CN103848782A - Application of compound to preparation of drugs for treating glaucoma - Google Patents
Application of compound to preparation of drugs for treating glaucoma Download PDFInfo
- Publication number
- CN103848782A CN103848782A CN201210534928.9A CN201210534928A CN103848782A CN 103848782 A CN103848782 A CN 103848782A CN 201210534928 A CN201210534928 A CN 201210534928A CN 103848782 A CN103848782 A CN 103848782A
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- Prior art keywords
- compound
- preparation
- injection
- glaucoma
- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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- C—CHEMISTRY; METALLURGY
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a compound as well as a drug composition and new application thereof. The compound is applied to drugs for treating glaucoma diseases. The compound has very obvious effects on treating glaucoma.
Description
Technical field
The present invention relates to a class and treat glaucomatous compound and pharmacologically acceptable salt and its analogue, 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 the purposes of analogue in the glaucomatous medicine of preparation treatment thereof.
Background technology
Glaucoma is a kind of eye disease that endangers whole world human health, and the title of so-called " green light " eye is to suffer from this patient have the reflective of cyan and gain the name with the visible pupil of irradiate light from ancient times.Mainly be divided into primary glaucoma, secondary glaucoma, congenital glaucoma, patient's main manifestations of suffering from this illness is increasing of intraocular pressure (IOP).Because glaucoma can cause the vision loss of non-reversibility, therefore the World Health Organization is classified as great diseases causing blindness.
Scientific circles there is no final conclusion for glaucomatous pathogenic factor at present, be known as by many reasons and cause, congenital glaucoma is mainly due to factors such as heredity, mainly due to diabetes, blood pressure are undesired etc., factors causes secondary glaucoma, agnogenio owing to producing, therefore the means for the treatment of are very limited.Operation means misery recurs more greatly and easily, on clinical treatment, removing at present more acute glaucoma illness uses outside trabeculectomy, most of glaucoma illnesss are taking pharmacological agent as main, not very good in the result for the treatment of of the glaucomatous medicine for the treatment of clinically at present.Because patient colony is very large and harm is very large, glaucoma has become social problem, needs a kind of effectively medicine badly and treats.
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 glaucomatous medicine of preparation treatment, there is no report for this compounds for treating glaucoma at present.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the glaucomatous medicine of preparation treatment.
Technical scheme of the present invention is as follows:
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat glaucoma disease, and analogue, the structure of described compound is as follows:
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 this compounds of discovery can greatly alleviate glaucoma symptom, 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 to glaucomatous colony 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
Preparation containing compd A injection:
1. altogether 50mg and 900mg 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 200mg 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 10mg 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 20mg 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. get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer 50mg and 100mg altogether
Formula (E) compound in water for injection, mix and make it dissolve;
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 rat angle closure glaucoma
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 high intraocular pressure, 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 rat angle closure glaucoma model.Raise and measured rathole pressure record to the 15th day.
1.3 experimental result
Experimental result is in table 1
The intraocular pressure result (mmHg, n=10) of glaucoma rat under the each group of table 1 drug treatment
With relatively * P < 0.05**P < 0.01 of model group
The treatment experiment of compd A-E to rabbit open angle glaucoma
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 glaucomatous effect of good treatment.
Claims (6)
1. a compounds or its pharmacologically acceptable salt, and analogue, the structure of described compound is as follows:
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 glaucomatous medicine of preparation treatment described in claim 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210534928.9A CN103848782A (en) | 2012-12-06 | 2012-12-06 | Application of compound to preparation of drugs for treating glaucoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210534928.9A CN103848782A (en) | 2012-12-06 | 2012-12-06 | Application of compound to preparation of drugs for treating glaucoma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103848782A true CN103848782A (en) | 2014-06-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210534928.9A Pending CN103848782A (en) | 2012-12-06 | 2012-12-06 | Application of compound to preparation of drugs for treating glaucoma |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103848782A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
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|---|---|---|---|---|
| CN101198325A (en) * | 2004-10-13 | 2008-06-11 | 默克公司 | Ophthalmic compositions for treating ocular hypertension |
| CN101253166A (en) * | 2005-08-30 | 2008-08-27 | 旭化成制药株式会社 | Sulfonamide compound |
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845334A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845321A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845330A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103896899A (en) * | 2012-12-25 | 2014-07-02 | 韩冰 | Compounds for reducing intraocular pressure and preparation method 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 CN201210534928.9A patent/CN103848782A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101198325A (en) * | 2004-10-13 | 2008-06-11 | 默克公司 | Ophthalmic compositions for treating ocular hypertension |
| CN101253166A (en) * | 2005-08-30 | 2008-08-27 | 旭化成制药株式会社 | Sulfonamide compound |
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845334A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845321A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103845330A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
| CN103896899A (en) * | 2012-12-25 | 2014-07-02 | 韩冰 | Compounds for reducing intraocular pressure and preparation method 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 (3)
| Title |
|---|
| V. BAGGA等: "A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors", 《SAR AND QSAR IN ENVIRONMENTAL RESEARCH》 * |
| 张筠: "《眼科护理基本知识与技能500问》", 30 June 2010, 北京：科学出版社 * |
| 蔡际群: "《药物治疗与疾病》", 30 April 2008, 上海：上海科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| 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 |