CN103664737A - Compounds for treating narrow chamber angle and application thereof - Google Patents
Compounds for treating narrow chamber angle and application thereof Download PDFInfo
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- CN103664737A CN103664737A CN201210371792.4A CN201210371792A CN103664737A CN 103664737 A CN103664737 A CN 103664737A CN 201210371792 A CN201210371792 A CN 201210371792A CN 103664737 A CN103664737 A CN 103664737A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses compounds, and a pharmaceutical composition and new application thereof in preparing medicines for treating narrow chamber angle. The compounds for treating narrow chamber angle can have very obvious effect.
Description
Technical field
The present invention relates to three kinds and treat compound and pharmacologically acceptable salt and its analogue that angle, room is narrow, the pharmaceutical composition of being prepared by above-claimed cpd and pharmacologically acceptable salt thereof and its analogue, and described compound or pharmaceutically acceptable salt thereof and analogue thereof the purposes in the narrow medicine in preparation treatment angle, room.
Background technology
The sickness rate that angle, room is narrow surpasses 1% in China; and produce agnogenio; likely genetic; also be likely insecondary, majority directly translates into the associated conditions such as angle, room is narrow, angle, room is blocked, angle, acute room is closed, angle, chronic room is closed, and clinical manifestation in early stage is " room Jiao Guan likely occurs to close one's eyes "; often can cause ophthalmodynia; headache, nauseating, vomiting, visual deterioration etc.
If angle, room narrow or close do not carry out in time and suitably treatment, once peripheral iris has been stopped up angle, room, aqueous humor exhaust channel is obstructed for a long time, aqueous humor is discharged and is further obstructed, and then cause intraocular part pressure to continue to raise, and cause that wall of eyeball pressure is large, continue to cause primary angle-closure glaucoma, then periphery iris and trabecular meshwork produce permanent adhesion, enter chronic progressive stage then or cause blind.Can say that the harm that angle, room is narrow is very large.
Narrow for angle, room or close at present, Direct Surgery is carried out in clinical unique confirmation comparatively effectively approach exactly, is mainly to do peripheral iridectomy, Laser peripheral iridotomy or eye external drainage art, does like this and has for good and all destroyed angle, room, and the later stage is easily sent out again, sufferer is painful large.For angle, temporary treatment room way narrow or that close, be to drip with miotic clinically, commonly use and have pilocarpine, accompany to use simultaneously and suppress the medicine that aqueous humor produces, this measure effect is very limited, result for the treatment of does not often catch up with disease progression, even if controlled intraocular pressure, cures the symptoms, not the disease yet, angle, room cannot be solved narrow or close, effectively treatment can not be carried out thoroughly.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof the purposes in the medicine of the narrow disease in preparation treatment angle, room.This group compound and similar compound thereof or its pharmacologically acceptable salt can make narrow angle, room angle of release become large, or the angle, room of closing reopens, and avoids goniosynechia, makes room contend gradually restore funcitons, aqueous humor are discharged smooth, thereby reduce intraocular pressure.This group medicine has fundamentally been treated narrow or angle, room, angle, room and has been closed the significant damage of bringing.Or room angle narrow for this angle, group compounds for treating room closed and be there is no report at present.
Summary of the invention
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat the narrow disease in angle, room, and analogue, the structure of described compound is as follows:
Compound (C);
The present invention also provides a kind of pharmaceutical composition, and it comprises compound (A), (B), (C); Said composition can also comprise auxiliary material etc.Described pharmaceutical composition can be through topical, and the various preparations of gastrointestinal administration or parenteral administration, comprise ordinary preparation, controlled release preparation, targeting preparation etc.Described controlled release preparation comprises superpolymer or film material, described superpolymer is selected from: one or more in polylactic-co-glycolic acid, poly-acid anhydrides, polyoxyalkylene, polymeric amide, polyester, polyacrylic resin, polyethers, polyphosphonitrile or glycan, or be selected from the multipolymer between the different monomers of described superpolymer, preferably, described superpolymer is selected from: poly lactic coglycolic acid, lactic-co-glycolic acid-glycol copolymer, PGA, glycollide rac-Lactide-ethylene glycol-glycollide rac-Lactide triblock copolymer, polyoxyethylene glycol, sebacic anhydride-glycol copolymer, octadecane diacid acid anhydride-ethylene glycol segmented copolymer, poly butyric ester, polybutylcyanoacrylate, poly(lactic acid), polymaleic anhydride, poly sebacic polyanhydride, polyvinyl alcohol, NIPA-acrylic copolymer, chitosan, polyethersulfone, Mierocrystalline cellulose, dextran, alginates, dextran, hyaluronic acid, gelatin, poloxamer, Fibrinogen, one or more in albumin or collagen protein etc.Described film material comprises that Yelkin TTS, fabaceous lecithin, phosphatidylethanolamine, cholesterol, kephalin, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, Glycocholate sodium, Yolk lecithin, phosphatidyl silk amino acid, phosphatidylinositols, sphingomyelin, sphingomyelin, two Cetyl Phosphates, two Pork and beans acyl Yelkin TTS, stearylamide, phosphatidic acid, phosphatidylserine etc. comprise natural or synthetic phosphatide, lipoid or its combination.
The present invention also provides compound (A), (B), (C), or its pharmacologically acceptable salt and the purposes of analogue in the medicine of the narrow disease in preparation treatment angle, room thereof.Described purposes comprises compound (A), (B), (C) or its pharmacologically acceptable salt and analogue thereof is prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration, comprise that ordinary preparation, controlled release preparation, targeting preparation etc. treat for the narrow animal model in angle, room.Described local administration preparation is the powder injection through dosing eyes, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, aqueogel etc.; Described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule, emulsion etc.; Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, intracardiac injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.The dosage of described medicine is 0.1mg-500mg.
At the international level, angle, room is narrow mainly with Aisa people, fall ill more, yellow is more common, especially China, angle, women room is more narrower, so sickness rate is higher compared with the male sex, at present scientific circles for angle, room the narrow or reason of closing also do not study clear, it is likely genetic analyzing, also be likely insecondary, above morbidity in 40 years old is more, it is narrow that majority directly translates into angle, room, angle, room is blocked, angle, acute room is closed, the associated conditions such as is closed in angle, chronic room, clinical manifestation in early stage is " room Jiao Guan likely occurs to close one's eyes ", patient Chang Hui feels ophthalmodynia, headache, feel sick, vomiting, visual deterioration etc.If angle, room is narrow or do not close and suitably treat, once peripheral iris has been stopped up angle, room, aqueous humor exhaust channel is obstructed for a long time, aqueous humor is discharged and is further obstructed, and then cause intraocular part pressure to continue to raise, and cause that wall of eyeball pressure is large, continue to cause primary angle-closure glaucoma, then periphery iris and trabecular meshwork produce permanent adhesion, enter chronic progressive stage then or cause blind.Can say that the harm that angle, room is narrow is very large.Narrow for angle, room or close at present, Direct Surgery is carried out in clinical unique confirmation comparatively effectively approach exactly, is mainly to do peripheral iridectomy, Laser peripheral iridotomy or eye external drainage art, does like this and has for good and all destroyed angle, room, and the later stage is easily sent out again, sufferer is painful large.For angle, temporary treatment room way narrow or that close, be to drip with miotic clinically, commonly use and have pilocarpine, accompany to use simultaneously and suppress the medicine that aqueous humor produces, this measure effect is very limited, result for the treatment of does not often catch up with disease progression, even if controlled intraocular pressure, cures the symptoms, not the disease yet, angle, room cannot be solved narrow or close, effectively treatment can not be carried out thoroughly.The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof the purposes in the medicine of the narrow disease in preparation treatment angle, room.This group compound and similar compound thereof or its pharmacologically acceptable salt can make narrow angle, room angle of release become large, or the angle, room of closing reopens, and avoids goniosynechia, makes room contend gradually restore funcitons, aqueous humor are discharged smooth, thereby reduce intraocular pressure.This group medicine has fundamentally been treated narrow or angle, room, angle, room and has been closed the significant damage of bringing.Or room angle narrow for this angle, group compounds for treating room closed and be there is no report at present.The onset and there is long-term treatment purposes rapidly of this group medicine.Contriver finds pleasantly surprisedly, and all there is again opening in various degree at angle, the room narrow or animal of closing, angle, all rooms after medication, and recovers angle, room function, can make aqueous humor discharge, and has extraordinary result for the treatment of.
Embodiment
The present invention's compound used can be purchased, and also can be prepared according to relevant disclosed preparation method, and it does not limit the scope of the invention.Below in conjunction with embodiment, the present invention is further explained.
Effect embodiment
Described compd A structure is:
Described compd B structure is:
Described Compound C structure is:
Compound (C);
Preparation containing compd A lyophilized injectable powder:
1. altogether 100mg and 400mg formula (A) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd B lyophilized injectable powder:
1. altogether 100mg and 400mg formula (B) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.Preparation containing Compound C lyophilized injectable powder:
1. altogether 100mg and 400mg formula (C) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
The effect that open at the angle, room that 1 compd A, B, C and similar compound thereof or its pharmacologically acceptable salt make angle, room block rat
1.1 laboratory animal and grouping
Healthy adult Wistar rat, body weight 200-250 gram, without any eye disease.Raise environment 25 ℃ ± 1 ℃ of temperature, relative humidity 70%, specialty the personnel of raising raise.Before modeling, with tonometer, measure animal intraocular pressure, continue observed and recorded intraocular pressure 1 week, estimate that normal intraocular tension is interval, reject intraocular pressure higher or lower than normal intraocular tension interval person, take out 10 as Normal group, other animals start modeling, after modeling 1 week, by animal pattern random packet: i.e. model group, the medication group of compd A, B, C, positive drug group latanoprost eye drop and positive oral contrast medicine group timolol.All animals continue modeling, start administration after grouping, and the medication group of compd A, B, C adopts intraocular injection administration, positive oral pharmaceutical group oral administration, and the positive is put drops in one's eyes and is adopted eye drip administration, and Normal group does not process.
The foundation of 1.2 animal models
Healthy adult Wistar, in rat anterior chamber, divide four times totally 28 days, injection diameter is the mixed solution of pipe/polyhenylethylene nano grain, hyaluronic acid and the carboxymethyl cellulose of 10 microns, blocks behind trabecular network and angle, room, thereby it is obstructed that aqueous humor is discharged, cause intraocular pressure (IOP) to raise.
1.3 tonometry
Rat is opened to eyelid, and tonometer is measured intraocular pressure, measuring result record.All rat tonometries are completed by same people.
1.4 Histomorphological
Within after administration the 28th day, put to death each 5 of every group of mouse, extract immediately bilateral rathole, take out lens and vitreum.It is two halves that every group of mouse experimental eye and contrast eye take that central authorities cut as axle sagittal.Two halves wall of eyeball is put into respectively to 4% paraformaldehyde and 2.5% glutaraldehyde solution fixing, make light microscopy specimen tissues observed form.
1.5 statistical analysis
Ge Zu rat observation post total according to this mean ± standard deviation (x ± s) represents, carries out t check between group.
1.6 angle, rooms block rat experiment result
Normal group average intraocular pressure is all the time in 15mmHg left and right, have no considerable change, with Normal group comparison, after the modeling of model group rat, intraocular pressure starts to raise, visible is to cause that because Fang Jiaochu gets clogged intraocular pressure raises, and along with continuing modeling time lengthening, raise gradually (P < 0.05), medicine A, B, each medicine group of C all flows out aqueous humor to opening up Kai Fangjiao, and then the rising of inhibition intraocular pressure has effect, 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).Visible compd A, B, C, for opening up Kai Fangjiao, are further opened angle, room, and recovery angle, room function makes aqueous humor discharge rapid-action and acting duration is long (in Table 1).
Rat tonometry result (mmHg, n=10) is blocked at angle, table 1 room
With control group comparison
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
1.7 histological observation results
Result shows: normal rathole (contrast eye) undertissue's layer is the layer of fibers of gland sample layer and deep layer, and conjunctival epithelium layer is that thin cylindrical epithelium forms, and has thinner blood vessel in conjunctiva; Sclera is fibrillar connective tissue; There is one deck non-pigment epithelial cell on ciliary body surface, is pigment epithelial cell layer below, is rich in blood vessel in ciliary process, and orbiculus ciliaris only has one deck ciliary muscle.Plastosome and microfilament are visible, and endochylema is abundant, and normally open at angle, room.Model group conjunctive bulbi oedema, inflammatory cell infiltration; Corneal stromal edema, inflammatory cell infiltration, angle, room is inaccessible, wherein gets clogged, some openings very narrow.Blood vessel is interstitial edema around.Cornea periphery blood vessel slits and forms, and part-blood pipe range enters corneal stroma; Ciliary process non-pigment epithelial lining is heap shape, and surface forms reticular tissue; Eyeball expansion, scleral walls attenuation.Medicine A, B, C treatment group chemosis state and inflammatory cell infiltration alleviate, effect is better than positive control drug, and open at angle, visible room, have no very narrow angle, room, angle, room opened condition is obviously better than model group and positive drug control group, eyeball is without obvious expansion, and scleral walls variation in thickness is not obvious.The histological examination showed inflammatory cell of the animal model of positive drug control group is invaded profit degree will show curative effect lower than model group, but still angle, visible room gets clogged, and has no angle, room and opens, and also has no the experimental result that angle, room opening degree is better than model group.Totally it seems, medicine A, B, C all can improve that angle, room is closed, obstruction or narrow pathological change, and can recover angle, room function, impel angle, room to discharge aqueous humor and reduce intraocular pressure.
The provide protection that 2 compd As, B, C and similar compound thereof or its pharmacologically acceptable salt are closed angle, rat room
2.1 laboratory animal and grouping
Experiment adopts Thirty male rats, body weight 200g-250g.Before modeling, by animal random packet: i.e. the intraocular injection group of blank group, model group, compd A, B, C, positive drug group pilocarpine eye drop group.All medicines all after modeling all in administration in the 1st day weekly, wherein positive control drug administration 2 times weekly, all animals all continue medication 4 weeks, compd A, B, C group are intraocular injection administration, the administration of positive drug pilocarpine eye drop group eye drip.
The foundation of 2.2 animal models
It is experimental eye that all animals are all established right eye, and left eye is contrast eye.First by Animal Anesthesia, ketamine for rat (50mg/kg) and Xylazine (5mg/kg) mixed solution abdominal injection, with compound tropicamide eye drops eye droppings, carry out rat right eye mydriasis for 1 time, rat is fully anaesthetized to rear ventricumbent position is fixed on operating table simultaneously, in conjunctiva of right eye capsule, point 1% content in tetracaine hydrochloride eye drops is 1 time, then carry out a surface anesthesia, under optical operation microscope with disposable syringe syringe needle carry out corneoscleral junction puncture of anterior chamber and suction before aqueous humor, make obliteratio camerae anterior.Adopt multiwavelength laser machine to carry out light to cornea of right eye edge (angle, room) and coagulate, optical maser wavelength 532 nanometers, 50 microns of spot diameters, 0.5 second time, power 0.40W, carries out 3 episclera vein blood vessel light simultaneously and coagulates.Postoperative double ocellus ofloxacin eye drops, right eye is coated with coromegine ointment to prevent pupil reblocking.By utilizing slit lamp and the postoperative conjunctiva of anterior ocular segment optical coherence tomography (prosthomere OCT) systematic observation, cornea and angle, anterior chamber room, thereby judge whether to cause the narrow or model of closing in angle, room, and various medication is for the change at angle, room.
2.3 tonometry
Rat is opened to eyelid, and tonometer is measured intraocular pressure, measuring result record.All rat tonometries are completed by same people.
Morphological observation before and after 2.4 angle, room treatments
After administration the 28th day by every group of mouse each 5, by anterior ocular segment optical coherence tomography (prosthomere OCT), in the situation that eyeball is not applied to any external force, eyeball is not carried out to vertical scan direction by pupil, after scanning, image is analyzed.
2.5 statistical analysis
Ge Zu rat observation post total according to this mean ± standard deviation (x ± s) represents, carries out t check between group.
2.6 experimental result
Normal group average intraocular pressure is all the time in 15mmHg left and right, have no considerable change, with Normal group comparison, after the modeling of model group rat, intraocular pressure starts to raise, visible is because Fang Jiaochu causes angle, room narrow or close, it is obstructed that thereby aqueous humor is discharged, cause that intraocular pressure raises, and along with continuing modeling time lengthening, raise gradually (P < 0.05), medicine A, B, each medicine group of C is all to opening up Kai Fangjiao, make angle, room narrow or close and open, thereby make not restenosis discharge aqueous humor of angle, room, suppress intraocular pressure rising and have effect, and action effect is all better than eye drip positive controls pilocarpine eye drop (P < 0.05).
Angle, table 2 rat room is narrow or close the intraocular pressure result (mmHgn=10) of experiment
With control group comparison
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
2.7 optical coherence tomography results
The imaging results checking from 4 weeks, medicine A, medicine B, medicine C can avoid rat in animal model to close and adhesion because laser photocoagulation causes angle, room significantly, make that angle, room is narrow opens gradually, contrast with model group, medicine A, B, C can open significantly angle, room and (see Figure of description, Fig. 1: after medication, the angle, room of each treated animal opens and closes situation), angle, room expansion situation and blank category are seemingly.
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C) medicine of preparing all can obviously make angle, room from narrow or closing condition becomes opened condition, and can again recover angle, room function, discharge aqueous humor, thereby reduction intraocular pressure is narrow or the control of relative disease has extraordinary therapeutic action to angle, room, its result for the treatment of is significantly better than medicine used clinically at present.
Accompanying drawing explanation: Fig. 1: after medication, the angle, room of each treated animal opens and closes situation.Figure is followed successively by blank group, model group, positive drug medication group, medicine A group, medicine B group, medicine C group from left to right.
Claims (10)
1. a class can be treated the compound or pharmaceutically acceptable salt thereof that angle, room is narrow, and analogue, and the structure of described compound is as follows:
Compound (C).
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and pharmacologically acceptable salt and its analogue.
3. the pharmaceutical composition of claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc., the packaging material of described controlled release preparation is selected from: the natural or synthetic superpolymer of one or more in polylactic-co-glycolic acid, polyoxyethylene glycol, poly-acid anhydrides, polymeric amide, polyester, polyene, polyethers, polyphosphonitrile or glycan, or natural or synthetic phosphatide, lipoid or its combination.
4. described in claim 1, compound and pharmacologically acceptable salt thereof and its analogue are treated the purposes in the medicine that angle, room is narrow in preparation.
5. the purposes of claim 4, the narrow treatment in angle, described room comprise to angle, narrow, acute room, angle, heredity room close, the treatment of the associated conditions such as angle, chronic room is closed.
6. the purposes of claim 5, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
7. the purposes of claim 6, described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.
8. the purposes of claim 6, described local administration preparation is the powder injection through dosing eyes, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.
9. the purposes of claim 6, described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule, emulsion etc.
10. the purposes of claim 6, described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
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| CN101405282A (en) * | 2006-01-23 | 2009-04-08 | 安姆根有限公司 | Aurora kinase modulators and method of use |
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| CN1319090A (en) * | 1998-09-25 | 2001-10-24 | 贝林格尔英格海姆法玛公司 | Novel substuted indolimones, their preparation process and use as medicine |
| CN1780627A (en) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis |
| CN101405282A (en) * | 2006-01-23 | 2009-04-08 | 安姆根有限公司 | Aurora kinase modulators and method of use |
| WO2011031842A1 (en) * | 2009-09-11 | 2011-03-17 | Amgen Inc. | N-4 ( - ( ( 3- ( 2 -amino-4 pyrimidinyl) -2 -pyridinyl) oxy) phenyl) -4- (4-methyl-2-thienyl) -1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer |
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Application publication date: 20140326 |