CN103127096B - The Benzazole compounds that pyrrole radicals replaces is in the application for the treatment of glaucoma - Google Patents
The Benzazole compounds that pyrrole radicals replaces is in the application for the treatment of glaucoma Download PDFInfo
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- CN103127096B CN103127096B CN201110396160.9A CN201110396160A CN103127096B CN 103127096 B CN103127096 B CN 103127096B CN 201110396160 A CN201110396160 A CN 201110396160A CN 103127096 B CN103127096 B CN 103127096B
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Abstract
The invention discloses the application of Benzazole compounds at treatment glaucoma of pyrrole radicals replacement.This research finds that the Benzazole compounds replaced by low dose repeatedly intraocular injection administration, collyrium multiple dosing pyrrole radicals can treat glaucoma, after the Benzazole compounds that further research finds to use liposome pyrrole radicals to replace or the nanometer formulation Benzazole compounds that pyrrole radicals replaces being prepared into high polymer parcel, microball preparation and aqueogel, can continued treatment glaucoma and effect of drugs is remarkable by medicine intraocular injection.
Description
Technical field
The present invention relates to the application of Benzazole compounds at treatment glaucoma of a kind of pyrrole radicals replacement.
Background technology
Glaucoma is the Eye disease that a class is feature with Progressive symmetric erythrokeratodermia optic nerve injury, 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 the glaucoma sufferer of which kind of type, the main manifestations of patient is intraocular pressure (IOP) and increases.Glaucoma can cause irreversibility visual deprivation, about has 1,400,000,000 glaucoma patients in the world at present, but about the people of half does not recognize this disease.World Health Organization (WHO) is classified as second largest diseases causing blindness, and in China, glaucomatous sickness rate about 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 the aqueous humor of 98% 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 aqueous humor can be caused to pile up and cause intraocular pressure (IOP) to increase.
Normal eye is intrinsic pressure usually between 11 to 21mmHg, and the intraocular pressure of rising directly by nerve compression or minimizing blood flow, can make the axonal injury of retinal ganglion cells.The information that aixs cylinder is carried from eyes passes to brain by optic nerve.Axonal loss can cause ganglion cell death, finally causes the forfeiture of optic atrophy and vision.
Usually according to the form of glaucoma patient angle of anterior chamber, disease is divided into two types, i.e. open angle glaucoma and angle closure glaucoma.In open angle glaucoma, although angle of anterior chamber seems not get clogged, discharge deficiency due to aqueous humor and intraocular pressure can be caused to raise.In angle closure glaucoma, only have and intraocular pressure just can be caused to raise when iris distortion blocks the outflow of aqueous humor.
Reducing intraocular pressure is the comparatively effective approach of current clinical unique confirmation.Treatment is by three kinds of approach: medicine, laser surgery and open surgery, and specifically adopts which kind of mode by glaucomatous type decided.Medicine and laser surgery (trabeculoplasty) can improve existing aqueous humor and discharge approach, and open surgery (trabeculectomy, pipeline shunt art), be then to reproduce a new aqueous humor to discharge system.Current clinical setting is: perform the operation and to carry out according to symptom, cure the symptoms, not the disease, painful great Yi recurrence, and 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 there is untoward reaction:
Receptor stimulating agent, untoward reaction and deficiency: blurred vision, front metopodynia, myopia, night dysphotia.When being used alone, be not as effective as beta-blockers.
Cholinesterase inhibitor, is applied to angle-closure glaucoma at the moment, because its strong miosis function can cause cataract and detachment of retina.Compared with receptor stimulating agent, the systemic effect brought 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: the side effect such as the change of anorexia, fatigue, the sense of taste, depression, paraesthesia, renal calculus, blood dyscrasia after use, can be brought.
Carbonic anhydrase inhibitors (local application), the untoward reaction caused obviously reduces, but can make there is the bad sense of taste in oral cavity.
Non-selective 3 adrenergic receptor agonists (local application), normal and miotic is adjoint to be used, do not have selective ' beta '3 adrenergic energy receptor stimulating agent curative effect so reliable, and cause probability that is irritated and toxic reaction (as hypertension, tachycardia) higher.
α 2-selective ' beta '3 adrenergic energy receptor stimulating agent (local application) is not enough: system response (as) more non-selective not obvious, apraclonidine easily causes anaphylaxis, and brimonidine easily causes xerostomia.
Beta-blockers (local application), system 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), not enough: the pigmentation increasing iris and skin, may uveitis be worsened.Cause muscle, joint, back pain, erythra.
Mannitol and glycerol, have serious system response.
All there is different side effect in current existing glaucoma, and most importantly therapeutic effect is not fully up to expectations, no matter be any class medicine, all cannot produce good therapeutic effect now, the glaucoma sufferer of at present no matter various pathogenic factor is caused to get more and more, and morbidity is more and more heavier, the vision of serious threat sufferer.A kind of novel effective Drug therapy glaucoma of exploitation is particularly important to sufferer.
Summary of the invention
Technical problem to be solved by this invention is to provide the application of Benzazole compounds at treatment glaucoma of a kind of pyrrole radicals replacement.This research finds that the Benzazole compounds replaced by low dose repeatedly intraocular injection administration, collyrium multiple dosing pyrrole radicals of the present invention can treat glaucoma, after the Benzazole compounds that further research finds to use pyrrole radicals described in liposome to replace or the nanometer formulation Benzazole compounds that described pyrrole radicals replaces being prepared into high polymer parcel, microball preparation and aqueogel, by can continued treatment glaucoma and effect of drugs is remarkable after medicine intraocular injection.
For solving the problems of the technologies described above, the technical solution adopted in the present invention is:
The compound of formula (I) or the application of its pharmaceutically acceptable salt in preparation treatment glaucoma medicine,
Wherein, R
1be selected from hydrogen, halogen, alkyl, cycloalkyl, aromatic radical, heteroaryl, heteroalicyclyl, 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
20; Wherein, described R
20for 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
12; Wherein, R
11for 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
14be independently from each other hydrogen, alkyl, through hydroxyl, alkyl amino, cyanoalkyl, cycloalkyl, aromatic radical or heteroaryl replace low alkyl; Or R
13and R
14can in conjunction with formation 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
14; With
R is 1,2,3 or 4.
Further, described R
6for-C (O) R
10, described R
10for-NR
11(CH
2)
nr
12; Wherein, R
11for 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
6for 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.
The alkyl of described low alkyl to be carbon number be 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 be prepared by the method recorded in prior art, has some compounds also can be obtained by 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 be prepared by conventional method.
Further, described long-acting slow-release preparation is the long-acting slow-release preparation of high polymer parcel, and wherein, long-acting slow-release preparation prepared by described high polymer is nano particle preparations, microball preparation, aqueogel or Liposomal formulation.
Further, described high polymer be selected from condensing model, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyphosphazene or polysaccharide one or more, or the copolymer between the different monomers being selected from 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 disease that a class is feature with Progressive symmetric erythrokeratodermia optic nerve injury, can cause optic atrophy and defect of visual field, and the main manifestations of patient is intraocular pressure (IOP) and increases.The drug treatment of the Benzazole compounds replaced by pyrrole radicals, can be administered to sufferer by administering modes such as eye drop, intraocular injection agent by the Benzazole compounds that pyrrole radicals replaces, with this effectively by ocular hypotension, to play the effect controlling optic atrophy.
Research finds, directly the Benzazole compounds that pyrrole radicals of the present invention replaces is injected into eye or the Benzazole compounds that pyrrole radicals replaces is prepared into collyrium multiple dosing, and greatly can alleviate symptoms of glaucoma, further research display, after the Benzazole compounds that described pyrrole radicals replaces is prepared into slow releasing preparation, can only intraocular injection once, effect is better and can treat and reach one month.Its long action time, decreases the misery of sufferer, also reduces originally just very little side effect simultaneously, will remove painful for following countless glaucoma patient.To greatly reduce glaucomatous blind rate, improve the quality of life of glaucoma patients.
Specific embodiment mode
Below in conjunction with specific embodiment, enter-walk and set forth the present invention.But these embodiments are only limitted to illustrate that the present invention and being not used in limits the scope of the 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 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 in capsulae vacuus, both obtain oral hard capsule.
Embodiment 2
1. get in N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide powder pass into solutions;
2. sodium carboxymethyl cellulose and mannitol is inserted in 1.;
3. lyophilizing both common ophthalmic injectable powder.
Embodiment 3
1. taking 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 to make it to dissolve;
3. another by 10g boric acid, 8g Borax, 3g sodium chloride adds wherein;
4. adjusted to ph is suitable for eye use;
5. aseptic filtration, obtains 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. 10ml dichloromethane and 1ml methanol mixed is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 2.5mgN-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2. also evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 1% is got,
5. the organic facies that 3. step obtains is added in 4. obtained outer aqueous phase;
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. get 35mg condensing model to join in 1ml acetone and dissolve;
2. by 5mgN-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide joins in solution obtained 1., and homogenizer high-speed stirred forms colostrum;
3. with syringe, the solution in 2. is slowly injected in the Oleum Gossypii semen containing 0.1% egg yolk ovum Oletum Trogopterori, after 1500r/min stirs 15min, reduces rotating speed and continue to stir 4h to 200r/min;
4. to step 3. in add 20ml petroleum ether, the centrifugal 10min of 8000r/min after 30min;
5. microsphere is collected, petroleum ether and volatilizing.
Embodiment 6
1. 0.01molL is used
-1sodium hydroxide solution as solvent;
2. in obtained solution, add 60 μ l Polyethylene Glycol, stir and make its mix homogeneously;
3. add 60mg poly lactic coglycolic acid in the solution 2. obtained to step, stir and make its mix homogeneously;
4. in above-mentioned solution, add 5mgN-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides;
5. take 2.0g polyvinyl alcohol to join in 4. obtained solution, under magnetic agitation, make it be uniformly dispersed, 4 DEG C of conditions place more than 24 hours, make gel fully swelling, are uniformly dispersed and obtain clear and bright solution.
Embodiment 7
1. take 0.9g phospholipid, 0.3g cholesterol in 50ml small beaker, add dehydrated alcohol 1-2ml, be placed in 65-70 DEG C of water-bath, be stirred to dissolve, rotate this small beaker and make the ethanol of phospholipid film forming on wall of cup, with rubber pipette bulb featheriness wind, ethanol is flung to;
2. N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-is separately got, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide solution 30ml in small beaker, with being placed in 65-70 DEG C of water-bath, insulation, stand-by;
3. N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-of preheating is got, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide solution 30ml, add in the small beaker containing phospholipid and cholesterol ester plasma membrane, 65-70 DEG C of stirred in water bath aquation 10min.Subsequently small beaker is placed on magnetic stirring apparatus, stirring at room temperature 30-60min, mix and obtain N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide liposomees.
Embodiment 8
1. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 3mgN-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2., evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 3mgN-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2., evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 3mgN-[2-(diethylamino) ethyl]-5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2., evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 3mgN-[2-(1-nafoxidine base) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2., evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. 3mgN-[2-(ethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides are joined in organic facies obtained 2., evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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. 10ml dichloromethane and the mixing of 2ml dimethyl sulfoxide is got;
2. get 25mg PLGA join 1ml 1. in be prepared into organic facies;
3. by 3mg2-{ [5-(5-chloro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrroles-3-formamido group] ethyl } diethylamine-N-oxide to join 2. in obtained organic facies, evenly ultrasonic;
4. the aqueous solution that polyvinyl alcohol makes 0.8% is got,
5. organic facies step 3. obtained evenly is added drop-wise in 4. obtained outer aqueous phase;
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
Because methazolamide be current clinical practice comparatively widely and be proved to be and can be used for primary open angle glaucoma, the medication of the multiple glaucomatous disease such as angle closure glaucoma and secondary glaucoma, therefore comparison medicine is elected as, and glaucoma pathogenesis is complicated, no matter be intravitreal excitatory amino acid or induction optic nerve injury in current existing glaucoma animal model, all still disputable in the world, can only 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 cannot break away from germline, disease time, persistent period, the impact of modeling not easily many interference factors such as homogeneous and other foeign elements, we choose and burn the outer vein of eye and glucose causes the such mechanism of Bulbi hypertonia clear, similar and received animal model is tested with glaucoma clinical symptoms.Devise short-term and long-term glaucoma animal model pharmacodynamic experiment.
The short-term of Benzazole compounds different dosage form that same class pyrrole radicals replaces and long term effect experiment have been carried out in our design, and the short-term of the Benzazole compounds replaced with the inhomogeneity pyrrole radicals of one dosage type low temperature and long term effect are tested.
Test example 1
1, short-term N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl) the various dosage formulation of-2,4-dimethyl-1H-pyrrole-3-carboxamides are to the pharmacodynamic experiment of glaucoma disease:
Laboratory animal and grouping:
Body weight is the healthy adult rabbit 45 of 2.5 ~ 3.0kg, and male and female are not limit.Be divided into oral N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-at random, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group (embodiment 1), N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide common ophthalmic preparation is (by N-[2-(lignocaine) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide eye drop group (embodiment 3), N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer formulation (embodiment 4), N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide microball preparation (embodiment 5), N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer water-setting preparation (embodiment 6), N-[2-(lignocaine) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide Liposomal formulation (embodiment 7), methazolamide administration group and blank group, totally 9 groups, often organize 5 rabbits.(corresponding with following table)
Method:
The acute high intraocular pressure symptom comparison caused by 5% glucose respectively organizes pharmacodynamic effects: before experiment, anaesthetize sb. generally with urethane (dosage 1g/kg body weight), instill 1% tetracaine within the eye and carry out local anesthesia, the intraocular pressure tonometer of every rabbit is measured, measures and repeatedly get its meansigma methods as its normal intraocular tension.Each experimental group is via the glucose solution of rabbit ear edge i.v. bolus 5% concentration, and dosage is according to 15ml/kg body weight.Bulbi hypertonia is caused rapidly with this, each group of administration is as follows: making Ocular hypertensive model first 1 hour, by N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-is dripped in 4-dimethyl-1H-pyrrole-3-carboxamide eye drop animal groups animal eye, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide collyrium 8, within every 5 minutes, drip once, making Ocular hypertensive model first 5 minutes, intraocular injection correspondence to all the other each test group of animals respectively organizes N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide preparation 10mg.Start modeling, after modeling, measure the intraocular pressure of 5,10,20,30 and 40 minutes respectively, respectively organize the difference of intraocular pressure value, carry out medical statistics subsequently.
Result:
N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides respectively organize preparation and matched group causes the ocular hypertensive reducing iop of Rabbits with Acute (unit: mmHg) (as following table 1) 5% glucose
Table 1:
Compare with acute high IOP model group, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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, visible N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide controls better to it, after 30 minutes, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide is respectively organized and has been showed intraocular pressure and return to lower state, methazolamide group raises more remarkable after intravenous injection 5% glucose, demonstrate the effect controlling intraocular pressure and be inferior to N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide (P < 0.05).The reducing iop of N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides is better than methazolamide.Can draw from experimental result, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, each group of 4-dimethyl-1H-pyrrole-3-carboxamide, comprise oral group and the glaucomatous disease of the simulation of eye drop group to short-term has obvious pharmacodynamic action, each durative action preparation group also all shows rapid-action, that part-time application is similar to ordinary preparation action character.
2, over a long time the various dosage formulation of N-[2-(diethylamino) ethyl]-5-(5-fluoro-2-oxo-1,2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
Cleaning grade healthy adult Wistar rat 45, body weight (180 ± 20) g.Be divided into oral N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-at random, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide common ophthalmic preparation is (by N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide eye drop group, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide microball preparation, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer formulation, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide Liposomal formulation, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide nanometer water-setting preparation, methazolamide and blank group, totally 9 groups, often organize 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.By the rat of experimental group with after volume fraction 10% chloral hydrate (350mgkg-1) intraperitoneal injection of anesthesia, iron and close each 3 scleral veins of rat eyes, after modeling, adopt weekly pen type tonometer to measure after intraocular pressure 1 time to modeling 4 weeks.Blank group rat is closed except scleral veins except not ironing, and all the other operations are with model treated animal.Rat average intraocular pressure is modeling success more than 30mmHg person.Each ejection preparation group gives intraocular injection each preparation after first time modeling when 4 weeks, inject no longer administration in the rear experimental period continuing 4 weeks.The Benzazole compounds group that oral azole base replaces to be taken medicine 3mg every day, and eye drop group every day every drips medicine two, continues 4 weeks.All test group of animals are put to death after 1 month.The preparation of specimen: rat is put to death in the excessive anesthesia of 10% chloral hydrate, and complete taking-up eyeball is inserted rapidly in phosphate buffer, and cut eyeball along corneoscleral junction coronalplane, discard anterior ocular segment, after careful complete separation retina, suck dry moisture is for subsequent use as far as possible with filter paper.Extract each group of total serum IgE, after amplified production, through agarose gel electrophoresis.By the relative amount obtaining THY-1 after taking pictures under uviol lamp with the analysing amplified band of Labworks image acquisition and analysis software.The expression of the THY-1 of glaucoma patient is on the low side, therefore the higher representative of the expression of THY-1 is normally more close, with the pharmacodynamic effects that this comparison is respectively organized, by Image-J software analysis, obtain the chiaroscuro effect after the taking pictures under uviol lamp of different group, namely represent the relative amount of THY-1 with chiaroscuro effect sequence, judge the expression of THY-1 with this, infer each group of glaucomatous long-term effect of Drug therapy.
Result:
Because glaucomatous THY-1 expresses 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 is consistent, the therapeutic effect after the administration of each group is evaluated out by the expression effect of THY-1.N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides respectively organize slow releasing preparation, collyrium group does not have statistical significance with normal group THY-1mRNA differential expression.Represent N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide respectively organizes slow releasing preparation and collyrium group all produces good result, only need disposable injection or repeatedly drip collyrium, both having produced the glaucomatous effect for the treatment of preferably.From the expression of THY-1mRNA, be reflected in the pharmacodynamics of long-term treatment glaucoma conditions: N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide common intraocular injection agent group is slightly inferior to long-acting sustained-release agent group, oral N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group is slightly inferior to N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide common intraocular injection agent group, oral N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide group is better than methazolamide group.
Test example 2
1, short-term, the long-acing nano grain preparation prepared of Benzazole compounds that replaces of various pyrrole radicals was to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
Body weight is the healthy adult rabbit 40 of 2.5 ~ 3.0kg, and male and female are not limit.Be divided into N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1 at random, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 8), N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group (embodiment 11), N-[2-(ethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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, often organize 5 rabbits.
Method:
The acute high intraocular pressure symptom comparison caused by 5% glucose respectively organizes pharmacodynamic effects: before experiment, anaesthetize sb. generally with urethane (dosage 1g/kg body weight), instill 1% tetracaine within the eye and carry out local anesthesia, the intraocular pressure tonometer of every rabbit is measured, measures and repeatedly get its meansigma methods as its normal intraocular tension.Each experimental group is via the glucose solution of rabbit ear edge i.v. bolus 5% concentration, and dosage is according to 15ml/kg body weight.Bulbi hypertonia is caused rapidly with this, each group of administration is as follows: making Ocular hypertensive model first 1 hour, by the administration of methazolamide preparation, making Ocular hypertensive model first 5 minutes, except the corresponding each group leader of intraocular injection of blank group all the other each test group of animals export-oriented imitates nano particle preparations 10mg.Start modeling, after modeling, measure the intraocular pressure of 5,10,20,30 and 40 minutes respectively, respectively organize the difference of intraocular pressure value, carry out medical statistics subsequently.
Result:
The nanoparticle durative action preparation of the Benzazole compounds that various pyrrole radicals replaces, methazolamide and matched group cause the ocular hypertensive reducing iop of Rabbits with Acute (unit: mmHg) (as following table 2) 5% glucose
Table 2:
Compare with acute high IOP model group, below the Benzazole compounds durative action preparation respectively organizing pyrrole radicals replacement does not all cause too high intraocular pressure to raise after intravenous injection 5% glucose, visible each group of durative action preparation controls better to intraocular pressure, after 30 minutes, the Benzazole compounds nanoparticle durative action preparation that pyrrole radicals replaces respectively is organized and has been showed intraocular pressure falling, methazolamide group raises comparatively remarkable after intravenous injection 5% glucose, demonstrates the effect controlling intraocular pressure and is inferior to each group of nanoparticle durative action preparation (P < 0.05).The reducing iop of nanoparticle durative action preparation prepared by each group of compound is better than methazolamide.Can draw from experimental result, the glaucomatous disease of the simulation of nanoparticle durative action preparation to short-term prepared by each group of compound has obvious pharmacodynamic action, and each durative action preparation group also all shows rapid-action, that part-time application is similar to ordinary preparation action character.
Nanoparticle durative action preparation prepared by the Benzazole compounds 2, respectively organizing pyrrole radicals replacement is over a long time to glaucomatous pharmacodynamic experiment:
Laboratory animal and grouping:
Cleaning grade healthy adult Wistar rat 40, body weight (180 ± 20) g.Be divided into N-[2-(1-nafoxidine base) ethyl]-5-(5-chloro-2-oxo-1 at random, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(diethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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-(the fluoro-2-oxo-1 of 5-, 2-indoline-3-ylidenylmethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide long-acing nano preparation administration group, N-[2-(ethylamino) ethyl]-5-(the fluoro-2-oxo-1 of 5-, 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, often organize 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.By the rat of experimental group volume fraction 10% chloral hydrate (350mgkg
-1) after intraperitoneal injection of anesthesia, iron and close each 3 scleral veins of rat eyes, adopt weekly pen type tonometer to measure after intraocular pressure 1 time to modeling after modeling 4 weeks.Blank group rat is closed except scleral veins except not ironing, and all the other operations are with model treated animal.Rat average intraocular pressure is modeling success more than 30mmHg person.The Benzazole compounds nanoparticle durative action preparation of each group of pyrrole radicals replacement all gives intraocular injection when 4 weeks after first time modeling, injects no longer administration in the rear experimental period continuing 4 weeks.All test group of animals are put to death after 1 month.The preparation of specimen: rat is put to death in the excessive anesthesia of 10% chloral hydrate, and complete taking-up eyeball is inserted rapidly in phosphate buffer, and cut eyeball along corneoscleral junction coronalplane, discard anterior ocular segment, after careful complete separation retina, suck dry moisture is for subsequent use as far as possible with filter paper.Extract each group of total serum IgE, after amplified production, through agarose gel electrophoresis.By the relative amount obtaining THY-1 after taking pictures under uviol lamp with the analysing amplified band of Labworks image acquisition and analysis software.The expression of the THY-1 of glaucoma patient is on the low side, therefore the higher representative of the expression of THY-1 is normally more close, with the pharmacodynamic effects that this comparison is respectively organized, by Image-J software analysis, obtain the chiaroscuro effect after the taking pictures under uviol lamp of different group, namely represent the relative amount of THY-1 with chiaroscuro effect sequence, judge the expression of THY-1 with this, infer each group of 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 is consistent, the therapeutic effect after the administration of each group is evaluated out by the expression effect of THY-1.Each group leader imitates nanoparticle slow releasing preparation does not have statistical significance with normal group THY-1mRNA differential expression.Represent that the Benzazole compounds slow releasing preparation that each group of pyrrole radicals replaces all produces good result, only need disposable injection, both produced the glaucomatous effect for the treatment of preferably.From the expression of THY-1mRNA, be reflected in the pharmacodynamics of long-term treatment glaucoma conditions: the Benzazole compounds long-acing nano grain preparation that each group pyrrole radicals replaces is better than methazolamide group.
Obviously, the above embodiment of the present invention is only for example of the present invention is clearly described, and is not the 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 cannot give exhaustive to all embodiments.Every belong to technical scheme of the present invention the apparent change of extending out or variation be still in the row of protection scope of the present invention.
Claims (7)
1. following formula: compound or the application of its pharmaceutically acceptable salt in preparation treatment glaucoma medicine,
；
；
；
；
Wherein, described glaucoma is primary glaucoma and/or congenital glaucoma.
2. following formula: compound or the application of its pharmaceutically acceptable salt in preparation treatment glaucoma medicine,
Described glaucoma is primary glaucoma and/or congenital glaucoma.
3. the application according to any one of claim 1-2, is characterized in that, described medicine is collyrium, common flour injection or long-acting slow-release preparation.
4. the application according to any one of claim 1-2, is characterized in that described compounds for treatment of glaucoma can not only reduce intraocular pressure, and can protect optic nerve.
5. application according to claim 3, 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.
6. application according to claim 5, it is characterized in that, described high polymer be selected from condensing model, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyether sulfone, polyphosphazene or polysaccharide one or more, or the copolymer between the different monomers being selected from described high polymer.
7. application according to claim 6, 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.
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1711089A (en) * | 2002-11-15 | 2005-12-21 | 苏根公司 | Combination administration of an indolinone with a chemotherapeutic agent for cell proliferation disorders |
| CN101163473A (en) * | 2005-05-12 | 2008-04-16 | 辉瑞大药厂 | Anticancer combination therapy using sunitinib malate |
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| CN1711089A (en) * | 2002-11-15 | 2005-12-21 | 苏根公司 | Combination administration of an indolinone with a chemotherapeutic agent for cell proliferation disorders |
| CN101163473A (en) * | 2005-05-12 | 2008-04-16 | 辉瑞大药厂 | Anticancer combination therapy using sunitinib malate |
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