CN104151303A - Intraocular tension reducing compound and preparation method and use thereof - Google Patents
Intraocular tension reducing compound and preparation method and use thereof Download PDFInfo
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- CN104151303A CN104151303A CN201310051771.9A CN201310051771A CN104151303A CN 104151303 A CN104151303 A CN 104151303A CN 201310051771 A CN201310051771 A CN 201310051771A CN 104151303 A CN104151303 A CN 104151303A
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- intraocular pressure
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- WFKWFBUCJRXLPB-UHFFFAOYSA-N CCOC(c(cc1)ccc1NC(C1=CC=CCC1C)C(OC(CO)=CC1=O)=C1O)=O Chemical compound CCOC(c(cc1)ccc1NC(C1=CC=CCC1C)C(OC(CO)=CC1=O)=C1O)=O WFKWFBUCJRXLPB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
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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 and a pharmaceutical composition and preparation method and use thereof, the use is the use of the compound in preparation of intraocular tension reducing drugs, and the compound has very obvious intraocular tension reducing effects.
Description
Technical field
The present invention relates to a class and reduce compound of intraocular pressure and its production and use, 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 has prepared one group of compound and similar compound or its pharmacologically acceptable salt, and this group compound and similar compound thereof or its pharmacologically acceptable salt have beyond thought outstanding effect on the medicine of preparation reduction intraocular pressure.
Summary of the invention
The invention provides the preparation of one group of compound and similar compound or its pharmacologically acceptable salt and the new purposes in the medicine of preparation reduction intraocular pressure thereof.
Technical scheme of the present invention is as follows:
One compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein R
1be selected from methyl, n-propyl, normal-butyl; R
2be selected from methyl, n-propyl, normal-butyl; X is selected from C or N element.
The present invention has specifically prepared following 3 compounds:
Compound (A);
Compound (B);
Compound (C).
The synthetic route of compound of the present invention is as follows:
Wherein R1 is selected from methyl, n-propyl, normal-butyl; R2 is selected from methyl, n-propyl, normal-butyl; X is selected from C or N element.
Compound or pharmaceutically acceptable salt thereof of the present invention and analogue thereof reduce the purposes in the medicine of intraocular pressure in preparation, are specially can reduce the intraocular pressure being caused by a variety of causes and raise.
Compound of the present invention 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 organ administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, implant, 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 discovery: this compounds can greatly be alleviated ocular hypertension shape, and from the result of pharmacodynamic experiment, the effect of the step-down of this compounds exceeds the medicine of current clinical application.The exploitation of this new compound by for to future high intraocular pressure patient recovery play very large effect.For removing sufferer misery, the quality of life that improves patient is significant.
Brief description of the drawings
Fig. 1: the nuclear magnetic spectrum of compound (A).
Fig. 2: the nuclear magnetic spectrum of compound (B).
Fig. 3: the nuclear magnetic spectrum of compound (C).
Embodiment
preparation Example
Preparation Example 1(compd A is the preparation of compound A-13)
Compd A 1 is under sulfur oxychloride and methyl alcohol effect, and normal-temperature reaction generates compd A 2 for 24 hours, and compd A 2 is under compound a 1 and a2 acting in conjunction, and in the ethanolic soln of 10 volumes, normal-temperature reaction generates compound A-13 for 24 hours.
Preparation Example 2(compd B is the preparation of compd B 3)
compound B-11 refluxes and within 3 hours, generates B2 in sulfur oxychloride and ethanolic soln, and compd B 2 is under the compound b1 and b2 acting in conjunction of equimolar amount, and in ethanolic soln, normal-temperature reaction obtains compd B 3 for 24 hours.
Preparation Example 3
Prepare compound (C) according to the method identical with Preparation Example 2.
Medicine preparation example 1(is containing the preparation of the lyophilized injection of compd A):
1. altogether 50mg and 60mg 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.
Medicine preparation example 2-3
By compound (B)-compound (C) alternative compounds (A), and prepare the lyophilized injection containing compound (B)-compound (C) according to the method for medicine preparation example 1.
effect embodiment
The treatment experiment of compound (A-C) 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-C) 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
| Group | Value before medicine | 15 days |
| Normal group | 14.2±1.8 | 14.3±1.6 |
| Model group | 28.2±1.3 | 29.0±1.6 |
| Medicine A group | 28.0±1.3 | 16.1±1.4** |
| Medicine B group | 28.0±1.4 | 16.2±1.4** |
| Medicine C group | 28.1±1.4 | 15.8±1.3** |
| Positive drug eye drop group | 28.0±1.4 | 21.7±1.3* |
With relatively * P<0.05**P<0.01 of model group
Compd A-C 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-C) 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-C) group effect is the most obvious, and medicine (A-C) 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)
| Group | Value before medicine | 15 days |
| Model group | 36.0±5.0 | 28.0±5.1 |
| Medicine A group | 36.1±5.1 | 16.1±4.2** |
| Medicine B group | 35.7±5.2 | 16.2±4.2** |
| Medicine C group | 36.0±5.1 | 16.2±4.2** |
| Positive drug eye drop group | 36.2±5.4 | 20.0±4.3* |
With relatively * P<0.05**P<0.01 of model group
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), the medicine of (C) preparing all plays the effect of good reduction intraocular pressure.
Claims (6)
1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein R
1be selected from methyl, n-propyl, normal-butyl; R
2be selected from methyl, n-propyl, normal-butyl; X is selected from C or N element.
2. compound or pharmaceutically acceptable salt thereof claimed in claim 1 and analogue thereof, it is preferably from following compound:
Compound (A);
Compound (B);
Compound (C).
3. the preparation method of compound described in any one claim in claim 1-2, is characterized by according to following route synthetic:
Wherein R1 is selected from methyl, n-propyl, normal-butyl; R2 is selected from methyl, n-propyl, normal-butyl; X is selected from C or N element.
4. compound or pharmaceutically acceptable salt thereof and analogue thereof the purposes in the medicine of preparation reduction intraocular pressure described in claim 1-3 any one.
5. purposes claimed in claim 4, the effect that it is characterized in that described reduction intraocular pressure is specially and can reduces the intraocular pressure being caused by a variety of causes and raise.
6. the pharmaceutical composition that comprises any one compound or pharmaceutically acceptable salt thereof in claim 1-5 and analogue thereof, is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310051771.9A CN104151303A (en) | 2013-02-17 | 2013-02-17 | Intraocular tension reducing compound and preparation method and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310051771.9A CN104151303A (en) | 2013-02-17 | 2013-02-17 | Intraocular tension reducing compound and preparation method and use thereof |
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| Publication Number | Publication Date |
|---|---|
| CN104151303A true CN104151303A (en) | 2014-11-19 |
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| CN201310051771.9A Pending CN104151303A (en) | 2013-02-17 | 2013-02-17 | Intraocular tension reducing compound and preparation method and use thereof |
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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 |
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008076918A2 (en) * | 2006-12-15 | 2008-06-26 | University Of Maryland, Baltimore | Anti-cancer agents and androgen inhibition activity compound |
-
2013
- 2013-02-17 CN CN201310051771.9A patent/CN104151303A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008076918A2 (en) * | 2006-12-15 | 2008-06-26 | University Of Maryland, Baltimore | Anti-cancer agents and androgen inhibition activity compound |
Non-Patent Citations (1)
| Title |
|---|
| M. KONOPÍKOVÁ，等: "Reaction of 5-Hydroxy-2-hydroxymethyl-4H-pyran-4-one with Aromatic Aldehydes and Amines (Betti Reaction)", 《CHEM. PAPERS》 * |
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 |
| CN103848837A (en) * | 2012-12-06 | 2014-06-11 | 韩冰 | Compound for reducing intraocular pressure and application thereof |
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Application publication date: 20141119 |
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