arthritic symptom to occur.
The size of the arthritic incidence rate of table 1 and the pawl palm
Embodiment 7
1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone (AKF-PD) and Pirfenidone acute toxicity test comparison.
The Kunming mouse of experimental design: body weight 18g～22g (KM), male and female are held concurrently and are hugely had, and the department of the Chinese Academy of Sciences provides by the Xiangya Medical College, Zhongnan Univ laboratory animal.Get 50 of healthy KM mices, be divided into 5 groups at random, 10 every group, each 5 of male and female.Fasting 12h before the administration can't help water.Press 20ml/kg body weight gastric infusion, administration (AKF-PD or PFD) dosage is 1071mg/kg～6000mg/kg, and dosage group distance is than being 1:0.65 (this dosage and the ratio that faces low dosage mutually).The conventional raising behind all animals administers, chmice acute toxic reaction and death condition in 14 days behind the record single administration, and all dead animals are dissected, each internal organs of perusal change.
Calculate LD with the Bliss method
50And 95% fiducial limit.The malicious LD of the urgency of AKF-PD
50Be 2979.89mg/kg, the 95% credible 2402.70mg/kg～3695.73mg/kg that is limited to the results are shown in Table 2.The LD of PFD
50Be 955.4mg/kg, the 95% credible 550.9～1656.7mg/kg that is limited to the results are shown in Table 3.The acute toxicity of the PFD pirfenidone of the result of table 3 and bibliographical information as a result 1112mg/kg (" pharmaceutical services and research " 2005,5:4823) very close with 997.7mg/kg (US.P.5310562).These results show that the toxicity of AKF-PD of the present invention has only 1/3rd (2978mg/kg is than 955mg/kg) of PFD.
The LD of table 2.AKF-PD
50
The LD of the oral PFD of table 3. mice
50The acute toxicity tests
Claims (18)
1, to be used to prepare treatment TNF-α be the purposes of the pharmaceutical composition of mesomeric disease to 1-(substituted-phenyl)-5-methyl-2-(1H) pyridone (II) chemical compound with general formula I I:
2, purposes according to claim 1, wherein,
When n=1, substituent R is selected from F, Br, I, nitro, alkyl, alkoxyl or haloalkyl;
When n=2, substituent R is selected from F, Cl, Br, I, alkyl, alkoxyl or haloalkyl; And
R is ortho position, a position or para-position.
3, purposes according to claim 1 and 2, wherein, n=1 or 2, R are selected from straight chained alkyl, branched alkyl, straight chain alkoxyl or straight chain haloalkyl.
4, purposes according to claim 3, wherein, straight chained alkyl or branched alkyl have 1 to about 6 carbon.
5, according to claim 1,2,3 or 4 described purposes, wherein, described medical compounds comprises one or more chemical compounds that are selected from following group: 1-(2 '-bromophenyl)-5-methyl-2-(1H) pyridone; 1-(3 '-bromophenyl)-5-methyl-2-(1H) pyridone; 1-(4 '-bromophenyl)-5-methyl-2-(1H) pyridone; 1-(2 '-fluorophenyl)-5-methyl-2-(1H) pyridone; 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone; 1-(4 '-fluorophenyl)-5-methyl-2-(1H) pyridone; 1-(2 '-iodophenyl)-5-methyl-2-(1H) pyridone; 1-(3 '-iodophenyl)-5-methyl-2-(1H) pyridone; 1-(4 '-iodophenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', the 6-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 5 '-dibromo phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(2 ', 6 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(3 ', 5 '-Dichlorobenzene base)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 6 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 5 '-difluorophenyl)-5-methyl-2-(1H) pyridone; 1-(2 '-trifluoromethyl)-5-methyl-2-(1H) pyridone; 1-(4 '-trifluoromethyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 6 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone;-(3 ', 5 '-bis trifluoromethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(2 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(3 '-aminomethyl phenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 6 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 5 '-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone; 1-(2 '-methoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(3 '-methoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 3 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 4 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 5 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(2 ', 6 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 4 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone; 1-(3 ', 5 '-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone.
6, application according to claim 1, wherein, described compositions with every day about dosage of 25 to about 6000mg use.
7, application according to claim 1, wherein, said is that mesomeric disease comprises rheumatoid arthritis with α-Zhong Liuhuaisiyinzi, psoriasis, psoriasis arthropathica, asthma, scurvy or Crohn disease disease.
8, application according to claim 1, wherein, the form of medication of described pharmaceutical composition is oral administration, drug administration by injection, dosing eyes and/or topical administration.
9, application according to claim 1, wherein, it is that the effective dose of mesomeric disease is every day about 25 to about 6000mg that the chemical compound of the tool structural formula II that contains in the described pharmaceutical composition is used for the treatment of α-Zhong Liuhuaisiyinzi.
10, application according to claim 1, wherein, it is that the effective dose of mesomeric disease is every day about 50 to about 2000mg that the chemical compound of the tool structural formula II that contains in the described pharmaceutical composition is used for the treatment of α-Zhong Liuhuaisiyinzi.
11, application according to claim 1, wherein, it is that the effective dose of mesomeric disease is every day about 100 to about 1000mg that the chemical compound of the tool structural formula II that contains in the described pharmaceutical composition is used for the treatment of α-Zhong Liuhuaisiyinzi.
12,5-methyl isophthalic acid a kind of low toxicity, that have general formula I I-(substituted-phenyl)-2-(1H) pyridinone compounds is used for the treatment of with α-Zhong Liuhuaisiyinzi in preparation is the application of the pharmaceutical composition of mesomeric disease, in this compound structure, and n=1, R=F,
13, application according to claim 12, wherein, substituent R is 3 fluorine, this chemical compound is 1-(3 '-fluorophenyl)-5-methyl-2-(1H) pyridone.
14, according to claim 12 or 13 described application, wherein, this pharmaceutical composition comprises the general formula I I chemical compound of effective dose, and this effective dose is every day about 25 to about 6000mg.
15, according to claim 12 or 13 described application, wherein, this pharmaceutical composition comprises the general formula I I chemical compound of effective dose, and this effective dose is every day about 50 to about 2000mg.
16, according to claim 12 or 13 described application, wherein, this pharmaceutical composition comprises the general formula I I chemical compound of effective dose, and this effective dose is every day about 100 to about 1000mg.
17, according to claim 12 or 13 described application, wherein, said is that mesomeric disease comprises rheumatoid arthritis with α-Zhong Liuhuaisiyinzi, psoriasis, psoriasis arthropathica, asthma, scurvy or Crohn disease.
18, according to claim 12 or 13 described application, wherein, the dosage form of this pharmaceutical composition is oral agents, injection, ophthalmology medicament and/or topical agent.
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| CN105085383A (en) * | 2015-08-19 | 2015-11-25 | 四川大学 | 5-methyl-2(1H)pyridone derivatives, and preparation method and application thereof |
| CN105130884A (en) * | 2015-07-30 | 2015-12-09 | 四川大学 | 5-methyl-2(1H)pyridone derivatives, preparation method and applications thereof |
| CN111991393A (en) * | 2019-09-26 | 2020-11-27 | 深圳先进技术研究院 | Application of pirfenidone in preparation of medicine for preventing and treating rheumatoid arthritis |
| CN113456636A (en) * | 2021-07-09 | 2021-10-01 | 中南大学 | Application of flufenidone in preparation of acute liver injury medicine |
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| CN101235013A (en) * | 2008-03-10 | 2008-08-06 | 广东东阳光药业有限公司 | Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application |
| WO2010135470A1 (en) * | 2009-05-19 | 2010-11-25 | Intermune, Inc. | Pifenidone derivatives for treating bronchial asthma |
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| US5716632A (en) * | 1989-11-22 | 1998-02-10 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5962478A (en) * | 1995-09-19 | 1999-10-05 | Margolin; Solomon B. | Inhibition of tumor necrosis factor α |
| CN1218942C (en) * | 2002-06-11 | 2005-09-14 | 中南大学湘雅医学院 | Antifibrosis pyridinone medicine and its prepaing process |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130884A (en) * | 2015-07-30 | 2015-12-09 | 四川大学 | 5-methyl-2(1H)pyridone derivatives, preparation method and applications thereof |
| CN105085383A (en) * | 2015-08-19 | 2015-11-25 | 四川大学 | 5-methyl-2(1H)pyridone derivatives, and preparation method and application thereof |
| CN105085383B (en) * | 2015-08-19 | 2017-09-01 | 四川大学 | 5 methyl 2 (1H) Pyridione derivatives and its production and use |
| CN111991393A (en) * | 2019-09-26 | 2020-11-27 | 深圳先进技术研究院 | Application of pirfenidone in preparation of medicine for preventing and treating rheumatoid arthritis |
| CN113456636A (en) * | 2021-07-09 | 2021-10-01 | 中南大学 | Application of flufenidone in preparation of acute liver injury medicine |
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