CN105796562A - Application of compound to preparation of drug for preventing and treating glaucoma - Google Patents

Application of compound to preparation of drug for preventing and treating glaucoma Download PDF

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CN105796562A
CN105796562A CN201610199374.XA CN201610199374A CN105796562A CN 105796562 A CN105796562 A CN 105796562A CN 201610199374 A CN201610199374 A CN 201610199374A CN 105796562 A CN105796562 A CN 105796562A
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medicine
preparation
compound
glaucoma
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杨子娇
侯恺
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Abstract

The invention discloses new application of a compound and similar compounds thereof or pharmaceutical salt of the compound.The new application is application to preparation of a drug for reducing intraocular pressure to prevent and treat glaucoma.The compound can achieve a very remarkable effect on reducing intraocular pressure to prevent and treat glaucoma.

Description

Compound purposes in the medicine of preparation preventing and treating glaucoma
Technical field
The present invention relates to three kinds of purposes reducing the medicine of intraocular pressure preventing and treating glaucoma, be specifically related to 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone and similar compound thereof or its officinal salt,N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group oxygen base] quinolyl-4] oxygen base] phenyl]-N’-(4-fluorophenyl)-1,1-cyclopropyl diformamide and similar compound thereof or its officinal salt, 5-are chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino and similar compound or its officinal salt thereof reduce the purposes in the medicine of intraocular pressure preventing and treating glaucoma disease in preparation.
Background technology
Glaucoma is the Eye disease that a class harm is very big, it is 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 which type of glaucoma sufferer, the main manifestations of patient is intraocular pressure (IOP) and increases.Glaucoma may result in irreversibility visual deprivation, there are about 1,400,000,000 glaucoma patients at present in the world, but about the people of half does not recognize this disease.World Health Organization (WHO) is classified as great diseases causing blindness, is about 0.12%-1.64% at Chinese glaucomatous sickness rate, accounts for the 14.36% of ophthalmic diseases.Calculating according to epidemiological study, to the year two thousand twenty, the glaucoma patient number of China is up to 6,000,000.
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 generally between 11 to 21mmHg, and the intraocular pressure of rising can directly reduce blood flow, makes nethike embrane and eyeball structure change, ultimately results in the forfeiture of vision.
Reducing intraocular pressure is the comparatively effective approach of the unique confirmation of clinic at present.Treatment can pass through two kinds of approach: medicine and operation.Current clinical setting is: operation is cured 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: conventional medicine has beta-blockers, receptor stimulating agent, prostaglandin analogue, mannitol, glycerol and Chinese medicine etc., overall curative effect is bad, and untoward reaction and deficiency have perspiration, have a headache, tremble, blurred vision, front metopodynia, cause dysphotia, cause allergy and toxic reaction.
All there is different side effect in current existing glaucoma, and most importantly therapeutic effect is not fully up to expectations, no matter it is any class medicine, all cannot produce good therapeutic effect now, the glaucoma sufferer causing at present no matter various pathogenic factors gets 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.
Present inventors have surprisingly found that 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone and similar compound thereof or its officinal salt, N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group oxygen base] quinolyl-4] oxygen base] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide and similar compound thereof or its officinal salt, 5-are chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino and similar compound or its officinal salt thereof reduce the novel purposes in the medicine of intraocular pressure preventing and treating glaucoma disease in preparation.The another name of three kinds of series compounds is respectively as follows: KW2449, XL880 and TAE684, is some antitumor drug of discovered in recent years, reduces intraocular pressure preventing and treating glaucoma for these several compounds at present and there is no report.
Summary of the invention
The invention provides 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone and similar compound thereof or its officinal salt new application in reducing the intraocular pressure glaucomatous medicine of preventing and treating, N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group oxygen base] quinolyl-4] oxygen base] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide and similar compound or its officinal salt thereof prevent and treat the new application in glaucomatous medicine at reduction intraocular pressure, and 5-is chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino and similar compound or its officinal salt thereof prevent and treat the new application in glaucomatous medicine at reduction intraocular pressure.
Technical scheme is as follows:
Three kinds of compound or pharmaceutically acceptable salt thereofs prevent and treat the new application in glaucoma at reduction intraocular pressure.Described compound is 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone.Structure is (A):
(A)
Described compound is N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group oxygen base] quinolyl-4] oxygen base] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide.Structure is (B):
(B)
Described compound is that 5-is chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino.Structure is (C):
(C)
By these compounds and the like or or its officinal salt prepare into the various preparations through dosing eyes, gastrointestinal administration or parenteral administration, treat for glaucoma animal model including ordinary preparation, controlled release preparation, targeting preparation etc..
Glaucoma is 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 which type of glaucoma sufferer, the main manifestations of patient is intraocular pressure (IOP) and increases.Effectively by ocular hypotension, slow down to play, control secondary disease and be particularly important, prepare the animal model of high intraocular pressure, compound (A-C) is administered, obtain beyond thought miraculous effects, intraocular pressure reduces, and glaucoma symptom is eased, and the therapeutic effect of compound (A-C) is much stronger than positive drug clinical at present.
Detailed description of the invention
Compound used by the present invention can be purchased, it is also possible to being prepared according to relevant disclosed preparation method, it is not limiting as protection scope of the present invention.Below in conjunction with embodiment, the present invention is further explained.
Effect example
Described compound A is 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone.Structure is (A):
(A)
Described compound B is N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group oxygen base] quinolyl-4] oxygen base] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide.Structure is (B):
(B)
Described compound C is that 5-is chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino.Structure is (C):
(C)
1 compound (A-C) and similar compound thereof or the protective effect to corticosteroid hormone glaucoma rat of its officinal salt
1.1 laboratory animals and packet
Healthy adult Wistar rat, body weight 200-250 gram, without any ocular disease.Raising environment temperature 25 DEG C ± 1 DEG C, relative humidity 70%, specialty the personnel of raising raise.Animal eye is measured with tonometer intrinsic pressure before modeling, continuous observation record intraocular pressure 1 week, estimate that normal intraocular tension is interval, rejecting intraocular pressure higher or lower than normal intraocular tension interval person, take out 10 and be only used as Normal group, other animals start modeling, after modeling 1 week, by animal pattern random packet: i.e. model group, the Liposomal formulation group of compound (A-C), collyrium group, common powder injection formulation group and oral gastro-intestinal administration group, positive drug group latanoprost eye drops and oral comparison medicine group timolol.All animals continue modeling, administration is started after packet, the Liposomal formulation group of compound (A-C) carries out ophthalmic direct injection, compound (A-C) collyrium group eye drop administration, compound (A-C) normal injection group adopts intravenously administrable, oral drugs group oral administration, and the positive is put drops in one's eyes employing eye drop administration, oral comparison medicine medicine is taked to be administered orally, and Normal group does not process.
The foundation of 1.2 animal models
Healthy adult Wistar rat experiment group with 10% chloral hydrate with after 0.375ml.100g-1 row intraperitoneal anesthesia, the next day of with the syringe of l milliliter, timing is at right eye sub-conjunctival injection dexamethasone 0.25mg (0.05ml), left eye is comparison eye, counts 14 times, totally 28 days.
1.3 tonometries
Before each sub-conjunctival injection modeling medicine, rat opening eyelid, tonometer measures intraocular pressure, and measurement result takes the intraocular pressure that the coefficient of variation is 5%, record.All rat tonometries are completed by same people.
1.4 statistical analysis
Each group rat is observed the data obtained and represents with mean ± standard deviation (x ± s), carries out t inspection between group.
1.5 corticosteroid hormone glaucoma rat intraocular pressure results
Normal group average intraocular pressure is all the time at about 14-15mmHg, have no significant change, compare with Normal group, after model group rats modeling, 1 week (before administration) intraocular pressure afterwards starts to raise, and gradually rise (P < 0.05) along with continuing modeling time lengthening, intraocular pressure is all raised by each medicine group of medicine (A-C) all inhibitory action, and action effect is all better than eye drip positive controls prostatitis element eye drop and oral medicine positive controls timolol (P < 0.05 or P < 0.01).Compound (A-C) is rapid-action and acting duration is long (see table 1).Illustrate that medicine (A-C) can have the effect and persistent substantially reducing intraocular pressure.
Table 1 corticosteroid hormone glaucoma rat intraocular pressure result (mmHg, n=10)
Group It is worth before medicine 1 week 2 weeks 3 weeks 4 weeks
Normal group 14.61±1.73 14.92±1.64 14.72±1.84 14.83±1.98 14.69±1.79
Model group 27.21±1.67## 27.87±1.87## 28.74±1.85## 29.88±1.96## 30.15±1.81##
Medicine A liposome group 27.34±1.57 20.14±1.22* 17.14±1.11** 15.19±1.04** 14.73±1.01**
Medicine B liposome group 27.30±1.56 20.10±1.43* 17.14±1.09** 15.20±1.24** 14.73±1.24**
Medicine C liposome group 27.32±1.62 20.12±1.32* 17.27±1.06** 15.29±1.11** 14.73±1.23**
Medicine A eye drop group 27.22±1.75 20.94±1.30* 17.86±1.32** 15.75±1.12** 14.84±1.10**
Medicine B eye drop group 27.18±1.59 20.92±1.31* 17.24±1.30** 15.72±1.21** 14.82±1.15**
Medicine C eye drop group 27.19±1.54 20.86±1.33* 17.28±1.13** 15.69±1.10** 14.90±1.10**
Medicine A powder pin group 27.20±1.71 21.48±1.29* 17.23±1.12** 15.83±1.12** 14.91±1.09**
Medicine B powder pin group 27.23±1.68 21.64±1.03* 17.74±1.15** 15.81±0.89** 14.87±1.10**
Medicine C powder pin group 27.18±1.55 21.63±1.24* 17.47±1.17** 15.78±0.92** 14.86±1.26**
Medicine A is administered orally group 27.25±1.67 22.85±1.34 18.98±1.25* 18.34±1.20* 16.30±1.25*
Medicine B is administered orally group 27.25±1.67 22.85±1.34 18.98±1.25* 18.34±1.20* 16.30±1.25*
Medicine C is administered orally group 27.25±1.67 22.85±1.34 18.98±1.25* 18.34±1.20* 16.30±1.25*
Eye drip positive drug group 27.28±1.74 23.98±1.25 21.95±1.30* 20.48±1.23* 19.52±1.21*
Oral comparison medicine group 27.23±1.63 24.99±1.41 22.13±1.22* 21.01±1.25* 20.03±1.33*
Compare with matched group##P < 0.01, compares * P < 0.05**P < 0.01 with model group
2 compound A, B, the C protective effect to rabbit open angle glaucoma
2.1 laboratory animals and packet
Healthy regular grade rabbit, male and female half and half, about body weight 2.5kg, examination with slitlamp microscope is without anterior ocular segment pathological changes.Before non-modeling, randomly select experimental rabbit 20, respectively at many point in time measurement rabbit bilateral intraocular pressure record every day.After Continuous Observation one week, to determine this group experimental rabbit normal intraocular tension scope.Modeling 1 Zhou Houhou, by animal pattern random packet: i.e. model group, the Liposomal formulation group of compound (A-C), eye drop group, oral group, normal injection group, positive drug group metipranolol (VUFB-6453) eye drop and oral comparison medicine group timolol.
The foundation of 2.2 animal models
Often group 12 position paracentesis of anterior chamber of 10 rabbit cornea of right eye edge, extract aqueous humor 0.1-0.2 milliliter out.0.3% carbomer and 0.025% dexamethasone 0.1-0.2 milliliter are injected to anterior chamber through puncture orifice, and left eye is comparison eye, and continuous modeling starts administration after one week.
2.3 testing indexs
2.3.1 tonometry
After animal administration, measuring the 1st, 4,7,14,28 days intraocular pressure after being administered with tonometer, measurement result takes the intraocular pressure that the coefficient of variation is 5% record.
2.3.2 Histomorphological
After administration, the 1st, 7,14,28 days four time periods injected 20ml air with auricular vein, put to death often each 2 of rabbit of group, extractd bilateral lagophthalmos immediately, take out crystalline lens and vitreous body.Often group rabbit experimental eye and comparison eye cut as two halves with central authorities for axle sagittal.Two halves wall of eyeball is respectively put in 4% paraformaldehyde and 2.5% glutaraldehyde solution fixing, makes light microscopy specimen.
2.4 statistical analysis
Each group is observed the data obtained and is represented with mean ± standard deviation (x ± s).T inspection is carried out between group.
2.5 experimental results
2.5.1 the medicine impact on glaucoma lagophthalmos pressure
Rabbit modeling one week after (before administration) intraocular pressure raises, namely each medication therapy groups does not have any difference before administration, after administration, intraocular pressure is raised by each medicine group all inhibitory action (P < 0.05 or P < 0.01), wherein the liposome group effect of compound (A-C) is the most obvious, and each administering mode group therapeutic effect of medicine (A-C) is all better than positive drug group (P < 0.05), rapid-action and acting duration is long (see table 2).Illustrating that this medicine can actually substantially reduce intraocular pressure, not only rapid-action but also persistent, than the better efficacy of existing medicine.
The medicine impact (n=8) on glaucoma lagophthalmos pressure respectively organized by table 2
Group It is worth before medicine 1 day 4 days 7 days 14 days 28 days
Model group 36.2±4.3 37.1±5.6 37.2±6.1 32.5±5.4 30.2±7.1 28.1±6.1
Medicine A liposome group 37.1±5.6 21.5±4.9* 15.5±6.8** 14.1±4.2** 13.4±3.2** 12.1±2.9**
Medicine B liposome group 37.0±5.2 21.4±4.8* 15.6±6.0** 14.0±4.0** 13.4±3.6** 12.0±2.7**
Medicine C liposome group 37.0±5.0 20.5±5.0* 15.3±5.8** 13.9±4.4** 13.2±2.2** 11.9±2.3**
Medicine A eye drop group 36.9±5.5 21.2±5.8* 16.7±6.1** 13.3±4.7** 13.4±3.6** 12.3±2.6**
Medicine B eye drop group 37.0±5.0 21.0±5.7* 16.9±5.7** 13.3±4.5** 13.5±4.0** 12.5±3.6**
Medicine C eye drop group 36.9±5.4 21.2±5.3* 17.1±5.5** 13.6±4.3** 13.4±4.6** 12.3±3.4**
Medicine A powder pin group 37.0±6.0 21.2±5.8* 17.1±4.9** 15.2±5.3** 14.4±3.9** 12.7±2.4**
Medicine B powder pin group 36.9±6.0 21.2±5.6* 17.5±4.8** 15.0±5.7** 14.4±4.1** 12.9±5.4**
Medicine C powder pin group 37.0±5.3 21.1±5.8* 17.0±5.0** 15.1±4.1** 14.4±3.6** 12.5±4.7**
Medicine A is administered orally group 37.0±6.1 28.7±6.2 21.7±6.1* 19.5±5.5* 17.2±4.8* 14.5±4.9*
Medicine B is administered orally group 37.1±5.3 28.4±5.8 21.3±6.0* 19.4±5.1* 17.4±4.9* 14.9±4.6*
Medicine C is administered orally group 37.0±5.9 28.2±4.5 21.5±5.2* 19.9±5.0* 17.6±5.8* 14.2±4.3*
Positive drug group 36.7±5.1 29.1±5.9 24.1±5.7* 22.3±5.3* 21.3±4.5* 20.4±4.3*
Oral comparison medicine group 36.9±4.9 31.2±5.7 25.2±5.9* 23.4±5.0* 21.1±4.3* 20.7±4.6*
* P < 0.05**P < 0.01 is compared with model group
2.5.2 light microscopic result
Result shows: normal lagophthalmos (comparison eye) undertissue's layer is the fibrous layer of gland sample layer and deep layer, and the layer 2-4 columnar epithelium that conjunctival epithelium layer is thin is constituted, and has thinner blood vessel in conjunctiva；Sclera is fibrous connective tissue；Angle of anterior chamber is managed without Schlemm；There is one layer of nonpigmented epithelial cells on corpus ciliare surface, and pigment epithelium cell layer is presented herein below, and rich in blood vessel in ciliary processes, orbiculus ciliaris only has one layer of ciliary muscle.Mitochondrion and microfilament are visible, and endochylema enriches.Model group lagophthalmos chemosis, inflammatory cell infiltration；Corneal stromal edema, inflammatory cell infiltration, angle, room is inaccessible.Interstitial edema around blood vessel.Cornea periphery blood vessel slits and is formed, and part-blood pipe range enters corneal stroma；Ciliary processes non-pigment epithelial layer is stack, and surface forms connective tissue；Eyeball is expanded, and scleral walls is thinning.Medicine (A-C) treatment group chemosis, inflammatory cell infiltration alleviate, and effect is better than comparison medicine.Experimental result explanation; medicine (A-C) all can improve the pathological change of rabbit open angle glaucoma; this animal model had protective effect; and the better effects if of the liposome ophthalmic preparation of compound (A-C); corneal edema can be made to alleviate; part corneal epithelial cell is thinning, descemet's membrane gauffer；Visible mild inflammatory cell infiltration around the sclera broken ends of fractured bone；The corpus ciliare broken ends of fractured bone is a small amount of pigment granule as seen.Eyeball is without obvious expansion, and the change of scleral walls thickness is inconspicuous.Experimental result illustrates, medicine group (A-C) all can improve the pathological change of rabbit open angle glaucoma, and medicine (A-C) is better than the clinical medicine applied at present, and the better effects if of the liposome ophthalmic preparation of compound (A-C).
3 compounds (A-C) or its officinal salt durative action preparation protective effect to rat angle closure glaucoma
3.1 laboratory animals and packet
Experiment adopts Thirty male rats, body weight 200g-250g.Before modeling, by animal random packet: i.e. blank group, model group, the oral medicine group of compound (A-C), positive drug group pilocarpine eye drop and oral positive control drug group dorzolamide.All medicines are Isosorbide-5-Nitrae after modeling all, administration in 7,10 days, positive drug pilocarpine eye drop group eye drop administration, and oral comparison medicine dorzolamide is taked to be administered orally.
The foundation of 3.2 animal models
Rat is lumbar injection 4% chloral hydrate (200mg.kg-1), then 1% lignocaine local anesthesia cornea of rats before experiment.High intraocular pressure (IOP) period, every half an hour lumbar injection 4% chloral hydrate 0.1-0.2 milliliter maintain the animal on narcotism.Adopting pulley-suture system to make rat right eye intraocular pressure (IOP) raise, left side eyeball compares.Be respectively that an identical weight is dispelled code by 70 centimetres of surgical sutures two ends, in the middle of suture be a circle for 2 millimeters after rat canthus limbus of sclera, rat eye is pressed continually and steadily by the code of dispelling at two ends by one group of pulley respectively.Counterweight pressure is 15 grams, and continuous 6 hours then causes rat angle-closure glaucoma eye model.Raise and put to death to the 14th day, observe and look each layer thickness change of nipple peripheral retinal tear.
3.3 experimental results
Model group is compared with Normal group, retina full thickness, internal layer thickness all thinning (P < 0.01), display modeling success, medicine group (A-C) compares with model group, medicine group can be obviously improved by the thinning retina holostrome caused of retinochrome thinning, its Chinese medicine group (A-C) effect is better than positive drug group, refers to table 3.The blood supply of retinochrome relies on Zinn's artery; cellular metabolism is vigorous; this makes the cell in this region compare with ectoretina and is more susceptible to damage; and the medicine of medicine (A-C) each group can be obviously improved its pathological change; so angle closure glaucoma can be played extraordinary protective effect and therapeutical effect effect all relatively positive drug group good (P < 0.05) by medicine (A-C).
The impact on angle closure glaucoma rat retina of table 3 medicine
Group Full thickness (μm) Internal layer thickness (μm)
Normal group 214.1±1.3 90.2±0.6
Model group 167.8±3.6### 63.2±1.7###
Medicine A group 207.4±2.6** 85.4±1.2**
Medicine B group 204.5±2.2** 83.6±1.3**
Medicine C group 201.9±4.6* 80.3±1.3*
Positive drug group 185.8±3.7* 74.8±1.5*
Oral comparison medicine group 181.3±3.3* 73.9±1.4*
Compare with matched group###P < 0.001, compares * P < 0.05**P < 0.01 with model group
Summary experimental result concludes that compound (A), (B), (C) medicine prepared all can substantially reduce intraocular pressure preventing and treating glaucoma, alleviate the symptom of the derivative ocular disease of glaucoma, playing good therapeutical effect, its therapeutic effect is significantly better than the relatively good medicine of current clinical effectiveness.

Claims (6)

1. one group of compound or pharmaceutically acceptable salt thereof prevents and treats the purposes in glaucoma in preparation.
2. the purposes of claim 1, described compound and officinal salt thereof can reduce intraocular pressure, alleviate glaucoma related symptoms.
3. the purposes of claim 1, it is characterised in that described compound is that 5-is chloro-N 2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N 4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino, structure is:
。
4. the purposes any one of claim 1-3, it is characterised in that compound or pharmaceutically acceptable salt thereof is prepared into the various preparations through dosing eyes, gastrointestinal administration or parenteral administration, including ordinary preparation, controlled release preparation, targeting preparation etc..
5. the purposes of claim 4, described dosing eyes preparation is eye drop, injectable powder, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, aqueogel etc..
6. the purposes of claim 5, described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule, Emulsion etc..
CN201610199374.XA 2012-09-10 2012-09-10 Application of compound to preparation of drug for preventing and treating glaucoma Pending CN105796562A (en)

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CN1390220A (en) * 1999-09-17 2003-01-08 艾博特股份有限两合公司 Kinase inhibitors as therapeutic agents
CN101370792A (en) * 2005-11-01 2009-02-18 塔格根公司 Bi-aryl meta-pyrimidine inhibitors of kinases
CN101687822A (en) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 Di(arylamino)aryl compound
CN102348708A (en) * 2009-03-11 2012-02-08 奥克兰联合服务有限公司 Prodrug forms of kinase inhibitors and their use in therapy

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US9539259B2 (en) * 2012-05-23 2017-01-10 The Johns Hopkins University Compounds and methods of use thereof for treating neurodegenerative disorders

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Publication number Priority date Publication date Assignee Title
CN1390220A (en) * 1999-09-17 2003-01-08 艾博特股份有限两合公司 Kinase inhibitors as therapeutic agents
CN101370792A (en) * 2005-11-01 2009-02-18 塔格根公司 Bi-aryl meta-pyrimidine inhibitors of kinases
CN101687822A (en) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 Di(arylamino)aryl compound
CN102348708A (en) * 2009-03-11 2012-02-08 奥克兰联合服务有限公司 Prodrug forms of kinase inhibitors and their use in therapy

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