CN103848837A - Compound for reducing intraocular pressure and application thereof - Google Patents
Compound for reducing intraocular pressure and application thereof Download PDFInfo
- Publication number
- CN103848837A CN103848837A CN201210534964.5A CN201210534964A CN103848837A CN 103848837 A CN103848837 A CN 103848837A CN 201210534964 A CN201210534964 A CN 201210534964A CN 103848837 A CN103848837 A CN 103848837A
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- Prior art keywords
- compound
- intraocular pressure
- preparation
- injection
- acceptable salt
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- RMEJOKBKYQYOOW-UHFFFAOYSA-N CC(C1C(Nc2c(C)cccc2)=O)Nc2nnn[n]2C1c(cc1)cc(OC)c1OCc1ccccc1 Chemical compound CC(C1C(Nc2c(C)cccc2)=O)Nc2nnn[n]2C1c(cc1)cc(OC)c1OCc1ccccc1 RMEJOKBKYQYOOW-UHFFFAOYSA-N 0.000 description 1
- YHURVAYABRHZJK-UHFFFAOYSA-N CC(C1C(Nc2cnccc2)=O)Nc2nnn[n]2C1c(cc1)cc(OC)c1OCc1ccccc1 Chemical compound CC(C1C(Nc2cnccc2)=O)Nc2nnn[n]2C1c(cc1)cc(OC)c1OCc1ccccc1 YHURVAYABRHZJK-UHFFFAOYSA-N 0.000 description 1
- WLLFXIBTYRDIKZ-UHFFFAOYSA-N CC(C1C(Nc2cnccc2)=O)Nc2nnn[n]2C1c(cc1)ccc1OCc1ccccc1 Chemical compound CC(C1C(Nc2cnccc2)=O)Nc2nnn[n]2C1c(cc1)ccc1OCc1ccccc1 WLLFXIBTYRDIKZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a compound as well as a drug composition and new application thereof. The compound is applied to preparation of drugs for reducing intraocular pressure. The compound has very obvious effects on reducing intraocular pressure.
Description
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue that a class reduces intraocular pressure, 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 reduce the purposes in the medicine of intraocular pressure in preparation.
Background technology
Intraocular pressure (IOP) is a kind of eye disease that endangers whole world human health because a variety of causes raises, and patient's main manifestations is intraocular pressure short-term or increases for a long time.Because intraocular pressure rising can cause the vision loss of non-reversibility, therefore this is a kind of very serious diseases causing blindness.
At present scientific circles there is no final conclusion for the pathogenic factor that reduces intraocular pressure, are known as by many reasons and cause, not very good in the result for the treatment of of medicine that reduces intraocular pressure clinically at present.Because patient colony is very large and harm is very large, need a kind of effectively medicine badly and treat.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof have an unexpected effect on the medicine of preparation reduction intraocular pressure, reduce intraocular pressure for this compounds at present and there is no report.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the medicine of preparation reduction intraocular pressure.
Technical scheme of the present invention is as follows:
The invention provides one group of compound or pharmaceutically acceptable salt thereof that can reduce intraocular pressure disease, and analogue, the structure of described compound is as follows:
compound (A);
compound (B);
compound (C);
compound (D);
compound (E).
Above formula compound and analogue thereof or its pharmacologically acceptable salt can be prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is through the powder injection of dosing eyes, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The inventor studies and finds that this compounds can greatly reduce intraocular pressure, and from the result of pharmacodynamic experiment, the effect of this compounds exceeds the medicine of current clinical application.Great role is played in the recovery of the sufferer colony to high intraocular pressure by the exploitation of this new compound, is significant for the misery of removing sufferer and its family.
Embodiment
The present invention's compound used all can be purchased, and also can be prepared according to disclosed preparation method, and it does not limit therapeutic domain of the present invention.
Medicine Preparation Example
compound (A);
compound (B);
compound (C);
compound (D);
compound (E).
Preparation containing compd A injection:
1. altogether 50mg and 100mg 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 freeze-drying therapeutical agent and auxiliary materials;
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 injection:
1. altogether 50mg and 300mg 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 freeze-drying therapeutical agent and auxiliary materials;
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 injection:
1. altogether 50mg and 20mg 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 freeze-drying therapeutical agent and auxiliary materials;
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 D injection:
1. altogether 50mg and 50mg formula (D) 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 freeze-drying therapeutical agent and auxiliary materials;
4. carry out procedural freeze-drying;
6. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd E injection:
1. altogether 50mg and 500mg formula (E) 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 freeze-drying therapeutical agent and auxiliary materials;
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.
Effect embodiment
The treatment experiment of compound (A-E) to high intraocular pressure in rats
1.1 laboratory animal and grouping
Experiment adopts Thirty male rats, body weight 220g left and right.Before modeling, by animal random packet: i.e. blank group; Model group; Compound (A-E) group, is administered once every 5 days intravitreal injections, dosage 0.1mg injection/kg; Positive drug group selection pilocarpine eye drop, be administered once every day, one time one.All administrations continue 15 days.
The foundation of 1.2 animal models
Abdominal injection rat 4% Chloral Hydrate (200mg.kg-1) before experiment, then uses 1% lignocaine toponarcosis cornea of rats.During preparing high intraocular pressure model, keep every half an hour 0.2 milliliter of abdominal injection 4% Chloral Hydrate make the state of animal continuous narcosis.Adopt pulley-suture system that rat right eye intraocular pressure is raise, left side eyeball contrasts simultaneously.Be respectively an identical heavy counterweight by surgical sutures two ends, hitch a circle in the middle of suture for around after rat canthus limbus of sclera 2 millimeters, the counterweight at two ends is exerted pressure to rat eyes continually and steadily by pulley.It is 20 grams that counterweight is exerted pressure, and continuous 6 hours, causes high intraocular pressure in rats model.After administration, raise and within 15 days, measure rathole pressure record.
1.3 experimental result
Experimental result is in table 1
The intraocular pressure result (mmHg, n=10) of rat under the each group of table 1 drug treatment
With relatively * P < 0.05**P < 0.01 of model group
Compd A-E is to the ocular hypertensive treatment experiment of rabbit
2.1 laboratory animal and grouping
Healthy regular grade rabbit, male and female half and half, body weight 2.3kg left and right, examination with slitlamp microscope is without anterior ocular segment pathology., before modeling, do not choose at random 20 of experimental rabbits, respectively at every day many point in time measurement rabbit bilateral intraocular pressure record.After Continuous Observation one week, to determine this group experimental rabbit normal intraocular tension scope.After modeling 1 week, by animal pattern random packet: by animal random packet: i.e. blank group; Model group; Compound (A-E) group, is administered once every 5 days intravitreal injections, injection administration 0.5mg injection in every lagophthalmos; VUFB-6453 eye drop is selected in positive drug group selection, and be administered once every day.All administrations continue 15 days.
The foundation of 2.2 animal models
12 position puncture of anterior chamber of every group 10 rabbit cornea of right eye edge, extract 0.2 milliliter of aqueous humor out.0.2 milliliter of 0.3% carbomer and 0.025% dexamethasone are injected to anterior chamber through puncture orifice, and left eye is contrast eye, and modeling started administration after one week.
2.3 measure intraocular pressure
After animals administer, with the 15th day intraocular pressure record after tonometer measurement administration.
2.4 experimental result
After rabbit modeling, intraocular pressure raises, and the intraocular pressure of each medication therapy groups all raises, and shows the success of modeling type.After administration, each medicine group raises and all has restraining effect intraocular pressure, and wherein compound (A-E) group effect is the most obvious, and medicine (A-E) group result for the treatment of is all better than positive drug group.
Lagophthalmos under the each group of table 2 drug treatment is pressed result (n=10)
With relatively * P < 0.05**P < 0.01 of model group
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C), (D), the medicine of (E) preparing all plays the effect of good reduction intraocular pressure.
Claims (6)
1. a compounds or its pharmacologically acceptable salt, and analogue, the structure of described compound is as follows:
compound (A);
compound (B);
compound (C);
compound (D);
compound (E).
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.
4. the pharmaceutical composition of claim 2, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
5. topical described in claim 4 is the various preparations of dosing eyes.
6. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation reduction intraocular pressure described in claim 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210534964.5A CN103848837A (en) | 2012-12-06 | 2012-12-06 | Compound for reducing intraocular pressure and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210534964.5A CN103848837A (en) | 2012-12-06 | 2012-12-06 | Compound for reducing intraocular pressure and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103848837A true CN103848837A (en) | 2014-06-11 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210534964.5A Pending CN103848837A (en) | 2012-12-06 | 2012-12-06 | Compound for reducing intraocular pressure and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103848837A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848782A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Application of compound to preparation of drugs for treating glaucoma |
| CN111406752A (en) * | 2020-04-23 | 2020-07-14 | 中国农业科学院植物保护研究所 | Application of dihydropyrrolopyrazolone derivative as chitinase inhibitor or nematicide |
Citations (5)
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| CN101279966A (en) * | 2008-05-14 | 2008-10-08 | 北京润德康医药技术有限公司 | Optical isomer of Nipradilol, preparation and medical use thereof |
| CN103845334A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103848782A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Application of compound to preparation of drugs for treating glaucoma |
| CN103845330A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN104151303A (en) * | 2013-02-17 | 2014-11-19 | 韩冰 | Intraocular tension reducing compound and preparation method and use thereof |
-
2012
- 2012-12-06 CN CN201210534964.5A patent/CN103848837A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101279966A (en) * | 2008-05-14 | 2008-10-08 | 北京润德康医药技术有限公司 | Optical isomer of Nipradilol, preparation and medical use thereof |
| CN103845334A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103848782A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Application of compound to preparation of drugs for treating glaucoma |
| CN103845330A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN104151303A (en) * | 2013-02-17 | 2014-11-19 | 韩冰 | Intraocular tension reducing compound and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| V. BAGGA ET AL.: "A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors", 《SAR AND QSAR IN ENVIRONMENTAL RESEARCH》 * |
| 唐细兰 等: "青光眼药物治疗进展", 《中国药物杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848782A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Application of compound to preparation of drugs for treating glaucoma |
| CN111406752A (en) * | 2020-04-23 | 2020-07-14 | 中国农业科学院植物保护研究所 | Application of dihydropyrrolopyrazolone derivative as chitinase inhibitor or nematicide |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140611 |