CN1837169A - Compound capable of inhibiting zinc ion metalloproteinases - Google Patents
Compound capable of inhibiting zinc ion metalloproteinases Download PDFInfo
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- CN1837169A CN1837169A CNA2006100657305A CN200610065730A CN1837169A CN 1837169 A CN1837169 A CN 1837169A CN A2006100657305 A CNA2006100657305 A CN A2006100657305A CN 200610065730 A CN200610065730 A CN 200610065730A CN 1837169 A CN1837169 A CN 1837169A
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Abstract
The invention discloses a 1,2,3-trihydroxy benzene and derivant or pharmacy acceptable salt for zinc ion metal-prolease inhibition, which is characterized by the following: theses compounds is used for selective depressant of zinc ion metal-prolease (such as MT1-MMP, gelatinase A, B and collagenase, matrilysins, metal-elastase and stromelysin-1); these depressants can adjust physiological and pathology course with MMPs, ADAMs, ADAM-TS such as vessel rebirth, wound healing, organ transplantation, fecundation course and reactivation capability, rebuilding bone and ache, which is used for treating cancer, cardiovascular disease, arthritis, periodontal disease, multiple sclerosis, inflammation, adenomyosis, cornea ulcer, bacterial meningitis, diabetic syndrome, kidney disease, nerve retrogression disease, AIDS, bleb, anaphylaxis, adenomyosis, osteoporosis, asthma and so on; theses blocking agents can be used for antisenescence, antibiosis, commercial manufacture addition agent of cell epimatrix, collagen product, cosmetics and make-up preparation, which can used for animals and other living bodies.
Description
Technical field
The present invention relates to the compound that a class can suppress the zine ion metalloprotease, its purposes and the pharmaceutical composition that contains this compound.
Background technology
Matrix metalloproteinase is Matrix Metalloproteinases, is called for short MMPs, is the Zn by emiocytosis
2+The general name of Zinc metalloproteinase family participates in the degraded of extracellular matrix (ECM).MMPs is a Zn
2+The dependence protein enzyme family, the mainly synthetic and secretion by inoblast, endotheliocyte, scavenger cell, neutrophil leucocyte etc. reaches Ca usually under neutrallty condition
2+Play a role under participating in, found 23 kinds of people source MMPs at present.Various MMPs generally have following feature: the cDNA sequence of 1. different MMPs has homology.2. all with the zymogen forms secretion, be subjected to proteolytic enzyme or other factor activator, one or more ECM can degrade after the activation.3. enzymic activity relies on the Zn of enzyme active center
2+And Ca
2+4. enzymic activity is suppressed by specificity matrix metalloprotease tissue depressant (TIMPs), suppressed by sequestrant.
Extracellular matrix (ECM) not only plays machinery support and ligation between cell and the cell, also is the bridge that signal transmits between cell and the cell.MMPs is the ECM proteolytic ferment, can become to assign to regulate running balance between its degraded and the reorganization by decomposing ECM, eliminate some distinctive signal to reach, manifest some implicit signal even make already present biologically active substance release or activated purpose in the matrix, and then participate in the various forms and the changes of function of cell and histoorgan.These change growth, propagation, the differentiation that had both comprised each tissue and cell; Physiological change such as endometrial periodical change, ovulation, blastocyst implantation also comprise the infiltration and the transfer of tumour cell in the reproductive process, pathological changes such as the generation of inflammation and diffusion.The biological function of MMPs is except that the degraded of pair cell epimatrix (ECM), they play a significant role in the synthetic and secretion of the regulating cell factor, somatomedin, hormone and cell adhesion molecule acceptor etc., and then participate in a series of pathology and physiological processs such as apoptosis, form generation, propagation and growth.And the keying action in MMPs growth in the generation of tumour, evolution, infiltration, transfer, neonate tumour blood vessel and the apoptosis is established.The exploitation of MMPs inhibitor comprises that for important diseases cancer, nerve degenerative diseases such as senile dementia, cardiovascular disorder and all kinds of inflammation pharmacological agent have broad prospects.
The zine ion metalloprotease also comprises ADAMs (a disintegrin and metalloproteinase) proteolytic ferment.The ADAMs MDC (metalloproteinase/disintergrin/cystein-rich) that is otherwise known as is a newfound in recent years class transmembrane glycoprotein, kind of ADAMs surplus people have found 30 at present.ADAMs distributes very wide in biology, in multicellular animals, as cell, tissue and the organ of people, pig, rat, Xenopus laevis, fruit bat, nematode etc., locate as brain, testis, testis, ovary, mammary gland, placenta, small intestine, colon, the heart, liver, lung, bone, muscle etc.Although although this family member is contained quite conservative structure function territory, the biological action of their tissue distribution, active function and performance has nothing in common with each other.They may have vital role in the cellular activities such as adhesion, cytogamy and signal conduction at hydrolysis, cell one cell and the cell-matrix of extracellular matrix.This family is in the propagation of smart ovum combination, neurodevelopment, myotube formation, cell and the vital role in a plurality of physiological processs such as differentiation, extracellular matrix reconstruction and angiogenesis.Simultaneously, ADAMs is in generation, infiltration and the transfer of tumour, and senile dementia also has crucial effect in a plurality of pathologic processes such as sacroiliitis and cardiovascular disorder.
ADAM-TS (a disintegrin and metalloprotease with thrombospondin motif) is a kind surplus the existing people of a nearest newfound class zine ion metalloprotease have found 20.ADAM-TS has middle expression organizing of multiple animal such as Mammals, fruit bat, nematodes.ADAM-TS and ADAMs family have some common constitutional featuress, contain signal peptide, leading peptide, metalloprotease district, desintegration protein region successively and be rich in the halfcystine district as proteinic aminoterminal, but, ADAM-TS does not contain epidermal growth factor-like duplicate domain and membrane-spanning domain, replaces I type thrombospondin (thrombospondin 1) repeating structure of different numbers.Main participate in the adhesion of degradation of extracellular matrix, cell and matrix and the reconstruct of histoorgan, in physiology such as ovulation, fetal development and connective tissue disease, tumour and pathologic process, play an important role.
For ADAMs that has found and ADAM-TS, its catalytic activity position all comprises Zn
2+Bonded HEXXH conserved sequence, the structural similitude in the active centre of this and MMPs.Therefore, the inhibitor of MMPs also should have similar effect for ADAMs and ADAM-TS.
The exploitation of MMP inhibitor is an important branch of academic and industrial research.In phase later 1990s, the how tame pharmaceuticals in the whole world all shows keen interest to the screening of MMPs and inhibitor thereof, and several wide spectrums, the MMP inhibitor that is used for a few types tumour of small molecular weight is by clinical assessment.Though these small-molecule drugs in preclinical experimentation on animals, can suppress the activity of MMP efficiently, and effectively stop growth of tumor and transfer, the result who treats cancer clinically is also unsatisfactory, has finally caused the failure of later stage Clinical Laboratory.This mainly is that the specificity of these inhibitor is not strong because the complicacy of MMP family is not understood fully, has also played influence in various degree for the normal physiological function of the MMP of other kinds.The notion that with MMP is the treatment of diseases target spot is complicated, because MMP is that to keep the normal physiological environment necessary, and their functional diversities, have expression and activity that repeatability and background rely on.Although the research history in 40 years is arranged, synthetic and tested thousands of compound, have only a kind of collagenase inhibitors (Periostat, doxycycline hyclate) by the U.S. FDA authentication, and as treatment periodontal disease medicine.Therefore, seek efficiently, the MMP inhibitor of high specificity is the emphasis of this field work at present, also is the focus of domestic and international developing anti-tumor medicaments.Simultaneously, because MMPs is closely related with numerous disease, these MMPIs very likely will be used for the treatment of cardiovascular disorder from now on; Sacroiliitis; Periodontal disease; Multiple sclerosis; Inflammation; Pain; Keratohelcosis; Bacterial meningitis; Diabetic syndrome; Wound healing; Ephrosis; Nerve degenerative diseases; AIDS; Bleb; Allergy; Endometriosis; Osteoporosis; Asthma; Can be used for organ transplantation; Control to fertilization process and regenerative power; These inhibitor can also be used for anti-ageing; Antibiotic; As extracellular matrix/collagen product, makeup, the industrial additive of cosmetics.
Summary of the invention
We find and have proved that 1 and derivative thereof have restraining effect to the zine ion metalloprotease.1 and derivative thereof have ubiquity and specificity to the restraining effect of zine ion metalloprotease.Wherein three key positions that adjacent hydroxyls are inhibition, and these three adjacent hydroxyls must be on benzene ring structure, are in same plane.We have proved that further 1 is competitive inhibition or competitive advantage restraining effect to the mechanism that matrix metalloproteinase suppresses,
On the one hand, the present invention relates to formula I compound or its pharmacy acceptable salt and be used for suppressing the application of the medicine of zine ion metalloprotease in preparation, described formula I compound is
R wherein
1, R
2And R
3Independently be hydrogen atom, replace or unsubstituted C
1-C
18Alkyl is by the replacement of one or several discontinuous O atomic separation or unsubstituted C
2-C
18Alkyl, or quilt-CO-,-COO-,-OCO-,-OCOO-,-CO-N (R
4)-,-N (R
4)-CO-,-N (R
4)-CO-N (R
4)-,-[N (R
4)]
2-CO-,-N (R
4)-COO-replacement or unsubstituted C at interval
2-C
18Alkyl, substituting group independently are selected from-OR
5,-OCO-R
5,-COO-R
5,-N (R
4)-R
5,-N (R
4)-CO-R
5With-CO-N (R
4)-R
5C
2-C
12Alkenyl or by the C of one or several discontinuous O atomic separation
2-C
12Alkenyl; Replace or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N;-CO-OR
4Or-CO-N (R
4)
2Perhaps R
1And R
2, or R
2And R
3Common formation replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N; R
4And R
5Separate is hydrogen, C
1-C
18Alkyl is by the C of one or several discontinuous O atomic separation
2-C
18Alkyl, C
3-C
12Cycloalkyl, C
2-C
18Alkenyl replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N.
The medicine that suppresses the zine ion metalloprotease is preferred for regulating physiology and the pathologic process that matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in.Physiology and the preferred angiogenesis of pathologic process that its matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in, wound healing, organ transplantation, to the control of fertilization process and regenerative power, the reconstruction of bone or pain.
The medicine that suppresses the zine ion metalloprotease is preferred for treatment and preventing cancer, cardiovascular disorder, sacroiliitis, periodontal disease, multiple sclerosis, inflammation, keratohelcosis, bacterial meningitis, diabetic syndrome, ephrosis, nerve degenerative diseases, AIDS, bleb, allergy, endometriosis, osteoporosis, asthma, anti-ageing or antibiotic.More preferably be used for the treatment of and preventing cancer, cardiovascular disorder or sacroiliitis.
On the other hand, the present invention also provides formula I compound or its salt to be used to suppress the application of zine ion metalloprotease as additive in protective foods, makeup or articles for daily use.
The preferred Jiao's property of formula I compound end gallate-based, last gallate-based propyl ester, Weibull, myricetin, baicalin, last gallate-based, Xanthaurine, scutellarin, Strictinin, robinetin, quercetagetin, Myricitroside, Progallin LA, gallo catechin, delphinidol or benserazide.More preferably Jiao's property end gallate-based.
Pyrogallol (Pyrogallic acid)
3,4,5-Propylgallate (Propyl gallic acid)
Gallic acid (Gallic acid)
Myricetin (Myricetin)
Noroxylin (Baicalein)
Delphinidol (Delphinidin)
Scutellarin (Scutellarein)
Strictinin (Strictinin)
Robinetin (Robinetin)
Quercetagetin (Quercetagetin)
Myricitroside (Myricitrin)
Progallin LA (Lauryl gallate)
Gallo catechin (Gallocatechol)
Benserazide (Benserazide)
Methanone
Rufigallol
Tricetin
Another aspect of the present invention provides the pharmaceutical composition as the zine ion inhibitors of metalloproteinase, comprises formula I compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, thinner or vehicle.
This pharmaceutical composition is preferred for regulating physiology and the pathologic process that matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in.Physiology and the preferred angiogenesis of pathologic process that matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in, wound healing, organ transplantation, to the control of fertilization process and regenerative power, the reconstruction of bone or pain.
Aforementioned pharmaceutical compositions is preferred for treatment and preventing cancer, cardiovascular disorder, sacroiliitis, periodontal disease, multiple sclerosis, inflammation, keratohelcosis, bacterial meningitis, diabetic syndrome, ephrosis, nerve degenerative diseases, AIDS, bleb, allergy, endometriosis, osteoporosis, asthma, anti-ageing or antibiotic.More preferably be used for the treatment of and preventing cancer cardiovascular disorder or sacroiliitis.
Further aspect of the present invention provides has protective foods, makeup or the articles for daily use composition that suppresses the effect of zine ion metalloprotease, comprises formula I compound or its salt as additive.
Description of drawings: Fig. 1 is the enzyme spectrum analysis histogram.
Embodiment
The following example illustrates in greater detail the present invention, but is not the present invention will be defined as embodiment.
Embodiment 11 and derivative thereof have restraining effect to the zine ion metalloprotease
The zymetology experimental procedure:
Used buffering liquid is 50mM HEPES (pH7.5), with 0.2M NaCl, 10mM CaCl
2, and 0.05%Brij-35, used substrate are DQ-Gelatin and P126; Measure at ambient temperature, the reaction cumulative volume is 100ml.When being added with inhibitor, enzyme and inhibitor should be hatched in buffer solution system 30 minutes, and then added substrate mensuration.The instrument of all detections is FLX800 fluorescence microplate reader (Bio-Tek), for DQ-Gelatin excitation wavelength 495nm, and emission wavelength 515nm, and for P126, excitation wavelength 328nm, emission wavelength 393nm.
The assaying reaction time is 8 minutes, and the slope of getting the line that the point of fluorescent value formed is a speed, wherein not inhibiting be designated as V
0, inhibiting be V
i, with V
i/ V
0The inhibition degree of expression inhibitor; Concentration with institute's inhibiting is X-coordinate then, with V
i/ V
0Value be ordinate zou, make response curve; At V
i/ V
0The concentration that is the inhibitor of 0.5 place correspondence is IC50.
We utilize the method for Dixon plot that the inhibition mechanism of 1 to MMP-2 is detected: the concentration with 1 is X-coordinate, and 1/V is an ordinate zou, gets three different concentration of substrate, can make three straight lines; These three collinear intersection points are between the negative semiaxis of Y-axis positive axis and X-axis, and this illustrates that its mechanism is competitive or based on the inhibition mechanism of competitiveness.We have proved that further 1 is competitive inhibition or competitive advantage restraining effect to the mechanism that matrix metalloproteinase suppresses, and see Table 1.
The IC50 (μ M) that table 11 and several derivative thereof suppress the zine ion metalloprotease
| MMP-1 | MMP-2 | MMP-3 | MMP-7 | MMP-9 | MMP-14 | MMP-16 | MMP-26 | |
| 1; 2,3-trihydroxy benzene/Pyrogallic acid PYROGALLIC ACID (μ M) Propyl gallic acid PROPYL GALLIC ACID (μ M) tannic acid TANNIC | 2.51 ±0.1 7 ND 0.258 | 4.67± 0.17 ＞500 0.779 | 12.77 ±0.36 ND 10.40 | 0.84± 0.04 ＞500 0.017 | 4.11± 0.54 394.24 0.145 | 35.09 ±0.84 296.41 0.111 | 33.22 ±5.69 22.69 0.129 | 34.91 ±4.59 approx imate 150 51.2 |
| The wild baicalein Scutellarein of the last gallate-based gallic acid of ACID (μ M) myricetin MYRICETIN (μ M) scutelloside BAICALEIN (μ M) EGCG (μ M) (μ M) quercetin Tricetin (μ M) (μ M) 1-O-Galloyl-4,6-hexahydroxydiphenoyl-beta-D-glucose Strictinin (μ M) Rufigallol (μ M) robinetin Robinetin (μ M) quercetagetin Quercetagetin (μ M) myricetrin Myricitrin (μ M) Methanone (μ M) dodecyl gallate Lauryl gallate (μ M) gallo catechin Gallocatechol (μ M) delphinidin Delphinidin (μ M) | 8±0 .008 1.05 ±0. 07 ND ND ND ND ND ND ND ND ND ND ND ND ND ND | ±0.0 86 1.69 ±0.1 4 13.85 ±0.3 3 6 51.6 15.2 5.4 0.6 22.8 9.7 6.6 8.7 15.6 18.2 12.2 2.1 | ± 1.30 4.26 ±0.6 3 ND ND ND ND ND ND ND ND ND ND ND ND ND ND | ±0.0 00 0.46 ±0.0 04 5.70 ±0.1 1 1.5 147 8.3 4.2 0.23 ND ND ND ND ND ND ND ND | ±0.0 01 0.59 ±0.0 2 7.53 ±1.2 9 0.8 80 18.5 2.5 1.1 54.1 2.6 15.2 32.1 18.6 3.6 8.7 0.7 | ±0.0 02 0.75 ±0.0 2 44.93 ±6.9 2 81.67 ＞200 ND ND ND ND ND ND ND ND ND ND ND | ±0.0 09 0.72 ±0.1 7 5.69 ±1.5 3 0.9 ND 21.6 30.8 5.2 ND 14.5 22.3 18.3 23.4 10.2 23.2 1.5 | 0.23 ±0.0 4 35.1 ND 161.9 ND ND ND ND ND ND ND ND ND ND ND |
| Benserazide Benserazide (μ M) | ND | 12.1 | ND | ND | 1.1 | ND | 14.8 | ND |
The anti-tumor experiment of embodiment 2 pyrogallols
1. pyrogallol is to the inhibition of HT1080 tumor cell adhesion and stretching, extension
Stick experiment:
The HT1080 cell that will be in logarithmic phase through digest resuspended after, carry out cell counting, then with 10
3The cell density in/hole imports in 24 orifice plates, Jiao's property that adds specified amount there is not forefinger acid, makes the medicine final concentration in every hole be followed successively by 0 μ M, 2 μ M, 5 μ M, 10 μ M, 20 μ M are behind the DMEM substratum mixing of the 10%FBS of every then hole adding 1ml, put into 37 ℃ of incubators and cultivate back taking-up about 30min, leave heart 5min with orifice plate whizzer 1000, inhale then and remove supernatant, under inverted microscope, observe the cell quantity that each the inside, hole is attached on the orifice plate bottom.
Stretch test:
The HT1080 cell that will be in logarithmic phase through digest resuspended after, carry out cell counting, then with 10
4The cell density in/hole imports in 24 orifice plates, Jiao's property that adds specified amount there is not forefinger acid, makes the medicine final concentration in every hole be followed successively by 0 μ M, 2 μ M, 5 μ M, 10 μ M, 20 μ M, every then hole adds the DMEM substratum mixing of the 10%FBS of 1ml, putting into 37 ℃ of incubators cultivates, be respectively 30min in the cell cultures time, in the time of 45min and 60min, utilize the form and the growing state of inverted microscope observation of cell.
Sticking of tumour cell is relevant with MMPs with stretching, extension, and experimental result proves: the 1 of different concns has restraining effect to HT1080 tumor cell adhesion and stretching, extension.
2. pyrogallol is to the inhibition of HT1080 tumor cell migration
Earlier in 24 orifice plates with 10
4The cell density in/hole is cultivated the HT1080 cell, treat cell grow into account for diapire about 80% the time, culture plate is taken out, supernatant liquor is removed in suction, liquid-transfering gun head with 200 μ L is cultivated standardized oblique line that width is identical in the plate hole at each, Jiao's property that adds specified amount then there is not forefinger acid, make the medicine final concentration in every hole be followed successively by 0 μ M, 2 μ M, 5 μ M, 10 μ M, 20 μ M, and the substratum final volume that makes every hole is 1mL, puts into 37 ℃ incubator then, observes the situation of filling and leading up of line part in each hole of culture plate behind the 12h.
The migration of tumour cell is relevant with MMPs.The 1 of different concns has restraining effect to the migration of HT1080 tumour cell.
3. pyrogallol is to the inhibition of HT1080 tumor cell invasion
Need before the experiment 1 of 24 well culture plate, the Transwell cell several, Matrigel, several were put in 200uL rifle head in 4 ℃ of refrigerators more than 5 hours, and transferred to the super clean bench the inside with ice chest.During experiment, earlier the Matrigel that adds 70 μ L/ holes with the rifle head of 200 μ L of precooling goes among the Transwell, generally adds at twice.After 24 orifice plates were sealed, putting into about 37 ℃ of incubator 20min and configuring final concentration with the DMEM substratum of 10%FBS was 0 μ M, 2 μ M, and 5 μ M, 10 μ M, the cell suspension of 20 μ M (contains about 10 with standby in every part of suspension
6Individual HT1080 cell).24 orifice plates behind the gel are taken out, and the bottom adds the NIH 3T3 cell conditioned medium in 150 μ L/ holes as chemotactic liquid, and the Matrigel on top goes up the cell suspension that adding has prepared.Put into 37 ℃ incubator then and cultivated 2-3 days, take out orifice plate and remove Matrigel on the Transwell cell, under inverted microscope, observe what of saturating theca cell quantity in each hole after with saturating theca cell dyeing with the Giemsa dye liquor.
The infiltration of tumour cell is relevant with MMPs.The 1 of different concns has restraining effect to the infiltration of HT1080 tumour cell.
4. pyrogallol is to the influence of Hela, HT1080 tumor cell proliferation
The propagation of tumour cell is relevant with MMPs.We with mtt assay measure different concns down do not have the kill rank of forefinger acid to the HT1080 cell, experimental technique is as follows: the HT1080 cell of the animated period of will grow, hang turbid later with the DMEM substratum of 10%FBS with 10
4The final concentration in/hole adds in 96 orifice plates, cultivates one day, treats that cell attachment growth reaches 70% of diapire, changes the culture medium culturing one day of 2% serum (FBS) again into.Then 0 μ M, 2 μ M, 5 μ M, 10 μ M, the concentration administration of 20 μ M are pressed in each hole.Overnight incubation, every hole continue to cultivate 4h after adding 20 μ l MTT.The careful suction removed supernatant, and every hole adds the DMSO of 150 μ l, vibration gently, the Viola crystallina of the formation hole in is fully dissolved after, read the OD value of each hole under 490nm with microplate reader.
The 1 of different concns has restraining effect to Hela, HT1080 tumor cell proliferation.1 is respectively 41.7 μ M and 56.8 μ M to the half-inhibition concentration IC50 of Hela, HT1080 tumor cell proliferation.
5. pyrogallol anti-tumor in vivo experiment
The anti-tumor in vivo experiment:
Under aseptic condition, extract the H22 hepatic ascites cell of inoculation 7 ~ 8d, transferring cell concn is 1 * 10
8/ ml, every mouse left hind subcutaneous vaccination 0.1ml, inoculation random packet next day, 12 every group, gastric infusion every day 1 time (administration according to dosage).Successive administration 10 days was weighed 1 time in per 3 days, and dislocation execution next day mouse claims knurl heavy, and is calculated as follows tumour inhibiting rate after the last administration.
Table 2 pyrogallol is to mouse H
22The restraining effect of lotus knurl growth
| Group | Dosage (mg/kg) | Number of animals (only) | Knurl heavy (g) | Tumour inhibiting rate (%) |
| Control group | 12/12 | 1.57±0.31 |
| Pyrogallol 5- | 100 20 | 12/12 12/12 | 0.745±0.18 0.503±0.43 | 53 68 |
Pyrogallol when 100mg/kg to tumor-bearing mice H
22The inhibiting rate of tumour is 53%, illustrates that pyrogallol has the vivo antitumor activity.Heavily there were significant differences for medication group and control group knurl (P＜0.05 〉
The pharmacological agent atherosclerosis of embodiment 3 specificitys antagonism MMP
One, atherosclerosis and MMPs
Atherosclerosis is the pathologic basis of clinical syndromes such as acute myocardial infarction and unstable angina pectoris, and matrix metalloproteinase MMPs plays an important role in cardiovascular reconstruction by the degradation of cell epimatrix.MMPs expresses both relevant with the instability of intimal thickening, patch, also relevant with the formation of restenotic lesions.The MMPs of up-regulated comprises MMP-1 in the detected atherosclerosis ,-2 ,-7 ,-9 ,-12.A lot of MMPs reinvent relevant with the matrix of arteriosclerosis damage, MMP-1 for example ,-2 ,-3 ,-7 ,-9 ,-12 ,-13 ,-14.Therefore the development of the medicine of specificity antagonism MMP will help the formation of the atherosis development of prevention of arterial, plaque rupture and restenosis.
1, atherosclerosis intimal thickening: atherosclerosis can be started by the chemistry or the physical abuse of endothelium, and monocyte enters inner membrance by changeing the endothelium osmosis in the blood immediately, and they activate or synthetic many cytokines and somatomedin there.Corresponding to these stimulations, vascular smooth muscle cell therefrom film is adjourned to inner membrance and has been experienced breeding.Substrate degradation is the prerequisite of monocyte and vascular smooth muscle cells migration, and is because cell has to pass through the extracellular obstacle, subcutaneous and around the basilar membrane of each smooth muscle cell in comprising.These observe the migration that explanation MMPs has participated in the effect, particularly vascular smooth muscle cell of intimal thickening.
2, plaques stabilize: unstable spot easily causes thrombosis and obturation in the coronary artery, triggers acute coronary syndrome (ACS).In atherosclerotic plaque, can detect enhanced MMPs and express, and MMPs can cause the weakening of patch fibrous cap by degraded ECM, so the activity of MMP family is relevant with plaque rupture.
3, restenosis: the treatment ischemic heart disease that develops into of percutaneous coronary intervention (PCI) provides a strong method, but many patients symptom in some months shows effect once more, because at original position restenosis has taken place.This is because the migration of middle level vascular smooth muscle cell and quick the growth produce the feature pathology of inner membrance fibroblast proliferation.Be reported in that balloon injured has raised impaired artery gelatinases expression in bovine in the animal model.Due to the PCI expansion in the patch degradation of extracellular matrix be convenient to the activation of blood circulation and exogenous cruor pathway and contact, and the migration of vascular smooth muscle cell with tissue factor in the vessel wall.This explanation is reinvented with restenosis relevant in the MMPs level that coronary artery increases with the migration and the blood vessel due to the thrombosis of vascular smooth muscle cell.
Two, Atherosclerosis Model makes up
Rat is used high fat method for breeding always, and high fat was raised three months at least, 5% egg yolk (be rich in cholesterol, crumb), 10% lard, 0.2% Methylthiouracil, 1% cholesterol; After 3 months, aorta abdominalis forms tangible patch.With balloon injured method research vascular remodeling and restenosis.
Three, detect index
The mechanism of action possible according to MMPs, use the MMP inhibitor in the balloon injury model of rat, investigate the influence of MMP inhibitor to this disease, this experiment is that the carotid artery with rat is research object, get started abdominal injection robinetin 300mg/kg after the modeling, continue 70 days.The correlation detection index is as follows:
1, inner chamber narrows down and neointima forms: put to death animal during different number of days after modeling, get the artery segment, and fixing embedded section, the inner chamber of measuring the different treatment group narrows down, neointima formation, the degree of vessel lesion and reconstruct.Inner chamber narrows down and considers from three aspects: absolute inner chamber area of section (LA); LA ratio (the internal dielectric membrane area of LA ratio=LA loss/contrast, LAratio=LA injury/IEL area of reference); The ratio that the inner chamber area of section that is formed by neointima narrows down=(IELarea-LA)/IEL area.Neointima forms also with the ratio evaluation of inner membrance to the middle layer, the i.e. absolute area in the absolute area/middle layer of I/M ratio=neointima.
2, vessel wall reconstruct: the degree of reconstruct not have vessel wall area (EEL AREA) ratio of standard part of damage definite by total vessel wall area (EEL AREA) of balloon injured part and join, promptly the reconstruct ratio (remodeling ratio, RR).Vessel wall area (EEL AREA) is to calculate (A=C by girth
2/ 4 π).Constriction reconstruct (feminine gender) RR＜0.95, expansion property reconstruct (positive) RR＞1.05.
3, enzyme spectrum analysis: rat is got carotid artery vascular freezing preservation in damping fluid after putting to death, protein content is surveyed in the centrifugal back of homogenate, and separate in the saturated SDS-PAGE of gelatin with the albumen of equivalent, the dyeing back is analyzed the density of each band and is represented enzymic activity with density type analyzer.
Four, interpretation of result
1, inner chamber narrows down and neointima formation
After administration 35 days and 70 days, all there were significant differences for inner chamber area and new membrane area and inner chamber area ratio, and after administration 3 days difference not obvious (as table 3).
Table 3 techtology data
| 3 days | 35 days | 70 days | ||||
| Control group | The administration group | Control group | The administration group | Control group | The administration group | |
| Inner chamber area (mm 2) | 0.44±0.0 6 | 0.50±0. 11 | 0.16±0.09 | 0.44±0. 12 a | 0.13±0.0 8 | 0.51±0 .08 a |
| New membrane area (mm 2) | 0 | 0 | 0.25±0.12 | 0.06±0. 02 c | 0.26±0.1 1 | 0.05±0 .02 a |
| Middle layer area (mm 2) | 0 | 0 | 0.08±0.02 | 0.11±0. 02 | 0.11±0.0 4 | 0.13±0 .05 |
| The I/M ratio | 7±7 | 13±3 | 3.08±1.66 | 0.55±0. 19 b | 2.17±0.4 2 | 0.38±0 .08 a |
| The inner chamber area ratio | 0.88±0.1 3 | 1.24±0. 36 c | 0.28±0.05 | 0.87±0. 16 a | 0.18±0.0 7 | 1.48±0 .22 a |
| The reconstruct ratio | 0.88±0.1 3 | 1.20±0. 31 c | 0.78±0.12 | 1.02±0. 14 c | 0.67±0.1 2 | 1.56±0 .43 a |
ap＝0.0001
bp＝0.001
cp＝0.01
After behind the animal sacculus blood vessel injury 35,70 days, the drug combination group gets positive controls with administration not and compares with individually dosed group, and absolute neointima area, I/M ratio obviously reduce, and the inner chamber area ratio obviously increases.Modeling after three months Movat dyeing compared with the administration group as seen that tangible inner chamber narrows down and new film forms.
2, vessel wall reconstruct
By the data of reconstruct ratio in the table 1 as can be seen, at the 3rd day, 35 days and 70 days, all there were significant differences for the reconstruct ratio of administration group and control group.By the data of table 2 reconfiguration classification as can be seen, the administration group is compared with control group, and constriction reconstruct obviously reduces, and illustrates that medicine has restraining effect to the constriction of vascular remodeling.
Table 4 reconfiguration classification
| Control group (20) | Administration group (20) | |
| Constriction reconstruct (n=19) | 18 | 1 |
| No reconstruct (n=8) | 2 | 6 |
| The reconstruct (n=13) of | 0 | 13 |
3, enzyme spectrum analysis
The carotid artery of getting rat after the balloon injured in 3 days carries out enzyme spectrum analysis, analyzes the relative density of MMP-2 band by density type analyzer.Positive controls is obviously than 3 administration groups and negative control group big (as Fig. 1).Illustrate that medication can reduce the activity of MMP.
Fig. 1 X-coordinate is from left to right represented positive controls successively, the administration group of three various dose, and negative control group.Positive controls (100 ± 13) is obviously than 3 administration groups (72 ± 10,69 ±/12,35 ± 5; P＜0.001) and negative control group (25 ±/3, P＜0.001) big.
Five, conclusion: using the MMP inhibitor in the atherosclerosis balloon injury model of rat, is research object with the carotid artery of rat, prove that abdominal injection MMP inhibitor robinetin has this disease to treat and mitigation.
The experimental study of embodiment 4 exogenous substrates metalloprotease ihibitors for treatment endometriosis
Endometriosis is to take place after endometrial gland soaks into healthy tissues.Endometriosis is the process of an infiltration.Matrix metalloproteinase is essential for reinventing of extracellular matrix.Matrix metalloproteinase participates in the turnover of normal tissue metabolism, the interior film rupture when comprising the menstrual cycle.Ample evidence shows that metalloprotease and their tissue depressant participate in the pathologic process of endometriosis, and is relevant with the development of endometriosis.Metalloprotease of finding relevant with endometriosis and their tissue depressant comprise MMP-1, MMP-2, MMP-3, MMP-9, TACE and TIMP-1, TIMP-3 at present.(endometriosis, EMs) model carry out the treatment of exogenous substrates inhibitors of metalloproteinase by rat endometrium dystopy disease in this research.The result of treatment of exogenous substrates inhibitors of metalloproteinase to endometriosis understood in variation by Ectopic Endometrium focus size before and after the treatment.And finish back 3 months serum sex hormone level, hepatic and renal function and, understand the side reaction of this methods of treatment and the recurrence situation of disease the influence of important organ by detecting the intervention of inhibitor for treating group.For seeking the new active drug based theoretical of treatment EMs, EMs provides theoretical foundation for its clinical treatment.
The exogenous substrates inhibitors of metalloproteinase is a delphinidol.
1. the foundation of rat endometrium dystopy disease model
Adopt from body uterine endometrium pelvic cavity transfer methods according to Vernon, improve and set up rat endometrium dystopy disease animal model.Around after the modeling, open abdomen once more, observe the growing state of graft.EM model modeling success visual inspection standard: transplant that stove is long-pending to be increased, be transparent nodositas, cryptomere, have clarified liq to gather, graft is covered by reticular tissue and vascularization is arranged, and quality is soft, as cardinal principle criterion.And get its ectopic focus and carry out histological observation.Histopathology is observed: visible inner membrance survival of transplanting, and the superficial epithelium hyperplasia is column, and body of gland is sparse, and the lumen of gland form is owed rule, but still visible glandular epithelium and mesenchymal cell, glandular epithelium is column, cubic or flats, and the visible nuclear of part is cavity down.Between the matter densification, mesenchymal cell is little and sparse.
Rat after the modeling success is divided into five groups, 10 every group at random.Experimental group A is that exogenous inhibitor delphinidol is controlled abdominal injection, once-a-day, and around being total to.C is exogenous inhibitor delphinidol treatment group: 150mg/kg, abdominal injection, once-a-day, around being total to.
The positive control group of control group D: GuRH-A (LHRH-A)-nafarelin 0.1mg/kg, subcutaneous injection, once-a-day, around being total to.The negative control group of E: 0.9% physiological saline 0.5ml/kg, abdominal injection, once-a-day, around being total to.
2. observation index:
1) exogenous inhibitor, nafarelin are to the influence of experimental model of endometriosis ectopic focus volume
By the mensuration to ectopic focus volume change before and after each group rat treatment, the result shows: respectively organize ectopic focus volume there was no significant difference (P＞0.05) before the treatment; And the exogenous inhibitor for treating group show dose in treatment back is a little less than the effect of 50mg/kg, and dosage is that 100mg/kg, 150mg/kg treatment group curative effect are better.B, C treatment group and western medicine group ectopic focus volume obviously dwindle or atrophy, inhibiting rate obviously raises, compare difference highly significant (P＜0.05) with model group, exogenous inhibitor for treating group ectopic focus is compared with western medicine group does not then have obvious statistical significance (P＞0.05), this shows, exogenous substrates metal deactivator, nafarelin treatment EMs, its Ectopic Endometrium growth has been subjected to obvious suppression, and the exogenous substrates metal deactivator is similar to the restraining effect of nafarelin.
2) exogenous inhibitor, nafarelin are to the tissue morphology and the Ultrastructural influence of experimental model of endometriosis inner membrance on the throne and Ectopic Endometrium
Gross examination of skeletal muscle
Locate the length of Ectopic Endometrium respectively at when 4 weeks (after the administration) measurement uterus crotch, ovary and stomach wall etc. after (postoperative is during 4 weeks) and the pharmacological agent before each group rat administration, calculate its cumulative volume (V1, V2), calculate and respectively organize the inhibiting rate of medicine Ectopic Endometrium.
After each treated animal is put to death, open the abdominal cavity and see that adhesion is extensive in the model group rat abdominal cavity, 10 all visible grafts of mouse, about 1-5mm
3Differ in size, what have is the capsule vesicle that contains courageous and upright liquid, what have is to contain the capsule vesicle that colourless liquid is transparence, what have is the capsule reality, 3 rat implantation things and big net, intestinal tube, uterus, the extensive adhesion of pelvic peritoneum are arranged, form agglomerate, have 2 rat implantation thing surfaces to form the reticular tissue parcel, there is 1 ectopic focus to dwindle atrophy.In the exogenous inhibitor for treating group rat abdominal cavity adhesion seldom, all atrophys of stomach wall and crotch focus (not seeing liquid in it), 80% graft disappears, only is vestige, the bilateral ovaries graft obviously dwindles 50%-70%, has 3 1-3mm to occur
3About white matter hard tubercle.Graft good absorption in the nafarelin group rat abdominal cavity, what have obviously dwindles, the disappearance that has, with exogenous inhibitor for treating category seemingly.Normal control group (sham operated rats) is seen the pelvic cavity structural integrity, only has an example the slight adhesion of mesentery and incision of abdominal wall place to occur, but is easy to separate.
Om observation
As seen paraffin section dyes through HE:
1. normal rat uterine endometrium mucous epithelium is complete, and epithelial cell is high column or column, and mesenchymal cell is evenly distributed in the mucous layer, and body of gland quantity is many, and lumen of gland is complete, and glandular epithelium mostly is column, and cavity and top will be secreted down can to see nuclear.
2. the visible inner membrance survival of transplanting of model group, the obvious hyperplasia of epithelial cell is column, cubic or flats, part can be seen nuclear cavity and apocrine secretion down, shows and the approaching synchronous cyclomorphosis of uterine endometrium on the throne, and mesenchymal cell is little and sparse, it is inactive to grow, and body of gland quantity reduces, and the body of gland form that has changes, be slot-shaped, the lumen of gland that has extremely enlarges, and papilla is arranged, and can see hemosiderin cell and foam cell in the lumen of gland that has, the body of gland that has disappears, rich blood vessel.
3. exogenous inhibitor for treating group internal film tissue on the throne lumen of gland form changes, but gland structure is complete, glandular epithelium marshalling, a matter densification; The Ectopic Endometrium tissue is slot-shaped change, and superficial epithelium is short cubic, the epithelial cell arrangement disorder, and the inner membrance body of gland reduces, the glandular epithelium atrophy, vascular surface reduces, and mesenchymal cell is little and sparse.
4. internal film tissue on the throne body of gland form change is organized in the nafarelin treatment, expansion that has such as sphere, and the atrophy that has does not have lumen of gland, and epithelial cell is imperfect; Ectopic Endometrium is organized epithelial cell sex change, necrosis, and the tumour blister cavities dwindles, the cyst wall attenuation, and the body of gland reduced number, lumen of gland is little, and glandular epithelium is atrophy slightly.
3. conclusion
Use the MMP inhibitor in rat endometrium dystopy disease model, prove that abdominal injection MMP inhibitor delphinidol has treatment and mitigation to this disease.
The application of embodiment 5 matrix metalloproteinases (MMP) inhibitor in rabbit osteoarthritis model
(Osteoarthritis OA) is the sex change of joint cartilage to osteoarthritis, and destruction and hyperosteogeny are the chronic joint disease of feature, are the modal joint property diseases of China, also is to cause the elderly's pain and disabled one of the main reasons.Its pathogenesis it be unclear that, but has obtained many-sided the elaboration about the mechanism of its cartilage degradation.The basic purpose of OA treatment is a relief of symptoms, improves function, and delay of progression and correction deformity should be conceived to diagnosis early, early treatment, the long course of treatment to OA, promptly just should adopt complex therapy when mild appears in the patient.Multiple MMPs has Degradation to the articular chondrocytes epimatrix, and the joint cartilage matrix structure is changed, and the external force resistance effect descends, and finally causes carrying out property of joint cartilage destruction.Therefore using MMP inhibitor for treating osteoarthritis is to realize that cartilage protection is to delay the important means of PD.
＜experiment progress 〉
First week: 24 capable respectively ACL operations of large ear rabbits.
The three-five week: animal is divided into three groups at random, is respectively A group (joint cavity injection physiological saline), and B organizes (joint cavity injection 100mg/ml scutellarin solution), and C organizes (joint cavity injection 100mg/ml Xanthaurine solution).
After six weeks: put to death.Carry out clinical manifestation and observe gross examination of skeletal muscle, pathological observation, statistical analysis.
＜modelling 〉
The mould rabbit with 3% vetanarcol (30mg/kg) auricular vein injecting anesthetic, is lain on the back and fixes on operating table, the local depilation of right knee joint, preserved skin, sterilization, drape, strict aseptic technique.Get the longitudinal incision that the knee joint inboard is about 4cm, detect in the joint cavity and cut off MCL behind the no primary affection, further excise medial meniscus and front and back ligamentaum cruciatum, note not damaging articular cartilage face, thoroughly hemostasis, the flushing joint cavity, after the row drawer experiment positive, the layer-by-layer suture joint capsule, subcutaneous, skin, aseptic dressing wrapping injury will not be fixed.Postoperative intramuscular injection every day penicillin 200,000 U, wound is changed dressings, and continuous seven days with preventing infection.The characteristics of incidence of OA appears in advance according to super tired activity clinically, operation 1 week of back, forced animal activity every day 30 minutes, and drive at twice, promptly obtain stable OA model after 4 weeks.
The observation of＜osteoarthritis clinical manifestation 〉
After the 6th all administrations finish, assess with the knee joint clinical assessment rank of Lequesne MG.
1. local pain irritant reaction:, be divided into 4 grades by irritant reaction degree difference with finger extruding knee joint.
I level: no abnormal pain reaction; II level: suffer from limb and shrink; III level: suffer from limb contraction, spasm, accompany slight systemic reaction, suck as trembling all over the body, later licking etc.; The IV level: the trouble limb acutely shrinks, spasm, is all of a tremble, and runs helter-skelter, struggles.
2. gait changes: by suffer from the limb walking, gait when running is divided into 4 grades.
The I level: suffering from limb does not have limping, and it is normal to run, and it is strong to pedal ground; The II level: suffer from when limb is run and slightly walking lamely, it is strong to pedal ground; III level: suffer from limb and participate in walking, but walk lamely obviously; IV level: suffer from limb and can not participate in walking, can not contact to earth, pedal ground.
3. range of motion: be divided into 4 grades (stretch is 0 °) by suffering from limb knee joint scope of activity.
I level: more than 90 °; II level: 45 °～90 °; III level: 15 °～45 °; IV level: 15 °.
4. arthroncus: be divided into 3 grades by knee joint swelling degree: the I level: no swelling, the bone mark is clearly visible; The II level: mild swelling, the bone mark shoals; The III level: obviously swelling, the bone mark disappears.
3 groups of rabbit knee osteoarthritis of table 5 clinical manifestation appraisal result (n=8)
| Group | The pain stimulation reaction | Gait changes | Range of motion | Arthroncus | |||||||||||
| I | II | III | IV | I | II | III | IV | I | II | III | IV | I | II | III | |
| A group B | 0 1 2 | 1 3 4 | 2 4 2 | 3 0 0 | 0 2 3 | 1 4 4 | 4 2 1 | 1 0 0 | 0 3 4 | 2 3 2 | 3 2 1 | 1 0 1 | 1 4 4 | 3 4 3 | 2 0 1 |
More than 4 groups of indexs, A group is compared p＜0.01 with B group, C group respectively.
＜gross examination of skeletal muscle 〉
White Rabbits are put to death in operation 6 week backs, and observe knee joint and have or not hydrarthrosis and synovial membrane swelling hyperemia, and observe the pathological change of condyle of femur articulum down in dissecting microscope, by following principle scoring: 0 minute, the articulum polishing, color and luster is as usual; 1 minute, articulum was coarse, had little crack and color and luster gloomy; 2 minutes, the articulum erosion, cartilage defect reaches cartilage table middle level deeply; 3 minutes, articulum ulceration, the damaged cartilage deep layer that reaches deeply; 4 minutes, cartilage stripped off, and subchondral bone matter exposes.
| The macroscopic observation scoring | |
| The A group | 2.83±0.56 |
| The B group | 2.03±0.66 |
| The C group | 2.11±0.44 |
Last table data, the A group is compared with B group, C group, and there were significant differences on p＜0.05 level.
＜Histological evaluation 〉
An about week of the knee joint of 10% formalin fixed decalcification in decalcifying agent.The complete patella of decalcification is cross-section in the plane ahead of the curve, so intermediary and lateral circulation kept, and two one side of something embeddings in paraffin.Primary section is cut off with two steps with the interval of 150 μ m.These sections are with Toluidine blue staining, and light microscopic is observed down, are used to estimate cartilage destruction and spur and form.The following system evaluation of cartilage destruction: 1=has only the least surface zone, and 2=slightly expands to the zone, middle and upper part, and 3=suitably gos deep into the intermediary zone, and 4=indicates deep regional but be not climax that thickening fully that 5=is serious degenerates to climax.The quantity of cartilage destruction determines that according to 1/3,2/3 or 3/3 of histology part surface above mark multiply by 1,2 or 3 respectively, to react the scope of the tibial plate that participates in respectively.The size scoring that spur is measured with an eyepiece micrometer: 1,2 or 3 be respectively slight, moderate or serious.
| Gross score | The shin bone mark | The femur mark | The spur mark | |
| The A group | 10.1±0.6 | 7.1±0.4 | 1.2±0.3 | 1.8±0.1 |
| The B group | 4.4±0.5 | 3.5±0.4 | 0.2±0.1 | 0.9±0.1 |
| The C group | 6.9±2.4 | 5.1±1.6 | 0.7±1.5 | 1.1±0.5 |
Data A group is compared with B group, C group in the last table, and there were significant differences on p＜0.05 level.
＜conclusion 〉
Use the MMP inhibitor in rabbit osteoarthritis model, prove that joint cavity injection MMP inhibitor scutellarin and Xanthaurine solution have treatment and mitigation to this disease.
Claims (10)
1, formula I compound or its pharmacy acceptable salt are used for suppressing the application of the medicine of zine ion metalloprotease in preparation, and described formula I compound is
R wherein
1, R
2And R
3Independently be hydrogen atom, replace or unsubstituted C
1-C
18Alkyl is by the replacement of one or several discontinuous O atomic separation or unsubstituted C
2-C
18Alkyl, or quilt-CO-,-COO-,-OCO-,-OCOO-,-CO-N (
4)-,-N (R
4)-CO-,-N (R
4)-CO-N (R
4)-,-[N (R
4)]
2-CO-,-N (R
4)-COO-replacement or unsubstituted C at interval
2-C
18Alkyl, substituting group independently are selected from-OR
5,-OCO-R
5,-COO-R
5,-N (R
4)-R
5,-N (R
4)-CO-R
5With-CO-N (R
4)-R
5C
2-C
12Alkenyl or by the C of one or several discontinuous O atomic separation
2-C
12Alkenyl; Replace or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N;-CO-OR
4Or-CO-N (R
4)
2Perhaps R
1And R
2, or R
2And R
3Common formation replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N; R
4And R
5Separate is hydrogen, C
1-C
18Alkyl is by the C of one or several discontinuous O atomic separation
2-C
18Alkyl, C
3-C
12Cycloalkyl, C
2-C
18Alkenyl replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N.
2, application as claimed in claim 1, the medicine that wherein suppresses the zine ion metalloprotease are used to regulate physiology and the pathologic process that matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in.
3, application as claimed in claim 2, physiology and pathologic process that its matrix metalloproteinase (MMPs), ADAMs or ADAM-TS participate in are angiogenesiss, wound healing, organ transplantation, to the control of fertilization process and regenerative power, the reconstruction of bone or pain.
4, application as claimed in claim 1, the medicine that wherein suppresses the zine ion metalloprotease is used for the treatment of and preventing cancer cardiovascular disorder, sacroiliitis, periodontal disease, multiple sclerosis, inflammation, keratohelcosis, bacterial meningitis, diabetic syndrome, ephrosis, nerve degenerative diseases, AIDS, bleb, allergy, endometriosis, osteoporosis or asthma.
5, application as claimed in claim 1, the medicine that wherein suppresses the zine ion metalloprotease is used for the treatment of and preventing cancer, cardiovascular disorder or sacroiliitis.
6, application as claimed in claim 1, the medicine that wherein suppresses the zine ion metalloprotease is used for anti-ageing or antibiotic.
7, formula I compound or its salt is used to suppress the application of zine ion metalloprotease as additive in protective foods, makeup or articles for daily use, and described formula I compound is
R wherein
1, R
2And R
3Independently be hydrogen atom, replace or unsubstituted C
1-C
18Alkyl is by the replacement of one or several discontinuous O atomic separation or unsubstituted C
2-C
18Alkyl, or quilt-CO-,-COO-,-OCO-,-OCOO-,-CO-N (R
4)-,-N (R
4)-CO-,-N (R
4)-CO-N (R
4)-,-[N (R
4)]
2-CO-,-N (R
4)-COO-replacement or unsubstituted C at interval
2-C
18Alkyl, substituting group independently are selected from-OR
5,-OCO-R
5,-COO-R
5,-N (R
4)-R
5,-N (R
4)-CO-R
5With-CO-N (R
4)-R
5C
2-C
12Alkenyl or by the C of one or several discontinuous O atomic separation
2-C
12Alkenyl; Replace or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N;-CO-OR
4Or-CO-N (R
4)
2Perhaps R
1And R
2, or R
2And R
3Common formation replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N; R
4And R
5Separate is hydrogen, C
1-C
18Alkyl is by the C of one an or youngster discontinuous O atomic separation
2-C
18Alkyl, C
3-C
12Cycloalkyl, C
2-C
18Alkenyl replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N.
8, as each described application in the claim 1 to 7, its Chinese style I compound is Jiao's property end gallate-based, last gallate-based propyl ester, Weibull, myricetin, baicalin, last gallate-based, Xanthaurine, scutellarin, Strictinin, robinetin, quercetagetin, Myricitroside, Progallin LA, gallo catechin, delphinidol or benserazide.
9, as each described application in the claim 1 to 7, its Chinese style I compound is Jiao's property end gallate-based.
10, as the pharmaceutical composition of zine ion inhibitors of metalloproteinase, comprise formula I compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, thinner or vehicle,
R wherein
1, R
2And R
3Independently be hydrogen atom, replace or unsubstituted C
1-C
18Alkyl is by the replacement of one or several discontinuous O atomic separation or unsubstituted C
2-C
18Alkyl, or quilt-CO-,-COO-,-OCO-,-OCOO-,-CO-N (R
4)-,-N (R
4)-CO-,-N (R
4)-CO-N (R
4)-,-[N (R
4)]
2-CO-,-N (R
4)-COO-replacement or unsubstituted C at interval
2-C
18Alkyl, substituting group independently are selected from-OR
5,-OCO-R
5,-COO-R
5,-N (R
4)-R
5,-N (R
4)-CO-R
5With-CO-N (R
4)-R
5C
2-C
12Alkenyl or by the C of one or several discontinuous O atomic separation
2-C
12Alkenyl; Replace or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N;-CO-OR
4Or-CO-N (R
4)
2Perhaps R
1And R
2, or R
2And R
3Common formation replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N; R
4And R
5Separate is hydrogen, C
1-C
18Alkyl is by the C of one or several discontinuous O atomic separation
2-C
18Alkyl, C
3-C
12Cycloalkyl, C
2-C
18Alkenyl replaces or unsubstituted C
6-C
20Aryl, or replacement or unsubstituted C
4-C
20The heteroaryl that contains O, S or N, substituting group independently is selected from hydroxyl, halogen, O, S, C
1-C
8Alkyl, C
1-C
8Alkylthio, C
1-C
8Alkoxyl group, C
6-C
20Aryl, C
4-C
20The heteroaryl that contains O, S or N, C
6-C
20Aryloxy and C
4-C
20The heteroaryl oxygen base that contains O, S or N.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100657305A CN1837169A (en) | 2006-03-14 | 2006-03-14 | Compound capable of inhibiting zinc ion metalloproteinases |
| PCT/CN2007/000742 WO2007104242A1 (en) | 2006-03-14 | 2007-03-08 | Compounds capable of inhibiting zinc ion metalloproteinases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100657305A CN1837169A (en) | 2006-03-14 | 2006-03-14 | Compound capable of inhibiting zinc ion metalloproteinases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1837169A true CN1837169A (en) | 2006-09-27 |
Family
ID=37014701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100657305A Pending CN1837169A (en) | 2006-03-14 | 2006-03-14 | Compound capable of inhibiting zinc ion metalloproteinases |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1837169A (en) |
| WO (1) | WO2007104242A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100902768B1 (en) * | 2007-05-22 | 2009-06-15 | 바이오스펙트럼 주식회사 | Agents for Preventing Hair Loss Comprising Delphinidin as an Active Ingredient |
| CN101591321B (en) * | 2009-06-25 | 2011-08-17 | 昆明制药集团股份有限公司 | Method for preparing 5,6,7,4'-tetrahydroxyflavone |
| CN103989694A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第四军医大学 | Application of myricetrin for preventing and treating osteoporosis |
| CN106727470A (en) * | 2016-12-09 | 2017-05-31 | 中国药科大学 | Application of the benserazide hydrochloride in the medicine for preparing treatment acute inflammation |
| CN107550901A (en) * | 2017-10-31 | 2018-01-09 | 上海华堇生物技术有限责任公司 | The medicinal usage of robinetin |
| CN112791003A (en) * | 2021-01-26 | 2021-05-14 | 上海澄穆生物科技有限公司 | Use of retinoic acid receptor agonist compounds in cosmetic compositions |
| CN115957225A (en) * | 2022-12-23 | 2023-04-14 | 广东植肤生物科技有限公司 | MMP-1 expression inhibitor, skin external composition and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005247319B2 (en) | 2004-04-28 | 2011-12-01 | Molecules For Health, Inc. | Methods for treating or preventing restenosis and other vascular proliferative disorders |
| US9526707B2 (en) | 2007-08-13 | 2016-12-27 | Howard L. Elford | Methods for treating or preventing neuroinflammation or autoimmune diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6428818B1 (en) * | 1999-03-30 | 2002-08-06 | Purdue Research Foundation | Tea catechin formulations and processes for making same |
| ES2171142B1 (en) * | 2000-12-22 | 2003-12-16 | Consejo Superior Investigacion | CONJUGATES OF FLAVANOLES AND CISTEAMINE. |
| US7358383B2 (en) * | 2003-01-24 | 2008-04-15 | University Of South Florida | Polyphenol proteasome inhibitors, synthesis, and methods of use |
| WO2005000330A1 (en) * | 2003-05-28 | 2005-01-06 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Angiogenic agents from plant extracts, gallic acid, and derivatives |
| ES2318287T3 (en) * | 2003-05-30 | 2009-05-01 | Astellas Pharma Inc. | PEPTIDOS DE GALOILO. |
| CN1234353C (en) * | 2004-03-10 | 2006-01-04 | 牛凤兰 | Applicaton of gallic acid in prepn. of medicine for antitumor |
| JP2005281164A (en) * | 2004-03-29 | 2005-10-13 | Api Co Ltd | Gallic ester compound, method for producing the same, anticancer agent and preparation |
-
2006
- 2006-03-14 CN CNA2006100657305A patent/CN1837169A/en active Pending
-
2007
- 2007-03-08 WO PCT/CN2007/000742 patent/WO2007104242A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100902768B1 (en) * | 2007-05-22 | 2009-06-15 | 바이오스펙트럼 주식회사 | Agents for Preventing Hair Loss Comprising Delphinidin as an Active Ingredient |
| CN101591321B (en) * | 2009-06-25 | 2011-08-17 | 昆明制药集团股份有限公司 | Method for preparing 5,6,7,4'-tetrahydroxyflavone |
| CN103989694A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第四军医大学 | Application of myricetrin for preventing and treating osteoporosis |
| CN106727470A (en) * | 2016-12-09 | 2017-05-31 | 中国药科大学 | Application of the benserazide hydrochloride in the medicine for preparing treatment acute inflammation |
| CN106727470B (en) * | 2016-12-09 | 2019-10-01 | 中国药科大学 | Application of the benserazide hydrochloride in the drug of preparation treatment acute inflammation |
| CN107550901A (en) * | 2017-10-31 | 2018-01-09 | 上海华堇生物技术有限责任公司 | The medicinal usage of robinetin |
| CN112791003A (en) * | 2021-01-26 | 2021-05-14 | 上海澄穆生物科技有限公司 | Use of retinoic acid receptor agonist compounds in cosmetic compositions |
| CN115957225A (en) * | 2022-12-23 | 2023-04-14 | 广东植肤生物科技有限公司 | MMP-1 expression inhibitor, skin external composition and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007104242A1 (en) | 2007-09-20 |
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