CN104230728A - 1,2-diketone naphthalene compound as well as preparation method and application thereof - Google Patents
1,2-diketone naphthalene compound as well as preparation method and application thereof Download PDFInfo
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- 0 *c(cc1)ccc1NC(c(cccc1)c1C1=O)=CC1=O Chemical compound *c(cc1)ccc1NC(c(cccc1)c1C1=O)=CC1=O 0.000 description 11
- TYYDOINBFLRGBU-UHFFFAOYSA-N CCN(C(c(cccc12)c1c1ccc2NC(C2C(C3=O)=CCCC2)=CC3=O)=O)C1=O Chemical compound CCN(C(c(cccc12)c1c1ccc2NC(C2C(C3=O)=CCCC2)=CC3=O)=O)C1=O TYYDOINBFLRGBU-UHFFFAOYSA-N 0.000 description 1
- AOQMVIPQGPPCJP-UHFFFAOYSA-N O=C(C=C(c1c2cccc1)Nc(cc1)cc(C=C3)c1OC3=O)C2=O Chemical compound O=C(C=C(c1c2cccc1)Nc(cc1)cc(C=C3)c1OC3=O)C2=O AOQMVIPQGPPCJP-UHFFFAOYSA-N 0.000 description 1
- XRNHFUCTBZMUKU-UHFFFAOYSA-N OC(c(cccc1)c1C(Nc1ccc2OCC(C=O)=Cc2c1)=C1)C1=O Chemical compound OC(c(cccc1)c1C(Nc1ccc2OCC(C=O)=Cc2c1)=C1)C1=O XRNHFUCTBZMUKU-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a 1,2-diketone naphthalene compound which has a general structural formula (I) described in the specification, wherein Ar represents benzene ring, naphthalene ring, quinoline ring or isoquinoline ring, naphthalene diimide ring or coumarin ring; amino acid is directly connected with the Ar; when a substituent group exists on the Ar, R is an electron-withdrawing, electron-donating or neutral group. The invention further discloses a preparation method of the compound and application of the compound to preparation of inflammation-resistant and immunocompetence-resistant drugs. The compound is relatively good in inflammation and immunological competence resistance, is a CRAC (Ca<2+> release activated Ca<2+>) blocker with a novel structure, and can be used as a lead compound of the inflammation-resistant and immunocompetence-resistant drugs. According to the preparation method, the reaction condition is mild, raw materials are cheap and easily available, and the operation and the post-treatment process are simple.
Description
Technical field
The present invention relates to a kind of 1,2-diketone naphthalene compounds and preparation method thereof and application, belong to technical field of medicine synthesis.
Background technology
Calcium ion (Ca
2+) be maximum positively charged ion in human body, the calcium about containing 1 kg in the body of a grownup, in human body, most calcium mainly exists in bone, tooth in the form of phosphate, and small portion is present in body fluid and cartilaginous tissue.And in cell, calcium major storage is in intracellular calcium storehouse (plastosome, endoplasmic reticulum or sarcoplasmic reticulum).The outer Ca of born of the same parents
2+concentration be approximately 10
-3m, the concentration of intracellular calcium ion is approximately 10
-7-10
-8m.Both differences more than 10000 times.Although the content of calcium constituent is very little on a cellular level, it is very crucial to maintaining a lot of Metabolic activity in cell.Calcium channel is to maintenance intraor extracellular Ca
2+balance has vital role.Ca
2+as second messenger, concern normally carrying out of the physiological process on many bases, can participate in a large amount of physiological activity, as the growth of the composition and decomposition of vasomotion, genetic transcription, tramsmitter release, glycogen metabolism, protein, cell, propagation, differentiation and apoptosis, cell recognition and endocytosis etc.The calcium channel be positioned on neural system, endocrine system, cardiovascular systems cytolemma is by voltage-controlled, be called valtage-gated type calcium channel (voltage-operated Ca
2+channel, VOC channel).On the other hand, be positioned on the inflammatory cells such as lymphocyte, T cell, mastocyte and neutrophil leucocyte and also there is a class not by voltage-controlled calcium channel.That wherein studies is clear that calcium activates the calcium channel (Ca of release most
2+release Activated Ca
2+, CRAC).CRAC passage is made up of ORAI and STIM (stromal interaction molecule).STIM albumen is positioned in endoplasmic reticulum, and be the susceptor of calcium ion, ORAI albumen is positioned on cytolemma, and the post polymerization that is upset becomes tetramer, forms CRAC channel part.When being subject to external stimulus, the receptors bind of part and the surface of cell membrane such as g protein coupled receptor or immunity receptor, thus activation of phospholipase C (PLC), hydrolysis phosphatidylinosital biphosphate (phosphatidylinositol 4,5 bisphosphate, PIP
2), cause l in kytoplasm, 4,5-phosphoinositide (inositol l, 4,5trisphosphate, IP
3) concentration rising, make the IP on endoplasmic reticulum
3acceptor (IP
3r) channel opener, causes Ca in endoplasmic reticulum
2+concentration outflows, Ca in endoplasmic reticulum
2+the exhaustion of concentration, makes the calcium calmodulin binding domain CaM on STIM1 dimer lose Ca
2+, structure changes thereupon, thus is activated.And now, the Orai1 monomer on plasma membrane is also spontaneous is assembled into tetramer CRAC passage, the STIM1 dimer be activated moves and gathers the Nodes near plasma membrane, triggers CRAC passage and opens.After CRAC channel opener, a large amount of Ca
2+cell is entered, Ca from born of the same parents
2+a large amount of in flow to and responsive courier---nuclear factor of activated T cells (NFAT) of calcium important in activated T cell, the expression starting downstream gene in nucleus will be entered after NFAT is activated, the gene amplification of induction core inner cell immune factor, expression, synthesize a large amount of immune cell factor and comprise interleukin-(IL-2) etc., and the proliferation and differentiation of inducing T cell, thus produce immune response.Therefore, CRAC passage all plays an important role for the activation of T cell, proliferation and apoptosis.In addition, some para-immunity diseases, as the generation of immune deficiency, allergy, thrombus and mammary cancer etc., is also found abnormal with the activity of CRAC passage relevant.Therefore the coupling process of selectivity retardance Orail passage or blocking-up Orail and STIMI, just can abnormal immune be suppressed selectively to react, and not affect the normal immunologic function of body, this will become a kind of desirable remedy measures.Therefore, targeting is just expected to be used for the treatment of the disease such as inflammatory reaction and excessive immune reaction in the medicine of CRAC passage.Although have been found that CRAC passage can as treatment inflammatory reaction and the target spot of autoimmune disorder, also fail now to obtain the clinical medicine of selectivity retardance CRAC passage, even also fewer to the research of CRAC channel blocker.Having found that there is a few compounds has good blocking activity to CRAC passage at present, as SKF 96365, Econazole, and L-651582 etc., but the activity and selectivity of these compounds is also relatively low, is all not enough to be used as drug candidate molecule.
Summary of the invention
The lead compound of the present invention to the good novel structure of activity that early stage finds carries out structure of modification, has found active better drug candidate molecule.First utilize the early stage CRAC passage homology model that builds in Specs database 300, more than 000 compound has carried out docking, screening, therefrom selects a good compound YZ-01 of activity, obtains its IC by active testing
50value is that (61.5 ± 8 μMs) are suitable with the activity of positive control SKF 96365, its IC
50value is (25.7 ± 1 μMs).Then carry out reasonably optimizing using compound YZ-01 as lead compound, learn that it has 3 kinds of tautomeric structures by observing its activity, structural formula is as follows:
Reasonably optimizing, synthesis and activity rating has been carried out as guide using wherein the third structure C R21, obtain and there is new framework structure, safer and more effective CRAC channel blocking molecule, obtained 30 1 altogether, the compound of 2-diketone naphthalene class, experiment proves above-mentioned 1, the compound of 2-diketone naphthalene class has stronger anti-inflammatory, anti-immunocompetence, can be used as the candidate molecules of medicine.
The invention provides 1,2-diketone naphthalene compounds.
Present invention also offers the preparation method of 1,2-diketone naphthalene compounds.
The present invention also provides a kind of anti-inflammatory, immuno suppressive drug compositions of 1, the 2-diketone naphthalene compounds containing significant quantity.
For achieving the above object, the present invention adopts following technical scheme:
A kind of 1,2-diketone naphthalene compounds, this compound structure is as shown in general formula (I):
In formula, Ar represents phenyl ring, naphthalene nucleus, quinoline ring or isoquinoline 99.9 ring, benzene-naphthalene diimide ring or coumarin ring; Amino is directly connected with Ar; When Ar there being substituting group, R is electrophilic, supplied for electronic or neutral group.
Preferably, described R is hydrogen, halogen, methyl, methoxyl group or sulfonic group.
Concrete, described 1,2-diketone naphthalene compounds, its structural formula is as follows:
In formula, R
1, R
2, R
3, R
4, be all selected from hydrogen, halogen, methyl, methoxyl group or sulfonic group respectively.
Further, 1,2-diketone naphthalene compounds of the present invention is following compound:
4-phenylamino-1,2-diketone naphthalene (CR-1)
4-((the fluoro-phenyl of 4-) is amino)-1,2-diketone naphthalene (CR-2)
4-((the chloro-phenyl of 4-) is amino)-1,2-diketone naphthalene (CR-3)
4-((the bromo-phenyl of 4-) is amino)-1,2-diketone naphthalene (CR-4)
4-((4-methylphenyl) is amino)-1,2-diketone naphthalene (CR-5)
4-((4-methoxyl group-phenyl) is amino)-1,2-diketone naphthalene (CR-6)
4-((4-sulfonic group-phenyl) is amino)-1,2-diketone naphthalene (CR-7)
4-((naphthalene-2-is amino)-1,2-diketone naphthalene (CR-8)
4-((the fluoro-naphthyl of 6--2-is amino)-1,2-diketone naphthalene (CR-9)
4-((the chloro-naphthyl of 6--2-is amino)-1,2-diketone naphthalene (CR-10)
4-((the bromo-naphthyl of 6--2-is amino)-1,2-diketone naphthalene (CR-11)
4-((6-methyl-naphthyl-2-is amino)-1,2-diketone naphthalene (CR-12)
4-((6-methoxy-naphthyl-2-is amino)-1,2-diketone naphthalene (CR-13)
4-((6-sulfonic group-naphthyl-2-is amino)-1,2-diketone naphthalene (CR-14)
4-((naphthalene-1-is amino)-1,2-diketone naphthalene (CR-15)
4-(the fluoro-naphthalene of 4--1-is amino)-1,2-diketone naphthalene (CR-16)
4-(the chloro-naphthalene of 4--1-is amino)-1,2-diketone naphthalene (CR-17)
4-(the bromo-naphthalene of 4--1-is amino)-1,2-diketone naphthalene (CR-18)
4-(4-methyl-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-19)
4-(4-methoxyl group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-20)
4-(4-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-21)
4-(the fluoro-naphthalene of 6--1-is amino)-1,2-diketone naphthalene (CR-22)
4-(the chloro-naphthalene of 6--1-is amino)-1,2-diketone naphthalene (CR-23)
4-(the bromo-naphthalene of 6--1-is amino)-1,2-diketone naphthalene (CR-24)
4-(6-methyl-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-25)
4-(6-methoxyl group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-26)
4-(6-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-27)
4-(isoquinoline 99.9-6-is amino)-1,2-diketone naphthalene (CR-28)
4-(1,8-naphthalimide base-4-is amino)-1,2-diketone naphthalene (CR-29)
4-(2-ketone group-2H-chromene-6-is amino)-1,2-diketone naphthalene (CR-30).
The preparation method of 1,2-diketone naphthalene compounds provided by the present invention, the preparation method of its formula of (I) compound is as follows:
With 1,2-naphthoquinones-4-sodium sulfonate and substituted aromatic amines for starting raw material, by 1,2-naphthoquinones-4-sodium sulfonate and K
2cO
3soluble in water, in the above-mentioned aqueous solution, add the ethanolic soln of substituted aromatic amines again, room temperature reaction 0.5-1.5 h, suction filtration, cleaning filter residue, dry, recrystallization, to obtain final product;
In the described aqueous solution, the concentration of 1,2-naphthoquinones-4-sodium sulfonate is 0.004 mmol/mL, K
2cO
3concentration be 0.004-0.008mmol/mL;
In the ethanolic soln of described substituted aromatic amines, the concentration of substituted aromatic amines is 0.08mmol/mL;
The add-on of the ethanolic soln of substituted aromatic amines and the volume ratio of the aqueous solution are 1:10.
The aromatic group of described substituted aromatic amines is phenyl ring, naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, coumarin ring or benzene-naphthalene diimide ring.
The synthetic route of 1,2-diketone naphthalene compounds of the present invention is as follows:
Meanwhile, the invention still further relates to above-mentioned 1,2-diketone naphthalene compounds and pharmaceutical salts is preparing the application in anti-inflammatory, anti-rejection medication.
The present invention also provides a kind of anti-inflammatory, immuno suppressive drug compositions of 1, the 2-diketone naphthalene compounds containing significant quantity.
This pharmaceutical composition can make pharmaceutical preparation with one or more pharmaceutically acceptable carriers or vehicle.
Described pharmaceutical preparation is oral preparations or injection formulations, and form of medication is oral administration or parenteral admin.
Beneficial effect of the present invention:
(1) 1,2-diketone naphthalene compounds provided by the invention has stronger anti-inflammatory, anti-immunocompetence, is the CRAC calcium ion channel blocker of novel structure, can be used as anti-inflammatory, the lead compound of anti-rejection medication is used.
(2) preparation method's reaction conditions provided by the invention is gentle, and raw material is cheaply easy to get, operation and aftertreatment simple.
Embodiment
The present invention is further illustrated in conjunction with the embodiments, should be noted that following explanation is only to explain the present invention, not limiting its content.
The preparation of embodiment 1:4-((4-chloro-phenyl-) is amino)-1,2-diketone naphthalene (CR-3)
By 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and K
2cO
3(43 mg, 0.2 mmol) is dissolved in 50 mL water, is stirred to solution clarification, again p-Chlorobenzoic acid amide (51 mg, 0.4 mmol) is dissolved in 5 mL dehydrated alcohols, more slowly joins in the above-mentioned aqueous solution, solution reddens rapidly, and produces red precipitate.1 h reaction terminates, and filter, filter residue distilled water cleans, vacuum drying at room temperature, obtains red powder 46.6 mg, and reaction yield is 83.2%, m.p:243-265 DEG C.
1H-NMR(300MHz,CDCl
3):δ＝8.33(d,J＝7.8Hz,1H),8.07(dd,J＝7.5Hz,J＝1.2Hz,1H),7.89(t,J＝7.8Hz,1H),8.07(dt,J＝7.8Hz,J＝0.9Hz,1H),7.55(d,J＝11.4Hz,2H),7.24(br.s,2H),5.94(br.s,1H)；ESI-HRMS:m/z?calcd?for?C
16H
10ClNO
2[(M+H)
+],284.0478；found,284.0546。
The preparation of embodiment 2:4-((4-sulfonic group phenyl) is amino)-1,2-diketone naphthalene (CR-7)
With 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and Sulphanilic Acid (70 mg, 0.4 mmol) for raw material reacts, preparation method, with embodiment 1, obtains red powder 45 mg, and productive rate is 68.1%.m.p:189-208℃。
1H-NMR(300?MHz,CDCl
3):δ＝11.67(brs,1H),8.02(dt,J＝6.9Hz,J＝0.9Hz,2H),7.96(d,J＝1.5Hz,1H),7.94(t,J＝1.2Hz,1H),7.87～7.78(m,4H),6.18(s,1H)；ESI-HRMS:m/z?calcd?for?C
16H
11NO
5S[(M-H)
-],328.0280；found,328.0318。
Embodiment 3:4-(the preparation of (naphthalene-2-is amino)-1,2-diketone naphthalene (CR-8)
With 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and 2-naphthylamines (58 mg, 0.4 mmol) for raw material reacts, preparation method, with embodiment 1, obtains red powder 48.2 mg, and productive rate is 82.6%, m.p:285-292 DEG C.
1H-NMR(300MHz,CDCl
3):δ＝8.41(d,J＝7.8Hz,1H),8.10～8.06(m,3H),8.00～7.93(m,2H),7.90～7.88(m,1H),7.80～7.75(m,1H),7.59～7.53(m,2H),7.52(br.s,1H),6.20(br.s,1H)；ESI-HRMS:m/z?calcd?for?C
20H
13NO
2[(M+H)
+],300.1025；found,300.0989。
Embodiment 4:4-(the preparation of (the bromo-naphthyl of 6--2-is amino)-1,2-diketone naphthalene (CR-11)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and the bromo-2-amino naphthalenes of 6-(90 mg, 0.4 mmol), preparation method, with embodiment 1, obtains red powder 62 mg, and productive rate is 83.7%.m.p:273-290℃。
1H-NMR(300MHz,CDCl
3):δ＝9.88(s,1H),8.40(d,J＝6.3Hz,1H),8.26(s,1H),8.09～8.01(m,3H),7.92～7.87(m,2H),7.79(t,J＝7.5Hz,1H),7.47～7.46(m,1H),5.50(s,1H)；ESI-HRMS:m/z?calcd?for?C
20H
12BrNO
2[(M+H)
+],378.0130,380.0109；found,378.0163,380.0148。
Embodiment 5:4-(the preparation of (naphthalene-1-is amino)-1,2-diketone naphthalene (CR-15)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and naphthalidine (58 mg, 0.4 mmol), preparation method, with embodiment 1, obtains red powder 42 mg, and productive rate is 70.0%, m.p:213-222 DEG C.
1H-NMR(300?MHz,CDCl
3):δ＝8.56(d,J＝7.8Hz,1H),8.12(dd,J＝7.8Hz,J＝1.2Hz,1H),8.04(d,J＝7.8Hz,1H),7.95(dt,J＝7.5Hz,J＝1.5Hz,2H),7.83～7.77(m,2H),7.64～7.51(m,3H),7.23(br.s,1H),5.71(br.s,1H)；ESI-HRMS:m/z?calcd?for?C
20H
13NO
2[(M+H)
+],300.1025；found,300.0990。
The preparation of embodiment 6:4-(4-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-21)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and 1,6-Ke Liefu acid (89 mg, 0.4 mmol), preparation method, with embodiment 1, obtains red powder 43 mg, and productive rate is 56.6%.m.p:>300℃。
1H-NMR(300?MHz,CDCl
3):δ＝10.70(br.s,1H),8.59(d,J＝7.8Hz,1H),8.25(s,1H),8.11(d,J＝7.2Hz,1H),7.95(t,J＝7.5Hz,1H),7.82～7.72(m,3H),7.65(t,J＝7.5Hz,1H),7.20(br.s,1H),5.70(br.s,1H)；ESI-HRMS:m/z?calcd?for?C
20H
13NO
5S[(M-H)
-],378.0436；found,378.0433。
The preparation of embodiment 7:4-(6-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene (CR-27)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and 6-amino-1-naphthalene sulfonic aicd (89 mg, 0.4 mmol), preparation method, with embodiment 1, obtains red powder 52 mg, and productive rate is 68.4%.m.p:280-295℃。
1H-NMR(300?MHz,CDCl
3):δ＝8.89(d,J＝9Hz,1H),8.46(d,J＝7.5Hz,1H),8.05(dd,J＝7.5Hz,J＝1.2Hz,1H),7.91～7.79(m,3H),7.73(dt,J＝7.5Hz,J＝0.9Hz,1H),7.54(s,1H),7.46～7.41(m,1H),7.34(dd,J＝8.7Hz,J＝1.2Hz,1H),5.86(s,1H)；ESI-HRMS:m/z?calcd?for?C20H13NO5S[(M-H)
-],378.0436；found,378.0434。
The preparation of embodiment 8:4-(isoquinoline 99.9-6-is amino)-1,2-diketone naphthalene (CR-28)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and 6-aminoisoquinoline (58 mg, 0.4 mmol), preparation method, with embodiment 1, obtains red powder 55.3 mg, and productive rate is 91.6%.m.p:183-215℃。
1H-NMR(300MHz,CDCl
3):δ＝9.72(s,1H),8.62(d,J＝6.3Hz,1H),8.53(d,J＝8.7Hz,1H),8.38(d,J＝7.8Hz,1H),8.31(d,J＝6.6Hz,1H),8.12(dd,J＝7.8Hz,J＝4.2Hz,1H),7.93(dt,J＝7.5Hz,J＝1.5Hz,1H),7.85～7.83(m,2H),7.76～7.69(m,1H),6.20(s,1H)；ESI-HRMS:m/z?calcd?for?C
19H
12N
2O
2[(M+H)
+],301.0977；found,301.0968。
The preparation of embodiment 9:4-(1,8-naphthalimide base-4-is amino)-1,2-diketone naphthalene (CR-29)
React with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and amino-1, the 8-naphthalimide (104 mg, 0.4 mmol) of N-ethyl-4-, preparation method, with embodiment 1, obtains red powder 52 mg, and productive rate is 65.8%.m.p:242-268℃。
1H-NMR(300?MHz,CDCl
3):δ＝11.07(s,1H),8.62～8.52(m,3H),8.44(t,J＝8.4Hz,1H),8.14(dd,J＝7.5Hz,J＝0.9Hz,1H),7.95(dt,J＝7.5Hz,J＝1.2Hz,1H),7.85～7.78(m,2H),7.30(d,J＝7.5Hz,1H),6.04(s,1H),4.16～4.03(m,2H),1.27～1.03(m,3H)；ESI-HRMS:m/z?calcd?for?C
24H
16N
2O
4[(M+H)
+],397.1188；found,397.1166。
The preparation of embodiment 10:4-(2-ketone group-2H-chromene-6-is amino)-1,2-diketone naphthalene (CR-30)
First be dissolved in 20 mL acetic acid by 6-nitro tonka bean camphor (64 mg, 0.4 mmol), gradation adds Zn powder (260 mg, 4mmol) stirring at room temperature, reacts 24 h, stopped reaction.Filter, filter residue CH
2cl
2(30 mL × 3) are rinsed, merging filtrate.Evaporated under reduced pressure solvent, obtains yellow oil CR-10a crude product, and this compound is unstable, does not therefore carry out purifying, directly carries out next step.According to the method for embodiment 1, react with 1,2-naphthoquinones-4-sodium sulfonate (52 mg, 0.2 mmol) and CR-10a, obtain red powder 26 mg, two step overall yields are 41%.m.p:281-295℃。
1H-NMR(300?MHz,CDCl
3):δ＝8.37(d,J＝7.5Hz,1H),8.15～8.02(m,3H),7.93～7.82(m,2H),7.79～7.70(m,2H),7.54～7.47(m,2H),6.59(d,J＝9.3Hz,1H)；ESI-HRMS:m/z?calcd?for?C
19H
11NO
4[(M+H)
+],318.0766；found,318.0774。
Biological activity determination:
Poison carotene (Thapsigargin, TG) induction can make CRAC channel opener, causes Ca
2+interior stream, intracytoplasmic Ca
2+increase and NFAT will be made to activate, the NFAT be activated will enter in core by kytoplasm.This experiment utilizes GFP-NFAT surely to make the transition cell, uses IN Cell Analyzer 6000 laser confocal imaging analytical system to carry out imaging, then uses the green intensity in Pipeline Plot software analysis kytoplasm, karyon.And then calculating both strength ratios---green glow nuclear-cytoplasmic ratio, this just can be used for weighing GFP-NFAT and enter core ratio.We select SKF 96265 as positive control drug in testing, and dimethyl sulfoxide (DMSO) (DMSO) group is as blank.Adopt the experiment of GFP-NFAT nuclear translocation, make use of the principle that CRAC channel blocker can block TG-NFAT path, measure its blocking activity to CRAC calcium channel, calculate IC
50.
The cell kind that surely made the transition by GFP-NFAT, on 384 orifice plates, after cytotostatic, adds testing compound and the positive control SKF 96265 of gradient concentration, then stimulates with TG, and blank group adds the DMSO of equivalent.After reacting 1 h, be fixed with 4% paraformaldehyde (PFA) solution, under room temperature, carry out 10 ~ 15 minutes.After PBS cleaning, then use 0.1 M NH
4cl cancellation 10 min, carries out 10 ~ 15 minutes under room temperature.Dye 10 ~ 15 minutes under using DAPI (1 μ g/mL) room temperature afterwards, after cleaning, add PBS.Open IN Cell Analyzer 6000 laser confocal imaging analytical system and carry out imaging.NAFT translocation operating protocol in use PipelinePlot software carrys out the green intensity in analysis of cells core and tenuigenin, and calculates nucleus and cytoplasmic beam intensity ratio (nuclear-cytoplasmic ratio).Stdn conversion is carried out to the nuclear-cytoplasmic ratio of each compound and positive control.The nuclear-cytoplasmic ratio of the blank group adding TG is set to 1; The nuclear-cytoplasmic ratio not adding the blank group of TG is set to 0.The stdn caryoplasm ratio of compound is=the blank group nuclear-cytoplasmic ratio that stimulates of (the blank group nuclear-cytoplasmic ratio that compound nuclear-cytoplasmic ratio-do not add TG stimulates)/add TG.Map according to the concentration of stdn nuclear-cytoplasmic ratio and compound and calculate the IC of compound
50value, the results are shown in Table 1.
Table 11,2-cyclohexadione compounds is to the blocking activity of CRAC calcium channel
Note: IC
50for compound is by the concentration of CRAC calcium channel retardance 50%.
Screening active ingredients is carried out to above-mentioned 30 compounds, they the blocking activity of CRAC calcium channel is listed in table 1.
As shown in Table 1, the Compound C R21 activity difference as the structure of YZ-01 resonance is more, and this may be cause compound rigidity to be destroyed after the double bond of imines converts singly-bound to, have impact on the activity of compound.CR3, CR28 and CR30 are to the blocking activity IC of CRAC passage
50value is about 10 times of lead compound YZ-01.All do not have sulfonic group in the structure of these three compounds, this just illustrates that sulfonic group is not active necessary group.Compound C R3 has changed aromatic ring structure in primary structure into phenyl ring by naphthalene nucleus in addition, and activity is retained, and this illustrates that aromatic moieties can also carry out structure replacement, transforms further.Compound C R28 has changed naphthalene nucleus into isoquinoline 99.9 ring, and activity increases greatly.
Activity research shows, above-mentioned 1,2-cyclohexadione compounds has the activity of retardance CRAC calcium channel, is the CRAC calcium ion channel blocker of novel structure, can be used as anti-inflammatory, the lead compound of anti-rejection medication is used.
1,2-diketone naphthalene compounds of the present invention and pharmaceutical salts thereof are preparing the application in anti-inflammatory, anti-rejection medication.
Preparation, pharmaceutical composition, dosage and taking
1,2-diketone naphthaline derivatives of the present invention can exist in a free form or in the form of salts.Those skilled in the art oneself know pharmacy acceptable salt of chemical compound lot type and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises season that such compound alkali and inorganic or organic acid formed by salt.
Compound of the present invention can form hydrate or solvate.The hydrate that one skilled in the art is known to be formed compound during freeze-drying together with water or form the method for solvate when concentrating with suitable organic solvent in the solution.
The present invention comprises the medicine of the compounds of this invention containing therapeutic dose, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, glucose, water, glycerine, and ethanol and their binding substances, hereafter discuss in more detail.If needed, said composition can also comprise wetting agent or the emulsifying agent of comparatively a small amount of, or pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional firewood mixture and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Optionally preparation and determining, preparation can design mixing, granulates and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The dosage of 1,2-diketone naphthalene compounds of the present invention is different with differences such as patient age, sex, the state of an illness, and the dosage of general adult is about 10-500 mg/ day.
The pharmaceutical carrier used can be, such as, and solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise one or more may simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agents; It can also be encapsulating material.In the powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents mixes with suitable ratio with the carrier with necessary compression property in tablets, with the shape needed and size compression.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, such as, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
Typical liquid vehicle comprises syrup, peanut oil, sweet oil, water, etc.Liquid vehicle for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premixs as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, and viscosity modifier, stablizes shape or osmo-regulators.Suitable example for the liquid vehicle of oral and administered parenterally comprises water and (partly comprises as above-mentioned additive, such as derivatived cellulose, preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, such as ethylene glycol) and their derivative, and oils (such as fractionated coconut oil and peanut oil).Carrier for administered parenterally can also be that grease is as ethyl oleate and isopropyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.Liquid vehicle for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, such as, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.Can push or inject gradually by single during injection, entering the interior perfusion of passages through which vital energy circulates of 30 minutes.This compound can also with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, light propyl methocel, methyl methacrylate etc.When preparation is used for oral, generally acknowledges that 0.01% tween 80 in PHOSALPG-50 is used for the preparation of the acceptable oral preparations of other compounds, the preparation of the various compound of the present invention can be adapted to.Medicament forms miscellaneous can be used when giving the compounds of this invention.If use solid carrier, preparation can be tablet, is placed into powder in hard capsule or piller form or lozenge or Lozenge forms.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If use liquid vehicle, preparation can be syrup, emulsion, soft capsule, the aseptic injectable solution in the liquid suspension of ampulla or bottle or non-water or suspension.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, concentration range from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, fatty alcohol or the light fatty acid ester of glycerine etc.
Various release system is known and may be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, injectable solution, the capsule in liposome, particulate, microcapsule, etc.The method introduced includes, but are not limited to skin, intracutaneous, and intramuscular is endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (usually preferred) oral route.Compound can pass through easily any or other suitable administration, such as by injecting or bolus injection, by epithelium or mucous membrane circuit (such as, oral mucosa, rectum and intestinal mucosa, etc.) to absorb or by the support of carrying medicament and can in other biological promoting agent together administration.Can whole body or topical.For nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Claims (10)
1. a diketone naphthalene compounds, is characterized in that, this compound structure is as shown in general formula (I):
In formula, Ar represents phenyl ring, naphthalene nucleus, quinoline ring or isoquinoline 99.9 ring, benzene-naphthalene diimide ring or coumarin ring; Amino is directly connected with Ar; When Ar there being substituting group, R is electrophilic, supplied for electronic or neutral group.
2. a kind of 1,2-diketone naphthalene compounds as claimed in claim 1, it is characterized in that, described R is hydrogen, halogen, methyl, methoxyl group or sulfonic group.
3. 1,2-diketone naphthalene compounds as claimed in claim 1 a kind of, is characterized in that, it is the following compound of structural formula,
In formula, R
1, R
2, R
3, R
4all be selected from hydrogen, halogen, methyl, methoxyl group or sulfonic group respectively.
4. a kind of 1,2-diketone naphthalene compounds as claimed in claim 1, it is characterized in that, this compound is selected from:
4-phenylamino-1,2-diketone naphthalene;
4-((the fluoro-phenyl of 4-) is amino)-1,2-diketone naphthalene;
4-((the chloro-phenyl of 4-) is amino)-1,2-diketone naphthalene;
4-((the bromo-phenyl of 4-) is amino)-1,2-diketone naphthalene;
4-((4-methylphenyl) is amino)-1,2-diketone naphthalene;
4-((4-methoxyl group-phenyl) is amino)-1,2-diketone naphthalene;
4-((4-sulfonic group-phenyl) is amino)-1,2-diketone naphthalene;
4-((naphthalene-2-is amino)-1,2-diketone naphthalene;
4-((the fluoro-naphthyl of 6--2-is amino)-1,2-diketone naphthalene;
4-((the chloro-naphthyl of 6--2-is amino)-1,2-diketone naphthalene;
4-((the bromo-naphthyl of 6--2-is amino)-1,2-diketone naphthalene;
4-((6-methyl-naphthyl-2-is amino)-1,2-diketone naphthalene;
4-((6-methoxy-naphthyl-2-is amino)-1,2-diketone naphthalene;
4-((6-sulfonic group-naphthyl-2-is amino)-1,2-diketone naphthalene;
4-((naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(the fluoro-naphthalene of 4--1-is amino)-1,2-diketone naphthalene;
4-(the chloro-naphthalene of 4--1-is amino)-1,2-diketone naphthalene;
4-(the bromo-naphthalene of 4--1-is amino)-1,2-diketone naphthalene;
4-(4-methyl-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(4-methoxyl group-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(4-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(the fluoro-naphthalene of 6--1-is amino)-1,2-diketone naphthalene;
4-(the chloro-naphthalene of 6--1-is amino)-1,2-diketone naphthalene;
4-(the bromo-naphthalene of 6--1-is amino)-1,2-diketone naphthalene;
4-(6-methyl-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(6-methoxyl group-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(6-sulfonic group-naphthalene-1-is amino)-1,2-diketone naphthalene;
4-(isoquinoline 99.9-6-is amino)-1,2-diketone naphthalene;
4-(1,8-naphthalimide base-4-is amino)-1,2-diketone naphthalene; Or
4-(2-ketone group-2H-chromene-6-is amino)-1,2-diketone naphthalene.
5. the preparation method of 1,2-diketone naphthalene compounds described in any one of Claims 1-4, is characterized in that, by 1,2-naphthoquinones-4-sodium sulfonate and K
2cO
3mixing, is dissolved in water, adds the ethanolic soln of substituted aromatic amines in the aqueous solution, and reaction 0.5-1.5h, filters, cleaning filter residue, and dry, recrystallization, to obtain final product;
The aromatic group of described substituted aromatic amines is for being phenyl ring, naphthalene nucleus, quinoline ring, isoquinoline 99.9 ring, coumarin ring or benzene-naphthalene diimide ring.
6. as claimed in claim 51, the preparation method of 2-diketone naphthalene compounds, it is characterized in that, described substituted aromatic amines is p-Chlorobenzoic acid amide, Sulphanilic Acid, 2-naphthylamines, the bromo-2-amino naphthalenes of 6-, naphthalidine, 1,6-Ke Liefu is sour, 6-is amino-amino-1, the 8-naphthalimide of 1-naphthalene sulfonic aicd, 6-aminoisoquinoline or N-ethyl-4-.
7. 1,2-diketone naphthalene compounds described in any one of Claims 1-4 is preparing the application in anti-inflammatory, anti-rejection medication.
8. anti-inflammatory, an immuno suppressive drug compositions, is characterized in that, the arbitrary compound or pharmaceutically acceptable salt thereof wherein containing Claims 1-4 or ester are as effective constituent.
9. anti-inflammatory, an anti-rejection medication preparation, is characterized in that, comprises arbitrary compound and one or more pharmaceutically acceptable carriers or the vehicle of Claims 1-4.
10. anti-inflammatory, anti-rejection medication preparation as claimed in claim 9, it is characterized in that, described pharmaceutical preparation is oral preparations or injection formulations.
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