CN1201734C - Use of Sulfocanbamide derivative in medicine for treating eye yellow spot variation - Google Patents
Use of Sulfocanbamide derivative in medicine for treating eye yellow spot variation Download PDFInfo
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- CN1201734C CN1201734C CN 03113041 CN03113041A CN1201734C CN 1201734 C CN1201734 C CN 1201734C CN 03113041 CN03113041 CN 03113041 CN 03113041 A CN03113041 A CN 03113041A CN 1201734 C CN1201734 C CN 1201734C
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Abstract
反式-1-苯基-3-{3-甲氧基-2-丙氧基-5-[4-(3，4，5-三甲氧基苯基)-1，3-二氧戊环-2-基]苯基}硫脲(ZX-5)，能引起细胞释放一氧化氮，选择性增加眼脉络膜血流，对虹膜和睫状体血流没有影响，能对老年性常见眼病AMD(年龄相关性黄斑变性)的脉络膜新生血管形成有抑制作用，可用于早期AMD的治疗或预防。trans-1-phenyl-3-{3-methoxy-2-propoxy-5-[4-(3,4,5-trimethoxyphenyl)-1,3-dioxolane -2-yl]phenyl}thiourea (ZX-5), can cause cells to release nitric oxide, selectively increase eye choroidal blood flow, has no effect on iris and ciliary body blood flow, and can treat AMD, a common senile eye disease (age-related macular degeneration) choroidal neovascularization has inhibitory effect, and can be used for the treatment or prevention of early AMD.
Description
Technical field
The invention belongs to a kind of nitric oxide donors thiourea derivative in pharmaceutically application, be specially the purposes of trans thiourea derivative aspect control age related oculopathy.
Background technology
Age-related macular degeneration (AMD) is a kind of common senile disease, and only just there are 200～3,000,000 patients in the U.S., and number is more in China, has 1200～15,000,000 approximately.The characteristic performance of AMD is that drusen appears in macular area, and associated with choroidal new vessels (CNV) forms or ground pattern maculae atrophicae.Recently, retina light is used for the treatment of low vision patient central fovea side and recurrent CNV with fixed attention.Yet can this treatment prevent inpairment of vision it be unclear that.The central fovea other CNV patient (most of fluorescein angiographic be typical AMD person) fair as for those visions passes through optical dynamic therapy (PDT), has the half patient to obtain effect.At present, the AMD of pattern maculae atrophicae does not treat way over the ground.In other words, have only 1/3rd or AMD patient still less can carry out PDT treatment, and wherein have only half patient to keep vision and be unlikely to blind through treatment.
In most of AMD patients, the main cause that CNV forms is the early stage choroid circulatory disturbance of AMD.Prevent AMD to take place, must improve and promote the choroid blood flow.Therefore, the task of top priority is to seek the medicine that the energy selectivity increases the choroid blood flow.
Summary of the invention
The technical problem to be solved in the present invention is to seek a kind of medicine that can prevent and treat AMD, and it can optionally promote the choroid blood flow of eye, eliminates choroid circulatory disturbance, and the choroidal neovascularization that suppresses AMD forms.
For addressing the above problem, the invention provides following technical proposals.
Anti-form-1-phenyl-3-{3-methoxyl group-2-propoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-yl] phenyl } application of thiourea in the medicine of preparation treatment or prevention of age-related macular degeneration; It is characterized in that: be used to prepare the medicine that selectivity improves the choroid blood flow; It is characterized in that: be used to prepare the medicine that suppresses choroidal neovascularization formation.
Aforementioned anti-form-1-phenyl-3-{3-methoxyl group-2-propoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-yl] phenyl } application of thiourea in the medicine of preparation treatment or prevention of age-related macular degeneration, it is characterized in that: be used to prepare the external medicament for the eyes.
Anti-form-1-phenyl-3-{3-methoxyl group-2-propoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-yl] phenyl } thiourea impels cell to discharge application in the nitric oxide production medicine in preparation; Especially impel a cell to discharge application in the nitric oxide production medicine in preparation.
The inventor finds the result of study of nitric oxide donors (NO Donor), the thiourea (code name ZX-5) that the N-phenyl replaces, chemical name is: anti-form-1-phenyl-3-{3-methoxyl group-2-propoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-yl] phenyl } thiourea, can cause that cultured cell discharges volume NO, and can increase lagophthalmos choroid blood flow, but to iris and the not influence of corpus ciliare blood flow.Its isomer (code name ZX-4) cis-1-phenyl-3-{3-methoxyl group-2-propoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-yl] phenyl } thiourea, cause that neither NO discharges, and does not increase ocular tissue's blood flow yet.
The increase of choroid blood flow may be the result that NO discharges at choroid.It is very valuable that ZX-5 eye dripping energy selectivity improves the choroid blood flow, because choroid is positioned at the eyeball rear portion, after the medicine eye dripping is described, by systemic circulation or sclera-tunica uvea-optic nerve approach, can arrive choroid fast, choroidal neovascularization to AMD is formed with inhibitory action, is expected to be used for treatment or the prevention of early stage AMD.
1. chemosynthesis
The synthetic of ZX-4 and ZX-5 is initiation material with Galla Turcica (Galla Helepensis) aldehyde 1, getting epoxide 2,2 through phase-transfer-catalyzed reactions gets glycol 3,3 through hydrolysis and gets dioxolane compound 4 with the condensation of nitro aromatic aldehyde, column chromatography separate cis-trans-isomer 5 and 6, they through the reduction respectively corresponding amino substance 7 and 8.7 and 8 and phenyl isothiocyanate react ZX-4 and ZX-5.Synthetic route illustrates referring to nextpage.
Synthesizing of 1-(3,4, the 5-trimethoxyphenyl) oxirane (2)
With Galla Turcica (Galla Helepensis) aldehyde (39.2g, 200mmol), Tetrabutylammonium bromide (1.58g, 4.91mmol), CH
2Cl
280mL drops in the round-bottomed flask, stirs to make its dissolving, splashes into cold 50%NaOH solution 80mL, drips in about 15 minutes to finish, add again the iodate trimethylsulfonium (40.8g, 200mmol), back flow reaction 15h.Add water 180mL, divide oil-yielding stratum, water layer is with CH
2Cl
2Extraction, anhydrous magnesium sulfate drying boils off solvent, solidify little yellow solid, recrystallizing methanol, white crystals 33.98g, yield 81.3%, mp54～56 ℃.
1-(3,4, the 5-trimethoxyphenyl) ethane-1,2-glycol (3) synthetic
With chemical compound 2 (11.2g, 0.053mol), distilled water (200mL) adds in the 500mL three-necked bottle, room temperature mechanical stirs, and slowly drips 0.8mL perchloric acid, vigorous stirring reaction 5h, solution is clear gradually, stopped reaction.Use NaHCO
3Adjust pH is about 7, extracts with ethyl acetate (50mL * 4), merges organic facies, with saturated aqueous common salt (50mL * 3) washing, anhydrous MgSO
4Dried overnight concentrates, and gets faint yellow oily thing 10.1g, yield 82.2%.
Suitable/anti--2-(3-methoxyl group-5-nitro-4-positive propoxy phenyl)-4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes (5,6) synthetic
With chemical compound 3 (5.6g, 24.6mmol), 5-nitro 4-hydroxyl-3-methoxylbenxaldehyde (3.2g, 13.38mmol), PPTS (2.8g, 11.1mmol) and the 60mL dry benzene add in the 100ml three-necked bottle, reflux water-dividing finished in 8 hours under the nitrogen protection.Boil off most of benzene fast, add the 100mL ethyl acetate in the reactant liquor, remove PPTS, anhydrous magnesium sulfate drying with saturated aqueous common salt (50mL * 3) washing, filter, filtrate concentrate 4, column chromatography [ethyl acetate/petroleum ether (60～90 ℃), V: V=1: 4], it is (trans to get the white powder solid, 6) 1.9g, yield 31.7%, 46～48 ℃ of mp; Cis-product (5) is faint yellow oily thing 1.12g, yield 18.7%.
Synthetic route chart
Suitable/anti--2-positive propoxy-3-methoxyl group-5-[4-(3,4, the 5-trimethoxyphenyl)-1,3-dioxolanes-2-] aniline (7,8) synthetic
(200mg 0.445mmol) is dissolved among the 20mLTHF, adds entry 20mL with cis nitro thing 5, iron powder (56mg, 1mmol), ammonium chloride (53.5mg, 1mmol), reflux 6h, cold slightly, tell the upper strata organic layer, water layer extracts with ethyl acetate (20ml * 3), merges organic layer, spends the night with anhydrous sodium sulfate drying, filter, evaporate to dryness filtrate gets a faint yellow oily thing 125.7mg, yield 67.4%.Synthetic method with reference to 7 gets the trans aniline compound 8 of faint yellow oily (104.3mg, yield 56%).
ZX-4 and ZX-5's is synthetic
Chemical compound 7 and 8 (0.048mmol) is mixed with isothiocyanate phenyl ester (0.1mmol), oxolane (5mL) respectively, in the time of 70 ℃ behind the stirring reaction 12h, concentrate, column chromatography is separated [ethyl acetate/petroleum ether (60～90 ℃)/dichloromethane, V: V: V=1: 3: 1] and is promptly got product ZX-4 and ZX-5.
MS
Chemical combination IRv
mp/℃ (ESI)
1H NMR(CDCl
3)δ
Thing
/cm
-1
(M+H)
+
ZX-4 oil 555.2 3311 0.9(t，3H，CH
3，J＝7.3Hz)，1.57～1.64(m，2H，CH
2)，3.63～
1595 3.90(m，15H，4OCH
3，OCH
2，C-5 CH)，4.27～4.32(m，1H，
C-5 CH)，5.12～5.16(m，1H，C-4 CH)，5.87(s，1H，
C-2 CH)，6.71～7.82(m，9H，ArH)
ZX-5 43～46 555.2 3319 0.92(t，3H，CH
3，J＝6.9Hz)，1.60～1.65(m，2H，CH
2)，
1593 3.66～3.91(m，15H，4OCH
3，OCH
2，C-5 CH)，4.48～4.52
(m，1H，C-5 CH)，5.12～5.16(m，1H，C-4 CH)，6.1(s，1H，
C-2CH)，6.71～7.77(m，9H，ArH)
Chemical compound elementary analysis (%)
Found(Calcd.)
N C H
ZX-4 5.04(5.05)，62.43(62.82)，6.10(6.14)
ZX-5 5.13(5.05)，62.65(62.82)，6.08(6.14)
Description of drawings
The amount effect curve that Fig. 1: ZX-5 and ZX-4 impel NO to generate
The specific embodiment
Embodiment:
Pharmacological testing
1, RLG cell culture
The immortal reason for rabbit lachrymal gland acinus epithelial cell (RLG cell) of selection is that its effect is similar to the blood vessel epithelial cell, can increase the generation of C-GMP, thereby increase tear and blood flow respectively.Cell culture is at 37 ℃, 5%CO
2Incubator in carry out.Culture medium is DMEM/F-12, additional 5%Nu serum I V, 1 μ M dexamethasone, 0.1mg/ml soybean trypsin inhibitor, 10 μ l/ml insulins, 5.5 μ g/ml transferrinss, 6.7ng/ml sodium selenite, 10ng/ml EGF and 10 μ g/ml gentamycin (Sigma, St.Louis, MO).With lining with the culture dish of matrigel in conjunction with 0.25% trypsin-EDTA with scrape division and carry out passage.
2, cell viability is measured
The vigor of cultured cell is measured with the MTT cell proliferation method.MTT measures (cell viability and cell growth index) principle: great-hearted cell can be reduced into insoluble navy blue Formazan to MTT from the water solublity weld.MTT is dissolved among (5mg/ml) PBS, aseptic filtration.After this, the culture medium in the 6 hole culture dishs changes 500 μ l into does not have phenol red medium, and every hole adds 50 μ l MTT solution, rocks mixing, puts into incubator after 4 hours, inhales and removes supernatant.Every hole adds 1ml DMSO dissolving Formazan, rocks 2 minutes mixings.With the every hole light absorption of the board-like spectrophotometer measurement culture dish power of wavelength 570nm, blank well is 500 μ l same medium and 50 μ l MTT, adds 1ml DMSO after removing culture medium.
Draw 570nm wavelength light MTT absorbing power and cell number standard curve.The cell that covers with is moved to 6 hole culture dishs from the 100cm culture dish.Next day, MTT mensuration is done in 3 holes in each culture dish, and cell counting is carried out with Trypan blueexclusion method in 3 holes in addition.Before the cell counting, digest earlier and scrape from cell.From the 2ml cell suspension, draw 500 μ l, add 200 μ l Trypan blue dyestuffs and mix.Get 10 μ l mixed liquors and be placed on the blood counting chamber, amplify 100 times at microscopically and carry out cell counting.Calculate 3 porocyte means, make it corresponding with the MTT average absorption power in other 3 holes.After this, other 5 culture dishs are repeated aforesaid operations, measure back 5 days cell growing states, draw 6 standard curves.
3, NO generates and measures
Adopt nitric acid/nitrite colorimetric determination test kit (Cayman Chemical, AnnArbor, MI) concentration of NO in the mensuration culture medium.Contain nitrate reductase (special-purpose concentration) in the test kit, nitrate reduction enzyme co-factor (special-purpose concentration), reagent buffer, Chile saltpeter standard, sodium nitrite standard and Griess reagent.Cultivating 24 hours with medicine or solvent, during 80% cell fusion, measuring nitric acid and nitrous acid product content in the culture fluid in the 6 hole culture dishs.Every hole is adopted 80 μ l equivalents and is added 96 hole microdetermination plates from 6 hole culture dishs, with repeating injector 10 μ l nitrate reductases and 10 μ l cofactor preparations (preparing in advance by explanation in the test kit) is added in specimen hole and the gauge orifice fast.Incubated at room temperature is 3 hours behind the microdetermination plate overlay film, subsequently 50 μ l Griess reagent R1 and R2 is added in each specimen hole and the gauge orifice incubated at room temperature 10 minutes.Record the reading of microdetermination plate with the board-like spectrophotometer of wavelength 540nm.By demarcating known nitrate concentration ratio A540, be every group of experiment drawing standard curve.The final concentration μ M/10 of nitrate+nitrite in every increment basis
6Cell is represented.
4, lagophthalmos measuring of blood flow
New Zealand white rabbit weighs 2.5～3.0 kilograms, mixes back intramuscular injection anesthesia with 35mg/kg ketamine and 5mg/kg xylazine, per hour keeps anesthesia with half intramuscular injection of initial amount.Rising left eye intraocular pressure is to 40mmHg, and this intraocular pressure makes a blood flow reduce to 1/3 of normal value.To left ventricle, be used for injectable microsphere through the right carotid intubate; Femoral arteriography is used for blood sampling.1% medicine or solvent 50 μ l point left eyes, 0,30,60 and 120 minute eye blood flow behind the some medicine with the high intraocular pressure lagophthalmos of color micro-sphere technical measurement.At each time point, inject 0.2ml (containing 200 ten thousand) microsphere, put in order in 60 seconds through the femoral artery blood sampling immediately after microsphere injects, and place the heparinization anticoagulant tube, the record blood sampling volume.After the last blood sampling, put to death animal, win the left eye ball, separate retina, choroid, iris and corpus ciliare, record organization weight with the quiet notes of the phenobarbital of 100mg/kg.
The concrete operation method of sample disposal and microsphere counting is provided by E-ZTrac company.Briefly be described below: hemolytic factor adds the blood sample pipe, behind the mixing centrifugal 30 minutes with the rotating speed of 6000rpm, after removing supernatant, add tissue/blood digestion factor I and II, after adding a cover mixing, centrifugal at the same rate 15 minutes, abandon supernatant, the microsphere counting factor makes microsphere keep suspending, and carries out the microsphere counting with the blood counting chamber.
To organize/blood digestion factor I is added to the tissue specimen pipe, adds a cover back 95 ℃ of water-baths 15 minutes, and concussion mixing reheat after 30 seconds is to organizing dissolving fully.Take advantage of heat to add tissue/blood digestion factor II, add a cover mixing after, with the rotating speed of 6000rpm centrifugal 30 minutes, later operation was counted identical with blood preparation with microsphere.
The following formula of the calculating of each time point tissue blood flow: Qm=(Cm * Qr)/Cr.Wherein Qm represents tissue blood flow, the μ l/ branch/mg of unit; Cm is every milligram and organizes the microsphere number; Qr is a blood flow, the μ l/ of unit branch; Cr is the blood microsphere number as reference.
5, result
ZX-5 generates significantly NO to be increased
By the RLG cell culture, detect ZX-5 and NO generated obviously increase, and with the concentration relevant (Fig. 1) of ZX-5.Amount effect curve smooth (Fig. 1) when on the other hand, using ZX-4.Experimental result is clear to be shown, transconfiguration has the NO of generation activity, and cis does not have.
ZX-5 optionally increases the choroid blood flow of eye
Compare with matched group, at all somes observing time (30,60,120 minutes), all recording ZX-5 can significantly increase choroid blood flow (table 1).On the other hand, behind the ZX-4 eye dripping, all do not measure it to choroid blood flow influential (table 2) in any observation station.What is interesting is that ZX-5 only increases the choroid blood flow, and to iris (table 3) and the not influence of corpus ciliare (table 4) blood flow.It is generally acknowledged that the retina of white rabbit is close to vesselless tissue, change so be difficult to observe blood flow.The ZX-5 selectivity increase choroid blood flow (table 1) and do not influence iris (table 3) and corpus ciliare (table 4) blood flow significant, it may be used to treatment or the prevention of AMD (age-related macular degeneration).
The ocular choroid blood flow is exempted from table 1 ZX-5 (1%50 μ l) selectivity increase in vain
Time T reatment N Mean ± SE P value
(branch) (μ l/ branch/mg) (two tails)
0 matched group 5 14.1 ± 1.8
Treatment organizes 5 23.3 ± 4.5 0.11
30 matched groups 5 8.1 ± 1.7
Treatment organizes 5 16.4 ± 2.5
*0.03
60 matched groups 5 4.2 ± 0.7
Treatment organizes 5 14.3 ± 2.9
*0.02
120 matched groups, 5 3.1+0.4
Treatment organizes 5 10.5 ± 1.8
*0.01
*Remarkable increase is compared in expression with matched group
Table 2 ZX-4 (1%50 μ l) dialogue is exempted from the influence of ocular choroid blood flow
Time T reatment N Mean ± SE P value
(branch) (μ l/ branch/mg) (two tails)
0 matched group 5 14.1 ± 1.8
Treatment organizes 5 22.4 ± 4.9 0.18
30 matched groups 5 8.1 ± 1.7
Treatment organizes 5 11.1 ± 2.9 0.40
60 matched groups 5 4.2 ± 0.7
Treatment organizes 5 11.3 ± 3.4 0.10
120 matched groups 5 3.1 ± 0.4
Treatment organizes 5 6.8 ± 1.7 0.09
Table 3 ZX-5 (1%50 μ l) dialogue is exempted from an influence of iris blood flow
Time T reatment N Mean ± SE P value
(branch) (μ l branch/mg) (two tails)
0 matched group 5 2.6 ± 0.4
Treatment organizes 5 3.4 ± 0.9 0.42
30 matched groups 5 1.7 ± 0.4
Treatment organizes 5 2.6 ± 0.7 0.27
60 matched groups 5 1.4 ± 0.3
Treatment organizes 5 2.1 ± 0.6 0.32
120 matched groups 5 0.9 ± 0.2
Treatment organizes 5 1.4 ± 0.5 0.33
Table 4 ZX-5 (1%50 μ l) dialogue is exempted from an influence of corpus ciliare blood flow
Time T reatment N Mean ± SE P value
(branch) (μ l/ branch/mg) (two tails)
0 matched group 5 3.0 ± 0.2
Treatment organizes 5 9.0 ± 4.3 0.24
30 matched groups 5 2.0 ± 0.5
Treatment organizes 5 5.4 ± 1.8 0.13
60 matched groups 5 1.3 ± 0.3
Treatment organizes 5 4.9 ± 1.7 0.10
120 matched groups 5 1.2 ± 0.3
Treatment organizes 5 3.8 ± 1.3 0.12
Claims (5)
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| CN 03113041 CN1201734C (en) | 2003-03-24 | 2003-03-24 | Use of Sulfocanbamide derivative in medicine for treating eye yellow spot variation |
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| CN 03113041 CN1201734C (en) | 2003-03-24 | 2003-03-24 | Use of Sulfocanbamide derivative in medicine for treating eye yellow spot variation |
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