CN103768067A - Type of compounds for treating narrow chamber angle and use of compounds - Google Patents
Type of compounds for treating narrow chamber angle and use of compounds Download PDFInfo
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- CN103768067A CN103768067A CN201210418581.1A CN201210418581A CN103768067A CN 103768067 A CN103768067 A CN 103768067A CN 201210418581 A CN201210418581 A CN 201210418581A CN 103768067 A CN103768067 A CN 103768067A
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- OQUSPUQQYDIZLJ-UHFFFAOYSA-N CC(C(C)(C)C)N(C)Cc1cc(CC(C)(C)N=O)c(cc(-c2n[nH]c3c2[s]c(-c2c[nH]nc2)c3)[nH]2)c2c1 Chemical compound CC(C(C)(C)C)N(C)Cc1cc(CC(C)(C)N=O)c(cc(-c2n[nH]c3c2[s]c(-c2c[nH]nc2)c3)[nH]2)c2c1 OQUSPUQQYDIZLJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a type of compounds, as well as pharmaceutical compositions and novel use thereof. The novel use is that the compounds are used for preparing medicines for treating a narrow chamber angle. The compounds have very remarkable effects in treating the narrow chamber angle.
Description
Technical field
The present invention relates to three kinds and treat compound and officinal salt and its analog that angle, room is narrow, the pharmaceutical composition of being prepared by above-claimed cpd and officinal salt thereof and its analog, and described compound or pharmaceutically acceptable salt thereof and analog thereof the purposes in the narrow medicine in preparation treatment angle, room.
Background technology
The sickness rate that angle, room is narrow exceedes 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 ophthalmalgia; 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 passing away is obstructed for a long time, aqueous humor is discharged and is further obstructed, and then cause intraccular 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.To drip with miotic for angle, temporary treatment room way narrow or that close clinically, commonly use and have pilocarpine, accompany to use simultaneously and suppress the medicine that aqueous humor produces, this measure effect is very limited, therapeutic effect 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 officinal 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 officinal 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 analog, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
The present invention also provides a kind of pharmaceutical composition, and it comprises compound (A), (B), (C); Said composition can also comprise adjuvant 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 high polymer or film material, described high polymer is selected from: one or more in polylactic-co-glycolic acid, poly-anhydride, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyphosphazene or polysaccharide, or be selected from the copolymer between the different monomers of described high polymer, preferably, described high polymer is selected from: poly lactic coglycolic acid, lactic-co-glycolic acid-glycol copolymer, PGA, Acetic acid, hydroxy-, bimol. cyclic ester lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide triblock copolymer, Polyethylene Glycol, sebacic anhydride-glycol copolymer, octadecane diacid acid anhydride-ethylene glycol block copolymer, poly butyric ester, polybutylcyanoacrylate, polylactic acid, polymaleic anhydride, poly sebacic polyanhydride, polyvinyl alcohol, NIPA-acrylic copolymer, chitosan, polyether sulfone, cellulose, glucosan, alginate, dextran, hyaluronic acid, gelatin, poloxamer, Fibrinogen, one or more in albumin or collagen protein etc.Described film material comprises that lecithin, fabaceous lecithin, PHOSPHATIDYL ETHANOLAMINE, cholesterol, cephalin, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, natrii tauroglycocholas, Yolk lecithin, phosphatidyl silk amino acid, phosphatidylinositols, sphingomyelin, sphingo, two Cetyl Phosphates, two lima bean acyl lecithin, stearmide, phosphatidic acid, Phosphatidylserine etc. comprise natural or synthetic phospholipid, lipoid or its combination.
The present invention also provides compound (A), (B), (C), or its officinal salt and the purposes of analog in the medicine of the narrow disease in preparation treatment angle, room thereof.Described purposes comprises compound (A), (B), (C) or its officinal salt and analog 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 through the injectable powder of 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 dosage form 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 more with Aisan's morbidity, yellow is more common, especially China, angle, women room is more narrower, so sickness rate is higher compared with male, 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, within 40 years old, fall ill above 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 ophthalmalgia, 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 passing away is obstructed for a long time, aqueous humor is discharged and is further obstructed, and then cause intraccular 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.To drip with miotic for angle, temporary treatment room way narrow or that close clinically, commonly use and have pilocarpine, accompany to use simultaneously and suppress the medicine that aqueous humor produces, this measure effect is very limited, therapeutic effect 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 officinal 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 officinal 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.Inventor 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 therapeutic effect.
Accompanying drawing explanation
Fig. 1 is that the angle, room of each treated animal after medication opens and closes situation, and 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.
The specific 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:
Compound (A);
Described compd B structure is:
Compound (B);
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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
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 mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
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 officinal salt make angle, room block rat
1.1 laboratory animals and grouping
Healthy adult Wistar rat, body weight 200-250 gram, without any ocular disease.Raise environment 25 ℃ of temperature, relative humidity 70%, specialty the personnel of raising raise.Before modeling, measure animal eye with tonometer intrinsic pressure, continue observed and recorded intraocular pressure 1 week, estimate normal intraocular tension 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 drugs 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 divides four times 28 days totally in rat anterior chamber, and injection diameter is the mixed liquor of granules of polystyrene, hyaluronic acid and the carboxymethyl cellulose of 10 microns, block behind trabecular reticulum and angle, room, thereby it is obstructed that aqueous humor is discharged, and causes intraocular pressure to raise.
1.3 tonometry
Rat is opened to eyelid, and tonometer is measured intraocular pressure, measurement result record.All rat tonometries are repeatedly averaged.
1.4 Histomorphological
Within after administration the 28th day, put to death each 5 of every group of Mus, extract immediately bilateral rathole, take out crystalline lens and vitreous body.Every group of Mus experimental eye cuts as two halves take central authorities as axle sagittal with contrast eye.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
Each group rat is observed the data obtained, and with mean ± standard deviation, (x ± s) represent 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 significant 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 raise gradually along with continuing modeling time lengthening (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 matched 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 fibrous layer of gland sample layer and deep layer, and conjunctival epithelium layer is that thin columnar epithelium forms, and has thinner blood vessel in conjunctiva; Sclera is fibrous connective tissue; There is one deck non-pigment epithelial cell on corpus ciliare surface, is pigment epithelium cell layer below, is rich in blood vessel in ciliary processes, and orbiculus ciliaris only has one deck ciliary muscle.Mitochondrion and microfilament are visible, and endochylema is abundant, and normally open at angle, room.Model group conjunctive bulbi edema, inflammatory cell infiltration; Corneal stromal edema, inflammatory cell infiltration, angle, room obturation, 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 processes non-pigment epithelial layer is heap shape, and surface forms connective 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 opening is obviously better than model group and positive drug control group, eyeball is without obvious expansion, and scleral walls varied 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, lower than model group, show curative effect, 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 protective effect that 2 compd As, B, C and similar compound thereof or its officinal salt are closed angle, rat room
2.1 laboratory animals 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 liquor lumbar injection, carry out rat right eye mydriasis for 1 time with compound tropicamide eye drops eye dripping, rat is fully anaesthetized to rear ventricumbent position is fixed on operating-table simultaneously, point 1% content in tetracaine hydrochloride eye drops 1 time in conjunctiva of right eye capsule, then carry out a topical anesthesia, under optical operation microscope with disposable syringe syringe needle carry out corneoscleral junction paracentesis 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 atropine ointment to prevent pupil posterior synechiae.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.
Morphological observation before and after 2.3 angle, room treatments
After administration the 28th day by each 5 of every group of Mus, by anterior ocular segment optical coherence tomography (prosthomere OCT), in the situation that eyeball is not applied to any external force, eyeball is carried out to vertical scan direction by pupil, after scanning, image is analyzed.
2.4 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 closed condition becomes opening, and can again recover angle, room function, discharge aqueous humor, thereby reduction intraocular pressure is narrow or the control of relevant disease has extraordinary therapeutical effect to angle, room, its therapeutic effect is significantly better than medicine used clinically at present.
Claims (10)
1. a class can be treated the compound or pharmaceutically acceptable salt thereof that angle, room is narrow, and analog, and the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C).
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and officinal salt and its analog.
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 high polymer of one or more in polylactic-co-glycolic acid, Polyethylene Glycol, poly-anhydride, polyamide, polyester, polyene, polyethers, polyphosphazene or polysaccharide, or natural or synthetic phospholipid, lipoid or its combination.
4. described in claim 1, compound and officinal salt thereof and its analog 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, heritability room close, the treatment of the associated conditions such as angle, chronic room is closed.
6. the purposes of claim 5, described compound and officinal salt thereof and its analog 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 through the injectable powder of 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 dosage form of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080293714A1 (en) * | 2005-12-20 | 2008-11-27 | Joerg Martin Bentzien | Tec Kinase Inhibitors |
| CN101820915A (en) * | 2007-08-16 | 2010-09-01 | Irm责任有限公司 | Methods and compositions for treating cancers |
| US20120142703A1 (en) * | 2009-05-14 | 2012-06-07 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080293714A1 (en) * | 2005-12-20 | 2008-11-27 | Joerg Martin Bentzien | Tec Kinase Inhibitors |
| CN101820915A (en) * | 2007-08-16 | 2010-09-01 | Irm责任有限公司 | Methods and compositions for treating cancers |
| US20120142703A1 (en) * | 2009-05-14 | 2012-06-07 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
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Application publication date: 20140507 |