CN103655566B - Compound purposes in the medicine of preparation preventing and treating glaucoma - Google Patents
Compound purposes in the medicine of preparation preventing and treating glaucoma Download PDFInfo
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- CN103655566B CN103655566B CN201210331056.6A CN201210331056A CN103655566B CN 103655566 B CN103655566 B CN 103655566B CN 201210331056 A CN201210331056 A CN 201210331056A CN 103655566 B CN103655566 B CN 103655566B
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Classifications
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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 three kinds of compounds and similar compound thereof or the new application of its officinal salt, described new application is the purposes in preparation reduces the medicine of intraocular pressure preventing and treating glaucoma.Above-claimed cpd reduces intraocular pressure preventing and treating glaucoma can reach to act on the effect of highly significant.
Description
Technical field
The present invention relates to three kinds of purposes of medicine reducing intraocular pressures preventing and treating glaucomas, be specifically related to 4-[2-(1H-indole-
3-yl) vinyl] phenyl-peiperazinyl-ketone and similar compound thereof or its officinal salt, N-[3-fluoro-4-[[6-methoxy
Base-7-[3-(4-morpholinyl) propyl group epoxide] quinolyl-4] epoxide] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformazan
Amide and similar compound thereof or its officinal salt, the chloro-N of 5-2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidines-
1-yl] phenyl]-N4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino and similar compound thereof or its can
Pharmaceutical salts purposes in preparation reduces the medicine of intraocular pressure preventing and treating glaucoma disease.
Background technology
Glaucoma is a class the biggest Eye disease of harm, is divided into primary glaucoma, secondary glaucoma, congenital
Glaucoma, wherein primary glaucoma is divided into again primary angle closure glaucoma and primary open angle glaucoma, no matter which kind of type
Glaucoma sufferer, the main performance of patient is intraocular pressure (IOP) and increases.Glaucoma may result in irreversibility visual deprivation,
There are about at present 1,400,000,000 glaucoma patients in the world, but the people of about half does not recognize this disease.World health
Tissue is classified as great diseases causing blindness, at the sickness rate about 0.12%-1.64% of China's glaucoma, accounts for ophthalmic diseases
14.36%.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, the aqueous humor of 98% by angle of anterior chamber through trabecular reticulum,
Schlemm's canal and corpus ciliare and choroidal vascular system are discharged.If angle of anterior chamber is inaccessible, aqueous humor flows out and is obstructed, and can cause aqueous humor
Accumulation causes intraocular pressure (IOP) to increase.Normal eye is intrinsic pressure generally between 11 to 21mmHg, and the intraocular pressure of rising can be direct
Reduce blood flow, make nethike embrane and eyeball structure change, ultimately result in the forfeiture of vision.
Reducing intraocular pressure is the more effective approach of the most clinical unique confirmation.Treatment can pass through two kinds of approach: medicine and
Operation.Clinical setting is at present: operation is cured the symptoms, not the disease, painful great Yi recurrence, and Drug therapy damage is little, but therapeutic effect
Not good enough.
The Drug therapy of glaucoma has following several method at present, and not only therapeutic effect is the best enough but also but all exist bad
Reaction: conventional medicine has beta-blockers, receptor stimulating agent, prostaglandin analogue, mannitol, glycerol and Chinese medicine etc., whole
Physical exercise therapy 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 the most such as
People's will, either which class medicine, the most all cannot produce preferable therapeutic effect, causes the green grass or young crops of the most various pathogenic factors at present
Light oculopathy is suffered from more and more, and morbidity is more and more heavier, the vision of serious threat sufferer.A kind of novel effective Drug therapy of exploitation
Glaucoma is particularly important to sufferer.
Present inventors have surprisingly found that 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone and class thereof
Like compound or pharmaceutically acceptable salt thereof, N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group epoxide] quinolyl-4]
Epoxide] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide and similar compound thereof or its officinal salt, 5-are chloro-
N2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N4-[2-[(1-Methylethyl) sulfonyl]
Phenyl]-pyrimidine-2,4-diamino and similar compound thereof or its officinal salt reduce the medicine of intraocular pressure preventing and treating glaucoma disease in preparation
Novel purposes in thing.The another name of three kinds of series compounds is respectively as follows: KW2449, XL880 and TAE684, is discovered in recent years
Some antitumor drug, reduce 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 chemical combination thereof
Thing or its officinal salt new application in the medicine reducing intraocular pressure preventing and treating glaucoma, N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-
(4-morpholinyl) propyl group epoxide] quinolyl-4] epoxide] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide and
Similar compound or its officinal salt new application in the medicine reducing intraocular pressure preventing and treating glaucoma, the chloro-N of 5-2-[2-methoxyl group-
4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-N4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,
4-diamino and similar compound thereof or its officinal salt new application in the medicine reducing intraocular pressure preventing and treating glaucoma.
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):
Described compound is N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group epoxide] quinolyl-4] oxygen
Base] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide.Structure is (B):
Described compound is the chloro-N of 5-2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-
N4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino.Structure is (C):
By these compounds and the like or or its officinal salt be prepared as through dosing eyes, gastrointestinal administration or
The various preparations of parenteral administration, are carried out for glaucoma animal model including ordinary preparation, controlled release preparation, targeting preparation etc.
Treatment.
Glaucoma is divided into primary glaucoma, secondary glaucoma, congenital glaucoma, and wherein primary glaucoma divides again
For primary angle closure glaucoma and primary open angle glaucoma, no matter which type of glaucoma sufferer, the main performance of patient
It is intraocular pressure (IOP) to increase.Effectively by ocular hypotension, slow down to play, control secondary disease and be particularly important, prepare intraocular pressure
High animal model, is administered compound (A-C), obtains beyond thought miraculous effects, and intraocular pressure reduces, and glaucoma symptom obtains
To alleviating, the therapeutic effect of compound (A-C) is much stronger than the most clinical positive drug.
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 also
It is not intended to 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):
Described compound B is N-[the fluoro-4-of 3-[[6-methoxyl group-7-[3-(4-morpholinyl) propyl group epoxide] quinolyl-4]
Epoxide] phenyl]-N '-(4-fluorophenyl)-1,1-cyclopropyl diformamide.Structure is (B):
Described compound C is the chloro-N of 5-2-[2-methoxyl group-4-[4-(4-methylpiperazine-1-yl) piperidin-1-yl] phenyl]-
N4-[2-[(1-Methylethyl) sulfonyl] phenyl]-pyrimidine-2,4-diamino.Structure is (C):
1 compound (A-C) and similar compound or its officinal salt thereof are to corticosteroid hormone glaucoma rat
Protective effect
1.1 laboratory animals and packet
Healthy adult Wistar rat, body weight 200-250 gram, without any ocular disease.Raise environment in temperature 25 DEG C ± 1
DEG C, relative humidity 70%, specialty the personnel of raising raise.Animal eye is measured with tonometer intrinsic pressure, continuous observation record eye before modeling
Press 1 week, estimate that normal intraocular tension is interval, reject intraocular pressure and be only used as normal control higher or lower than normal intraocular tension interval person, taking-up 10
Group, other animals start modeling, after modeling 1 week, by animal pattern random packet: i.e. model group, the liposome of compound (A-C)
Preparation group, collyrium group, common powder injection formulation group and oral gastro-intestinal administration group, positive drug group latanoprost eye drops and mouth
Clothes comparison medicine group timolol.All animals continue modeling, start to be administered, the Liposomal formulation group of compound (A-C) after packet
Carrying out ophthalmic direct injection, compound (A-C) collyrium group eye drop administration, compound (A-C) normal injection group uses
Intravenously administrable, oral drugs group oral administration, the positive puts drops in one's eyes employing eye drop administration, and oral comparison medicine medicine is taked to be administered orally, just
Often matched group does not processes.
The foundation of 1.2 animal models
Healthy adult Wistar rat experiment group with 10% chloral hydrate with 0.375ml.100g-1 row intraperitoneal anesthesia after,
With timing next day of the syringe of 1 milliliter at right eye sub-conjunctival injection dexamethasone 0.25mg (0.05ml), left eye is comparison eye,
Count 14 times, totally 28 days.
1.3 tonometry
Every time before sub-conjunctival injection modeling medicine, rat opening eyelid, tonometer measures intraocular pressure, and measurement result takes Variation Lines
Number is the intraocular pressure of 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, all the time at about 14-15mmHg, has no significant change, compares with Normal group,
After model group rats modeling, 1 week (before administration) intraocular pressure afterwards starts to raise, and gradually rises along with continuing modeling time lengthening
(P ＜ 0.05), 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) rapid-action and acting duration is long (being shown in Table 1).Illustrate medicine (A-C) can have substantially reduce intraocular pressure effect and
And persistent.
Table 1 corticosteroid hormone glaucoma rat intraocular pressure result (mmHg, n=10)
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 sick without anterior ocular segment
Become.Before non-modeling, randomly select experimental rabbit 20, respectively at many point in time measurement rabbit bilateral intraocular pressure record every day.See continuously
After examining 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 (three
First cordialina) 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 is injected to anterior chamber through puncture orifice, and left eye is comparison eye, and continuous modeling started after one week
It is administered.
2.3 testing index
2.3.1 tonometry
After animal is administered, measuring the 1st, 4,7,14,28 days intraocular pressure after being administered with tonometer, measurement result takes the coefficient of variation
It is the intraocular pressure of 5%, and 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,
Extract bilateral lagophthalmos immediately, take out crystalline lens and vitreous body.Often group rabbit experimental eye and comparison eye cut with central authorities for axle sagittal and are
Two halves.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 result
2.5.1 the medicine impact on glaucoma lagophthalmos pressure
Rabbit modeling one week after (before administration) intraocular pressure raises, i.e. each medication therapy groups does not has any difference before administration, gives
After medicine, intraocular pressure is raised by each medicine group all inhibitory action (P ＜ 0.05 or P ＜ 0.01), the wherein fat of compound (A-C)
Plastid group effect 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 (being shown in Table 2).Illustrate that this medicine can actually substantially reduce intraocular pressure, no
But rapid-action and persistent, than the better efficacy of existing medicine.
The medicine impact (n=8) on glaucoma lagophthalmos pressure respectively organized by table 2
* 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 gland sample layer and the fibrous layer of deep layer, and conjunctival epithelium layer is
Thin layer 2-4 columnar epithelium is constituted, and has thinner blood vessel in conjunctiva；Sclera is fibrous connective tissue；Angle of anterior chamber is without Schlemm
Pipe；There is one layer of nonpigmented epithelial cells on corpus ciliare surface, and pigment epithelium cell layer is presented herein below, rich in blood vessel, ciliary in ciliary processes
Body par only has one layer of ciliary muscle.Mitochondrion and microfilament are visible, and endochylema enriches.Model group lagophthalmos chemosis, inflammation is thin
Born of the same parents infiltrate；Corneal stromal edema, inflammatory cell infiltration, angle, room is inaccessible.Interstitial edema around blood vessel.Cornea periphery blood vessel slits shape
Becoming, part-blood pipe range enters corneal stroma；Ciliary processes non-pigment epithelial layer is stack, and surface forms connective tissue；Eyeball is expanded,
Scleral walls is thinning.Medicine (A-C) treatment group chemosis, inflammatory cell infiltration alleviate, and effect is better than comparison medicine.Experimental result
Illustrating, medicine (A-C) all can improve the pathological change of rabbit open angle glaucoma, this animal model is had protective effect, and changes
The effect of the liposome ophthalmic preparation of compound (A-C) is more preferable, and corneal edema can be made to alleviate, and part corneal epithelial cell is thinning, after
Elastic layer gauffer；Visible mild inflammatory cell infiltration around the sclera broken ends of fractured bone；A small amount of pigment granule seen from the corpus ciliare broken ends of fractured bone.Eyeball without
Substantially expansion, the change of scleral walls thickness is inconspicuous.Experimental result illustrates, medicine group (A-C) all can improve rabbit open angle glaucoma
Pathological change, medicine (A-C) is better than the clinical medicine applied at present, and the liposome ophthalmic preparation of compound (A-C)
Effect is more preferable.
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 uses Thirty male rats, body weight 200g-250g.Before modeling, by animal random packet: i.e. blank
Matched group, model group, the oral medicine group of compound (A-C), positive drug group pilocarpine eye drop and oral positive control
Medicine group dorzolamide.All medicines all Isosorbide-5-Nitraes after modeling, are administered for 7,10 days, and positive drug pilocarpine eye drop group eye drip is given
Medicine, 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) before experiment, and then 1% lignocaine local anesthesia is big
Mus cornea.High intraocular pressure (IOP) period, every half an hour lumbar injection 4% chloral hydrate 0.1-0.2 milliliter maintain the animal on fiber crops
Liquor-saturated state.Using pulley-suture system to make rat right eye intraocular pressure (IOP) raise, left side eyeball compares.By 70 centimetres of surgeries
Suture two ends are respectively that an identical weight is dispelled code, in the middle of suture be a circle for 2 millimeters after rat canthus limbus of sclera, two ends
Code of dispelling by respectively one group of pulley pressure continual and steady to rat eye.Counterweight pressure is 15 grams, continuous 6 hours, then
Cause rat angle-closure glaucoma eye model.Raise and put to death to the 14th day, observe and regard the change of nipple peripheral retinal tear each layer thickness.
3.3 experimental result
Model group is compared with Normal group, and retina full thickness, internal layer thickness the most thinning (P ＜ 0.01), display is made
Mould success, medicine group (A-C) compares with model group, and medicine group can be obviously improved by the thinning retina caused of retinochrome complete
Layer is thinning, and its Chinese medicine group (A-C) effect is better than positive drug group, refers to table 3.The blood supply of retinochrome relies on retinal centre
Tremulous pulse, cellular metabolism is vigorous, and this makes the cell in this region compare more susceptible to damage with ectoretina, and medicine (A-C)
The medicine of each group can be obviously improved its pathological change, so angle closure glaucoma can be played extraordinary by medicine (A-C)
Protective effect, and therapeutical effect effect all good compared with positive drug group (P ＜ 0.05).
The impact on angle closure glaucoma rat retina of table 3 medicine
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), and medicine prepared by (C) all can substantially reduce eye
Pressure preventing and treating glaucoma, alleviates glaucoma and derives the symptom of ocular disease, play preferable therapeutical effect, and its therapeutic effect is the best
In the relatively good medicine of current clinical effectiveness.
Claims (9)
1. the compound or pharmaceutically acceptable salt thereof purposes in preparation reduces the medicine of intraocular pressure, it is characterised in that described compound
For 4-[2-(1H-indol-3-yl) vinyl] phenyl-peiperazinyl-ketone, structure is:
。
2. the purposes in the medicine of preparation treatment glaucoma of the compound or pharmaceutically acceptable salt thereof described in claim 1.
3. the purposes described in claims 1 or 2, it is characterised in that be prepared as commonly making by described compound or pharmaceutically acceptable salt thereof
Agent, controlled release preparation or targeting preparation.
4. the purposes described in claim 3, it is characterised in that the route of administration of described preparation is gastrointestinal administration or parenteral route
It is administered.
5. the purposes of claim 4, the described dosing eyes preparation in parenteral administration mode be eye drop, injectable powder,
Aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation or aqueogel.
6. the purposes of claim 5, described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule or breast
Agent.
7. the purposes described in claim 2, it is characterised in that described glaucoma is primary glaucoma, secondary glaucoma or elder generation
Nature glaucoma.
8. the purposes described in claim 7, it is characterised in that described primary glaucoma is primary angle closure glaucoma or primary
Open angle glaucoma.
9. the purposes described in claim 2,7 or 8, it is characterised in that described compound or pharmaceutically acceptable salt thereof is used for reducing eye
Pressure.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210331056.6A CN103655566B (en) | 2012-09-10 | 2012-09-10 | Compound purposes in the medicine of preparation preventing and treating glaucoma |
| CN201610199374.XA CN105796562A (en) | 2012-09-10 | 2012-09-10 | Application of compound to preparation of drug for preventing and treating glaucoma |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210331056.6A CN103655566B (en) | 2012-09-10 | 2012-09-10 | Compound purposes in the medicine of preparation preventing and treating glaucoma |
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| CN201610199374.XA Division CN105796562A (en) | 2012-09-10 | 2012-09-10 | Application of compound to preparation of drug for preventing and treating glaucoma |
| CN201610199370.1A Division CN105796569A (en) | 2012-09-10 | 2012-09-10 | Application of compound to preparation of drug for preventing and treating glaucoma |
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| CN103655566A CN103655566A (en) | 2014-03-26 |
| CN103655566B true CN103655566B (en) | 2016-12-21 |
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| CN201610199374.XA Pending CN105796562A (en) | 2012-09-10 | 2012-09-10 | Application of compound to preparation of drug for preventing and treating glaucoma |
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| WO2013177367A2 (en) * | 2012-05-23 | 2013-11-28 | The Johns Hopkins University | Compounds and methods of use thereof for treating neurodegenerative disorders |
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| UA99899C2 (en) * | 2005-11-01 | 2012-10-25 | Таргеджен, Инк. | Bi-aryl meta-pyrimidine inhibitors of kinases |
| TWI389893B (en) * | 2007-07-06 | 2013-03-21 | Astellas Pharma Inc | Di (arylamino) ary1 compound |
| EP2406262B1 (en) * | 2009-03-11 | 2016-02-17 | Auckland UniServices Limited | Prodrug forms of kinase inhibitors and their use in therapy |
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| WO2013177367A2 (en) * | 2012-05-23 | 2013-11-28 | The Johns Hopkins University | Compounds and methods of use thereof for treating neurodegenerative disorders |
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| HDAC INHIBITORS POTENTIATE THE ACTIVITY OF THE BCR/ABL KINASE INHIBITOR KW-2449 IN IMATINIB-SENSITIVE OR RESISTANT BCR/ABL+ LEUKEMIA CELLS IN VITRO AND IN VIVO;Tri Nguyen et al.;《Clin Cancer Res.》;20110515;第17卷(第10期);3219–3232 * |
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| CN105796562A (en) | 2016-07-27 |
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