CN103127096A - Application of pyrryl-substituted indole compound in curing glaucoma - Google Patents
Application of pyrryl-substituted indole compound in curing glaucoma Download PDFInfo
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- CN103127096A CN103127096A CN2011103961609A CN201110396160A CN103127096A CN 103127096 A CN103127096 A CN 103127096A CN 2011103961609 A CN2011103961609 A CN 2011103961609A CN 201110396160 A CN201110396160 A CN 201110396160A CN 103127096 A CN103127096 A CN 103127096A
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Abstract
The invention discloses application of pyrryl-substituted indole compound in curing glaucoma. The pyrryl-substituted indole compound can cure glaucoma through small-dose multiple intraocular injection medicine administration and eye drop multiple medicine administration. Furthermore, after the pyrryl-substituted indole compound is coated by lipidosome or is prepared into high-polymer-coated nanometer medicine, micro-ball drug medicine and hydrogel medicine, glaucoma can be cured continuously after intraocular medicine injection to achieve obvious medicine effects.
Description
Technical field
The present invention relates to a kind of Benzazole compounds of pyrrole radicals replacement in the application for the treatment of glaucoma.
Background technology
Glaucoma is the eye pathological changes of a class take carrying out property optic nerve injury as feature, be divided into primary glaucoma, secondary glaucoma, congenital glaucoma, wherein primary glaucoma is divided into again former angle closure glaucoma and former open angle glaucoma, no matter being intraocular pressure (IOP), the glaucoma sufferer of which kind of type, patient's main manifestations increase.Glaucoma can cause the irreversibility visual deprivation, and 1,400,000,000 glaucoma patients are approximately arranged at present in the world, but approximately the people of half does not recognize this disease.World Health Organization (WHO) classifies it as second largest diseases causing blindness, and in China, glaucomatous sickness rate approximately 0.12%～1.64% accounts for 14.36% of ophthalmic diseases.Calculate according to epidemiological study, to the year two thousand twenty, the glaucoma patient number of China will reach 6,000,000.
The glaucomatous cause of disease
The edge of iris and cornea is angle of anterior chamber at the angle of anterior chamber formation, and 98% aqueous humor is discharged through trabecular reticulum, Schlemm's canal and corpus ciliare and choroidal vascular system by angle of anterior chamber.If angle of anterior chamber is inaccessible, aqueous humor flows out and is obstructed, and can cause that the aqueous humor accumulation causes intraocular pressure (IOP) to increase.
The normal eye is intrinsic pressure usually between 11 to 21mmHg, the intraocular pressure of rising can be directly by nerve compression or reduce blood flow, make the axonal injury of retinal ganglion cells.Aixs cylinder is carried and is crossed optic nerve from the information exchange of eyes and pass to brain.Axonal loss can cause that ganglionic cell is dead, finally causes the forfeiture of optic atrophy and vision.
Usually the form according to the glaucoma patient angle of anterior chamber is divided into two types with disease, i.e. open angle glaucoma and angle closure glaucoma.In open angle glaucoma, although angle of anterior chamber seems not get clogged, because can causing intraocular pressure, aqueous humor discharge deficiency raises.In angle closure glaucoma, can cause just when only having the outflow of having blocked aqueous humor when the iris distortion that intraocular pressure raises.
Reducing intraocular pressure is comparatively effectively approach of clinical unique confirmation at present.Treatment can be by three kinds of approach: medicine, laser surgery and the operation of operating on, and specifically adopt which kind of mode by glaucomatous type decided.Medicine and laser surgery (trabeculoplasty) can improve existing aqueous humor and discharge approach, and operate on operation (trabeculectomy, pipeline shunt art), are to reproduce a new aqueous humor discharge system.Clinical setting is at present: operation is carried out according to symptom, cures the symptoms, not the disease, painful Da Yi recurrence, and the Drug therapy damage is little, but therapeutic effect is not good enough.
Glaucomatous Drug therapy has following several method at present, not only therapeutic effect all not good enough but also but all have untoward reaction:
Receptor stimulating agent, untoward reaction and deficiency: blurred vision, front metopodynia, myopia, night dysphotia.When using separately, be not so good as beta-blockers effective.
Cholinesterase inhibitor is when being applied to angle closure glaucoma, because its strong miosis function can cause cataract and detachment of retina.Compare with receptor stimulating agent, the systemic effect that brings comprises perspiration, has a headache, trembles, sialorrhea, abdominal part are twitched, diarrhoea and feeling sick.
Carbonic anhydrase inhibitors (oral or intravenous injection), side effect and deficiency: can bring the side effect such as anorexia, fatigue, sense of taste change, depression, paraesthesia, renal calculus, blood dyscrasia after use.
Carbonic anhydrase inhibitors (local application), the untoward reaction that causes obviously reduces, but can make, the bad sense of taste is arranged in the oral cavity.
Non-selective 3 adrenergic receptor agonists (local application), normal and miotic is followed use, do not have selective ' beta '3 adrenergic energy receptor stimulating agent curative effect so reliable, and cause that the probability of irritated and toxic reaction (as hypertension, tachycardia) is higher.
α 2-selective ' beta '3 adrenergic energy receptor stimulating agent (local application), deficiency: system response (as) more non-selective not obvious, apraclonidine easily causes anaphylaxis, and brimonidine easily causes xerostomia.
Beta-blockers (local application), system's side reaction comprises: bronchospasm, depression, fatigue, erectile dysfunction, alopecia, bradycardia.Care should be used to is used in diabetes and myasthenia gravis person.
Prostaglandin analogue (local application), deficiency: increase the pigmentation of iris and skin, may worsen uveitis.Cause muscle, joint, back pain, erythra.
Mannitol and glycerol have serious system response.
All there is different side effect in present existing glaucoma, and most importantly therapeutic effect is not fully up to expectations, no matter be any class medicine, all can't produce therapeutic effect preferably now, cause the glaucoma sufferer of present no matter various pathogenic factors more and more, and it is more and more heavier to fall ill, the vision of serious threat sufferer.Develop a kind of novel effective Drug therapy glaucoma particularly important to sufferer.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of Benzazole compounds of pyrrole radicals replacement in the application for the treatment of glaucoma.This research is found and can be treated glaucoma by the Benzazole compounds that repeatedly intraocular injection administration of low dose, collyrium multiple dosing pyrrole radicals of the present invention replace, after further research is found to use the Benzazole compounds that the described pyrrole radicals of liposome replaces or the Benzazole compounds that described pyrrole radicals replaces is prepared into nanometer formulation, microball preparation and the aqueogel of high polymer parcel, with can the continued treatment glaucoma after the medicine intraocular injection and effect of drugs remarkable.
For solving the problems of the technologies described above, the technical solution adopted in the present invention is:
The application in preparation treatment glaucoma medicine of the compound of formula (I) or its pharmaceutically acceptable salt,
Wherein, R
1Be selected from hydrogen, halogen, alkyl, cycloalkyl, aromatic radical, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl ,-(CO) R
15,-NR
13R
14,-(CH
2)
rR
16With-C (O) NR
8R
9
R
2Be selected from hydrogen, halogen, alkyl, trihalomethyl group, hydroxyl, alkoxyl, cyano group ,-NR
13R
14,-NR
13C (O) R
14,-C (O) R
15, aromatic radical, heteroaryl and-S (O)
2NR
13R
14
R
3Be selected from hydrogen, halogen, alkyl, trihalomethyl group, hydroxyl, alkoxyl ,-(CO) R
15,-NR
13R
14, aromatic radical, heteroaryl ,-NR
13S (O)
2R
14,-S (O)
2NR
13R
14,-NR
13C (O) R
14,-NR
13C (O) OR
14With-SO
2R
20Wherein, described R
20Be alkyl, aromatic radical, aralkyl, heteroaryl and heteroarylalkyl;
R
4Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl and-NR
13R
14
R
5Be selected from hydrogen and alkyl;
R
6Be selected from-C (O) R
10, wherein, described R
10For-NR
11(CH
2)
nR
12Wherein, R
11Be hydrogen or unsubstituted low alkyl; N is 2 or 3; And R
12For-NR
13R
14Or-N
+(O) R
13R
14
R
7Be selected from hydrogen, alkyl, aromatic radical and heteroaryl;
R
8And R
9Be independently from each other hydrogen, alkyl and aromatic radical;
R
13And R
14The low alkyl that is independently from each other hydrogen, alkyl, replaces through hydroxyl, alkyl amino, cyano group alkyl, cycloalkyl, aromatic radical or heteroaryl; Or R
13And R
14Can be in conjunction with forming heterocyclic group;
R
15Be selected from hydrogen, hydroxyl, alkoxyl and aryloxy group;
R
16Be selected from hydroxyl ,-C (O) R
15,-NR
13R
14With-C (O) NR
13R
14With
R is 1,2,3 or 4.
Further, described R
6For-C (O) R
10, described R
10For-NR
11(CH
2)
nR
12Wherein, R
11Be hydrogen or unsubstituted low alkyl; N is 2 or 3; And R
12For-NR
13R
14, wherein, R
13And R
14Be unsubstituted low alkyl independently of one another; And R
7Be selected from hydrogen, alkyl, aromatic radical and heteroaryl.
Further, described R
6Be N-(2-(dimethylamino) ethyl) formamido, N-(2-(diethylamino) ethyl) N-METHYLFORMAMIDE base, N-(3-(dimethylamino) propyl group) formamido, N-(2-(diethylamino) ethyl) formamido, N-(2-(ethylamino) ethyl) formamido, N-(3-(ethylamino) propyl group) formamido or N-(3-(diethylamino) propyl group) formamido.
Described low alkyl is that carbon number is the alkyl of 1-4.
Further, described formula (I) compound or its pharmaceutically acceptable salt are:
Above-claimed cpd is the Benzazole compounds that pyrrole radicals replaces, and it can prepare by the method for putting down in writing in prior art, has some compounds also can obtain by the commercialization approach.
Glaucoma of the present invention is former open angle glaucoma, former angle closure glaucoma, secondary glaucoma, congenital glaucoma.Also can be used for ophthalmologic operation and reduce intraocular pressure.
Described medicine is collyrium, oral formulations, common flour injection or long-acting slow-release preparation.These pharmaceutical preparatioies all can prepare by the method for routine.
Further, described long-acting slow-release preparation is the long-acting slow-release preparation of high polymer parcel, and wherein, the long-acting slow-release preparation of described high polymer preparation is nano particle preparations, microball preparation, aqueogel or Liposomal formulation.
Further, described high polymer is selected from one or more in poly-anhydride, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyphosphazene or polysaccharide, or is selected from the copolymer between the different monomers of described high polymer.
further, described high polymer is selected from polylactic-co-glycolic acid, polylactic-co-glycolic acid-ethylene glycol copolymer, polymaleic anhydride, poly sebacic polyanhydride, polyvinyl alcohol, Polyethylene Glycol, sebacic anhydride-glycol copolymer, NIPA-acrylic copolymer, polybutylcyanoacrylate, polylactic acid, octadecane diacid acid anhydride-glycol copolymer, poly butyric ester, Acetic acid, hydroxy-, bimol. cyclic ester lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide triblock copolymer, polyether sulfone, PGA, cellulose, chitosan, glucosan, gelatin, one or more in polyhydroxybutyrate etc.
Technical scheme of the present invention can reach following technique effect:
Glaucoma is the eye pathological changes of a class take carrying out property optic nerve injury as feature, can cause optic atrophy and defect of visual field, and patient's main manifestations is intraocular pressure (IOP) and increases.The drug treatment of the Benzazole compounds that replaces by pyrrole radicals can be administered to sufferer with the Benzazole compounds that pyrrole radicals replaces by administering modes such as eye drop, intraocular injection agent, with this effectively with ocular hypotension, to play the effect of controlling optic atrophy.
Research is found, the Benzazole compounds that directly pyrrole radicals of the present invention is replaced is injected into eye or the Benzazole compounds that pyrrole radicals is replaced is prepared into the collyrium multiple dosing, can reach the earth and alleviate the glaucoma symptom, further studies show that, after the Benzazole compounds that described pyrrole radicals is replaced is prepared into slow releasing preparation, only intraocular injection once, effect is better and can treat and reach one month.Its long action time has reduced the misery of sufferer, has also reduced just very little side effect originally simultaneously, will be future countless glaucoma patients remove painful.To greatly reduce glaucomatous blind rate, improve the quality of life of glaucoma patients.
The specific embodiment mode
Below in conjunction with specific embodiment, advance-go on foot to set forth the present invention.But these embodiment only limit to the present invention is described and are not used in restriction protection scope of the present invention.In following embodiment, method therefor is conventional method if no special instructions.
Embodiment 1
1. get gelatin and prepare capsulae vacuus;
2. insert glycerol as the adjuvant plasticizer, insert agar and sodium carboxymethyl cellulose and strengthen viscosity and plasticity thereof;
3. add N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide powder had both got oral hard capsule to capsulae vacuus.
Embodiment 2
1. get N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in 4-dimethyl-1H-pyrrole-3-carboxamide powder pass into solution;
2. insert sodium carboxymethyl cellulose and mannitol in 1.;
3. lyophilizing both common ophthalmic injectable powder.
Embodiment 3
1. taking the 5g meglumine is dissolved in 1000ml water for injection;
2. add N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide 5g makes it dissolving;
3. separately with 10g boric acid, the 8g Borax, 3g sodium chloride adds wherein;
4. adjust pH value and be suitable for eye use;
5. aseptic filtration gets N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide collyrium.
Embodiment 4
1. get 10ml dichloromethane and 1ml methanol mixed;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 2.5mgN-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, also evenly ultrasonic in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2.;
4. get polyvinyl alcohol and make 1% aqueous solution,
5. the organic facies that 3. step is made is added to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 5
1. getting the poly-anhydride of 35mg joins in 1ml acetone and dissolves;
2. with 5mgN-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the solution that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 1., the homogenizer high-speed stirred forms colostrum;
3. the solution in will be 2. slowly is injected in the Oleum Gossypii semen that contains 0.1% egg yolk ovum Oletum Trogopterori with syringe, after 1500r/min stirs 15min, reduces rotating speed and continues to stir 4h to 200r/min;
4. add the 20ml petroleum ether, the centrifugal 10min of 8000r/min after 30min to step in 3.;
5. collect microsphere, petroleum ether and volatilizing.
Embodiment 6
1. use 0.01molL
-1Sodium hydroxide solution as solvent;
2. add 60 μ l Polyethylene Glycol in the solution that makes, stir and make its mix homogeneously;
3. add the 60mg poly lactic coglycolic acid in the solution that 2. makes to step, stir and make its mix homogeneously;
4. add 5mgN-[2-(diethylamino) ethyl in mentioned solution]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
5. take the 2.0g polyvinyl alcohol and join 4. in prepared solution, under magnetic agitation, it is uniformly dispersed, 4 ℃ of conditions were placed more than 24 hours, made the abundant swelling of gel, and being uniformly dispersed obtains clear and bright solution.
Embodiment 7
1. take 0.9g phospholipid, 0.3g cholesterol in the 50ml small beaker, add dehydrated alcohol 1-2ml, be placed in 65-70 ℃ of water-bath, be stirred to dissolve, rotate ethanol film forming on wall of cup that this small beaker makes phospholipid, with rubber pipette bulb featheriness wind, ethanol is flung to;
2. separately get N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide solution 30ml with being placed in 65-70 ℃ of water-bath, is incubated in small beaker, and is stand-by;
3. get N-[2-(diethylamino) ethyl of preheating]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide solution 30ml, add in the small beaker that contains phospholipid and cholesterol ester plasma membrane 65-70 ℃ of stirred in water bath aquation 10min.Subsequently small beaker is placed on magnetic stirring apparatus, stirring at room 30-60min, mixing namely gets N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide liposome.
Embodiment 8
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 9
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 10
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg N-[2-(diethylamino) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(diethylamino) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 11
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg N-[2-(1-nafoxidine base) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(1-nafoxidine base) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 12
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg N-[2-(ethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, in the organic facies that the 4-dimethyl-the 1H-pyrrole-3-carboxamide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain N-[2-(ethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide nanoparticle solution.
Embodiment 13
1. getting 10ml dichloromethane and 2ml dimethyl sulfoxide mixes;
2. getting the 25mg PLGA joins 1ml and is prepared into organic facies in 1.;
3. with 3mg 2-{[5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrroles-3-formamido group] ethyl } in organic facies that diethylamine-the N-oxide makes in joining 2., evenly ultrasonic;
4. get polyvinyl alcohol and make 0.8% aqueous solution,
5. the organic facies that 3. step is made evenly is added drop-wise to the outer aqueous phase that 4. makes;
6. remove organic solvent, obtain 2-{[5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrroles-3-formamido group] ethyl } diethylamine-N-oxidate nano grain solution.
3 medicines are tested glaucomatous therapeutic effect
be proved to be comparatively widely and and can be used for primary open angle glaucoma because methazolamide is present clinical practice, the medication of the multiple glaucomatous disease such as angle closure glaucoma and secondary glaucoma, therefore elect the comparison medicine as, and glaucoma pathogenesis is complicated, no matter be the intravitreal excitatory amino acid in present existing glaucoma animal model or induce optic nerve injury, all still disputable in the world, can only be as the animal model of some Mechanism Study, and luminescence method, laser method, the outer vein ligation of eye, the methods such as ischemia-reperfusion can't be broken away from kind of a system, disease time, persistent period, modeling is difficult for the impact of many interference factors such as homogeneous and other foeign elements, we choose and burn eye outer vein and glucose and cause that the such mechanism of high intraocular pressure is clear, test with the similar and received animal model of glaucoma clinical symptoms.Short-term and long-term glaucoma animal model pharmacodynamic experiment have been designed.
Short-term and the long-term pharmacodynamic experiment of the Benzazole compounds different dosage form that the same class pyrrole radicals replaces carried out in our design, and short-term and the long-term pharmacodynamic experiment of the Benzazole compounds that replaces of the inhomogeneity pyrrole radicals of same dosage form.
Test example 1
1, short-term N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, the pharmacodynamic experiment of the various dosage formulation of 4-dimethyl-1H-pyrrole-3-carboxamide to the glaucoma disease:
Laboratory animal and grouping:
Body weight is 45 of the healthy adult rabbit of 2.5～3.0kg, and male and female are not limit.be divided at random oral N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group (embodiment 1), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, the common ophthalmic preparation of 4-dimethyl-1H-pyrrole-3-carboxamide (with N-[2-(lignocaine) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, after 4-dimethyl-1H-pyrrole-3-carboxamide powder suspendible, direct injection is pleasing to the eye) (embodiment 2), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide eye drop group (embodiment 3), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer formulation (embodiment 4), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide microball preparation (embodiment 5), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer water-setting preparation (embodiment 6), N-[2-(lignocaine) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide Liposomal formulation (embodiment 7), methazolamide administration group and blank group, totally 9 groups, every group of 5 rabbits.(corresponding with following table)
Method:
Respectively organize the pharmacodynamics effect by the acute high intraocular pressure symptom comparison that 5% glucose causes: before experiment, anaesthetize sb. generally with urethane (dosage 1g/kg body weight), splash within the eye 1% tetracaine and carry out local anesthesia, intraocular pressure to every rabbit is measured with tonometer, measures and repeatedly gets its meansigma methods as its normal intraocular tension.Each experimental group is via the glucose solution of rabbit ear edge vein fast injection 5% concentration, and dosage is according to the 15ml/kg body weight.cause rapidly high intraocular pressure with this, it is as follows that each organizes administration: making Ocular hypertensive model front 1 hour, with N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide oral formulations and the administration of methazolamide preparation, simultaneously to N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, drip N-[2-(diethylamino) ethyl in 4-dimethyl-1H-pyrrole-3-carboxamide eye drop animal groups animal eye]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-8 of 1H-pyrrole-3-carboxamide collyrium, dripped once in every 5 minutes, making Ocular hypertensive model front 5 minutes, respectively organize N-[2-(diethylamino) ethyl to the intraocular injection correspondence of all the other each experimental group animals]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide preparation 10mg.The intraocular pressure of 5,10,20,30 and 40 minutes is measured respectively in the beginning modeling after modeling, respectively organize the difference of intraocular pressure value, carries out subsequently medical statistics.
Result:
N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide is respectively organized preparation and matched group 5% glucose is caused the ocular hypertensive reducing iop of Rabbits with Acute (unit: mm Hg) (as following table 1)
Table 1:
compare with the acute high IOP model group, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide does not cause too high intraocular pressure to raise after intravenous injection 5% glucose, as seen N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide is controlled better it, after 30 minutes, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide has showed intraocular pressure and has returned to lower state, the methazolamide group raises more remarkable after intravenous injection 5% glucose, demonstrate the effect of controlling intraocular pressure and be inferior to N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, each group (P＜0.05) of 4-dimethyl-1H-pyrrole-3-carboxamide.N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, the reducing iop of 4-dimethyl-1H-pyrrole-3-carboxamide is better than methazolamide.Can draw from experimental result, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide, comprising oral group and eye drop group has obvious pharmacodynamic action to the glaucomatous disease of the simulation of short-term, and each durative action preparation group also all shows the effect characteristics rapid-action, that part-time application is similar to ordinary preparation.
2, N-[2-(diethylamino) ethyl over a long time]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2, the various dosage formulation of 4-dimethyl-1H-pyrrole-3-carboxamide are to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
45 of cleaning level healthy adult Wistar rats, body weight (180 ± 20) g.be divided at random oral N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, the common ophthalmic preparation of 4-dimethyl-1H-pyrrole-3-carboxamide (with N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, after 4-dimethyl-1H-pyrrole-3-carboxamide powder suspendible, direct injection is pleasing to the eye), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide eye drop group, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide microball preparation, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer formulation, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide Liposomal formulation, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer water-setting preparation, methazolamide and blank group, totally 9 groups, every group of 5 Mus.
Method:
Carry out Ocular hypertensive model preparation and use RNA post transcription cloning method (RT-PCR) to detect after each treated animal administration THY1 Messenger RNA (THY-1mRNA) content in retina.With the rat of experimental group with volume fraction 10% chloral hydrate (350mgkg-1) intraperitoneal injection of anesthesia after, iron and close each 3 scleral veins of rat eyes, adopt weekly the pen type tonometer to measure intraocular pressure 1 time 4 weeks to the modeling after modeling.Blank group rat is closed scleral veins except not ironing, and all the other operate with the model treated animal.The rat average intraocular pressure is the modeling success the above person of 30mmHg.Each ejection preparation group 4 weeks after modeling for the first time the time give intraocular injection each preparation, continue no longer administration in the experimental period in 4 weeks after injection.Oral pyrrole radicals replaces the Benzazole compounds group 3mg that takes medicine every day drips two of medicines at every of eye drop group every day, continues for 4 weeks.Put to death all experimental group animals after 1 month.The preparation of specimen: rat is put to death in the 10% excessive anesthesia of chloral hydrate, and complete taking-up eyeball is inserted rapidly in phosphate buffer, cuts eyeball along the corneoscleral junction coronalplane, discards anterior ocular segment, and after careful complete separation retina, suck dry moisture is standby as far as possible with filter paper.Extract and respectively organize total RNA, after amplified production, through agarose gel electrophoresis.By the rear relative amount that obtains THY-1 with gel imaging analysis systematic analysis amplified band of taking pictures under uviol lamp.The expression of the THY-1 of glaucoma patient is on the low side, therefore the higher representative of expression of THY-1 is more approaching normal, compare the pharmacodynamics effect of each group with this, by the Image-J software analysis, obtain not the chiaroscuro effect after taking pictures on the same group under uviol lamp, namely represent the relative amount of THY-1 with the chiaroscuro effect sequence, judge the expression of THY-1 with this, infer and respectively organize the glaucomatous long-term effect of Drug therapy.
Result:
Because it is generally on the low side that glaucomatous THY-1 expresses, the THY-1 that the glaucoma state of an illness is lighter expresses more, otherwise less, and under the state of an illness was consistent, each therapeutic effect of organizing after administration was estimated out by the expression effect of THY-1.N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide is respectively organized slow releasing preparation, the collyrium group does not have statistical significance with normal group THY-1mRNA differential expression.Expression N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide respectively organizes slow releasing preparation and the collyrium group all produces good result, only need disposable injection or repeatedly drip collyrium, both produced and treated preferably glaucomatous effect.expression from THY-1mRNA, be reflected in the pharmacodynamics of long-term treatment glaucoma disease: N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-common intraocular injection the agent of 1H-pyrrole-3-carboxamide group slightly is inferior to the long-acting sustained-release agent group, oral N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group slightly is inferior to N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-common intraocular injection the agent of 1H-pyrrole-3-carboxamide group, oral N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group is better than the methazolamide group.
Test example 2
1, the long-acing nano grain preparation of the short-term Benzazole compounds preparation that replaces of various pyrrole radicals is to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
Body weight is 40 of the healthy adult rabbit of 2.5～3.0kg, and male and female are not limit.be divided at random N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 8), N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 9), N-[2-(diethylamino) ethyl]-5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 10), N-[2-(1-nafoxidine base) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 11), N-[2-(ethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 12), 2-{[5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrroles-3-formamido group] ethyl } diethylamine-N-oxide long-acing nano preparation administration group (embodiment 13), methazolamide administration group and blank group, totally 8 groups, every group of 5 rabbits.
Method:
Respectively organize the pharmacodynamics effect by the acute high intraocular pressure symptom comparison that 5% glucose causes: before experiment, anaesthetize sb. generally with urethane (dosage 1g/kg body weight), splash within the eye 1% tetracaine and carry out local anesthesia, intraocular pressure to every rabbit is measured with tonometer, measures and repeatedly gets its meansigma methods as its normal intraocular tension.Each experimental group is via the glucose solution of rabbit ear edge vein fast injection 5% concentration, and dosage is according to the 15ml/kg body weight.Cause rapidly high intraocular pressure with this, it is as follows that each organizes administration: making Ocular hypertensive model front 1 hour, with the administration of methazolamide preparation, making Ocular hypertensive model front 5 minutes, except corresponding each group leader of intraocular injection of export-oriented all the other each experimental group animals of blank group is imitated nano particle preparations 10mg.The intraocular pressure of 5,10,20,30 and 40 minutes is measured respectively in the beginning modeling after modeling, respectively organize the difference of intraocular pressure value, carries out subsequently medical statistics.
Result:
Nanoparticle durative action preparation, methazolamide and the matched group of the Benzazole compounds that various pyrrole radicals replace causes the ocular hypertensive reducing iop of Rabbits with Acute (unit: mm Hg) (as following table 2) to 5% glucose
Table 2:
Compare with the acute high IOP model group, the Benzazole compounds durative action preparation of below respectively organizing the pyrrole radicals replacement does not all cause too high intraocular pressure to raise after intravenous injection 5% glucose, as seen each group leader is imitated preparation to intraocular pressure control better, after 30 minutes, each group of the Benzazole compounds nanoparticle durative action preparation that pyrrole radicals replaces has showed the intraocular pressure falling, the methazolamide group raises more remarkable after intravenous injection 5% glucose, and the effect that demonstrates the control intraocular pressure is inferior to respectively organizes nanoparticle durative action preparation (P＜0.05).Each reducing iop of organizing the nanoparticle durative action preparation of compound preparation is better than methazolamide.Can draw from experimental result, each nanoparticle durative action preparation of organizing the compound preparation has obvious pharmacodynamic action to the glaucomatous disease of the simulation of short-term, and each durative action preparation group also all shows the effect characteristics rapid-action, that part-time application is similar to ordinary preparation.
2, the nanoparticle durative action preparation of respectively organizing over a long time the Benzazole compounds preparation that pyrrole radicals replaces is to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
40 of cleaning level healthy adult Wistar rats, body weight (180 ± 20) g.be divided at random N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(diethylamino) ethyl]-5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(1-nafoxidine base) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(ethylamino) ethyl]-5-(5-fluoro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, 2-{[5-(5-chloro-2-oxo-1, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrroles-3-formamido group] ethyl } diethylamine-N-oxide long-acing nano preparation administration group, methazolamide administration group and blank group, totally 8 groups, every group of 5 Mus.
Method:
Carry out Ocular hypertensive model preparation and use RNA post transcription cloning method (RT-PCR) to detect after each treated animal administration THY1 Messenger RNA (THY-1mRNA) content in retina.Rat volume fraction 10% chloral hydrate (350mgkg with experimental group
-1) after intraperitoneal injection of anesthesia, iron and close each 3 scleral veins of rat eyes, adopt weekly the pen type tonometer to measure intraocular pressure 1 time 4 weeks to the modeling after modeling.Blank group rat is closed scleral veins except not ironing, and all the other operate with the model treated animal.The rat average intraocular pressure is the modeling success the above person of 30mmHg.Each is organized Benzazole compounds nanoparticle durative action preparation that pyrrole radicals replaces and all gives intraocular injection during 4 week after modeling for the first time, continues no longer administration in the experimental period in 4 weeks after injection.Put to death all experimental group animals after 1 month.The preparation of specimen: rat is put to death in the 10% excessive anesthesia of chloral hydrate, and complete taking-up eyeball is inserted rapidly in phosphate buffer, cuts eyeball along the corneoscleral junction coronalplane, discards anterior ocular segment, and after careful complete separation retina, suck dry moisture is standby as far as possible with filter paper.Extract and respectively organize total RNA, after amplified production, through agarose gel electrophoresis.By the rear relative amount that obtains THY-1 with gel imaging analysis systematic analysis amplified band of taking pictures under uviol lamp.The expression of the THY-1 of glaucoma patient is on the low side, therefore the higher representative of expression of THY-1 is more approaching normal, compare the pharmacodynamics effect of each group with this, by the Image-J software analysis, obtain not the chiaroscuro effect after taking pictures on the same group under uviol lamp, namely represent the relative amount of THY-1 with the chiaroscuro effect sequence, judge the expression of THY-1 with this, infer and respectively organize the glaucomatous long-term effect of Drug therapy.
Result:
Because the expression of glaucomatous THY-1 is generally on the low side, the THY-1 that the glaucoma state of an illness is lighter expresses more, otherwise less, and under the state of an illness was consistent, each therapeutic effect of organizing after administration was estimated out by the expression effect of THY-1.Each group leader is imitated the nanoparticle slow releasing preparation does not have statistical significance with normal group THY-1mRNA differential expression.The Benzazole compounds slow releasing preparation that the pyrrole radicals replacement is respectively organized in expression all produces good result, only needs disposable injection, has both produced and has treated preferably glaucomatous effect.From the expression of THY-1mRNA, be reflected in the pharmacodynamics of long-term treatment glaucoma disease: each Benzazole compounds long-acing nano grain preparation of organizing the pyrrole radicals replacement is better than the methazolamide group.
Obviously, the above embodiment of the present invention is only for example of the present invention clearly is described, and is not to be restriction to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here can't give all embodiments exhaustive.Everyly belong to the row that apparent variation that technical scheme of the present invention extends out or change still are in protection scope of the present invention.
Claims (9)
1. the compound of formula (I) or its pharmaceutically acceptable salt application in preparation treatment glaucoma medicine,
Wherein, R
1Be selected from hydrogen, halogen, alkyl, cycloalkyl, aromatic radical, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl ,-(CO) R
15,-NR
13R
14,-(CH
2)
rR
16With-C (O) NR
8R
9
R
2Be selected from hydrogen, halogen, alkyl, trihalomethyl group, hydroxyl, alkoxyl, cyano group ,-NR
13R
14,-NR
13C (O) R
14,-C (O) R
15, aromatic radical, heteroaryl and-S (O)
2NR
13R
14
R
3Be selected from hydrogen, halogen, alkyl, trihalomethyl group, hydroxyl, alkoxyl ,-(CO) R
15,-NR
13R
14, aromatic radical, heteroaryl ,-NR
13S (O)
2R
14,-S (O)
2NR
13R
14,-NR
13C (O) R
14,-NR
13C (O) OR
14With-SO
2R
20Wherein, described R
20Be alkyl, aromatic radical, aralkyl, heteroaryl and heteroarylalkyl;
R
4Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl and-NR
13R
14
R
5Be selected from hydrogen and alkyl;
R
6Be selected from-C (O) R
10, wherein, described R
10For-NR
11(CH
2)
nR
12Wherein, R
11Be hydrogen or unsubstituted low alkyl; N is 2 or 3; And R
12For-NR
13R
14Or-N
+(O) R
13R
14
R
7Be selected from hydrogen, alkyl, aromatic radical and heteroaryl;
R
8And R
9Be independently from each other hydrogen, alkyl and aromatic radical;
R
13And R
14The low alkyl that is independently from each other hydrogen, alkyl, replaces through hydroxyl, alkyl amino, cyano group alkyl, cycloalkyl, aromatic radical or heteroaryl; Or R
13And R
14Can be in conjunction with forming heterocyclic group;
R
15Be selected from hydrogen, hydroxyl, alkoxyl and aryloxy group;
R
16Be selected from hydroxyl ,-C (O) R
15,-NR
13R
14With-C (O) NR
13R
14With
R is 1,2,3 or 4.
2. application according to claim 1, is characterized in that, R
6For-C (O) R
10, described R
10For-NR
11(CH
2)
nR
12Wherein, R
11Be hydrogen or unsubstituted low alkyl; N is 2 or 3; And R
12For-NR
13R
14, wherein, R
13And R
14Be unsubstituted low alkyl independently of one another; And R
7Be selected from hydrogen, alkyl, aromatic radical and heteroaryl.
3. application according to claim 1, is characterized in that, R
6Be N-(2-(dimethylamino) ethyl) formamido, N-(2-(diethylamino) ethyl) N-METHYLFORMAMIDE base, N-(3-(dimethylamino) propyl group) formamido, N-(2-(diethylamino) ethyl) formamido, N-(2-(ethylamino) ethyl) formamido, N-(3-(ethylamino) propyl group) formamido or N-(3-(diethylamino) propyl group) formamido.
4. application according to claim 1, is characterized in that, described formula (I) compound or its pharmaceutically acceptable salt are:
5. according to claim 1-4 arbitrary described application, is characterized in that, described glaucoma is former open angle glaucoma, former angle closure glaucoma, secondary glaucoma or congenital glaucoma.
6. according to claim 1-4 arbitrary described application, is characterized in that, described medicine is collyrium, common flour injection or long-acting slow-release preparation.
7. application according to claim 6, it is characterized in that, described long-acting slow-release preparation is the long-acting slow-release preparation of high polymer parcel, and wherein, the long-acting slow-release preparation of described high polymer parcel is nano particle preparations, microball preparation, aqueogel or Liposomal formulation.
8. application according to claim 7, it is characterized in that, described high polymer is selected from one or more in poly-anhydride, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyphosphazene or polysaccharide, or is selected from the copolymer between the different monomers of described high polymer.
9. application according to claim 8, it is characterized in that, described high polymer is selected from polylactic-co-glycolic acid, polylactic-co-glycolic acid-ethylene glycol copolymer, polymaleic anhydride, poly sebacic polyanhydride, polyvinyl alcohol, Polyethylene Glycol, sebacic anhydride-glycol copolymer, NIPA-acrylic copolymer, polybutylcyanoacrylate, polylactic acid, octadecane diacid acid anhydride-glycol copolymer, poly butyric ester, Acetic acid, hydroxy-, bimol. cyclic ester lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide triblock copolymer, polyether sulfone, PGA, cellulose, chitosan, glucosan, gelatin, one or more in polyhydroxybutyrate etc.
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